Glutamine analogs

Abstract

The invention relates to novel glutamine analogs, a composition containing the glutamine analogs and the use thereof.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, a stereoisomer thereof, a tautomer thereof, and an isotopic substitution thereof, wherein the compound is selected from: TABLE-US-00017 1 isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 2 methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid 4 ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 5 isopropyl (S)-6-diazo-2-(2-methoxyacetamido)-5-oxohexanoate 6 isopropyl (S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate 7 isopropyl (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate 8 isopropyl (S)-6-diazo-2-((S)-2-hydroxy-4-methylpentanamido)-5- oxohexanoate 9 isopropyl (S)-6-diazo-2-((S)-2-ethoxypropanamido)-5-oxohexanoate 10 isopropyl (S)-6-diazo-2-((S)-2-isopropoxypropanamido)-5- oxohexanoate 11 isopropyl (S)-6-diazo-2-(2-hydroxyacetamido)-5-oxohexanoate 12 isopropyl (S)-6-diazo-2-((S)-2-hydroxybutanamido)-5-oxohexanoate 13 isopropyl (S)-6-diazo-2-((S)-2-methoxybutanamido)-5-oxohexanoate 14 isopropyl (S)-6-diazo-2-((S)-2-ethoxybutanamido)-5-oxohexanoate 15 isopropyl (S)-6-diazo-2-((S)-2-isopropoxybutanamido)-5-oxohexanoate 16 isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate 17 isopropyl (S)-6-diazo-2-((S)-2-methoxy-3-methylbutanamido)-5- oxohexanoate 18 isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3-methylbutanamido)-5- oxohexanoate 19 isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-3-methylbutanamido)-5- oxohexanoate 20 isopropyl (S)-6-diazo-2-((2S,3R)-2-hydroxy-3-methylpentanamido)-5- oxohexanoate 21 isopropyl (S)-6-diazo-2-((2S,3R)-2-methoxy-3-methylpentanamido)-5- oxohexanoate 22 isopropyl (S)-6-diazo-2-((2S,3R)-2-ethoxy-3-methylpentanamido)-5- oxohexanoate 23 isopropyl (S)-6-diazo-2-((2S,3R)-2-isopropoxy-3-methylpentanamido)- 5-oxohexanoate 24 isopropyl (S)-6-diazo-2-((S)-2-hydroxypentanamido)-5-oxohexanoate 25 isopropyl (S)-6-diazo-2-((S)-2-methoxypentanamido)-5-oxohexanoate 26 isopropyl (S)-6-diazo-2-((S)-2-ethoxypentanamido)-5-oxohexanoate 27 isopropyl (S)-6-diazo-2-((S)-2-isopropoxypentanamido)-5- oxohexanoate 28 isopropyl (S)-6-diazo-2-((S)-2-methoxy-4-methylpentanamido)-5- oxohexanoate 29 isopropyl (S)-6-diazo-2-((S)-2-ethoxy-4-methylpentanamido)-5- oxohexanoate 30 isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-4-methylpentanamido)-5- oxohexanoate 31 isopropyl (S)-6-diazo-2-((S)-2-hydroxy-3,3-dimethylbutanamido)-5- oxohexanoate 32 isopropyl (S)-6-diazo-2-((S)-2-methoxy-3,3-dimethylbutanamido)-5- oxohexanoate 33 isopropyl (S)-6-diazo-2-((S)-2-ethoxy-3,3-dimethylbutanamido)-5- oxohexanoate 34 isopropyl (S)-6-diazo-2-((S)-2-isopropoxy-3,3-dimethylbutanamido)-5- oxohexanoate 35 isopropyl (S)-6-diazo-2-((S)-2-hydroxyhexanamido)-5-oxohexanoate 36 isopropyl (S)-6-diazo-2-((S)-2-methoxyhexanamido)-5-oxohexanoate 37 isopropyl (S)-6-diazo-2-((S)-2-ethoxyhexanamido)-5-oxohexanoate 38 isopropyl (S)-6-diazo-2-((S)-2-isopropoxyhexanamido)-5-oxohexanoate 39 isopropyl (S)-6-diazo-2-(3-methoxy-2-oxopropanamido)-5- oxohexanoate 40 isopropyl (S)-6-diazo-2-(3-hydroxy-2-oxopropanamido)-5- oxohexanoate 41 isopropyl (S)-6-diazo-2-(3-hydroxypropanamido)-5-oxohexanoate 42 isopropyl (S)-6-diazo-2-((S)-3-hydroxybutanamido)-5-oxohexanoate 43 isopropyl (S)-6-diazo-2-(3-methoxypropanamido)-5-oxohexanoate 44 isopropyl (S)-6-diazo-2-((S)-3-methoxybutanamido)-5-oxohexanoate 45 isopropyl (S)-6-diazo-2-((S)-3-hydroxy-2-methylpropanamido)-5- oxohexanoate 46 isopropyl (S)-6-diazo-2-((S)-3-methoxy-2-methylpropanamido)-5- oxohexanoate 47 isopropyl (S)-6-diazo-2-((2S,3R)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 48 isopropyl (S)-6-diazo-2-((2S,3R)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 49 isopropyl (S)-6-diazo-2-((2R,3R)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 50 isopropyl (S)-6-diazo-2-((2R,3R)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 51 isopropyl (S)-6-diazo-2-((2R,3S)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 52 isopropyl (S)-6-diazo-2-((2R,3S)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 53 isopropyl (S)-6-diazo-2-((R)-3-hydroxybutanamido)-5-oxohexanoate 54 isopropyl (S)-6-diazo-2-((2S,3S)-3-hydroxy-2-methylbutanamido)-5- oxohexanoate 55 isopropyl (S)-6-diazo-2-((2S,3S)-3-methoxy-2-methylbutanamido)-5- oxohexanoate 56 isopropyl (S)-6-diazo-2-((R)-3-methoxybutanamido)-5-oxohexanoate 57 isopropyl (S)-6-diazo-2-((R)-3-hydroxy-2-methylpropanamido)-5- oxohexanoate 58 isopropyl (S)-6-diazo-2-((R)-3-methoxy-2-methylpropanamido)-5- oxohexanoate 59 tert-butyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 60 tert-butyl (S)-6-diazo-2-((R)-2-methoxypropanamido)-5-oxohexanoate 61 isopropyl (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoate 62 isopropyl (S)-6-diazo-2-(2-hydroxy-2-methylpropanamido)-5- oxohexanoate 63 methyl (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoate 64 methyl (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate 65 methyl (S)-6-diazo-2-(2-isopropoxyacetamido)-5-oxohexanoate 66 (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoic acid 67 isopropyl (S)-6-diazo-2-(2-isopropoxyacetamido)-5-oxohexanoate 68 methyl (S)-6-diazo-2-(2-methoxyacetamido)-5-oxohexanoate 69 S-isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanethioate 70 (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoic acid 71 isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 72 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoic acid 73 methyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 74 ethyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5-oxohexanoate 75 S-isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanethioate 76 isopropyl (S)-6-diazo-2-((S)-2-(methoxy-d3)-4-(methylthio) butanamido)-5-oxohexanoate 77 methyl-d3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 78 ethyl-2,2,2-d3 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanoate 79 isopropyl (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5- oxohexanoate 80 isopropyl (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5-oxohexanoate 81 ethyl-d5 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate 82 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanoate 83 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-hydroxypropanamido)-5- oxohexanoate 84 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate 85 propan-2-yl-d7 (S)-6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate 86 S-(propan-2-yl-d7) (S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanethioate 87 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-methoxy-4-(methylthio) butanamido)-5-oxohexanoate 88 methyl-d3 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 89 ethyl-2,2,2-d3 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 90 ethyl-d5 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 91 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanoate 92 propan-2-yl-d7 (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5- oxohexanoate 93 S-(propan-2-yl-d7) (S)-6-diazo-2-((S)-2-(methoxy-d3)propanamido)-5- oxohexanethioate 94 propan-2-yl-d7 (S)-6-diazo-2-((S)-2-(methoxy-d3)-4- (methylthio)butanamido)-5-oxohexanoate 95 propan-2-yl-d7 (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5- oxohexanoate 96 methyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d 97 ethyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d 98 isopropyl 6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate-2-d 99 isopropyl 6-diazo-2-(2-ethoxyacetamido)-5-oxohexanoate-2-d 100 S-isopropyl 6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanethioate-2-d 101 isopropyl 6-diazo-2-((S)-2-methoxy-4-(methylthio)butanamido)-5- oxohexanoate-2-d 102 isopropyl 6-diazo-2-((S)-2-hydroxypropanamido)-5-oxohexanoate-2-d 103 isopropyl 6-diazo-2-((S)-2-hydroxy-3-methylbutanamido)-5- oxohexanoate-2-d 104 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-(methoxy- d3)propanamido)-5-oxohexanoate 105 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-(ethoxy-2,2,2-d3) acetamido)-5-oxohexanoate 106 S-(propan-2-y1-1,1,1,3,3,3-d6) (S)-6-diazo-2-((S)-2-(methoxy- d3)propanamido)-5-oxohexanethioate 107 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-(methoxy-d3)-4- (methylthio)butanamido)-5-oxohexanoate 108 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5- oxohexanoate 109 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-hydroxypropanamido)- 5-oxohexanoate 110 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-hydroxy-3- methylbutanamido)-5-oxohexanoate 111 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-(methoxy-d3) propanamido)-5-oxohexanoate 112 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-(ethoxy-2,2,2-d3)acetamido)-5- oxohexanoate 113 S-(propan-2-y1-1,1,1-d3) (2S)-6-diazo-2-((S)-2-(methoxy- d3 )propanamido)-5-oxohexanethioate 114 propan-2-yl-1, 1,1-d3 (2S)-6-diazo-2-((S)-2-(methoxy-d3)-4- (methylthio)butanamido)-5-oxohexanoate 115 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-(ethoxy-d5)acetamido)-5- oxohexanoate 116 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-hydroxypropanamido)-5- oxohexanoate 117 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-hydroxy-3- methylbutanamido)-5-oxohexanoate 118 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-methoxypropanamido)- 5-oxohexanoate 119 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-(2-ethoxyacetamido)-5- oxohexanoate 120 S-(propan-2-y1-1,1,1,3,3,3-d6) (S)-6-diazo-2-((S)-2- methoxypropanamido)-5-oxohexanethioate 121 propan-2-yl-1,1,1,3,3,3-d6 (S)-6-diazo-2-((S)-2-methoxy-4- (methylthio)butanamido)-5-oxohexanoate 122 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-methoxypropanamido)-5- oxohexanoate 123 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-(2-ethoxyacetamido)-5- oxohexanoate 124 S-(propan-2-y1-1,1,1-d3) (2S)-6-diazo-2-((S)-2-methoxypropanamido)- 5-oxohexanethioate 125 propan-2-yl-1,1,1-d3 (2S)-6-diazo-2-((S)-2-methoxy-4- (methylthio)butanamido)-5-oxohexanoate.

2. A pharmaceutical composition comprising the compound, the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof according to claim 1; and a pharmaceutically acceptable carrier, diluent or excipient.

3. The compound or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof according to claim 1, wherein the compound is selected from: ##STR00646##

4. The compound or the pharmaceutically acceptable salt thereof, the stereoisomer thereof, the tautomer thereof, and the isotopic substitution thereof according to claim 1, wherein the compound is ##STR00647##

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 shows the plasma stability of compounds after incubation for 4 hours in the presence of dog, monkey, swine and human plasma.

(2) FIG. 2 shows the body weight changes following administration of Reference compound A and Compound 2 in C57BL/6 mice bearing MC38 tumors.

(3) FIG. 3 shows the anti-tumor efficacy of Reference compound A and Compound 2 in C57BL/6 mice bearing MC38 tumors.

(4) FIG. 4 shows the body weight changes following administration of Reference compound A and Compound 2 in CES1/ mice bearing MC38 tumors.

(5) FIG. 5 shows the anti-tumor efficacy of Reference compound A and Compound 2 in CES1/ mice bearing MC38 tumors.

(6) FIG. 6 shows the body weight changes following administration of Compound 2, compound 3, compound 81, compound 443 and compound 459 in C57BL/6 mice bearing MC38 tumors.

(7) FIG. 7 shows the anti-tumor efficacy of Compound 2, compound 3, compound 81, compound 443 and compound 459 in C57BL/6 mice bearing MC38 tumors.

DEFINITION

(8) The term halogen, as used herein, unless otherwise indicated, means fluoro, chloro, bromo or iodo. The preferred halogen groups include F, Cl and Br. The terms haloC.sub.1-6alkyl, haloC.sub.2-6alkenyl, haloC.sub.2-6alkynyl and haloC.sub.1-6alkoxy mean a C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.2-6alkynyl or C.sub.1-6alkoxy in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. In some embodiment, preferred are fluoroC.sub.1-6alkyl, fluoroC.sub.2-6alkenyl, fluoroC.sub.2-6alkynyl and fluoroC.sub.1-6alkoxy groups, in particular fluoroC.sub.1-3alkyl, for example, CF.sub.3, CHF.sub.2, CH.sub.2F, CH.sub.2CH.sub.2F, CH.sub.2CHF.sub.2, CH.sub.2CF.sub.3 and fluoroC.sub.1-3alkoxy groups, for example, OCF.sub.3, OCHF.sub.2, OCH.sub.2F, OCH.sub.2CH.sub.2F, OCH.sub.2CHF.sub.2 or OCH.sub.2CF.sub.3, and most especially CF.sub.3, OCF.sub.3 and OCHF.sub.2.

(9) The term alkyl, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight branched or cyclic moieties. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, cyclobutyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C.sub.1-6, as in C.sub.1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbon atoms in a linear or branched arrangement.

(10) The term alkylene means a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. For example, methylene (i.e., CH.sub.2), ethylene (i.e., CH.sub.2CH.sub.2 or CH(CH.sub.3)) and propylene (i.e., CH.sub.2CH.sub.2CH.sub.2, CH(CH.sub.2CH.sub.3) or CH.sub.2CH(CH.sub.3)).

(11) The term alkenyl means a straight or branch-chained hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms in length. For example, C.sub.2-6alkenyl contains from 2 to 6 carbon atoms. Alkenyl group include, but are not limited to, for example, ethenyl, propenyl, butenyl, 2-methyl-2-buten-1-yl, hepetenyl, octenyl and the like.

(12) The term alkynyl contains a straight or branch-chained hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms in length. For example, C.sub.2-6alkynyl contains from 2 to 6 carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octynyl and the like.

(13) The term alkoxy radicals are oxygen ethers formed from the previously described alkyl groups.

(14) The term aryl, as used herein, unless otherwise indicated, refers to an unsubstituted or substituted mono or polycyclic aromatic ring system containing carbon ring atoms. The preferred aryls are mono cyclic or bicyclic 6-10 membered aromatic ring systems. Phenyl and naphthyl are preferred aryls.

(15) The term heterocyclyl, as used herein, unless otherwise indicated, refers to unsubstituted and substituted mono or polycyclic non-aromatic ring system containing one or more heteroatoms, which comprising monocyclic heterocyclic ring, bicyclic heterocyclic ring, bridged heterocyclic ring, fused heterocyclic ring or spiro heterocyclic ring. Preferred heteroatoms include N, O, and S, including N-oxides, sulfur oxides, and dioxides. Preferably the ring is three to ten membered and is either fully saturated or has one or more degrees of unsaturation. Multiple degrees of substitution, preferably one, two or three, are included within the present definition. Examples of such heterocyclic groups include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxoazepinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone and oxadiazolyl.

(16) The term heteroaryl, as used herein, unless otherwise indicated, represents an aromatic ring system containing carbon(s) and at least one heteroatom. Heteroaryl may be monocyclic or polycyclic, substituted or unsubstituted. A monocyclic heteroaryl group may have 1 to 4 heteroatoms in the ring, while a polycyclic heteroaryl may contain 1 to 10 hetero atoms. A polycyclic heteroaryl ring may contain fused, spiro or bridged ring junction, for example, bicyclic heteroaryl is a polycyclic heteroaryl. Bicyclic heteroaryl rings may contain from 8 to 12 member atoms. Monocyclic heteroaryl rings may contain from 5 to 8 member atoms (carbons and heteroatoms). Examples of heteroaryl groups include, but are not limited to thienyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adeninyl, quinolinyl or isoquinolinyl.

(17) The term cycloalkyl refers to a substituted or unsubstituted monocyclic ring, bicyclic ring bridged ring, fused ring, spiro ring non-aromatic ring system one containing carbon atoms. Exemplary cycloalkyl groups includes but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and so on.

