Glutamate aggrecanase inhibitors

Description of equivalent WO 2007008994 A2

GLUTAMATE AGGRECANASE INHIBITORS

[0001] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. [0002] This patent disclosure contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction by anyone of the patent document or the patent disclosure, as it appears in the U.S. Patent and Trademark Office patent file or records, but otherwise reserves any and all copyright rights whatsoever.

Related Application

[0003] This application claims the benefit under 35 U.S.C. § 119(e) of U.S.

Provisional Application No. 60/697,590 filed on July 11, 2005, which is hereby incorporated by reference herein in its entirety.

Field of the Invention

[0004] The present invention relates to compounds and their use as, for example, metalloproteinase inhibitors.

Background of the Invention

[0005] Metalloproteinases, including matrix metalloproteinases and aggrecanases, are known to have a role in the breakdown of connective tissue. Matrix metalloproteinases ("MMPs") constitute a superfamily of proteolytic enzymes that are genetically related and capable of degrading almost all the constituents of extracellular matrix and basement membrane that restrict cell movement. Aggrecanases are members of the ADAMTS (A disintegrin and metalloproteinase with thrombospondin motifs) family of proteins. Aggrecanase-1 and aggrecanase-2 have been designated ADAMTS -4 and ADAMTS-5, respectively (Tang BL, IntJBiochem Cell Biol 2001, 33, 33-44). [0006] The ADAMTS family is involved in cleaving aggrecan, a cartilage component also known as the large aggregating chondroitin sulphate proteoglycan (Abbaszade I et al., J Biol Chem 1999, 274, 23443-23450), procollagen processing (Colige A et al., Proc Natl Acad Sd USA 1997, 94, 2374-2379), angiogenesis (Vazquez F et al., J Biol Chem 1999, 274, 23349-23357), inflammation (Kuno K et al., J Biol Chem 1997, 272, 556-562) and tumor invasion (Masui T. et al., J Biol Chem 1997, 272, 556- 562). MMPs have been shown to cleave aggrecan as well.

[0007] The loss of aggrecan has been implicated in the degradation of articular cartilage in arthritic diseases, for example osteoarthritis is a debilitating disease which affects at least 30 million Americans. Degradation of articular cartilage and the resulting chronic pain can severely reduce quality of life. An early and important characteristic of the osteoarthritic process is loss of aggrecan from the extracellular matrix, resulting in deficiencies in the biomechanical characteristics of the cartilage. Likewise, MMPs and aggrecanases are known to play a role in many disorders in which extracellular protein degradation or destruction occurs, such as cancer, asthma, chronic obstructive pulmonary disease ("COPD"), atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.

[0008] Therefore, metalloproteinase inhibitors, including inhibitors of MMPs and aggrecanases, are needed. [0009] The present invention is directed to these and other important ends.

Summary of the Invention

[0010] In one embodiment, the invention provides compounds of the Formula (I):

<img file="EP1902014A2_D0001.tif" />

(I) and pharmaceutically acceptable salts thereof, wherein

W is -C(O)-, -OC(O)-, -NHC(O)-, -C(O)O-, or -C(O)NH-;

R₁ is phenyl, heteroaryl, biphenyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each optionally substituted with one or more of R₅ or R₆, and when R₁ is substituted with more than one of R₅ or R₆, the substituents can be identical or different;

R₂ is hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)JR₁₁, -OH, or -0-(C₁-C₆) alkyl;

R₃ is -CO₂H, -CONH₂, -CONHOH, -CONHSO₂R₇, tetrazole, -SO₂NHR₇, -SO₃H, -PO(OH)NH₂, -PO(OH)OR₇, -CONHR₇, -COOR₇, an acid mimetic group, or a 5 or 6-membered heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, N, S;

R₄Is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀;

R₅ is aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -CO-(C₁-C₆) alkyl, -CO- aryl, -CO-heteroaryl, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -NHSO₂-(C₁-C₆) alkyl, -NHSO₂-aryl, -NHSOrheteroaryl, -NHCO-aryl, -NHCO-heteroaryl, -CONH-aryl, -CONH-heteroaryl, (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH- (C₁-C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, or -CONH-(C₃-C₆) cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R₆, and when R₅ is substituted with more than one R₆, the substituents can be identical or different;

R₆ and R₁₂ are each independently hydrogen, halogen, -CN, -OCF₃, -CF₃, -NO₂, -OH, -SH, -NR₇R₈, -CONR₇R₈, -NR₈COR₇, -NR₈CO₂R₇₅ -CO₂R₇, -COR₇, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂R₇, -NR₇SO₂R₈, -SO₂NR₇R₈, (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH-(C₁- C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, -CONH-(C₃-C₆) cycloalkyl, heterocycloalkyl, -(Ci-C₆) alkyl-OR₇, (C₂-C₆) alkynyl, (C₂-C₆) alkenyl, -0-(Ci-C₆) alkyl-(C₃-C₆) cycloalkyl, -O-alkenyl, -0-(Ci-C₆) alkyl substituted with aryl, aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, or -S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of

R13;

R₇ and R₈ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂- C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, -(CH₂)_n-aryl, or -(CH₂)_n- heteroaryl; or R₇ and R₈ together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₉ and R_1O are each independently hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkyl-OH,

(C₁-C₆) alkyl-O-(C₁-C₆) alkyl, aryl, cycloalkyl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more R₁₂; or R₉ and R₁₀ together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₁₁ is aryl, heteroaryl, or cycloalkyl;

R₁₃ is halogen, -0-(C₁-C₆) alkyl, -CO₂H, -OH, -CF₃, hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, cycloalkyl substituted with -OH, aryl substituted with -NH₂, aryl substituted with -O- (C₁-C₆) alkyl, -(CH₂)_n-aryl, or -(CH₂)_n-heteroaryl; m is 0-4; n is 0-4; and p is 0-2.

[0011] In another embodiment, the invention provides compounds of the Formula

(H): <img file="EP1902014A2_D0002.tif" />

(π) and pharmaceutically acceptable salts thereof, wherein

R₂ is hydrogen, (Ci-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)_pR_π, -OH, or -0-(C₁-C₆) alkyl;

R₁₄ and R₁₅ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, heterocycloalkyl -(CH₂)_n- aryl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl optionally substituted with one or more Ri₂; or Ri₄ and R₁₅ together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S; p is 0-2, and

R₁, R₁₁, R₁₂, and n are as described above for compounds of the Formula (I). [0012] In another embodiment, the compounds or pharmaceutically acceptable salts of the compounds of Formula (I) or Formula (II) are useful as pharmaceutical compositions comprising compounds or pharmaceutically acceptable salts of compounds of Formula (I) or Formula (U) and a pharmaceutically acceptable carrier. [0013] In one embodiment, the compounds or pharmaceutically acceptable salts of the compounds of the Formula (I) or Formula (II) are useful as metalloproteinase modulators.

[0014] In one embodiment, the invention provides methods for treating a metalloproteinase-related disorder, comprising administering to an animal in need thereof the compounds or pharmaceutically acceptable salts of compounds of Formula (I) or Formula (H) in an amount effective to treat a metalloproteinase-related disorder. [0015] In one embodiment, the invention provides methods of synthesizing the compounds or pharmaceutically acceptable salts of compounds of Formula (I) or Formula (U). In another embodiment, the invention provides compounds or pharmaceutically acceptable salts of compounds of Formula (I) or Formula (II) made by particular processes.

Description of the Invention

[0016] All recitations of a group, such as alkyl, are understood for the purposes of this specification to encompass both substituted and unsubstituted forms. [0017] The term "alkyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted aliphatic hydrocarbon chain and includes, but is not limited to, straight and branched chains containing from 1 to 12 carbon atoms, or in some instances, from 1 to 6 carbon atoms, unless explicitly specified otherwise. For example, methyl, ethyl, propyl, isopropyl, butyl, i-butyl and t-butyl are encompassed by the term "alkyl." (C₁-C₆)-alkyl includes straight and branched chain aliphatic groups having from 1 to 6 carbons. Specifically included within the definition of "alkyl" are those aliphatic hydrocarbon chains that are optionally substituted. The alkyl may suitably be a (C₁-C₃)-alkyl. In one embodiment, an alkyl is optionally substituted with one or more of the following groups: -halogen, -N(R')₂, methylenedioxo, ethylenedioxo, - NHSO₂R', -NR'COR', -NHCO₂R', -NO₂, -SO₂N(R')₂, -SO₂R', -OR', -COR', -CO₂R', - CON(R')₂, or -CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)- alkyl, or unsubstituted aryl.

[0018] The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like.

[0019] The term "alkenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted hydrocarbon chain and includes, but is not limited to, straight and branched chains having 2 to 8 carbon atoms e.g. 2 to 6 carbon atoms and containing at least one double bond. In one embodiment, the alkenyl moiety has 1 or 2 double bonds. Such alkenyl moieties may exist in the E or Z conformations and the compounds of this invention include both conformations. (C₂-C₆) alkenyl includes a 2 to 6 carbon straight or branched chain having at least one carbon- carbon double bond. Specifically included within the definition of "alkenyl" are those aliphatic hydrocarbon chains that are optionally substituted. In one embodiment, a heteroatom, such as O, S or N, attached to an alkenyl is not attached to a carbon atom that is bonded to a double bond. In one embodiment, an alkenyl is optionally substituted with one or more of the following groups: -halogen, -N(R')₂, methylenedioxo, ethylenedioxo, - NHSO₂R', -NR'COR', -NHCO₂R', -NO₂, -SO₂N(R')₂, -SO₂R', -OR', -COR', -CO₂R', - CON(R')₂, or -CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)- alkyl, or unsubstituted aryl.

[0020] The term "alkynyl", as used herein, whether used alone or as part of another group, refers to a hydrocarbon moiety containing at least one carbon-carbon triple bond. (C₂-C₆) alkynyl includes a 2 to 6 carbon straight or branched chain having at least one carbon-carbon triple bond. Ih one embodiment, an alkynyl is optionally substituted with one or more of the following groups: -halogen, -N(R')₂, methylenedioxo, ethylenedioxo, -NHSO₂R', -NR'COR', -NHCO₂R', -NO₂, -SO₂N(R')₂, -SO₂R', -OR', - COR', -CO₂R', -CON(R' )₂, or -CN, wherein each R' is independently hydrogen, unsubstituted (Q-C^-alkyl, or unsubstituted aryl.

[0021] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, fused, bridged, or spiro monovalent saturated or unsaturated non-aromatichydrocarbon ring system of 3-15 carbon atoms e.g. 3 to 6 carbon atoms. Any suitable ring position of the cycloalkyl moiety may be covalently linked to the defined chemical structure. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, spiro[4.5]decanyl, and homologs, isomers, and the like. C₃-C₆ cycloalkyl includes monocyclic, saturated rings of 3 to 6 carbons. In one embodiment, a cycloalkyl is optionally substituted with one or more of the following groups: -V-halogen, -(C₁-C₆)- alkyl, -(C₂-C₆)-alkenyl, -(C₂-C₆)-alkynyl, -V-N(R' )₂, methylenedioxo, ethylenedioxo, -V- NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V- COR', -V-CO₂R', -V-CON(R' )₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (CrC₆)-alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (C₁-C₆)-alkyl. Cycloalkylalkyl when used herein refers to a (CrC₆)-alkyl group as defined above substituted by a C₃ to C₁₅ cycloalkyl group as defined above, e.g. cyclohexylmethyl and cyclohexylethyl. [0022] "Heteroaryl" refers to a 5 to 6 membered aromatic heterocyclic ring which contains from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms in the ring, and to which may be fused with a carbocyclic or heterocyclic ring at any possible position (e.g. fused to one or more carbocyclic or heterocyclic rings, each having 5-8 ring atoms, the fused heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms in the ring), e.g. it is suitably a bicyclic or tricyclic ring. Exemplary heteroaryl groups include, but are not limited to, furanyl, furazanyl, homopiperazinyl, imidazolinyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrimidinyl, phenanthridinyl, pyranyl, pyrazinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolinyl, thiadiazinyl, thiadiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, and triazolyl. In one embodiment, a heteroaryl is optionally substituted with one or more of the following groups: -V-halogen, -(C_rC₆)-alkyl, -(C₂-C₆)-alkenyl, -(C₂-C₆)-alkynyl, -V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR' COR', -V-NHCO₂R', -V-NO₂, - V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V-COR', -V-CO₂R', -V-CON(R')₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted <img file="EP1902014A2_D0003.tif" /> or unsubstituted aryl; and wherein each V is independently a bond or (Ci-C₆)-alkyl. [0023] "Heterocycloalkyl" refers to a 5 to 7-membered saturated or unsaturated nonaromatic ring containing carbon atoms and from 1 to 4 heteroatoms selected from N, O, and S which may suitably be monocylic or may be fused to one or more further rings to provide a polycyclic moiety e.g. a bicyclic or tricyclic moiety. The further ring(s) may be carbocyclic rings(s) or they may contain from 1 to 4 further heteroatoms selected from N, O and S, preferably they are carbocyclic rings. The further ring(s) may be saturated, unsaturated or aromatic rings(s), preferably they are non-aromatic rings. Exemplary heterocycloalkyl groups include, but are not limited to, azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, and thiomorpholinyl. In one embodiment, a heterocycloalkyl is optionally substituted with one or more of the following: -V-halogen, -(Ci-C₆)-alkyl, -(C₂-C₆)-alkenyl, -(C₂-C₆)-alkynyl, -V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, - V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V-COR', -V-CO₂R', -V-C0N(R')₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted <img file="EP1902014A2_D0004.tif" /> or unsubstituted aryl; and wherein each V is independently a bond or (CrC₆)-alkyl. [0024] The term " aryl" as used herein as a group or part of a group refers to an aromatic carbocyclic ring system, e.g., of from 6 to 14 carbon atoms such as phenyl, which may be optionally substituted. An aryl group may be fused with a carbocyclic or heterocyclic ring at any possible position (e.g. fused to one or more carbocyclic or heterocyclic rings, each having 5-8 ring atoms, the fused heterocyclic ring containing from 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur atoms in the ring). "Phenyl", as used herein, whether used alone or as part of another group, refers to a substituted or unsubstituted phenyl group. The aryl fused with a carbocyclic ring may suitably be a bicyclic aryl or a tricyclic aryl. In one embodiment, an aryl group such as phenyl is optionally substituted with one or more of the following: - V-halogen, <img file="EP1902014A2_D0005.tif" /> -(C₂-C₆)-alkenyl, -(C₂-C₆)-alkynyl, -V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, - V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V-COR', -V-CO₂R', -V-C0N(R')₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)-alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (C₁-Ce)-alkyl. [0025] The term "biphenyl" as used herein refers to two phenyl groups connected at one carbon site on each ring. In one embodiment, one or both phenyl groups is independently optionally substituted with one or more of the following groups: -V- halogen, -(Q-Ce^alkyl, -(C₂-C₆)-alkenyl, -(C₂-C₆)-alkynyl, -V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V- SO₂R', -V-OR', -V-COR', -V-CO₂R', -V-CON(R')₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)-alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (C₁-C₆)-alkyl.

[0026] The term "biaryl" as used herein refers to two aryl groups connected at one carbon site on each ring. Li one embodiment, one or both aryl groups is independently optionally substituted with one or more of the following groups: -V-halogen, -(C₁-C₆)- alkyl, -(C₂-C₆)-alkenyl, -(C₂-C₆)-alkynyl, -V-N(R')₂, methylenedioxo, ethylenedioxo, -V- NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V- COR', -V-CO₂R', -V-CON(R' )₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (Q-C^-alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (Ci-C₆)-alkyl.

[0027] The term "bicyclic aryl" as used herein refers to two fused carbocyclic groups, wherein one or both of the carbocyclic groups is aromatic. For example, a bicyclic aryl can contain from 8 to 12 ring atoms. In one embodiment, one or both carbocyclic groups of the bicyclic aryl is independently optionally substituted with one or more of the following groups: -V-halogen, -(Ci-C₆)-alkyl, -(C₂-C₆)-alkenyl, -(C₂-C₆)- alkynyl, - V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', -V- NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V-COR', -V-CO₂R', -V- CON(R' )₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)- alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (C₁-C₆)-alkyl. [0028] The term "tricyclic aryl" as used herein refers to three fused carbocyclic groups, wherein two or three of the carbocyclic groups is aromatic. For example, a tricyclic aryl can contain from 13 to 18 ring atoms. In one embodiment, one or more of the carbocyclic groups of the tricyclic aryl are independently optionally substituted with one or more of the following groups: -V-halogen, -(Ci-C₆)-alkyl, -(C₂-C₆)-alkenyl, -(C₂- C₆)-alkynyl, - V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', - V-NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V-COR', -V-CO₂R', -V- CON(R' )₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)- alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (C₁-C₆)-alkyl. [0029] The term "bicyclic heteroaryl" as used herein refers to two fused cyclic groups, wherein one or both of the cyclic groups is aromatic and contains one to four heteroatoms selected from O, S, and N. For example, a bicyclic heteroaryl can contain from 8 to 12 ring atoms, and from 1 to 3 heteroatoms selected from O, N, and S in each ring. In one embodiment, one or both cyclic groups is independently optionally substituted with one or more of the following groups: -V-halogen, -(Q-C^-alkyl, -(C₂- C₆)-alkenyl, -(C₂-C₆)-alkynyl, - V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V-COR', -V- CO₂R', -V-CON(R' )₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)-alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (C₁-C₆)-alkyl. [0030] The term "tricyclic heteroaryl" as used herein refers to three fused cyclic groups, wherein two or three of the cyclic groups is aromatic and at least one aromatic group contains 1 to 4 heteroatoms selected from O, S, and N. For example, a tricyclic aryl can contain from 13 to 18 ring atoms, and from 1 to 3 heteroatoms selected from O, N, and S in each ring. In one embodiment, the cyclic groups are independently substituted with one or more of the following groups: -V-halogen, -(d-C₆)-alkyl, -(C₂- C₆)-alkenyl, -(C₂-C₆)-alkynyl, - V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V-SO₂R', -V-OR', -V-COR', -V- CO₂R', -V-CON(R' )₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (C₁-C₆)-alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (Q-C^-alkyl.

[0031] An optionally substituted moiety may be substituted with one or more substituents, examples of which are as illustrated herein. Li one embodiment, an "optionally substituted" moiety is substituted with one or more of the following: -V- halogen, -(C₁-C₆)-alkyl, -(C₂-C₆)-alkenyl, -(C₂-C₆)-alkynyl, - V-N(R')₂, methylenedioxo, ethylenedioxo, -V-NHSO₂R', -V-NR'COR', -V-NHCO₂R', -V-NO₂, -V-SO₂N(R')₂, -V- SO₂R', -V-OR', -V-COR', -V-CO₂R', -V-C0N(R')₂, or -V-CN, wherein each R' is independently hydrogen, unsubstituted (Ci-C₆)-alkyl, or unsubstituted aryl; and wherein each V is independently a bond or (C₁-C₆)-alkyl.

[0032] When such moieties are substituted, for example, they may typically be mono-, di-, tri- or persubstituted. Examples for a halogen substituent include 1-bromo vinyl, 1-fluoro vinyl, 1,2-difluoro vinyl, 2,2-difluorovinyl, 1,2,2-trifluoro vinyl, 1,2- dibromo ethane, 1,2 difluoro ethane, l-fluoro-2-bromo ethane, CF₂F₃, CF₂CF₂CF₃, and the like.

[0033] The term halogen includes bromine, chlorine, fluorine, and iodine.

[0034] For the sake of simplicity, connection points ("-") are not depicted. When an atom or compound is described to define a variable, it is understood that it is intended to replace the variable in a manner to satisfy the valency of the atom or compound. For example, if "X*" was C(R*)=C(R*), both carbon atoms form a part of the ring in order to satisfy their respective valences. Likewise, when divalent substituents are presented, it is understood that they are not limited to the order listed, for example, as used in this specification "OCH₂" encompasses CH₂O and OCH₂. [0035] The term "administer", "administering", or "administration", as used herein refers to either directly administering a compound or pharmaceutically acceptable salt of the compound or a composition to a animal, or administering a prodrug derivative or analog of the compound or pharmaceutically acceptable salt of the compound or composition to the animal, which can form an equivalent amount of active compound within the animal's body.

[0036] The term "animal" as used herein includes, without limitation, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, monkey, chimpanzee, baboon, or rhesus. In one embodiment, the animal is a mammal. In another embodiment, the animal is a human.

[0037] The term "amine protecting group" as used herein refers to a moiety that temporarily blocks an amine reactive site in a compound. Generally, this is done so that a chemical reaction can be carried out at another reactive site in a multifunctional compound or to otherwise stabilize the amine. In one embodiment, an amine protecting group is selectively removable by a chemical reaction. An exemplary amine protecting group is a 9-fluorenylmethoxycarbonyl protecting group. Another exemplary amine protecting group is a carbamate protecting group. Carbamate protecting groups include, without limitation, t-butyl carbamate, methyl carbamate, ethyl carbamate, 2,2,2- trichloroethyl carbamate, 2-(trimethylsilyl)ethyl carbamate, l,l-dimethyl-2,2,2- trichloroethyl carbamate, benzyl carbamate, p-methoxybenzyl carbamate, p- nitrobenzylcarbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, and 2,4- dichlorobenzyl carbamate. See, Greene and Wuts, Protecting Groups in Organic Synthesis, Second Edition, John Wiley &amp; Sons (1991).

[0038] The term "carboxylic acid protecting group" as used herein refers to a moiety that temporarily blocks a carboxylic acid reactive site in a compound. Generally, this is done so that a chemical reaction can be carried out at another reactive site in a multifunctional compound or to otherwise stabilize the carboxylic acid. In one embodiment, a carboxylic acid protecting group is selectively removable by a chemical reaction. An exemplary carboxylic acid protecting group is an alkyl ester protecting group, such as a tert-butyl ester.

[0039] The term "acid mimetic group" as used herein refers to a moiety that has chemical and physical similarities producing broadly similar biological properties to an acid. In one embodiment, an acid mimetic group is a 5 or 6-membered heterocycle containing 1 to 4 heteroatoms selected from O, N, S. Exemplary acid mimetic groups include:

<img file="EP1902014A2_D0006.tif" />

[0040] The term "conditions effective to" as used herein refers to synthetic reaction conditions which will be apparent to those skilled in the art of synthetic organic chemistry.

[0041] The term "effective amount" as used herein refers to an amount of a compound or pharmaceutically acceptable salt of a compound that, when administered to an animal, is effective to prevent, to at least partially ameliorate, or to cure, a condition from which the animal suffers or is suspected to suffer.

[0042] The term "metalloproteinase-related disorder" used herein refers to a condition for which it would be beneficial to modulate activity of the metalloproteinase. Exemplary metalloproteinase-related disorders include, without limitation, arthritic disorders, osteoarthritis, cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.

[0043] The term "metalloproteinase modulator" refers to a compound that is capable of modulating the expression of a metalloproteinase. For example, a metalloproteinase modulator may enhance metalloproteinase expression. A metalloproteinase modulator may also be an inhibitor of a metalloproteinase. [0044] The term "isolated and purified" as used herein refers to an isolate that is separate from other components of a reaction mixture or a natural source. In certain embodiments, the isolate contains at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or at least about 98% of the compound or pharmaceutically acceptable salt of the compound by weight of the isolate. [0045] As used herein, a compound of the invention includes a pharmaceutically acceptable salt thereof. The term "pharmaceutically acceptable salt" as used herein refers to a salt of an acid and a basic nitrogen atom of a compound of the present invention. Exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, napthalenesulfonate, propionate, succinate, fumarate, maleate, malonate, mandelate, malate, phthalate, and pamoate. The term "pharmaceutically acceptable salt" as used herein also refers to a salt of a compound of the present invention having an acidic functional group, such as a carboxylic acid functional group, and a base. Exemplary bases include, but are not limited to, hydroxide of alkali metals including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine; pyridine; N-methyl, N- ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-OH-(C₁-C₆)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl- D-glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like. The term "pharmaceutically acceptable salt" also includes a hydrate of a compound of the present invention.

[0046] The term "substantially free of its corresponding opposite enantiomer" as used herein means that the compound contains no more than about 10% by weight of its corresponding opposite enantiomer. In other embodiments, the compound that is substantially free of its corresponding opposite enantiomer contains no more than about 5%, no more than about 1%, no more than about 0.5%, or no more than about 0.1% by weight of its corresponding opposite enantiomer. An enantiomer that is substantially free of its corresponding opposite enantiomer includes a compound that has been isolated and purified or has been prepared substantially free of its corresponding opposite enantiomer. [0047] The term "tautomer" as used herein refers to compounds produced by the phenomenon wherein a proton of one atom of a molecule shifts to another atom. See, Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley &amp; Sons, pages 69-74 (1992).

[0048] The following abbreviations as used herein mean: Ac is acetate; boc is t- butyl carbamate; Bu is butyl; DIEA is diisopropylethylamine; DMF is dimethylformamide; DMSO is dimethylsulfoxide; ESI is electrospray ionization; Et is ethyl; HPLC is high pressure liquid chromatography; HRMS is high resolution mass spectrometry; Me is methyl; MS is mass spectrometry; m/z is mass-to-charge ratio; r.t. is retention time; TFA is trifluoroacetic acid; THF is tetrahydrofuran; FMOC is 9- fluorenylmethoxycarbonyl; DEA is diethylamine; DME is dimethoxyethane; Bop is benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate; PyBop is benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; HBTU is O-benzotriazole-N,N,N',N'-tetramethyl-uronium-hexafluoro-phosphate; and EDC is 1- (3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride.

Compounds and Pharmaceutically Acceptable Salts of Compounds of the Invention

[0049] The compounds or pharmaceutically acceptable salts of compounds of the present invention can contain an asymmetric carbon atom and some of the compounds or pharmaceutically acceptable salts of compounds of the invention can contain one or more asymmetric centers, and can thus give rise to optical isomers and diastereomers. While depicted without respect to stereochemistry in the compounds or pharmaceutically acceptable salts of compounds of the present invention, the present invention includes such optical isomers and diastereomers, as well as racemic and resolved, enantiomerically pure R and S stereoisomers, and also other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Where a stereoisomer is provided, it can in some embodiments be provided substantially free of its corresponding opposite enantiomer. [0050] In addition, the compounds and pharmaceutically acceptable salts of compounds of the present invention can exist as tautomers. Such tautomers can be transient or isolatable as a stable product. These tautomers are within the scope of the present invention.

[0051] Prodrugs of the compounds or pharmaceutically acceptable salts of compounds are also within the scope of the present invention.

Compounds of the Formula (I)

[0052] In one embodiment, the present invention is directed to compounds of the Formula (I):

<img file="EP1902014A2_D0007.tif" />

(I) and pharmaceutically acceptable salts thereof, wherein

W is -C(O)-, -OC(O)-, -NHC(O)-, -C(O)O-, or -C(O)NH-; R₁ is phenyl, heteroaryl, biphenyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each optionally substituted with one or more of R₅ or R₆, and when R₁ is substituted with more than one of R₅ or R₆, the substituents can be identical or different; R₂ is hydrogen, (Cj-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)_nRn, -OH, or -0-(C₁-C₆) alkyl; R₃ is -CO₂H, -CONH₂, -CONHOH, -CONHSO₂R₇, tetrazole, -SO₂NHR₇, -SO₃H,

-PO(OH)NH₂, -PO(OH)OR₇, -CONHR₇, -COOR₇, an acid mimetic group, or a 5 or 6-membered heterocycloalkyl or heteroaryl containing 1 to 4 heteroatoms selected from O, N, S; R₄Is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀; R₅ is aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -CO-(C₁-C₆) alkyl, -CO- aryl, -CO-heteroaryl, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂NH-JUyI, -SO₂NH-heteroaryl, -NHSO₂-(C₁-C₆) alkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHCO-aryl, -NHCO-heteroaryl, -CONH-aryl, -CONH-heteroaryl, (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH- (C₁-C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, or -CONH-(C₃-C₆) cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R₆, and when R₅ is substituted with more than one R₆, the substituents can be identical or different;

R₆ and R₁₂ are each independently hydrogen, halogen, -CN, -OCF₃, -CF₃, -NO₂, -OH, -SH, -NR₇R₈, -CONR₇R₈, -NR₈COR₇, -NR₈CO₂R₇₅ -CO₂R₇, -COR₇, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂R₇, -NR₇SO₂R₈, -SO₂NR₇R₈; (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH-(C₁- C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, -CONH-(C₃-C₆) cycloalkyl, heterocycloalkyl, -(C₁-C₆) alkyl-OR₇, (C₂-C₆) alkynyl, (C₂-C₆) alkenyl, -0-(C₁-C₆) alkyl-(C₃-C₆) cycloalkyl, -O-alkenyl, -0-(C₁-C₆) alkyl substituted with aryl, aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, or -S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of

Ri₃;

R₇ and R₈ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂- C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, -(CH₂)_n-aryl, or -(CH₂)_n- heteroaryl; or R₇ and R₈ together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₉ and R₁₀ are each independently hydrogen, (C₁-C₆) alkyl, (Ci-C₆) alkyl-OH, (C₁-C₆) alkyl-O-CCi-Ce) alkyl, aryl, cycloalkyl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more R₁₂; or R₉ and R₁₀ together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₁₁ is aryl, heteroaryl, or cycloalkyl;

R₁₃ is halogen, -O-(C_rC₆) alkyl, -CO₂H, -OH, -CF₃, hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, cycloalkyl substituted with -OH, aryl substituted with -NH₂, aryl substituted with -O- (C₁-C₆) alkyl, -(CH₂)_n-aryl, or -(CH₂)_n-heteroaryl; m is 0-4; n is 0-4; and p is 0-2.

[0053] In one embodiment, W is -CO.

[0054] In another embodiment, R₃ is -CO₂H.

[0055] In one embodiment, R₁ is bicyclic aryl optionally substituted with one or more of R₅ and R₆.

[0056] In another embodiment, R₁ is tricyclic aryl optionally substituted with one or more of R₅ and R₆.

[0057] In one embodiment, R₁ is biphenyl optionally substituted with one or more of R₅ and R₆.

[0058] In one embodiment, m is 0-2. In another embodiment, m is 0.

[0059] In one embodiment, p is 0-2. In another embodiment, p is 2.

[0060] In another embodiment, m is 0 and p is 2. [0061] In another embodiment, R₃ is

<img file="EP1902014A2_D0008.tif" />

[0062] In another embodiment, R₅ is

<img file="EP1902014A2_D0009.tif" />

wherein X' is O, S, or NH.

[0063] In one embodiment, R₄ is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀.

[0064] In one embodiment, W is -CO, R₂ is hydrogen, R₃ is -CO₂H, R₁ is biphenyl optionally substituted with one or more of R₅ and R₆, R₄ is -CONR₉R₁O, m is 0, and p is 2.

[0065] In another embodiment, when R₄ is other than hydrogen, the compound or pharmaceutically acceptable salt of the compound is the S-enantiomer with respect to the carbon to which R₄ is bound.

[0066] In one embodiment, R₂ is hydrogen,

<img file="EP1902014A2_D0010.tif" />

[0067] In one embodiment, R₂ is hydrogen,

R₄ is <img file="EP1902014A2_D0011.tif" /> , and each R₁₂ is -OCH₃.

[0068] In another embodiment, R₂ is hydrogen; and <img file="EP1902014A2_D0012.tif" />

Compounds of the Formula (Ia)

[0069] In one embodiment, the invention is directed to compounds of the Formula

(Ia):

<img file="EP1902014A2_D0013.tif" />

(Ia) and pharmaceutically acceptable salts thereof, wherein

R₁ is phenyl, heteroaryl, biphenyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each optionally substituted with one or more of R₅ or R₆, and when R₁ is substituted with more than one of R₅ or R₆, the substituents can be identical or different;

R₂ is hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)_nR_n, -OH, or -0-(C₁-C₆) alkyl;

R₄Is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀;

R₅ is aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -CO-(C₁-C₆) alkyl, -CO- aryl, -CO-heteroaryl, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -NHSO₂-(C₁-C₆) alkyl, -NHSO₂-aryl, -NHSOrheteroaryl, -NHCO-aryl, -NHCO-heteroaryl, -CONH-aryl, -CONH-heteroaryl, (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH- (C₁-C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, or -CONH-(C₃-C₆) cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R₆, and when R₅ is substituted with more than one R₆, the substituents can be identical or different;

R₆ and R₁₂ are each independently hydrogen, halogen, -CN, -OCF₃, -CF₃, -NO₂, -OH, -SH, -NR₇R₈, -CONR₇R₈, -NR₈COR₇, -NR₈CO₂R₇₅ -CO₂R₇, -COR₇, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂R₇, -NR₇SO₂R₈, -SO₂NR₇R₈; (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH-(C₁- C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, -CONH-(C₃-C₆) cycloalkyl, heterocycloalkyl, -(C₁-C₆) alkyl-OR₇, (C₂-C₆) alkynyl, (C₂-C₆) alkenyl, -0-(C₁-C₆) alkyl-(C₃-C₆) cycloalkyl, -O-alkenyl, -0-(C₁-C₆) alkyl substituted with aryl, aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, or -S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of

Ri₃;

R₇ and R₈ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂- C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, -(CH₂)_n-aryl, or -(CH₂)_n- heteroaryl; or R₇ and R₈ together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₉ and R₁₀ are each independently hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkyl-OH,

(C₁-C₆) alkyl-O-(Ci-C₆) alkyl, aryl, cycloalkyl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more R₁₂; or R₉ and R₁₀ together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₁₁ is aryl, heteroaryl, or cycloalkyl; R₁₃ is halogen, -0-(C₁-C₆) alkyl, -CO₂H, -OH, -CF₃, hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, cycloalkyl substituted with -OH, aryl substituted with -NH₂, aryl substituted with -O- (C₁-C₆) alkyl, -(CH₂)_n-aryl, or -(CH₂)_n-heteroaryl; and n is 0-4.

[0070] In one embodiment, R₁ is bicyclic aryl optionally substituted with one or more of R₅ and R₆.

[0071] In another embodiment, Ri is tricyclic aryl optionally substituted with one or more of R₅ and R₆.

[0072] In one embodiment, Ri is biphenyl optionally substituted with one or more of R₅ and R₆.

[0073] In one embodiment, R₄ is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀.

[0074] In one embodiment, Ri is biphenyl optionally substituted with one or more of R₅ and R₆, and R₄ is -CONR₉R₁₀.

[0075] In another embodiment, R₅ is

<img file="EP1902014A2_D0014.tif" />

_y -or C₀XX₇ wherein X' is O, S, or NH.

[0076] In another embodiment, when R₄ is other than hydrogen, the compound or pharmaceutically acceptable salt of the compound is the S-enantiomer with respect to the carbon to which R₄ is bound.

[0077] In one embodiment, R₂ is hydrogen,

<img file="EP1902014A2_D0015.tif" />

[0078] In one embodiment, R₂ is hydrogen,

R₄ is <img file="EP1902014A2_D0016.tif" /> [0079] In another embodiment, R₂ is hydrogen; and

<img file="EP1902014A2_D0017.tif" />

Compounds of the Formula (Ib)

[0080] In one embodiment, the invention is directed to compounds of the Formula

(Ib):

<img file="EP1902014A2_D0018.tif" />

(Ib) and pharmaceutically acceptable salts thereof, wherein

X, Y, and Z are each independently (CH₂)_n, O, S, NR₇, CO, or SO₂; or X, Y, and Z form a benzene in ring B; ring A and ring B are each independently optionally substituted with one or more of R₅ and R₆;

R₂ is hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)_nRπ, -OH, or -0-(C₁-C₆) alkyl;

R₄Is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀;

R₅ is aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -0-heteroaryl, -S- aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -CO-(C₁-C₆) alkyl, -CO- aryl, -CO-heteroaryl, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -NHSO₂-(C₁-C₆) alkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHCO-aryl, -NHCO-heteroaryl, -CONH-aryl, -CONH-heteroaryl, (C₁-C₆) alkyl, -O-(C_rC₆) alkyl, -S-(C₁-C₆) alkyl, -NH- (C₁-C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, or -CONH-(C₃-C₆) cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R₆, and when R₅ is substituted with more than one R₆, the substituents can be identical or different;

R₆ and R₁₂ are each independently hydrogen, halogen, -CN, -OCF₃, -CF₃, -NO₂, -OH, -SH, -NR₇R₈, -CONR₇R₈, -NR₈COR₇, -NR₈CO₂R₇, -CO₂R₇, -COR₇, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂R₇, -NR₇SO₂R₈, -SO₂NR₇R₈; (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH-(C₁- C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, -CONH-(C₃-C₆) cycloalkyl, heterocycloalkyl, -(C₁-C₆) alkyl-OR₇, (C₂-C₆) alkynyl, (C₂-C₆) alkenyl, -0-(C₁-C₆) alkyl-(C₃-C₆) cycloalkyl, -O-alkenyl, -0-(C₁-C₆) alkyl substituted with aryl, aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, or -S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of

R13;

R₇ and R₈ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂- C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, -(CH₂)_n-aryl, or -(CH₂)_n- heteroaryl; or R₇ and R₈ together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₉ and R₁₀ are each independently hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkyl-OH,

(C₁-C₆) alkyl-O-(Ci-C₆) alkyl, aryl, cycloalkyl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more R₁₂; or R₉ and R₁O together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S; R₁₁ is aryl, heteroaryl, or cycloalkyl;

R₁₃ is halogen, -0-(C₁-C₆) alkyl, -CO₂H, -OH, -CF₃, hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, cycloalkyl substituted with -OH, aryl substituted with -NH₂, aryl substituted with -O- (C₁-C₆) alkyl, -(CH₂)_n-aryl, or -(CH₂)_n-heteroaryl; and n is 0-4.

[0081] In one embodiment, R₄ is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁O-

[0082] In another embodiment, when R₄ is other than hydrogen, the compound or pharmaceutically acceptable salt of the compound is the S-enantiomer with respect to the carbon to which R₄ is bound. [0083] In one embodiment, R₂ is hydrogen,

;

<img file="EP1902014A2_D0019.tif" />

[0085] In another embodiment, R₂ is hydrogen; and

<img file="EP1902014A2_D0020.tif" />

Compounds of the Formula (Ic)

[0086] In one embodiment, the invention is directed to compounds of the Formula

(Ic):

<img file="EP1902014A2_D0021.tif" />

(Ic) and pharmaceutically acceptable salts thereof, wherein

X, Y, and Z are each independently (CH₂)_n, O, S, NR₇, CO, or SO₂; or X, Y, and

Z form a benzene in ring B; ring A, ring B, and ring C are each independently optionally substituted with one or more of R₅ and R₆;

R₂ is hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)_nR_π, -OH, or -0-(C₁-C₆) alkyl;

R₄Is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀;

R₅ is aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -CO-(C₁-C₆) alkyl, -CO- aryl, -CO-heteroaryl, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂NH-aryl, -S0₂NH-heteroaryl, -NHSO₂-(C₁-C₆) alkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHCO-aryl, -NHCO-heteroaryl, -CONH-aryl, -CONH-heteroaryl, (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH- (C₁-C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, or -CONH-(C₃-C₆) cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R₆, and when R₅ is substituted with more than one R₆, the substituents can be identical or different;

R₆ and R₁₂ are each independently hydrogen, halogen, -CN, -OCF₃, -CF₃, -NO₂, -OH, -SH, -NR₇R₈, -CONR₇R₈, -NR₈COR₇, -NR₈CO₂R₇, -CO₂R₇, -COR₇, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂R₇, -NR₇SO₂R₈, -SO₂NR₇R₈; (C₁-C₆) alkyl, -0-(Ci-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH-(C₁- C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, -CONH-(C₃-C₆) cycloalkyl, heterocycloalkyl, -(C₁-C₆) alkyl-OR₇, (C₂-C₆) alkynyl, (C₂-C₆) alkenyl, -0-(C₁-C₆) alkyl-(C₃-C₆) cycloalkyl, -O-alkenyl, -0-(Ci-C₆) alkyl substituted with aryl, aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, or -S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of

RB;

R₇ and R₈ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂- C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, -(CH₂)_n-aryl, or -(CH₂)_n- heteroaryl; or R₇ and R₈ together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₉ and R_1O are each independently hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkyl-OH,

(Ci-C₆) alkyl-O-(Ci-C₆) alkyl, aryl, cycloalkyl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more Ri₂; or Rg and Rio together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

Rn is aryl, heteroaryl, or cycloalkyl;

Ri₃ is halogen, -0-(C_rC₆) alkyl, -CO₂H, -OH, -CF₃, hydrogen, (Ci-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, cycloalkyl substituted with -OH, aryl substituted with -NH₂, aryl substituted with -O- (Ci-C₆) alkyl, -(CH₂)_n-aryl, or -(CH₂)_n-heteroaryl; and n is 0-4.

