Compounds for inhibiting β-amyloid peptide release and/or its synthesis

A compound of the formula:

• wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• R2 is selected from the group consisting of:
• (a) substituted alkyl provided that such substituted alkyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
• (b) substituted alkenyl provided that such substituted alkenyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkenyl,
• (c) substituted alkynyl provided that such substituted alkynyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkynyl,
• (d) optionally substituted saturated heterocyclic,
• (e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, and optionally substituted heteroaryl, and
• (f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted optionally substituted heteroaryl group then there is at least one other substituent which is not alkyl;
• each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is —C(O)Y or —C(S)Y where Y is selected from the group consisting of
• (a) alkyl or cycloalkyl,
• (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl or α-OC(O)aryl groups,
• (c) alkoxy or thioalkoxy,
• (d) substituted alkoxy or substituted thioalkoxy,
• (e) hydroxy,
• (f) optionally substituted aryl,
• (g) optionally substituted heteroaryl,
• (h) optionally substituted heterocyclic,
• (i) —NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
• (j) —NHSO2—R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• (k) —NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and
• (l) —ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• n is an integer equal to 1 or 2,
• but excluding the following compounds:
• (i) wherein n is 2, R1 is n-C17H35, R2 is —CH2OH, the first R4 is —(CH2)2COOH, the second R4 is isopropyl, X′, X″ and each R5 is hydrogen, and X is —C(O)NHCH(—(CH2)4NH2)C(O)NHCH (benzyl)CH2Cl;
• (ii) wherein n is 2, R′ is —CH2C(O)OCH3, R2 is —(CH2)2Cl, the first R4 is isopropyl, and the second R4 is —(CH2)4NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, —C(O)NHCH(C(O)CH3)CH2phenyl or —C(O)NHCH(C(O)CF3)CH2phenyl;
• (iii) wherein n is 2, R′ is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl;
• (iv) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• (v) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R5 is hydrogen, and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• and
• (vi) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl.

A compound of the formula:

• wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R4 is selected to be:
• (a) substituted alkyl provided that such substituted alkyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
• (b) substituted alkenyl provided that such substituted alkenyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkenyl,
• (c) substituted alkynyl provided that such substituted alkynyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkynyl,
• (d) optionally substituted saturated heterocyclic,
• (e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, and optionally substituted heteroaryl, and
• (f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy, optionally substituted thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is —C(O)Y or —C(S)Y where Y is selected from the group consisting of
• (a) alkyl or cycloalkyl,
• (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl or α-OC(O)aryl groups,
• (c) alkoxy or thioalkoxy,
• (d) substituted alkoxy or substituted thioalkoxy,
• (e) hydroxy,
• (f) optionally substituted aryl,
• (g) optionally substituted heteroaryl,
• (h) optionally substituted heterocyclic,
• (i) —NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
• (j) —NHSO2—R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• (k) —NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and
• (l) —ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• n is an integer equal to 1 or 2,
• but excluding the following compounds:
• (i) wherein n is 1, R1 is phenyl, X′, X″ and R5 are each hydrogen, R2 and R4 are each methyl and X is —C(O)OCH3;
• (ii) wherein n is 2, R1 is n-C17H35, R2 is —CH2OH, the first R4 is —CH2)2COOH, the second R4 is isopropyl, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(—(CH2)4NH2)C(O)NHCH(benzyl)CH2Cl;
• (iii) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl and the second R4 is —(CH2)4NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, or —C(O)NHCH(C(O)CH3)CH2phenyl, —C(O)NHCH(C(O)CF3)CH2phenyl;
• (iv) wherein n is 2, R1 is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl;
• (v) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• (vi) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R4 is hydrogen and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• and
• (vii) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl.

A compound of the formula:

• wherein R1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is selected from the group consisting of
• (a) —C(O)-alkyl,
• (b) —C(O)-substituted alkoxy or substituted thioalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl,
• (c) —C(O)-aryl wherein the aryl group is substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl,
• (d) —C(O)-heteroaryl wherein the heteroaryl group is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy and thioaryloxy
• (e) —C(O)—NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of amino, thiol, alkoxy, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• provided that R′ and R″ are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl;
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• n is an integer equal to 1 or 2;
• but excluding the following compounds:
• (i) wherein R1 is iso-propyl, R2 is phenyl, R4 is methyl, R5 is hydrogen, X′ and X″ are hydrogen, n is 2, the second R4 at the carboxy terminus is methyl, and X is —C(O)NH-pNO2-φ;
• (ii) wherein n is 2, R1 is n-C17H35, R2 is —CH2OH, the first R4 is —(CH2)2COOH, the second R4 is isopropyl, X′, X″ and each R5 is hydrogen, and X is —C(O)NHCH(—(CH2)4NH2)C(O)NHCH (benzyl)CH2Cl;
• (iii) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2Cl, the first R4 is isopropyl and the second R4 is —(CH2)4NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, —C(O)NHCH(C(O)CH3)CH2phenyl or —C(O)NHCH(C(O)CF3)CH2phenyl;
• (iv) wherein n is 2, R1 is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl,
• (v) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• and
• (vi) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• and
• (vii) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl.