(18) wherein the term substituted refers to a group mentioned above in which one or more (preferably 1-6, more preferably 1-3) hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents include, but are not limited to, T, C.sub.1-6alkyl, C.sub.1-6alkoxy, C.sub.3-20 cycloalkyl, OR.sub.13, SR.sub.13, O, S, C(O)R.sub.13, C(S)R.sub.13, NR.sub.13, C(O)OR.sub.13, C(S)OR.sub.13, NR.sub.13R.sub.14, C(O)NR.sub.13R.sub.14, cyano, nitro, S(O).sub.2R.sub.13, OS(O.sub.2)OR.sub.13, OS(O).sub.2R.sub.13, or OP(O)(OR.sub.13)(OR.sub.14); wherein each T is independently a halogen (F, Cl, Br or I), and R.sub.13 and R.sub.14 is independently selected from H, C.sub.1-6 alkyl and C.sub.1-6 haloalkyl. In some embodiments, the substituent(s) is independently selected from the group consisting of F, Cl, Br, I, OH, trifluoromethoxy, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, CHF.sub.2, methoxy, ethoxy, propyloxy, iso-propyloxy, n-butyloxy, isobutyloxy, t-butyloxy, SCH.sub.3, SC.sub.2H.sub.5, formaldehyde group, C(OCH.sub.3), cyano, nitro, CF.sub.3, OCF.sub.3, amino, dimethylamino, methyl thio, sulfonyl and acetyl. Particularly preferred substituent(s) is F, Cl or Br.

(19) The term composition, as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the present invention as the active ingredient as well as methods of preparing the instant compounds are also part of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents and such solvates are also intended to be encompassed within the scope of this invention.

(20) The compounds of the present invention may also be present in the form of pharmaceutically acceptable salt(s). For use in medicine, the salts of the compounds of this invention refer to non-toxic pharmaceutically acceptable salt(s). The pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic/anionic or basic/cationic salts. The pharmaceutically acceptable acidic/anionic salt generally takes a form in which the basic nitrogen is protonated with an inorganic or organic acid. Representative organic or inorganic acids include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic. Pharmaceutically acceptable basic/cationic salts include, and are not limited to aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc.

(21) The present invention includes within its scope the prodrugs of the compounds of this invention. In general, such prodrugs will be functional derivatives of the compounds that are readily converted in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term administering shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.

(22) It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques know in the art as well as those methods set forth herein.

(23) The present invention includes compounds described can contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof.

(24) The present invention includes all stereoisomers of the compound and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers as well as isolated specific stereoisomers are also included. During the course of the synthetic procedures used to prepare such compounds or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.

(25) The term stereoisomer as used in the present invention refers to an isomer in which atoms or groups of atoms in the molecule are connected to each other in the same order but differ in spatial arrangement, including conformational isomers and conformational isomers. The configuration isomers include geometric isomers and optical isomers, and optical isomers mainly include enantiomers and diastereomers. The invention includes all possible stereoisomers of the compound.

(26) The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium and tritium. The isotopes of hydrogen can be denoted as .sup.1H(hydrogen), .sup.2H(deuterium) and .sup.3H(tritium). They are also commonly denoted as D for deuterium and T for tritium. In the application, CD.sub.3 denotes a methyl group wherein all of the hydrogen atoms are deuterium. Isotopes of carbon include .sup.13C and .sup.14C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent.

(27) When a tautomer of the compound exists, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, except where specifically stated otherwise.

(28) When the compound and pharmaceutically acceptable salts thereof exist in the form of solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. A type of a solvent that forms the solvate is not particularly limited so long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone or the like can be used.

(29) The term pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound of the present invention is acidic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. When the compound of the present invention is basic, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Since the compounds are intended for pharmaceutical use they are preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% are on a weight for weight basis).

(30) The pharmaceutical compositions of the present invention comprise a compound (or a pharmaceutically acceptable salt thereof) as an active ingredient, a pharmaceutically acceptable carrier and optionally other therapeutic ingredients or adjuvants. The compositions include compositions suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

(31) In practice, the compounds or a prodrug or a metabolite or pharmaceutically acceptable salts thereof, of this invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention can be presented as discrete units suitable for oral administration such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient. Further, the compositions can be presented as a powder, as granules, as a solution, as a suspension in an aqueous liquid, as a non-aqueous liquid, as an oil-in-water emulsion or as a water-in-oil liquid emulsion. In addition to the common dosage forms set out above, the compound or a pharmaceutically acceptable salt thereof, may also be administered by controlled release means and/or delivery devices. The compositions may be prepared by any of the methods of pharmacy. In general, such methods include a step of bringing into association the active ingredient with the carrier that constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both. The product can then be conveniently shaped into the desired presentation.

(32) Thus, the pharmaceutical compositions of this invention may include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt. The compounds or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

(33) The pharmaceutical carrier employed can be, for example, a solid, liquid or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen. In preparing the compositions for oral dosage form, any convenient pharmaceutical media may be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets may be coated by standard aqueous or nonaqueous techniques.

(34) A tablet containing the composition of this invention may be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Each tablet preferably contains from about 0.05 mg to about 5 g of the active ingredient and each cachet or capsule preferably containing from about 0.05 mg to about 5 g of the active ingredient. For example, a formulation intended for the oral administration to humans may contain from about 0.5 mg to about 5 g of active agent, compounded with an appropriate and convenient amount of carrier material which may vary from about 0.05 to about 95 percent of the total composition. Unit dosage forms will generally contain between from about 0.01 mg to about 2 g of the active ingredient, typically 0.01 mg, 0.02 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg or 1000 mg.

(35) Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

(36) Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

(37) Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder or the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations may be prepared, utilizing a compound of this invention or a pharmaceutically acceptable salt thereof, via conventional processing methods. As an example, a cream or ointment is prepared by admixing hydrophilic material and water, together with about 0.05 wt % to about 10 wt % of the compound, to produce a cream or ointment having a desired consistency.

(38) Pharmaceutical compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories may be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.

(39) In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above may include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including antioxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound or pharmaceutically acceptable salts thereof, may also be prepared in powder or liquid concentrate form.

(40) Generally, dosage levels on the order of from about 0.001 mg/kg to about 150 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions or alternatively about 0.05 mg to about 7 g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system (CNS), may be effectively treated by the administration of from about 0.001 to 50 mg of the compound per kilogram of body weight per day or alternatively about 0.05 mg to about 3.5 g per patient per day.

(41) It is understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

(42) These and other aspects will become apparent from the following written description of the invention.

EXAMPLES

(43) The following examples are provided to better illustrate the present invention. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The following abbreviations have been used in the examples:

(44) TABLE-US-00002 DMF N,N-Dimethylformamide EA Ethyl acetate MeONa Sodium methanolate MeOH Methanol DCM Dichloromethane DCE 1,2-Dichloroethane EtOH Ethanol THF Tetrahydrofuran MeCN Acetonitrile NMM 4-Methylmorpholine DIPEA N,N-Diisopropylethylamine TEA Triethylamine Ts 4-methyl benzenesulfonyl HATU 2-(7-Azabenzotriazol-1-yl)-N,N,N,N- tetramethyluronium hexafluorophosphate XtalFluor-E N,N-Diethyl-S,S-difluorosulfiliminium tetrafluoroborate TCFH N-(chloro(dimethylamino)methylene)-N- methylmethanaminium hexafluorophosphate(V) BOP 1H-Benzotriazol-1-yloxytris(dimethylamino)phosphonium Hexafluorophosphate RT Room temperature min minute(s) h hour(s) aq aqueous sat saturated FLASH Medium pressure chromatograph Prep - TLC Preparative thin layer chromatography Pre-HPLC High pressure chromatograph

Intermediate A1

(45) ##STR00036##

(46) Intermediate A1 was prepared referring to the compound 3 in WO2017023774 in Scheme 1 at page 82.

(47) The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.

(48) ##STR00037##

Intermediate B1

(49) ##STR00038##

(50) Step a: To a solution of 7-Fluoroindole (308 mg, 2.279 mmol) and Ytterbium(III) triflate hydrate (219 mg, 343.119 mol) in Chloroform (3 mL) was added (2S)-Methylglycidate (121 mg, 1.185 mmol) under N.sub.2. The mixture was heated to 85 C. and stirred for 3 h. The reaction mixture was cooled to RT. The reaction mixture was quenched with Na.sub.2CO.sub.3 (aq) (10 mL), and adjusted the pH to 5-6 with 2M HCl. The aqueous layer was separated and extracted with DCM (210 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by silica chromatography eluting with EtOAc/Hexane(1:2) to afford methyl (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoate (136 mg, 573.292 mol). MS: m/z 238(M+H).sup.+.

(51) Step b: To a solution of methyl (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoate (136 mg, 573.292 mol) in water (1 mL) was added LiOH (2M solution in water, 1 mL). The mixture was stirred for overnight at RT-60 C., Citric acid(solid) was added, diluted with water (5 mL) and extracted with EA (210 mL). The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoic acid (165 mg, 739.247 mol) which was used in next step without any further purification. MS: m/z (224).sup.+.

Intermediate B2

(52) ##STR00039##

(53) Step a: To a solution of Indole (302 mg, 2.578 mmol) in DMF (3 mL) was added NaH (217 mg, 9.043 mmol) at ice-water bath for 1 h. (2S)-Methylglycidate (685 mg, 6.710 mmol) was added and the mixture was stirred over night at RT. The reaction mixture was quenched with H.sub.2O, and adjusted the pH to 3-4 with citric acid. The aqueous layers were extracted with EA. The combined organic layers were dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was purified by FLASH with H.sub.2O/MeCN (5%-95%) to afford (S)-2-hydroxy-3-(1H-indol-1-yl)propanoic acid (222 mg, 1.082 mmol). MS: m/z 206(M+H).sup.+.

(54) The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.

(55) ##STR00040## ##STR00041## ##STR00042##

Intermediate C1

(56) ##STR00043##

(57) Step a: To a solution of Methyl (S)-()-lactate (1099 mg, 10.5567 mmol), Iodoethane (3726 mg, 23.8900 mmol) in Diethyl ether (10 mL) was added Ag.sub.2O (4772 mg, 20.5925 mmol) under N.sub.2. The reaction mixture was stirred over night at RT by light-avoiding. The reaction mixture was monitored by TLC. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by THF (3 mL), MeOH (3 mL), H.sub.2O (3 mL) and then the reaction mixture was added LiOH (246 mg, 10.2721 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was monitored by TLC and adjusted the pH to 2 with 1N HCl. The reaction mixture was concentrated under reduced pressure to 5 mL. The aqueous layers were extracted with EA (310 mL). The combined organic layers were washed with saturated solution of NaCl (310 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford (S)-2-ethoxypropanoic acid (772 mg, 6.5351 mmol). MS: m/z 119(M+H).sup.+.

Intermediate C2

(58) ##STR00044##

(59) Step a: To a solution of 2-hydroxy-4-(methylthio)butanoic acid (0.68 g, 4.5274 mmol), CH.sub.3I (3.35 g, 23.6019 mmol) in Diethyl ether (10 mL) was added Ag.sub.2O (4.41 g, 19.0303 mmol). The reaction mixture was stirred over night at RT. The reaction mixture was monitored by LC-MS. The reaction mixture was filtered and concentrated under reduced pressure. The residue was dissolved by MeOH (6 mL), H.sub.2O (2 mL) and then the reaction mixture was added NaOH (318 mg, 7.9506 mmol). The reaction mixture was stirred for 3 h at RT. The reaction mixture was monitored by TLC and adjusted the pH to 3 with 1M HCl. The reaction mixture was concentrated under reduced pressure to 5 mL. The aqueous layers were extracted with EA (310 mL). The combined organic layers were washed with saturated solution of NaCl (310 mL) and dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure to afford 2-methoxy-4-(methylthio)butanoic acid (128 mg, 779.4318 mol). MS: m/z 165(M+H).sup.+.

Intermediate C3

(60) ##STR00045##

(61) Step a: To a solution of 2-hydroxy-3-(1H-indol-3-yl)propanoic acid (152 mg, 740.706 mol) in THF (10 mL) was added NaH (55 mg, 2.292 mmol). The reaction mixture was stirred for 20 min at RT and then CH.sub.3I (370 mg, 2.607 mmol) was added. The reaction mixture was monitored by LC-MS. CH.sub.3I (358 mg, 2.522 mmol) was added again. The reaction mixture was monitored by LC-MS. The reaction mixture was stirred for 3 h at 40 C. The reaction mixture was added H.sub.2O (5 mL) and extracted with EA (10 mL). The aqueous layers were combined and purified by FLASH with H.sub.2O/MeCN (0%-100%, 40 min, C18). The product layers were concentrated under reduced pressure to afford 2-methoxy-3-(1-methyl-1H-indol-3-yl)propanoic acid (119 mg, 510.155 mol). MS: m/z 234 (M+H).sup.+.

(62) The following compounds were synthesized using the above procedure or modification procedure with the corresponding starting materials.

(63) ##STR00046## ##STR00047## ##STR00048## ##STR00049## ##STR00050## ##STR00051## ##STR00052## ##STR00053## ##STR00054## ##STR00055##

Intermediate D1

(64) ##STR00056##

(65) Step a: To a solution of methyl (S)-2-hydroxy-3-(1H-indol-3-yl)propanoate(2 g, 9.123 mmol) in DCM (20 mL) was added Imidazole(2061 mg, 30.274 mmol) and TBDMS-Cl (2980 mg, 19.772 mmol). The mixture was stirred for overnight at RT. The reaction mixture was quenched with Water (10 mL) and extracted with DCM (10 mL). The reaction mixture was separated and organic extracts were collected. The aqueous solution was extracted with DCM (210 mL). The residue was purified by wet column chromatography with EA/Hex (0-20%). The product's solution was concentrated under reduced pressure. The methyl (S)-2-((tert-butyldimethylsilyl)oxy)-3-(1H-indol-3-yl)propanoate (3099 mg) was obtained. MS: m/z 334(M+H).sup.+.

(66) Step b: To a 78 C. solution of methyl (S)-2-((tert-butyldimethylsilyl)oxy)-3-(1H-indol-3-yl)propanoate (3.099 g, 9.292 mmol) in THF (30 mL) was added LiHMDS (10.5 mL, 10.491 mmol). The mixture was stirred for 30 min at 78 C. Then Carbobenzyloxy chloride (4623 mg, 27.100 mmol) was dropped into the mixture at 78 C. The reaction mixture was stirred for 1 h at this temperature. Quenched the reaction with sat. NH.sub.4Cl, and the aqueous solution was extracted with EA (210 mL). The combined organic extracts were washed with brine (310 mL), dried over anhydrous Na.sub.2SO.sub.4. The organic phase was concentrated under reduced pressure. The benzyl (S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (4345 mg) was obtained. MS: m/z 468(M+H).sup.+.

(67) Step c: To a solution of benzyl(S)-3-(2-((tert-butyldimethylsilyl)oxy)-3-methoxy-3-oxopropyl)-1H-indole-1-carboxylate (4.345 g, 9.292 mmol) in THF (30 mL) was added Tetrabutylammonium fluoride (5 mL). The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The residue was purified by FLASH with EA/Hex(0-60%). The product's solution was concentrated under reduced pressure. The benzyl 3-[(2S)-2-hydroxy-3-methoxy-3-oxo-propyl]indole-1-carboxylate (2.21 g) was obtained. MS: m/z 354(M+H).sup.+.

(68) Step d: To a solution of benzyl 3-[(2S)-2-hydroxy-3-methoxy-3-oxo-propyl]indole-1-carboxylate(103 mg, 291.481 mol), and 4 molecular sieve in CH.sub.3I (1 mL) was added Silver oxide(216 mg, 932.098 mol). The mixture was stirred for overnight at RT. The reaction mixture was concentrated under reduced pressure. The reaction mixture was diluted with EA (5 mL) and filtered, the filtrate was concentrated to afford benzyl (S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylate (107.088 mg, 100.000% yield). MS: m/z 368(M+H).sup.+.

(69) Step e: To a solution of benzyl(S)-3-(2,3-dimethoxy-3-oxopropyl)-1H-indole-1-carboxylate (0.107 g, 291.240 mol) in THF (5 mL) and MeOH(5 mL) was added NaOH(3 mL, 3M/L). The mixture was stirred for 1 h at RT. The reaction mixture was adjusted the pH to 3 with 1M HCl. The aqueous solution was extracted with EA (210 mL). The combined organic extracts were washed with brine (310 mL), dried over anhydrous Na.sub.2SO.sub.4. The organic phase was concentrated under reduced pressure and (S)-3-(1H-indol-3-yl)-2-methoxypropanoic acid (71 mg) was obtained. MS: m/z 220(M+H).sup.+.

(70) The following compounds were synthesized using intermediate D1 and the above procedure or modification procedure with the corresponding starting materials.