[0087] In one embodiment, R₄ is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉Ri₀.

[0088] hi another embodiment, when R₄ is other than hydrogen, the compound or pharmaceutically acceptable salt of the compound is the S-enantiomer with respect to the carbon to which R₄ is bound. [0089] In one embodiment, R₂ is hydrogen,

<img file="EP1902014A2_D0022.tif" />

[0090] In one embodiment, R₂ is hydrogen;

R₄ is <img file="EP1902014A2_D0023.tif" /> , and each R₁₂ is -OCH₃.

[0091] In another embodiment, R₂ is hydrogen; and

<img file="EP1902014A2_D0024.tif" />

Compounds of the Formula (Id)

[0092] In one embodiment, the invention is directed to compounds of the Formula

(Id):

<img file="EP1902014A2_D0025.tif" />

(Id) and pharmaceutically acceptable salts thereof, wherein ring A and ring B are each independently optionally substituted with one or more of R₅ and R₆; R₂ is hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)_nRπ, -OH, or -0-(C₁-C₆) alkyl;

R₄Is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀;

R₅ is aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -CO-(C₁-C₆) alkyl, -CO- aryl, -CO-heteroaryl, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -NHSO₂-(C₁-C₆) alkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHCO-aryl, -NHCO-heteroaryl, -CONH-aryl, -CONH-heteroaryl, (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C_rC₆) alkyl, -NH- (C₁-C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, or -CONH-(C₃-C₆) cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R₆, and when R5 is substituted with more than one R₆, the substituents can be identical or different;

R₆ and R₁₂ are each independently hydrogen, halogen, -CN, -OCF₃, -CF₃, -NO₂, -OH, -SH, -NR₇R₈, -CONR₇R₈, -NR₈COR₇, -NR₈CO₂R₇, -CO₂R₇, -COR₇, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂R₇, -NR₇SO₂R₈, -SO₂NR₇R₈; (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH-(C₁- C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, -CONH-(C₃-C₆) cycloalkyl, heterocycloalkyl, -(C₁-C₆) alkyl-OR₇, (C₂-C₆) alkynyl, (C₂-C₆) alkenyl, -0-(C₁-C₆) alkyl-(C₃-C₆) cycloalkyl, -O-alkenyl, -0-(C₁-C₆) alkyl substituted with aryl, aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, or -S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of

Ri₃;

R₇ and R₈ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂- C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, -(CH₂)_n-aryl, or -(CH₂)_n- heteroaryl; or R₇ and R₈ together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S; Rg and R_1O are each independently hydrogen, (C₁-C₆) alkyl, (C₁-C₆) alkyl-OH,

(C₁-C₆) alkyl-O-(Ci-C₆) alkyl, aryl, cycloalkyl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more R₁₂; or R₉ and R_1O together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₁₁ is aryl, heteroaryl, or cycloalkyl;

R₁₃ is halogen, -0-(C₁-C₆) alkyl, -CO₂H, -OH, -CF₃, hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, cycloalkyl substituted with -OH, aryl substituted with -NH₂, aryl substituted with -O- (C₁-C₆) alkyl, -(CH₂)_n-aryl, or -(CH₂)_n-heteroaryl; and n is 0-4.

[0093] In one embodiment, R₄ is -CO₂H, -CONH₂, -(CH₂)_nOR₇, or -CONR₉R₁₀.

[0094] In another embodiment, when R₄ is other than hydrogen, the compound or pharmaceutically acceptable salt of the compound is the S-enantiomer with respect to the carbon to which R₄ is bound.

[0095] In one embodiment, R₂ is hydrogen,

O

R₄ I .,s &gt;t H ^λ ' , and R₁₂ is -F.

[0096] In one embodiment, R₂ is hydrogen;

<img file="EP1902014A2_D0026.tif" />

[0097] In another embodiment, R₂ is hydrogen; and <img file="EP1902014A2_D0027.tif" />

Compounds of the Formula (II)

[0098] In another embodiment, the invention provides compounds of the Formula

(D):

<img file="EP1902014A2_D0028.tif" />

(H) and pharmaceutically acceptable salts thereof, wherein

R₁ is phenyl, (C₁-C₆) alkyl substituted with phenyl, heteroaryl, biphenyl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl, each optionally substituted with one or more of R₅ or R₆, and when R₁ is substituted with more than one of R₅ or R₆, the substituents can be identical or different;

R₂ is hydrogen, (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, -(CH₂)_PR_U, -OH, or -0-(C₁-C₆) alkyl;

R₅ is aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -0-heteroaryl, -S- aryl, -S-heteroaryl, -NH-aryl, -NH-heteroaryl, -CO-(C₁-C₆) alkyl, -CO- aryl, -CO-heteroaryl, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂NH-aryl, -SO₂NH-heteroaryl, -NHSO₂-(C₁-C₆) alkyl, -NHSO₂-aryl, -NHSO₂-heteroaryl, -NHCO-aryl, -NHCO-heteroaryl, -CONH-aryl, -CONH-heteroaryl, (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH- (C₁-C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, or -CONH-(C₃-C₆) cycloalkyl; each alkyl, aryl, cycloalkyl, or heteroaryl optionally substituted with one or more of R₆, and when R₅ is substituted with more than one R₆, the substituents can be identical or different;

R₆ and R₁₂ are each independently hydrogen, halogen, -CN, -OCF₃, -CF₃, -NO₂, -OH, -SH, -NR₇R₈, -CONR₇R₈, -NR₈COR₇, -NR₈CO₂R₇₅ -CO₂R₇, -COR₇, -SO₂-(C₁-C₆) alkyl, -SO₂-aryl, -SO₂-heteroaryl, -SO₂R₇, -NR₇SO₂R₈, -SO₂NR₇R₈; (C₁-C₆) alkyl, -0-(C₁-C₆) alkyl, -S-(C₁-C₆) alkyl, -NH-(C₁- C₆) alkyl, -NHCO-(C₁-C₆) alkyl, -CONH-(C₁-C₆) alkyl, -0-(C₃-C₆) cycloalkyl, -S-(C₃-C₆) cycloalkyl, -NH-(C₃-C₆) cycloalkyl, -NHCO-(C₃- C₆) cycloalkyl, -CONH-(C₃-C₆) cycloalkyl, heterocycloalkyl, -(C₁-C₆) alkyl-OR₇, (C₂-C₆) alkynyl, (C₂-C₆) alkenyl, -0-(C₁-C₆) alkyl-(C₃-C₆) cycloalkyl, -O-alkenyl, -0-(C₁-C₆) alkyl substituted with aryl, aryl, heteroaryl, -(CH₂)_n-aryl, -(CH₂)_n-heteroaryl, -O-aryl, -O-heteroaryl, -S- aryl, or -S-heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, alkenyl, or alkynyl optionally substituted with one or more of

R13;

R₇ and R₈ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂- C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, -(CH₂)_n-aryl, or -(CH₂)_n- heteroaryl; or R₇ and R₈ together with the atom to which they are attached may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S;

R₁₁ is aryl, heteroaryl, or cycloalkyl;

R₁₃ is halogen, -0-(C₁-C₆) alkyl, -CO₂H, -OH, -CF₃, hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, cycloalkyl substituted with -OH, aryl substituted with -NH₂, aryl substituted with -O- (C₁-C₆) alkyl, -(CH₂)_n-aryl, or -(CH₂)_n-heteroaryl;

R₁₄ and R₁₅ are each independently hydrogen, (C₁-C₆) alkyl, aryl, heteroaryl, (C₂-C₆) alkenyl, (C₂-C₆) alkynyl, cycloalkyl, heterocycloalkyl -(CH₂)_n- aryl, bicyclic aryl, tricyclic aryl, bicyclic heteroaryl, or tricyclic heteroaryl; each alkyl, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl optionally substituted with one or more R₁₂; or R₁₄ and R_1S together may form a five- to seven-membered cyclic group containing up to 3 heteroatoms selected from N, O, or S; n is 0-4, and p is 0-2.

[0099] In one embodiment, R₁ is bicyclic aryl optionally substituted with one or more of R₅ and R₆.

[0100] In another embodiment, Ri is tricyclic aryl optionally substituted with one or more of R₅ and R₆.

[0101] In one embodiment, R₁ is biphenyl optionally substituted with one or more of R₅ and R₆.

[0102] In another embodiment, R₅ is

<img file="EP1902014A2_D0029.tif" />

wherein X' is O, S, or NH.

[0103] In another embodiment, R₂ is hydrogen.

[0104] In one embodiment, the compound of Formula (I) is N²-(4- benzoylbenzoylVN^benzyl-L-α-glutamine, N-(4-benzoylbenzoyl)~L-glutamic acid, N¹-

( 1 ,3-benzodioxol-5-ylmethyl)-iV²-(l , 1 '-biphenyl-4-ylcarbonyl)-L-α-glutamine, N²-(l , V- biphenyl-4-ylcarbonyl)-iV -butyl-L-α-glutamine, N -(l,l'-biphenyl-4-ylcarbonyl)-iV - cyclopropyl-L-α-glutamine, N²-(l , l'-biphenyl^-ylcarbony^-N^cyclohexyl-L-α- glutamine, iV¹-benzyl-iV²-(4-thien-2-ylbenzoyl)-L-α-glutamine, iV¹-benzyl-iV²-[4-(2- furyl)benzoyl]-L-α-glutamine, N¹-benzyl-N²-[(4'-ethynyl-l,r-biphenyl-4-yl)carbonyl]-L- α-glutamine, N²-(l , 1 '-biphenyl-4-ylcarbonyl)-Λ/^rl-(4-fluorobenzyl)-L-α-glutamine, N²- (l,l'-biphenyl-4-ylcarbonyl)-N¹-cyclooctyl-L-a-glutamine, A/^rl-benzyl-Λ/²-(4- bromobenzoyl)-L-α-glutamine, N¹-benzyl-N²-[(2',5'-dimethyl-l,r-biphenyl-4- yl)carbonyl]-L-α-glutamine, N -(l,r-biphenyl-4-ylcarbonyl)-N -(3,4-dimethoxybenzyl)- L-α-glutamine, Λ/^rl-benzyl-iV²-(4-pyridin-4-ylbenzoyl)-L-α-glutainine, N¹-benzyl-N²- [(3^5^l-dimethyl-l,^-biρhenyl-4-yl)carbonyl]-L-α-glutaInine, iV¹-benzyl-N²-[(4'-ethyl-l,l'- biphenyl-4-yl)carbonyl]-L-α-glutamine, N¹-benzyl-iV²-[(3'-ethoxy-l,r-biphenyl-4- yl)carbonyl]-L-α-glutamine, N¹-benzyl-N²-[(2'-ethoxy- 1 , 1 ^?-biphenyl-4-yl)carbonyl] -L-α- glutamine, iV¹-benzyl-N²-[(2',6'-dimethyl-l , 1 '-biphenyl-4-yl)carbonyl]-L-α-glutamine, N²- (1 , l'-biphenyl-4-ylcarbonyl)-iV^rl-cyclopentyl-L-α-glutamine, N¹-[2-(acetylamino)ethyl]- N²-( 1 , 1 '-biphenyl-4-ylcarbonyl)-L-α-glutamine, N¹ -2-adamantyl-N²-( 1 , 1 '-biphenyl-4- ylcarbonyl)-L-α-glutamine, Λ/^rl-(2-adamantylmethyl)-Λ/²-(l,r-biphenyl-4-ylcarbonyl)-L- α-glutamine, N¹-benzyl-N²-(4-pyridin-2-ylbenzoyl)-L-α-glutamine, N¹-benzyl-N²-(4- pyridin-3-ylbenzoyl)-L-α-glutamine, N¹-benzyl-N²-[4-(l,3-thiazol-2-yl)benzoyl]-L-α- glutamine, N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(4-methoxybenzyl)-L-α-glutamine, N²- (1,1 '-biphenyl-4-ylcarbonyl)-iV¹-[2-(3,4-dimethoxyphenyl)ethyl]-L-α-glutamine, N²-(l , 1 '- biphenyl-4-ylcarbonyl)-N -(2-methoxyethyl)-L-α-glutamine, N -(l,l'-biphenyl-4- ylcarbonyl)-N¹-[2-(4-methoxyphenyl)ethyl]-L-α-glutamine, N²-(l , l'-biphenyl-4- ylcarbonyl)-N¹-(l-naphthylmethyl)-L-α-glutamine, N²-(l,r-biphenyl-4-ylcarbonyl)-A/^rl- (3 -methylbenzyl)-L-α-glutamine, N²-( 1 , 1 '-biphenyM-ylcarbony^-iV¹ -(2-furylmethyl)-L- α-glutamine, N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-(3-methoxybenzyl)-L-α-glutamine, iV²- (1,1 '-biphenyl-4-ylcarbonyl)-N¹-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N²-(l , 1 '- biphenyl-4-ylcarbonyl)-iV¹-(2,4-dichlorobenzyl)-L-α-glutamine, N²-(l,l'-biphenyl-4- ylcarbonyl)-^¹- [4-(trifluoromethoxy)benzyl]-L-α-glutamine, N²-( 1 , 1 '-biphenyl-4- ylcarbonyl)-iV -[3-(trifluoromethoxy)benzyl]-L-α-glutamine, N -(l,l'-biphenyl-4- ylcarbony^-^-K-^ethylthio^enzylJ-L-a-glutamine, N²-(l,l'-biphenyl-4-ylcarbonyl)- N¹-(4-phenoxybenzyl)-L-α-glutamine, N²-(l , 1¹-biρhenyl-4-ylcarbonyl)-iV¹-[2-(3- methoxyphenyl)ethyl]-L-α-glutamine, N²-(l , 1 ^l-biphenyl-4-ylcarbonyl)-iV¹-(2,4- dimethoxybenzyl)-L-α-glutamine, Λ/²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(2- methoxybenzyl)-L-α-glutamine, N²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(3,4- dichlorobenzyl)-L-α-glutamine, N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3,5-difluorobenzyl)- L-α-glutamine, N²-(l , 1 '-biphenyl^-ylcarbony^-Λ^-hydroxy-N^tS- (trifluoromethoxy)benzyl]-L-glutamamide, N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N⁵-hydroxy- N¹-[2-(3-methoxyphenyl)ethyl]-L-glutamamide, W²-(l,r-biphenyl-4-ylcarbonyl)-iV⁵- hydroxy-N^SAS-trimemoxybenzyiyL-glutamamide, N²-(l , l'-biphenyl-4-ylcarbonyl)- ^-(S^-dimethoxybenzyty-L-α-glutamine, iV²-(l , l'-biphenyl-4-ylcarbonyl)-iV¹-(3,5- dimethoxybenzyl)-iV⁵-hydroxy-L-glutamamide, N¹-benzyl-iV²-[(4'-vinyl-l,r-biphenyl-4- yl)carbonyl]-L-α-glutamine, ^-(lJ'-biphenyl^-ylcarbony^-N^CS^-dimethylbenzy^-L- α-glutamine, N¹-benzyl-iV²-[(4^l-ethoxy-l,r-biphenyl-4-yl)carbonyl]-L-α-glutamine, iV¹- benzyl-N²-[(4'-propoxy- 1 , 1 '-biphenyl-4-yl)carbonyl]-L-α-glutamine, N¹-benzyl-iV²-[(4'- butoxy- 1 , 1 '-biphenyl-4-yl)carbonyl]-L-α-glutamine, Λ^-benzyl-iV²- { [4'- (cyclobutylmethoxy)- 1 , 1 '-biphenyl-4-yl]carbonyl } -L-α-glutamine, N^benzyl-Λ/²- { [4¹- (cyclohexylmethoxy)-l , 1 '-biphenyl-4-yl]carbonyl } -L-α-glutamine, N²- { [4'-(allyloxy)- 1 , 1 '-biphenyl-4-yl]carbonyl } -N¹ -benzyl-L-α-glutamine, N²-( 1 , 1 '-biphenyl-4-ylcarbonyl)- ^-(S^-dimethylbenzy^-Λ^-hydroxy-L-glutaniamide, Λ/²-(l,l'-biphenyl-4-ylacetyl)-N¹- (3-methoxybenzyl)-L-α-glutamine, ^-[(S-fluoropheny^acetyll-^-CS-methoxybenzy^-L- α-glutamine, N²- { [4'-(acetylamino)- 1 , 1 '-biphenyl-4-yl]carbonyl } -N¹ -benzyl-L-α- glutamine, N¹ -benzyl-iV²- { [4'-(2-f uroylamino)- 1 , 1 '-biphenyl-4-yl] carbonyl } -L-α- glutamine, N¹ -benzyl-Ν²-( { 4'- [(4-fluorobenzoyl)amino] -1,1 '-biphenyl-4-yl } carbonyl)-L- α-glutamine, N²- { [4'-(benzoylamino)- 1 , 1 '-biphenyl-4-yl]carbonyl } -N¹ -benzyl-L-α- glutamine, N¹ -benzyl-N²-(5-phenyl-2-furoyl)-L-α-glutamine, iV^benzyl-Λ^-fS-CS- ethoxyphenyl)-2-furoyl]-L-α-glutamine, iV¹-benzyl-Λ/²-[5-(3,5-dimethylphenyl)-2- furoyl]-L-α-glutamine, N¹-benzyl-iV²-(2,2'-bifuran-5-ylcarbonyl)-L-α-glutamine, N¹- benzyl-N²-(5-thien-2-yl-2-furoyl)-L-α-glutamine, N²-[(2,2'-dimethyl-l,r-biρhenyl-4- y^carbony^-N^CS-methoxybenzy^-L-α-glutamine, /^-(lJ'-biphenyl^-ylcarbony^-N¹- (2-phenylethyl)-L-α-glutamine, N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-[3- (trifluoromethyl)benzyl]-L-α-glutamine, N -(4-aminobenzyl)-N -(l,l'-biphenyl-4- ylcarbonyl)-L-α-glutamine, iV¹-(3-aminobenzyl)-N²-(l,r-biphenyl-4-ylcarbonyl)-L-α- glutamine, N²-(l , 1 ^l-biphenyl-4-ylcarbonyl)-N¹-[2-(trifluoromethyl)benzyl]-L-α- glutamine, N¹-benzyl-N²-[(2-fluoro-l , r-biphenyl-4-yl)carbonyl]-L-α-glutamine, N²-(l , 1'- biphenyl-4-ylcarbonyl)-Λ'^rl-(3-fluorobenzyl)-L-α-glutamine, N²-(l , 1 '-biphenyl-4- ylcarbony^-N^CS-phenylpropy^-L-α-glutamine, iV^benzyl-i^-C^l'-biphenyl-S- ylcarbonyl)-L-α-glutamine, N¹-benzyl-N²-(3-thien-2-ylbenzoyl)-L-α-glutamine, N¹- benzyl-^-tCS-chloro-l.r-biphenyl^-yOcarbonyll-L-α-glutamine, N¹-benzyl-N²-[(3-fluoro-l,r-biphenyl-4-yl)carbonyl]-L-α-glutamine, N¹-benzyl-iV²-[(2,6- dimethoxy- 1 , 1 '-biphenyl-4-yl)carbonyl]-L-α-glutamine, N²-(l , 1 '-biphenyl-4-ylcarbonyl)- N^2-(3-chlorophenyl)ethyl]-L-α-glutamine, N²-(l , 1 '-biphenyl^-ylcarbony^-N^Cl- fluorobenzyl)-L-α-glutamine, Λ'²-(l,l'-biphenyl-4-ylcarbonyl)-Λ/^'1-(3,4-difluorobenzyl)-L- α-glutamine, iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(2-methylbenzyl)-L-α-glutamine, N¹- benzyl-iV²-( {4'- [(3-methoxybenzyl)oxy] -1,1 '-biphenyl-4-yl } carbonyl)-L-α-glutamine, N¹- benzyl-Λ/²-({4'-[(3,5-dimethoxybenzyl)oxy]-l,r-biphenyl-4-yl}carbonyl)-L-α-glutaniine, iV^benzyl-JV²- { [4'-(2-naphthylmethoxy)- 1 , 1 '-biphenyl-4-yl]carbonyl } -L-α-glutamine, N²- (1,1¹-biρhenyl-4-ylcarbonyl)-N¹-2,3-dihydro-lH-inden-2-yl-L-α-glutamine, iV²-(l , 1 '- biphenyl-4-ylcarbonyl)-iV -(2,3-dimethylbenzyl)-L-α-glutamine, N -(l,l'-biphenyl-4- ylcarbonyl)-N¹-(4-phenylbutyl)-L-α-glutamine, N¹-(2-benzylphenyl)-iV²-(l,r-biphenyl-4- ylcarbonyl)-L-α-glutamine, N²-( 1 , 1 '-biphenyl-4-ylcarbonyl)-N¹ -(4-methoxy- 1,1'- biphenyl-3-yl)-L-α-glutamine, N²-(l,r-biphenyl-4-ylcarbonyl)-ΛT¹-(4-methylbenzyl)-L-α- glutamine, N²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-[4-fluoro-3-(trifluoromethyl)benzyl]-L-α- glutamine, N²-( 1 , 1 ^l-biphenyl-4-ylcarbonyl)-iV¹-heptyl-L-α-glutamine, N²-( 1 , 1 '-biphenyl- 4-ylcarbonyl)-N¹-(3-iodobenzyl)-L-α-glutamine, N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3- vinylbenzyl)-L-α-glutamine, N²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(3-thien-2-ylbenzyl)-L- α-glutamine, N²-( 1 , 1 '-biphenyl^-ylcarbonyl)-//¹ - [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] - L-α-glutamine,N -benzyl-N -[(β-phenylpyridin-S-y^carbonyll-L-α-glutamine, N -(3- methoxybenzyl)-N²-[(6-phenylpyridin-3-yl)carbonyl]-L-α-glutamine, N²-(l,l'-biphenyl- 4-ylcarbonyl)-iV¹-(4-fert-butylbenzyl)-L-α-glutainine, N²-(l , 1 '-biphenyl-4-ylcarbonyl)- jV¹-(4-iodobenzyl)-L-α-glutamine, ΛT²-(1 , r-biphenyl-4-ylcarbonyl)-N¹-(4-vinylbenzyl)-L- α-glutamine, /^-(lJ'-biphenyl^-ylcarbonyO-N^Csec-buty^-L-α-glutamine, iV²-(l , 1 ^l-biphenyl-4-ylcarbonyl)-iV¹-(cyclopropylmethyl)-L-α-glutamine, iV²-(biphenyl-4- ylcarbonyl)-N¹-[4-(dimethylamino)benzyl]-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)- Λ/^rl-[2-(4-bromophenyl)ethyl]-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-iV¹-(2-biphenyl- 4-ylethyl)-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(2'-ethoxybiphenyl-4- yl)ethyl]-L-α-glutamine,N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4'-ethynylbiphenyl-4- yl)ethyl]-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹- { 2-[4-(2-thienyl)phenyl]ethyl } - L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-pyridin-2-ylphenyl)ethyl]-L-a- glutamine, N²-φiphenyl-4-ylcarbonyl)-N¹-[3-(dimethylamino)benzyl]-L-α-glutaniine, N²- (biphenyl^-ylcarbony^-^-CS.S-diphenylpropy^-L-α-glutamine, Λ^-Cbiphenyl^- ylcarbony^-iV^CSjS-dimethylbuty^-L-α-glutainine, Λ^-Cbiphenyl^-ylcarbonyl)-^¹- isopropyl-L-α-glutamine, Λ/²-(biphenyl-4-ylcarbonyl)-N¹-(pyridin-4-ylmethyl)-L-α- glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹,Λ/^rl-diethyl-L-α-glutamine, N²-(biphenyl-4- ylcarbonyl)-N -(l,l-dimethylpropyl)-L-α-glutamine, N -(biphenyl-4-ylcarbonyl)-iV -[2- (4'-formylbiphenyl-4-yl)ethyl]-L-α-glutaniine, N²-(biphenyl-4-ylcarbonyl)-N¹-{2-[4'- (trifluoromethyl)biphenyl-4-yl]ethyl}-L-α-glutamine, N -(biphenyl-4-ylcarbonyl)-N -[2- (4'-formylbiphenyl-3-yl)ethyl]-L-α-glutamine, Λ/²-(biphenyl-4-ylcarbonyl)-N¹-{2-[4'- (trifluoromethyl)biphenyl-3-yl]ethyl } -L-α-glutamine, Λ/²-(biphenyl-4-ylcarbonyl)-N¹-[2- (4'-methoxybiphenyl-3-yl)ethyl]-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'- methoxybiphenyl-4-yl)ethyl]-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(3- bromophenyl)ethyl] -L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹ -pentyl-L-α- glutamine,N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-pyridin-4-ylphenyl)ethyl]-L-α-glutainine, N²-(biphenyl-4-ylcarbonyl)-N¹-(tert-butyl)-L-α-glutaniine, iV²-(biphenyl-4-ylcarbonyl)- ^-{^'-(trifluoromethy^biphenyl-S-y^methylJ-L-α-glutamine, iV²-(biphenyl-4- ylcarbonyl)-N¹-(2,2-dimethylpropyl)-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-[(4'- ethynylbiphenyl-3-yl)methyl]-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-(3-pyridin- 2-ylbenzyl)-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-(l,l-dimethyl-2-phenylethyl)- L-α-glutamine,Λ/²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4-chlorophenyl)-l,l-dimethylethyl]-L- α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-hexyl-L-α-glutamine, iV²-(biphenyl-4-

1 0 1 ylcarbonyl)-iV -(l-methyl-l-phenylethyl)-L-α-glutamine, N -(biphenyl-4-ylcarbonyl)-iV - (l,l,3,3-tetramethylbutyl)-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-(2-morpholin- 4-ylethyl)-L-a-glutamine,N²-(biphenyl-4-ylcarbonyl)-N¹-(2-hydroxy-l,l-dimethylethyl)- L-α-glutamine, Λ/²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-fluorophenyl)ethyl]-L-α-glutamine, N²-φiphenyl-4-ylcarbonyl)-iV¹-[2-(2-fluorophenyl)e%l]-L-α-glutamine, N²-(biphenyl-4- ylcarbonyl)-N¹-[2-(4-chlorophenyl)ethyl]-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹- [2-(2-thienyl)ethyl]-L-α-glutamine, N²-(biρhenyl-4-ylcarbonyl)-N¹-[2-(2- chlorophenyl)ethyl]-L-α-glutamine, ^-(biphenyl^-ylcarbony^-N^Cό-hydroxyhexyO-L- α-glutamine, N²-(biphenyl-4-ylcarbonyl)-iV¹-(5-hydroxypentyl)-L-α-glutamine, 3- [(biphenyl-4-ylmethyl)amino]-3-oxopropanoic acid, N²-(biphenyl-4-ylcarbonyl)-iV¹- propyl-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4-fluorophenyl)- 1,1- dimethylethyl]-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4-fluorophenyl)-l,l- dimethylethyl]-D-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-iV^rl-[2-(3-pyridin-2- ylphenyl)ethyl]-L-α-glutamine, N²-2-naphthoyl-iV¹-(3-phenylpropyl)-L-α-glutamine, N²- (9H-fluoren-2-ylcarbonyl)-N¹-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N²-(9H-fluoren- l-ylcarbony^-N^CS^.S-trimethoxybenzy^-L-α-glutamine, N²-[(9-oxo-9H-fluoren-2- yl)carbonyl]-N¹-(3,4,5-trimethoxybenzyl)-L-α-glutamine, iV²-(9H-fluoren-2-ylcarbonyl)- N^3-phenylpropyl)-L-α-glutamine, N²-(9H-fluoren-l-ylcarbonyl)-N¹-(3-phenylpropyl)- L-α-glutamine, N²-(4-phenoxybenzoyl)-N¹-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N²- (9H-fluoren-2-ylcarbonyl)-iV¹-hexyl-L-α-glutamine, N^ΘH-fluoren-l-ylcarbonyty-N¹- hexyl-L-α-glutamine, N¹-hexyl-N²-(4-phenoxybenzoyl)-L-α-glutamine, N¹-hexyl-iV²-[(9- oxo-9H-fluoren-2-yl)carbonyl]-L-α-glutamine, N -[(9-oxo-9H-fluoren-2-yl)carbonyl]-N - (3-phenylpropyl)-L-α-glutamine, Λ/²-(4-phenoxybenzoyl)-iV¹-(3-phenylpropyl)-L-α- glutamine, iV-[4-(pyrimidin-2-ylamino)benzoyl]-L-glutamic acid, N-(l,l'-biphenyl-4- ylcarbonyl)-D-glutamic acid, N-[4-(pyrimidin-2-ylamino)benzoyl]-L-α-glutamine, N²- (1,1 '-biphenyl-4-ylcarbonyl)-D-α-glutamine, N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-(4- hydroxybutyl)-L-α-glutamine, N^benzyl-Ν^Cl , 1 '-biphenyl-4-ylcarbonyl)-L-α-glutamine, N¹ -benzyl-N²- [4-(pyrimidin-2-ylamino)benzoyl] -L-α-glutamine, (4S)-4- [(1,1 '-biphenyl-4- ylcarbonyl)amino]-5-hydroxypentanoic acid, N-({4'-[(phenylacetyl)amino]-l,r-biphenyl- 4-yl } carbonyl)-L-glutamic acid, N- [(4'- { [(3-methyl- 1 -benzofuran-2-yl)carbonyl] amino } - l,r-biphenyl-4-yl)carbonyl]-L-glutamic acid, N- { [4'-(2-furoylamino)-l,r-biphenyl-4- yl]carbonyl}-L-glutamic acid, N-{ [4'-(acetylamino)-l,r-biphenyl-4-yl]carbonyl}-L- glutamic acid, N-{[4'-(benzoylaniino)-l,r-biphenyl-4-yl]carbonyl}-L-glutamic acid, N- ({4'-[(l-benzofuran-2-ylcarbonyl)amino]-l,r-biphenyl-4-yl}carbonyl)-L-glutamic acid, N¹-(l,l-dimethyl-2-phenylethyl)-N²-(9Η-fluoren-2-ylcarbonyl)-L-α-glutamine, N¹-[2-(4- chlorophenyl)-l,l-dimethylethyl]-N²-(9H-fluoren-2-ylcarbonyl)-L-α-glutamine, N²-(9H- fluoren-2-ylcarbonyl)-N¹-(6-hydroxyhexyl)-L-α-glutamine, N¹-(6-hydroxyhexyl)-N²-(4- phenoxybenzoyl)-L-α-glutamine, N²-(9H-fluoren-9-ylcarbonyl)-N¹-(6-hydroxyhexyl)-L- α-glutaπύne, N²-(9H-fluoren-9-ylcarbonyl)-N¹-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N²-(3-phenoxybenzoyl)-N¹-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N²-(9H-fluoren-4- ylcarbony^-^-CS^^-trimethoxybenzy^-L-α-glutamine, N¹-l-adamantyl-iV²-[(9-oxo-9H- fluoren-2-yl)carbonyl]-L-α-glutamine, N¹-l-adamantyl-Λ/²-(4-phenoxybenzoyl)-L-α- glutamine, JV¹ - 1 -adamantyl-iV²-(9H-fluoren-2-ylcarbonyl)-L-α-glutamine, N¹ - 1 - adamantyl-N²-(9H-fluoren-9-ylcarbonyl)-L-α-glutamine, N²-(9H-fluoren-2-ylcarbonyl)- N¹-(3-methylbenzyl)-L-α-glutamine, N¹-(3-methylbenzyl)-N²-[(9-oxo-9H-fluoren-2- yl)carbonyl]-L-α-glutamine, iV²-(9H-fluoren-9-ylcarbonyl)-iV¹-(3-methylbenzyl)-L-α- glutamine, N²-(9H-fluoren-2-ylcarbonyl)-iV^rl -propyl-L-α-glutamine, N¹ -benzyl-iV²- [(9- oxo-9H-fluoren-2-yl)carbonyl]-L-α-glutamine, N¹-benzyl-N²-(9H-fluoren-2-ylcarbonyl)- L-α-glutamine, N¹-benzyl-Λ/²-(9H-fluoren-9-ylcarbonyl)-L-α-glutamine, N^benzyl-N²- (3-phenoxybenzoyl)-L-α-glutamine, N¹-(l-methyl-l-phenylethyl)-Λ/^r2-[(9-oxo-9H-fluoren- 2-yl)carbonyl] -L-α-glutamine, N²-(9H-fluoren-9-ylcarbonyl)-N¹ -( 1 -methyl- 1 - phenylethyl)-L-α-glutamine, N¹-(l-methyl-l-phenylethyl)-N²-(3-phenoxybenzoyl)-L-α- glutamine, N²-(biphenyl-4-ylcarbonyl)-N¹-[(lS)-l-phenylethyl]-L-α-glutamine, N²-(9H- fluoren-2-ylcarbonyl)-N -[(lS)-l-phenylethyl]-L-α-glutamine, N -(biphenyl-4- ylcarbonyl)-^¹ -[(1S)-I -(4-fluorophenyl)ethyl] -L-α-glutamine, tert-butyl N²-(biphenyl-4- ylcarbony^-^-Cl-phenylethyO-L-α-glutaminate, N²-(biphenyl-4-ylcarbonyl)-N¹-[(lR)-l- (4-fluorophenyl)ethyl] -L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-iV¹ - [( 1 R)- 1 - phenylemyl]-L-α-glutamine, N²-(9H-fluoren-2-ylcarbonyl)-N¹-[(lR)-l-phenylethyl]-L-α- glutamine, Λ/^α-(9H-fluoren-l-ylcarbonyl)-N¹-(6-hydroxyhexyl)-L-α-glutamine, ^-(6- hydroxyhexyl)-N²-[(9-oxo-9H-fluoren-2-yl)carbonyl]-L-α-glutamine, N²-(biphenyl-4- ylcarbonyl)-N¹-9H-fluoren-9-yl-L-α-glutamine, iV²-(9H-fluoren-2-ylcarbonyl)-N¹-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N²- [(3 '-ethoxybiphenyl-4-yl)carbonyl] - N-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N²-[(2'-ethoxybiphenyl-4-yl)carbonyl]-N- (3,4,5-trimethoxybenzyl)-L-α-glutamine, N²-[(4'-methoxybiphenyl-4-yl)carbonyl]-N- (3 ,4,5-trimethoxybenzyl)-L-α-glutamine, N²-(4-bromobenzoyl)-iV-(3 ,4,5- trimethoxybenzyl)-L-α-glutamine, N²-[(3'-methoxybiphenyl-4-yl)carbonyl]-N-(3,4,5- trimethoxybenzyl)-L-α-glutamine, 4'-{ [((lS)-3-carboxy-l-{ [(3,4,5- trimethoxybenzyl)amino]carbonyl}propyl)amino] carbonyl}biphenyl-3-carboxylic acid, N²-[(4^l-ethylbiphenyl-4-yl)carbonyl]-Λ/-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N- benzyl-N²-[4-(2-naphthyl)benzoyl] -L-α-glutamine, JV²-[(3',4'-dimethoxybiphenyl-4- yl)carbonyl]-N-(3,4,5-trimethoxybenzyl)-L-α-glutamine, iV²-[(2',4'-dimethoxybiphenyl-4- yl)carbonyl]-N-(3,4,5-trimethoxybenzyl)-L-α-glutamine, //-(S^jS-trimethoxybenzy^-iV²- [(3',4',5'-trimethoxybiphenyl-4-yl)carbonyl]-L-α-glutamine, N-(l-adamantylmethyl)-N²- (biphenyl-4-ylcarbonyl)-L-α-glutamine, AT-(I, l-dimethyl-2-phenylethyl)-N²-[(3'- methoxybiphenyl-4-yl)carbonyl]-L-α-glutamine, Λ^r2-[(3',4'-dimethoxybiphenyl-4- yl)carbonyl] -N-( 1 , 1 -dimethyl-2-phenylethyl)-L-α-glutamine, N-(I₅I -dimethyl-2- phenylethyl)-N²-[(2'-ethoxybiphenyl-4-yl)carbonyl]-L-α-glutamine, N-(l,l-dimethyl-2- phenylethyl)-N²-[(3'-fluoro-4^l-methylbiphenyl-4-yl)carbonyl]-L-α-glutamine, N²-(4- bromobenzoyl)-N-( 1 , 1 -dimethyl-2-phenylethyl)-L-α-glutamine, N- [( 1 S)- 1 -benzyl-2- hydroxyethyl] -N²-(biphenyl-4-ylcarbonyl)-L-α-glutamine, N- [( 1 S)- 1 -benzyl-2- hydroxyethyl]-N²-(9H-fluoren-2-ylcarbonyl)-L-a-glutamine, N-(l-adamantylmethyl)-N²- (4-bromobenzoyl)-L-α-glutamine, N-(I -adamantylmethyl)-N²- [(4'-hydroxybiphenyl-4- yl)carbonyl]-L-α-glutamine, N -[4-(1 ,3-benzodioxol-5-yl)benzoyl]-N-(l , 1 -dimethyl-2- phenylethyl)-L-α-glutamine, N²-[(2',4'-dimethoxybiphenyl-4-yl)carbonyl]-N-(l,l- dimethyl-2-phenylethyl)-L-α-glutamine, N²- [(3 '-fluoro-4'-methylbiphenyl-4-yl)carbonyl] - N-(3,4,5-tximethoxybenzyl)-L-α-glutamine, N²-({4'-[(3,5- dimethoxybenzyl)oxy]biphenyl-4-yl } carbonyl)-N-(3 ,4,5-trimethoxybenzyl)-L-α- glutamine, N-(l-adamantylmethyl)-N²-({4'-[(3-methoxybenzyl)oxy]biphenyl-4- yl}carbonyl)-L-α-glutamine, N-(l-adamantylmethyl)-N²-({4'-[(3,5- dimethoxybenzyl)oxy]biphenyl-4-yl } carbonyl)-L-α-glutamine, N²-(biphenyl-4- ylcarbonyl)-N-methyl-N-(2-phenylethyl)-L-α-glutamine, N²-[(4'-sec-butylbiphenyl-4- yl)carbonyl] -N-( 1 , 1 -dimethyl-2-phenylethyl)-L-α-glutamine, N-( 1 , 1 -dimethyl-2- phenyletnyl)-N²-[(4'-isopropylbiphenyl-4-yl)carbonyl]-L-α-glutamine, N-(l,l-dimethyl- 2-phenylethyl)-N²-(l,r:4',l"-terphenyl-4-ylcarbonyl)-L-α-glutamine, N²-({4'-[(3,5- dimethoxybenzyl)oxy]biphenyl-4-yl}carbonyl)-N-(l,l-dimethyl-2-phenylethyl)-L-α- glutamine, N²-[(4'-hydroxybiphenyl-4-yl)carbonyl]-N-(3,4,5-tximethoxybenzyl)-L-α- glutamine, N-(l-adamantylmethyl)-N²-({3^l-[(dimethylamino)carbonyl]biphenyl-4- yl}carbonyl)-L-α-glutamine, N-(l-adamantylmethyl)-N²-[(3',5'-dimethylbiphenyl-4- yl)carbonyl]-L-α-glutamine, N²-(9H-fluoren-2-ylcarbonyl)-N-methyl-N-(2-phenylethyl)- L-α-glutamine, N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-N²-[(3'-methylbiρhenyl-4- yl)carbonyl]-L-α-glutamine, N²-({4'-[(3,5-dimethylbenzyl)oxy]biphenyl-4-yl}carbonyl)- N-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N²-[(4'-{ [3,5- bis(trifluoromethyl)benzyl]oxy}biphenyl-4-yl)carbonyl]-N-(3,4,5-trimethoxybenzyl)-L- α-glutamine, N -[(3'-isopropylbiphenyl-4-yl)carbonyl]-iV-(3,4,5-trimethoxybenzyl)-L-α- glutamine, N -[(4'-isopropylbiphenyl-4-yl)carbonyl]-iV-(3,4,5-trimethoxybenzyl)-L-α- glutamine, N-(l-adamantylmethyl)-N²-[4-(l-benzofuran-5-yl)benzoyl]-L-α-glutamine, N- (l-adamantylmethyl)-N²-[4-(lH-indol-5-yl)benzoyl]-L-a-glutaniine, N²-[(3'- ethoxybiphenyl-4-yl)carbonyl]-N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-α-glutamine, N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-N²-[(3'-methoxybiphenyl-4-yl)carbonyl]-L-a- glutamine, N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -N²- [(3 '-isopropylbiphenyl-4- yl)carbonyl]-L-α-glutamine, N²-[(3'-fluoro-4'-methylbiphenyl-4-yl)carbonyl]-N-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N- [2-(4-fluorophenyl)- 1,1- dimethylethyl]-N²-[(4'-isobutylbiρhenyl-4-yl)carbonyl]-L-α-glutamine, N²-(l,r:4',l"- terphenyl-4-ylcarbonyl)-N-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N-benzyl-N²-{[3'- (hydroxymethyl)biphenyl-4-yl]carbonyl} -L-α-glutamine, N-benzyl-N²-({4'-[(3- fluorobenzyl)oxy]biphenyl-4-yl } carbonyl)-L-α-glutamine, N-benzyl-N²- { [4- (benzyloxy)biphenyl-4-yl]carbonyl } -L-α-glutamine, N-benzyl-N²- [4-