A compound of the formula:

• wherein R1 is selected from the group consisting of:
• (a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (c) cycloalkenyl,
• (d) substituted alkyl provided that the substituent is not optionally substituted aryl and/or optionally substituted heteroaryl groups,
• (e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,
• (f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and
• (h) optionally substituted saturated heterocyclic;
• R2 is selected from the group consisting of
• (a) substituted alkyl provided that such substituted alkyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
• (b) substituted alkenyl provided that such substituted alkenyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkenyl,
• (c) substituted alkynyl provided that such substituted alkynyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkynyl,
• (d) optionally substituted saturated heterocyclic,
• (e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, and optionally substituted heteroaryl, and
• (f) a optionally substituted heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, optionally substituted thioalkoxy, thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
• each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is —C(O)Y or —C(S)Y where Y is selected from the group consisting of
• (a) alkyl or cycloalkyl,
• (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl or α-OC(O)aryl groups,
• (c) alkoxy or thioalkoxy,
• (d) substituted alkoxy or substituted thioalkoxy,
• (e) hydroxy,
• (f) optionally substituted aryl,
• (g) optionally substituted heteroaryl,
• (h) optionally substituted heterocyclic,
• (i) —NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
• (j) —NHSO2—R8 where R5 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• (k) —NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and
• (l) —ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, alkoxy, thiol, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X and X″ together form an oxo group, and
• n is an integer equal to 1 or 2;
• but excluding the following compounds:
• (i) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl and the second R4 is —(CH2)4NH2 X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, —C(O)NHCH(C(O)CH3)CH2phenyl, or —C(O)NHCH(C(O)CF3)CH2phenyl;
• (ii) wherein n is 2, R1 is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl;
• (iii) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• (iv) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• (v) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl;
• and
• (vi) wherein R1 is fluoro substituted aryl, n is 1, X′ and X″ are each hydrogen, R5 is hydrogen or methyl, X is —C(O)Y where Y is haloalkyl, alkoxy, thioalkoxy, heterocyclic, —CH2 heterocyclic, mono-substituted alkyl having its single substituent at the terminal position and wherein said substituent is diazo, —C(O)OR′, —C(O)alkylOR′ or —C(O)NR′, R″ wherein R′ and R″ are independently hydrogen, alkyl, phenyl, benzyl or phenethyl, or Y is selected from the groups —CH2OR′, —CH2SR′, —CH2NR′R″ or —NR′R″ wherein R′ and R″ are independently hydrogen alkyl, phenyl, benzyl or phenethyl.

A compound of the formula:

• wherein R′ is selected from the group consisting of:
• (a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (c) cycloalkenyl,
• (d) substituted alkyl provided that the substituent is not optionally substituted aryl and/or optionally substituted heteroaryl groups,
• (e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,
• (f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and
• (h) optionally substituted saturated heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R4 is selected to be:
• (a) substituted alkyl provided that such substituted alkyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
• (b) substituted alkenyl provided that such substituted alkenyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkenyl,
• (c) substituted alkynyl provided that such substituted alkynyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkynyl,
• (d) optionally substituted saturated heterocyclic,
• (e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, and optionally substituted heteroaryl, and
• (f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy, optionally substituted thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is —C(O)Y or —C(S)Y where Y is selected from the group consisting of
• (a) alkyl or cycloalkyl,
• (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl or α-OC(O)aryl groups,
• (c) alkoxy or thioalkoxy,
• (d) substituted alkoxy or substituted thioalkoxy,
• (e) hydroxy,
• (f) optionally substituted aryl,
• (g) optionally substituted heteroaryl,
• (h) optionally substituted heterocyclic,
• (i) —NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
• (j) —NHSO2—R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• (k) —NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and
• (l) —ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, alkoxy, thiol, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• n is an integer equal to 1 or 2;
• but excluding the compounds:
• (i) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl and the second R4 is —(CH2)4NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, —C(O)NHCH(C(O)CH3)CH2phenyl, or —C(O)NHCH(C(O)CF3)CH2phenyl;
• (ii) wherein n is 2, R1 is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl
• (iii) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• (iv) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• and
• (v) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl.