(71) ##STR00057## ##STR00058## ##STR00059## ##STR00060##

Example 1

Isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate (Compound 1)

(72) ##STR00061##

(73) To a solution of (2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoic acid (0.165 g, 739.247 mol) and isopropyl (2S)-2-amino-6-diazo-5-oxo-hexanoate(123 mg, 576.834 mol) in DCM (2 mL) was added N,N-Diisopropylcarbodiimide (95 mg, 752.779 mol), 2,4,6-Collidine (115 mg, 949.008 mol) and

(74) Ethyl cyanoglyoxylate-2-oxime (83 mg, 584.044 mol) at 0 C. The mixture was stirred at RT for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC, and concentrated under reduced pressure to afford isopropyl (2S)-6-diazo-2-[[(2S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxy-propanoyl]amino]-5-oxo-hexanoate (41.6 mg, 99.422 mol) by lyophilization. MS: m/z 419(M+H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 8.47-8.39 (m, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.21-7.19 (m, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.05 (td, J=7.9, 4.8 Hz, 1H), 6.93 (dd, J=10.8, 7.8 Hz, 1H), 5.09 (s, 1H), 5.03 (dt, J=12.5, 6.3 Hz, 1H), 4.53-4.45 (m, 1H), 4.43 (s, 1H), 3.29 (ddd, J=21.3, 14.8, 5.4 Hz, 2H), 2.73-2.60 (m, 1H), 2.43-2.25 (m, 1H), 2.18-1.98 (m, 2H), 1.97-1.80 (m, 1H), 1.30-1.22 (m, 6H).

Example 2

Isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (Compound 2)

(75) ##STR00062##

(76) To a solution of (S)-2-methoxypropanoic acid (267 mg, 2.565 mmol) and isopropyl (2S)-2-amino-6-diazo-5-oxo-hexanoate(0.152 g, 712.835 mol) in DMF (5 mL) was added N,N-Diisopropylcarbodiimide (327 mg, 2.591 mmol), 2,4,6-Collidine (412 mg, 3.400 mmol) and Ethyl cyanoglyoxylate-2-oxime (375 mg, 2.639 mmol) at 0 C. The mixture was stirred at RT for 15 h. The reaction mixture was quenched with saturated NH.sub.4Cl (50 mL) and extracted with EA (20 mL3). The combined organic layers were washed with brine (50 mL3) and concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H2O=5-100%, 40 min) and concentrated under reduced pressure to afford isopropyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (60.2 mg, 201.1211 mol, easily dissolved in water). MS: m/z 300(M+H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.22-7.08 (m, 1H), 5.12-5.01 (m, 1H), 4.57 (td, J=8.7, 4.8 Hz, 1H), 3.77 (dt, J=6.7, 5.7 Hz, 1H), 3.45 (s, 3H), 2.82-2.58 (m, 1H), 2.50-2.22 (m, 2H), 2.09-1.85 (m, 1H), 1.44-1.35 (m, 3H), 1.31-1.26 (m, 6H).

Example 3

Methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (Compound 3)

(77) ##STR00063##

(78) To a solution of (S)-2-methoxypropanoic acid (2.06 g, 19.7879 mmol) and methyl (S)-2-amino-6-diazo-5-oxohexanoate (2308 mg, 12.4635 mol) in DMF (5 mL) was added NMM (3.73 g, 36.8770 mmol) and HATU (6.26 g, 16.4637 mmol) at 0 C. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H.sub.2O=0-100%, min) and concentrated under reduced pressure to afford methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (2.87 g, 10.5799 mmol, easily dissolved in water). MS: m/z 272(M+H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 4.46 (dd, J=8.9, 4.8 Hz, 1H), 3.79-3.74 (m, 1H), 3.72 (s, 3H), 3.40 (s, 3H), 2.43 (s, 2H), 2.33-2.15 (m, 1H), 2.08-1.90 (m, 1H), 1.33 (d, J=6.7 Hz, 3H).

Example 4

(S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid (Compound 4)

(79) ##STR00064##

(80) To a solution of methyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (0.96 g, 3.5389 mmol) in THF (10 mL) was added a solution of NaOH (176 mg, 4.4003 mmol) in water (5 mL) at 0 C. The mixture was stirred at RT for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H.sub.2O=0-80%, 30 min) and concentrated under reduced pressure to afford (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid (866 mg, 3.3665 mmol, easily dissolved in water). MS: m/z 258(M+H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 4.27 (t, J=5.8 Hz, 1H), 3.72 (q, J=6.6 Hz, 1H), 3.40 (s, 3H), 2.46-2.27 (m, 2H), 2.28-2.13 (m, 1H), 2.06-1.91 (m, 1H), 1.33 (d, J=6.7 Hz, 3H).

Example 5

Isopropyl (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate (Compound 5)

(81) ##STR00065##

(82) To a solution of isopropyl (S)-6-diazo-2-((S)-3-(7-fluoro-1H-indol-3-yl)-2-hydroxypropanamido)-5-oxohexanoate (0.166 g, 396.7325 mol) in DMF (3.5 mL) was added pyridine (189 mg, 2.3894 mmol) and acetic anhydride (104 mg, 1.0187 mmol) at RT. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H.sub.2O=2-80%) and concentrated under reduced pressure to afford isopropyl (S)-2-((S)-2-acetoxy-3-(7-fluoro-1H-indol-3-yl)propanamido)-6-diazo-5-oxohexanoate (75.2 mg, 163.3196 mol). MS: m/z 461(M+H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.39 (d, J=7.9 Hz, 1H), 7.17 (s, 1H), 6.96 (dd, J=13.4, 6.4 Hz, 1H), 6.88-6.76 (m, 1H), 5.24 (t, J=5.4 Hz, 1H), 4.96 (dt, J=12.4, 6.3 Hz, 1H), 4.27 (d, J=8.7 Hz, 1H), 3.28 (d, J=5.6 Hz, 2H), 2.26-2.13 (m, 1H), 2.10 (s, 3H), 2.05 (d, J=10.2 Hz, 2H), 1.88-1.75 (m, 1H), 1.22 (t, J=6.8 Hz, 6H).

Example 6

Ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (Compound 6)

(83) ##STR00066##

(84) To a solution of (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoic acid (104 mg, 404.2870 mol) and EtOH (96 mg, 2.0839 mmol) in DMF (5 mL) was added NMM (117 mg, 1.1567 mmol) and HATU (237 mg, 623.3081 mol) at 0 C. The mixture was stirred at RT for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by pre-HPLC (C18, MeCN/H.sub.2O=0-100%, min) and concentrated under reduced pressure to afford ethyl (S)-6-diazo-2-((S)-2-methoxypropanamido)-5-oxohexanoate (0.0332 g, 116.3705 mol, easily dissolved in water). MS: m/z 286(M+H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 4.49-4.35 (m, 1H), 4.23-4.13 (m, 2H), 3.83-3.71 (m, 1H), 3.44-3.35 (m, 3H), 2.43 (s, 2H), 2.30-2.15 (m, 1H), 2.08-1.93 (m, 1H), 1.36-1.31 (m, 3H), 1.29-1.24 (m, 3H).

(85) The following compounds were synthesized using the above procedure or modification procedure of the above schemes with the corresponding starting materials.