(phenylethynyl)benzoyl] -L-α-glutamine, N-benzyl-N²- {4- [(9-hydroxy-9H-fluoren-9- yl)ethynyl]benzoyl} -L-α-glutamine, N-benzyl-N²-{4-[(lE)-3-oxo-3-phenylprop-l-en-l- yl]benzoyl}-L-α-glutamine, N-(3,4,5-trimethoxybenzyl)-N²-[(2',4',6'-trimethylbiphenyl-4- yl)carbonyl]-L-α-glutamine, N-(l,l-dimethyl-2-ρhenylethyl)-N²-({4'-[(3- methoxybenzyl)oxy]biphenyl-4-yl } carbonyl)-L-α-glutamine, N-( 1 , 1 -dimethyl-2- phenylethyl)-N²-[(4'-hydroxybiphenyl-4-yl)carbonyl]-L-α-glutamine, N-(l,l-dimethyl-2- ρhenylethyl)-N²-[(3'-ethoxybiphenyl-4-yl)carbonyl]-L-α-glutamine, N²-({4'-[(3,5- dimethoxybenzyl)oxy]biphenyl-4-yl}carbonyl)-N-(6-hydroxyhexyl)-L-α-glutamine, N²- ({4'-[(3-methoxybenzyl)oxy]biphenyl-4-yl}carbonyl)-N-(3,4,5-trimethoxybenzyl)-L-α- glutamine, N²-(4-bromobenzoyl)-N-(3-methylbenzyl)-L-α-glutamine, N²-[4-(l ,3- benzodioxol-5-yl)benzoyl]-N-(3-methylbenzyl)-L-α-glutamine, N²-(biphenyl-4- ylcarbonyl)-N-butyl-N-methyl-L-α-glutamine, N- [2-(4-fluorophenyl)- 1,1 -dimethylethyl] - N²-[(4'-hydroxybiphenyl-4-yl)carbonyl]-L-α-glutamine, N-butyl-N²-(9H-fluoren-2- ylcarbonyl)-N-methyl-L-α-glutamine, N²-(biphenyl-4-ylcarbonyl)-N-[2-(3,4- dimethoxyphenyl)ethyl]-N-methyl-L-α-glutamine, N²-[4-(l,3-benzodioxol-5-yl)benzoyl]- N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-α-glutamine, N-[2-(3,4- dimethoxyphenyl)ethyl]-N²-(9H-fluoren-2-ylcarbonyl)-N-methyl-L-α-glutamine, N²-(9H- fluoren-2-ylcarbonyl)-iV-[(2R)-2-phenylpropyl]-L-α-glutamine, N²-(biphenyl-4- ylcarbonyl)-N-[(2R)-2-phenylpropyl]-L-α-glutaπύne, N-benzyl-N²-{4-[(4- hydroxycyclohexyl)ethynyl]benzoyl } -L-α-glutamine, N²- { 4- [(3- aminophenyl)ethynyl]benzoyl } -N-benzyl-L-α-glutamine, N-benzyl-N²-[4-(3-hydroxy- 3 ,3-diphenylprop- 1 -yn- 1 -yl)benzoyl] -L-α-glutamine, iV-benzyl-N²- { 4- [(3 - methoxyphenyl)ethynyl]benzoyl} -L-α-glutamine, N²-[(3'-hydroxybiphenyl-4- yl)carbonyl]-iV-(3,4,5-trimethoxybenzyl)-L-α-glutamine, N-(l,l-dimethyl-2-phenylethyl)- N²- { [4'-(hydroxymethyl)biphenyl-4-yl]carbonyl } -L-α-glutamine, N-(1 , 1 -dimethyl-2- phenylethyl)-N²-[(4'-methylbiphenyl-4-yl)carbonyl]-L-α-glutamine, N²-(biphenyl-4- ylcarbonyl)-N¹-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-glutamamide, N²-({4'-[(3-tert- butylphenoxy)methyl]biphenyl-4-yl } carbonyl)-N-( 1 , 1 -dimethyl-2- phenylethyl)-L-α- glutamine, N²-({4'-[(3,5-di-tert-butylphenoxy)methyl]biphenyl-4-yl}carbonyl)-N-(l,l- dimethyl-2 -phenylethyl)-L-α-glutamine, N-(I, l-dimethyl-2-phenylethyl)-N²-({4'-[(3- ethylphenoxy)methyl]biphenyl-4-yl } carbonyl)-L-α-glutamine, N-(1 , 1 -dimethyl-2- phenylethyl)-N²-( { 4'- [(3 -methoxyphenoxy)methyl]biphenyl-4-yl } carbonyl)-L-α- glutamine, N-[2-(4-fluorophenyl)- 1 , l-dimethylethyl]-N²-[(3'-hydroxybiphenyl-4- yl)carbonyl] -L-α-glutamine, N²-(biphenyl-4ylcarbonyl)-N¹-[2-(4-fluoropenyl)-l,2- dimethylethyl] -N⁵-hydroxy-L-glutamanide, N²- [4-(5-bromo-2-thienyl)benzoyl] -N- [2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N- [2-(5-chloro-2-thienyl)- 1,1- dimethylethyl]-N²-[(3'-fluorobiphenyl-4-yl)carbonyl]-L-α-glutaniine, N²-[(3¹,4'- difluorobiphenyl-4-yl)carbonyl]-N-[2-(4-fluoroplienyl)-l , 1 -dimethylethyl]-L-α- glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[(3',4'-difluorobiphenyl-4- yl)carbonyl]-L-α-glutamine, N-[2-(4-clilorophenyl)-l,l-dimethylethyl]-N²-[(2',4'- difluorobiphenyl-4-yl)carbonyl] -L-α-glutamine, N- [2-(4-chlorophenyl)- 1,1- dimethylethyl]-N²-[(2',5'-difluorobiphenyl-4-yl)carbonyl]-L-α-glutamine, N-[2-(4- chlorophenyl)-l,l-dimethylethyl]-N²-[(2',6'-difluorobiphenyl-4-yl)carbonyl]-L-α- glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[(3',5'-difluorobiphenyl-4- yl)carbonyl]-L-α-glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[(2',3'- difluorobiphenyl-4-yl)carbonyl]-L-α-glutamine, N-(l,l-dimethyl-2-phenylethyl)-N²-(4- pyrimidin-5-ylbenzoyl)-L-α-glutamine, N²-[(3',4'-difluorobiphenyl-4-yl)carbonyl]-N- (l,l-dimethyl-2-phenylethyl)-L-α-glutamine, N²-[(3',5'-difluorobiphenyl-4-yl)carbonyl]- N-(l,l-dimethyl-2-phenylethyl)-L-α-glutamine, iV-[2-(5-chloro-2-thienyl)-l,l- dimethylethyl]-N²-[(3',4'-difluorobiphenyl-4-yl)carbonyl]-L-a-glutainine, N²-(biphenyl-4- ylcarbonyl)-N-[2-(5-chloro-2-tMenyl)-l,l-dimethylethyl]-L-α-glutamine, N²-{[5-(3- chloro-4-fluorophenyl)-2-thienyl]carbonyl } -iV-[2~(5-chloro-2-thienyl)- 1 , 1 -dimethylethyl] - L-α-glutamine, N²-{[4'-(hydroxymethyl)biphenyl-4-yl]carbonyl}-iV-(3,4,5- trimethoxybenzyl)-L-α-glutamine, N²- { [4'-(bromomethyl)biphenyl-4-yl]carbonyl } -N- (3 ,4,5-trimethoxybenzyl)-L-α-glutamine, N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -N²- [4-(2-thienyl)benzoyl]-L-α-glutamine, N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-N²-[4- (2-furyl)benzoyl]-L-α-glutamine, N²-{[4'-(hydroxymethyl)biphenyl-4-yl]carbonyl}-N-(3- methylbenzyl)-L-α-glutamine, ^-{[S'-Chydroxymethy^biphenyl^-yllcarbonylJ-N-CS- methylbenzyl)-L-α-glutamine, N²-[4-(2,3-dihydro-l-benzofuran-5-yl)benzoyl]-N-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N²- [(3 '-chloro-4'-fluorobiphenyl-4- yl)carbonyl]-N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-a-glutamine, N²-{[3'- (bromomethyl)biphenyl-4-yl]carbonyl}-N-(3-methylbenzyl)-L-α-glutamine, N-[2-(4- fluorophenyl)-l,l-dimethylethyl]-N²-[4-(3-thienyl)benzoyl]-L-α-glutamine, N-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -N²- [4-(5-methyl-2-thienyl)benzoyl] -L-α-glutamine, N²-[4-(5-chloro-2-thienyl)benzoyl]-N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-α- glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[4-(2-thienyl)benzoyl]-L-α- glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-{[5-(3-methoxyphenyl)-2- thienyl]carbonyl } -L-α-glutamine, N-[2-(4-chlorophenyl)-l , 1 -dimethylethyl] -N²- [(5- phenyl-2-thienyl)carbonyl]-L-α-glutamine, N²-(2,2^l-bithien-5-ylcarbonyl)-N-[2-(4- chlorophenyl)-l,l-dimethylethyl]-L-α-glutamine, N²-[4-(2,3-dihydro-l-benzofuran-6- yl)benzoyl]-N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-α-glutamine, N-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -N²- { [6-(3-methoxyphenyl)pyridin-3-yl]carbonyl } -L-α- glutamine, N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -N²- [(6-phenylpyridin-3- yl)carbonyl]-L-α-glutamine, N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-N²-[(5-phenyl-2- thienyl)carbonyl]-L-α-glutamine, N²-[(3-fluorobiphenyl-4-yl)carbonyl]-N-[2-(4- fluorophenyl)-l , 1 -dimethylethyl] -L-α-glutamine, N-[2-(4-chlorophenyl)-l , 1- dimethylethyl]-N²-[(5-pyridin-4-yl-2-tnienyl)carbonyl]-L-α-glutamine, N²- { [5-(3-chloro- 4-fluorophenyl)-2-thienyl]carbonyl } -N-[2-(4-chlorophenyl)- 1 , 1 -dimethylethyl]-L-α- glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[4-(2,3-dihydro-l-benzofuran-6- yl)benzoyl]-L-α-glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[(5-pyridin-3- yl-2-thienyl)carbonyl]-L-α-glutamine, iV²-[4-(2,3-dihydro-l-benzofuran-6-yl)benzoyl]-N- (l,l-dimethyl-2-phenylethyl)-L-α-glutamine, iV²-{[5-(3-chloro-4-fluorophenyl)-2- thienyl]carbonyl}-N-(l,l-dimethyl-2-phenylethyl)-L-α-glutamine, N-(l,l-dimethyl-2- phenylethyl)-N²-[4-(2-thienyl)benzoyl]-L-α-glutaπύne,^(l,l-dimethyl-2-phenylethyl)- N²- { [5-(3-methoxyphenyl)-2-thienyl]carbonyl } -L-α-glutamine, N-(1, 1 -dimethyl-2- phenylethyl)-N²-[(5-phenyl-2-thienyl)carbonyl]-L-α-glutamine, N²-(2,2'-bithien-5- ylcarbonyl)-N-(l , 1 -dimethyl-2-phenylethyl)-L-α-glutamine, N-(I , l-dimethyl-2- phenylethyl)-N²-[(5-pyridin-4-yl-2-thienyl)carbonyl]-L-α-glutamine, N-(l,l-dimethyl-2- phenylethyl)-N²-[(5-pyridin-3-yl-2-thienyl)carbonyl]-L-α-glutamine, N-[2-(4- chlorophenyl)-l,l-dimethylethyl]-N²-[4-(5-chloro-2-thienyl)benzoyl]-L-α-glutamine, N²- {[6-(5-chloro-2-thienyl)pyridin-3-yl]carbonyl}-N-(l,l-dimethyl-2-phenylethyl)-L-α- glutamine, N-( 1 , 1 -dimethyl-2-phenylethyl)-N²- [(6-phenylpyridin-3 -yl)carbonyl] -L-α- glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-Λ/²-(5-phenyl-2-furoyl)-L-α- glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-{[6-(5-chloro-2-thienyl)pyridin- 3-yl]carbonyl}-L-α-glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[(6- phenylpyridin-3 -yl)carbonyl] -L-α-glutamine, N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] - N²- { [5-(3 -methoxyphenyl)-2-thienyl] carbonyl } -L-α-glutamine, N- [2-(4-fluorophenyl)- l,l-dimethylethyl]-N²-[(5-pyridin-3-yl-2-thienyl)carbonyl]-L-α-glutamine, N²-{[5-(3- chloro-4-fluorophenyl)-2-thienyl]carbonyl } -N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L- α-glutamine, N²-(2,2'-bithien-5-ylcarbonyl)-N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L- α-glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[4-(5-formyl-2- thienyl)benzoyl]-L-α-glutamine, N²-[4-(5-acetyl-2-thienyl)benzoyl]-N-[2-(4- chlorophenyl)- 1 , 1 -dimethylethyl]-L-α-glutamine, N-[2-(4-chlorophenyl)- 1,1- dimethylethyl]-N²-[4-(l,3-thiazol-2-yl)benzoyl]-L-α-glutamine, N-(l,l-dimethyl-2- ρhenylethyl)-N²-[4-(l,3-thiazol-2-yl)benzoyl]-L-α-glutamine, N-(l,l-dimethyl-2- phenylethyl)-N²-(5-phenyl-2-furoyl)-L-α-glutamine, N-(I₅I -dimethyl-2-phenylethyl)-N²- [4-(5-formyl-2-thienyl)benzoyl]-L-α-glutamine, N²-[4-(5-acetyl-2-thienyl)benzoyl]-N-

(l,l-dimethyl-2-phenylethyl)-L-α-glutamine, N- [2-(4-chlorophenyl)~ 1,1 -dimethylethyl] - iV²-[3-(5-chloro-2-thienyl)benzoyl]-L-α-glutamine, N-[2-(4-chloroρhenyl)-l,l- dimethylethyl]-iV²-[3-(2-thienyl)benzoyl]-L-α-glutainine,

N~[2-(4-chlorophenyl)- 1 , 1 -dimethylethyl] -N²- { [5-(4-chlorophenyl)-2-thienyl]carbonyl } - L-α-glutamine, iV-[2-(4-chlorophenyl)-l,l-dimethylethyl]-Λ/²-{[5-(4-fluorophenyl)-2- thienyl]carbonyl}-L-α-glutamine, iV²-[4-(5-bromo-2-thienyl)benzoyl]-iV-[2-(4- chlorophenyl)-l,l-dimethylethyl]-L-α-glutamine, iV²-[4-(5-bronio-2-thienyl)benzoyl]-N- (l,l-dimethyl-2-phenylethyl)-L-α-glutamine, iV-(l,l-dimethyl-2-phenylethyl)-N²-{[5-(4- fluorophenyl)-2-thienyl]carbonyl } -L-α-glutamine, N²-[3-(5-chloro-2-thienyl)benzoyl]-N- (1,1 -dimethyl-2-phenylethyl)-L-α-glutamine, N-(I₅I -dimethyl-2-phenylethyl)-N²- [3-(2- thienyl)benzoyl] -L-α-glutamine, N²- [(3 '-chlorobiphenyl-4-yl)carbonyl] -N- [2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N²-[(4'-chlorobiphenyl-4-yl)carbonyl] - N-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-α-glutamine, N²-[(4'-fluorobiphenyl-4- yl)carbonyl]-N-[2-(4-fluorophenyl)-l,l-diniethylethyl]-L-α-glutamine, N²-[(3'- fluorobiphenyl-4-yl)carbonyl] -N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-[(3-phenyl-2-thienyl)carbonyl]-L-α- glutamine, N²- [(4'-chlorobiphenyl-4-yl)carbonyl] -N- [2-(4-chlorophenyl)- 1,1- dimethylethyl] -L-α-glutamine, N²- [(3 '-chlorobiphenyl-4-yl)carbonyl] -N- [2-(4- chlorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N-[2-(4-fluorophenyl)-l , 1- dimethylethyl]-N²-{ [5-(4-fluorophenyl)-2-thienyl]carbonyl} -L-α-glutamine, N²-{ [5-(4- chlorophenyl)-2-thienyl]carbonyl } -N-(1 , 1 -dimethyl-2-phenylethyl)-L-α-glutamine, N- (l,l-dimethyl-2-phenylethyl)-N²-[(3-phenyl-2-thienyl)carbonyl]-L-α-glutamine, N²-(4- bromobenzoyl)-N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, N-(I₉I- dimethyl-2-phenylethyl)-N²- [(4'-fluorobiphenyl-4-yl)carbonyl] -L-α-glutamine, N-( 1 , 1 - dimethyl-2-phenylethyl)-N²-[(3'-fluorobiphenyl-4-yl)carbonyl]-L-α-glutamine, N²-[4-(5- chloro-2-thienyl)benzoyl] -N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -D-α-glutamine, N²- {[6-(5-chloro-2-thienyl)pyridin-3-yl]carbonyl}-N-[2-(4-fluorophenyl)-l,l-dimethylethyl]- L-α-glutamine, N²- { [5-(4-chlorophenyl)-2-thienyl]carbonyl } -N-[2-(4-fluorophenyl)- 1 , 1 - dimethylethyl] -L-α-glutamine, N²-{[5-(3,4-difluorophenyl)-2-thienyl]carbonyl}-N-[2-(4- fluorophenyl)-l,l-dimethylethyl]-L-α-glutamine, N²-[(4'-{ [3,5- bis(trifluoromethyl)phenoxy]methyl}biphenyl-4-yl)carbonyl]-N-(l,l-dimethyl-2- phenylethyl)-L-α-glutamine, N²-({4'-[(l,3-benzodioxol-5-yloxy)methyl]biphenyl-4- ylJcarbony^-N-ClJ-diniethyl-l-phenylethy^-L-α-glutamine^^itS'- (benzyloxy)biphenyl-4-yl]carbonyl}-N-(3,4,5-trimethoxybenzyl)-L-a-glutamine, N²-({3'- [(3,5-dimethoxybenzyl)oxy]biphenyl-4-yl}carbonyl)-iV-(3,4,5-trimethoxybenzyl)-L-α- glutamine, N²-( { 3 '- [(3-methoxybenzyl)oxy]biphenyl-4-yl } carbonyl)-iV-(3 ,4,5- trimethoxybenzyl)-L-α-glutamine, N²-({4'-[(3,5-dimethoxybenzyl)oxy]biphenyl-4- yl } carbonyl)-N- [2-(4-fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutamine, iV-benzyl-iV²- { [4^T- (biphenyl-3 -ylmethoxy)biphenyl-4-yl] carbonyl } -L-α-glutamine, N-benzyl-N²-({4'-[(3'-methoxybiphenyl-3-yl)methoxy]biρhenyl-4-yl}carbonyl)-L-α- glutamine, N²-( { 4'- [(3 ,5-dimethoxyphenoxy)methyl]biphenyl-4-yl } carbonyl)-iV-(3 - methylbenzyl)-L-α-glutamine, iV²-({3'-[(3,5-diinethoxyphenoxy)methyl]biphenyl-4- yl}carbonyl)-N-(3-methylbenzyl)-L-α-glutamine, N²-[(3'-{ [3,5- bisCtrifluoromethy^phenoxyjmethyllbiphenyl^-y^carbonylJ-N-CS-methylbenzy^-L-α- glutamine, N²-({3'-[(3-ethylphenoxy)methyl]biphenyl-4-yl}carbonyl)-iV-(3- methylbenzyl)-L-α-glutamine, N-benzyl-N²- { [4'-(biphenyl-2-ylmethoxy)biphenyl-4- yl]carbonyl} -L-α-glutamine, orN-benzyl-N²-({4'-[(3'-methoxybiphenyl-2- yl)methoxy]biphenyl-4-yl } carbonyl)-L-α-glutamine.

Methods for Making the Compounds and Pharmaceutically Acceptable Salts of Compounds of the Invention

[0105] The compounds and pharmaceutically acceptable salts of compounds of the present invention can be prepared using a variety of methods starting from commercially available compounds, known compounds, or compounds prepared by known methods. General synthetic routes to many of the compounds of the invention are included in the following schemes. It is understood by those skilled in the art that protection and deprotection steps not shown in the Schemes may be required for these syntheses, and that the order of steps may be changed to accommodate functionality in the target molecule.

[0106] As used in the schemes, PG₁ is an amine protecting group; PG₂ is a carboxylic acid protecting group; and R₁, R₂, R₆, R₁₂, R₁₃, R₁₄, and R₁₅ are defined as above. General synthetic schemes for preparation of compounds

<img file="EP1902014A2_D0030.tif" />

R₁₄NH₂/CH₃CN

<img file="EP1902014A2_D0031.tif" />

[0107] The amide formation between a carboxylic acid and an amine is carried out using a coupling reagent in a solvent such as DMF. Coupling reagents that may be used include benzotriazole- 1 -yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (Bop reagent), benzotriazole- 1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBop reagent), O-benzotriazole-N,N,N',N'-tetramethyl-uronium- hexafluoro-phosphate (HBTU), l-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDC), and other known or commercially available coupling reagents. [0108] Cross coupling is generally referred to as Suzuki or Stille coupling reactions.

[0109] The amine protecting group is cleaved under mild conditions with an amine base to afford the free amine. A variety of amine bases may be used, including for example, diethylamine, piperidine, morpholine, dicyclohexylamine, p- dimethylaminopyridine, or diisopropylethylamine in a solvent, such as acetonitrile or DMF.

[0110] Hydrolysis of the carboxylic acid protecting group is carried out using

TFA, NaOH, LiOH, potassium carbonate, or the like. [0111] Scheme 1 demonstrates the preparation of compounds of the invention in two steps from N-(4-aminobenzoyl)-L-glutarnic diethyl ester (1). Heating an aryl or heteroaryl chloride such as chloropyridine with N-(4-aminobenzoyl)-L-glutamic diethyl ester gave the diethyl ester (2), which was hydrolyzed with bases such as NaOH, LiOH, or the like to provide (3).

<img file="EP1902014A2_D0032.tif" />

[0112] Scheme 2 provides the preparation of a compound of the invention in two steps from biphenylcarboxylic acid (4). Amide formation was carried out using a coupling reagent, such as EDC. Hydrolysis of the diethyl ester (S) under basic conditions gave the final product dicarboxylic acid (d).

Scheme 2

<img file="EP1902014A2_D0033.tif" />

[0113] Scheme 3 provides the preparation of compounds of the invention in two steps. Coupling of the amine and carboxylic acid (T) was carried out using a coupling reagent such as EDC. The tert-butyl protecting group on (8) was hydrolyzed in acidic conditions (TFA in dichloromethane) to provide the product (9).

Scheme 3 <img file="EP1902014A2_D0034.tif" />

[0114] Scheme 4 demonstrates the synthesis of a compound or pharmaceutically acceptable salt of a compound of the Formula (H). As shown in Scheme 4, a compound of the Formula (HI) is treated with an amine under conditions effective to provide a compound of the Formula (IV). Hydrolysis of the alkyl ester provides a compound of the Formula (H).

Scheme 4

<img file="EP1902014A2_D0035.tif" />

(III) (IV) (»)

[0115] Scheme 5 provides the synthesis of compounds of the Formula (II) following the general procedures set forth in Scheme 4. Coupling of commercially available amines, amines known in the literature, or other amines with biphenylcarboxylic acid (4, or fluorencarboxylic acids or other carboxylic acids) can be carried out in EDC, PyBop/DIEA, or other coupling reagents as described above in the general scheme. Hydrolysis of the tert-butyl ester (W) was carried out using TFA. The second coupling reaction of the carboxylic acid Ql) with a variety of amines was carried out using a similar procedure as employed in the first step. Finally, the methyl ester (12) was hydrolyzed with NaOH/MeOH in THF to provide (13). Scheme 5

<img file="EP1902014A2_D0036.tif" />

10 11

R₁₄NH₂ EDC or PyBop, DIEA

<img file="EP1902014A2_D0037.tif" />

13 12

[0116] Scheme 6 demonstrates the synthesis of a compound or pharmaceutically acceptable salt of a compound of the Formula (H). As shown in Scheme 6, a compound of the Formula (V) is treated with an amine under conditions effective to provide a compound of the Formula (VI). Hydrolysis of the amine protecting group provides a compound of the Formula (VII), which is coupled with a carboxylic acid under conditions effective to provide a compound of the Formula (VIH). Hydrolysis of the protected carboxylic acid provides a compound of the Formula (II).

Scheme 6

<img file="EP1902014A2_D0038.tif" />

(VIII) (VII)

<img file="EP1902014A2_D0039.tif" />

(II)

[0117] Scheme 7 provides the synthesis of compounds of the Formula (II) following the general procedures set forth in Scheme 6. In scheme 7, Fmoc-glu(Obut)OH (14) was reacted with a known or or commercially available primary or secondary amine. Hydrolysis of the Fmoc protecting group of (15) was carried out with diethylamine in acetonitrile. The amine (16) was then coupled with a carboxylic acid (e.g. 4- biphenylcarboxylic acid or fluorencarboxylic acid) and the resulting tert-butyl ester (17) was hydrolyzed using TFA in dichloromethane to provide (18). Scheme 7

<img file="EP1902014A2_D0040.tif" />

18 17

[0118] Scheme 8 demonstrates the preparation of compounds of the invention similar to the procedure described in scheme 7. Bromo or iodophenethylamine (or bromo or iodo benzylamine) was coupled with the Fmoc protected amino acid (14). Removal of the Fmoc protecting group of (19) was carried out in base and the resulting compound (20) was reacted with 4-biphenylcarboxylic acid (or fluorencarboxylic acid or other carboxylic acid). Cross-coupling of the bromo or iodo intermediate (21) with a boronic ester or stannyl reagent (via Suzuki or Stille method) gave the coupling product t-butyl ester (22), which was then hydrolyzed to give the final carboxylic acid product (23).

Scheme 8

<img file="EP1902014A2_D0041.tif" />

20

14 1£&gt; acid

<img file="EP1902014A2_D0042.tif" /> 23

[0119] Scheme 9 demonstrates the preparation of compounds of the invention in three steps from bromo compounds. Cross coupling of (25) with either a boronic ester or a stannyl compound using either Suzuki or Stille coupling gave the tert-butyl ester (26), which was then hydrolyzed to the carboxylic acid (27).

Scheme 9

K₂CO₃, <img file="EP1902014A2_D0043.tif" />

<img file="EP1902014A2_D0044.tif" />

27 26

[0120] Scheme 10 provides compounds of the invention prepared in three or four steps from bromo compounds. Suzuki coupling of (25) with the 4-hydroxyphenylboronic acid gave the intermediate (28). Path A: Alkylation of the phenolic compound with an alkylhalide or benzyl halide provided (29), followed by acid hydrolysis to give the carboxylic acid (30). Path B: The brominated compound (31) was treated with an alcohol to give (32), followed by acid hydrolysis to give the carboxylic acid (33). Path C: The intermediate (28) was treated a bromobenzylbromide compound to provide (52), followed by treatment with phenylboronic acid to provide (53), which was then acid hydrolized to give (54).

Scheme 10

<img file="EP1902014A2_D0045.tif" />

[0121] Scheme 11 provides compounds of the invention prepared in a similar manner described in scheme 10, except 5-bromofuroic acid was used in the first coupling reaction step. The bromo intermediate (34) was then reacted with a boronic acid and hydrolysis of the resulting tert-butyl ester (35) in acid provided the carboxylic acid (36).

Scheme 11

<img file="EP1902014A2_D0046.tif" />

34 24

R₁₃-B(OH)₂

Pd(PPhg)₄, K₂CO₃, DME

<img file="EP1902014A2_D0047.tif" />

35

[0122] Scheme 12 provides compounds of the invention prepared according to the procedure described in scheme 11, except 6-bromonicotinic acid was used to couple with the amino intermediate (37) to afford (38).

Scheme 12

<img file="EP1902014A2_D0048.tif" />

37 38

[0123] Scheme 13 provides compounds of the invention prepared according to the procedure described in scheme 10, except 4-(4,4,5,5)-tetramethyl-l,3,2-dioxoborolan-2- yl)aniline was used in the Suzuki coupling reaction with (25). The amino intermediate (39) was then acylated with an acid chloride and the tert-butyl ester (40) was hydrolyzed in acidic conditions to give the desired carboxylic acid (41).

Scheme 13

<img file="EP1902014A2_D0049.tif" />

39

R₇COCI Proton Sponge

<img file="EP1902014A2_D0050.tif" />

[0124] Scheme 14 demonstrates the preparation of compounds of the invention in four steps. The L-glutamic acid α-tert-butyl ester γ-ethyl ester was reacted with 4- biphenylcarboxylic acid (4, or other carboxylic acid) using EDC, PyBop, Bop, or other coupling agent. Hydrolysis of the alpha tert-butyl ester (42) in trifluoroacetic acid gave the alpha carboxylic acid intermediate (43) in good yield. Treatment of the acid with a base (e.g. triethylamine) and ethyl chloroformate followed by sodium borohydride gave the corresponding alcohol (44). The ethyl ester was then hydrolyzed in basic conditions to give the final product (45). Scheme 14

<img file="EP1902014A2_D0051.tif" />

42 43

c .r,Λ NaBH₄ OH

<img file="EP1902014A2_D0052.tif" />

45 44

[0125] Scheme 15 provides compounds of the invention prepared in four steps from bromobenzoic acid. L-glutamic acid di-tert butyl ester was coupled with the bromobenzoic acid (46). Suzuki coupling of the bromo compound (47) with 4-(4,4,5,5)~ tetramethyl-l,3,2-dioxoborolan-2-yl)aniline gave the amino intermediate (48) in good yield. Acylation of the amine with an acid chloride gave the acylated product (49), and hydrolysis of the tert-butyl ester in acidic conditions gave the final dicarboxylic acid (50).

Scheme 15

<img file="EP1902014A2_D0053.tif" />

R₇COOH EDCI

<img file="EP1902014A2_D0054.tif" />

50 49 [0126] Scheme 16 provides compounds of the invention prepared in a single step from a carboxylic acid. A carboxylic acid of the invention (17) is reacted with Bop, hydroxylamine hydrochloride, and DIEA to afford the hydroxamic acid (51).

Scheme 16

<img file="EP1902014A2_D0055.tif" />

17 51

[0127] One of skill in the art will recognize that Schemes 1-16 can be adapted to produce other compounds and pharmaceutically acceptable salts of compounds according to the present invention.

Therapeutic Administration

[0128] When administered to an animal, the compounds or pharmaceutically acceptable salts of the compounds of the invention can be administered neat or as a component of a composition that comprises a physiologically acceptable carrier or vehicle. A composition of the invention can be prepared using a method comprising admixing the compound or a pharmaceutically acceptable salt of the compound and a physiologically acceptable carrier, excipient, or diluent. Admixing can be accomplished using methods well known for admixing a compound or a pharmaceutically acceptable salt of the compound and a physiologically acceptable carrier, excipient, or diluent. [0129] The present compositions, comprising compounds or pharmaceutically acceptable salts of the compounds of the invention can be administered orally. The compounds or pharmaceutically acceptable salts of compounds of the invention can also be administered by any other convenient route, for example, by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral, rectal, vaginal, and intestinal mucosa, etc.) and can be administered together with another therapeutic agent. Administration can be systemic or local. Various known delivery systems, including encapsulation in liposomes, microparticles, microcapsules, and capsules, can be used.

[0130] Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topical, particularly to the ears, nose, eyes, or skin. In some instances, administration will result of release of the compound or a pharmaceutically acceptable salt of the compound into the bloodstream. The mode of administration is left to the discretion of the practitioner. [0131] In one embodiment, the compound or a pharmaceutically acceptable salt of the compound is administered orally.

[0132] In another embodiment, the compound or a pharmaceutically acceptable salt of the compound is administered intravenously.

[0133] In another embodiment, it may be desirable to administer the compound or a pharmaceutically acceptable salt of the compound locally. This can be achieved, for example, by local infusion during surgery, topical application, e.g., in conjunction with a wound dressing after surgery, by injection, by means of a catheter, by means of a suppository or edema, or by means of an implant, said implant being of a porous, non- porous, or gelatinous material, including membranes, such as sialastic membranes, or fibers.

[0134] In certain embodiments, it can be desirable to introduce the compound or a pharmaceutically acceptable salt of the compound into the central nervous system, circulatory system or gastrointestinal tract by any suitable route, including intraventricular, intrathecal injection, paraspinal injection, epidural injection, enema, and by injection adjacent to the peripheral nerve. Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.

[0135] Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant. In certain embodiments, the compound or a pharmaceutically acceptable salt of the compound can be formulated as a suppository, with traditional binders and excipients such as triglycerides. [0136] In another embodiment, the compound or a pharmaceutically acceptable salt of the compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 1990, 249, 1527-1533 and Treat et al., Liposomes in the Therapy of Infectious Disease and Cancer 1989, 317-327 and 353-365.

[0137] In yet another embodiment, the compound or a pharmaceutically acceptable salt of the compound can be delivered in a controlled-release system or sustained-release system {see, e.g., Goodson, in Medical Applications of Controlled Release 1984, vol. 2, 115-138). Other controlled or sustained-release systems discussed in the review by Langer, Science 1990, 249, 1527-1533 can be used. In one embodiment, a pump can be used (Langer, Science 1990, 249, 1527-1533; Sefton, CRC Crit. Ref. Biomed. Eng. 1987, 14, 201; Buchwald et al., Surgery 1980, 88, 507; and Saudek et al., N. Engl. J Med. 1989, 321, 574). In another embodiment, polymeric materials can be used (see Medical Applications of Controlled Release (Langer and Wise, eds., 1974); Controlled Drug Bioavailability, Drug Product Design and Performance (Smolen and Ball, eds., 1984); Ranger and Peppas, J. Macromol. ScL Rev. Macromol. Chem. 1983, 2, 61; Levy et al., Science 1935, 228, 190; During et al., Ann. Neural. 1989, 25, 351; and Howard et al., /. Neurosurg. 1989, 71, 105).

[0138] In yet another embodiment, a controlled- or sustained-release system can be placed in proximity of a target of the compound or a pharmaceutically acceptable salt of the compound, e.g., the reproductive organs, thus requiring only a fraction of the systemic dose.

[0139] The present compositions can optionally comprise a suitable amount of a physiologically acceptable excipient.

[0140] Such physiologically acceptable excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The physiologically acceptable excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In addition, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used. In one embodiment the physiologically acceptable excipients are sterile when administered to an animal. The physiologically acceptable excipient should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microorganisms. Water is a particularly useful excipient when the compound or a pharmaceutically acceptable salt of the compound is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable physiologically acceptable excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The present compositions, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents. [0141] Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups, and elixirs. The compound or pharmaceutically acceptable salt of the compound of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both, or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives including solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particular containing additives as above, e.g., cellulose derivatives, including sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant. [0142] The present compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained- release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the composition is in the form of a capsule. Other examples of suitable physiologically acceptable excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro, ed., 19th ed. 1995). [0143] In one embodiment, the compound or a pharmaceutically acceptable salt of the compound is formulated in accordance with routine procedures as a composition adapted for oral administration to humans. Compositions for oral delivery can be in the form of tablets, lozenges, buccal forms, troches, aqueous or oily suspensions or solutions, granules, powders, emulsions, capsules, syrups, or elixirs for example. Orally administered compositions can contain one or more agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation. In powders, the carrier can be a finely divided solid, which is an admixture with the finely divided compound or pharmaceutically acceptable salt of the compound. In tablets, the compound or pharmaceutically acceptable salt of the compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to about 99% of the compound or pharmaceutically acceptable salt of the compound.

[0144] Capsules may contain mixtures of the compounds or pharmaceutically acceptable salts of the compounds with inert fillers and/or diluents such as pharmaceutically acceptable starches {e.g., corn, potato, or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (such as crystalline and microcrystalline celluloses), flours, gelatins, gums, etc.

[0145] Tablet formulations can be made by conventional compression, wet granulation, or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents (including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrroldine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, and ion exchange resins. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminum silicate, and triethanolamine.

[0146] Moreover, when in a tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding an osmotically active driving compound or a pharmaceutically acceptable salt of the compound are also suitable for orally administered compositions. In these latter platforms, fluid from the environment surrounding the capsule can be imbibed by the driving compound, which swells to displace the agent or agent composition through an aperture. These delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations. A time-delay material such as glycerol monostearate or glycerol stearate can also be used. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment the excipients are of pharmaceutical grade.

[0147] In another embodiment, the compound or a pharmaceutically acceptable salt of the compound can be formulated for intravenous administration. Typically, compositions for intravenous administration comprise sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for intravenous administration can optionally include a local anesthetic such as lignocaine to lessen pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container such as an ampule or sachette indicating the quantity of active agent. Where the compound or a pharmaceutically acceptable salt of the compound is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the compound or a pharmaceutically acceptable salt of the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. [0148] In another embodiment, the compound or pharmaceutically acceptable salt of the compound can be administered transdermally thorugh the use of a transdermal patch. Transdermal administrations include administrations across the surface of the body and the inner linings of the bodily passages including epithelial and mucosal tissues. Such administrations can be carried out using the present compounds or pharmaceutically acceptable salts of the compounds, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (e.g., rectal or vaginal).

[0149] Transdermal administration can be accomplished through the use of a transdermal patch containing the compound or pharmaceutically acceptable salt of the compound and a carrier that is inert to the compound or pharmaceutically acceptable salt of the compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams or ointments, pastes, gels, or occlusive devices. The creams or ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the compound or pharmaceutically acceptable salt of the compound into the blood stream, such as a semi-permeable membrane covering a reservoir containing the compound or pharmaceutically acceptable salt of the compound with or without a carrier, or a matrix containing the active ingredient. [0150] The compounds or pharmaceutically acceptable salts of the compounds of the invention may be administered rectally or vaginally in the form of a conventional suppository. Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water-soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.

[0151] The compound or a pharmaceutically acceptable salt of the compound can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art. Such dosage forms can be used to provide controlled- or sustained-release of one or more active ingredients using, for example, hydropropylmethyl cellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with the active ingredients of the invention. The invention thus encompasses single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release. [0152] In one embodiment a controlled- or sustained-release composition comprises a minimal amount of the compound or a pharmaceutically acceptable salt of the compound to treat or prevent a metalloproteinase-related disorder in a minimal amount of time. Advantages of controlled- or sustained-release compositions include extended activity of the drug, reduced dosage frequency, and increased compliance by the animal being treated. In addition, controlled- or sustained-release compositions can favorably affect the time of onset of action or other characteristics, such as blood levels of the compound or a pharmaceutically acceptable salt of the compound, and can thus reduce the occurrence of adverse side effects.

[0153] Controlled- or sustained-release compositions can initially release an amount of the compound or a pharmaceutically acceptable salt of the compound that promptly produces the desired therapeutic or prophylactic effect, and gradually and continually release other amounts of the compound or a pharmaceutically acceptable salt of the compound to maintain this level of therapeutic or prophylactic effect over an extended period of time. To maintain a constant level of the compound or a pharmaceutically acceptable salt of the compound in the body, the compound or a pharmaceutically acceptable salt of the compound can be released from the dosage form at a rate that will replace the amount of the compound or a pharmaceutically acceptable salt of the compound being metabolized and excreted from the body. Controlled- or sustained-release of an active ingredient can be stimulated by various conditions, including but not limited to, changes in pH, changes in temperature, concentration or availability of enzymes, concentration or availability of water, or other physiological conditions or compounds.

[0154] In certain embodiments, the present invention is directed to prodrugs of the compounds or pharmaceutically acceptable salts of compounds of the present invention. Various forms of prodrugs are known in the art, for example as discussed in Bundgaard, ed., Design of Prodrugs, Elsevier (1985); Widder et al., ed., Methods in Enzymology, vol. 4, Academic Press (1985); Kgrogsgaard-Larsen et al., ed., "Design and Application of Prodrugs", Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard et al., Journal of Drug Delivery Reviews 1992, 8, 1-38; Bundgaard et al., J. Pharmaceutical Sciences 1988, 77, 285 et seq.; and Higuchi and Stella, eds., Prodrugs as Drug Delivery Systems, American Chemical Society (1975).