A compound of the formula:

• wherein R1 is selected from the group consisting of:
• (a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (c) cycloalkenyl,
• (d) substituted alkyl provided that the substituent is not optionally substituted aryl and/or optionally substituted heteroaryl groups,
• (e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,
• (f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and
• (h) optionally substituted heterocyclic;
• R2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is selected from the group consisting of
• (a) —C(O)-alkyl,
• (b) —C(O)-substituted alkoxy or substituted thioalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl,
• (c) —C(O)-aryl wherein the aryl group is substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl,
• (d) —C(O)-heteroaryl wherein the heteroaryl group is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy and thioaryloxy
• (e) —C(O)—NR′R″ where R1 and R″ are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of amino, thiol, alkoxy, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• provided that R′ and R″ are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl;
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• n is an integer equal to 1 or 2;
• but excluding the compounds:
• (i) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl and the second R4 is —(CH2)4NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, —C(O)NHCH(C(O)CH3)CH2phenyl, or —C(O)NHCH(C(O)CF3)CH2phenyl;
• (ii) wherein n is 2, R1 is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl
• (iii) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• (iv) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• and
• (v) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl.

A compound of the formula:

• wherein R1 is selected from the group consisting of:
• (a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (c) cycloalkenyl,
• (d) substituted alkyl provided that the substituent is not optionally substituted aryl and/or optionally substituted heteroaryl groups,
• (e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,
• (f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and
• (h) optionally substituted heterocyclic;
• R2 is selected from the group consisting of
• (a) substituted alkyl provided that such substituted alkyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
• (b) substituted alkenyl provided that such substituted alkenyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkenyl,
• (c) substituted alkynyl provided that such substituted alkynyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkynyl,
• (d) optionally substituted saturated heterocyclic,
• (e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, and optionally substituted heteroaryl, and
• (f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy, optionally substituted thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
• R4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R4 is selected to be:
• (a) substituted alkyl provided that such substituted alkyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkyl, or a side-chain of a naturally occurring amino acid,
• (b) substituted alkenyl provided that such substituted alkenyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkenyl,
• (c) substituted alkynyl provided that such substituted alkynyl groups do not include optionally substituted aryl or optionally substituted heteroaryl substituted alkynyl,
• (d) optionally substituted saturated heterocyclic,
• (e) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl, and
• (f) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy, optionally substituted thioaryloxy provided that if there is an alkyl substituent on the substituted heteroaryl group then there is at least one other substituent which is not alkyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is selected from the group consisting of
• (a) —C(O)-alkyl,
• (b) —C(O)-substituted alkoxy or substituted thioalkoxy provided that the substituted alkoxy groups do not include benzyl and phenethyl,
• (c) —C(O)-aryl wherein the aryl group is substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl,
• (d) —C(O)-heteroaryl wherein the heteroaryl group is substituted with 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, optionally substituted aryl, alkaryl, optionally substituted aryloxy, halo, nitro, optionally substituted heteroaryl, thioalkoxy and optionally substituted thioaryloxy
• (e) —C(O)—NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl or alkoxy groups, and
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of amino, thiol, alkoxy, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• provided that R′ and R″ are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl;
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• n is an integer equal to 1 or 2;
• but excluding the following compounds:
• (i) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl and the second R4 is —(CH2)4NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, —C(O)NHCH(C(O)CH3)CH2phenyl, or —C(O)NHCH(C(O)CF3)CH2phenyl;
• (ii) wherein n is 2, R1 is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl
• (iii) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• (iv) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• and
• (v) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl.

A compound of the formula:

• wherein R′ is selected from the group consisting of:
• (a) aryl group substituted with from 1 to 3 substituents selected from the group consisting of hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (b) a heteroaryl group substituted with 1 to 3 substituents selected from the group consisting hydroxy, acyl, acyloxy, alkyl, alkoxy, alkenyl, alkynyl, amino, aminoacyl, alkaryl, optionally substituted aryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, cyano, halo, nitro, optionally substituted heteroaryl, and trihalomethyl provided that at least one of said substituents is selected from acyl, acyloxy, alkenyl, alkynyl, aminoacyl, alkaryl, optionally substituted aryloxy, carboxyl, carboxylalkyl, carboxylamido, fluoro and optionally substituted heteroaryl,
• (c) cycloalkenyl,
• (d) substituted alkyl provided that the substituent is not optionally substituted aryl and/or optionally substituted heteroaryl groups,
• (e) substituted alkenyl provided that the substituent is not aralkenyl or heteroaralkenyl,
• (f) substituted alkynyl provided that the substituent is not aralkynyl or heteroaralkynyl, and
• (h) optionally substituted saturated heterocyclic;
• R2 is selected from the group consisting of alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic and substituted alkyl which is an alkyl group of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from the group consisting of alkoxy, substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocyclyloxy, acyl, acylamino, amino, aminoacyl, aminocarboxy esters, cyano, cycloalkyl, halogen, hydroxyl, carboxyl, carboxylalkyl, oxyacyl, oxyacylamino, thiol, thioalkoxy, substituted thioalkoxy, optionally substituted heteroaryl, optionally substituted heterocyclic, nitro, and mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, mono- and di-arylamino, mono- and di-heteroarylamino, mono- and di-heterocyclic amino, and unsymmetric di-substituted amines having different substituents selected from alkyl, substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic;
• each R4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, cycloalkyl, cycloalkenyl, optionally substituted heteroaryl, optionally substituted heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl;
• each R5 is selected from hydrogen and methyl or together with R4 forms a cycloalkyl group of from 3 to 6 carbon atoms;
• X is —C(O)Y or —C(S)Y where Y is selected from the group consisting of
• (a) alkyl or cycloalkyl,
• (b) substituted alkyl with the proviso that the substitution on said substituted alkyl do not include α-haloalkyl, α-diazoalkyl, α-OC(O)alkyl or α-OC(O)aryl groups,
• (c) alkoxy or thioalkoxy,
• (d) substituted alkoxy or substituted thioalkoxy,
• (e) hydroxy,
• (f) optionally substituted aryl,
• (g) optionally substituted heteroaryl,
• (h) optionally substituted heterocyclic,
• (i) —NR′R″ where R′ and R″ are independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, where one of R′ or R″ is hydroxy or alkoxy, and where R′ and R″ are joined to form a cyclic group having from 2 to 8 carbon atoms optionally containing 1 to 2 additional heteroatoms selected from oxygen, sulfur and nitrogen and optionally substituted with one or more alkyl, alkoxy or carboxyalkyl groups,
• (j) —NHSO2-R8 where R8 is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• (k) —NR9NR10R10 where R9 is hydrogen or alkyl, and each R10 is independently selected from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic, and
• (l) —ONR9[C(O)O]zR10 where z is zero or one, R9 and R10 are as defined above;
• X can also be —CR6R6Y′ where each R6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic and Y′ is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phthalimido, —OC(O)R7, —SSR7, —SSC(O)R7 where R7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl and optionally substituted heterocyclic,
• X′ is hydrogen, hydroxy or fluoro;
• X″ is hydrogen, hydroxy or fluoro, or X′ and X″ together form an oxo group, and
• n is an integer equal to 1 or 2;
• but excluding the compounds:
• (i) wherein R1 is o-fluorophenyl, R2 is 3,4-dichlorophenyl or ethyl, R4 and R5 are hydrogen, X′, and X″ are hydrogen and X is —C(O)OCH3;
• (ii) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl and the second R4 is —(CH2)4NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CH2Cl)CH2phenyl, —C(O)NHCH(C(O)CH3)CH2phenyl, or —C(O)NHCH(C(O)CF3)CH2phenyl;
• (iii) wherein n is 2, R1 is —(CH2)6COOH, R2 is isopropyl, the first R4 is —(CH2)4NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is —C(O)CH2Cl
• (iv) wherein n is 2, R1 is —(CH2)3COOH, R2 is isopropyl, the first R4 is —(CH2)3NH2, the second R4 is benzyl, X′, X″ and each R5 is hydrogen and X is acetyl;
• (v) wherein n is 2, R1 is —CH2C(O)OCH3, R2 is —(CH2)2COOH, the first R4 is isopropyl, the second R4 is —(CH2)3NH2, X′, X″ and each R5 is hydrogen and X is —C(O)NHCH(C(O)CF3)CH2phenyl;
• (vi) wherein n is 1, R1 is —CH(isopropyl)CH2COOH, Z is a bond, R2 is —(CH2)3NH2, R4 is benzyl, X′, X″ and R5 are hydrogen, and X is —C(O)CH2Cl;
• and
• (vii) wherein R′ is fluoro substituted aryl, n is 1, X′ and X″ are each hydrogen, R5 is hydrogen or methyl, X is —C(O)Y where Y is haloalkyl, alkoxy, thioalkoxy, heterocyclic, —CH2 heterocyclic, mono-substituted alkyl having its single substituent at the terminal position and wherein said substituent is diazo, —C(O)OR′, —C(O) alkyl OR′ or —C(O)NR′, R″ wherein R′ and R″ are independently hydrogen, alkyl, phenyl, benzyl or phenethyl, or Y is selected from the groups —CH2OR′, —CH2SR′, —CH2NR′R″ or —NR′R″ wherein R′ and R″ are independently hydrogen alkyl, phenyl, benzyl or phenethyl.