(86) TABLE-US-00003 Com- pound Structure IUPAC Name .sup.1HNMR & MS: (M + H).sup.+ 7 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(7- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate MS: m/z 431 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 8.41 (s, 1H), 7.28 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 2.2 Hz, 1H), 7.04 (t, J = 7.9 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 5.08- 4.95 (m, 2H), 4.47 (td, J = 8.1, 4.3 Hz, 1H), 4.40 (dd, J = 10.6, 4.9 Hz, 1H), 3.94 (s, 3H), 3.26 (ddd, J = 21.3, 14.7, 5.5 Hz, 2H), 2.66 (d, J = 4.9 Hz, 1H), 2.15-2.01 (m, 2H), 2.01-1.80 (m, 2H), 1.24 (dd, J = 7.6, 6.4 Hz, 6H). 8 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate MS: m/z 401 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 8.19 (d, J = 20.1 Hz, 1H), 7.70 (t, J = 8.6 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.19-6.98 (m, 3H), 5.03 (dd, J = 13.1, 7.0 Hz, 2H), 4.54 (s, 1H), 4.44 (s, 1H), 3.33 (dd, J = 37.0, 16.6 Hz, 2H), 2.62- 2.51 (m, 1H), 2.39-2.24 (m, 1H), 2.15-2.05 (m, 1H), 2.01-1.85 (m, 1H), 1.27 (t, J = 5.9 Hz, 6H). 9 isopropyl (S)-6- diazo-2-(2- methoxyacetamido)- 5-oxohexanoate 286 10 0 isopropyl (S)-6- diazo-2-(2- ethoxyacetamido)- 5-oxohexanoate MS: m/z 300 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.08-4.95 (m, 1H), 4.46- 4.37 (m, 1H), 4.02-3.89 (m, 2H), 3.67-3.47 (m, 2H), 2.44 (s, 2H), 2.29-2.11 (m, 1H), 2.10-1.92 (m, 1H), 1.26 (s, 9H). 11 isopropyl (S)-6- diazo-2-((S)-2- hydroxypropanamido)- 5- oxohexanoate MS: m/z 286 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.09-4.95 (m, 1H), 4.42- 4.32 (m, 1H), 4.18-4.08 (m, 1H), 2.42 (s, 2H), 2.30-2.13 (m, 1H), 2.08-1.88 (m, 1H), 1.40-1.31 (m, 3H), 1.26 (s, 6H). 12 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3- phenylpropanamido)- 5-oxohexanoate MS: m/z 362 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.34-7.12 (m, 5H), 5.05- 4.92 (m, 1H), 4.38-4.22 (m, 2H), 3.09 (d, 1H), 2.94-2.76 (m, 1H), 2.27-1.97 (m, 3H), 1.94-1.77 (m, 1H), 1.25 (d, J = 3.7 Hz, 6H). 13 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3- phenylpropanamido)- 5-oxohexanoate MS: m/z 376 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.35-7.17 (m, 9H), 7.02 (d, J = 8.5 Hz, 1H), 5.15 (s, 1H), 5.02 (dt, J = 12.3, 6.3 Hz, 1H), 4.55-4.44 (m, 1H), 3.95-3.87 (m, 1H), 3.46- 3.38 (m, 3H), 3.21-3.09 (m, 1H), 3.01-2.89 (m, 1H), 2.19-1.91 (m, 3H), 1.89- 1.76 (m, 1H), 1.24 (t, J = 6.2 Hz, 6H). 14 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-4- methylpentanamido)- 5-oxohexanoate MS: m/z 328 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.08 (d, J = 7.9 Hz, 1H), 5.23 (s, 1H), 5.04-4.91 (m, 1H), 4.46 (td, J = 8.4, 4.7 Hz, 1H), 4.13-4.03 (m, 1H), 2.73- 2.55 (m, 1H), 2.41-2.28 (m, 1H), 2.20-2.09 (m, 1H), 2.02-1.90 (m, 1H), 1.87- 1.74 (m, 1H), 1.57-1.39 (m, 2H), 1.22-1.16 (m, 6H), 0.90 (dd, J = 6.6, 3.1 Hz, 6H). 15 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- phenylacetamido)- 5-oxohexanoate MS: m/z 348 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.48 (d, J = 6.8 Hz, 2H), 7.42- 7.20 (m, 3H), 5.18-4.91 (m, 2H), 4.46-4.18 (m, 1H), 2.34 (s, 2H), 2.28-2.08 (m, 1H), 2.11-1.90 (m, 1H), 1.21 (s, 6H). 16 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- phenylacetamido)- 5-oxohexanoate MS: m/z 362 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.40 (d, J = 34.5 Hz, 5H), 4.99 (s, 1H), 4.67 (s, 1H), 4.35 (s, 1H), 3.43 (s, 3H), 2.33 (s, 2H), 2.18 (s, 1H), 1.99 (s, 1H), 1.24 (s, 6H). 17 isopropyl (S)-2- ((S)-2-(2- cyanoacetoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate MS: m/z 468 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.67-7.53 (m, 1H), 7.39-7.26 (m, 1H), 7.22- 7.14 (m, 1H), 7.14-6.88 (m, 2H), 5.40-5.27 (m, 1H), 5.03-4.90 (m, 1H), 4.31- 4.11 (m, 1H), 3.32 (s, 1H), 3.24-3.08 (m, 1H), 2.22-1.58 (m, 4H), 1.22 (s, 6H). 18 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(pivaloyloxy) propanamido)- 6-diazo-5- oxohexanoate MS: m/z 485 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.62 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.15- 7.08 (m, 2H), 7.03 (t, J = 7.4 Hz, 1H), 5.59 (s, 1H), 5.21 (t, J = 6.0 Hz, 1H), 4.99 (dt, J = 12.4, 6.1 Hz, 1H), 4.35-4.26 (m, 1H), 3.31-3.26 (m, 2H), 2.31-2.17 (m, 1H), 2.17- 1.98 (m, 2H), 1.92-1.78 (m, 1H), 1.25 (t, J = 6.3 Hz, 6H), 1.18 (s, 9H). 19 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1H- indol-1- yl)propanamido)-5- oxohexanoate MS: m/z 401 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.62 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 8.2 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.6 Hz, 1H), 7.16 (s, 1H), 7.11 (t, J = 7.4 Hz, 1H), 6.52 (s, 1H), 5.22 (s, 1H), 5.02 (dt, J = 12.3, 6.3 Hz, 1H), 4.67-4.56 (m, 1H), 4.52-4.38 (m, 2H), 4.35-4.19 (m, 1H), 2.97- 2.88 (m, 1H), 2.33-2.20 (m, 1H), 2.19-2.07 (m, 1H), 2.01-1.86 (m, 1H), 1.29- 1.22 (m, 6H). 20 0 isopropyl (S)-6- diazo-2-((S)-2-(4- fluorophenyl)-2- hydroxyacetamido)- 5-oxohexanoate MS: m/z 366 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.52 (t, J = 6.1 Hz, 2H), 7.09 (td, J = 8.8, 3.0 Hz, 2H), 5.06 (s, 1H), 5.00 (dq, J = 12.9, 6.4 Hz, 1H), 4.38 (td, J = 9.5, 5.0 Hz, 1H), 2.56-2.32 (m, 2H), 2.30-2.14 (m, 1H), 2.12- 1.89 (m, 1H), 1.27-1.09 (m, 6H). 21 isopropyl (S)-6- diazo-2-(2-((4- fluorobenzyl)oxy) acetamido)-5- oxohexanoate MS: m/z 380 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.40-7.30 (m, 2H), 7.06 (t, J = 8.4 Hz, 2H), 5.13-4.98 (m, 1H), 4.67-4.48 (m, 3H), 4.06-3.87 (m, 2H), 2.57-2.30 (m, 2H), 2.31-1.85 (m, 2H), 1.32-1.19 (m, 6H). 22 isopropyl (S)-2- ((S)-3-(7-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 426 23 isopropyl (S)-2- ((S)-3-(6-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 426 24 isopropyl (S)-2- ((S)-3-(5-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 426 25 isopropyl (S)-2- ((S)-3-(4-cyano- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 426 26 isopropyl (S)-2- ((S)-3-(6-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 440 27 isopropyl (S)-2- ((S)-3-(6-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 440 28 isopropyl (S)-2- ((S)-3-(5-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 440 29 isopropyl (S)-2- ((S)-3-(4-cyano- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 440 30 0 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(6- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate 431 31 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(5- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate 431 32 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(4- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate 431 33 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(6- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate 445 34 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(5- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate 445 35 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(4- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate 445 36 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(7- methoxy-1H-indol- 3-yl)propanamido)- 5-oxohexanoate 445 37 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1- methyl-1H- imidazol-4- yl)propanamido)-5- oxohexanoate 380 38 isopropyl (2S)-6- diazo-2-(2- hydroxy-3-(1H- indol-3-yl)-2- methylpropanamido)- 5-oxohexanoate 415 39 isopropyl (S)-6- diazo-2-((S)-3-(6- fluoro-1H-indol-3- yl)-2- hydroxypropanamido)- 5- oxohexanoate 419 40 00 isopropyl (S)-6- diazo-2-((S)-3-(5- fluoro-1H-indol-3- yl)-2- hydroxypropanamido)- 5- oxohexanoate 419 41 01 isopropyl (S)-6- diazo-2-((S)-3-(4- fluoro-1H-indol-3- yl)-2- hydroxypropanamido)- 5- oxohexanoate 419 42 02 isopropyl (S)-6- diazo-2-((S)-3-(7- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate 433 43 03 isopropyl (S)-6- diazo-2-((S)-3-(6- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate 433 44 04 isopropyl (S)-6- diazo-2-((S)-3-(5- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate 433 45 05 isopropyl (S)-6- diazo-2-((S)-3-(4- fluoro-1H-indol-3- yl)-2- methoxypropanamido)- 5- oxohexanoate 433 46 06 isopropyl (S)-2- ((S)-3-(7-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 435 47 07 isopropyl (S)-2- ((S)-3-(6-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 435 48 08 isopropyl (S)-2- ((S)-3-(5-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 435 49 09 isopropyl (S)-2- ((S)-3-(4-chloro- 1H-indol-3-yl)-2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 435 50 0 isopropyl (S)-2- ((S)-3-(7-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 449 51 isopropyl (S)-2- ((S)-3-(6-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 449 52 isopropyl (S)-2- ((S)-3-(5-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 449 53 isopropyl (S)-2- ((S)-3-(4-chloro- 1H-indol-3-yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate 449 54 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(7- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 415 55 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(6- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 415 56 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(5- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 415 57 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(4- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 415 58 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(7- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 429 59 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(6- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 429 60 0 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(5- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 429 61 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(4- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate 429 62 isopropyl (S)-6- diazo-2-((S)-3-(7- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5-oxohexanoate 444 63 isopropyl (S)-6- diazo-2-((S)-3-(6- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5- oxohexanoate 444 64 isopropyl (S)-6- diazo-2-((S)-3-(5- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5- oxohexanoate 444 65 isopropyl (S)-6- diazo-2-((S)-3-(4- (dimethylamino)- 1H-indol-3-yl)-2- hydroxypropanamido)- 5- oxohexanoate 444 66 isopropyl (S)-6- diazo-2-((S)-3-(7- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate 458 67 isopropyl (S)-6- diazo-2-((S)-3-(6- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate 458 68 isopropyl (S)-6- diazo-2-((S)-3-(5- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate 458 69 isopropyl (S)-6- diazo-2-((S)-3-(4- (dimethylamino)- 1H-indol-3-yl)-2- methoxypropanamido)- 5- oxohexanoate 458 70 0 S-isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanethioate MS: 417 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.63 (d, J = 8.0 Hz, 1H), 7.33 (t, J = 8.8 Hz, 1H), 7.17 (s, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.01 (m, 1H), 5.24 (s, 1H), 4.44 (t, J = 4.8 Hz, 1H), 4.31 (m, 1H), 3.60-3.47 (m, 1H), 3.26-3.17 (m, 2H), 2.11 (s, 1H), 2.03-1.87 (m, 1H), 1.66 (m, 2H), 1.28 (m, 3H), 1.27 (d, J = 2.6 Hz, 3H). 71 isopropyl (S)-6- diazo-2-((S)-2- ethoxypropanamido)- 5-oxohexanoate MS: 314 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.39 (dd, J = 9.0, 4.9 Hz, 1H), 3.84 (q, J = 6.8 Hz, 1H), 3.66-3.45 (m, 2H), 2.43 (s, 2H), 2.27-1.92 (m, 2H), 1.33 (d, J = 6.8 Hz, 3H), 1.28-1.21 (m, 9H). 72 isopropyl (S)-6- diazo-2-((S)-2- isopropoxypropanamido)- 5- oxohexanoate 328 73 isopropyl (S)-2- ((S)-2- cyclopropoxypropanamido)- 6-diazo-5- oxohexanoate 326 74 isopropyl (S)-6- diazo-2-(2- hydroxyacetamido)- 5-oxohexanoate MS: 272 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.02 (dt, J = 12.5, 6.2 Hz, 1H), 4.44 (dd, J = 8.7, 5.1 Hz, 1H), 4.01 (s, 2H), 2.44 (s, 2H), 2.30-1.95 (m, 2H), 1.26 (d, J = 6.2 Hz, 6H). 75 isopropyl (S)-2-(2- cyclopropoxyacetamido)- 6-diazo-5- oxohexanoate 312 76 isopropyl (S)-6- diazo-2-((S)-2- hydroxybutanamido)- 5-oxohexanoate 300 77 isopropyl (S)-6- diazo-2-((S)-2- methoxybutanamido)- 5-oxohexanoate MS: 314 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 5.02 (dt, J = 12.3, 6.3 Hz, 1H), 4.41 (dd, J = 9.3, 4.8 Hz, 1H), 3.62- 3.55 (m, 1H), 3.41 (s, 3H), 2.44 (s, 2H), 2.27-1.91 (m, 2H), 1.86-1.59 (m, 2H), 1.26 (dd, J = 6.1, 3.4 Hz, 6H), 0.95 (t, J = 7.4 Hz, 3H). 78 isopropyl (S)-6- diazo-2-((S)-2- ethoxybutanamido)- 5-oxohexanoate 328 79 isopropyl (S)-6- diazo-2-((S)-2- isopropoxybutanamido)- 5- oxohexanoate 342 80 0 isopropyl (S)-2- ((S)-2- cyclopropoxybutanamido)- 6-diazo-5- oxohexanoate 340 81 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3- methylbutanamido)- 5-oxohexanoate MS: 314 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.80 (s, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.39 (dd, J = 8.7, 5.1 Hz, 1H), 3.86 (d, J = 3.8 Hz, 1H), 2.43 (s, 2H), 2.25-1.91 (m, 3H), 1.30- 1.21 (m, 6H), 1.01 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 82 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3- methylbutanamido)- 5-oxohexanoate MS: 328 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.02 (dt, J = 12.5, 6.2 Hz, 1H), 4.41 (dd, J = 9.2, 4.9 Hz, 1H), 3.41 (s, 3H), 3.38 (d, J = 5.2 Hz, 1H), 2.45 (s, 2H), 2.26-2.14 (m, 1H), 2.06-1.92 (m, 2H), 1.26 (dd, J = 6.1, 3.8 Hz, 6H), 0.98 (d, J = 6.9 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H). 83 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3- methylbutanamido)- 5-oxohexanoate 342 84 isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-3- methylbutanamido)- 5-oxohexanoate 356 85 isopropyl (S)-2- ((S)-2- cyclopropoxy-3- methylbutanamido)- 6-diazo-5- oxohexanoate 354 86 isopropyl (S)-6- diazo-2-((2S,3R)-2- hydroxy-3- methylpentanamido)- 5-oxohexanoate 328 87 isopropyl (S)-6- diazo-2-((2S,3R)-2- methoxy-3- methylpentanamido)- 5-oxohexanoate 342 88 isopropyl (S)-6- diazo-2-((2S,3R)-2- ethoxy-3- methylpentanamido)- 5-oxohexanoate 356 89 isopropyl (S)-6- diazo-2-((2S,3R)-2- isopropoxy-3- methylpentanamido)- 5-oxohexanoate 370 90 0 isopropyl (S)-2- ((2S,3R)-2- cyclopropoxy-3- methylpentanamido)- 6-diazo-5- oxohexanoate 368 91 isopropyl (S)-6- diazo-2-((S)-2- hydroxypentanamido)- 5-oxohexanoate 314 92 isopropyl (S)-6- diazo-2-((S)-2- methoxypentanamido)- 5- oxohexanoate 328 93 isopropyl (S)-6- diazo-2-((S)-2- ethoxypentanamido)- 5-oxohexanoate 342 94 isopropyl (S)-6- diazo-2-((S)-2- isopropoxypentanamido)- 5- oxohexanoate 356 95 isopropyl (S)-2- ((S)-2- cyclopropoxypentanamido)- 6-diazo-5- oxohexanoate 354 96 isopropyl (S)-6- diazo-2-((S)-2- methoxy-4- methylpentanamido)- 5-oxohexanoate 342 97 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-4- methylpentanamido)- 5-oxohexanoate 356 98 isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-4- methylpentanamido)- 5-oxohexanoate 370 99 isopropyl (S)-2- ((S)-2- cyclopropoxy-4- methylpentanamido)- 6-diazo-5- oxohexanoate 368 100 0 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3,3- dimethylbutanamido)- 5-oxohexanoate 328 101 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3,3- dimethylbutanamido)- 5-oxohexanoate 342 102 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3,3- dimethylbutanamido)- 5-oxohexanoate 356 103 isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-3,3- dimethylbutanamido)- 5-oxohexanoate 370 104 isopropyl (S)-2- ((S)-2- cyclopropoxy-3,3- dimethylbutanamido)- 6-diazo-5- oxohexanoate 368 105 isopropyl (S)-6- diazo-2-((S)-2- hydroxyhexanamido)- 5-oxohexanoate 328 106 isopropyl (S)-6- diazo-2-((S)-2- methoxyhexanamido)- 5-oxohexanoate 342 107 isopropyl (S)-6- diazo-2-((S)-2- ethoxyhexanamido)- 5-oxohexanoate 356 108 isopropyl (S)-6- diazo-2-((S)-2- isopropoxyhexanamido)- 5- oxohexanoate 370 109 isopropyl (S)-2- ((S)-2- cyclopropoxyhexanamido)- 6-diazo-5- oxohexanoate 368 110 0 isopropyl (S)-2- ((S)-2-cyclopentyl- 2- hydroxyacetamido)- 6-diazo-5- oxohexanoate 340 111 isopropyl (S)-2- ((S)-2-cyclopentyl- 2- methoxyacetamido)- 6-diazo-5- oxohexanoate 354 112 isopropyl (S)-2- ((S)-2-cyclopentyl- 2- ethoxyacetamido)- 6-diazo-5- oxohexanoate 368 113 isopropyl (S)-2- ((S)-2-cyclopentyl- 2- isopropoxyacetamido)- 6-diazo-5- oxohexanoate 382 114 isopropyl (S)-2- ((S)-2-cyclopentyl- 2- cyclopropoxyacetamido)- 6-diazo-5- oxohexanoate 380 115 isopropyl (S)-2- ((S)-3-cyclopentyl- 2- hydroxypropanamido)- 6-diazo-5- oxohexanoate 354 116 isopropyl (S)-2- ((S)-3-cyclopentyl- 2- methoxypropanamido)- 6-diazo-5- oxohexanoate 368 117 isopropyl (S)-2- ((S)-3-cyclopentyl- 2- ethoxypropanamido)- 6-diazo-5- oxohexanoate 382 118 isopropyl (S)-2- ((S)-3-cyclopentyl- 2- isopropoxypropanamido)- 6-diazo-5- oxohexanoate 396 119 isopropyl (S)-2- ((S)-3-cyclopentyl- 2- cyclopropoxypropanamido)- 6-diazo-5- oxohexanoate 394 120 0 isopropyl (S)-2- ((S)-2-cyclohexyl- 2- hydroxyacetamido)- 6-diazo-5- oxohexanoate 354 121 isopropyl (S)-2- ((S)-2-cyclohexyl- 2- methoxyacetamido)- 6-diazo-5- oxohexanoate 368 122 isopropyl (S)-2- ((S)-2-cyclohexyl- 2- ethoxyacetamido)- 6-diazo-5- oxohexanoate 382 123 isopropyl (S)-2- ((S)-2-cyclohexyl- 2- isopropoxyacetamido)- 6-diazo-5- oxohexanoate 396 124 isopropyl (S)-2- ((S)-2-cyclohexyl- 2- cyclopropoxyacetamido)- 6-diazo-5- oxohexanoate 394 125 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-2- phenylacetamido)- 5-oxohexanoate 376 126 isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-2- phenylacetamido)- 5-oxohexanoate 390 127 isopropyl (S)-2- ((S)-2- cyclopropoxy-2- phenylacetamido)- 6-diazo-5- oxohexanoate 388 128 isopropyl (S)-6- diazo-2-((S)-2-(4- fluorophenyl)-2- methoxyacetamido)- 5-oxohexanoate 380 129 isopropyl (S)-2- ((S)-2-(4- chlorophenyl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 396 130 0 isopropyl (S)-2- ((S)-2-(4- chlorophenyl)-2- hydroxyacetamido)- 6-diazo-5- oxohexanoate 382 131 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(4- methoxyphenyl) acetamido)-5- oxohexanoate 378 132 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(4- methoxyphenyl) acetamido)-5- oxohexanoate 392 133 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(4- hydroxyphenyl) acetamido)-5- oxohexanoate 364 134 isopropyl (S)-6- diazo-2-((S)-2-(4- hydroxyphenyl)-2- methoxyacetamido)- 5-oxohexanoate 378 135 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(p- tolyl)acetamido)-5- oxohexanoate 362 136 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(p- tolyl)acetamido)-5- oxohexanoate 376 137 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3- phenylpropanamido)- 5-oxohexanoate 390 138 isopropyl (S)-6- diazo-2-((S)-2- isopropoxy-3- phenylpropanamido)- 5-oxohexanoate 404 139 isopropyl (S)-2- ((S)-2- cyclopropoxy-3- phenylpropanamido)- 6-diazo-5- oxohexanoate 402 140 00 isopropyl (S)-6- diazo-2-((S)-3-(4- fluorophenyl)-2- hydroxypropanamido)- 5- oxohexanoate 380 142 01 isopropyl (S)-6- diazo-2-((S)-3-(4- fluorophenyl)-2- methoxypropanamido)- 5- oxohexanoate 394 143 02 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(4- fluorophenyl) propanamido)-5- oxohexanoate 408 144 03 isopropyl (S)-6- diazo-2-((S)-3-(4- fluorophenyl)-2- isopropoxypropanamido)- 5- oxohexanoate 422 145 04 isopropyl (S)-2- ((S)-2- cyclopropoxy-3-(4- fluorophenyl) propanamido)-6-diazo-5- oxohexanoate 420 146 05 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(4- hydroxyphenyl) propanamido)-5- oxohexanoate 378 147 06 isopropyl (S)-6- diazo-2-((S)-3-(4- hydroxyphenyl)-2- methoxypropanamido)- 5- oxohexanoate 392 148 07 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(4- hydroxyphenyl) propanamido)-5- oxohexanoate 406 149 08 isopropyl (S)-6- diazo-2-((S)-3-(4- hydroxyphenyl)-2- isopropoxypropanamido)- 5- oxohexanoate 420 150 09 isopropyl (S)-2- ((S)-2- cyclopropoxy-3-(4- hydroxyphenyl) propanamido)-6-diazo- 5-oxohexanoate 418 151 0 isopropyl (S)-6- diazo-2-(1- hydroxycyclobutane- 1-carboxamido)- 5-oxohexanoate 312 152 isopropyl (S)-6- diazo-2-(1- methoxycyclobutane- 1-carboxamido)- 5-oxohexanoate 326 153 isopropyl (S)-6- diazo-2-(3- hydroxyoxetane-3- carboxamido)-5- oxohexanoate 314 154 isopropyl (S)-6- diazo-2-(3- methoxyoxetane-3- carboxamido)-5- oxohexanoate 328 155 isopropyl (S)-6- diazo-2-(1- hydroxycyclopentane- 1-carboxamido)- 5-oxohexanoate 326 156 isopropyl (S)-6- diazo-2-(1- methoxycyclopentane- 1-carboxamido)- 5-oxohexanoate 340 157 isopropyl (2S)-6- diazo-2-(3- hydroxytetrahydrofuran- 3- carboxamido)-5- oxohexanoate 328 158 isopropyl (2S)-6- diazo-2-(3- methoxytetrahydrofuran- 3- carboxamido)-5- oxohexanoate 342 159 isopropyl (S)-6- diazo-2-(1- hydroxycyclohexane- 1-carboxamido)- 5-oxohexanoate 340 160 isopropyl (S)-6- diazo-2-(1- methoxycyclohexane- 1-carboxamido)- 5-oxohexanoate 354 161 0 isopropyl (S)-6- diazo-2-(4- hydroxy-1- methylpiperidine-4- carboxamido)-5- oxohexanoate 355 162 isopropyl (S)-6- diazo-2-(4- methoxy-1- methylpiperidine-4- carboxamido)-5- oxohexanoate 369 163 isopropyl (2S)-6- diazo-5-oxo-2- (tetrahydrofuran-2- carboxamido) hexanoate 312 164 isopropyl (2S)-6- diazo-5-oxo-2- (tetrahydro-2H- pyran-2- carboxamido) hexanoate 326 165 isopropyl (2S)-6- diazo-2- (hexahydro-1H- cyclopenta[c]furan- 1-carboxamido)-5- oxohexanoate 352 166 isopropyl (S)-2-(2- (cyclopropylmethoxy) acetamido)-6- diazo-5- oxohexanoate MS: 326 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 5.02 (dt, J = 12.5, 6.3 Hz, 1H), 4.44 (dd, J = 8.8, 5.0 Hz, 1H), 4.09- 3.89 (m, 2H), 3.40 (d, J = 6.9 Hz, 2H), 2.45 (s, 2H), 2.11 (ddq, J = 37.1, 14.6, 7.3 Hz, 2H), 1.34-1.20 (m, 6H), 1.12 (tt, J = 12.4, 6.2 Hz, 1H), 0.56 (d, J = 8.0 Hz, 2H), 0.26 (d, J = 3.7 Hz, 2H). 167 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- phenylpropanamido)- 5-oxohexanoate MS: 362 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.62-7.56 (m, 2H), 7.35- 7.28 (m, 2H), 7.28-7.22 (m, 1H), 4.93 (dt, J = 12.5, 6.3 Hz, 1H), 4.31 (dd, J = 8.9, 5.1 Hz, 1H), 2.42 (s, 2H), 2.29- 1.94 (m, 2H), 1.75 (s, 3H), 1.13 (dd, J = 19.5, 6.3 Hz, 6H). 168 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- phenylpropanamido)- 5-oxohexanoate MS: 362 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.63-7.58 (m, 2H), 7.37- 7.30 (m, 2H), 7.28-7.23 (m, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.29 (dd, J = 9.2, 4.5 Hz, 1H), 2.29-2.09 (m, 3H), 1.99-1.87 (m, 1H), 1.73 (s, 3H), 1.24 (dd, J = 6.2, 3.2 Hz, 5H). 169 isopropyl (S)-2- ((S)-2-(2- cyanoacetoxy)-3- (7-fluoro-1H-indol- 3-yl)propanamido)- 6-diazo-5- oxohexanoate MS: 486 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.47-7.35 (m, 1H), 7.24- 7.13 (m, 1H), 6.93 (td, J = 7.8, 4.0 Hz, 1H), 6.84-6.72 (m, 1H), 5.36 (s, 1H), 5.07- 4.91 (m, 1H), 4.43-4.32 (m, 1H), 4.43-4.19 (m, 2H), 4.32- 4.19 (m, 1H), 3.23-3.09 (m, 2H), 2.12-1.60 (m, 4H), 1.27-1.13 (m, 6H). 170 isopropyl (S)-6- diazo-2-((S)-3-(7- fluoro-1H-indol-3- yl)-2- (isobutyryloxy) propanamido)-5- oxohexanoate 489 171 0 1-methylpiperidin- 4-yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate 355 172 isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydrofuran-2- carboxamido)hexanoate MS: 312 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.83 (s, 1H), 5.01 (dt, J = 12.6, 6.2 Hz, 1H), 4.38-4.27 (m, 2H), 4.07-3.97 (m, 1H), 3.93-3.82 (m, 1H), 2.43 (s, 2H), 2.31-2.12 (m, 2H), 2.07- 1.83 (m, 4H), 1.29-1.23 (m, 6H). 173 isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydro-2H- pyran-2- carboxamido)hexanoate 326 174 isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydrofuran-3- carboxamido)hexanoate MS: 312 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 5.00 (dt, J = 12.5, 6.2 Hz, 1H), 4.32 (dd, J = 9.1, 5.2 Hz, 1H), 3.97- 3.90 (m, 1H), 3.91-3.74 (m, 3H), 3.14-3.03 (m, 1H), 2.44 (s, 2H), 2.22-2.06 (m, 3H), 2.00-1.88 (m, 1H), 1.25 (dd, J = 6.2, 4.1 Hz, 6H). 175 isopropyl (S)-6- diazo-5-oxo-2-((S)- tetrahydro-2H- pyran-3- carboxamido)hexanoate 326 176 isopropyl (S)-6- diazo-2-(3- methoxy-2- oxopropanamido)- 5-oxohexanoate 314 177 isopropyl (S)-6- diazo-2-(3- hydroxy-2- oxopropanamido)- 5-oxohexanoate 300 178 cyclobutyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate MS: 312 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 5.04-4.91 (m, 1H), 4.49-4.29 (m, 1H), 3.76 (p, J = 6.8 Hz, 1H), 3.44- 3.34 (m, 3H), 2.51-2.29 (m, 4H), 2.25-1.98 (m, 4H), 1.88- 1.76 (m, 1H), 1.73-1.62 (m, 1H), 1.33 (d, J = 6.8 Hz, 3H). 179 cyclopentyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate MS: 326 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.27-5.07 (m, 1H), 4.43- 4.30 (m, 1H), 3.76 (p, J = 6.6 Hz, 1H), 3.46-3.34 (m, 3H), 2.57-2.34 (m, 2H), 2.26- 2.12 (m, 1H), 2.06-1.93 (m, 1H), 1.94-1.82 (m, 2H), 1.81- 1.56 (m, 6H), 1.34 (d, J = 6.8 Hz, 3H). 180 2-(pyrrolidin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 355 181 0 (pivaloyloxy)methyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate 372 182 isopentyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate MS: 328 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 4.48-4.36 (m, 1H), 4.17 (dt, J = 6.6, 4.3 Hz, 2H), 3.76 (p, J = 6.8 Hz, 1H), 3.45- 3.33 (m, 3H), 2.51-2.37 (m, 2H), 2.28-2.15 (m, 1H), 2.07- 1.93 (m, 1H), 1.71 (dt, J = 13.4, 6.7 Hz, 1H), 1.62-1.49 (m, 2H), 1.37-1.29 (m, 3H), 0.93 (d, J = 6.6 Hz, 6H). 183 isopropyl (S)-6- diazo-2-(3- hydroxypropanamido)- 5- oxohexanoate MS: 286 (M + H)+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.00 (dt, J = 12.7, 6.5 Hz, 1H), 4.37 (dd, J = 9.0, 5.1 Hz, 1H), 3.81 (dd, J = 10.2, 5.3 Hz, 2H), 2.55-2.37 (m, 4H), 2.22-2.08 (m, 1H), 1.99- 1.83 (m, 1H), 1.37-1.17 (m, 6H). 184 isopropyl (S)-6- diazo-2-((S)-3- hydroxybutanamido)- 5-oxohexanoate MS: 286 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.00 (dt, J = 12.5, 6.2 Hz, 1H), 4.35 (dd, J = 8.6, 5.2 Hz, 1H), 4.14 (dd, J = 12.6, 6.3 Hz, 1H), 2.50-2.28 (m, 4H), 2.15 (td, J = 13.6, 6.9 Hz, 1H), 1.93 (td, J = 15.2, 7.9 Hz, 1H), 1.25 (d, J = 6.2 Hz, 6H), 1.21 (d, J = 6.1 Hz, 3H). 185 isopropyl (S)-6- diazo-2-(3- methoxypropanamido)- 5- oxohexanoate MS: 300 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.00 (dt, J = 12.4, 6.2 Hz, 1H), 4.36 (dd, J = 8.9, 5.1 Hz, 1H), 3.70-3.55 (m, 2H), 3.33 (s, 3H), 2.58-2.35 (m, 4H), 2.14 (td, J = 13.5, 7.2 Hz, 1H), 1.91 (td, J = 15.1, 7.8 Hz, 1H), 1.30-1.20 (m, 6H). 186 isopropyl (S)-6- diazo-2-((S)-3- methoxybutanamido)- 5-oxohexanoate 314 187 isopropyl (S)-6- diazo-2-((S)-3- hydroxy-2- methylpropanamido)- 5-oxohexanoate MS: 300 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 5.00 (dt, J = 12.4, 6.3 Hz, 1H), 4.34 (dd, J = 8.7, 5.1 Hz, 1H), 3.73- 3.63 (m, 1H), 3.56-3.45 (m, 1H), 2.56 (dd, J = 13.6, 6.7 Hz, 1H), 2.44 (s, 2H), 2.22- 2.08 (m, 1H), 2.02-1.88 (m, 1H), 1.25 (d, J = 6.2 Hz, 6H), 1.11 (d, J = 6.9 Hz, 3H). 188 isopropyl (S)-6- diazo-2-((S)-3- methoxy-2- methylpropanamido)- 5-oxohexanoate MS: 314 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 5.00 (dt, J = 12.5, 6.3 Hz, 1H), 4.33 (dd, J = 9.0, 5.2 Hz, 1H), 3.53 (dd, J = 9.3, 8.1 Hz, 1H), 3.38- 3.33 (m, 1H), 3.33 (s, 3H), 2.68 (dd, J = 13.4, 7.1 Hz, 1H), 2.43 (s, 2H), 2.25-2.08 (m, 1H), 2.02-1.86 (m, 1H), 1.25 (dd, J = 6.2, 2.7 Hz, 6H), 1.10 (d, J = 7.0 Hz, 3H). 189 isopropyl (S)-6- diazo-2-((S)- oxetane-2- carboxamido)-5- oxohexanoate MS: 298 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 5.12-4.98 (m, 2H), 4.83-4.64 (m, 2H), 4.45 (dd, J = 9.2, 4.9 Hz, 1H), 3.11- 2.95 (m, 1H), 2.70-2.55 (m, 1H), 2.45 (s, 2H), 2.30- 2.18 (m, 1H), 2.10-1.94 (m, 1H), 1.31-1.27 (m, 6H). 190 isopropyl (S)-6- diazo-2-((2S,3R)-3- hydroxy-2- methylbutanamido)- 5-oxohexanoate 314 191 0 isopropyl (S)-6- diazo-2-((2S,3R)-3- methoxy-2- methylbutanamido)- 5-oxohexanoate 328 192 isopropyl (S)-6- diazo-2-((2R,3R)- 3-hydroxy-2- methylbutanamido)- 5-oxohexanoate 314 193 isopropyl (S)-6- diazo-2-((2R,3R)- 3-methoxy-2- methylbutanamido)- 5-oxohexanoate 328 194 isopropyl (S)-6- diazo-2-((2R,3S)-3- hydroxy-2- methylbutanamido)- 5-oxohexanoate 314 195 isopropyl (S)-6- diazo-2-((2R,3S)-3- methoxy-2- methylbutanamido)- 5-oxohexanoate 328 196 isopropyl (S)-6- diazo-2-((R)-3- hydroxybutanamido)- 5-oxohexanoate 300 197 isopropyl (S)-6- diazo-2-((2S,3S)-3- hydroxy-2- methylbutanamido)- 5-oxohexanoate 314 198 isopropyl (S)-6- diazo-2-((2S,3S)-3- methoxy-2- methylbutanamido)- 5-oxohexanoate 328 199 isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydrofuran-2- carboxamido)hexanoate 312 200 isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydro-2H- pyran-2- carboxamido)hexanoate 326 201 0 isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydrofuran-3- carboxamido)hexanoate MS: 312 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 4.99 (dt, J = 12.5, 6.2 Hz, 1H), 4.32 (dd, J = 9.1, 5.2 Hz, 1H), 3.99- 3.93 (m, 1H), 3.91-3.84 (m, 1H), 3.83-3.74 (m, 2H), 3.14- 2.98 (m, 1H), 2.45 (s, 2H), 2.21-2.06 (m, 3H), 1.93 (dt, J = 14.4, 7.5 Hz, 1H), 1.24 (dd, J = 6.2, 4.3 Hz, 6H). 202 isopropyl (S)-6- diazo-5-oxo-2-((R)- tetrahydro-2H- pyran-3- carboxamido)hexanoate 326 203 isopropyl (S)-6- diazo-2-((R)-3- methoxybutanamido)- 5-oxohexanoate 314 204 isopropyl (S)-6- diazo-5-oxo-2-((R)- 3,3,3-trifluoro-2- methoxypropanamido) hexanoate 354 205 isopropyl (S)-6- diazo-5-oxo-2-((R)- 3,3,3-trifluoro-2- hydroxypropanamido) hexanoate 340 206 isopropyl (S)-6- diazo-5-oxo-2-((S)- 3,3,3-trifluoro-2- methoxypropanamido) hexanoate 354 207 isopropyl (S)-6- diazo-5-oxo-2-((S)- 3,3,3-trifluoro-2- hydroxypropanamido) hexanoate 340 208 isopropyl (S)-6- diazo-2-((R)- oxetane-2- carboxamido)-5- oxohexanoate MS: 298 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.85 (s, 1H), 5.09-4.96 (m, 2H), 4.80-4.60 (m, 2H), 4.43 (dd, J = 9.0, 5.0 Hz, 1H), 3.11- 2.97 (m, 1H), 2.70-2.56 (m, 1H), 2.50 (s, 2H), 2.35- 2.19 (m, 1H), 2.17-1.99 (m, 1H), 1.26 (d, J = 6.3 Hz, 6H). 209 isopropyl (S)-6- diazo-2-(oxetane-3- carboxamido)-5- oxohexanoate 298 210 isopropyl (S)-6- diazo-2-((R)-3- hydroxy-2- methylpropanamido)- 5-oxohexanoate 300 211 0 isopropyl (S)-6- diazo-5-oxo-2- (tetrahydro-2H- pyran-4- carboxamido)hexanoate 326 212 isopropyl (2S)-6- diazo-5-oxo-2- ((1S)-tetrahydro- 1H,3H-furo[3,4- c]furan-1- carboxamido)hexanoate 354 213 isopropyl (2S)-6- diazo-5-oxo-2- ((1R)-tetrahydro- 1H,3H-furo[3,4- c]furan-1- carboxamido)hexanoate 354 214 isopropyl (S)-2- ((S)-2-cyano-2- hydroxyacetamido)- 6-diazo-5- oxohexanoate 297 215 isopropyl (S)-2- ((S)-2-cyano-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 311 216 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3- oxobutanamido)-5- oxohexanoate 328 217 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3- oxobutanamido)-5- oxohexanoate 314 218 isopropyl (S)-6- diazo-2-((R)-3- methoxy-2- methylpropanamido)- 5-oxohexanoate MS: 298 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.78 (s, 1H), 5.00 (dt, J = 12.5, 6.3 Hz, 1H), 4.36 (dd, J = 9.5, 4.9 Hz, 1H), 3.52 (t, J = 9.1 Hz, 1H), 3.35-3.32 (m, 4H), 2.74-2.59 (m, 1H), 2.45 (s, 2H), 2.23-2.08 (m, 1H), 1.98-1.82 (m, 1H), 1.25 (dd, J = 6.1, 4.7 Hz, 6H), 1.08 (d, J = 7.0 Hz, 3H). 219 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiazol-4- yl)acetamido)-5- oxohexanoate 367 220 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(thiazol- 4-yl)acetamido)-5- oxohexanoate 355 221 0 isopropyl (S)-2- ((R)-2-cyano-2- hydroxyacetamido)- 6-diazo-5- oxohexanoate 297 222 isopropyl (S)-2- ((R)-2-cyano-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 311 223 isopropyl (S)-6- diazo-2-((R)-2- methoxy-3- oxobutanamido)-5- oxohexanoate 328 224 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-3- oxobutanamido)-5- oxohexanoate 314 225 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiazol-4- yl)acetamido)-5- oxohexanoate 369 226 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(thiazol- 4-yl)acetamido)-5- oxohexanoate 355 227 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate 351 228 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate 351 229 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate 337 230 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate 337 231 0 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate 353 232 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate 339 233 isopropyl (S)-6- diazo-2-((S)-2- (furan-2-yl)-2- methoxyacetamido)- 5-oxohexanoate 352 234 isopropyl (S)-6- diazo-2-((S)-2- (furan-3-yl)-2- methoxyacetamido)- 5-oxohexanoate 352 235 isopropyl (S)-6- diazo-2-((S)-2- (furan-2-yl)-2- hydroxyacetamido)- 5-oxohexanoate 338 236 isopropyl (S)-6- diazo-2-((S)-2- (furan-3-yl)-2- hydroxyacetamido)- 5-oxohexanoate 338 237 isopropyl (S)-2- ((S)-2-(1H- imidazol-4-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 352 238 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- imidazol-4- yl)acetamido)-5- oxohexanoate 338 239 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate 351 240 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate 351 241 00 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- pyrrol-2- yl)acetamido)-5- oxohexanoate 337 242 01 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- pyrrol-3- yl)acetamido)-5- oxohexanoate 337 243 02 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate 353 244 03 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(oxazol- 4-yl)acetamido)-5- oxohexanoate 339 245 04 isopropyl (S)-6- diazo-2-((R)-2- (furan-2-yl)-2- methoxyacetamido)- 5-oxohexanoate 352 246 05 isopropyl (S)-6- diazo-2-((R)-2- (furan-3-yl)-2- methoxyacetamido)- 5-oxohexanoate 352 247 06 isopropyl (S)-6- diazo-2-((R)-2- (furan-2-yl)-2- hydroxyacetamido)- 5-oxohexanoate 338 248 07 isopropyl (S)-6- diazo-2-((R)-2- (furan-3-yl)-2- hydroxyacetamido)- 5-oxohexanoate 338 249 