[0155] The amount of the compound or a pharmaceutically acceptable salt of the compound is an amount that is effective for treating or preventing a metalloproteinase- related disorder. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed can also depend on the route of administration, the condition, the seriousness of the condition being treated, as well as various physical factors related to the individual being treated, and can be decided according to the judgment of a health-care practitioner. Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, and about every two months. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner. The effective dosage amounts described herein refer to total amounts administered; that is, if more than one compound or a pharmaceutically acceptable salt of the compound is administered, the effective dosage amounts correspond to the total amount administered. [0156] The amount of the compound or a pharmaceutically acceptable salt of the compound that is effective for treating or preventing a metalloproteinase-related disorder will typically range from about 0.001 mg/kg to about 250 mg/kg of body weight per day, in one embodiment, from about 1 mg/kg to about 250 mg/kg body weight per day, in another embodiment, from about 1 mg/kg to about 50 mg/kg body weight per day, and in another embodiment, from about 1 mg/kg to about 20 mg/kg of body weight per day. [0157] In one embodiment, the pharmaceutical composition is in unit dosage form, e.g., as a tablet, capsule, powder, solution, suspension, emulsion, granule, or suppository. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage form can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such unit dosage form may contain from about 1 mg/kg to about 250 mg/kg, and may be given in a single dose or in two or more divided doses.

[0158] The compound or a pharmaceutically acceptable salt of the compound can be assayed in vitro or in vivo for the desired therapeutic or prophylactic activity prior to use in humans. Animal model systems can be used to demonstrate safety and efficacy. [0159] Thus, in one embodiment, the invention provides a composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of the present invention and a pharmaceutically acceptable carrier. [0160] In another embodiment, the pharmaceutically acceptable carrier is suitable for oral administration and the composition comprises an oral dosage form.

Therapeutic or Prophylactic Uses

[0161] In one embodiment, the compounds or pharmaceutically acceptable salts of the compounds of the present invention are useful as metalloproteinase modulators.

Accordingly, the compounds and pharmaceutically acceptable salts of the compounds of the present invention are useful for treating an animal with a metalloproteinase-related disorder.

[0162] In one embodiment, the invention provides a method for treating a metalloproteinase-related disorder, comprising administering to an animal in need thereof a compound or a pharmaceutically acceptable salt of the compound of Formula (I) or

Formula (II) in an amount effective to treat a metalloproteinase-related disorder. In another embodiment, the compound or pharmaceutically acceptable salt of the compound is of the Formula (Ia), (Ib), (Ic), or (Id).

[0163] In one embodiment, the metalloproteinase is a matrix metalloproteinase or an aggrecanase.

[0164] In another embodiment, the aggrecanase is aggrecanase- 1 or aggrecanase-

2.

[0165] In one embodiment, the metalloproteinase-related disorder is selected from the group consisting of arthritic disorders, osteoarthritis, cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.

[0166] In another embodiment, the metalloproteinase-related disorder is osteoarthritis.

[0167] In one embodiment, the present invention is directed to a method for modulating the activity of a metalloproteinase in an animal in need thereof, comprising contacting the metalloproteinase with an effective amount of a compound or pharmaceutically acceptable salt of the compound of Formula (I) or Formula (II). In one embodiment, the method further comprises determining the activity of the metalloproteinase. In one embodiment, the step of determining the activity of the metalloproteinase is performed before the step of contacting the metalloproteinase with the compound or a pharmaceutically acceptable salt of the compound. In another embodiment, the step of determining the activity of the metalloproteinase is performed after the step of contacting the metalloproteinase with the compound or a pharmaceutically acceptable salt of the compound. In another embodiment, the compound or pharmaceutically acceptable salt of the compound is of the Formula (Ia),

(Ib), (Ic), or (Id).

[0168] The compounds and pharmaceutically acceptable salts of the compounds of Formula (I) or Formula (II) are also useful in the manufacture of medicaments for treating a metalloproteinase-related disorder in an animal. In another embodiment, the compound or pharmaceutically acceptable salt of the compound is of the Formula (Ia),

(Ib), (Ic), or (Id).

[0169] Accordingly, in one embodiment, the invention provides the use of a compound or pharmaceutically acceptable salt of the compound of Formula (I) or

Formula (II) for the manufacture of a medicament for treating a metalloproteinase-related disorder. In another embodiment, the compound or pharmaceutically acceptable salt of the compound is of the Formula (Ia), (Ib), (Ic), or (Id).

[0170] In one embodiment, the metalloproteinase is a matrix metalloproteinase or an aggrecanase. [0171] In another embodiment, the aggrecanase is aggrecanase-1 or aggrecanase-

2.

[0172] In one embodiment, the metalloproteinase-related disorder is selected from the group consisting of arthritic disorders, osteoarthritis, cancer, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, atherosclerosis, age-related macular degeneration, myocardial infarction, corneal ulceration and other ocular surface diseases, hepatitis, aortic aneurysms, tendonitis, central nervous system diseases, abnormal wound healing, angiogenesis, restenosis, cirrhosis, multiple sclerosis, glomerulonephritis, graft versus host disease, diabetes, inflammatory bowel disease, shock, invertebral disc degeneration, stroke, osteopenia, and periodontal diseases.

[0173] In another embodiment, the metalloproteinase-related disorder is osteoarthritis.

[0174] In one embodiment, the present invention is directed to the use of a compound or pharmaceutically acceptable salt of the compound of Formula (I) or

Formula (II) for the manufacture of a medicament for modulating the activity of a metalloproteinase. In one embodiment, the medicament is also for determining the activity of the receptor. In another embodiment, the compound or pharmaceutically acceptable salt of the compound is of the Formula (Ia), (Ib), (Ic), or (Id).

Examples

<img file="EP1902014A2_D0056.tif" />

3

Example 1; iV-[4-(pyrimidin-2-ylamino)benzoyll-L-glutamic acid

<img file="EP1902014A2_D0057.tif" />

[0175] Step A: 2-[4-(pyrimidin-2-ylamino)-benzoylamino]-pentanedioic acid diethyl ester 2-Chloropyrimidine (0.72 g, 6.3 mmol) and N-(4-aminobenzoyl)-L-glutamic acid diethyl ester (2.04 g, 6.3 mmol, 1 equiv.) were dissolved in DMF (4 mL) and the resulting mixture was heated to 110⁰C for 3 hrs. Reaction was complete as determined by TLC. The mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO₄, and concentrated by rotavap. The residue was purified by column chromatography (silica gel, 50% EtOAc/hexane) to afford 1.75 g of desired product 2-[4-(pyrimidin-2-ylamino)- benzoylamino]-pentanedioic acid diethyl ester in 69% yield. MS (ESI) m/z 399. [0176] Step B: N-[4-(pyrimidin-2-ylamino)benzoyl]-L-glutamic acid

A solution of 2-[4-(pyrimidin-2-ylamino)-benzoylamino]-pentanedioic acid diethyl ester (250 mg, 0.62 mmol) in THF (4 mL) was added to MeOH (4 mL), followed by the addition of IN NaOH solution (5 mL, 5 mmol, 8 equiv.). The mixture was stirred at room temperature overnight. Reaction was complete as determined by HPLC. Solvents were removed by rotavap and a small amount of water (5 mL) was added to make a homogeneous solution. IN HCl was added dropwise until the solution reached a pH of 4. The solid precipitate was collected by filtration, washed with EtOAc, and dried in vacuum oven. The product N-[4-(pyrimidin-2-ylamino)benzoyl]-L-glutamic acid (120 mg) was isolated in 45% yield. MS (ESI) m/z 343.

Scheme 2

<img file="EP1902014A2_D0058.tif" />

Example 2; N-(l,l^?-biphenyl-4-ylcarbonyl)-D-glutamic acid

<img file="EP1902014A2_D0059.tif" />

[0177] Step A: 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid diethyl ester A solution of 4-biphenylcarboxylic acid (670 mg, 3.4 mmol) and (809 mg, 3.4 mmol, 1 equiv.) in dry DMF (20 mL) was added to EDCI (801 mg, 5.1 mmol, 1.5 equiv.), triethylamine (853 mg, 8.4 mmol, 2.5 equiv.) and DMAP (82 mg, 0.7 mmol, 20%). The mixture was stirred at room temperature overnight. Reaction was complete as determined by TLC. The mixture was diluted with EtOAc and washed with H₂O, brine, and dried over magnesium sulfate. Solvent was removed and the residue subject to column chromatography (silica gel, 50% EtOAc/hexane). 660 mg of desired product 2- [(Biphenyl-4-carbonyl)-amino]-pentanedioic acid diethyl ester was isolated in 51% yield. MS (ESI) m/z 382.

[0178] Step B: N-(l,l'-biphenyl-4-ylcarbonyl)-D-glutamic acid

A solution of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid diethyl ester (250 mg, 0.65 mmol) in THF (6 mL) was added to MeOH (6 mL), followed by the addition of IN NaOH solution (5.2 mL, 5.2 mmol, 8 eq.). The mixture was stirred at room temperature overnight. Reaction was complete as determined by HPLC. Solvents were removed by rotavap and a small amount of water (5 mL) was added to make a homogeneous solution. IN HCl was added dropwise until the solution reached a pH of 4. The solid precipitate was collected by filtration, washed with EtOAc, and dried in vacuum oven. Product N- (l,r-biphenyl-4-ylcarbonyl)-D-glutamic acid (189 mg) was isolated in 89% yield. MS (ESI) m/z 326.

Scheme 3

<img file="EP1902014A2_D0060.tif" />

7 8 9

Example 3: N²-r4-(pyrimidin-2-ylamino)benzovn-L-aIpha-gIutamine

[0179] Step A: 4-Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino]-butyric acid tert-butyl ester

4-(Pyrimidin-2-ylamino)-benzoic acid (1.80 g, 8.4 mmol, 1 equiv.) and EDCI (2.41 g, 12.6 mmol, 1.5 equiv.) were dissolved in DMF (60 mL) under N₂. The mixture was stirred at room temperature for 20 minutes, followed by the addition of H-GIu (OtBu)- NH₂ (2 g, 8.4 mmol, 1 equiv), Et₃N (2.92 mL, 20.9 mmol, 2.5 equiv.), and DMAP (0.512 g, 4.2 mmol, 0.5 equiv). The mixture was allowed to stir at room temperature overnight. Reaction was complete as determined by TLC. DMF was removed by rotovap and the residue was dissolved in EtOAc. The organic layer was washed with brine and dried over MgSO₄. Most of the solvent was removed by rotavap and a solid was precipitated from the mixture during solvent evaporation. The solid was collected by filtration and washed with EtOAc. 823 mg of 4-Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino] -butyric acid tert-butyl ester was obtained in 25 % yield. MS (ESI) m/z 400. [0180] Step B: N²-[4-(pyrirnidin-2-ylamino)benzoyl]-L-alpha-glutamine

4-Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino] -butyric acid tert-butyl ester was dissolved in dichloroethane (10 mL), followed by the addition of TFA (5 mL). The mixture was stirred at room temperature for 4 hrs. TLC indicated the reaction was complete. Solvents were then removed by rotavap and the residue was washed with EtOAc. A solid was collected by filtration and dried in vacuum oven overnight. 4- Carbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino] -butyric acid was obtained in quantitative yield (285 mg). MS (ESI) m/z 344.

Example 4: N²-(l.l'-biphenyl-4-yIcarbonyl)-D-alpha-glutainine

[0181] The title compound was prepared according to the procedures similar to that described for Example 3. Yield 95%, MS (ESI) m/z 327.

Scheme 5

<img file="EP1902014A2_D0061.tif" /> 13 IE Example 5; N²-(l.l^&gt;-biphenyl-4-ylcarbonyl)-N¹-(4-hvdroxybutylVL-alpha-glutamine

[0182] Step A: 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 1-tert-butyl ester 5-methyl ester

A solution of 4-diphenyl carboxylic acid (3.57 g, 18 mmol, 1.0 equiv.) in DMF (40 mL) was added to EDCI (4.28 g, 22.3 mmol, 1.24 equiv.) and stirred at room temperature for 0.5 hrs. H-GIu(OMe)Ot-Bu (5.02 g, 19.8 mmol, 1.1 equiv.) was added, followed by the addition of Et₃N (6.77 mL, 48.6 mmol, 2.7 equiv.) and DMAP (330 mg, 2.7 mmol, 15%). The mixture was stirred overnight under N₂. Reaction was complete as determined by TLC. The reaction mixture was diluted with EtOAc, washed with H₂O, then brine solution. The organic layer was separated and then dried over MgSO₄. After concentration, crude was purified by column chromatography (Silica gel, 20% EtOAc / Hexane) to afford 3.2 g of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 1-tert- butyl ester 5-methyl ester in 44.7% yield. MS (ESI) m/z 396.

[0183] Step B: 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5-methyl ester

A solution of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 1-tert-butyl ester 5- methyl ester (1.5 g, 3.8 mmol) in dichloroethane (26 mL) was added to TFA (13 mL) at room temperature. The mixture was stirred for 4 hrs. and TLC indicated the reaction was complete. Solvent was removed by rotovap. The solid thus obtained was dried under vacuum to provide 1.128 g of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5- methyl ester [G9591-161-1] in 87% yield. MS (ESI) m/z 342.

[0184] Step C: 4-[(Biphenyl-4-carbonyl)-amino]-4-(4-hydroxy-butylcarbamoyl)- butyric acid methyl ester

A solution of 2-[(Biphenyl-4-carbonyl)-amino]-pentanedioic acid 5-methyl ester (400 mg, 1.2 mmol, 1 equiv.) in DMF (10 mL) was added to EDCI (337 mg, 1.8 mmol, 1.5 equiv.). The solution was stirred at room temperature under N₂ for 40 min. 4-Amino-l-butanol (0.11 mL, 1.2 mmol, 1 equiv.) was added, followed by addition of Et₃N (0.41 mL, 2.9 mmol, 2.5 equiv.) and DMAP (72 mg, 0.59 mmol, 0.5 equiv.). The mixture was stirred overnight under N₂. The reaction mixture was then poured into cold water and a solid precipitated from the solution. The solid was collected by filtration and dried under vacuum to give 229 mg of 4-[(Biphenyl-4-carbonyl)-amino]-4-(4-hydroxy- butylcarbamoyl)-butyric acid methyl ester in 47% yield. MS (ESI) m/z 413. [0185] Step D: N²-(l,l'-biρhenyl-4-ylcarbonyl)-N¹-(4-hydroxybutyl)-L-alpha- glutamine

A solution of 4-[(Biphenyl-4-carbonyl)-amino]-4-(4-hydroxy-butylcarbamoyl)-butyric acid methyl ester (229 mg, 0.56 mmol, 1 equiv.) in THF (10 mL) and MeOH (2.8 mL) was added to IN NaOH (2.8 mL, 2.8 mmol, 5 equiv.). The solution was stirred at room temperature for 2.5 hrs. After TLC indicated the reaction was complete, the solvent was evaporated and the residue was dissolved in H₂O. After adjusting the pH of the solution to 3 using IN HCl, a solid precipitated from the solution. The solid was collected by filtration and washed with water. After drying, 120 mg of N²-(l,l'-biphenyl-4- ylcarbonyl)-N¹-(4-hydroxybutyl)-L-alpha-glutamine was isolated in 54.1% yield. MS (ESI) m/z 399.

Example 6:

[0186] The following compounds were prepared according to the procedures similar to those described in Example 5.

Example 6A; ^-(l.l'-biphenvI^-ylcarbonvD-N^l^-dihvdro-lH-inden-l-yl-L-q- glutamine

[0187] Step C: methyl N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-2,3-dihydro-lH-inden-

2-yl-L-α-glutaminate

Described as above according to the procedure in Example 5, except PyBop/DIEA (or

Bop/DffiA) was used. MS (ESI) m/z 457.2; MS (ESI) m/z 913.4; HRMS: calcd for

C₂₈H₂₈N₂O₄ + H+, 457.21218; found (ESI-FTMS, [M+H]¹⁺), 457.21403.

[0188] Step D: N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-2,3-dihydro-lH-inden-2-yl-L- α-glutamine

MS (ESI) m/z 441.2; MS (ESI) m/z 883.3; HRMS: calcd for C₂₇H₂₆N₂O₄ + H+,

443.19653; found (ESI-FTMS, [M+H]¹⁺), 443.19699.

Example 6B: N²-(biphenyl-4-ylcarbonyl)-N¹-(2-hvdroxy-l,l-dimethyIethylVL-α- glutamine

[0189] Step C: methyl N²-(biρhenyl-4-ylcarbonyl)-N¹-(2-hydroxy-l,l- dimethylethyl)-L-α-glutaminate Described as above according to the procedure in Example 5, except PyBop/DIEA (or

Bop/DIEA) was used. MS (ESI) m/z 413.1; MS (ESI) m/z 825.2; HRMS: calcd for

C₂₃H₂₈N₂O₅ + H+, 413.20710; found (ESI-FTMS, [M+H]¹⁺), 413.20705.

[0190] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(2-hydroxy-l,l-dimethylethyl)-L- α-glutamine

MS (EST) m/z 399.1; MS (ESI) m/z 797.3; HRMS: calcd for C₂₂H₂₆N₂O₅ + H+,

399.19145; found (ESI-FTMS, [M+H]¹⁺), 399.19217.

Example 6C; N²-(biphenyl-4-ylcarbonyl)-N¹-(l,1.3.3-tetramethylbutyl)-L-α- glutamine

[0191] Step C: methyl N²-(biphenyl-4-ylcarbonyl)-N¹-(l , 1 ,3,3-tetramethylbutyl)-

L-α-glutaminate

Described as above according to the procedure in Example 5, except PyBop/DIEA (or

Bop/DIEA) was used. MS (ESI) m/z 453.2; MS (ESI) m/z 905.4; HRMS: calcd for

C₂₇H₃₆N₂O₄ + H+, 453.27478; found (ESI-FTMS, [M+H]¹⁺), 453.27588.

[0192] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(l,l,3,3-tetramethylbutyl)-L-α- glutamine

MS (ESI) m/z 439.2; MS (ESI) m/z 877.4; HRMS: calcd for C₂₆H₃₄N₂O₄ + H+,

439.25913; found (ESI-FTMS, [M+H]¹⁺), 439.25974.

Example 6D: N¹-(l.l-dimethvI-2-phenylethyl)-N²-(9H-fluoren-2-ylcarbonvI)-L-α- glutamine

[0193] Step A: 1-tert-butyl 5-methyl-N-(9H-fluoren-2-ylcarbonyl)-L-glutamate

Described as above according to the procedure in Example 5, except 2-fluorenecarboxylic acid was used. MS (ESI) m/z 410.2; MS (ESI) m/z 819.4; HRMS: calcd for C₂₄H₂₇NO₅ +

Na+, 432.17814; found (ESI-FTMS, [M+Na]¹⁺), 432.17902.

[0194] Step B: (2S)-2-[(9H-fluoren-2-ylcarbonyl)amino]-5-methoxy-5- oxopentanoic acid

MS (ESI) m/z 354.1; MS (ESI) m/z 707.3; HRMS: calcd for C₂₀H₁₉NO₅ + H+,

354.13360; found (ESI-FTMS, [M+H]¹⁺), 354.13428.

[0195] Step C: methyl N¹-(l,l-dimethyl-2-phenylethyl)-N²-(9H-fluoren-2- ylcarbonyl)-L-α-glutaminate MS (ESI) m/z 485.3; MS (ESI) m/z 969.5; MS (ESI) m/z 507.3; HRMS: calcd for

C₃₀H₃₂N₂O₄+ Na+, 507.22543; found (ESI-FTMS, [M+Na]¹⁺), 507.22863.

[0196] Step D: N¹-(l,l-dimethyl-2-phenylethyl)-N²-(9H-fluoren-2-ylcarbonyl)-L- α-glutamine

MS (ESI) m/z 471.3; MS (ESI) m/z 941.5.

Example 6E; N¹-r2-(4-chIorophenvn-l.l-dimethylethvU-N²-(9H-fluoren-2- ylcarbonylVL-α-glutamine

[0197] Step A: described as above according to the procedure in Example 5, except 2-fluorenecarboxylic acid was used.

[0198] Step C: methyl N¹-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-(9H- fluoren-2-ylcarbonyl)-L-α-glutaminate

MS (ESI) m/z 519.2; MS (ESI) m/z 1037.5; HRMS: calcd for C₃₀H₃₁ClN₂O₄ + H+,

519.20451; found (ESI-FTMS, [M+H]¹⁺), 519.20406.

[0199] Step D: N¹-[2-(4-chlorophenyl)-l,l-dimethylethyl]-N²-(9H-fluoren-2- ylcarbonyl)-L-α-glutamine

MS (ESI) m/z 505.2; MS (ESI) m/z 1009.5.

Scheme 7

<img file="EP1902014A2_D0062.tif" />

18 17 Example 7: JV¹-(1.3-benzodioxoI-5-ylmethylViV²-(l,l'-biphenyl-4-ylcarbonylVL-α- glutamine

[0200] Step A: tert-bntyϊ N^l ,3-benzodioxol-5-ylmethyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

In a 50 mL round bottom flask, Fmoc-L-Glu-(OtBu)-OΗ (2.127 g, 5 mmol) was dissolved in DMF (10 mL) and stirred at room temperature under nitrogen. PyBOP (2.6 g, 5 mmol) was added to the stirring mixture followed by piperonylamine (0.755 g, 5 mmol), and DIEA (1.2 equivalent) added dropwise. The mixture was stirred overnight (18-24 hr) at room temperature under nitrogen. The reaction mixture was then poured into 150 mL of water and the solid was collected and washed with water. The wet solid was then dissolved in ethyl acetate (ca. 500 mL), and washed consecutively with 10% HCl (aq.), NaHCO₃ (satd.), and NaCl (satd.). The organic phase was dried over MgSO₄ (anh.) and concentrated. The crude product was redissolved in acetone and hexanes were added. The precipitated solid was filtered, washed with hexanes and dried in a vacuum desiccator overnight to give 1.56 g of tert-butyl N¹-(l,3-benzodioxol-5-ylmethyl)-N²-[(9H-fluoren- 9-ylmethoxy)carbonyl]-L-α-glutaminate as fine white solid. MS (ESI) m/z 559.1; ΗRMS: calcd for C₃₂H₃₄N₂O₇ + H+, 559.24388; found (ESI_FT, [M+H]¹⁺), 559.24348. [0201] Step B: tert-butyl N¹ -(I ,3-benzodioxol-5-ylmethyl)-L-α-glutaminate

The Fmoc-ester product (1.5 g, 2.7 mmol) was (partially) dissolved in acetonitrile (17 mL) and stirred at room temperature under nitrogen. The mixture was fully dissolved about 30 min after addition of diethylamine (4.2 mL) and was stirred for two hours. After reaction completion, the mixture is carefully concentrated (&lt;30°C) under reduced pressure by rotary evaporator. The crude product (clear oil) was then filtered through a short flash column. The column was gradient eluted starting with 5% Acetone/CH₂Cl₂ until the Fmoc byproduct was removed and ramped to 50% Acetone/CH₂C1₂ while the product eluted. The desired fractions were collected and concentrated giving 0.8 g clear oil. MS (ESI) m/z 337.1; HRMS: calcd for C₁₇H₂₄N₂O₅ + H+, 337.17580; found (ESI_FT, [M+H]¹⁺), 337.17605.

[0202] Step C: tert-butyl N^x-(1 ,3-benzodioxol-5-ylmethyl)-iV²-(l , 1 '-biphenyl-4- ylcarbonyl)-L-α-glutaminate The free amine (0.36 g, 1.07 mmol) was dissolved in DMF (5 mL) and stirred at rt under nitrogen. 4-Biphenyl carboxylic acid (0.557 g, 1.07 mtnol) was added followed by PyBOP reagent (0.21 g, 1.07 mmol) with vigorous stirring. The reaction mixture was cooled to 0°C and DIEA (1.2 equiv.) was added dropwise. The reaction was complete in 14-24 hours. The reaction mixture was then poured into 100 mL water and the solid collected. The solid was redissolved in ethyl acetate and washed with 10% HCl (aq.), NaHCO₃ (satd.), and NaCl (satd.). The organic phase was dried over Na₂SO₄ (anh.) and concentrated. Acetone was added to the residue and diluted with hexanes. The precipitate was collected and dried in a vacuum desiccator overnight to give 0.4 g of desired product. MS (ESI) m/z 517.2; HRMS: calcd for C₃₀H₃₂N₂O₆ + H+, 517.23331; found (ESI_FT, [M+H]¹⁺), 517.23311.

[0203] Step D: iV¹-(l,3-benzodioxol-5-ylmethyl)-iV²-(l,l'-biphenyl-4-ylcarbonyl)-

L-α-glutamine

The t-butyl ester (0.31 g, 0.6 mmol) was dissolved in CH₂Cl₂ (4 mL) and stirred at rt under nitrogen. Trifluoroacetic acid (4 mL) dissolved in CH₂Cl₂ (4 mL) is added to the solution and the light yellow solution is stirred at rt for 2 hours. The mixture is evaporated and diluted toluene (10 mL), evaporated to fully remove the TFA. A solid is obtained and dissolved in minimum acetone (ca. 25-50 mL) warmed slightly and hexanes added. The white solid was collected and dried in a vacuum desiccator to yield 0.214 g product. MS (ESI) m/z 461.1; HRMS: calcd for C₂₆H₂₄N₂O₆ + H+, 461.17071; found (ESI_FT, [M+H]¹⁺), 461.1704.

Example 8;

[0204] The following compounds were prepared according to the procedures similar to those of Example 7.

Example SAt ^-dΛ'-biphenyl^-ylcarbonvD-^-cyclohexyI-L-α-glutamine

[0205] Step A: tert-butyl N¹-cyclohexyl-iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 507.2; ΗRMS: calcd for C₃₀H₃₈N₂O₅ + H+, 507.28535; found (ESI_FT,

PVM-H]¹⁺), 507.28583.

[0206] Step B: tert-butyl N^cyclohexyl-L-α-glutaminate

MS (ESI) m/z 285.2; HRMS: calcd for C₁₅H₂₈N₂O₃ + H+, 285.21727; found (ESI_FT, [MH-H]¹⁺), 285.21644.

[0207] Step C: tert-butyl iV²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-cyclohexyl-L-α- glutaminate

MS (ESI) m/z 465.2; HRMS: calcd for C₂₈H₃₆N₂O₄ + H+, 465.27478; found (ESI_FT,

[M+H]¹⁺), 465.27386.

[0208] Step D: N²-(l,l'-biρhenyl-4-ylcarbonyl)-N¹-cyclohexyl-L-α-glutamine

HRMS: calcd for C₂₄H₂₈N₂O₄ + H+, 409.21218; found (ESI_FT, [MH-H]¹⁺), 409.21163.

Example 8B: iV²-(l,l'-biphenyl-4-vIcarbonyl)-N¹-cvcIopropyI-L-α-gIutamine

[0209] Step A: tert-butyl N¹-cyclopropyl-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 465.1; ΗRMS: calcd for C₂₇H₃₂N₂O₅ + H+, 465.23840; found (ESI_FT,

[MH-H]¹⁺), 465.23816.

[0210] Step C: tert-butyl iV²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-cycloρroρyl-L-α- glutaminate

MS (ESI) m/z 423.2; HRMS: calcd for C₂₅H₃₀N₂O₄ + H+, 423.22783; found (ESI_FT,

[MH-H]¹⁺), 423.22725.

[0211] Step D: N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-cyclopropyl-L-α-glutamine

MS (ESI) m/z 367.1; MS (ESI) m/z 1332; HRMS: calcd for C₂jH₂₂N₂O₄ + H+,

367.16523; found (ESI_FT, [MH-H]¹⁺), 367.16454.

Example 8C: N²-(lΛ'-biphenyl-4-ylcarbonyl)-N¹-butyI-L-α-glutamine

[0212] Step A: tert-butyl N¹-butyl-N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-α- glutaminate

MS (ESI) m/z 481.2; MS (ESI) m/z 503.2; ΗRMS: calcd for C₂₈H₃₆N₂O₅ + H+,

481.26970; found (ESI_FT, [MH-H]¹⁺), 481.26789.

[0213] Step C: tert-butyl N²-(l, 1 '-biphenyl^-ylcarbony^-iV^butyl-L-a- glutaminate

MS (ESI) m/z 439.1; MS (ESI) m/z 877.3; HRMS: calcd for C₂₆H₃₄N₂O₄ + H+,

439.25913; found (ESI_FT, [MH-H]¹⁺), 439.25884.

[0214] Step D: iV²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-butyl-L-α-glutamine

MS (ESI) m/z 381.2; MS (ESI) m/z 763.3; HRMS: calcd for C₂₂H₂₆N₂O₄ + H+, 383.19653; found (ESI_FT, [MH-H]¹⁺), 383.19514.

Example 8D; iV²-(lΛ'-biphenyl-4-ylcarbonyl)-A'^rl-(4-fluorobenzyl)-L-α-gIutamine

[0215] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(4- fluorobenzyl)-L-α-glutarninate

MS (ESI) m/z 533.2; ΗRMS: calcd for C₃₁H₃₃FN₂O₅ + H+, 533.24463; found (ESI_FT,

[M+H]¹⁺), 533.24546.

[0216] Step B: tert-butyl N¹-(4-fluorobenzyl)-L-a-glutaminate

MS (ESI) m/z 311.1; HRMS: calcd for C₁₆H₂₃FN₂O₃ + H+, 311.17655; found (ESI_FT,

[M+H]¹⁺), 311.17696.

[0217] Step C: tert-butyl N²-(l , 1 ^l-biphenyl-4-ylcarbonyl)-iV¹-(4-fluorobenzyl)-L- α-glutaminate

MS (ESI) m/z 491.2; HRMS: calcd for C₂₉H₃₁FN₂O₄ + H+, 491.23406; found (ESI_FT,

[M+H]¹⁺), 491.23339.

[0218] Step D: N²-{\ , 1¹-biphenyl-4-ylcarbonyl)-Λ'^rl-(4-fluorobenzyl)-L-α- glutamine

MS (ESI) m/z 435.1; HRMS: calcd for C₂₅H₂₃FN₂O₄ + H+, 435.17146; found (ESI_FT,

[M+H]¹⁺), 435.17056.

Example SEi ^-dΛ'-biphenyl^-vIcarbonvD-^-cvclooctyl-L-α-glutamine

[0219] Step A: tert-butyl N¹-cyclooctyl-Λ/^α-[(9H-fluoren-9-ylmethoxy)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 535.2; ΗRMS: calcd for C₃₂H₄₂N₂O₅ + H+, 535.31665; found (ESI_FT, [M+H]¹⁺), 535.31782.

[0220] Step B: tert-butyl iV^cyclooctyl-L-α-glutaminate

MS (ESI_FT) m/z 313.24821; MS (ESI_FT) m/z 313.24857; HRMS: calcd for C₁₇H₃₂N₂O₃ + H+, 313.24857; found (ESI_FT, [M+H]¹⁺), 313.24821. [0221] Step C: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-cyclooctyl-L-α- glutaminate

MS (ESI) m/z 493.4; MS (ESI) m/z 985.6; HRMS: calcd for C₃₀H₄₀N₂O₄ + H+, 493.30608; found (ESI_FTMS, [M+H]¹⁺), 493.30412.

[0222] Step D: N²-(l , 1 '-biphenyl^-ylcarbony^-N^cyclooctyl-L-a-glutamine MS (EST) m/z 437.3; MS (ESI) m/z 873.6; HRMS: calcd for C₂₆H₃₂N₂O₄ + H+, 437.24348; found (ESI_FT, [M+H]¹⁺), 437.24272.

Example SFt ^-dΛ'-biphenyl^-ylcarbonvD-^-O^-dimethoxybenzvD-L-α- glutamine

[0223] Step A: tert-butyl iV¹-(3,4-dimethoxybenzyl)-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 575.3; MS (ESI) m/z 1149.6; ΗRMS: calcd for C₃₃H₃₈N₂O₇ + H+,

575.27518; found (ESI_FT, [M+H]¹⁺), 575.27609.

[0224] Step B : tert-butyl N^3,4-dimethoxybenzyl)-L-α~glutaminate

MS (ESI+) m/z 353.2; MS (ESI+) m/z 297.1; HRMS: calcd for C₁₈H₂₈N₂O₅ + H+,

353.20710; found (ESI_FT, [M+H]¹⁺), 353.20629.

[0225] Step C: tert-butyl iV²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-(3,4- dimethoxybenzyl)-L-α-glutaminate

MS (ESI+) m/z 533.3; HRMS: calcd for C₃₁H₃₆N₂O₆ + H+, 533.26461; found (ESI_FT,

[M+H]¹⁺), 533.26323.

[0226] Step D: N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3,4-dimethoxybenzyl)-L-α- glutamine

MS (ESI-) m/z 475.3; HRMS: calcd for C₂₇H₂₈N₂O₆ + H+, 477.20201; found (ESI_FT,

[M+H]¹⁺), 477.20053.

Example 8G: iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-cvclopentyl-L-α-glutamine

[0227] Step A: tert-butyl N¹-cyclopentyl-Λ/²-[(9H-fluoren-9-ylmethoxy)carbonyl]-

L-α-glutaminate

MS (ESI+) m/z 493.3; MS (ESI+) m/z 437.2; ΗRMS: calcd for C₂₉H₃₆N₂O₅ + H+, 493.26970; found (ESI_FT, [M+H]¹⁺), 493.26812. [0228] Step B: tert-butyl iV^cyclopentyl-L-α-glutaminate

MS (ESI) m/z 271.2; HRMS: calcd for C₁₄H₂₆N₂O₃ + H+, 271.20162; found (ESI_FT, [M+H]¹⁺), 271.202.

[0229] Step C: tert-butyl iV²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-cyclopentyl-L-a- glutaminate

MS (ESI) m/z 451.3; MS (ESI) m/z 901.6; HRMS: calcd for C₂₇H₃₄N₂O₄ + H+, 451.25913; found (ESI_FT, [M+H]¹⁺), 451.25803.

[0230] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-cycloρentyl-L-α-glutamine

MS (ESI) m/z 395.2; MS (ESI) m/z 789.4; HRMS: calcd for C₂₃H₂₆N₂O₄ + H+, 395.19653; found (ESI_FT, [M+H]¹⁺), 395.19564.

Example 8Hi JV¹ -2-adamantyl-iV²-(l.l'-biphenyl-4-ylcarbonvI)-L-α-glutainine

[0231] Step A: tert-butyl N¹-2-adamantyl-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 559.4; MS (ESI) m/z 1117.7; ΗRMS: calcd for C₃₄H₄₂N₂O₅ + H+,

559.31665; found (ESI_FT, [M+H]¹⁺), 559.31524.

[0232] Step B: tert-butyl N¹-2-adamantyl-L-α-glutaminate

MS (ESI) m/z 337.2; MS (ESI) m/z 673.5; HRMS: calcd for C₁₉H₃₂N₂O₃ + H+,

337.24857; found (ESI_FT, [M+H]¹⁺), 337.2475.

[0233] Step C: tert-butyl N¹-2-adamantyl-N²-(l , 1 -biphenyl-4-ylcarbonyl)-L-α- glutaminate

MS (ESI) m/z 517.3; MS (ESI) m/z 1033.6; HRMS: calcd for C₃₂H₄₀N₂O₄ + H+,

517.30608; found (ESI_FT, [M+H]¹⁺), 517.30505.

[0234] Step D: N¹-2-adamantyl-iV²-(l , 1 '-biphenyl-4-ylcarbonyl)-L-α-glutamine

MS (ESI) m/z 461.3; MS (ESI) m/z 921.5; HRMS: calcd for C₂₈H₃₂N₂O₄ + H+,

461.24348; found (ESI_FT, [M+H]¹⁺), 461.24227.

Example 81: N¹-(2-adamantylmethyl)-iV²-(l.l'-biphenyl-4-ylcarbonyl)-L-α- glutamine

[0235] Step A: tert-butyl N¹-(2-adamantylmethyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 573.3; MS (ESI) m/z 1145.5; ΗRMS: calcd for C₃₅H₄₄N₂O₅ + H+,

573.33230; found (ESI_FT, [M+H]¹⁺), 573.33089.

[0236] Step B: tert-butyl N¹-(2-adamantylmethyl)-L-α-glutaminate

MS (ESI) m/z 351.2; HRMS: calcd for C₂₀H₃₄N₂O₃ + H+, 351.26422; found (ESI_FT,

[MH-H]¹⁺), 351.26491.

[0237] Step C: tert-butyl N¹-(2-adamantylmethyl)-N²-(l,l'-biphenyl-4- ylcarbonyl)-L-α-glutaminate MS (ESI) m/z 531.3; MS (ESI) m/z 1061.4; HRMS: calcd for C₃₃H₄₂N₂O₄ + H+,

531.32173; found (ESI__FT, [M+H]¹⁺), 531.32031.

[0238] Step D: N¹-(2-adamantylmethyl)-N²-(l,r-biphenyl-4-ylcarbonyl)-L-α- glutamine

MS (ESI) m/z 475.2; MS (ESI) m/z 949.3; HRMS: calcd for C₂₉H₃₄N₂O₄ + H+,

475.25913; found (ESIJFT, [M+H]¹⁺), 475.25734.

Example 8.T: iV²-(lΛ'-biphenyl-4-vIcarbonyl)-iV¹-(2-methoxyethyl)-L-α-glutamine

[0239] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(2- methoxyethyl)-L-α-glutaminate

MS (ESI) m/z 483.2; MS (ESI) m/z 965.3; ΗRMS: calcd for C₂₇H₃₄N₂O₆ + H+,

483.24896; found (ESI_FT, [M+H]¹⁺), 483.24851.

[0240] Step B: tert-butyl N¹-(2-methoxyethyl)-L-α-glutaminate

MS (ESI) m/z 261.1; HRMS: calcd for Cj₂H₂₄N₂O₄ + H+, 261.18088; found (ESI_FT,

[M+H]¹⁺), 261.18071.

[0241] Step C: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(2-methoxyethyl)-L- α-glutaminate

MS (ESI) m/z 441.2; MS (ESI) m/z 881.3; HRMS: calcd for C₂₅H₃₂N₂O₅ + H+,

441.23840; found (ESI_FT, [M+H]¹⁺), 441.23803.

[0242] Step D: iV²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(2-metb.oxyethyl)-L-α- glutamine

MS (ESI) m/z 385.1; MS (ESI) m/z 769.2; HRMS: calcd for C₂₁H₂₄N₂O₅ + H+,

385.17580; found (ESI_FT, [M+H]¹⁺), 385.17538.

Example 8K; iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(4-methoxybenζyl)-L-α-gIutamine

[0243] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(4- methoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 545.2; MS (ESI) m/z 1089.3; ΗRMS: calcd for C₃₂H₃₆N₂O₆ + H+,

545.26461; found (ESI_FT, [MH-H]¹⁺), 545.26277.

[0244] Step B: tert-butyl N¹-(4-methoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 323.2; HRMS: calcd for C₁₇H₂₆N₂O₄ + H+, 323.19653; found (ESI_FT,

[M+H]¹⁺), 323.19702. [0245] Step C: tert-butyl JV²-(1 , 1¹-biρhenyl-4-ylcarbonyl)-N¹-(4-methoxybenzyl)-

L-α-glutaminate

MS (EST) m/z 503.2; MS (ESI) m/z 1005.4; HRMS: calcd for C₃₀H₃₄N₂O₅ + H+,

503.25405; found (ESI_FT, [M+H]¹⁺), 503.25435.

[0246] Step D: N²-(l,r-biρhenyl-4-ylcarbonyl)-iV¹-(4-methoxybenzyl)-L-α- glutamine

MS (ESI) m/z 445.2; MS (ESI) m/z 891.5; HRMS: calcd for C₂₆H₂₆N₂O₅ + H+,

447.19145; found (ESI_FT, [M+H]¹⁺), 447.19235.

Example 8L: iV²-(l.l'-biphenyl-4-ylcarbonvI)-iV¹-r2-(3.4-dimethoxyphenyl)ethvI]-L- α-glutamine

[0247] Step A: tert-butyl N¹-[2-(3,4-dimethoxyphenyl)ethyl]-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 589.2; MS (ESI) m/z 1177.3; ΗRMS: calcd for C₃₄H₄₀N₂O₇ + H+,

589.29083; found (ESI_FT, [M+H]¹⁺), 589.28932.

[0248] Step B : tert-butyl N¹-[2-(3,4-dimethoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 367.2; HRMS: calcd for C₁₉H₃₀N₂O₅ + H+, 367.22275; found (ESI_FT,

[M+H]¹⁺), 367.22308.

[0249] Step C: tert-butyl N²-(l , 1¹-biphenyl-4-ylcarbonyl)-iV¹-[2-(3,4- dimethoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 547.3; MS (ESI) m/z 1093.4; HRMS: calcd for C₃₂H₃₈N₂O₆ + H+,

547.28026; found (ESI_FT, [M+H]¹⁺), 547.280241.

[0250] Step D: iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-[2-(3,4- dimethoxyphenyl)ethyl] -L-α-glutamine

MS (ESI) m/z 491.2; MS (ESI) m/z 981.2; HRMS: calcd for C₂₈H₃₀N₂O₆ + H+,

491.21766; found (ESI_FT, [M+H]¹⁺), 491.21697.

Example 8M; iV²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-[2-(4-methoxyphenvI)ethyn-L-α- glutamine

[0251] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[2-(4- methoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 559.2; MS (ESI) m/z 1117.3; ΗRMS: calcd for C₃₃H₃₈N₂O₆ + H+, 559.28026; found (ESI_FT, [M+H]¹⁺), 559.27899.

[0252] Step B: tert-butyl Λ^¹-[2-(4-methoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 337.1; MS (ESI) m/z 673.3; HRMS: calcd for C₁₈H₂₈N₂O₄ + H+,

337.21218; found (ESI_FT, [M+H]¹⁺), 337.21196.

[0253] Step C: tert-butyl N²-(l , 1¹-biphenyl-4-ylcarbonyl)-iV¹-[2-(4- methoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 517.2; MS (ESI) m/z 1033.4; HRMS: calcd for C₃₁H₃₆N₂O₅ + H+,

517.26970; found (ESI_FT, [M+H]¹⁺), 517.26875.

[0254] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-[2-(4-methoxyphenyl)ethyl]-

L-α-glutamine

MS (ESI) m/z 461.2; MS (ESI) m/z 921.3; HRMS: calcd for C₂₇H₂₈N₂O₅ + H+,

461.20710; found (ESI_FT, [M+H]¹⁺), 461.2062.

Example 8N: iV²-(l.l'-biphenyl-4-ylcarbonyI)-iV¹-(l-naphthylmethyl)-L-α-glutaniine

[0255] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(l- naphthylmethyl)-L-α-glutaminate

MS (ESI) m/z 565.2; MS (ESI) m/z 1129.4; ΗRMS: calcd for C₃₅H₃₆N₂O₅ + H+,

565.26970; found (ESI_FT, [M+H]¹⁺), 565.26849.

[0256] Step B: tert-butyl ^-(l-naphthylmethyO-L-α-glutaminate

MS (ESI) m/z 343.1; MS (ESI) m/z 685.3; HRMS: calcd for C₂₀H₂₆N₂O₃ + H+,

343.20162; found (ESI_FT, [M+H]¹⁺), 343.2014.

[0257] Step C: tert-butyl N²-(l,r-biρhenyl-4-ylcarbonyl)-N¹-(l-naρhthylmethyl)-

L-α-glutaminate

MS (ESI) m/z 523.2; MS (ESI) m/z 1045.4; HRMS: calcd for C₃₃H₃₄N₂O₄ + H+,

523.25913; found (ESI_FT, [MH-H]¹⁺), 523.2583.

[0258] Step D: N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-(l-naρhthylmethyl)-L-α- glutamine

MS (ESI) m/z 467.2; MS (ESI) m/z 933.3; HRMS: calcd for C₂₉H₂₆N₂O₄ + H+,

467.19653; found (ESI_FT, [M+H]¹⁺), 467.19528.

Example δOt ^-d.l'-biphenvl^-vlcarbonvD-^-O-methvlbenzvD-L-α-glutamine [0259] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-A/^rl-(3- methylbenzyl)-L-α-glutaminate

MS (ESI) m/z 529.1; MS (ESI) m/z 1057.4; ΗRMS: calcd for C₃₂H₃₆N₂O₅ + H+,

529.26970; found (ESI_FT, [M+H]¹⁺), 529.26804.

[0260] Step B: tert-butyl ^-(S-methylbenzy^-L-α-glutaminate

MS (ESI) m/z 307.1; MS (ESI) m/z 613.3; HRMS: calcd for C₁₇H₂₆N₂O₃ + H+,

307.20162; found (ESI_FT, [MH-H]¹⁺), 307.20079.

[0261] Step C: tert-butyl iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3-methylbenzyl)-L- α-glutaminate

HRMS: calcd for C₃₀H₃₄N₂O₄ + H+, 487.25913; found (ESI_FT, [M+H]¹⁺), 487.25842.

[0262] Step D: N²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(3-methylbenzyl)-L-α- glutamine

HRMS: calcd for C₂₆H₂₆N₂O₄ + H+, 431.19653; found (ESI_FT, [M+H]¹⁺), 431.19568.

Example SPt ^-d.l'-biphenyl^-ylcarbonvD-iV^fΣ-furylmethvD-L-α-glutamine

[0263] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(2- furylmethyl)-L-α-glutaminate

MS (ESI) m/z 505.2; HRMS: calcd for C₂₉H₃₂N₂O₆ + H+, 505.23331; found (ESI_FT,

[M+H]¹⁺), 505.23263.

[0264] Step B: tert-butyl N¹-(2-furylmethyl)-L-α-glutaminate

HRMS: calcd for C₁₄H₂₂N₂O₄ + H+, 283.16523; found (ESI_FT, [M+H]¹⁺), 283.16497.

[0265] Step C: tert-butyl N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-(2-furylmethyl)-L- α-glutaminate

HRMS: calcd for C₂₇H₃₀N₂O₅ + H+, 463.22275; found (ESI_FT, [M+H]¹⁺), 463.22212.

[0266] Step D: N²-(l,l^l-biρhenyl-4-ylcarbonyl)-N¹-(2-furylmethyl)-L-α- glutamine

HRMS: calcd for C₂₃H₂₂N₂O₅ + H+, 407.16015; found (ESI_FT, [MH-H]¹⁺), 407.15957.

Example 80: ^-(lΛ'-biphenvI^-ylcarbonyD-^-O-methoxybenzvD-L-α-glutamine

[0267] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(3- methoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 545.3; MS (ESI) m/z 1089.5; ΗRMS: calcd for C₃₂H₃₆N₂O₆ + H+, 545.26461; found (ESI_FT, [M+H]¹⁺), 545.26286.

[0268] Step B: tert-butyl ^-(S-methoxybenzyty-L-α-glutaminate

MS (ESI) m/z 323.3; MS (ESI) m/z 645.7; HRMS: calcd for C₁₇H₂₆N₂O₄ + H+,

323.19653; found (ESI_FT, [M+H]¹⁺), 323.19687.

[0269] Step C: tert-butyl N²-(l , 1¹-biphenyl-4-ylcarbonyl)-N¹-(3-methoxybenzyl)-

L-α-glutaminate

MS (ESI) m/z 503.2; MS (ESI) m/z 1005.5; HRMS: calcd for C₃₀H₃₄N₂O₅ + H+,

503.25405; found (ESI_FT, [M+H]¹⁺), 503.25322.

[0270] Step D: N²-(l,l'-biphenyl-4-ylcarbonyl)-Λ^3-methoxybenzyl)-L-α- glutamine

MS (ESI) m/z 447.2; MS (ESI) m/z 893.3; HRMS: calcd for C₂₆H₂₆N₂O₅ + H+,

447.19145; found (ESI_FT, [M+H]¹⁺), 447.19079.

Example 8R; iV²-(l.l'-biDhenyl-4-ylcarbonvI)-iV¹-(3,4.5-triinethoxybenzylVL-α- glutamine

[0271] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-Λ^¹-(3,4,5- trimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 605.2; MS (ESI) m/z 1209 '.4; ΗRMS: calcd for C₃₄H₄₀N₂O₈ + H+,

605.28574; found (ESI_FT, [M+H]¹⁺), 605.28453.

[0272] Step B: tert-butyl iV^rl-(3,4,5-trimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 383.1; MS (ESI) m/z 765.3; HRMS: calcd for C₁₉H₃₀N₂O₆ + H+,

383.21766; found (ESI_FT, [M+H]¹⁺), 383.21755.

[0273] Step C: tert-butyl iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3,4,5- trimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 563.3; MS (ESI) m/z 1125.5; HRMS: calcd for C₃₂H₃₈N₂O₇ + H+,

563.27518; found (ESI_FT, [M+H]¹⁺), 563.2744.

[0274] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3,4,5-trimethoxybenzyl)-L-α- glutamine

MS (ESI) m/z 507.2; MS (ESI) m/z 1013.4; HRMS: calcd for C₂₈H₃₀N₂O₇ + H+,

507.21258; found (ESI_FT, [M+H]¹⁺), 507.21179.

Example 8S; N²-(l,l^t-biphenvI-4-ylcarbonyl)-iV¹-(2.,4-dichIorobenzyl)-L-α-glutamine [0275] Step A: tert-butyl N¹-(2,4-dichlorobenzyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 583.1; ΗRMS: calcd for C₃₁H₃₂Cl₂N₂O₅ + H+, 583.17610; found (ESL-FT,

[M+H]¹⁺), 583.1742.

[0276] Step B : tert-hvXyl iV¹-(2,4-dichlorobenzyl)-L-α-glutaminate

MS (ESI) m/z 361.1; MS (ESI) m/z 721.2; HRMS: calcd for Ci₆H₂₂Cl₂N₂O₃ + H+,

361.10802; found (ESI_FT, [M+H]¹⁺), 361.10891.

[0277] Step C: tert-butyl N²-(l , 1 ^l-biphenyl-4-ylcarbonyl)-N¹-(2,4- dichlorobenzyl)-L-α-glutaminate

MS (ESI) m/z 541.2; MS (ESI) m/z 1081.3; HRMS: calcd for C₂₉H₃₀Cl₂N₂O₄ + H+,

541.16554; found (ESI_FT, [M+H]¹⁺), 541.16693.

[0278] Step D: N²-(l,l'-biρhenyl-4-ylcarbonyl)-iV¹-(2,4-dichlorobenzyl)-L-α- glutamine

MS (ESI) m/z 483.1; MS (ESI) m/z 967.2; HRMS: calcd for C₂₅H₂₂Cl₂N₂O₄ + H+,

485.10294; found (ESI_FT, [M+H]¹⁺), 485.10231.

Example 8T; iV²-(l,l'-biphenyl-4-vIcarbonvI)-N¹-r4-(trifluoromethoxy)benzyl]-L-α- glutamine

[0279] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[4-

(trifluoromethoxy)benzyl]-L-α-glutaminate

MS (ESI) m/z 599.1; MS (ESI) m/z 1197.3; ΗRMS: calcd for C₃₂H₃₃F₃N₂O₆ + H+, 599.23635; found (ESI_FT, [M+H]¹⁺), 599.23521.

[0280] Step B: tert-butyl ^-^-(trifluoromethoxy^enzyll-L-α-glutaminate

MS (ESI) m/z 377.1; HRMS: calcd for Ci₇H₂₃F₃N₂O₄ + H+, 377.16827; found (ESI_FT, [M+H]¹⁺), 377.16901.

[0281] Step C: tert-butyl N^U'-biphenyl^-ylcarbonyD-iV¹-^-

(trifluoromethoxy)benzyl]-L-α-glutaminate

MS (ESI) m/z 557.2; MS (ESI) m/z 1113.4; HRMS: calcd for C₃₀H₃₁F₃N₂O₅ + H+, 557.22578; found (ESI_FT, [M+H]¹⁺), 557.22537.

[0282] Step D: ^-(lJ'-biphenyl^-ylcarbony^-^-^-^ifluoromethoxy^enzyl]-

L-α-glutamine

MS (ESI) m/z 501.2; MS (ESI) m/z 1001.3; HRMS: calcd for C₂₆H₂₃F₃N₂O₅ + H+, 501.16318; found (ESI_FT, [M+H]¹⁺), 501.16263.

Example SUi ^-d.l'-biphenyl^-ylcarbonvD-^-rS-ftrifluoromethoxylbenzvn-L-α- glutamine

[0283] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[3-

(txifluoromethoxy)benzyl]-L-α-glutaminate

MS (ESI) m/z 599.2; MS (ESI) m/z 1191 A; ΗRMS: calcd for C₃₂H₃₃F₃N₂O₆ + H+,

599.23635; found (ESI_FT, [M+H]¹⁺), 599.23596.

[0284] Step B: tert-butyl N^3-(trifluoromethoxy)benzyl]-L-α-glutarninate

MS (ESI) m/z 377.1; MS (ESI) m/z 753.3; HRMS: calcd for C₁₇H₂₃F₃N₂O₄ + H+,

377.16827; found (ESI_FT, [M+H]¹⁺), 377.1691.

[0285] Step C: tert-butyl iV^U'-biphenyM-ylcarbonyO-JV¹-^-

(trifluoromethoxy)benzyl]-L-α-glutaminate

MS (ESI) m/z 557.2; MS (ESI) m/z 1113.4; HRMS: calcd for C₃₀H₃₁F₃N₂O₅ + H+,

557.22578; found (ESI_FT, [M+H]¹⁺), 557.22558.

[0286] Step D: N²-(l,r-biρhenyl-4-ylcarbonyl)-N¹-[3-(trifluoromethoxy)benzyl]-

L-α-glutamine

MS (ESI) m/z 499.1; MS (ESI) m/z 999.3; HRMS: calcd for C₂₆H₂₃F₃N₂O₅ + H+,

501.16318; found (ESI_FT, [M+H]¹⁺), 501.16265.

Example 8V: iV²-(l,l'-biphenvI-4-ylcarbonvI)-N¹-[4-fmethylthio)benzyl]-L-α- glutamine

[0287] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[4-

(methylthio)benzyl]-L-α-glutaminate

MS (ESI) m/z 561.2; MS (ESI) m/z 1121.4; ΗRMS: calcd for C₃₂H₃₆N₂O₅S + H+, 561.24177; found (ESI_FT, [M+H]¹⁺), 561.24183.

[0288] Step B: tert-butyl N^4-(methylthio)benzyl]-L-α-glutaminate

MS (ESI) m/z 339.2; MS (ESI) m/z 6113; HRMS: calcd for C₁₇H₂₆N₂O₃S + H+, 339.17369; found (ESI_FT, [M+H]¹⁺), 339.1748. [0289] Step C: tert-butyl iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-[4-

(methylthio)benzyl] -L-α-glutaminate

MS (ESI) m/z 519.2; MS (ESI) m/z 1037.4; HRMS: calcd for C₃₀H₃₄N₂O₄S + H+, 519.23120; found (ESI_FT, [M+H]¹⁺), 519.23078.

[0290] Step D: N²-(l,l'-biplienyl-4-ylcarbonyl)-iV¹-[4-(methylthio)benzyl]-L-a- glutamine

MS (ESI) m/z 461.1; MS (ESI) m/z 923.3; HRMS: calcd for C₂₆H₂₆N₂O₄S + H+,

463.16860; found (ESI_FT, [MH-H]¹⁺), 463.16807.

Example 8W: N -(l,l'-biphenyl-4-ylcarbonyl)-iV -(4-phenoxybenzyl)-L-α-glutamine

[0291] Step A: tert-butyl Λ/²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(4- phenoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 607.3; MS (ESI) m/z 1213.5; ΗRMS: calcd for C₃₇H₃₈N₂O₆ + H+,

607.28026; found (ESI_FT, [MH-H]¹⁺), 607.27904.

[0292] Step B : tert-butyl iV¹-(4-phenoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 385.2; MS (ESI) m/z 769.4; HRMS: calcd for C₂₂H₂₈N₂O₄ + H+,

385.21218; found (ESI_FT, [MH-H]¹⁺), 385.21141.

[0293] Step C: tert-butyl Λ/^r2-(l,r-biphenyl-4-ylcarbonyl)-ΛT¹-(4-phenoxybenzyl)-

L-α-glutaminate

MS (ESI) m/z 565.3; MS (ESI) m/z 1129.5; HRMS: calcd for C₃₅H₃₆N₂O₅ + H+,

565.26970; found (ESI_FT, [MH-H]¹⁺), 565.27062.

[0294] Step D: N²-(l ,l'-biρhenyl-4-ylcarbonyl)-iV¹-(4-phenoxybenzyl)-L-α- glutamine

MS (ESI) m/z 507.2; MS (ESI) m/z 1015.4; HRMS: calcd for C₃₁H₂₈N₂O₅ + H+,

509.20710; found (ESI_FT, [MH-H]¹⁺), 509.20657.

Example 8X: iV²-(l.l'-biphenyl-4-ylcarbonvIVN¹-[2-(3-methoχyphenyl)ethyl]-L-α- glutamine

[0295] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-7V^rl-[2-(3- methoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 559.3; MS (ESI) m/z 1117.6; ΗRMS: calcd for C₃₃H₃₈N₂O₆ + H+,

559.28026; found (ESI_FT, [MH-H]¹⁺), 559.28074.

[0296] Step B: tert-butyl N¹-[2-(3-methoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 337.2; HRMS: calcd for C₁₈H₂₈N₂O₄ + H+, 337.21218; found (ESI_FT,

[MH-H]¹⁺), 337.21275. [0297] Step C: tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-[2-(3- methoxyphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 517.3; MS (ESI) m/z 1033.6; HRMS: calcd for C₃₁H₃₆N₂O₅ + H+,

517.26970; found (ESI_FT, [M+H]¹⁺), 517.27068.

[0298] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-[2-(3-methoxyphenyl)ethyl]-

L-α-glutamine

MS (ESI) m/z 461.2; MS (ESI) m/z 921.4; HRMS: calcd for C₂₇H₂₈N₂O₅ + H+,

461.20710; found (ESI_FT, [MH-H]¹⁺), 461.20723.

Example 8Y; iV²-(l.l'-biphenvI-4-ylcarbonvI)-iV¹-(2_&lt;4-dimethoxybenζvI)-L-α- glutamine

[0299] Step A: tert-butyl N¹-(2,4-dimethoxybenzyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 575.3; MS (ESI) m/z 1149.5; ΗRMS: calcd for C₃₃H₃₈N₂O₇ + H+,

575.27518; found (ESI_FT, [M+H]¹⁺), 575.275181.

[0300] Step B: tert-butyl N¹-(2,4-dimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 353.2; MS (ESI) m/z 705.4; HRMS: calcd for C₁₈H₂₈N₂O₅ + H+,

353.20710; found (ESI_FT, [M+H]¹⁺), 353.20767.

[0301] Step C: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(2,4- dimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 533.3; MS (ESI) m/z 1065.6; HRMS: calcd for C₃₁H₃₆N₂O₆ + H+,

533.26461; found (ESI_FT, [M+H]¹⁺), 533.26569.

[0302] Step D: iV²-(l , 1 '-biρhenyl-4-ylcarbonyl)-N¹-(2,4-dimethoxybenzyl)-L-α- glutamine

MS (ESI) m/z 477.2; MS (ESI) m/z 953.4; HRMS: calcd for C₂₇H₂₈N₂O₆ + H+,

477.20201; found (ESI_FT, [M+H]¹⁺), 477.2019.

Example 8Z: iV²-(l,l'-biphenyl-4-yIcarbonyI)-N¹-(2-methoxybenzyl)-L-α-glutamine

[0303] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(2- methoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 545.2; ΗRMS: calcd for C₃₂H₃₆N₂O₆ + H+, 545.26461; found (ESI_FT,

[M+H]¹⁺), 545.26356. [0304] Step B: tert-butyl Λ^-methoxybenzyl^L-α-glut-Uiunate

MS (ESI) m/z 323.2; MS (ESI) m/z 645.4; HRMS: calcd for C₁₇H₂₆N₂O₄ + H+,

323.19653; found (ESI_FT, [M+H]¹⁺), 323.19657.

[0305] Step C: tert-butyl iV²-(l , 1¹-biphenyl-4-ylcarbonyl)-iV¹-(2-methoxybenzyl)-

L-α-glutaminate

MS (ESI) m/z 503.2; MS (ESI) m/z 1005.5; HRMS: calcd for C₃₀H₃₄N₂O₅ + H+,

503.25405; found (ESI_FT, [MH-H]¹⁺), 503.2546.

[0306] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(2-methoxybenzyl)-L-α- glutamine

MS (ESI) m/z 447.2; MS (ESI) m/z 893.4; HRMS: calcd for C₂₆H₂₆N₂O₅ + H+,

447.19145; found (ESI_FT, [M+H]¹⁺), 447.19143.

Example 8AA: iV²-(l.l'-biphenyl-4-ylcarbonyl)-iV¹-(3.5-difluorobenzvn-L-α- glutamine

[0307] Step A: tert-butyl N¹-(3,5-difluorobenzyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 551.2; MS (ESI) m/z 1101.4; ΗRMS: calcd for C₃₁H₃₂F₂N₂O₅ + H+,

551.23521; found (ESI_FT, [MH-H]¹⁺), 551.23338.

[0308] Step B : tert-butyl ^-(S^-difluorobenzy^-L-a-glutaminate

MS (ESI) m/z 329.1; MS (ESI) m/z 657.3; HRMS: calcd for C₁₆H₂₂F₂N₂O₃ + H+,

329.16712; found (ESI_FT, [MH-H]¹⁺), 329.16762.

[0309] Step C: tert-butyl N²-(l,l^I-biphenyl-4-ylcarbonyl)-N¹-(3,5-difluorobenzyl)-

L-α-glutaminate

MS (ESI) m/z 509.2; MS (ESI) m/z 1017.3; HRMS: calcd for C₂₉H₃₀F₂N₂O₄ + H+,

509.22464; found (ESI_FTMS, [MH-H]¹⁺), 509.22463.

[0310] Step D: iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(3,5-difluorobenzyl)-L-α- glutamine

MS (ESI) m/z 451.1; MS (ESI) m/z 903.3; HRMS: calcd for C₂₅H₂₂F₂N₂O₄ + H+,

453.16204; found (ESI_FTMS, [MH-H]¹⁺), 453.16222.

Example 8BB: ^-(l.l'-biphenyl^-ylcarbonvD-iV^CS^-dichlorobenzvD-L-α- glutamϊne [0311] Step A: tert-butyl ^-(S^-dichlorobenzyl^Λ^-t^H-fluoren-θ- ylmethoxy)carbonyl] -L-α-glutaminate

MS (ESI) m/z 583.1; MS (ESI) m/z 1165.2; ΗRMS: calcd for C₃₁H₃₂Cl₂N₂O₅ + H+,

583.17610; found (ESI_FT, [M+H]¹⁺), 583.17528.

[0312] Step B: tert-butyl ^-(S^-dichlorobenzy^-L-α-glutaminate

MS (ESI) m/z 361.1; MS (ESI) m/z 721.2; HRMS: calcd for C₁₆H₂₂Cl₂N₂O₃ + H+,

361.10802; found (ESI_FT, [M+H]¹⁺), 361.10861.

[0313] Step C: tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3,4- dichlorobenζyl)-L-α-glutarninate

MS (ESI) m/z 541.2; MS (ESI) m/z 1081.3; HRMS: calcd for C₂₉H₃₀Cl₂N₂O₄ + H+,

541.16554; found (ESI_FT, [M+H]¹⁺), 541.16685.

[0314] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3,4-dichlorobenzyl)-L-α- glutarnine

MS (ESl) m/z 483.1; MS (ESI) m/z 967.2; HRMS: calcd for C₂₅H₂₂Cl₂N₂O₄ + H+,

485.10294; found (ESI_FTMS, [M+H]¹⁺), 485.10288.

Example 8CC; iV²-(l.l'-biphenvI-4-ylcarbonyl)-iV¹-(3.5-dimethoxybenzvI)-L-α- glutamine

[0315] Step A: tert-butyl N¹-(3,5-dimethoxybenzyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 575.3; ΗRMS: calcd for C₃₃H₃₈N₂O₇ + H+, 575.27518; found (ESI_FTMS, [M+H]¹⁺), 575.27468.

[0316] Step B: tert-butyl N^3,5-dimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 353.2; HRMS: calcd for C₁₈H₂₈N₂O₅ + H+, 353.20710; found (ESI_FTMS, [M+H]¹⁺), 353.20732.

[0317] Step C: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3,5- dimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 533.3; MS (ESI) m/z 1065.5; HRMS: calcd for C₃₁H₃₆N₂O₆ + H+, 533.26461; found (ESI_FTMS, [M+H]¹⁺), 533.26474.

[0318] Step D: N²-(l,l'-biplienyl-4-ylcarbonyl)-iV¹-(3,5-dimethoxybenzyl)-L-α- glutamine

MS (ESI) m/z All. ,2; MS (ESI) m/z 953.4; HRMS: calcd for C₂₇H₂₈N₂O₆ + H+, 477.20201; found (ESI-FTMS, [M+H]¹⁺), 477.202.

Example 8DD: ^-(lΛ'-biphenyl^-vIcarbonvD-iV^O^-dimethvIbenzvD-L-α- glutamine

[0319] Step A: terrtmtyl iV¹-(3,4-dimethylbenzyl)-iV^"2-[(9fl-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 543.3; MS (ESI) m/z 1085.4; HRMS: calcd for C₃₃H₃₈N₂O₅ + H+,

543.28535; found (ESI_FTMS, [M+H]¹⁺), 543.28604.

[0320] Step B : tert-butyl N¹ -(3 ,4-dimethylbenzyl)-L-α-glutaminate

MS (ESI) m/z 321.2; HRMS: calcd for C₁₈H₂₈N₂O₃ + H+, 321.21727; found (ESI_FTMS,

[M-HH]¹⁺), 321.21716.

[0321] Step C: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3,4- dimethylbenzyl)-L-α-glutaminate

MS (ESI) m/z 501.3; MS (ESI) m/z 1001.4; HRMS: calcd for C₃₁H₃₆N₂O₄ + H+,

501.27478; found (ESI_FTMS, [M+H]¹⁺), 501.2735.

[0322] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3,4-dimethylbenzyl)-L-α- glutamine

MS (ESI) m/z 445.2; MS (ESI) m/z 889.3; HRMS: calcd for C₂₇H₂₈N₂O₄ + H+,

445.21218; found (ESI_FTMS, [M+H]¹⁺), 445.21199.

Example 8EE; iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(2-methvIbenzyl)-L-α-glutamine

[0323] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(2- methylbenzyl)-L-α-glutaminate

MS (ESI) m/z 529.2; MS (ESI) m/z 1057.4; ΗRMS: calcd for C₃₂H₃₆N₂O₅ + H+, 529.26970; found (ESI_FTMS, [M+H]¹⁺), 529.27003. [0324] Step B : tert-butyl iV¹-(2-methylbenzyl)-L-α-glutaminate

MS (ESI) m/z 307.2; MS (ESI) m/z 613.4; HRMS: calcd for C₁₇H₂₆N₂O₃ + H+, 307.20162; found (ESI_FTMS, [MH-H]¹⁺), 307.20094.

[0325] Step C: tert-butyl iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(2-methylbenzyl)-L- α-glutaminate

MS (ESI) m/z 487.2; MS (ESI) m/z 973.3; HRMS: calcd for C₃₀H₃₄N₂O₄ + H+, 487.25913; found (ESI_FTMS, [M+H]¹⁺), 487.2588. [0326] Step D: N²-(l , 1¹-biphenyl-4-ylcarbonyl)-iV¹-(2-methylbenzyl)-L-α- glutamine

MS (ESI) m/z 431.2; MS (ESI) m/z 861.3; HRMS: calcd for C₂₆H₂₆N₂O₄ + H+,

431.19653; found (ESI_FTMS, [M-HH]¹⁺), 431.1966.

Example 8FF: JV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(3-phenylpropyl)-L-α-glutamine

[0327] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(3- phenylpropyl)-L-α-glutaminate

MS (ESI) m/z 543.3; ΗRMS: calcd for C₃₃H₃₈N₂O₅ + H+, 543.28535; found (ESI_FTMS,

[M+H]¹⁺), 543.2847.

[0328] Step B: tert-butyl Λ^3-phenylpropyl)-L-α~glutaminate

MS (ESI) m/z 321.2; MS (ESI) m/z 641.4; HRMS: calcd for C₁₈H₂₈N₂O₃ + H+,

321.21727; found (ESI_FTMS, [M+H]¹⁺), 321.2167.

[0329] Step C: tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-(3-phenylpropyl)-L- α-glutaminate

MS (ESI) m/z 501.3; HRMS: calcd for C₃₁H₃₆N₂O₄ + H+, 501.27478; found (ESI_FTMS,

[M+H]¹⁺), 501.2742.

[0330] Step D: iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3-ρhenylproρyl)-L-α- glutamine

MS (ESI) m/z 445.2; HRMS: calcd for C₂₇H₂₈N₂O₄ + H+, 445.21218; found (ESI_FTMS,

[M+H]¹⁺), 445.2121.

Example 8GG: iV²-(l.l'-biphenvI-4-ylcarbonyl)-iV¹-2.3-dihvdro-lfl^r-inden-2-yl-L-α- glutamine

[0331] Step A: tert-butyl iV¹-2,3-dihydro-lH-inden-2-yl-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 541.2; MS (ESI) m/z 1081.4; ΗRMS: calcd for C₃₃H₃₆N₂O₅ + H+,

541.26970; found (ESI-FTMS, [M+H]¹⁺), 541.27088.

[0332] Step B : tert-butyl N¹-2,3-dihydro- lH-inden-2-yl-L-α-glutaminate

MS (ESI) m/z 319.1; MS (ESI) m/z 637.3; ΗRMS: calcd for C₁₈H₂₆N₂O₃ + H+,

319.20162; found (ESI-FTMS, [M+H]¹⁺), 319.20275. [0333] Step C: tert-butyl iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-2,3-dihydro-lH- inden-2-yl-L-α-glutaminate

MS (ESI) m/z 499.2; MS (ESI) m/z 997.4; ΗRMS: calcd for C₃₁H₃₄N₂O₄ + H+,

499.25913; found (ESI-FTMS, [M+H]¹⁺), 499.258.

[0334] Step D: iV²-(l,l¹-biphenyl-4-ylcarbonyl)-N¹-2,3-dihydro-lH-inden-2-yl-L- α-glutamine

MS (ESI) m/z 441.2; MS (ESI) m/z 883.3; ΗRMS: calcd for C₂₇H₂₆N₂O₄ + H+,

443.19653; found (ESI-FTMS, [M+H]¹⁺), 443.19699.

Example 8HH: ^-(l.l'-biphenvI^-ylcarbonylViV^Cl^-dimethvIbenzvD-L-α- glutamine

[0335] Step A: tert-butyl N¹-(2,3-dimethylbenzyl)-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 543.2; MS (ESI) m/z 1085.4; ΗRMS: calcd for C₃₃H₃₈N₂O₅ + H+,

543.28535; found (ESI-FTMS, [M+H]¹⁺), 543.28623.

[0336] Step B : tert-bxxtyl N¹-(2,3-dimethylbenzyl)-L-α-glutaminate

MS (ESI) m/z 321.2; MS (ESI) m/z 641.4; HRMS: calcd for C₁₈H₂₈N₂O₃ + H+,

321.21727; found (ESI-FTMS, [M+H]¹⁺), 321.2186.

[0337] Step C: fert-butyl iV²-(l , 1¹-biphenyl-4-ylcarbonyl)-iV¹-(2,3- dimethylbenzyl)-L-α-glutaminate

MS (ESI) m/z 501.2; MS (ESI) m/z 1001.4; HRMS: calcd for C₃₁H₃₆N₂O₄ + H+,

501.27478; found (ESI-FTMS, [M+H]¹⁺), 501.27629.

[0338] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(2,3-dimethylbenzyl)-L-α- glutamine

MS (ESI) m/z 443.2; HRMS: calcd for C₂₇H₂₈N₂O₄ + H+, 445.21218; found (ESI-FTMS,

[M+H]¹⁺), 445.21354.

Example 811; JV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(4-phenvIbutyl)-L-α-glutamine

[0339] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(4- phenylbutyl)-L-α-glutaminate

MS (ESI) m/z 557.2; MS (ESI) m/z 1113.4; ΗRMS: calcd for C₃₄H₄₀N₂O₅ + H+, 557.30100; found (ESI-FTMS, [M+H]¹⁺), 557.30162. [0340] Step B : fert-butyl N¹-(4-phenylbutyl)-L-α-glutaminate

MS (ESI) m/z 335.2; HRMS: calcd for C₁₉H₃₀N₂O₃ + H+, 335.23292; found (ESI-FTMS,

[M+H]¹⁺), 335.23453;

[0341] Step C: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(4-phenylbutyl)-L- α-glutaminate

MS (ESI) m/z 515.3; MS (ESI) m/z 1029.5; HRMS: calcd for C₃₂H₃₈N₂O₄ + H+,

515.29043; found (ESI-FTMS, [M+H]¹⁺), 515.29152.

[0342] Step D: iV²-(l,l^l-biphenyl-4-ylcarbonyl)-iV¹-(4-phenylbutyl)-L-α- glutamine

MS (ESI) m/z 459.2; MS (ESI) m/z 917.4; HRMS: calcd for C₂₈H₃₀N₂O₄ + H+,

459.22783; found (ESI-FTMS, [M+H]¹⁺), 459.22972.

Example 8.T.T; iV²-(l,l'-biphenvI-4-ylcarbonyl)--/V¹-(3-iodobenzyl)-L-α-glutaiiiine

[0343] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(3- iodobenzyl)-L-α-glutaminate

MS (ESI) m/z 641.1; MS (ESI) m/z 1281.1; ΗRMS: calcd for C₃₁H₃₃IN₂O₅ + H+,

641.15070; found (ESI-FTMS, [M+H]¹⁺), 641.15111.

[0344] Step B: tert-butyl ^-(S-iodobenzy^-L-α-glutaminate

MS (ESI) m/z 419.1; MS (ESI) m/z 837.1; HRMS: calcd for C₁₆H₂₃IN₂O₃ + H+,

419.08262; found (ESI-FTMS, [M+H]¹⁺), 419.08459.

[0345] Step C: tert-butyl JV²-(1 , 1 '-biphenyl-4-ylcarbonyl)-N¹-(3-iodobenzyl)-L-α- glutaminate

MS (ESI) m/z 599.1; MS (ESI) m/z 1197.1; HRMS: calcd for C₂₉H₃₁IN₂O₄ + H+,

599.14013; found (ESI-FTMS, [M+H]¹⁺), 599.1414.

[0346] Step D: N²-(l,r-biρhenyl-4-ylcarbonyl)-N¹-(3-iodobenzyl)-L-α-glutamine

MS (ESI) m/z 543.1; MS (ESI) m/z 1085.1; MS (ESI) m/z 601.1; HRMS: calcd for

C₂₅H₂₃IN₂O₄ + H+, 543.07753; found (ESI-FTMS, [M+H]¹⁺), 543.07723.

Example 8KK: iV²-(l,l' -biphenyl-4-ylcarbonvI)-iV¹-(4-fe^-butylbenzylVL-α- glutamine

[0347] Step A: tert-butyl N¹-(4-fert-butylbenzyl)-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate MS (ESI) m/z 571.3; MS (ESI) m/z 1141.6; HRMS: calcd for C₃₅H₄₂N₂O₅ + H+,

571.31665; found (ESI_FT, [M+H]¹⁺), 571.31581.

[0348] Step B: tert-butyl N¹-(4-tert-butylbenzyl)-L-α-glutaminate

MS (ESI) m/z 349.2; HRMS: calcd for C₂₀H₃₂N₂O₃ + H+, 349.24857; found (ESI-FTMS,

[M+H]¹⁺), 349.2489.

[0349] Step C: tert-butyl N²-(l , 1¹-biphenyl-4-ylcarbonyl)-iV¹-(4-tert-butylbenzyl)-

L-α-glutaminate

MS (ESI) m/z 529.2; MS (ESI) m/z 1057.4; HRMS: calcd for C₃₃H₄₀N₂O₄ + H+,

529.30608; found (ESI-FTMS, [M+H]¹⁺), 529.30622.

[0350] Step D: iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(4-tert-butylbenzyl)-L-α- glutamine

MS (ESI) m/z 473.2; MS (ESI) m/z 945.3; MS (ESI) m/z 531.2; HRMS: calcd for

C₂₉H₃₂N₂O₄ + H+, 473.24348; found (ESI-FTMS, [M+H]¹⁺), 473.24348.

Example 8LL: iV²-(l,l'-biphenyl-4-vIcarbonyl)-iV¹-(4-iodobenzyl)-L-α-glutamine

[0351] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(4- iodobenzyl)-L-α-glutaminate

MS (ESI) m/z 641.1; MS (ESI) m/z 1281.1; ΗRMS: calcd for C₃₁H₃₃IN₂O₅ + H+,

641.15070; found (ESI-FTMS, [M+H]¹⁺), 641.15129.

[0352] Step B: tert-butyl N¹-(4-iodobenzyl)-L-α-glutaminate

MS (ESI) m/z 419; HRMS: calcd for C₁₆H₂₃IN₂O₃ + H+, 419.08262; found (ESI-FTMS,

[MH-H]¹⁺), 419.08332.

[0353] Step C: tert-butyl iV²-(l , 1 '-biphenyl-4-ylcarbonyl)-Λ'^rl-(4-iodobenzyl)-L-α- glutaminate

MS (ESI) m/z 599; MS (ESI) m/z 1197; HRMS: calcd for C₂₉H₃₁IN₂O₄ + H+, 599.14013; found (ESI-FTMS, [M+H]¹⁺), 599.1407.

[0354] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(4-iodobenzyl)-L-α-glutamine

MS (ESI) m/z 543; MS (ESI) m/z 1085; HRMS: calcd for C₂₅H₂₃IN₂O₄ + H+, 543.07753; found (ESI-FTMS, [M+H]¹⁺), 543.07755.

Example SMMi ^-Cbiphenvl^-vlcarbonvD-^-dΛ-dimethylpropvD-L-α-glutamine [0355] Step A: tert-butyl iV^l,l-dimethylpropyl)-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 495.3; ΗRMS: calcd for C₂₉H₃₈N₂O₅ + H+, 495.28535; found (ESI_FT,

[M+H]¹⁺), 495.28577.

[0356] Step B: tert-butyl ^-(l.l-dimethylpropyO-L-α-glutaminate

MS (ESI) m/z 273.2; HRMS: calcd for C₁₄H₂₈N₂O₃ + H+, 273.21727; found (ESI-FTMS,

[M+H]¹⁺), 273.21738.

[0357] Step C: tert-butyl N²-(biρhenyl-4-ylcarbonyl)-AT¹-(l,l-dimethylρropyl)-L- α-glutaminate

MS (ESI) m/z 453.2; MS (ESI) m/z 905.5; HRMS: calcd for C₂₇H₃₆N₂O₄ + H+,

453.27478; found (ESI-FTMS, [M+H]¹⁺), 453.27627.

[0358] Step D: N²-(biρhenyl-4-ylcarbonyl)-N¹-(l,l-dimethylρropyl)-L-α- glutamine

MS (ESI) m/z 397.2; MS (ESI) m/z 793.4; HRMS: calcd for C₂₃H₂₈N₂O₄ + H+,

397.21218; found (ESI-FTMS, [M+H]¹⁺), 397.2139.

Example 8NN; N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4-chIorophenyl)-l.l- dimethylethyI]-L-α-glutamine

[0359] Step A: tert-butyl N¹-[2-(4-chlorophenyl)-l,l-dimethylethyl]-iV²-[(9H- fluoren-9-ylmethoxy)carbonyl]-L-α-glutaminate «

MS (ESI) m/z 591.1; MS (ESI) m/z 1181.2; ΗRMS: calcd for C₃₄H₃₉ClN₂O₅ + H+,

591.26203; found (ESI-FTMS, [M+H]¹⁺), 591.26263.

[0360] Step B: tert-butyl N¹-[2-(4-chlorophenyl)-l,l-dimethylethyl]-L-α- glutaminate

MS (ESI) m/z 369.1; MS (ESI) m/z 1312; HRMS: calcd for C₁₉H₂₉ClN₂O₃ + H+,

369.19395; found (ESI-FTMS, [M+H]¹⁺), 369.19351.

[0361] Step C: tert-butyl N²-(biρhenyl-4-ylcarbonyl)-N¹-[2-(4-chlorophenyl)-l,l- dimethylethyl]-L-α-glutaminate

MS (ESI) m/z 549.1; MS (ESI) m/z 1097.2; RMS: calcd for C₃₂H₃₇ClN₂O₄ + H+,

549.25146; found (ESI-FTMS, [M+H]¹⁺), 549.25189.

[0362] Step D: ²-(biρhenyl-4-ylcarbonyl)-iV¹-[2-(4-chlorophenyl)-l,l- dimethylethyl]-L-α-glutamine MS (ESI) m/z 493.1; HRMS: calcd for C₂₈H₂₉ClN₂O₄ + H+, 493.18886; found (ESI- FTMS, [M+H]¹⁺), 493.1895.