08 isopropyl (S)-2- ((R)-2-(1H- imidazol-4-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 352 250 09 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- imidazol-4- yl)acetamido)-5- oxohexanoate 338 251 0 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate 368 252 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate 368 253 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate 354 254 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate 354 255 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiazol-2- yl)acetamido)-5- oxohexanoate 369 256 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(thiazol- 2-yl)acetamido)-5- oxohexanoate 355 257 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate 366 258 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate 352 259 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate 366 260 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate 352 261 0 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate 353 262 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate 339 263 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate 366 264 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1- methyl-1H- imidazol-4- yl)acetamido)-5- oxohexanoate 352 265 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate 353 266 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(oxazol- 2-yl)acetamido)-5- oxohexanoate 339 267 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate 368 268 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate 368 269 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (thiophen-2- yl)acetamido)-5- oxohexanoate 354 270 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (thiophen-3- yl)acetamido)-5- oxohexanoate 354 271 0 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (thiazol-2- yl)acetamido)-5- oxohexanoate 369 272 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(thiazol- 2-yl)acetamido)-5- oxohexanoate 355 273 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate 366 274 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1- methyl-1H- imidazol-2- yl)acetamido)-5- oxohexanoate 352 275 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (thiazol-5- yl)acetamido)-5- oxohexanoate 369 276 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(thiazol- 5-yl)acetamido)-5- oxohexanoate 355 277 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(1- methyl-1H- imidazol-5- yl)acetamido)-5- oxohexanoate 366 278 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1- methyl-1H- imidazol-5- yl)acetamido)-5- oxohexanoate 352 279 isopropyl (S)-2- ((R)-2-(1H- imidazol-2-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 352 280 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- imidazol-2- yl)acetamido)-5- oxohexanoate 338 281 0 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(oxazol- 5-yl)acetamido)-5- oxohexanoate 353 282 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(oxazol- 5-yl)acetamido)-5- oxohexanoate 339 283 isopropyl (S)-2- ((S)-2-(1H- imidazol-5-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 352 284 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(1H- imidazol-5- yl)acetamido)-5- oxohexanoate 338 285 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate 363 286 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate 349 287 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate 364 288 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate 350 289 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate 364 290 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate 350 291 0 isopropyl (S)-6- diazo-2-((S)-2-(3- fluoropyridin-4-yl)- 2- methoxyacetamido)- 5-oxohexanoate 381 292 isopropyl (S)-6- diazo-2-((S)-2-(3- fluoropyridin-4-yl)- 2- hydroxyacetamido)- 5-oxohexanoate 367 293 isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-2-yl)- 2- methoxyacetamido)- 5-oxohexanoate 381 294 isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-2-yl)- 2- hydroxyacetamido)- 5-oxohexanoate 367 295 isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-3-yl)- 2- methoxyacetamido)- 5-oxohexanoate 381 296 isopropyl (S)-6- diazo-2-((S)-2-(5- fluoropyridin-3-yl)- 2- hydroxyacetamido)- 5-oxohexanoate 367 297 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate 393 298 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate 379 299 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate 393 300 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate 379 301 0 isopropyl (S)-6- diazo-2-((S)-2- methoxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate 393 302 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate 379 303 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate 393 304 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(5- methoxypyridin-2- yl)acetamido)-5- oxohexanoate 379 305 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate 393 306 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(5- methoxypyridin-3- yl)acetamido)-5- oxohexanoate 379 307 isopropyl (S)-2- ((R)-2-(1H- imidazol-5-yl)-2- methoxyacetamido)- 6-diazo-5- oxohexanoate 352 308 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(1H- imidazol-5- yl)acetamido)-5- oxohexanoate 338 309 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate 363 310 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (pyridin-2- yl)acetamido)-5- oxohexanoate 349 311 0 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate 364 312 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (pyrimidin-4- yl)acetamido)-5- oxohexanoate 350 313 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate 364 314 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2- (pyrimidin-2- yl)acetamido)-5- oxohexanoate 350 315 isopropyl (S)-6- diazo-2-((R)-2-(3- fluoropyridin-4-yl)- 2- methoxyacetamido)- 5-oxohexanoate 381 316 isopropyl (S)-6- diazo-2-((R)-2-(3- fluoropyridin-4-yl)- 2- hydroxyacetamido)- 5-oxohexanoate 367 317 isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-2-yl)- 2- methoxyacetamido)- 5-oxohexanoate 381 318 isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-2-yl)- 2- hydroxyacetamido)- 5-oxohexanoate 367 319 isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-3-yl)- 2- methoxyacetamido)- 5-oxohexanoate 381 320 isopropyl (S)-6- diazo-2-((R)-2-(5- fluoropyridin-3-yl)- 2- hydroxyacetamido)- 5-oxohexanoate 367 321 0 isopropyl (S)-6- diazo-2-((R)-2- methoxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate 393 322 isopropyl (S)-6- diazo-2-((R)-2- hydroxy-2-(3- methoxypyridin-4- yl)acetamido)-5- oxohexanoate 379 323 tert-butyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 314 324 phenyl (S)-6-diazo- 2-((S)-2- methoxypropanamido)- 5- oxohexanoate 334 325 benzyl (S)-6-diazo- 2-((S)-2- methoxypropanamido)- 5- oxohexanoate 348 326 cyclohexyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 340 327 cycloheptyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 354 328 cyclooctyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 368 329 cyclooctyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate 368 330 tert-butyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate 314 331 0 phenyl (S)-6-diazo- 2-((R)-2- methoxypropanamido)- 5- oxohexanoate 334 332 benzyl (S)-6-diazo- 2-((R)-2- methoxypropanamido)- 5- oxohexanoate 348 333 cyclohexyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate 340 334 cycloheptyl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate 354 335 1-methylpiperidin- 4-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)- 5- oxohexanoate 355 336 pyridin-4-yl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 335 337 pyridin-4-ylmethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 349 338 tetrahydro-2H- pyran-4-yl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 342 339 1-methylpiperidin- 4-yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate 355 340 (R)-oxepan-4-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 356 341 00 (S)-oxepan-4-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 356 342 01 oxocan-5-yl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 370 343 02 pyridin-4-yl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate 335 344 03 pyridin-4-ylmethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)- 5- oxohexanoate 349 345 04 tetrahydro-2H- pyran-4-yl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate 342 346 05 1-methylpiperidin- 4-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)- 5- oxohexanoate 355 347 06 (R)-oxepan-4-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)- 5- oxohexanoate 356 348 07 (S)-oxepan-4-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)- 5- oxohexanoate 356 349 08 oxocan-5-yl (S)-6- diazo-2-((R)-2- methoxypropanamido)- 5- oxohexanoate 370 350 09 trifluoromethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 326 351 0 2,2,2-trifluoroethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 340 352 (S)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate 354 353 3,3,3- trifluoropropyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 354 354 (S)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 368 355 1,1,1-trifluoro-2- methylpropan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 368 356 4,4,4-trifluoro-2- methylbutan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 382 357 cyanic (S)-6-diazo- 2-((S)-2- methoxypropanamido)- 5-oxohexanoic anhydride 283 358 cyanomethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 297 359 (S)-1-cyanoethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 311 360 2-cyanoethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 311 361 0 1-cyanopropan-2-yl (2S)-6-diazo-2- ((S)-2- methoxypropanamido)- 5- oxohexanoate 325 362 2-cyanopropan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 325 363 1-cyano-2- methylpropan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)- 5- oxohexanoate 339 364 hydroxymethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 288 365 methoxymethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 302 366 ethoxymethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 316 367 isopropoxymethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 330 368 cyclopropoxymethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 328 369 cyclobutoxymethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 342 370 trifluoromethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 326 371 0 2,2,2-trifluoroethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 340 372 (S)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 354 373 (R)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 354 374 (R)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 368 375 (R)-1-cyanoethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 311 376 (R)-1-cyanopropan- 2-yl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 325 377 (R)-1,1,1- trifluoropropan-2- yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 354 378 3,3,3- trifluoropropyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 354 379 (S)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 368 380 (R)-4,4,4- trifluorobutan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 368 381 0 1,1,1-trifluoro-2- methylpropan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 368 382 4,4,4-trifluoro-2- methylbutan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 382 383 cyanic (S)-6-diazo- 2-((R)-2- methoxypropanamido)- 5-oxohexanoic anhydride 283 384 cyanomethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 297 385 (S)-1-cyanoethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 311 386 (R)-1-cyanoethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 311 387 2-cyanoethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 311 388 (S)-1-cyanopropan- 2-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 325 389 (R)-1-cyanopropan- 2-yl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 325 390 2-cyanopropan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 325 391 0 1-cyano-2- methylpropan-2-yl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 339 392 hydroxymethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 288 393 methoxymethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 302 394 ethoxymethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 316 395 isopropoxymethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 330 396 cyclopropoxymethy (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 328 397 cyclobutoxymethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 342 398 2-(pyrrolidin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 355 399 2-methoxyethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 316 400 2-ethoxyethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 330 401 0 2-isopropoxyethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 344 402 2-aminoethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 301 403 2- (methylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 315 404 2- (dimethylamino)ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 329 405 2-(ethylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 329 406 2- (isopropylamino)ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 343 407 2- (cyclopropylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 341 408 2- (cyclobutylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 355 409 2- (cyclopentylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 369 410 2- (cyclohexylamino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 383 411 0 2-(azetidin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 341 412 2-(piperidin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 369 413 2-(azepan-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 383 414 2-(azocan-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 397 415 2-morpholinoethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 371 416 2- (phenylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 377 417 2-(pyridin-4- ylamino)ethyl (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 378 418 2- (benzylamino)ethyl (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanoate 391 419 2-((pyridin-4- ylmethyl)amino) ethyl (S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 392 420 2-(4- methylpiperazin-1- yl)ethyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 384 421 0 2-methoxyethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 316 422 2-ethoxyethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 330 423 2-isopropoxyethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 344 424 2-aminoethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 301 425 2- (methylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 315 426 2- (dimethylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 329 427 2-(ethylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 329 428 2- (isopropylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 343 429 2- (cyclopropylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 341 430 2- (cyclobutylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 355 431 0 2- (cyclopentylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 369 432 2- (cyclohexylamino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 383 433 2-(azetidin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 341 434 2-(piperidin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 369 435 2-(azepan-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 383 436 2-(azocan-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 397 437 2-morpholinoethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 371 438 2- (phenylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 377 439 2-(pyridin-4- ylamino)ethyl (S)- 6-diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 378 440 2- (benzylamino)ethyl (S)-6-diazo-2-((R)- 2- methoxypropanamido)-5- oxohexanoate 391 441 00 2-((pyridin-4- ylmethyl)amino) ethyl (S)-6-diazo-2- ((R)-2- methoxypropanamido)-5- oxohexanoate 392 442 01 2-(4- methylpiperazin-1- yl)ethyl (S)-6- diazo-2-((R)-2- methoxypropanamido)-5- oxohexanoate 384 443 02 isopropyl (S)-6- diazo-2-((S)-2- methoxy-4- (methylthio) butanamido)-5- oxohexanoate MS: 360 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 7.23- 7.04 (m, 1H), 5.26 (s, 1H), 5.11-4.95 (m, 1H), 4.58- 4.44 (m, 1H), 3.86-3.68 (m, 1H), 3.50-3.35 (m, 3H), 2.64- 2.50 (m, 2H), 2.40 (s, 2H), 2.26-2.15 (m, 1H), 2.10- 2.05 (m, 3H), 2.06-1.86 (m, 3H), 1.29-1.19 (m, 6H). 444 03 isopropyl (S)-6- diazo-2-(2- hydroxy-2- methylpropanamido)- 5-oxohexanoate MS: 300 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 5.01 (dt, J = 12.5, 6.3 Hz, 1H), 4.33 (dd, J = 8.7, 5.1 Hz, 1H), 2.43 (s, 2H), 2.29-2.11 (m, 1H), 2.10- 1.90 (m, 1H), 1.36 (d, J = 3.3 Hz, 6H), 1.26 (dd, J = 6.2, 2.9 Hz, 6H). 