Example 800: N²-(l.l'-biphenyl-4-ylcarbonyl)-iV¹-r2-(4-fluorophenvI)-l.l- dimethylethyll-L-α-glutamine

[0363] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -L-α-glutaminate

MS (ESI) m/z 575.3; MS (ESI) m/z 1149.4; ΗRMS: calcd for C₃₄H₃₉FN₂O₅ + H+,

575.29158; found (ESI-FTMS, [M+H]¹⁺), 575.29261.

[0364] Step B: tert-butyl iV¹-[2-(4-fluorophenyl)-l,l-dimethylethyl]-L-α- glutaminate

MS (ESI) m/z 353.2; HRMS: calcd for C₁₉H₂₉FN₂O₃ + H+, 353.22350; found (ESI-

FTMS, [M+H]¹⁺), 353.22526.

[0365] Step C: tert-butyl iV²-(l , 1 ^l-biphenyl-4-ylcarbonyl)-N¹-[2-(4-fluoroρhenyl)-

1 , l-dimethylethyl]-L-α-glutaminate

MS (ESI) m/z 533.2; MS (ESI) m/z 1065.4; HRMS: calcd for C₃₂H₃₇FN₂O₄ + H+,

533.28101; found (ESI-FTMS, [M+H]¹⁺), 533.28063.

[0366] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-[2-(4-fluorophenyl)-l,l- dimethylethyl] -L-α-glutamine

MS (ESI) m/z 477..2; MS (ESI) m/z 953.3; HRMS: calcd for C₂₈H₂₉FN₂O₄ + H+,

477.21841; found (ESI-FTMS, [M+H]¹⁺), 477.21783.

Example 8PP: iV²-(biphenyl-4-ylcarbonyl)-iV¹-(l.l-dimethyl-2-phenylethyl)-L-α- glutamine

[0367] Step A: tert-butyl N¹-(l,l-dimethyl-2-phenylethyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 557.2; ΗRMS: calcd for C₃₄H₄₀N₂O₅ + H+, 557.30100; found (ESI-FTMS,

[M+H]¹⁺), 557.2994.

[0368] Step B: tert-butyl iV¹-(l,l-dimethyl-2-phenylethyl)-L-α-glutaminate

MS (ESI) m/z 335.1; MS (ESI) m/z 669.3; HRMS: calcd for C₁₉H₃₀N₂O₃ + H+,

335.23292; found (ESI-FTMS, [MH-H]¹⁺), 335.23259. 66

[0369] Step C: terf-butyl ^-(biphenyl^-ylcarbony^-N^Cl.l-dimethyl^- phenylethyl)-L-α-glutaminate

MS (ESI) m/z 515.2; MS (ESI) m/z 1029.3; HRMS: calcd for C₃₂H₃₈N₂O₄ + H+, 515.29043; found (ESI-FTMS, [M+H]¹⁺), 515.29018. <img file="EP1902014A2_D0063.tif" /> glutamine

MS (ESI) m/z 459.1; MS (ESI) m/z 917.3; HRMS: calcd for C₂₈H₃₀N₂O₄ + H+,

459.22783; found (ESI-FTMS, [M+H]¹⁺), 459.22858.

Example 8QQ ; ^-(biphenyl^-ylcarbonyD-^-fS-isopropoxypropyD-L-α-glutamine

[0371] Step A: tert-butyl iV²-[(9H-fluoren~9-ylmethoxy)carbonyl]-iV¹-(3- isopropoxypropyl)-L-α-glutaminate

MS (ESI) m/z 525.3; MS (ESI) m/z 1049.5; ΗRMS: calcd for C₃₀H₄₀N₂O₆ + H+,

525.29591; found (ESI-FTMS, [M+H]¹⁺), 525.29528.

[0372] Step B: tert-butyl ^-(S-isopropoxypropyty-L-α-glutaminate

MS (ESI) m/z 303.2; HRMS: calcd for C₁₅H₃₀N₂O₄ + H+, 303.22783; found (ESI-FTMS,

[M+H]¹⁺), 303.22747.

[0373] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-(3-isopropoxypropyl)-L- α-glutaminate

MS (ESI) m/z 483.3; MS (ESI) m/z 965.5; HRMS: calcd for C₂₈H₃₈N₂O₅ + H+,

483.28535; found (ESI-FTMS, [M+H]¹⁺), 483.28364.

[0374] Step D: Λ/^a-(biphenyl-4-ylcarbonyl)-iV¹-(3-isopropoxypropyl)-L-α- glutamine

MS (ESI) m/z 427.2; MS (ESI) m/z 853.4; MS (ESI) m/z 449.2; HRMS: calcd for

C₂₄H₃₀N₂O₅ + H+, 427. ,22275; found (ESI-FTMS, [M+H]¹⁺), Ml.22221.

Example 8RR: ^-(biphenyl^-ylcarbonvD-iV^O-methylbutvD-L-α-glutamine

[0375] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(3- methylbutyl)-L-α-glutaminate

MS (ESI) m/z 495.2; MS (ESI) m/z 989.5; ΗRMS: calcd for C₂₉H₃₈N₂O₅ + H+,

495.28535; found (ESI-FTMS, [M+H]¹⁺), 495.28729. [0376] Step B: tert-butyl ^-(S-methylbuty^-L-α-glutaminate

MS (ESI) m/z 273.2; HRMS: calcd for C₁₄H₂₈N₂O₃ + H+, 273.21727; found (ESI-FTMS,

[M+H]¹⁺), 273.21718.

[0377] Step C: tert-butyl N²-(biρhenyl-4-ylcarbonyl)-N¹-(3-methylbutyl)-L-α- glutaminate

MS (ESI) m/z 453.3; MS (ESI) m/z 905.5; MS (ESI) m/z 475.2; HRMS: calcd for

C₂₇H₃₆N₂O₄ + H+, 453.27478; found (ESI-FTMS, [M+H]¹⁺), 453.27427.

[0378] Step D: N²-(biρhenyl-4-ylcarbonyl)-N¹-(3-methylbutyl)-L-α-glutamine

MS (ESI) m/z 397.2; MS (ESI) m/z 793.3; HRMS: calcd for C₂₃H₂₈N₂O₄ + H+,

397.21218; found (ESI-FTMS, [M+H]¹⁺), 397.21129.

Example 8SS; -/V²-(biphenyl-4-ylcarbonyl)-iV¹-r2-(4-fluorophenvI)ethyl]-L-α- glutamine

[0379] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[2-(4- fluorophenyl)ethyl]-L-α-glutaminate

MS (EST) m/z 547. ,2; MS (ESI) m/z 1093.3; ΗRMS: calcd for C₃₂H₃₅FN₂O₅ + H+,

547.26028; found (ESI-FTMS, [M+H]¹⁺), 547.26067.

[0380] Step B: tert-butyl N¹-[2-(4-fluorophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 325.1; HRMS: calcd for C₁₇H₂₅FN₂O₃ + H+, 325.19220; found (ESI-

FTMS, [M+H]¹⁺), 325.19212.

[0381] Step C: tert-butyl iV²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4- fluorophenyl)ethyl] -L-α-glutaminate

MS (ESI) m/z 505.2; MS (ESI) m/z 1009.3; HRMS: calcd for C₃₀H₃₃FN₂O₄ + H+,

505.24971; found (ESI-FTMS, [M+H]¹⁺), 505.25021.

[0382] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-fluoroρhenyl)ethyl]-L-α- glutamine

MS (ESI) m/z 449.1; MS (ESI) m/z 897.2; HRMS: calcd for C₂₆H₂₅FN₂O₄ + H+,

449.18711; found (ESI-FTMS, [M+H]¹⁺), 449.18705.

Example 8TT; JV²-(biphenvI-4-ylcarbonylViV¹-[2-(2-fluorophenvI)ethyl1-L-α- glutamine [0383] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[2-(2- fluorophenyl)ethyl] -L-α-glutaminate

MS (ESI) m/z 547.2; MS (ESI) m/z 1093.3; ΗRMS: calcd for C₃₂H₃₅FN₂O₅ + H+,

547.26028; found (ESI-FTMS, [M+H]¹⁺), 547.26138.

[0384] Step B: tert-butyl iV^rl-[2-(2-fluorophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 325.1; MS (ESI) m/z 649.3; HRMS: calcd for C₁₇H₂₅FN₂O₃ + H+,

325.19220; found (ESI-FTMS, [MH-H]¹⁺), 325.19217.

[0385] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(2- fluorophenyl)ethyl] -L-α-glutaminate

MS (ESl) m/z 505.2; MS (ESI) m/z 1009.3; HRMS: calcd for C₃₀H₃₃FN₂O₄ + H+,

505.24971; found (ESI-FTMS, [M+H]¹⁺), 505.2497.

[0386] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(2-fluorophenyl)ethyl]-L-α- glutamine

MS (ESI) m/z 449.1; MS (ESI) m/z 897.2; HRMS: calcd for C₂₆H₂₅FN₂O₄ + H+,

449.18711; found (ESI-FTMS, [M+H]¹⁺), 449.18744.

Example 8UU: JV²-(biphenyl-4-ylcarboiiyl)-iV¹-r2-(4-chlorophenyl)ethvn-L-α- glutamine

[0387] Step A: tert-butyl iV¹-[2-(4-chlorophenyl)ethyl]-Λ^²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 563.1; MS (ESI) m/z 1125.2; ΗRMS: calcd for C₃₂H₃₅ClN₂O₅ + Na+, 585.21267; found (ESI-FTMS, [M+Na]¹⁺), 585.21454. [0388] Step B: tert-butyl N¹-[2-(4-chlorophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 341.1; MS (ESI) m/z 681.2; HRMS: calcd for C₁₇H₂₅ClN₂O₃ + H+, 341.16265; found (ESI-FTMS, [M+H]¹⁺), 341.16311. [0389] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4- chlorophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 521.2; MS (ESI) m/z 1041.3; HRMS: calcd for C₃₀H₃₃ClN₂O₄ + Na+, 543.20210; found (ESI-FTMS, [M+Na]¹⁺), 543.20393.

[0390] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-chlorophenyl)ethyl]-L-α- glutamine

MS (ESI) m/z 463.1; MS (ESI) m/z 927.1; HRMS: calcd for C₂₆H₂₅ClN₂O₄ + H+, 465.15756; found (ESI-FTMS, [M+H]¹⁺), 465.15776.

Example SWt ^-fbiphenyl^-ylcarbonvD-^-ri-fZ-chlorophenvDethvn-L-α- glutamine

[0391] Step A: tert-butyl N¹-[2-(2-chlorophenyl)ethyl]-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 563.1; MS (ESI) m/z 1125.2; ΗRMS: calcd for C₃₂H₃₅ClN₂O₅ + H+,

563.23073; found (ESI-FTMS, [M+H]¹⁺), 563.23042.

[0392] Step B: tert-butyl iV¹-[2-(2-chlorophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 341.2; MS (ESI) m/z 681.3; MS (ESI) m/z 703.3; HRMS: calcd for

C₁₇H₂₅ClN₂O₃ + H+, 341.16265; found (ESI-FTMS, [M+H]¹⁺), 341.16301.

[0393] Step C: tert-butyl N²-(biρhenyl-4-ylcarbonyl)-iV¹-[2-(2- chlorophenyl)ethyl]-L-α-glutarninate

MS (ESI) m/z 521.2; MS (ESI) m/z 1041.4; HRMS: calcd for C₃₀H₃₃ClN₂O₄ + H+,

521.22016; found (ESI-FTMS, [M+H]¹⁺), 521.22075.

[0394] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(2-cMorophenyl)ethyl]-L-α- glutarnine

MS (ESI) m/z 465; MS (ESI) m/z 487; HRMS: calcd for C₂₆H₂₅ClN₂O₄ + H+, 465.15756; found (ESI-FTMS, [M+H]¹⁺), 465.15834.

Example 8WW; iV²-(biphenyl-4-ylcarbonvIViV¹-r2-(2-thienvI)ethyl]-L-α-glutamϊne

[0395] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[2-(2- thienyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 535.1; MS (ESI) m/z 1069.2; ΗRMS: calcd for C₃₀H₃₄N₂O₅S + H+, 535.22612; found (ESI-FTMS, [M+H]¹⁺), 535.22756. [0396] Step B : tert-butyl N¹-[2-(2-thienyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 313.1; MS (ESI) m/z 625.2; HRMS: calcd for C₁₅H₂₄N₂O₃S + H+, 313.15804; found (ESI-FTMS, [M+H]¹⁺), 313.15788.

[0397] Step C: tert-butyl N²-(biρhenyl-4-ylcarbonyl)-N¹-[2-(2-thienyl)ethyl]-L-α- glutaminate

MS (ESI) m/z 493.2; MS (ESI) m/z 985.4; HRMS: calcd for C₂₈H₃₂N₂O₄S + H+, 493.21555; found (ESI-FTMS, [M+H]¹⁺), 493.21561. [0398] Step D: N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(2-thienyl)ethyl]-L-α-glutamine

MS (ESI) m/z 437.1; MS (ESI) m/z 873.3; HRMS: calcd for C₂₄H₂₄N₂O₄S + H+, 437.15295; found (ESI-FTMS, [M+H]¹⁺), 437.15163.

Example 8XX; ^-(l.l'-biphenyl^-ylcarbonylV^-O-fluorobenzvD-L-α-glutamine

[0399] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(3- fluorobenzyl)-L-α-glutaminate

MS (ESI) m/z 533.2; ΗRMS: calcd for C₃₁H₃₃FN₂O₅ + H+, 533.24463; found

(ESI_FTMS, [M+H]¹⁺), 533.2447.

[0400] Step B: tert-butyl W^3-fluorobenzyl)-L-α-glutaminate

MS (ESI) m/z 311.2; HRMS: calcd for C₁₆H₂₃FN₂O₃ + H+, 311.17655; found

(ESI_FTMS, [M+H]¹⁺), 311.1764.

[0401] Step C: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3-fluorobenzyl)-L- α-glutaminate

MS (ESI) m/z 491.2; MS (ESI) m/z 981.4; HRMS: calcd for C₂₉H₃₁FN₂O₄ + H+,

491.23406; found (ESI_FTMS, [M+H]¹⁺), 491.2339.

[0402] Step D: N²-(l,r-biρhenyl-4-ylcarbonyl)-N¹-(3-fluorobenzyl)-L-α- glutamine

MS (ESI) m/z 435.1; MS (ESI) m/z 869.2; HRMS: calcd for C₂₅H₂₃FN₂O₄ + H+,

435.17146; found (ESI_FTMS, [MH-H]¹⁺), 435.1712.

Example 8YY: ^-(lΛ'-biphenyl^-ylcarbonvD-iV^^-fS-chlorophenvDethvn-L-α- glutaniine

[0403] Step A: tert-butyl N¹-[2-(3-chlorophenyl)ethyl]-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS m/z 03-305496LMS; ΗRMS: calcd for C₃₂H₃₅ClN₂O₅ + H+, 563.23073; found

(ESL_.FTMS, [M+H]¹⁺), 563.2309.

[0404] Step B : <img file="EP1902014A2_D0064.tif" /> N¹-[2-(3-chlorophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 341.1; HRMS: calcd for C₁₇H₂₅ClN₂O₃ + H+, 341.16265; found

(ESLFTMS, [M+H]¹⁺), 341.1611.

[0405] Step C: tert-butyl iV²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-[2-(3- chlorophenyl)ethyl]-L-α-glutaminate MS (ESI) m/z 521.1; MS (ESI) m/z 1041.1; HRMS: calcd for C₃₀H₃₃ClN₂O₄ + H+,

521.22016; found (ESI-FTMS, [M+H]¹⁺), 521.22136.

[0406] Step D: iV²-(l,l^l-biphenyl-4-ylcarbonyl)-iV¹-[2-(3-chlorophenyl)ethyl]-L- α-glutamine

MS (ESI-) m/z 463.2; MS (ESI-) m/z 197; HRMS: calcd for C₂₆H₂₅ClN₂O₄ + H+,

465.15756; found (ESI-FTMS, [M+H]¹⁺), 465.15709.

Example 8ZZ: JV²-(l.l'-biphenyl-4-ylcarbonvI)-iV¹-(2-fluorobenzyl)-L-α-glutamine

[0407] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(2- fluorobenzyl)-L-α-glutaminate

MS (ESI) m/z 533.1; MS (ESI) m/z 1065.1; ΗRMS: calcd for C₃₁H₃₃FN₂O₅ + H+,

533.24463; found (ESI_FTMS, [M+H]¹⁺), 533.24461.

[0408] Step B: tert-butyl N¹-(2-fluorobenzyl)-L-α-glutaminate

MS (ESI) m/z 311.1; MS (ESI) m/z 621.2; HRMS: calcd for C₁₆H₂₃FN₂O₃ + H+,

311.17655; found (ESI_FTMS, [M+H]¹⁺), 311.1762.

[0409] Step C: tert-butyl N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-(2-fluorobenzyl)-L- α-glutaminate

MS (ESI) m/z 491.1; MS (ESI) m/z 981.2; HRMS: calcd for C₂₉H₃₁FN₂O₄ + H+,

491.23406; found (ESI-FTMS, [M+H]¹⁺), 491.23526.

[0410] Step D: iV²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(2-fluorobenzyl)-L-α- glutamine

MS (ESI-) m/z 433.1; HRMS: calcd for C₂₅H₂₃FN₂O₄ + H+, 435.17146; found (ESI-

FTMS, [M+H]¹⁺), 435.17161.

Example 8AAA; ^-(l.l'-biphenvI^-vIcarbonvD-iV^O^-difluorobenzvD-L-α- glutamine

[0411] Step A: tert-butyl N¹-(3,4-difluorobenzyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 551.2; MS (ESI) m/z 1101.4; ΗRMS: calcd for C_3IH₃₂F₂N₂O₅ + H+,

551.23521; found (ESI_FT, [M+H]¹⁺), 551.23407. [0412] Step B: tert-butyl ^-(S^-difluorobenzy^-L-a-glutaminate

MS (ESI) m/z 329; MS (ESI) m/z 657.2; HRMS: calcd for C₁₆H₂₂F₂N₂O₃ + H+,

329.16712; found (ESI_FTMS, [M+H]¹⁺), 329.1664.

[0413] Step C: tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3,4-difluorobenzyl)-

L-α-glutaminate

MS (ESI) m/z 509.1; MS (ESI) m/z 1017.1; HRMS: calcd for C₂₉H₃₀F₂N₂O₄ + H+,

509.22464; found (ESI-FTMS, [M+H]¹⁺), 509.22485.

[0414] Step D: N²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-(3,4-difluorobenzyl)-L-α- glutamine

MS (ESI-) m/z 451.1; HRMS: calcd for C₂₅H₂₂F₂N₂O₄ + H+, 453.16204; found (ESI-

FTMS, [M+H]¹⁺), 453.1614.

Example 8BBB: ^-(Ll'-biphenyl^-ylcarbonvD-iy^fsec-butyn-L-α-glutamine

[0415] Step A: tert-butyl N¹-(sec-butyl)-N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 481.2; ΗRMS: calcd for C₂₈H₃₆N₂O₅ + H+, 481.26970; found (ESI-FTMS,

[M+H]¹⁺), 481.26966.

[0416] Step B: tert-butyl N^sec-butyl)-L-α-glutaminate

MS (ESI) m/z 259.1; HRMS: calcd for C₁₃H₂₆N₂O₃ + H+, 259.20162; found (ESI-FTMS,

[M+H]¹⁺), 259.20164.

[0417] Step C: tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(sec-butyl)-L-α- glutaminate

MS (ESI) m/z 439.2; MS (ESI) m/z 877.4; HRMS: calcd for C₂₆H₃₄N₂O₄ + H+,

439.25913; found (ESI-FTMS, [M+H]¹⁺), 439.25972.

[0418] Step D: N²-(l , 1 '-biρhenyl-4-ylcarbonyl)-N¹-(sec-butyl)-L-α-glutamine

MS (ESI) m/z 383.1; MS (ESI) m/z 765.3; MS (ESI) m/z 441.2; HRMS: calcd for

C₂₂H₂₆N₂O₄ + H+, 383.19653; found (ESI-FTMS, [M+H]¹⁺), 383.19745.

Example 8CCC: ^-(lΛ'-biphenyl^-ylcarbonvD-iV^fcvclopropylmethvD-L-α- glutamine

[0419] Step A: tert-butyl N¹-(cycloρropylmethyl)-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate MS (ESI) m/z 479.2; MS (ESI) m/z 957.3; HRMS: calcd for C₂₈H₃₄N₂O₅ + H+,

479.25405; found (ESI-FTMS, [M+H]¹⁺), 479.25563.

[0420] Step B: tert-butyl ^-(cyclopropylmethyty-L-a-glutaminate

MS (ESI) m/z 257.1; HRMS: calcd for C₁₃H₂₄N₂O₃ + H+, 257.18597; found (ESI-FTMS,

[M+H]¹⁺), 257.18608.

[0421] Step C: tert-butyl iV²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-

(cyclopropylmethyl)-L-α-glutaminate

MS (ESI) m/z 437.2; MS (ESI) m/z 873.3; HRMS: calcd for C₂₆H₃₂N₂O₄ + H+,

437.24348; found (ESI-FTMS, [M+H]¹⁺), 437.24446.

[0422] Step D: N²-(l , 1¹-biphenyl-4-ylcarbonyl)-iV¹-(cyclopropylmethyl)-L-α- glutamine

MS (ESI) m/z 381.1; MS (ESI) m/z 761.2; HRMS: calcd for C₂₂H₂₄N₂O₄ + H+,

381.18088; found (ESI-FTMS, [M+H]¹⁺), 381.18186.

Example 8DDD : JV²-(biphenyl-4-vIcarbonyl)-iV¹-(2-morpholin-4-ylethyl)-L-α- glutamine

[0423] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(2- morpholin-4-ylethyl)-L-α-glutaminate

MS (ESI) m/z 538.3; ΗRMS: calcd for C₃₀H₃₉N₃O₆ + H+, 538.29116; found (ESI-FTMS,

[M+H]¹⁺), 538.29233.

[0424] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-iV^rl-(2-morpholin-4-ylethyl)-

L-α-glutaminate

MS (ESI) m/z 496.2; HRMS: calcd for C₂₈H₃₇N₃O₅ + H+, 496.28060; found (ESI-FTMS,

[M+H]¹⁺), 496.28079.

[0425] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(2-morpholin-4-ylethyl)-L-α- glutamine

MS (ESI) m/z 440.2; HRMS: calcd for C₂₄H₂₉N₃O₅ + H+, 440.21800; found (ESI-FTMS,

[MH-H]¹⁺), 440.21827.

Example 8EEE: ^-(biphenyl^-vIcarbonvD-^JV^diethyl-L-α-glutamine

[0426] Step A: tert-butyl iV¹,N¹-diethyl-N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-

L-α-glutaminate MS (ESI) m/z 481.3; MS (ESI) m/z 961.5; HRMS: calcd for C₂₈H₃₆N₂O₅ + Na+,

503.25164; found (ESI-FTMS, [M+Na]¹⁺), 503.25163.

[0427] Step B: tert-butyl N^-diethyl-L-α-glutaminate

MS (ESI) m/z 259.2; HRMS: calcd for C₁₃H₂₆N₂O₃ + H+, 259.20162; found (ESI-FTMS,

[M+H]¹⁺), 259.20149.

[0428] Step C: tert-butyl iV²-(biphenyl-4-ylcarbonyl)-iV¹,iV¹-diethyl-L-α- glutaminate

MS (ESI) m/z 439.2; MS (ESI) m/z 877.4; HRMS: calcd for C₂₆H₃₄N₂O₄ + H+,

439.25913; found (ESI-FTMS, [M+H]¹⁺), 439.26093.

[0429] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹,ΛT¹-diethyl-L-α-glutamine

MS (ESI) m/z 383.2; MS (ESI) m/z 765.4; HRMS: calcd for C₂₂H₂₆N₂O₄ + H+,

383.19653; found (ESI-FTMS, [M+H]¹⁺), 383.19675.

Example 8FFF: ivVl.r -biphenyl^-ylcarbonvD-iV^fl-phenvIethvD-L-α-gltttamine

[0430] Step A: tert-butyl N²-[(9H-fluoren~9-ylmethoxy)carbonyl]-iV¹-(2- phenylethyl)-L-α-glutaminate

MS (ESI) m/z 529.2; ΗRMS: calcd for C₃₂H₃₆N₂O₅ + H+, 529.26970; found (ESI_FTMS,

[M+H]¹⁺), 529.2693.

[0431] Step B: tert-butyl N¹-(2-ρhenylethyl)-L-α-glutaminate

HRMS: calcd for C₁₇H₂₆N₂O₃ + H+, 307.20162; found (ESI_FTMS, [M+H]¹⁺), 307.2011.

[0432] Step C: tert-butyl N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-(2-phenylethyl)-L-α- glutaminate

MS (ESI) m/z 487.2; MS (ESI) m/z 973.3; HRMS: calcd for C₃₀H₃₄N₂O₄ + H+,

487.25913; found (ESI_FTMS, [M+H]¹⁺), 487.2588.

[0433] Step D: N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(2-phenylethyl)-L-a-glutamine

MS (ESI) m/z 431.2; MS (ESI) m/z 861.3; HRMS: calcd for C₂₆H₂₆N₂O₄ + H+,

431.19653; found (ESI_FTMS, [M+H]¹⁺), 431.1963.

Example 8GGG: iV^d.l'-biphenvI^-vIcarbonvIV^-ra-ftrifluoromethvDbenzyll-L- α-glutamine

[0434] Step A: tert-butyl ΛT²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[3-

(trifluoromethyl)benzyl]-L-α-glutaminate MS (ESI) m/z 583.2; HRMS: calcd for C₃₂H₃₃F₃N₂O₅ + H+, 583.24143; found

(ESLFTMS, [M+H]¹⁺), 583.2409.

[0435] Step B : tert-butyl ^-[S-^rifluoromethy^benzyll-L-α-glutaminate

HRMS: calcd for C₁₇H₂₃F₃N₂O₃ + H+, 361.17335; found (ESI_FTMS, [M+H]¹⁺),

361.173.

[0436] Step C: tert-bniyl ^-(U'-biphenyM-ylcarbonyl^JV¹-^-

(trifluoromethyl)benzyl]-L-α-glutaminate

MS (ESI) m/z 541.2; MS (ESI) m/z 1081.3; HRMS: calcd for C₃₀H₃₁F₃N₂O₄ + H+,

541.23087; found (ESI_FTMS, [M+H]¹⁺), 541.2301.

[0437] Step D: iV²-(l,r-biρhenyl-4-ylcarbonyl)-N¹-[3-(trifluoromethyl)benzyl]-L- α-glutamine

MS (ESl) m/z 485.2; MS (ESI) m/z 969.3; HRMS: calcd for C₂₆H₂₃F₃N₂O₄ + H+,

485.16827; found (ESI_FTMS, [MH-H]¹⁺), 485.1682.

Example 8HHH; JV^dα'-biphenyl^-vIcarbonvD-iV^^-αrifluoromethvnbenzvn-L- ct-glutamine

[0438] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[2-

(trifluoromethyl)benzyl]-L-α-glutaminate

MS (ESI) m/z 583.2; ΗRMS: calcd for C₃₂H₃₃F₃N₂O₅ + H+, 583.24143; found (ESI_FT,

[M+H]¹⁺), 583.24162.

[0439] Step B: tert-butyl N¹-[2-(trifluoromethyl)benzyl]-L-α-glutaminate

HRMS: calcd for C₁₇H₂₃F₃N₂O₃ + H+, 361.17335; found (ESI_FTMS, [M+H]¹⁺),

361.1725.

[0440] Step C: tert-butyl N²-(l , 1 '-biphenyM-ylcarbonyl)-^¹-^-

(trifluoromethyl)benzyl]-L-α-glutaminate

MS (ESI) m/z 541.2; MS (ESI) m/z 1081.2; HRMS: calcd for C₃₀H₃₁F₃N₂O₄ + H+,

541.23087; found (ESI_FTMS, [M+H]¹⁺), 541.23091.

[0441] Step D: iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-[2-(trifluoromethyl)benzyl]-L- α-glutamine

MS (ESI) m/z 485; MS (ESI) m/z 969; HRMS: calcd for C₂₆H₂₃F₃N₂O₄ + H+, 485.16827; found (ESI_FTMS, [MH-H]¹⁺), 485.168.

Ill Example 8III: iV²-(l,l'-biphenvI-4-ylcarbonvI)-N¹-(4-methylbenzyl)-L-α-glutamine

[0442] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV^rl-(4- methylbenzyl)-L-α-glutaminate

MS (ESI) m/z 529.2; MS (ESI) m/z 1057.4; ΗRMS: calcd for C₃₂H₃₆N₂O₅ + H+,

529.26970; found (ESI_FT, [M+H]¹⁺), 529.26796.

[0443] Step B: tert-butyl N¹-(4-methylbenzyl)-L-α-glutaminate

HRMS: calcd for C₁₇H₂₆N₂O₃ + H+, 307.20162; found (ESI-FTMS, [M+H]¹⁺),

307.20274.

[0444] Step C: tert-butyl N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-(4-methylbenzyl)-L- α-glutaminate

HRMS: calcd for C₃₀H₃₄N₂O₄ + H+, 487.25913; found (ESI-FTMS, [M+H]¹⁺),

487.25856.

[0445] Step D: iV²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-(4-methylbenzyl)-L-α- glutamine

HRMS: calcd for C₂₆H₂₆N₂O₄ + H+, 431.19653; found (ESI-FTMS, [M+H]¹⁺),

431.19627.

Example 8.T.T.T: N²-(1Λ ' -biphenyl^-ylcarbonvD-^-heptyl-L-α-glutamine

[0446] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-heptyl-L-α- glutaminate

MS (ESI) m/z 523.3; MS (ESI) m/z 1045.5; ΗRMS: calcd for C₃₁H₄₂N₂O₅ + H+,

523.31665; found (ESI-FTMS, [M+H]¹⁺), 523.31783.

[0447] Step B: tert-butyl Λ^-heptyl-L-α-glutaminate

HRMS: calcd for C₁₆H₃₂N₂O₃ + H+, 301.24857; found (ESI-FTMS, [M+H]¹⁺), 301.2499.

[0448] Step C: tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-heptyl-L-α- glutaminate

HRMS: calcd for C₂₉H₄₀N₂O₄ + H+, 481.30608; found (ESI-FTMS, [MH-H]¹⁺),

481.30706.

[0449] Step D: Λ/²-(l,l'-biphenyl-4-ylcarbonyl)-iV^rl-heptyl-L-α-glutamine

HRMS: calcd for C₂₅H₃₂N₂O₄ + H+, 425.24348; found (ESI-FTMS, [MH-H]¹⁺),

425.24417. Example 8KKK; iV³-(biphenyl-4-ylcarbonyl)-iV¹-r2-(4-bromophenyl)ethvn-L-α- glutamine

[0450] Step A: tert-butyl iV¹-[2-(4-bromophenyl)ethyl]-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 607.1; ΗRMS: calcd for C₃₂H₃₅BrN₂O₅ + H+, 607.18021; found (ESI-

FTMS, [M+H]¹⁺), 607.18182.

[0451] Step B : tert-butyl Λ/'¹-[2-(4-bromoρhenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 385; HRMS: calcd for C₁₇H₂₅BrN₂O₃ + H+, 385.11213; found (ESI-FTMS,

[M+H]¹⁺), 385.11309.

[0452] Step C: tert-butyl iV²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4- bromophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 565.1; MS (ESI) m/z 1129.1; HRMS: calcd for C₃₀H₃₃BrN₂O₄ + H+,

565.16965; found (ESI-FTMS, [M+H]¹⁺), 565.17.

[0453] Step D: N²-(biρhenyl-4-ylcarbonyl)-iV¹-[2-(4-bromophenyl)etliyl]-L-α- glutamine

MS (ESI) m/z 507.2; HRMS: calcd for C₂₆H₂₅BrN₂O₄ + H+, 509.10705; found (ESI-

FTMS, [M+H]¹⁺), 509.10906.

Example 8LLL; ^-(biphenyl^-ylcarbonvD-^-O^-dimethylbtttvD-L-α-glutamine

[0454] Step A: tert-butyl iV¹-(3,3-dimethylbutyl)-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 509.3; MS (ESI) m/z 1017.5; ΗRMS: calcd for C₃₀H₄₀N₂O₅ + H+,

509.30100; found (ESI-FTMS, [M+H]¹⁺), 509.30165.

[0455] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-(3,3-dimethylbutyl)-L-α- glutaminate

MS (ESI) m/z 467.3; MS (ESI) m/z 933.5; MS (ESI) m/z 489.3; HRMS: calcd for

C₂₈H₃₈N₂O₄ + H+, 467.29043; found (ESI-FTMS, [M+H]¹⁺), 467.29134.

[0456] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(3,3-dimethylbutyl)-L-α-glutamine

HRMS: calcd for C₂₄H₃₀N₂O₄ + H+, 411.22783; found (ESI-FTMS, [MH-H]¹⁺),

411.22929. Example 8MMM: JV²-(biphenyI-4-vIcarbonylViV¹-r2-(3-bromophenyl)ethyl1-L-α- glutamine

[0457] Step A: tert-butyl iV¹-[2-(3-bromophenyl)ethyl]-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl] -L-α-glutaminate

MS (ESI) m/z 607.1; MS (ESI) m/z 1213.3; ΗRMS: calcd for C₃₂H₃₅BrN₂O₅ + H+,

607.18021; found (ESI-FTMS, [M+H]¹⁺), 607.18017.

[0458] Step B: tert-butyl N¹-[2-(3-bromophenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 385.1; MS (ESI) m/z 769.2; HRMS: calcd for C₁₇H₂₅BrN₂O₃ + H+,

385.11213; found (ESI-FTMS, [M+H]¹⁺), 385.11175.

[0459] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(3- bromophenyl)ethyl]-L-α-glutaminate

HRMS: calcd for C₃₀H₃₃BrN₂O₄ + H+, 565.16965; found (ESI-FTMS, [M+H]¹⁺),

565.16854.

[0460] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(3-bromophenyl)ethyl]-L-α- glutamine

HRMS: calcd for C₂₆H₂₅BrN₂O₄ + H+, 509.10705; found (ESI-FTMS, [M+H]¹⁺),

509.10648.

Example 8NNN: JV²-(l.l'-biphenyl-4-ylcarbonvn-iV¹-r4-fluoro-3-

(trifluoromethyl)benzyl]-L-α-glutamine

[0461] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[4-fluoro-3-

(trifluoromethyl)benzyl]-L-α-glutaminate

MS (ESI) m/z 601.2; MS (ESI) m/z 1201.3; ΗRMS: calcd for C₃₂H₃₂F₄N₂O₅ + H+,

601.23201; found (ESI-FTMS, [M+H]¹⁺), 601.23172.

[0462] Step B: tert-butyl V-^-fluoro-S-^ifluoromethy^benzyll-L-α-glutaminate

HRMS: calcd for C₁₇H₂₂F₄N₂O₃ + H+, 379.16393; found (ESI-FTMS, [M+H]¹⁺),

379.16566.

[0463] Step C: tert-butyl N²-(l , 1 '-biphenyl-4-ylcarbonyl)-N¹-[4-fluoro-3-

(trifluoromethyl)benzyl]-L-α-glutaminate

HRMS: calcd for C₃₀H₃₀F₄N₂O₄ + H+, 559.22145; found (ESI-FTMS, [M+H]¹⁺),

559.22077. [0464] Step D: N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-[4-fluoro-3-

(trifluoromethyl)benzyl]-L-α-glutamine

HRMS: calcd for C₂₆H₂₂F₄N₂O₄ + H+, 503.15885; found (ESI-FTMS, [M+H]¹⁺),

503.1582.

Example SOOOt ^-fbiphenvI^-ylcarbonvD-^-Q^-diphenylpropyD-L-α-glutamine

[0465] Step A: tert-butyl N^S^-diphenylpropylVΛ^-KΘH-fluoren-θ- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 619.3; MS (ESI) m/z 1237.6; HRMS: calcd for C₃₉H₄₂N₂O₅ + H+,

619.31665; found (ESI-FTMS, [M+H]¹⁺), 619.31658.

[0466] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-iV¹-(3,3-diphenylpropyl)-L- α-glutaminate

HRMS: calcd for C₃₇H₄₀N₂O₄ + H+, 577.30608; found (ESI-FTMS, [M+H]¹⁺),

577.30483.

[0467] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(3,3-diphenylρropyl)-L-α- glutamine

HRMS: calcd for C₃₃H₃₂N₂O₄ + H+, 521.24348; found (ESI-FTMS, [M+H]¹⁺),

521.24166.

Example 8PPP: N²-(biphenyl-4-ylcarbonyl)-iV¹-isopropyl-L-α-glutamine

[0468] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-isopropyl-L- α-glutaminate

MS (ESI) m/z 467.2; MS (ESI) m/z 933.5; ΗRMS: calcd for C₂₇H₃₄N₂O₅ + Na+,

489.23599; found (ESI-FTMS, [M+Na]¹⁺), 489.23577.

[0469] Step C: tert-butyl N^φiphenyM-ylcarbony^-Λ^-isopropyl-L-α- glutaminate

MS (ESI) m/z 425.2; MS (ESI) m/z 441.2; MS (ESI) m/z 871.4; HRMS: calcd for

C₂₅H₃₂N₂O₄ + Na+, 447.22543; found (ESI-FTMS, [M+Na]¹⁺), 447.22701.

[0470] Step D: Λ/²-(biphenyl-4-ylcarbonyl)-N¹-isopropyl-L-α-glutamine

MS (ESI) m/z 367.2; MS (ESI) m/z 735.3; MS (ESI) m/z 481.2; HRMS: calcd for

C₂₁H₂₄N₂O₄ + Na+, 391.16283; found (ESI-FTMS, [M+Na]¹⁺), 391.16451. Example 8QQQ: JV^-Cbiphenyl^-ylcarbonvD-^-fpyridin^-ylmethvD-L-α-glutamine

[0471] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(ρyridin-4- ylmethyl)-L-α-glutaminate

MS (ESI) m/z 516.3; ΗRMS: calcd for C₃₀H₃₃N₃O₅ + H+, 516.24930; found (ESI_FTMS,

[M+H]¹⁺), 516.24875.

[0472] Step C: tert-butyl iV²-(biphenyl-4-ylcarbonyl)-N¹-(pyridin-4-ylmethyl)-L- α-glutaminate

MS (ESl) m/z 474.2; HRMS: calcd for C₂₈H₃₁N₃O₄ + H+, 474.23873; found (ESI-FTMS,

[M+H]¹⁺), 474.24265.

[0473] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(ρyridin-4-ylmethyl)-L-α- glutamine

HRMS: calcd for C₂₄H₂₃N₃O₄ + H+, 418.17613; found (ESI-FTMS, [M+H]¹⁺),

418.17812.

Example 8RRR: iV²-(biphenyl-4-ylcarbonyl)-N¹-pentyl-L-α-glutamine

[0474] Step A: tert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-pentyl-L-α- glutaminate

MS (ESI) m/z 495.2; MS (ESI) m/z 989.5; ΗRMS: calcd for C₂₉H₃₈N₂O₅ + Na+,

517.26729; found (ESI-FTMS, [M+Na]¹⁺), 517.26785.

[0475] Step B: fert-butyl iV^pentyl-L-α-glutaminate

MS (ESI) m/z 273.2; HRMS: calcd for C₁₄H₂₈N₂O₃ + H+, 273.21727; found (ESI-FTMS,

[M+H]¹⁺), 273.21761.

[0476] Step C: tert-butyl Λ7²-(biphenyl-4-ylcarbonyl)-iV¹-pentyl-L-α-glutaminate

MS (ESI) m/z 453.2; MS (ESI) m/z 905.5; HRMS: calcd for C₂₇H₃₆N₂O₄ + H+,

453.27478; found (ESI-FTMS, [M+H]¹⁺), 453.27694.

[0477] Step D: N²-(biphenyl-4-ylcarbonyl)-iV¹-pentyl-L-α-glutamine

MS (ESI) m/z 397.2; MS (ESI) m/z 793.4; HRMS: calcd for C₂₃H₂₈N₂O₄ + H+,

397.21218; found (ESI-FTMS, [M+H]¹⁺), 397.2136.

Example 8SSS: JV²-fbiphenvl-4-ylcarbonvlViV¹-(ter/-butvl)-L-α-glutamϊne [0478] Step A: tert-butyl N¹-(tert-butyl)-N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 481.2; MS (ESI) m/z 961.5; ΗRMS: calcd for C₂₈H₃₆N₂O₅ + H+,

481.26970; found (ESI-FTMS, [MH-H]¹⁺), 481.27074.

[0479] Step B: tert-butyl ^-(tert-buty^-L-α-glutaminate

MS (ESI) m/z 259.1; MS (ESI) m/z 517.3; HRMS: calcd for C₁₃H₂₆N₂O₃ + H+,

259.20162; found (ESI-FTMS, [M+H]¹⁺), 259.20174.

[0480] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-(tert-butyl)-L-α- glutaminate

MS (ESI) m/z 439.2; MS (ESI) m/z 877.4; HRMS: calcd for C₂₆H₃₄N₂O₄ + H+,

439.25913; found (ESI-FTMS, [M+H]¹⁺), 439.25922.

[0481] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(tert-butyl)-L-α-glutamine

MS (ESI) m/z 383.2; MS (ESI) m/z 765.3; HRMS: calcd for C₂₂H₂₆N₂O₄ + H+,

383.19653; found (ESI-FTMS, [MH-H]¹⁺), 383.19812.

Example 8TTT: ^-(biphenyl^-ylcarbonvn-iV^d-methyl-l-phenylethvD-L-α- glutamine

[0482] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(l-methyl-

1 -phenylethyl)-L-α-glutaminate

MS (ESI) m/z 543.2; MS (ESI) m/z 1085.4; ΗRMS: calcd for C₃₃H₃₈N₂O₅ + H+,

543.28535; found (ESI-FTMS, [MH-H]¹⁺), 543.28707.

[0483] Step B: tert-butyl ^-(l-methyl-l-phenylethy^-L-α-glutaminate

MS (ESI) m/z 321.1; MS (ESI) m/z 641.3; HRMS: calcd for C₁₈H₂₈N₂O₃ + H+,

321.21727; found (ESI-FTMS, [MH-H]¹⁺), 321.21716.

[0484] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹ -(I -methyl- 1- phenylethyl)-L-α-glutaminate

MS (ESI) m/z 501.2; MS (ESI) m/z 1001.4; HRMS: calcd for C₃₁H₃₆N₂O₄ + H+,

501.27478; found (ESI-FTMS, [MH-H]¹⁺), 501.27462.

[0485] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(l-methyl-l-phenylethyl)-L-α- glutamine

HRMS: calcd for C₂₇H₂₈N₂O₄ + H+, 445.21218; found (ESI-FTMS, [MH-H]¹⁺),

445.21311. Example 8UUU: JV²-(biphenyl-4-ylcarbonyl)-iV¹-(2.,2-dimethylpropyl)-L-α-glutamine

[0486] Step A: tert-butyl iV¹-(2,2-dimethylpropyl)-iV²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 495.2; MS (ESI) m/z 989.4; ΗRMS: calcd for C₂₉H₃₈N₂O₅ + H+,

495.28535; found (ESI-FTMS, [M+H]¹⁺), 495.2859.

[0487] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-(2,2-dimethylρropyl)-L- α-glutaminate

MS (ESI) m/z 453.2; MS (ESI) m/z 905.4; HRMS: calcd for C₂₇H₃₆N₂O₄ + H+,

453.27478; found (ESI-FTMS, [M+H]¹⁺), 453.2764.

[0488] Step D: N²-(biphenyl-4-ylcarbonyl)-N¹-(2,2-dimethylproρyl)-L-α- glutamine

MS (ESI) m/z 397.1; MS (ESI) m/z 793.3; HRMS: calcd for C₂₃H₂₈N₂O₄ + H+,

397.21218; found (ESI-FTMS, [M+H]¹⁺), 397.21242.

Example 8VW: iV²-(biphenyl-4-ylcarbonvI)-N¹-hexyl-L-α-glutamine

[0489] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-hexyl-L-α- glutaminate

MS (ESI) m/z 509.3; MS (ESI) m/z 1017.5; ΗRMS: calcd for C₃₀H₄₀N₂O₅ + H+,

509.30100; found (ESI-FTMS, [M+H]¹⁺), 509.30265.

[0490] Step B: tert-butyl ^-hexyl-L-α-glutaminate

HRMS: calcd for C₁₅H₃₀N₂O₃ + H+, 287.23292; found (ESI-FTMS, [M+H]¹⁺),

287.23282.

[0491] Step C: tert-butyl ^-(biphenyl^-ylcarbony^-^-hexyl-L-a-glutaminate

MS (ESI) m/z 4612; MS (ESI) m/z 933.4; HRMS: calcd for C₂₈H₃₈N₂O₄ + H+,

467.29043; found (ESI-FTMS, [M+H]¹⁺), 467.29169.

[0492] Step D: iV²-(biphenyl-4-ylcarbonyl)-N¹-hexyl-L-α-glutamine

MS (ESI) m/z 411.1; MS (ESI) m/z 821.3; HRMS: calcd for C₂₄H₃₀N₂O₄ + H+,

411.22783; found (ESI-FTMS, [M+H]¹⁺), 411.22833.

Example 8WWW: iV²-(biphenvl-4-vlcarbonvl)-N¹-(5-hydroxypentyl)-L-α-glutamine [0493] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV^rl-(5- hydroxypentyl)-L-α-glutaminate

MS (ESI) m/z 511.2; MS (ESI) m/z 1021.4; ΗRMS: calcd for C₂₉H₃₈N₂O₆ + H+,

511.28026; found (ESI-FTMS, [M+H]¹⁺), 511.28078.

[0494] Step B: tert-butyϋV¹-(5-hydroxypentyl)-L-α-glutaminate

HRMS: calcd for C₁₄H₂₈N₂O₄ + H+, 289.21218; found (ESI-FTMS, [M+H]¹⁺),

289.21245.

[0495] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-(5-hydroxyρentyl)-L-α- glutaminate

HRMS: calcd for C₂₇H₃₆N₂O₅ + H+, 469.26970; found (ESI-FTMS, [M+H]¹⁺),

469.27133.

[0496] Step D: N²-(biphenyl-4-ylcarbonyl)-iV¹-(5-hydroxypentyl)-L-α-glutamine

HRMS: calcd for C₂₃H₂₈N₂O₅ + H+, 413.20710; found (ESI-FTMS, [M+H]¹⁺),

413.20657.

Example 8XXX: ^-(biphenyl^-ylcarbonvD-^-fό-hydroxyhexyD-L-α-glutamine

[0497] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-ΛT¹-(6- hydroxyhexyl)-L-α-glutaminate

MS (ESI) m/z 525.2; MS (ESI) m/z 1049.4; ΗRMS: calcd for C₃₀H₄₀N₂O₆ + Na+,

547.27786; found (ESI-FTMS, [M+Na]¹⁺), 547.27869.

[0498] Step B: tert-butyl ^-(δ-hydroxyhexy^-L-α-glutaminate

HRMS: calcd for C₁₅H₃₀N₂O₄ + H+, 303.22783; found (ESI-FTMS, [M+H]¹⁺),

303.22841.

[0499] Step C: tert-butyl iV²-(biphenyl-4-ylcarbonyl)-N¹-(6-hydroxyhexyl)-L-α- glutaminate

HRMS: calcd for C₂₈H₃₈N₂O₅ + H+, 483.28535; found (ESI-FTMS, [M+H]¹⁺),

483.28725.

[0500] Step D: iV²-(biphenyl-4-ylcarbonyl)-iV¹-(6-hydroxyhexyl)-L-α-glutarnine

HRMS: calcd for C₂₄H₃₀N₂O₅ + H+, 427.22275; found (ESI-FTMS, [M+H]¹⁺),

427.22304.

Example 8YYY: ^-(biphenvI^-ylcarbonvD-^-propyl-L-α-glutainine [0501] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-proρyl-L-α- glutaminate

MS (ESI) m/z 467.1; MS (ESI) m/z 933.1; MS (ESI) m/z 955.1; ΗRMS: calcd for

C₂₇H₃₄N₂O₅ + H+, 467.25405; found (ESI-FTMS, [M+H]¹⁺), 467.25527.

[0502] Step B : tert-butyl iV^propyl-L-α-glutaminate

MS (ESI) m/z 245.1; MS (ESI) m/z 489.2; HRMS: calcd for C₁₂H₂₄N₂O₃ + H+,

245.18597; found (ESI-FTMS, [M+H]¹⁺), 245.1861.

[0503] Step C: tert-butyl Λ^-φiphenyl^-ylcarbony^-N^propyl-L-α-glutaminate

HRMS: calcd for C₂₅H₃₂N₂O₄ + H+, 425.24348; found (ESI-FTMS, [M+H]¹⁺),

425.24455.

[0504] Step D: /^-(biphenyl^-ylcarbony^-N^propyl-L-α-glutamine

HRMS: calcd for C₂₁H₂₄N₂O₄ + H+, 369.18088; found (ESI-FTMS, [M+H]¹⁺),

369.18091.

Example 8ZZZ; N²-(biphenyl-4-ylcarbonyl)-N¹-r4-(dimethylamino)benζyl]-L-α- glutamine

[0505] Step A: tert-butyl N¹-[4-(dimethylamino)benzyl]-N²-[(9H-fluoren-9- ylmethoxy)carbonyl]-L-α-glutaminate

MS (ESI) m/z 558.2; ΗRMS: calcd for C₃₃H₃₉N₃O₅ + H+, 558.29625; found (ESI-FTMS,

[M+H]¹⁺), 558.29668.

[0506] Step B: tert-butyl ^-^-(dimethylamino^enzylJ-L-α-glutaminate

MS (ESI) m/z 336.2; MS (ESI) m/z 671.3; HRMS: calcd for C₁₈H₂₉N₃O₃ + H+,

336.22817; found (ESI-FTMS, [M+H]¹⁺), 336.22836.

[0507] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[4-

(dimethylamino)benzyl]-L-α-glutaminate

MS (ESI) m/z 516.2; HRMS: calcd for C₃₁H₃₇N₃O₄ + H+, 516.28568; found (ESI-FTMS,

[M+H]¹⁺), 516.28631.

[0508] Step D: iV²-(biρhenyl-4-ylcarbonyl)-N¹-[4-(dimethylamino)benzyl]-L-α- glutamine

MS (ESI) m/z 460.1; HRMS: calcd for C₂₇H₂₉N₃O₄ + H+, 460.22308; found (ESI-FTMS,

[M+H]¹⁺), 460.22347. Example 8AAA A: iV¹-(4-aininobenzyl)-iV²-(l.l' -biphenyl-4-ylcarbonyI)-L-ot- glutamine

[0509] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(4- nitrobenzyl)-L-α-glutaminate

MS (EST) m/z 560.3; MS (ESI) m/z 1119.5; ΗRMS: calcd for C₃₁H₃₃N₃O₇ + H+,

560.23913; found (ESI_FTMS, [M+H]¹⁺), 560.23944.

[0510] Step B: tert-butyl N¹-(4-nitrobenzyl)-L-α-glutaminate

MS (ESI) m/z 338.2; HRMS: calcd for C₁₆H₂₃N₃O₅ + H+, 338.17105; found (ESI-FTMS,

[M+H]¹⁺), 338.17116.

[0511] Step C: tert-butyl iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(4-nitrobenzyl)-L-a- glutaminate

MS (ESI) m/z 518.2; MS (ESI) m/z 1035.5; HRMS: calcd for C₂₉H₃₁N₃O₆ + H+,

518.22856; found (ESI-FTMS, [M+H]¹⁺), 518.22861.

[0512] Step C : Reductive alkylation of tert-butyl N²-(l,l'-biphenyl-4- ylcarbonyl)-N¹-(4-nitrobenzyl)-L-α-glutaminate with 30 % formalin in water and 10 %

Pd/C gave tert-butyl A/^rl-(4-aminobenzyl)-N²-(l,r-biphenyl-4-ylcarbonyl)-L-a- glutaminate

MS (ESI) m/z 488.2; MS (ESI) m/z 975.4; HRMS: calcd for C₂₉H₃₃N₃O₄ + H+,

488.25438; found (ESI_FTMS, [M+H]¹⁺), 488.2542.

[0513] Step D: N¹-(4-aminobenzyl)-N²-(l,r-biphenyl-4-ylcarbonyl)-L-α- glutamine

MS (ESI) m/z 432.2; HRMS: calcd for C₂₅H₂₅N₃O₄ + H+, 432.19178; found (ESI_FTMS,

[M+H]¹⁺), 432.1915.

Example SBBBBi ^-fbiphenyl^-ylcarbonvD-^-β-fdimethylamino^benzvn-L-α- glutamine

[0514] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(3- nitrobenzyl)-L-α-glutaminate

MS (ESI) m/z 560.3; MS (ESI) m/z 1119.4; ΗRMS: calcd for C₃₁H₃₃N₃O₇ + H+,

560.23913; found (ESI_FTMS, [M+H]¹⁺), 560.23892. [0515] Step B: tert-butyl ^-(B-nitrobenzyty-L-α-glutaminate

MS (ESI) m/z 338.1; MS (ESI) m/z 675.3; HRMS: calcd for C₁₆H₂₃N₃O₅ + H+, 338.17105; found (ESI-FTMS, [M+H]¹⁺), 338.17102.

[0516] Step C: tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3-nitrobenzyl)-L-α- glutaminate

MS (ESI) m/z 518.2; MS (ESI) m/z 1035.4; HRMS: calcd for C₂₉H₃₁N₃O₆ + H+, 518.22856; found (ESI-FTMS, [MH-H]¹⁺), 518.22868. [0517] Step C : Reductive alkylation of tert-butyl N²-(l, 1 -biρhenyl-4- ylcarbonyl)-N¹-(3-nitrobenzyl)-L-α-glutaminate 30 % formalin and 10% Pd/C gave tert- butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[3-(dimethylarnino)benzyl]-L-α-glutarninate MS (ESI) m/z 516.2; HRMS: calcd for C₃₁H₃₇N₃O₄ + H+, 516.28568; found (ESI-FTMS, [M+H]¹⁺), 516.28548.

[0518] Step D: N²-(biρhenyl-4-ylcarbonyl)-iV¹-[3-(dimethylamino)benzyl]-L-α- glutamine

MS (ESI) m/z 460.3; HRMS: calcd for C₂₇H₂₉N₃O₄ + H+, 460.22308; found (ESI-FTMS, [M+H]¹⁺), 460.22304.

Example SCCCCi ^-fLl'-biphenyl^-ylcarbonvD-JV^O-nitrobenzyn-L-α-glutamine

[0519] MS (ESI) m/z 462.2; MS (ESI) m/z 923.2; HRMS: calcd for C₂₅H₂₃N₃O₆ +

H+, 462.16596; found (ESI_FTMS, [M+H]¹⁺), 462.16599.

Example 8DDDD: JV^O-aminobenzvD-^-dΛ'-biphenyl^-ylcarbonvD-L-α- glutamine

[0520] HRMS: calcd for C₂₅H₂₅N₃O₄ + H+, 432.19178; found (ESI_FTMS,

[M+H]¹⁺), 432.1917.

Example 8EEEE; iV'-benzyl- iV²-α,l'-biphenvI-4-ylcarbonyl)-L-α-glutamϊne

[0521] Step A: tert-butyl N¹-benzyl-iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-L-α- glutaminate

MS (ESI) m/z 458 (M-tBut).

[0522] Step B: tert-butyl iV^benzyl-L-α-glutaminate

MS (ESI) m/z 293. [0523] Step C: fert-butyl ^-benzyl-N^U'-biphenyM-ylcarbonyl^L-α- glutaminate

MS (ESI) m/z 473.

[0524] Step D: N^benzyl-Λ^-ClJ'-biphenyl^-ylcarbony^-L-α-glutamine

MS (ESI) m/z All.

Example 8FFFF: N²-(biphenyl-4-vIcarbonyl)-iV¹42-(4-fluorophenvI)-l.l- dimethyIethyl]-D-α-glutamine

[0525] Step A: fert-butyl iV²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -D-α-glutaminate

Described as above according to the procedure of Example 7, except Fmoc-D-Glu-

(OtBu)-OH was used as starting material for the first step. HRMS: calcd for

C₃₄H₃₉FN₂O₅ + H+, 575.29158; found (ESI-FTMS, [M+H]¹⁺), 575.2927.

[0526] Step B: fcrt-butyl N¹-[2-(4-fluoroρhenyl)-l,l-dimethylethyl]-D-α- glutaminate

HRMS: calcd for Cj₉H₂₉FN₂O₃ + H+, 353.22350; found (ESI-FTMS, [M+H]¹⁺),

353.22483.

[0527] Step C: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-fluorophenyl)-l,l- dimethylethyl]-D-α-glutaminate

HRMS: calcd for C₃₂H₃₇FN₂O₄ + H+, 533.28101; found (ESI-FTMS, [M+H]¹⁺),

533.28347.

[0528] Step D: iV²-(biρhenyl-4-ylcarbonyl)-N¹-[2-(4-fluoroρhenyl)-l,l- dimethylethyl] -D-α-glutamine

MS (ESI) m/z All. I; MS (ESI) m/z 499; MS (ESI) m/z 953.1; HRMS: calcd for

C₂₈H₂₉FN₂O₄ + H+, 477.21841; found (ESI-FTMS, [M+H]¹⁺), 477.21815.

Example 8GGGG; N²-(biphenvI-4-vIcarbonyl)-iV¹-r2-(4-fluorophenvI)-l.l- dimethylethvn-ot-glutamine

[0529] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-[2-(4- fluorophenyl)- 1 , 1 -dimethylethyl] -α-glutaminate Described as above according to the procedure of Example 7, except Fmoc-DL-Glu-

(OtBu)-OH (racemic mixture) was used as starting material for the first step. HRMS: calcd for C₃₄H₃₉FN₂O₅ + H+, 575.29158; found (ESI-FTMS, [M+H]¹⁺), 575.29217.

[0530] Step B: tert-butyl iV¹-[2-(4-fluorophenyl)-l,l-dimethylethyl]-α- glutaminate

HRMS: calcd for C₁₉H₂₉FN₂O₃ + H+, 353.22350; found (ESI-FTMS, [M+H]¹⁺),

353.22429.

[0531] Step C: tert-butyl Λ/²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4-fluorophenyl)-l ,1- dimethylethyl]-α-glutaminate

HRMS: calcd for C₃₂H₃₇FN₂O₄ + H+, 533.28101; found (ESI-FTMS, [M+H]¹⁺),

533.28268.

[0532] Step D: N²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4-fluorophenyl)-l,l- dimethylethyl] -α-glutamine

MS (ESI) m/z 477.1; MS (ESI) m/z 953.1; HRMS: calcd for C₂₈H₂₉FN₂O₄ + H+,

477.21841; found (ESI-FTMS, [M+H]¹⁺), 477.21805.

Example 8HHHH: 4-Benzylcarbamoyl-4-r4-(pyrimidin-2-vIamino)-benzoylamino- butyric acid tert-butyric acid

[0533] Step C: 4-Benzylcarbamoyl-4-[4-(pyrimidin-2-ylamino)-benzoylamino- butyric acid tert-butyl ester

MS (ESI) m/z 488.

[0534] Step D: 4-Benzylcarbamoyl-4-[4-(pyrimidin-2-ylaniino)-benzoylamino~ butyric acid tert-butyric acid

MS (ESI) m/z 432.

Example SIIIIt ^-rP-g-fluoren-l-ylcarbonvD-^-fS-phenylpropyD-L-α-glutamine

[0535] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]- N¹ -{3- phenylpropyl)-L-α-glutaminate l,9(Fmoc)L-glutamic acid -tert-butylester monohydrate (1.33g, 3.00mmol) was dissolved in DMF (8mL) under nitrogen. BOP (1.33g, 3.00mmol) was added as a solid, followed by 3-phenyl-l-propylamine (427mL, 3mmol). Finally DIEA (627mL, 3.6mmol) was added dropwise. The reaction was monitored by TLC, and stirred for 24 hrs. The reaction mixture was then added to stirring H₂O (40OmL). After stirring for 1 hour, clumps of white solid were formed. The clumps were broken up with a spatula and stirred for an additional 30 minutes. The solid was filtered and washed with H₂O. The solid was then dissolved in CH₂Cl₂ and dried with Na₂SO4. The solution was filtered and concentrated, leaving a white solid. The solid was dissolved in minimal acetone and hexanes were added. The solvents were then removed and the white solid was dried under vacuum. Yield 1.58g of tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]- ^-(3- phenylpropyl)-L-α-glutaminate at 97% yield.

MS (ESI) m/z 543.3; HRMS: calcd for C₃₃H₃₈N₂O₅ + H+, 543.2853; found (ESI-FTMS, [M+H]¹⁺), 543.2847.

[0536] Step B: tert-butyl ^-(S-phenylpropy^-L-α-glutaminate rert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-(3-phenylpropyl)-L-α-glutaminate (1.5g, 2.76mmol) was partially dissolved in CH₃CN (15mL). DEA (2.9mL, 27.6mmol) was added, which was fully dissolved within 10 minutes. The reaction was monitored by TLC and was complete at 2 hrs. The solvent was removed and the remaining material dried under vacuum. The material was purified on a short silica column using 5%Acetone/CH₂Cl ₂ to elute the Fmoc by-product and then 50%Acetone/CH₂Cl₂ to elute the product. The clear oil present at the end was dried shortly under vacuum, and then taken to the next step immediately. It was never fully solvent free so the yield of tert- butyl N¹-(3-ρhenylpropyl)-L-α-glutaminate was 1.65g, and was assumed to be quantitative. MS (ESI) m/z 321.2; MS (ESI) m/z 641.4; HRMS: calcd for C₁₈H₂₈N₂O₃ + H+, 321.2173; found (ESI-FTMS, [M+H]¹⁺), 321.2167.

[0537] Step C: tert-butyl N²-(9H-fluoren-2-ylcarbonyl)-N¹-(3-ρhenylpropyl)-L-α- glutaminate

Tβrt-butyl N¹-(3-phenylpropyl)-L-α-glutaminate (350mg, 1.09mmol) was dissolved in DMF (5mL), in a 2OmL vial under nitrogen. 2-Fluorenecarboxylic acid (229mg, 1.09mmol) and BOP (53Omg, 1.20mmol) were added as solids and dissolved. Finally DIEA (228mL, 1.31mmol) was added, and the reaction stirred overnight. Monitored by TLC, the reaction was complete after stirring overnight. The reaction mixture was added to H₂O (10OmL), precipitating a pale yellow solid. The solid was filtered and dried in a dessicator overnight. Once dry, the solid was taken up in a small amount of acetone, and hexanes were added to precipitate a pale yellow solid. The solid was filtered, washed with hexanes and dried in a dessicator. Yield 293mg of tert-butyl iV²-(9H-fluoren-2- ylcarbonylV^-β-phenylpropyO-L-α-glutarrήnate at 52% yield. MS (ESI) m/z 513.3; MS (ESI) m/z 1025.6; MS (EST) m/z 535.3; ΗRMS: calcd for C₃₂H₃₆N₂O₄ + H+, 513.27478; found (ESI-FTMS, [MH-H]¹⁺), 513.2766.

[0538] Step D: iV²-(9H-fluoren-2-ylcarbonyl)-iV¹-(3-phenylproρyl)-L-α-glutamine

Tert-butyl iV²-(9H-fluoren-2-ylcarbonyl)-N¹-(3-phenylpropyl)-L-a-glutaminate (273mg, 0.533mmol) was dissolved in CH₂Cl₂ (1.5mL). TFA (1.23mL, 16.0mmol) was diluted in CH₂Cl₂ (2mL) and was then slowly added to the first solution. The reaction was monitored by TLC and complete at 2 hrs. The solvent was removed with a nitrogen blower and the remaining yellow oil dried under vacuum. The yellow oil was then dissolved in minimal acetone and hexanes was added precipitating a white solid. The solid was filtered, washed with hexanes and then dried under vacuum. The reaction yielded 194mg of iV²-(9H-fluoren-2-ylcarbonyl)-N¹-(3-phenylρropyl)-L-α-glutamine at an 80% yield. MS (ESI) m/z 457.3; MS (ESI) m/z 913.5.

Example S.T.TXTi ^-CgΗ-fluoren-l-ylcarbonv^-^-O-phenylpropyD-L-α-glutamine

[0539] Step C: tert-butyl iV²-(9H-fluoren-l-ylcarbonyl)-N¹-(3-phenylproρyl)-L-α- glutaminate

MS (ESI) m/z 513.3; MS (ESI) m/z 1025.6; ΗRMS: calcd for C₃₂H₃₆N₂O₄ + H+,

513.27478; found (ESI-FTMS, [M+H]¹⁺), 513.27653.

[0540] Step D: Λ/²-(9H-fluoren-l-ylcarbonyl)-N¹-(3-ρhenylpropyl)-L-α-glutamine

MS (ESI) m/z 457.3; MS (ESI) m/z 913.5; MS (ESI) m/z 479.3.

Example SKKKKt ^-CgΗ-fluoren-l-ylcarbonylViV^O^.S-trimethoxybenzvD-L-α- glutamine

<img file="EP1902014A2_D0065.tif" />

[0541] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-iV¹-(3,4,5- trimethoxybenzyl)-L-α-glutaminate MS (ESI) m/z 605.2; MS (ESI) m/z 1209.4; HRMS: calcd for C₃₄H₄₀N₂O₈ + H+,

605.28574; found (ESI_FT, [M+H]¹⁺), 605.28453.

[0542] Step B: tert-butyl ^-(S^^-trimethoxybenzy^-L-α-glutaminate

MS (ESI) m/z 383.1; MS (ESI) m/z 765.3; HRMS: calcd for C₁₉H₃₀N₂O₆ + H+,

383.21766; found (ESI_FT, [MH-H]¹⁺), 383.21755.

[0543] Step C: tert-butyl N²-(9H-fluoren-2-ylcarbonyl)-N¹ -(3,4,5- trimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 575.4; MS (ESI) m/z 1149.7; ΗRMS: calcd for C₃₃H₃₈N₂O₇ + H+,

575.27518; found (ESI-FTMS, [MH-H]¹⁺), 575.27604.

[0544] Step D: N²-(9H-fluoren-2-ylcarbonyl)-ΛT¹-(3,4,5-trimethoxybenzyl)-L-α- glutamine

MS (ESI) m/z 519.3; MS (ESI) m/z 1037.6; ΗRMS: calcd for C₂₉H₃₀N₂O₇ + H+,

519.21258; found (ESI-FTMS, [M+H]¹⁺), 519.2133.

Example SLLLLt ^-CPH-fluoren-l-ylcarbonvD-iV^O^.S-trimethoxybenzvD-L-α- glutamϊne

[0545] Step C: tert-butyl iV²-(9H-fluoren-l-ylcarbonyl)-iV¹-(3,4,5- trimethoxybenzyl)-L-α-glutarninate

MS (ESI) m/z 575.4; MS (ESI) m/z 1149.7; ΗRMS: calcd for C₃₃H₃₈N₂O₇ + H+,

575.27518; found (ESI-FTMS, [MH-H]¹⁺), 575.2761.

[0546] Step D: N²-(9H-fluoren-l-ylcarbonyl)-N¹-(3,4,5-trimethoxybenzyl)-L-α- glutamine

MS (ESI) m/z 519.3; MS (ESI) m/z 1037.6; MS (ESI) m/z 541.3; HRMS: calcd for

C₂₉H₃₀N₂O₇ + H+, 519.21258; found (ESI-FTMS, [MH-H]¹⁺), 519.21329.

Example 8MMMM: iV²-[(9-oxo-9g-fluoren-2-yl)carbonvn-iV¹-(3.4.5- trimethoxybenzyl)-L-α-glutamine

[0547] Step C: tert-butyl iV²-[(9-oxo-9H-fluoren-2-yl)carbonyl]-N¹-(3,4,5- trimethoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 589.4; MS (ESI) m/z 1177.7; MS (ESI) m/z 606.4; ΗRMS: calcd for C₃₃H₃₆N₂O₈ + H+, 589.25444; found (ESI-FTMS, [MH-H]¹⁺), 589.25507. [0548] Step D: N²-[(9-oxo-9H-fluoren-2-yl)carbonyl]-iV¹-(3,4,5- trimethoxybenzyl)-L-α-glutamine

MS (ESI) m/z 531.3; MS (ESI) m/z 1063.5; HRMS: calcd for C₂₉H₂₈N₂O₈ + H+,

533.19184; found (ESI-FTMS, [MH-H]¹⁺), 533.19236.

Example 8NNNN; N -(4-phenoxybenzovD-iV M3A5-trimethoxybenzyl)-L-α- glutamine

[0549] Step C: tert-butyl Λ/²-(4-phenoxybenzoyl)-N¹-(3,4,5-trimethoxybenzyl)-L- α-glutaminate

MS (ESI) m/z 579.3; MS (ESI) m/z 1157.7; HRMS: calcd for C₃₂H₃₈N₂O₈ + H+,

579.27009; found (ESI-FTMS, [M+H]¹⁺), 579.2719.

[0550] Step D: ΛT²-(4-phenoxybenzoyl)-iV^rl-(3,4,5-trimethoxybenzyl)-L-α- glutamine

MS (ESI) m/z 523.3; MS (ESI) m/z 1045.5.

Example SOOOOt ^-fPg-fluoren^-ylcarbonylV^-hexyl-L-α-glutamine

<img file="EP1902014A2_D0066.tif" />

[0551] Step A: tert-butyl N²-[(9H-fluoren-9-ylmethoxy)carbonyl]-N¹-hexyl-L-α- glutaminate

MS (ESI) m/z 509.3; MS (ESI) m/z 1017.5; ΗRMS: calcd for C₃₀H₄₀N₂O₅ + H+,

509.30100; found (ESI-FTMS, [M+H]¹⁺), 509.30265.

[0552] Step B: tert-butyl iV^hexyl-L-α-glutaminate

HRMS: calcd for C₁₅H₃₀N₂O₃ + H+, 287.23292; found (ESI-FTMS, [MH-H]¹⁺),

287.23282.

[0553] Step C: tert-butyl Λ/^r2-(9H-fluoren-2-ylcarbonyl)-N¹-hexyl-L-α-glutaminate

MS (ESI) m/z 479.1; MS (ESI) m/z 979.2; MS (ESI) m/z 501.1; ΗRMS: calcd for

C₂₉H₃₈N₂O₄ + H+, 479.29043; found (ESI-FTMS, [MH-H]¹⁺), 479.29145.

[0554] Step D: N²-(9H-fluoren-2-ylcarbonyl)-N¹-hexyl-L-α-glutamine

MS (ESI) m/z 423.3; MS (ESI) m/z 845.6; MS (ESI) m/z 445.3. Example 8PPPP: ^-(gH-fluoren-l-vIcarbonylV^-hexyl-L-α-glutamine

[0555] Step C: tert-butyl ^-(ΘH-fluoren-l-ylcarbony^-N^hexyl-L-α-glutaminate

MS (ESI) m/z 479.1; MS (ESI) m/z 957.3; MS (ESI) m/z 979.2; ΗRMS: calcd for C₂₉H₃₈N₂O₄ + H+, 479.29043; found (ESI-FTMS, [M+H]¹⁺), 479.29145. [0556] Step D: ^-(ΘH-fluoren-l-ylcarbony^-^-hexyl-L-α-glutamine

MS (ESI) m/z 423.3; MS (ESI) m/z 845.5; MS (ESI) m/z 445.3.

Example 8QOOQ: JV¹-hexyl-iV²-(4-phenoxybenzoyl)-L-α-glutamine

[0557] Step C: tert-butyl N¹-hexyl-N²-(4-phenoxybenzoyl)-L-α-glutaminate

MS (ESI) m/z 483.1; MS (ESI) m/z 965.3; MS (ESI) m/z 987.3; ΗRMS: calcd for C₂₈H₃₈N₂O₅ + H+, 483.28535; found (ESI-FTMS, [M+H]¹⁺), 483.28715. [0558] Step D: N¹-hexyl-N²-(4-phenoxybenζoyl)-L-α-glutamine

MS (ESI) m/z 427.3; MS (ESI) m/z 853.5; MS (ESI) m/z 449.3.

Example SRRRRz iV^hexyl-^^Cg-oxo-gH-fluoren^-vDcarbonvn-L-α-glutamine

[0559] Step C: tert-butyl N¹-hexyl-N²-[(9-oxo-9H-fluoren-2-yl)carbonyl]-L-α- glutaminate

MS (ESI) m/z 493.1; MS (ESI) m/z 985.3; ΗRMS: calcd for C₂₉H₃₆N₂O₅ + H+,

493.26970; found (ESI-FTMS, [M+H]¹⁺), 493.27119.

[0560] Step D: N¹-hexyl-N²-[(9-oxo-9H-fluoren-2-yl)carbonyl]-L-α-glutamine

MS (ESI) m/z 437.3; MS (ESI) m/z 873.5; MS (ESI) m/z 1309.8.

Example 8SSSS: iV²-(4-benζoylbenζoyl)-iV¹-benζyl-L-α-glutamine

[0561] Step C: fert-butyl Λ/²-(4-benzoylbenzoyl)-Λ/^rl-benzyl-L-α-glutaminate

MS (ESI) m/z 501.2; MS (ESI) m/z 523.2; ΗRMS: calcd for C₃₀H₃₂N₂O₅ + H+,

501.23840; found (ESI+, [M+H]¹⁺), 501.23859.

[0562] Step D: N²-(4-benζoylbenζoyl)-N^I-benζyl-L-α-glutamine

MS (ESI) m/z 445.2; HRMS: calcd for C₂₆H₂₄N₂O₅ + H+, 445.17580; found (ESI+,

[MH-H]¹⁺), 445.17619.

Example 8TTTT: N¹-(6-hvdroxyhexylVN²-(4-phenoxybenζoyl)-L-α-glutamine [0563] MS (ESI) m/z 443.2; MS (ESI) m/z 885.5; HRMS: calcd for C₂₄H₃ON₂O₆

+ H+, 443.21766; found (ESI-FTMS, [M+H]¹⁺), 443.21905.

Example 8UUUU: ^-(PH-fluoren^-ylcarbonvn-N^fό-hvdroxyhexylVL-α- glutamine

[0564] MS (ESI) m/z 437.3; MS (ESI) m/z 551.3; HRMS: calcd for C₂₅H₃ON₂O₅

+ H+, 439.22275; found (ESI-FTMS, [M+H]¹⁺), 439.22374.

Example 8VWV: N²-(9H-fluoren-9-ylcarbonyl)-N¹-(3.4.5-trimethoxybenzvn-L-α- glutamine

[0565] MS (ESI) m/z 519.1; MS (ESI) m/z 1037.2; MS (ESI) m/z 536.1; HRMS: calcd for C₂₉H₃₀N₂O₇ + H+, 519.21258; found (ESI-FTMS, [M+H]¹⁺), 519.213.

Example 8WWWW: N²-(3-phenoxybenzoyl)-N¹-(3.4.5-trimethoxybenzyl)-L-α- glutamine

[0566] MS (ESI) m/z 523.1; MS (ESI) m/z 1045.2; MS (ESI) m/z 545.1; HRMS: calcd for C₂₈H₃₀N₂O₈ + H+, 523.20749; found (ESI-FTMS, [M+H]¹⁺), 523.20712.

Example 8XXXX: ^-(PH-fluoren^-ylcarbonylVN^CS^.S-trimethoxybenzylVL-α- glutamine

[0567] MS (ESI) m/z 519.1; MS (ESI) m/z 1037.2; HRMS: calcd for C₂₉H₃₀N₂O₇

+ H+, 519.21258; found (ESI-FTMS, [M+H]¹⁺), 519.21308.

Example SYYYYi N^l-adamantyl-N^rCP-oxo-gH-fluoren^-vncarbonvn-L-α- glutamine

[0568] MS (ESI) m/z 485.3; MS (ESI) m/z 971.6; MS (ESI) m/z 521.3; HRMS: calcd for C₂₉H₃₀N₂O₅ + H+, 487.22275; found (ESI-FTMS, [MH-H]¹⁺), 487.22272.

Example 8ZZZZ: N¹-l-adamantyl-N²-(4-phenoxybenzoyl)-L-α-glutamine

[0569] MS (ESI) m/z 477.1; MS (ESI) m/z 953.3; MS (ESI) m/z 499.1; HRMS: calcd for C₂₈H₃₂N₂O₅ + H+, 477.23840; found (ESI-FTMS, [M+H]¹⁺), 477.23857. 6 027066

Example 8AAAAA; N¹-l-adamantyl-N²-(9H-fluoren-2-ylcarbonyl)-L-α-glutamine

[0570] MS (ESI) m/z 473.3; MS (ESI) m/z 945.5; HRMS: calcd for C₂₉H₃₂N₂O₄ +

H+, 473.24348; found (ESI-FTMS, [M+H]¹⁺), 473.24374.

Example 8BBBBB: N^l-adamantyl-^-fgH-fluoren-g-ylcarbonvD-L-α-glutamine

[0571] MS (ESI) m/z 471.3; MS (ESI) m/z 585.3; MS (ESI) m/z 943.6; HRMS: calcd for C₂₉H₃₂N₂O₄ + H+, 473.24348; found (ESI-FTMS, [M+H]¹⁺), 473.2437.

Example 8CCCCC: NV9H-fluoren-2-ylcarbonylVNV3-methylbenzyl)4L-α- glutamine

[0572] HRMS: calcd for C₂₇H₂₆N₂O₄ + H+, 443.19653; found (ESI-FTMS,

[M+H]¹⁺), 443.1974.

Example 8DDDDD; N^O-methylbenzvD-N^rfP-oxo^H-fluoren-l-vDcarboiivn-L-α- glutamine

[0573] HRMS: calcd for C₂₇H₂₄N₂O₅ + H+, 457.17580; found (ESI-FTMS,

[MH-H]¹⁺), 457.17616.

Example 8EEEEE: NV9H-fluoren-9-ylcarbonylVNV3-methylbenzyl)-L-α- glutamine

[0574] HRMS: calcd for C₂₇H₂₆N₂O₄ + H+, 443.19653; found (ESI-FTMS,

[M+H]¹⁺), 443.19709.

Example 8FFFFF; NVgH-fluoren^-ylcarbonylVNWoPyl-L-α-glutaimne

[0575] HRMS: calcd for C₂₂H₂₄N₂O₄ + H+, 381.18088; found (ESI-FTMS,

[M+H]¹⁺), 381.18117.

Example 8GGGGG: 4-r(9H-fluoren-9-carbonyl)-amino]-4-propylcarbamoyl-butyric acid

[0576] MS (ESI) m/z 395.1; MS (ESI) m/z 789.2; MS (ESI) m/z 811.2; HRMS: calcd for C₂₂H₂₄N₂O₄ + H+, 381.18088; found (ESI-FTMS, [M+H]¹⁺), 395.16097. Example 8HHHHH: 4-r(9-Oxo-9H-fluorene-2-carbonyl)-amino1-4-propylcarbamoyl- butyric acid

[0577] MS (ESI) m/z 381.1; MS (ESI) m/z 403.1; MS (ESI) m/z 761.2; HRMS: calcd for C₂₂H₂₂N₂O₅ + H+, 395.16015; found (ESI-FTMS, [M+H]¹⁺), 381.18165.

Example SIIIII; N¹-benzvI-N²-r(9-oxo-9H-fluoren-2-yl)carbonvn-L-α-glutamine

[0578] MS (ESI) m/z 441.2; MS (ESI) m/z 883.3; HRMS: calcd for C₂₆H₂₂N₂O₅ +

H+, 443.16015; found (ESI-FTMS, [M+H]¹⁺), 443.16063.

Example 8J.TJJJ: ^-benzyl-^-fgH-fluoren^-ylcarbonvD-L-α-glutamine

[0579] MS (ESI) m/z 427.2; MS (ESI) m/z 855.3; HRMS: calcd for C₂₆H₂₄N₂O₄ +

H+, 429.18088; found (ESI-FTMS, [M+H]¹⁺), 429.18148.

Example 8KKKKK; N¹-benzvI-N²-(9H-fluoren-9-ylcarbonyl)-L-α-glutamine

[0580] MS (ESI) m/z 429; MS (ESI) m/z 857; MS (ESI) m/z 451; HRMS: calcd for C₂₆H₂₄N₂O₄ + H+, 429.18088; found (ESI-FTMS, [M+H]¹⁺), 429.1815.

Example 8LLLLL: ^-benzyl-^-O-phenoxybenzovD-L-α-glutamine

[0581] MS (ESI) m/z 433; MS (ESI) m/z 455; MS (ESI) m/z 865; HRMS: calcd for C₂₅H₂₄N₂O₅ + H+, 433.17580; found (ESI-FTMS, [M+H]¹⁺), 433.17696.

Example δMMMMMi N^d-methyl-l-phenylethvD-N^rrg-oxo^H-fluoren^- yDcarbonyli-L-α-glutamine

[0582] MS (ESI) m/z 471.2; MS (ESI) m/z 941.5; MS (ESI) m/z 493.2; HRMS: calcd for C₂₈H₂₆N₂O₅ + H+, 471.19145; found (ESI-FTMS, [MH-H]¹⁺), 471.19271.