445 04 methyl (S)-6-diazo- 2-((S)-2-methoxy- 4- (methylthio) butanamido)-5- oxohexanoate 332 446 05 methyl (S)-6-diazo- 2-((S)-2-hydroxy- 3-(1H-indol-3- yl)propanamido)-5- oxohexanoate MS: 373 (M + H).sup.+ .sup.1H NMR (400 MHz, CD.sub.3OD) 7.61 (d, J = 7.9 Hz, 1H), 7.32 (d, J = 8.1 Hz, 1H), 7.14 (s, 1H), 7.11-7.03 (m, 1H), 7.03-6.94 (m, 1H), 5.23 (s, 1H), 4.38 (t, J = 4.9 Hz, 1H), 4.32-4.22 (m, 1H), 3.67 (s, 3H), 3.25-3.12 (m, 2H), 1.96- 1.84 (m, 1H), 1.81-1.60 (m, 3H). 447 06 methyl (S)-6-diazo- 2-((S)-2-hydroxy- 3- methylbutanamido)- 5-oxohexanoate MS: 286 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 4.46 (dd, J = 8.5, 5.1 Hz, 1H), 3.87 (d, J = 3.4 Hz, 1H), 3.73 (s, 3H), 2.54-2.33 (m, 2H), 2.29-2.14 (m, 1H), 2.15- 1.92 (m, 2H), 1.01 (d, J = 6.9 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H). 448 07 methyl (S)-6-diazo- 2-(2- isopropoxyacetamido)-5- oxohexanoate MS: 286 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 4.50 (dd, J = 8.7, 5.0 Hz, 1H), 4.05-3.88 (m, 2H), 3.74 (s, 3H), 3.72- 3.66 (m, 1H), 2.45 (s, 2H), 2.31-2.15 (m, 1H), 2.13- 1.92 (m, 1H), 1.30-1.15 (m, 6H). 449 08 (S)-6-diazo-2-((S)- 2- hydroxypropanamido)- 5-oxohexanoic acid 244 450 09 cyclopropyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate MS: 298 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 4.44-4.29 (m, 1H), 4.15 (dt, J = 8.8, 2.8 Hz, 1H), 3.82-3.70 (m, 1H), 3.42- 3.34 (m, 3H), 2.44 (s, 2H), 2.28-2.10 (m, 1H), 2.06- 1.91 (m, 1H), 1.35-1.31 (m, 3H), 0.78-0.63 (m, 4H). 451 0 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- methoxypropanamido)- 6-diazo-5- oxohexanoate MS: 415 (M + H).sup.+, .sup.1H NMR (400 MHz, CDCl.sub.3) 8.12- 8.00 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.17-7.05 (m, 3H), 6.92- 6.83 (m, 1H), 4.96 (dt, J = 12.6, 6.3 Hz, 1H), 4.76 (s, 1H), 4.46-4.34 (m, 1H), 4.00- 3.92 (m, 1H), 3.50-3.41 (m, 3H), 3.29-3.19 (m, 2H), 1.94-1.69 (m, 2H), 1.70- 1.59 (m, 2H), 1.21-1.16 (m, 6H). 452 isopropyl (S)-6- diazo-2-(2- isopropoxyacetamido)-5- oxohexanoate MS: 314 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 5.02 (dt, J = 12.5, 6.3 Hz, 1H), 4.42 (dd, J = 8.7, 5.0 Hz, 1H), 4.03-3.87 (m, 2H), 3.70 (dt, J = 12.2, 6.1 Hz, 1H), 2.44 (s, 2H), 2.27-2.14 (m, 1H), 2.10-1.93 (m, 1H), 1.26 (dd, J = 6.3, 2.1 Hz, 6H), 1.22 (dd, J = 6.1, 3.4 Hz, 6H). 453 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate MS: 429 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.57 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.15 (t, J = 7.1 Hz, 1H), 7.08-6.99 (m, 2H), 5.26 (s, 1H), 4.26-4.18 (m, 1H), 3.96 (t, J = 5.0 Hz, 1H), 3.75 (s, 3H), 3.48 (s, 3H), 3.22-3.16 (m, 2H), 1.95- 1.83 (m, 1H), 1.80-1.61 (m, 3H), 1.22 (dd, J = 8.6, 6.3 Hz, 6H). 454 isopropyl (S)-6- diazo-2-((R)-2- methoxy-3-(1- methyl-1H-indol-3- yl)propanamido)-5- oxohexanoate MS: 429 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.55 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.06-6.99 (m, 2H), 5.49 (s, 1H), 4.94 (dt, J = 12.5, 6.2 Hz, 1H), 4.21-4.09 (m, 1H), 3.94 (t, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.37 (s, 3H), 3.13 (ddd, J = 34.8, 14.5, 6.4 Hz, 2H), 2.06-1.85 (m, 3H), 1.82-1.69 (m, 1H), 1.20 (dd, J = 8.8, 6.3 Hz, 6H). 456 methyl (S)-6-diazo- 2-((S)-2-hydroxy- 2- phenylacetamido)- 5-oxohexanoate MS: 320 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.53- 7.43 (m, 2H), 7.42-7.22 (m, 3H), 5.05 (s, 1H), 4.45 (dd, J = 8.9, 4.8 Hz, 1H), 3.71 (s, 3H), 2.33 (s, 2H), 2.27-2.12 (m, 1H), 2.07-1.91 (m, 1H). 457 methyl (S)-6-diazo- 2-((S)-2-methoxy- 2- phenylacetamido)- 5-oxohexanoate MS: 334 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 7.47- 7.42 (m, 2H), 7.40-7.32 (m, 3H), 5.57 (s, 1H), 4.68 (s, 1H), 4.44 (dd, J = 9.4, 4.8 Hz, 1H), 3.71 (s, 3H), 3.42 (s, 3H), 2.32 (s, 2H), 2.26-2.12 (m, 1H), 2.05-1.97 (m, 1H). 458 methyl (S)-6-diazo- 2-(2- methoxyacetamido)- 5-oxohexanoate MS: 258 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.82 (s, 1H), 4.50 (dd, J = 8.8, 5.0 Hz, 1H), 3.93 (d, J = 4.0 Hz, 2H), 3.73 (s, 3H), 3.43 (s, 3H), 2.44 (s, 2H), 2.30-2.16 (m, 1H), 2.11-1.93 (m, 1H). 459 S-isopropyl (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate MS: 316 (M + H).sup.+, .sup.1H NMR (400 MHz, CD.sub.3OD) 5.81 (s, 1H), 4.51 (dd, J = 9.9, 4.6 Hz, 1H), 3.80 (q, J = 6.7 Hz, 1H), 3.59 (dt, J = 13.7, 6.9 Hz, 1H), 3.44 (s, 3H), 2.43 (s, 2H), 2.31-2.16 (m, 1H), 2.04- 1.87 (m, 1H), 1.35 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 6.9 Hz, 6H). 460 (S)-6-diazo-2-((S)- 2-methoxy-4- (methylthio) butanamido)-5- oxohexanoic acid 318 461 isopropyl (2S)-2-(2- acetoxy-3-(1H- indol-3- yl)propanamido)-6- diazo-5- oxohexanoate 442 462 0 isopropyl (2S)-2-(2- (2-cyanoacetoxy)- 3-(1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate 467 463 isopropyl (2S)-6- diazo-2-(2- ((dimethylglycyl) oxy)-3-(1H-indol-3- yl)propanamido)-5- oxohexanoate 486 464 isopropyl (2S)-2-(3- (1H-indol-3-yl)-2- (2-(2- oxopyrrolidin-1- yl)acetoxy)propanamido)- 6-diazo-5- oxohexanoate 526 465 isopropyl (2S)-6- diazo-2-(2- hydroxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate 400 466 isopropyl (S)-6- diazo-2-((S)-2-(2- hydroxyethoxy)-3- (1H-indol-3- yl)propanamido)-5- oxohexanoate 444 467 isopropyl (S)-2- ((S)-2-(2- acetamidoethoxy)- 3-(1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate 486 468 isopropyl (S)-2- ((S)-2-(2- cyanoethoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate 454 469 isopropyl (S)-2- ((S)-2- (cyanomethoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate 439 470 isopropyl (S)-6- diazo-2-((S)-2-(2- (dimethylamino)-2- oxoethoxy)-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate 486 471 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(2- (methylamino)-2- oxoethoxy)propanamido)- 6-diazo-5- oxohexanoate 472 472 0 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(2- oxopropoxy)propanamido)- 6-diazo-5- oxohexanoate 457 473 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-((tetrahydro- 2H-pyran-4- yl)oxy)propanamido)- 6-diazo-5- oxohexanoate 485 474 isopropyl (S)-2- ((S)-2-(3-amino-3- oxopropoxy)-3- (1H-indol-3- yl)propanamido)-6- diazo-5- oxohexanoate 472 475 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2-(3- (methylamino)-3- oxopropoxy)propanamido)- 6-diazo-5- oxohexanoate 486 476 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate 428 477 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1H- pyrrolo[3,2- b]pyridin-3- yl)propanamido)-5- oxohexanoate 415 478 isopropyl (S)-6- diazo-2-((S)-2- methoxy-3-(1H- pyrrolo[2,3- b]pyridin-3- yl)propanamido)-5- oxohexanoate 415 479 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1- methyl-1H- pyrrolo[3,2- b]pyridin-3- yl)propanamido)-5- oxohexanoate 415 480 isopropyl (S)-6- diazo-2-((S)-2- hydroxy-3-(1- methyl-1H- pyrrolo[2,3- b]pyridin-3- yl)propanamido)-5- oxohexanoate 415 481 isopropyl (S)-6- diazo-2-((S)-2- ethoxy-3-(7-fluoro- 1H-indol-3- yl)propanamido)-5- oxohexanoate 447 482 0 isopropyl (S)-6- diazo-2-((S)-3-(7- fluoro-1H-indol-3- yl)-2- isopropoxypropanamido)- 5- oxohexanoate 461 483 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- phenoxypropanamido)- 6-diazo-5- oxohexanoate 477 484 isopropyl (2S)-2-(3- (1H-indol-3-yl)-2- ((methylglycyl) oxy)propanamido)-6- diazo-5- oxohexanoate 472 485 isopropyl (2S)-6- diazo-2-(2- (glycyloxy)-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate 457 486 isopropyl (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate 303 487 (S)-6-diazo-2-((S)- 2-(methoxy- d3)propanamido)- 5-oxohexanoic acid 261 488 methyl (S)-6-diazo- 2-((S)-2-(methoxy- d3)propanamido)- 5-oxohexanoate 275 489 ethyl (S)-6-diazo-2- ((S)-2-(methoxy- d3)propanamido)- 5-oxohexanoate 289 490 S-isopropyl (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanethioate 319 491 isopropyl (S)-6- diazo-2-((S)-2- (methoxy-d3)-4- (methylthio) butanamido)-5- oxohexanoate 363 492 0 methyl-d3 (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 275 493 ethyl-2,2,2-d3 (S)- 6-diazo-2-((S)-2- methoxypropanamido)- 5- oxohexanoate 289 494 isopropyl (S)-6- diazo-2-(2-(ethoxy- 2,2,2- d3)acetamido)-5- oxohexanoate 303 495 isopropyl (S)-6- diazo-2-(2-(ethoxy- d5)acetamido)-5- oxohexanoate 305 496 ethyl-d5 (S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 291 497 propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 307 498 propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- hydroxypropanamido)-5- oxohexanoate 293 499 propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- hydroxy-3- methylbutanamido)- 5-oxohexanoate 321 500 propan-2-yl-d7 (S)- 6-diazo-2-(2- ethoxyacetamido)- 5-oxohexanoate 307 501 S-(propan-2-yl-d7) (S)-6-diazo-2-((S)- 2- methoxypropanamido)-5- oxohexanethioate 323 502 0 propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- methoxy-4- (methylthio) butanamido)-5- oxohexanoate 367 503 methyl-d3 (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate 278 504 ethyl-2,2,2-d3 (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate 292 505 ethyl-d5 (S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate 294 506 propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate 310 507 propan-2-yl-d7 (S)- 6-diazo-2-(2- (ethoxy-2,2,2- d3)acetamido)-5- oxohexanoate 310 508 S-(propan-2-yl-d7) (S)-6-diazo-2-((S)- 2-(methoxy- d3)propanamido)- 5-oxohexanethioate 326 509 propan-2-yl-d7 (S)- 6-diazo-2-((S)-2- (methoxy-d3)-4- (methylthio) butanamido)-5- oxohexanoate 370 510 propan-2-yl-d7 (S)- 6-diazo-2-(2- (ethoxy- d5)acetamido)-5- oxohexanoate 312 511 methyl 6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate-2-d 273 512 0 ethyl 6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate-2-d 287 513 isopropyl 6-diazo- 2-((S)-2- methoxypropanamido)-5- oxohexanoate-2-d 301 514 isopropyl 6-diazo- 2-(2- ethoxyacetamido)- 5-oxohexanoate-2- d 301 515 S-isopropyl 6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate- 2-d 317 516 isopropyl 6-diazo- 2-((S)-2-methoxy- 4-(methylthio) butanamido)-5- oxohexanoate-2-d 361 517 isopropyl 6-diazo- 2-((S)-2- hydroxypropanamido)-5- oxohexanoate-2-d 287 518 isopropyl 6-diazo- 2-((S)-2-hydroxy- 3- methylbutanamido)- 5-oxohexanoate-2- d 315 519 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanoate 309 520 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-(2- (ethoxy-2,2,2- d3)acetamido)-5- oxohexanoate 309 521 S-(propan-2-yl- 1,1,1,3,3,3-d6) (S)- 6-diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanethioate 325 522 0 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- (methoxy-d3)-4- (methylthio) butanamido)-5- oxohexanoate 369 523 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-(2- (ethoxy- d5)acetamido)-5- oxohexanoate 311 524 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- hydroxypropanamido)-5- oxohexanoate 292 525 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- hydroxy-3- methylbutanamido)- 5-oxohexanoate 320 526 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-(methoxy- d3)propanamido)- 5-oxohexanoate 306 527 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- (2-(ethoxy-2,2,2- d3)acetamido)-5- oxohexanoate 306 528 S-(propan-2-yl- 1,1,1-d3) (2S)-6- diazo-2-((S)-2- (methoxy- d3)propanamido)- 5-oxohexanethioate 322 529 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-(methoxy- d3)-4- (methylthio) butanamido)-5- oxohexanoate 366 530 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- (2-(ethoxy- d5)acetamido)-5- oxohexanoate 308 531 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2- hydroxypropanamido)-5- oxohexanoate 289 532 0 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-hydroxy-3- methylbutanamido)- 5-oxohexanoate 317 533 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanoate 306 534 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-(2- ethoxyacetamido)- 5-oxohexanoate 306 535 S-(propan-2-yl- 1,1,1,3,3,3-d6) (S)- 6-diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate 322 536 propan-2-yl- 1,1,1,3,3,3-d6 (S)- 6-diazo-2-((S)-2- methoxy-4- (methylthio) butanamido)-5- oxohexanoate 366 537 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2- methoxypropanamido)-5- oxohexanoate 303 538 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- (2- ethoxyacetamido)- 5-oxohexanoate 303 539 S-(propan-2-yl- 1,1,1-d3) (2S)-6- diazo-2-((S)-2- methoxypropanamido)-5- oxohexanethioate 319 540 propan-2-yl-1,1,1- d3 (2S)-6-diazo-2- ((S)-2-methoxy-4- (methylthio) butanamido)-5- oxohexanoate 363 541 methyl (S)-6-diazo- 2-((S)-2- (methylthio) propanamido)-5- oxohexanoate 288 542 00 ethyl (S)-6-diazo-2- ((S)-2- (methylthio) propanamido)-5- oxohexanoate 302 543 01 isopropyl (S)-6- diazo-2-((S)-2- (methylthio) propanamido)-5- oxohexanoate 316 544 02 isopropyl (S)-6- diazo-2-((S)-2- mercaptopropanamido)-5- oxohexanoate 302 545 03 isopropyl (S)-6- diazo-2-((S)-2- mercapto-3- methylbutanamido)- 5-oxohexanoate 330 546 04 isopropyl (S)-6- diazo-2-(2- (ethylthio)acetamido)- 5-oxohexanoate 316 547 05 S-isopropyl (S)-6- diazo-2-((S)-2- (methylthio) propanamido)-5- oxohexanethioate 332 548 06 isopropyl (S)-2- ((S)-2,4- bis(methylthio) butanamido)-6-diazo-5- oxohexanoate 376 549 07 isopropyl (S)-6- diazo-2-((S)-2- (ethylthio)-3-(1H- indol-3- yl)propanamido)-5- oxohexanoate 445 550 08 isopropyl (S)-2- ((S)-2-(acetylthio)- 4- (methylthio)butanamido)- 6-diazo-5- oxohexanoate 404 551 09 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- (methylthio)propanamido)- 6-diazo-5- oxohexanoate 431 552 0 isopropyl (S)-6- diazo-2-(2- (isopropylthio) acetamido)-5- oxohexanoate 330 553 isopropyl (S)-6- diazo-2-((S)-2- (methylthio)-3- phenylpropanamido)- 5-oxohexanoate 392 554 isopropyl (S)-6- diazo-2-((S)-2- (methylthio)-2- phenylacetamido)- 5-oxohexanoate 378 555 isopropyl (S)-6- diazo-2-((S)-2- (methylthio) butanamido)-5- oxohexanoate 330 556 isopropyl (S)-6- diazo-2-((S)-3- methyl-2- (methylthio) butanamido)-5- oxohexanoate 344 557 cyclopentyl (S)-6- diazo-2-((S)-2- (methylthio) propanamido)-5- oxohexanoate 342 558 isopropyl (S)-6- diazo-5-oxo-2-((S)- thietane-2- carboxamido) hexanoate 314 559 methyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate 304 560 ethyl (2S)-6-diazo- 2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate 318 561 isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate 332 562 0 isopropyl (2S)-6- diazo-2-(2- (ethylsulfinyl) acetamido)-5- oxohexanoate 332 563 S-isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanethioate 348 564 isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl)-4- (methylthio) butanamido)-5- oxohexanoate 392 565 isopropyl (2S)-6- diazo-2-((2S)-2- (ethylsulfinyl)-3- (1H-indol-3- yl)propanamido)-5- oxohexanoate 461 566 isopropyl (2S)-2- ((2S)-3-(1H-indol- 3-yl)-2- (methylsulfinyl) propanamido)-6-diazo- 5-oxohexanoate 447 567 isopropyl (2S)-6- diazo-2-(2- (isopropylsulfinyl) acetamido)-5- oxohexanoate 346 568 isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl)-3- phenylpropanamido)- 5-oxohexanoate 408 569 isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl)-2- phenylacetamido)- 5-oxohexanoate 394 570 isopropyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) butanamido)-5- oxohexanoate 346 571 isopropyl (2S)-6- diazo-2-((2S)-3- methyl-2- (methylsulfinyl) butanamido)-5- oxohexanoate 360 572 0 cyclopentyl (2S)-6- diazo-2-((2S)-2- (methylsulfinyl) propanamido)-5- oxohexanoate 358 573 methyl (S)-6-diazo- 2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate 320 574 ethyl (S)-6-diazo-2- ((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate 334 575 isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate 348 576 isopropyl (S)-6- diazo-2-(2- (ethylsulfonyl) acetamido)-5- oxohexanoate 348 577 S-isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanethioate 364 578 isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl)-4- (methylthio) butanamido)-5- oxohexanoate 408 579 isopropyl (S)-6- diazo-2-((S)-2- (ethylsulfonyl)-3- (1H-indol-3- yl)propanamido)-5- oxohexanoate 477 580 isopropyl (S)-2- ((S)-3-(1H-indol-3- yl)-2- (methylsulfonyl) propanamido)-6- diazo-5- oxohexanoate 463 581 isopropyl (S)-6- diazo-2-(2- (isopropylsulfonyl) acetamido)-5- oxohexanoate 362 582 0 isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl)-3- phenylpropanamido)- 5-oxohexanoate 424 583 isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl)-2- phenylacetamido)- 5-oxohexanoate 410 584 isopropyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) butanamido)-5- oxohexanoate 362 585 isopropyl (S)-6- diazo-2-((S)-3- methyl-2- (methylsulfonyl) butanamido)-5- oxohexanoate 376 586 cyclopentyl (S)-6- diazo-2-((S)-2- (methylsulfonyl) propanamido)-5- oxohexanoate 374

Synthesis of Control Compounds

(87) Compound 60 of WO2017023774 (named reference compound A) was obtained according to the synthesis route and operation steps of compound 60 in Page 124 of WO2017023774.

(88) Compound 25 of WO2017023774 (named reference compound 1) was obtained according to the synthesis route and operation steps of compound 25 in Page 100-101 of WO2017023774.

(89) Compound 9 of WO2017023774 (named reference compound 2) was obtained according to the synthesis route and operation steps of compound 9 in Page 87-88 of WO2017023774.

(90) Compound 47 of WO2017023774 (named reference compound 3) was obtained according to the synthesis route and operation steps of compound 47 in Page 115-116 of WO2017023774.

Example 7 Plasma Stability of Different Species

(91) Reference compound A, reference compound 1, reference compound 2, compound 2, compound 3, compound 81, compound 443, compound 459 were provided for assay of plasma stability of compounds in different species, and they were shown as below:

(92) ##STR00645##

(93) For metabolic stability, plasma from dog, monkey, swine and human were used. For stability, prodrugs (1 M) were spiked in respective solutions and incubated in an orbital shaker at 37 C. 50 L aliquots of the mixture in duplicate were removed, and the reaction quenched by addition of four times the volume of ice cold acetonitrile spiked with the internal standard (Dexamethasone 100 ng/mL). The samples were vortexed for 30 s and centrifuged at 15000 g for 5 min. 100 L of the supernatant was diluted with 100 L of water and transferred to the 0.6 mL plastic tubes on 96-well plate. Prodrug disappearance was monitored over time using a liquid chromatography and tandem mass spectrometry (LC-MS/MS).

(94) For LC-MS/MS, prodrugs were analyzed on a ExionLC AD HPLC system coupled to REF Triple Quad 5500+ mass spectrometer with an ESI interface on an Phenomenex Kinetex 5 m C18 100A (2.1*50) mm UPLC column. The autosampler was temperature controlled and was operated at 4 C. The mobile phase used for the chromatographic separation was composed of acetonitrile/water containing 0.10% formic acid and will run at a flow rate of 0.6 mL/min for 3.5 min using gradient elution. The column effluent was monitored using TSQ Vantage triple-quadrupole mass-spectrometric detector, equipped with an electrospray probe set in the positive ionization mode. Samples were introduced into the ionization source through a heated nebulized probe (400 C.). Disappearance of prodrugs will be measured from ratio of peak areas of analyte to IS.

(95) For quantification of compound remaining, disappearance of prodrugs was measured from ratio of peak areas of analyte to IS.

(96) FIG. 1 shows the plasma stability of compounds after incubation for 4 hours in the presence of dog, monkey, swine and human plasma. The data show that the Reference compound A, compound 2, compound 3, compound 81, compound 443, compound 459 was substantially intact in the presence of the dog, monkey, swine and human plasma for 4 hours, while few of reference compound 1 and reference compound 2 remained in such conditions.

Example 8 Stability of Liver Microsomes of Different Species

(97) Reference compound A, reference compound 1, reference compound 2, and compound 2, compound 3, compound 81, compound 443, compound 459 were provided for assay of stability of liver microsomes in different species.

(98) For metabolic stability, microsomes from human, monkey, dog, rat and mouse were used. For stability, prodrugs (1 M) were spiked in each microsomes matrix and incubated in an orbital shaker at 37 C. Aliquots of 50 L were taken from the reaction solution at 0, 15, 30, 45 and 60 min. The reaction was stopped by the addition of 4 volumes of cold acetonitrile with IS (100 nM alprazolam, 200 nM labetalol, 200 nM caffeine and 2 M ketoprofen). Samples were centrifuged at 3, 220 g for 40 minutes. Aliquot of 100 L of the supernatant was mixed with 100 L of ultra-pure H.sub.2O and then used for LC-MS/MS analysis.

(99) For LC-MS/MS, prodrugs were analyzed on an API 4000 instrument from AB Inc (Canada) with an ESI interface coupled to Shimadzu LC system on an Waters XSelect HSS T3 C18, 2.5 m, 2.130 mm column. The mobile phase used for the chromatographic separation was composed of Phase A: water (0.1% formic acid); Phase B: acetonitrile (0.1% formic acid) and will run at a flow rate of 1.0 mL/min for 1.0 min using gradient elution. Samples was introduced into the ionization source through a heated nebulized probe (500 C.). Disappearance of prodrugs will be measured from ratio of peak areas of analyte to IS.

(100) For data analysis, peak areas were determined from extracted ion chromatograms. The slope value, k, was determined by linear regression of the natural logarithm of the remaining percentage of the parent drug vs. incubation time curve. The in vitro half-life (in vitro t.sub.1/2) was determined from the slope value:
in vitro t.sub.1/2=(0.693/k)

(101) Conversion of the in vitro t.sub.1/2 (min) into the in vitro intrinsic clearance (in vitro CL.sub.int, in L/min/mg protein) was done using the following equation (mean of duplicate determinations):

(102) $\mathrm{in}\mathrm{vitro}{\mathrm{CL}}_{\mathrm{int}}=\frac{0.693}{t_{1/2}}\frac{\mathrm{volume}\mathrm{of}\mathrm{incubation}\left(\mathrm{.Math.L}\right)}{\mathrm{amount}\mathrm{of}\mathrm{proteins}\left(\mathrm{mg}\right)}$

(103) Table 1 shows the in vitro intrinsic clearance of compounds after incubation for 60 minutes in the presence of human, monkey, dog, rat and mouse liver microsomes.

(104) TABLE-US-00004 TABLE 1 In vitro Clint (L/min/mg protein) of Test Compounds in Different Species of Liver Microsomes Compounds Human Monkey Dog Rat Mouse Reference Compound 1 95.34 167.25 63.64 123.55 114.88 Reference Compound 2 110.42 280.56 50.25 437.21 125.68 Reference Compound A 118.61 393.20 60.41 95.16 152.92 Compound 2 43.44 31.78 12.70 62.43 67.14 Compound 3 124.33 46.39 10.90 49.47 71.15 Compound 81 16.82 25.97 5.49 268.83 60.81 Compound 443 73.52 179.92 81.89 238.84 407.55 Compound 459 18.88 130.50 9.57 114.96 71.74

Example 9 Examination on the Anti-Tumor Efficacy in MC38 Syngeneics in C57BL/6 Mouse

(105) Reference compound A, compound 2, compound 3, compound 81, compound 443, compound 459 were provided for the anti-tumor Efficacy in MC38 Syngeneics in C57BL/6 mouse.

(106) Animal species: Mus musculus; Strain: C57BL/6; Age: 6-8 weeks; Sex: female.

(107) The MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37 C., 5% CO.sub.2. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The culture MC38 were harvested, re-suspended in PBS containing 50% Matrigel at a density of 110.sup.7 cells/mL. Each mouse was inoculated subcutaneously in the right flank region with 110.sup.6 cells in 0.1 mL of PBS containing 50% Matrigel for tumor development.

(108) The treatments were started when the mean tumor size reached 79-118 mm.sup.3 (average tumor size 96 mm.sup.3). Each group contained 8 tumor bearing mice. Group 1 was treated with Vehicle (10% DMSO+90% Saline), S.C., QD. Group 2 was given treatments with reference compound A at 2 mol/kg, S.C., QD. Group 3 was given treatments with compound 2 at 2 mol/kg, S.C., QD. The administration of test articles in each study group was shown in the following Table 2.

(109) In vivo efficacy was examined according to absolute tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.

(110) TABLE-US-00005 TABLE 2 Dose Group Compound (mol/kg) Dosing Route Schedule 1 Vehicle 2 S.C. QD 16 2 Reference compound A 2 S.C. QD 26 3 Compound 2 2 S.C. QD 26
Body Weight

(111) The results of the body weight changes in the tumor-bearing mice are shown in Table 3, FIG. 2.

(112) TABLE-US-00006 TABLE 3 The body weight changes (%) of the mice in different groups Dose BW(g) (Mean SEM) BW Change Compound (mol/kg) Beginning (D6) End (D21) (%) Vehicle 2 21.9 0.4 24.9 0.4 +13.6 Reference 2 21.9 0.3 22.5 0.4 +2.8 Compound A Compound 2 2 21.7 0.2 22.4 0.2 + 3.3
Tumor Volumes

(113) The results of tumor sizes in different groups at different time points post tumor inoculation are shown in Table 4 and FIG. 3. The tumor growth inhibition is summarized in Table 5. The result showed that the other treatment groups showed significant anti-tumor effect when compared to the vehicle group. Statistical analysis of difference in tumor volume among the groups was performed using one-way ANOVA followed by individual comparisons using Games-Howell post-hoc test (equal variance not assumed). All data was analyzed using SPSS 22.0 software.

(114) TABLE-US-00007 TABLE 4 Mean tumor volume in the different treatment groups Dose TV (mm.sup.3) (Mean SEM) Compound (mol/kg) D6 D10 D14 D18 D21 D25 D28 D31 Vehicle 2 96 4 354 17 909 42 1732 114 2778 188 Reference 2 96 4 148 6 196 25 297 48 399 74 680 143 928 153 1358 213 compound A Compound 2 2 96 4 141 9 140 10 180 13 263 32 381 55 496 62 617 56

(115) TABLE-US-00008 TABLE 5 Anti-tumor activity of test compounds in MC38 syngeneic model Dose TV (mm.sup.3) at D21 T/C TGI Pvalue Compound (mol/kg) (Mean SEM) (%) (%) (vs. Vehicle) Vehicle 2 2778 188 Reference 2 399 74 14.4 85.6 0.000 Compound A Compound 2 2 263 32 9.5 90.5 0.000

Example 10 Examination on the Anti-Tumor Efficacy in MC38 Model in CES1c / Mouse

(116) Reference compound A and compound 2 obtained from example 2 were provided for the anti-tumor Efficacy in MC38 model in CES1c / mouse.

(117) Animal species: Mus musculus; Strain: C57BL/6-Ces1c.sup.emISmoc; Age: 6-8 weeks; Sex: female. (Shanghai Model Organisms). The MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37 C., 5% CO.sub.2. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The culture MC38 were harvested, re-suspended in PBS containing 50% Matrigel at a density of 110.sup.7 cells/mL. Each mouse was inoculated subcutaneously in the right flank region with 110.sup.6 in 0.1 mL of PBS containing 50% Matrigel for tumor development.

(118) The treatments were started when the mean tumor size reached 52-132 mm.sup.3 (average tumor size 95 mm.sup.3). Each group contained 5 tumor bearing mice. Group 1 was treated with Vehicle (10% DMSO+90% Saline), S.C., QD(Subcutaneous injection, quaque die). Group 2 was given treatments with reference compound A at 2 mol/kg, S.C., QD. Group 3 was given treatments with compound 2 at 2 mol/kg, S.C., QD. The administration of test articles in each study group was shown in the following Table 6.

(119) In vivo efficacy was examined according to absolute tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.

(120) TABLE-US-00009 TABLE 6 Dose Group Compound (mol/kg) Dosing Route Schedule 1 Vehicle 2 S.C. QD 21 2 Reference compound A 2 S.C. QD 21 3 Compound 2 2 S.C. QD 21
Body Weight

(121) Group treated with reference compound A showed some body weight loss, but the group treated with vehicle and the group treated with compound 2 were well-tolerated by the tumor-bearing mice. The results of the body weight changes in the tumor-bearing mice are shown in Table 7, FIG. 4.

(122) TABLE-US-00010 TABLE 7 The body weight changes (%) of the mice in different groups Dose BW(g) (Mean SEM) BW Change Compound (mol/kg) Beginning (D6) End (D26) (%) Vehicle 2 18.0 0.3 20.3 0.3 +12.8 Reference 2 19.2 0.2 17.6 0.9 8.3 Compound A Compound 2 2 19.1 0.3 19.5 0.3 +2.4
Tumor Volumes

(123) The results of tumor sizes in different groups at different time points post tumor inoculation are shown in Table 8 and FIG. 5. The tumor growth inhibition is summarized in Table 9. The result showed that all treatment groups showed significant anti-tumor effect when compared to the vehicle group. Statistical analysis of difference in tumor volume among the groups was performed using one-way ANOVA followed by individual comparisons using Games-Howell post-hoc test (equal variance not assumed). All data was analyzed using SPSS 22.0 software.

(124) TABLE-US-00011 TABLE 8 Mean tumor volume in the different treatment groups Dose TV (mm.sup.3) (Mean SEM) Compound (mol/kg) D6 D9 D12 D15 D20 D23 D26 Vehicle 2 95 13 259 13 275 22 448 29 825 85 1300 242 2234 413 Reference Compound A 2 95 6 275 33 147 5 195 23 196 33 183 33 274 81 Compound 2 2 95 11 193 20 103 15 131 21 169 19 219 21 313 35

(125) TABLE-US-00012 TABLE 9 Anti-tumor activity of test compounds in MC38 syngeneic model Dose TV (mm.sup.3) at D26 T/C TGI P value Compound (mol/kg) (Mean SEM) (%) (%) (vs. Vehicle) Vehicle 2 2234 413 Reference 2 274 81 12.3 87.7 0.046 Compound A Compound 2 2 313 35 14.0 86.0 0.052

Example 11 Examination on the Anti-Tumor Efficacy in MC38 Model in C57BL/6 Mouse

(126) Compound 2, compound 3, compound 81, compound 443 and compound 459 were provided for the anti-tumor Efficacy in MC38 model in C57BL/6 mouse.

(127) Animal species: Mus musculus; Strain: C57BL/6; Age: 6-8 weeks; Sex: female. The MC38 tumor cells were maintained in vitro in DMEM medium supplemented with 10% FBS at 37 C., 5% CO.sub.2. The cells growing in an exponential growth phase were harvested and counted for tumor inoculation. The culture MC38 were harvested, re-suspended in PBS containing 50% Matrigel at a density of 110.sup.7 cells/mL. Each mouse was inoculated subcutaneously in the right flank region with 110.sup.6 cells in 0.1 mL of PBS containing 50% Matrigel for tumor development.

(128) The treatments were started when the mean tumor size reached 82-129 mm.sup.3 (average tumor size 102 mm.sup.3). Each group contained 6 tumor bearing mice. Group 1 was treated with Vehicle (10% DMSO+90% Saline), S.C., QD. Group 2 was given treatments with compound 2 at 2 mol/kg, S.C., QD. Group 3 was given treatments with compound 81 at 2 mol/kg, S.C., QD. Group 4 was given treatments with compound 443 at 2 mol/kg, S.C., QD. Group 5 was given treatments with compound 459 at 2 mol/kg, S.C., QD. Group 6 was given treatments with compound 3 at 2 mol/kg, S.C., QD. The administration of test articles in each study group was shown in the following Table 10.

(129) In vivo efficacy was examined according to absolute tumor growth inhibition (TGI) and the safety was evaluated according to weight change and survival in mice.

(130) TABLE-US-00013 TABLE 10 Group Compound Dose (mol/kg) Dosing Route Schedule 1 Vehicle 2 S.C. QD 15 2 Compound 2 2 S.C. QD 15 3 Compound 81 2 S.C. QD 15 4 Compound 443 2 S.C. QD 15 5 Compound 459 2 S.C. QD 15 6 Compound 3 2 S.C. QD 15
Body Weight

(131) The results of the body weight changes in the tumor-bearing mice are shown in Table 11, FIG. 6.

(132) TABLE-US-00014 TABLE 11 The body weight changes (%) of the mice in different groups Dose BW(g) (Mean SEM) BW Change Compound (mol/kg) Beginning (D6) End (D20) (%) Vehicle 2 19.9 0.5 23.6 0.8 +18.6 Compound 2 2 19.8 0.2 21.1 0.3 +6.4 Compound 81 2 19.8 0.3 20.2 0.5 +1.9 Compound 443 2 19.9 0.6 22.3 0.5 +11.9 Compound 459 2 19.9 0.3 21.1 0.5 +6.3 Compound 3 2 19.9 0.5 21.5 0.4 +7.8
Tumor Volumes

(133) The results of tumor sizes in different groups at different time points post tumor inoculation are shown in Table 12 and FIG. 7. The tumor growth inhibition is summarized in Table 13. The result showed that the other treatment groups showed significant anti-tumor effect when compared to the vehicle group. Statistical analysis of difference in tumor volume among the groups was performed using one-way ANOVA followed by individual comparisons using Games-Howell post-hoc test (equal variance not assumed). All data was analyzed using SPSS 22.0 software.

(134) TABLE-US-00015 TABLE 12 Mean tumor volume in the different treatment groups Dose TV (mm.sup.3) (Mean SEM) Compound (mol/kg) D6 D10 D13 D17 D20 Vehicle 2 102 5 451 37 810 114 1537 216 2331 369 Compound 2 2 102 7 167 17 257 51 306 43 407 33 Compound 81 2 102 6 141 9 124 10 176 13 112 22 Compound 443 2 102 6 152 25 267 65 384 95 500 119 Compound 459 2 102 5 148 22 183 30 281 65 275 59 Compound 3 2 102 6 145 16 169 9 215 27 233 31

(135) TABLE-US-00016 TABLE 13 Anti-tumor activity of test compounds in MC38 syngeneic model Dose TV (mm.sup.3) at D21 T/C TGI P value Compound (mol/kg) (Mean SEM) (%) (%) (vs. Vehicle) Vehicle 2 2331 369 Compound 2 2 407 33 17.5 82.5 0.022 Compound 81 2 112 22 4.8 95.2 0.012 Compound 443 2 500 119 21.5 78.5 0.023 Compound 459 2 275 59 11.8 88.2 0.016 Compound 3 2 233 31 10.0 90.0 0.015