Example 8NNNNN: ^-(gH-fluoren^-ylcarbonvD-N^d-methyl-l-phenylethyD-L-α- glutamine

[0583] MS (ESI) m/z 455.1; MS (ESI) m/z 911.3; HRMS: calcd for C₂₈H₂₈N₂O₄ +

H+, 457.21218; found (ESI-FTMS, [MH-H]¹⁺), 457.214. Example 8OOOOO: N^d-methyl-l-phenylethvD-N^O-phenoxybenzovD-L-α- glutamine

[0584] MS (ESI) m/z 461.2; MS (ESI) m/z 921.5; MS (ESI) m/z 483.2; HRMS: calcd for C₂₇H₂₈N₂O₅ + H+, 461.20710; found (ESI-FTMS, [M+H]¹⁺), 461.20882.

Example 8PPPPP: NVbiphenyl-4-ylcarbonyl)-NVdS)-l-phenylethyl]-L-α- glutamine

[0585] MS (ESI) m/z 431.2; MS (ESI) m/z 861.4; MS (ESI) m/z 453.2; HRMS: calcd for C₂₆H₂₆N₂O₄ + H+, 431.19653; found (ESI-FTMS, [M+H]¹⁺), 431.19802.

Example 8OOOOO; N²-(9H-fluoreii-2-ylcarbonyl)-N¹-[(lS)-l-phenvIethvn-L-α- glutamine

[0586] MS (ESI) m/z 443.2; MS (ESI) m/z 885.4; MS (ESI) m/z 465.2; HRMS: calcd for C₂₇H₂₆N₂O₄ + H+, 443.19653; found (ESI-FTMS, [M+H]¹⁺), 443.19772.

Example 8RRRRR; N²-(biphenyl-4-ylcarbonyl)-NJ:-[(lSVl-(4-fluorophenyl)ethyl]-L- α-glutamine

[0587] MS (ESI) m/z 449.2; MS (ESI) m/z 897.4; HRMS: calcd for C₂₆H₂₅FN₂O₄

+ H+, 449.18711; found (ESI-FTMS, [M+H]¹⁺), 449.18839.

Example 8SSSSS: tert-butyl N²-(biphenyl-4-ylcarbonyl)-NVl-phenvIethylVL-α- glutaminate

[0588] MS(ESI) m/z 505.3.

Example 8TTTTT; N²-(biphenyl-4-ylcarbonyl)-N¹-[(lR)-l-(4-fluorophenyl)ethvn-L- α-ghitamine

[0589] MS (ESI) m/z 449.2; MS (ESI) m/z 897.5; MS (ESI) m/z 471.2; HRMS: calcd for C₂₆H₂₅FN₂O₄ + H+, 449.18711; found (ESI-FTMS, [MH-H]¹⁺), 449.18679.

Example 8UUUUU: N^fbiphenvI^-ylearbonvD-N^rdRl-l-phenylethvn-L-q- glutamine [0590] MS (ESI) m/z 431.2; MS (ESI) m/z 861.5; MS (ESI) m/z 453.2; HRMS: calcd for C₂₆H₂₆N₂O₄ + H+, 431.19653; found (ESI-FTMS, [M+H]¹⁺), 431.19828.

Example 8WVW: ^-(PH-fluoren-l-ylcarbonylVN^rd^-l-phenylethvn-L-α- glutamine

[0591] MS (ESI) m/z 443.2; MS (ESI) m/z 885.5; MS (ESI) m/z 465.2; HRMS: calcd for C₂₇H₂₆N₂O₄ + H+, 443.19653; found (ESI-FTMS, [M+H]¹⁺), 443.19676.

Example 8WWWWW: ^-(gH-fluoren-l-ylcarbonvD-N^Cό-hvdroxyhexyD-L-α- glutamine

[0592] MS (ESI) m/z 437.3; MS (ESI) m/z 875.5; HRMS: calcd for C₂₅H₃₀N₂O₅ +

H+, 439.22275; found (ESI-FTMS, [M+H]¹⁺), 439.22313.

Example 8XXXXX: N¹-(6-hvdroxyhexyI)-N²-[(9-oxo-9H-fluoren-2-yl)carbonyl]-L-α- glutamine ■

[0593] MS (ESI) m/z 453.2; HRMS: calcd for C₂₅H₂₈N₂O₆ + H+, 453.20201 ; found (ESI-FTMS, [M+H]¹⁺), 453.2027.

Example 8YYYYY: ^-(biphenyl^-ylcarbonvD-^^H-fluoren-g-yl-L-α-glutamine

[0594] MS (ESI) m/z 489.1 ; MS (ESI) m/z 979.2; HRMS: calcd for C₃₁H₂₆N₂O₄ +

H+, 491.19653; found (ESI-FTMS, [M+H]¹⁺), 491.19778.

Example 8ZZZZZ: N²-(9H-fluoren-2-ylcarbonyl)-N¹-r2-(4-fluorophenylVl,l- dimethylethyl] -L-α-glutamine

[0595] MS (ESI) m/z 489.2; MS (ESI) m/z 977.4; HRMS: calcd for C₂₉H₂₉FN₂O₄

+ H+, 489.21841; found (ESI-FTMS, [MH-H]¹⁺), 489.21827.

Example 8AAAAAA: N-(l-adamantyImethyl)-N²-(biphenyl-4-vIcarbonyl)-L-α- glutamine

[0596] MS (ESI) m/z 475.2; MS (ESI) m/z 949.5; HRMS: calcd for C₂₉H₃₄N₂O₄ +

H+, 475.25913; found (ESI-FTMS, [MH-H]¹⁺), 475.25916. Example 8BBBBBB: N-r(lS)-l-benzyl-2-hvdroxyethyll-N²-f9H-fluoren-2- ylcarbonylVL-α-glutamine

[0597] MS (ESI) m/z 473.2; MS (ESI) m/z 945.4; HRMS: calcd for C₂₈H₂₈N₂O₅ +

H+, 473.20710; found (ESI-FTMS, [M+H]¹⁺), 473.2073.

Example 8CCCCCC: N²-(biphenyl-4-ylcarbonyl)-N-methyl-N-(2-phenylethvI)-L-α- glutamine

[0598] MS (ESI) m/z 445.4; MS (ESI) m/z 889.7; HRMS: calcd for C₂₇H₂₈N₂O₄ +

H+, 445.21218; found (ESI-FTMS, [M+H]¹⁺), 445.21312.

Example 8DDDDDD: N²-(9H-fluoren-2-vIcarbonyl)-N-methyl-N-(2-phenylethyl)-L- α-glutamϊne

MS (ESI) m/z 457.4; MS (ESI) m/z 913.7; HRMS: calcd for C₂₈H₂₈N₂O₄ + H+, 457.21218; found (ESI-FTMS, [M+H]¹⁺), 457.21146.

Example 8EEEEEE; N²-(biphenvI-4-vIcarbonvI)-N-butyl-N-methyl-L-α-gltttamine

[0599] MS (ESI) m/z 397.2; MS (ESI) m/z 793.4; MS (ESI) m/z 419.2; HRMS: calcd for C₂₃H₂₈N₂O₄ + H+, 397.21218; found (ESI-FTMS, [M+H]¹⁺), 397.21249.

Example 8FFFFFF: N-butyl-N²-(9H-flttoren-2-vIcarbonyl)-N-methvI-L-α-glutamine

[0600] MS (ESI) m/z 409.3; MS (ESI) m/z 817.5; HRMS: calcd for C₂₄H₂₈N₂O₄ +

H+, 409.21218; found (ESI-FTMS, [MH-H]¹⁺), 409.21227.

Example 8GGGGGG; N²-(biphenyl-4-ylcarbonyl)-N-r2-(3.4- dimethoxyphenyl)ethyl1-N-methyl-L-α-glutamine

[0601] MS (ESI) m/z 505.3; MS (ESI) m/z 527.3; MS (ESI) m/z 1009.6; HRMS: calcd for C₂₉H₃₂N₂O₆ + H+, 505.23331; found (ESI-FTMS, [M+H]¹⁺), 505.23512.

Example 8HHHHHH: N²-r4-(1.3-benzodioxol-5-vnbenzoyl]-N-r2-(4-fluorophenyl)- 1,1-dimethvIethyli-L-α-glutamine

[0602] MS (ESI) m/z 521.1; MS (ESI) m/z 1041.3; HRMS: calcd for

C₂₉H₂₉FN₂O₆ + H+, 521.20824; found (ESI-FTMS, [M+H]¹⁺), 521.20872. Example N&gt;r2-(3.4-dimethoxyphenvnethvn-N²-⁽9H-fluoren-2-ylcarbonyl)-N- methyl-L-oc-glutamine

[0603] MS (ESl) m/z 517.2; MS (ESI) m/z 1033.3; HRMS: calcd for C₃₀H₃₂N₂O₆

+ H+, 517.23331; found (ESI-FTMS, [M+H]¹⁺), 517.23342.

Example 8.T.T_&gt;T.T.TJ: N²-(9H-fluoren-2-ylcarbonyl)-N-r(2R)-2-phenylpropyll-L-α- glutamine

[0604] MS (ESI) m/z 457.2; MS (ESI) m/z 913.3; MS (ESI) m/z 479.1; HRMS: calcd for C₂₈H₂₈N₂O₄H- H+, 457.21218; found (ESI-FTMS, [M+H]¹⁺), 457.21246.

Example 8KKKKKK: N²-(biphenyl-4-ylcarbonylVN-[(2RV2-phenylpropyn-L-α- glutamine

[0605] MS (ESI) m/z 445.2; MS (ESI) m/z 889.3; HRMS: calcd for C₂₇H₂₈N₂O₄ +

H+, 445.21218; found (ESI-FTMS, [M+H]¹⁺), 445.21285.

Example 8LLLLLL; N²-(biphenyl-4-ylcarbonyl)-N¹-r2-(4-fluorophenyl)-lΛ- dimethylethyl] -L-glutamamide

[0606] MS (ESI) m/z 476.2; MS (ESI) m/z 951.5; HRMS: calcd for C₂₈H₃₀FN₃O₃

+ H+, 476.23440; found (ESI-FTMS, [M+H]¹⁺), 476.23543.

Example 8MMMMMM; N-r(lS)-l-benzyl-2-hvdroxyethyll-N²-(biphenyl-4- ylcarbonyl)-L-α-glutamine

[0607] MS (ESI) m/z 461.2; MS (ESI) m/z 921.4; MS (ESI) m/z 943.4; HRMS: calcd for C₂₇H₂₈N₂O₅ + H+, 461.20710; found (ESI-FTMS, [M+H]¹⁺), 461.20748.

Example 8NNNNNN; N¹-benzyl-N²-(4-bromobenzoyl)-L-α-glutamine [0608] MS (ESI) m/z 419.1; MS (ESI) m/z 837.2; HRMS: calcd for

C₁₉H₁₉BrN₂O₄ + H+, 419.06009; found (ESI_FT, [M+H]¹⁺), 419.05998.

Example 8OOOQOO: N¹-[2-(acetylamlno)ethyl]-N²-(l.l'-biphenyl-4-ylcarbonylVL- α-glutamine [0609] MS (ESI) m/z 410.2; MS (ESI) m/z 821.5; HRMS: calcd for C₂₂H₂₅N₃O5

+ H+, 412.18670; found (ESI_FT, [M+H]¹⁺), 412.18628.

Example 8PPPPPP; ^-(l.l'-biphenyl^-ylacetvn-N^O-methoxybenzvn-L-α- glutamine

[0610] The title compound was prepared according to procedures similar to those described in Example 7, except biphenylacetic acid was used. MS (ESI) m/z 461.2; MS

(ESI) m/z 921.4; HRMS: calcd for C₂₇H₂₈N₂O₅ + H+, 461.20710; found (ESI_FTMS,

[M+H]¹⁺), 461.20514.

Example 80OO0OO; ^-(l-benzylphenylV^-dΛ'-biphenyl^-ylcarbonvn-L-α- glutamine

[0611] MS (ESI-) m/z 491.3; HRMS: calcd for C₃₁H₂₈N₂O₄ + H+, 493.21218; found (ESI-FTMS, [M+H]¹⁺), 493.21319.

Example SRRRRRR: ^-l-naphthoyl-N^O-phenvIpropyD-L-α-glutamine

[0612] MS (ESI) m/z 419.1; MS (ESI) m/z 837.1; MS (ESI) m/z 441.1; HRMS: calcd for C₂₅H₂₆N₂O₄ + H+, 419.19653; found (ESI-FTMS, [MH-H]¹⁺), 419.19678.

Example 8SSSSSS: N²-[(9-oxo-9H-fluoren-2-yl)carbonvI]-N¹-(3-phenylpropyl)-L-α- glutamine

[0613] MS (ESI) m/z 471.3; MS (ESI) m/z 941.5; HRMS: calcd for C₂₈H₂₆N₂O₅ +

H+, 471.19145; found (ESI-FTMS, [M+H]¹⁺), 471.19142.

Example 8TTTTTT: N²-(4-phenoxybenzoyl)-N¹-(3-phenylpropyl)-L-α-glutamine

[0614] HRMS: calcd for C₂₇H₂₈N₂O₅ + H+, 461.20710; found (ESI-FTMS,

[M+H]¹⁺), 461.20673.

Example 8UUUUUU: N^benzyl-^-N-rpyrimidin^-ylamino^benzoyli-L-α- glutamine

[0615] MS m/z 02-101699GMS. Example 8VWVW; N²-(9H-fluoren-2-ylcarbonvD-N¹-(6-hvdroxyhexylVL-α- glutamine

[0616] MS (ES]) m/z 439.2; HRMS: calcd for C₂₅H₃₀N₂O₅ + H+, 439.22275; found (ESI-FTMS, [M+H]¹⁺), 439.22379.

Example 8WWWWWW: JV²-r4-(5-bromo-2-thienvnbenzoyll-iV-r2-(4-fluorophenylV lΛ-dimethylethyl]-L-α-glutamine

[0617] MS (ESI) m/z 561.3; MS (ESI) m/z 1121.5; HRMS: calcd for

C₂₆H₂₆BrFN₂O₄S + H+, 561.08534; found (ESI-FTMS, [M+H]¹⁺), 561.08472.

Example 8XXXXXX; iV-r2-(5-chloro-2-thienyl)-l.l-dimethylethyl]-iV²-r(3'- fluorobiphenyl-4-yl)carbonyl1-L-α-glutamine

[0618] MS (ESI) m/z 517.3; MS (ESI) m/z 1033.5; MS (ESl) m/z 539.3; HRMS: calcd for C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.13517. [0619] MS (ESI) m/z 517.3; MS (ESI) m/z 1033.6; MS (ESI) m/z 539.3; HRMS: calcd for C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.13686.

Example 8YYYYYY: iV²-[(3'.4'-difluorobiphenyl-4-yl)carbonyl]-iV-[2-(4- fluorophenyl)-l,l-dimethylethyl]-L-(x-glutamine

[0620] MS (ESI) m/z 513.4; MS (ESI) m/z 1025.7; MS (ESI) m/z 535.3; HRMS: calcd for C₂₈H₂₇F₃N₂O₄ + H+, 513.19957; found (ESI-FTMS, [M+H]¹⁺), 513.19837. [0621] MS (ESI) m/z 513.4; MS (ESI) m/z 1025.8; MS (ESI) m/z 535.4; HRMS: calcd for C₂₈H₂₇F₃N₂O₄ + H+, 513.19957; found (ESI-FTMS, [M+H]¹⁺), 513.20152.

Example 8ZZZZZZ: iV-r2-(4-chlorophenvn-l.l-dimethylethvn-iV²-[(3',4^t- difluorobiphenyl-4-yI)carbonyl1-L-α-glutamine

[0622] MS (ESI) m/z 529.2; MS (ESI) m/z 1057.5; HRMS: calcd for

C₂₈H₂₇ClF₂N₂O₄ + H+, 529.17002; found (ESI-FTMS, [M+H]¹⁺), 529.16931.

Example 8AAAAAAA; iV-[2-(4-chlorophenyl)-lΛ-dimethylethvn-iV²-[(2',4'- difluorobiphenyl-4-yl)carbonvπ-L-α-glutamine [0623] MS (ESI) m/z 529.2; MS (ESI) m/z 1057.5; HRMS: calcd for

C₂₈H₂₇ClF₂N₂O₄ + H+, 529.17002; found (ESI-FTMS, [M+H]¹⁺), 529.16951.

Example 8BBBBBBB: iV-r2-(4-chloroDhenyl)-l.l-dimethylethvn-iV²-r(2^t.5'- difluorobiphenyl-4-yl)carbonvn-L-α-glutamine

[0624] MS (ESI) m/z 529.3; MS (ESI) m/z 1057.5; MS (ESI) m/z 551.2; HRMS: calcd for C₂₈H₂₇ClF₂N₂O₄ + H+, 529.17002; found (ESI-FTMS, [M+H]¹⁺), 529.16954.

Example 8CCCCCCC: iV-[2-(4-chlorophenyl)-l.l&gt;dimethvIethyl]-iV²-r(2',6'- difluorobiphenyl-4-yl)carbonvn-L-α-gIutamine

[0625] MS (ESI) m/z 529.2; MS (ESI) m/z 1057.4; HRMS: calcd for

C₂₈H₂₇ClF₂N₂O₄ + H+, 529.17002; found (ESI-FTMS, [M+H]¹⁺), 529.16943.

Example 8DDDDDDD; iV-[2-(4-chlorophenyl)-lΛ-dimethylethyl]-iV²-[(3'.5'- difluorobiphenyl-4-yl)carbonyl]-L-α-glutamine

[0626] MS (ESI) m/z 529.3; MS (ESI) m/z 1057.5; MS (ESI) m/z 551.3; HRMS: calcd for C₂₈H₂₇ClF₂N₂O₄ + H+, 529.17002; found (ESI-FTMS, [M+H]¹⁺), 529.17191.

Example 8EEEEEEE: iV-r2-(4-chlorophenyl)-l.l-dimethylethyl]-iV²-[(2',3^t- difluorobiphenyl-4-yl)carbonyl]-L-α-glutamine

[0627] HRMS : calcd for C₂₈H₂₇ClF₂N₂O₄ + H+, 529.17002; found (ESI-FTMS,

[MH-H]¹⁺), 529.17167.

Example 8FFFFFFF; iV-(l.l-dimethyl-2-pheiiylethyl)-iV²-(4-pyrimidin-5-ylbenζoyl)- L-α-glutamine

[0628] MS (ESI) m/z 461.2; MS (ESI) m/z 921.4; HRMS: calcd for C₂₆H₂₈N₄O₄ +

H+, 461.21833; found (ESI-FTMS, [M+H]¹⁺), 461.21863.

Example SGGGGGGGi ^-rrS'^'-difluorobiphenyl^-vDcarbonvn-iV-dΛ-dimethyl- 2-phenylethyl)-L-α-glutamine

[0629] MS (ESI) m/z 495.2; MS (ESI) m/z 989.4; HRMS: calcd for C₂₈H₂₈F₂N₂O₄

+ H+, 495.20899; found (ESI-FTMS, [M+H]¹⁺), 495.21035. Example 8HHHHHHH: iV²-r(3'.5'-difluorobiphenyl-4-vI)carbonvn-N-(l,l-dimethyl- 2-phenyIethyl)-L-α-glutamine

[0630] MS (ESI) m/z 495.2; MS (ESI) m/z 989.4; MS (ESI) m/z 517.2; HRMS: calcd for C₂₈H₂₈F₂N₂O₄ + H+, 495.20899; found (ESI-FTMS, [M+H]¹⁺), 495.21017.

Example iV-r2-(5-chloro-2-thienvn-lΛ-diniethylethvn-iV²-r(3'.4'- difluorobiphenyl-4-yl)carbonvn-L-α-glutamϊne

[0631] MS (ESI) m/z 533.3; MS (ESI) m/z 1067.7; HRMS: calcd for

C₂₆H₂₅ClF₂N₂O₄S + H+, 535.12644; found (ESI-FTMS, [M+H]¹⁺), 535.1267.

Example S.TJ.T.TJ.T.Tt ^-fbiphenyl^-ylcarbonvn-iV-^-fS-chloro^-thienvD-iα- dimethyIethyl]-L-α-glutamine

[0632] MS (ESI) m/z 499.4; MS (ESI) m/z 997.7; MS (ESI) m/z 521.4; HRMS: calcd for C₂₆H₂₇ClN₂O₄S + H+, 499.14528; found (ESI-FTMS, [M+H]¹⁺), 499.14616.

Example 8KKKKKKK; N²-{[5-(3-chloro-4-flttorophenyl)-2-thienvncarbonyll-iV-[2- (5-chloro-2-thienyl)-l,l-dimethylethvn-L-α-glutamine

[0633] MS (ESI) m/z 557.3; MS (ESI) m/z 1113.6; HRMS: calcd for

C₂₄H₂₃Cl₂FN₂O₄S₂ + H+, 557.05331; found (ESI-FTMS, [M+H]¹⁺), 557.05439.

Example 8LLLLLLL; iV²-{r4'-(hvdroxymethyl)biphenyl-4-vncarbonvU-iV-(3.4.5- trimethoxybenζyl)-L-α-glutamme

[0634] MS (ESI) m/z 537.1; MS (ESI) m/z 1073.3; HRMS: calcd for C₂₉H₃₂N₂O₈

+ H+, 537.22314; found (ESI-FTMS, [M+H]¹⁺), 537.22326.

Example 8MMMMMMM; iV²-{r4'-(bromomethyl)biphenyl-4-yl1carbonvU-N-(3,4.5- trimethoxybenzylVL-α-glutamine

[0635] MS (ESI) m/z 599.1; MS (ESI) m/z 1197.1; HRMS: calcd for

C₂₉H₃₁BrN₂O₇ + H+, 599.13874; found (ESI-FTMS, [M+H]¹⁺), 599.13934. Example 8NNNNNNN; iV-r2-(4-fluorophenvn-l.l-dimethylethvn-iV²-r4-(2- thienyl)benzoyl]-L-α-glutamine

[0636] MS (ESI) m/z 483.3; MS (ESI) m/z 965.5; HRMS: calcd for

C₂₆H₂₇FN₂O₄S + H+, 483.17483; found (ESI-FTMS, [M+H]¹⁺), 483.1743.

Example 8OOOOOOO; iV-r2-(4-fluorophenvI)-l.l-dimethylethvn-iV²-r4-(2- furyDbenzovLI -L-α-glutamine

[0637] MS (ESI) m/z 467.3; MS (ESI) m/z 933.6; HRMS: calcd for C₂₆H₂₇FN₂O₅

+ H+, 467.19768; found (ESI-FTMS, [M+H]¹⁺), 467.19704.

Example 8PPPPPPP: iV²-{[4'-(hvdroxymethvnbiphenyl-4-vncarbonyll-iV-(3- methylbenzvD-L-α-glutamine

[0638] MS (ESI) m/z 459.1; MS (ESI) m/z 919.5; HRMS: calcd for C₂₇H₂₈N₂O₅ +

H+, 461.20710; found (ESI-FTMS, [M+H]¹⁺), 461.20822.

Example 8OOOOOOO: iV²-{r3'-(hvdroxymethyl)biphenyl-4-yl1carbonvU-iV-(3- methylbenzylVL-α-glutamine

[0639] MS (ESI) m/z 459.2; HRMS: calcd for C₂₇H₂₈N₂O₅ + H+, 461.20710; found (ESI-FTMS, [M+H]¹⁺), 461.20807.

Example 8RRRRRRR: iV²-[4-(2.3-dihvdro-l-benzofuran-5-yl)benzovn-iV-[2-(4- fluorophenyl)-l,l-dimethylethvn-L-α-glutamine

[0640] MS (ESI) m/z 517.3; MS (ESI) m/z 1035.7; HRMS: calcd for C₃₀H₃₁FN₂O₅

+ H+, 519.22898; found (ESI-FTMS, [MH-H]¹⁺), 519.22989.

Example 8SSSSSSS: iV²-[(3'-chloro-4'-fluorobiphenyl-4-yl)carbonyl]-iV-r2-(4- fluorophenyl)-lΛ-dimethylethyl]-L-α-glutamin.e

[0641] MS (ESI) m/z 529.3; MS (ESI) m/z 1057.6; HRMS: calcd for

C₂₈H₂₇ClF₂N₂O₄ + H+, 529.17002; found (ESI-FTMS, [M+H]¹⁺), 529.17061.

Example 8TTTTTTT: iV²-ir3'-(bromomethyl)biphenyl-4-vIlcarbonvU-iV-(3- methylbenzyl)-L-α-glutamine [0642] MS (ESI) m/z 521.1; HRMS: calcd for C₂₇H₂₇BrN₂O₄ + H+, 523.12270; found (ESI-FTMS, [M+H]¹⁺), 523.12235.

Example 8UUUUUUU; iV-r2-(4-fluorophenylVl.l-dimethylethvn-iV²-r4-(3- thienvDbenzoyli -L-α-glutamine

[0643] MS (ESI) m/z 483.1; MS (ESI) m/z 965.3; HRMS: calcd for

C₂₆H₂₇FN₂O₄S + H+, 483.17483; found (ESI-FTMS, [M+H]¹⁺), 483.17572.

Example 8VWVWV: iV-r2-(4-fluorophenyl)-iα-dimethylethvn-iV²-[4-(5-methyl-2- thienvDbenzoyll -L-α-glutamine

[0644] MS (ESI) m/z 495.4; MS (ESI) m/z 991.7; HRMS: calcd for

C₂₇H₂₉FN₂O₄S + H+, 497.19048; found (ESI-FTMS, [M+H]¹⁺), 497.19118.

Example 8WWWWWWW; iV²-[4-(5-chloro-2-thienyl)benzoyl]-iV-[2-(4- fluorophenyl)-lΛ-dimethyIethyl]-L-α-gIutamine

[0645] MS (ESI) m/z 515.3; MS (ESI) m/z 1031.7; HRMS: calcd for

C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.13644. [0646] MS (ESI) m/z 515.3; MS (ESI) m/z 1031.6; HRMS: calcd for

C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.13658.

Example 8XXXXXXX: iV-[2-(4-chlorophenyl)-l.l-dimethvIethyl]-iV²-[4-(2- thienyDbenzoyl] -L-α-glutamine

[0647] MS (ESI) m/z 497.3; MS (ESI) m/z 995.6; HRMS: calcd for

C₂₆H₂₇ClN₂O₄S + H+, 499.14528; found (ESI-FTMS, [M+H]¹⁺), 499.14509.

Example 8YYYYYYY; N-[2-(4-chlorophenyl)-lΛ-dimethylethyl]-iV²-{[5-(3- methoχyphenyl)-2-thienvI]carbonylT-L-α-gIutamine

[0648] MS (ESI) m/z 529.3; MS (ESI) m/z 1057.5; HRMS: calcd for

C₂₇H₂₉ClN₂O₅S + H+, 529.15585; found (ESI-FTMS, [M+H]¹⁺), 529.15608.

Example 8ZZZZZZZ: iV-[2-(4-chlorophenyl)-l.l-dimethylethyl]-iV²-[(5-phenyl-2- thienyPcarbonyl] -L-α-glutamine [0649] MS (ESI) m/z 499.2; MS (ESI) m/z 997.5; HRMS: calcd for

C₂₆H₂₇ClN₂O₄S + H+, 499.14528; found (ESI-FTMS, [M+H]¹⁺), 499.14644.

Example 8AAAAAAAA: iV²-(2.2'-bithien-5-ylcarbonyl)-iV-r2-(4-chlorophenyl)-l.l- dimethylethyli-L-a-glutamine

[0650] MS (ESI) m/z 505.1; MS (ESI) m/z 1009.1; HRMS: calcd for

C₂₄H₂₅ClN₂O₄S₂ + H+, 505.10170; found (ESI-FTMS, [M+H]¹⁺), 505.10282.

Example 8BBBBBBBB: iV²-[4-(2.3-dihvdro-l-benζofuran-6-yl)benζovn-iV-[2-(4- fluorophenyl)-l.l-dimethylethyl]-L-α-glutamine

[0651] MS (ESI) m/z 517.5; MS (ESI) m/z 1035.9; HRMS: calcd for C₃₀H₃₁FN₂O₅

+ H+, 519.22898; found (ESI-FTMS, [MH-H]¹⁺), 519.22971.

Example 8CCCCCCCC; iV-[2-(4-fluorophenyl)-l.l-dimethylethyl]-iV²-{r6-(3- methoxyphenyl)pyridin-3-yl]carbonyl&gt;-L-α-glutamine

[0652] MS (ESI) m/z 508.4; HRMS: calcd for C₂₈H₃₀FN₃O₅ + H+, 508.22423; found (ESI-FTMS, [MH-H]¹⁺), 508.22472.

Example 8DDDDDDDD; Λr-[2-(4-fluorophenyl)-l.l-dimethylethvn-N²-[f6- phenylpyridin-3-yl)carbonyl]-L-α-gIutamine

[0653] MS (ESI) m/z 478.4; HRMS: calcd for C₂₇H₂₈FN₃O₄ + H+, 478.21366; found (ESI-FTMS, [MH-H]¹⁺), 478.21435.

Example 8EEEEEEEE: iV-[2-(4-fluorophenyl)-l.l-dimethvIethyl]-iV²-[(5-phenyl-2- thienyDcarbonyl] -L-α-glutamine

[0654] MS (ESI) m/z 483.2; MS (ESI) m/z 965.4; HRMS: calcd for

C₂₆H₂₇FN₂O₄S + H+, 483.17483; found (ESI-FTMS, [MH-H]¹⁺), 483.17576.

Example 8FFFFFFFF; N²-[(3-fluorobiphenyl-4-vncarbonyl]-iV-[2-(4-fluorophenyl)- l.l-dimethylethyl]-L-α-glutamine

[0655] MS (ESI) m/z 495.3; MS (ESI) m/z 989.6; HRMS: calcd for C₂₈H₂₈F₂N₂O₄

+ H+, 495.20899; found (ESI-FTMS, [MH-H]¹⁺), 495.20963. Example 8GGGGGGGG; iV-r2-(4-chlorophenylVl.l-dimethylethvn-iV²-r(5-pyridin- 4-vI-2-thienyl)carbonvn-L-α-gltttamine

[0656] MS (ESI) m/z 500.3; HRMS: calcd for C₂₅H₂₆ClN₃O₄S + H+, 500.14053; found (ESI-FTMS, [M+H]¹⁺), 500.13984.

Example δHHHHHHHHi ^-irS-Q-chloro^-fluorophenvD^-thienvncarbonvU-iV- r2-(4-chlorophenyl)-l.l-dimethylethyn-L-α-glutamine

[0657] MS (ESI) m/z 549.3; HRMS: calcd for C₂₆H₂₅Cl₂FN₂O₄S + H+,

551.09689; found (ESI-FTMS, [M+H]¹⁺), 551.09834.

Example iV-r2-(4-chlorophenyl)-l,l-dimethylethyl]-iV²-r4-(2.3-dihvdro-l- benzofuran-6-yl)benzoyl]-L-α-glutamine

[0658] MS (ESI) m/z 535.4; MS (ESI) m/z 1069.8; HRMS: calcd for

C₃₀H₃₁ClN₂O₅ + H+, 535.19943; found (ESI-FTMS, [M+H]¹⁺), 535.20047.

Example 8.TJ.T.T,TJ.T.T: iV-[2-(4-chlorophenyn-l,l-dimethylethyn-iV²-r(5-pyridin-3-vI-2- thienyPcarbonvU-L-q-glutamine

[0659] MS (ESI) m/z 500.3; HRMS: calcd for C₂₅H₂₆ClN₃O₄S + H+, 500.14053; found (ESI-FTMS, [M+H]¹⁺), 500.1423.

Example 8KKKKKKKK; iV²-[4-(2.3-dihvdro-l-benζofuran-6-ynbenζovn-iV-(l.l- dimethyl-2-phenylethyl)-L-α-gltttamine

[0660] MS (ESI) m/z 501.4; MS (ESI) m/z 1001.8; HRMS: calcd for C₃₀H₃₂N₂O₅

+ H+, 501.23840; found (ESI-FTMS, [M+H]¹⁺), 501.23954.

Example SLLLLLLLLt ^-irS-O-chloro^-fluorophenvD^-thienylicarbonyll-iV-

(lΛ-dimethyl-2-phenylethylVL-α-glutamine

[0661] MS (ESI) m/z 515.3; MS (ESI) m/z 1031.7; HRMS: calcd for

C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.13443. Example 8MMMMMMMM: JV-(l.l-dimethvI-2-phenylethvIViV²-r4-(2- thienyl)benzoyl1-L-α-glutaniine

[0662] MS (ESI) m/z 465.2; MS (ESI) m/z 929 A; HRMS: calcd for C₂₆H₂₈N₂O₄S

+ H+, 465.18425; found (ESI-FTMS, [M+H]¹⁺), 465.18402.

Example 8NNNNNNNN: iV-(l.l-dimethyl-2-phenvIethvI)-iV²-{r5-(3-methoxyphenvn- 2-thienyl]carbonyl}-L-α-glutamine

[0663] MS (ESI) m/z 495.2; MS (ESI) m/z 989.4; HRMS: calcd for C₂₇H₃₀N₂O₅S

+ H+, 495.19482; found (ESI-FTMS, [M+H]¹⁺), 495.1942.

Example 8OOOOOOOO: 7V-(l.l-dimethyl-2-phenylethyl)-iV²-[(5-phenvI-2- thienvDcar bonyli -L-α-glutamine

[0664] MS (ESI) m/z 465.2; MS (ESI) m/z 929 A; HRMS: calcd for C₂₆H₂₈N₂O₄S

+ H+, 465.18425; found (ESI-FTMS, [M+H]¹⁺), 465.18359.

Example 8PPPPPPPP: iV²-(2.2'-bithien-5-ylcarbonyl)-iV-(l.l-dimethyl-2- phenylethyD-L-α-glutamine

[0665] MS (ESI) m/z 469.3; MS (ESI) m/z 939.6; HRMS: calcd for C₂₄H₂₆N₂O₄S₂

+ H+, 471.14067; found (ESI-FTMS, [M+H]¹⁺), 471.1403.

Example 8OOOOOOOO; iV-(l.l-dimethyl-2-phenylethyl)-iV²-r(5-pyridin-4-yl-2- thienvDcarbonyl] -L-α-glutamine

[0666] MS (ESI) m/z 466.4; HRMS: calcd for C₂₅H₂₇N₃O₄S + H+, 466.17950; found (ESI-FTMS, [MH-H]¹⁺), 466.17836.

Example 8RRRRRRRR: iV-(l.l-dimethvI-2-phenylethyl)-N²-r(5-pyridin-3-yl-2- thienyl)carbonyl]-L-α-glutamine

[0667] MS (ESI) m/z 466.3; HRMS: calcd for C₂₅H₂₇N₃O₄S + H+, 466.17950; found (ESI-FTMS, [M+H]¹⁺), 466.17912.

Example 8SSSSSSSS: iV-r2-(4-chIorophenyl)-l.l-dimethylethyl]-iV²-r4-(5-chIoro-2- thienvDbenzoyl] -L-α-glutamϊne [0668] HRMS: calcd for C₂₆H₂₆Cl₂N₂O₄S + H+, 533.10631; found (ESI-FTMS,

[MH-H]¹⁺), 533.10629.

Example δTTTTTTTTz iV^irό-rS-chloro-l-thienvnpyridin-S-vncarbonvU-iV-ri.l- dimethyl-2-phenylethyl)-L-α-gIutamine

[0669] MS (ESI) m/z 500.3; MS (ESI) m/z 999.6; HRMS: calcd for

C₂₅H₂₆ClN₃O₄S + H+, 500.14053; found (ESI-FTMS, [M+H]¹⁺), 500.14123.

Example 8UUUUUUUU: iV-(l.l-dimethyl-2-phenvIethyl)-iV²-r(6-phenylpyridin-3- yDcarbonyl] -L-α-glutamine

[0670] MS (ESI) m/z 460.4; HRMS : calcd for C₂₇H₂₉N₃O₄ + H+, 460.22308; found (ESI-FTMS, [M+H]¹⁺), 460.22319.

Example 8VVVVVVVV: iV-r2-(4-chlorophenvI)-l.l-dimethvIethyll-iV²-(5-phenvI-2- furoyl)-L-α-glutamϊne

[0671] MS (ESl) m/z 483.3; MS (ESI) m/z 965.6; MS (ESI) m/z 987.6; HRMS: calcd for C₂₆H₂₇ClN₂O₅ + H+, 483.16813; found (ESI-FTMS, [M+H]¹⁺), 483.16818.

Example 8WWWWWWWW: iV-[2-(4-chIorophenvn-l.l-dimethylethyl]-iV²-{r6-(5- chloro-2-thienyl)pyridin-3-yl]carbonyl)-L-α-glutamine

[0672] MS (ESI) m/z 534.3; HRMS: calcd for C₂₅H₂₅Cl₂N₃O₄S + H+, 534.10156; found (ESI-FTMS, [MH-H]¹⁺), 534.10123.

Example 8XXXXXXXX: iV-r2-(4-chlorophenyl)-l.l-dimethylethyl]-iV²-r(6- phenyIpyridin-3-yl)carbonyl]-L-α-glutamine

[0673] MS (ESI) m/z 494.4; HRMS: calcd for C₂₇H₂₈ClN₃O₄ + H+, 494.18411; found (ESI-FTMS, [MH-H]¹⁺), 494.18423.

Example 8YYYYYYYY: iV-r2-(4-fluorophenyn-l.l-dimethylethyl]-iV²-{[5-(3- methoxyphenyl)-2-thienyUcarbonyO-L-α-glutaniine

[0674] MS (ESI) m/z 513.3; MS (ESI) m/z 1025.7; HRMS: calcd for

C₂₇H₂₉FN₂O₅S + H+, 513.18540; found (ESI-FTMS, [MH-H]¹⁺), 513.18635. Example 8ZZZZZZZZ: iV-r2-(4-fluorophenvn-l.l-dimethvIethvn-iV²-r(5-pyridin-3- yl-2-thienyl)carbonvn-L-α-glutaniine

[0675] MS (ESI) m/z 484.3; HRMS: calcd for C₂₅H₂₆FN₃O₄S + H+, 484.17008; found (ESI-FTMS, [M+H]¹⁺), 484.17109.

Example 8AAAAAAAAA: N -ir5-(3-chloro-4-fluorophenvI)-2-thienvncarbonvI)-iV^r- r2-(4-fluorophenyl)-l,l-dimethylethyIl-L-α-glutamϊne

[0676] MS (ESI) m/z 535.2; MS (ESI) m/z 557.2; MS (ESI) m/z 1069.5; HRMS: calcd for C₂₆H₂₅ClF₂N₂O₄S + H+, 535.12644; found (ESI-FTMS, [M+H]¹⁺), 535.12696. [0677] MS (ESI) m/z 533.3; MS (ESI) m/z 1067.6; HRMS: calcd for

C₂₆H₂₅ClF₂N₂O₄S + H+, 535.12644; found (ESI-FTMS, [M+H]¹⁺), 535.12796.

Example 8BBBBBBBBB: iV²-(2.2'-bithien-5-ylcarbonyl)-N-r2-(4-fluorophenyl)-l.l- dimethylethγl]-L-α-gIutamine

[0678] MS (ESI) m/z 489.3; MS (ESI) m/z 977.5; HRMS: calcd for

C₂₄H₂₅FN₂O₄S₂ + H+, 489.13125; found (ESI-FTMS, [M+H]¹⁺), 489.13208.

Example 8CCCCCCCCC: iV-[2-(4-chlorophenyl)-l.l-dimethylethyl]-iV²-[4-(5- formyl-2-thienyl)benzovπ-L-α-glutamine

[0679] MS (ESI) m/z 527.1; MS (ESI) m/z 1053.1; MS (ESI) m/z 549; HRMS: calcd for C₂₇H₂₇ClN₂O₅S + H+, 527.14020; found (ESI-FTMS, [M+H]¹⁺), 527.14185.

Example 8DDDDDDDDD; iV²-[4-(5-acetyl-2-thienvnbenzoyl]-N-r2-(4-chlorophenyl)- lΛ-dimethylethyli-L-α-glutamine

[0680] MS (ESI) m/z 541.1; MS (ESI) m/z 1081.2; MS (ESI) m/z 563.1; HRMS: calcd for C₂₈H₂₉ClN₂O₅S + H+, 541.15585; found (ESI-FTMS, [M+H]¹⁺), 541.15471.

Example 8EEEEEEEEE: iV-[2-(4-chlorophenvIVl.l-dimethylethvn-iV²-[4-(1.3- thiazoI-2-yl)benzoyl]-L-α-glutamine

[0681] MS (ESI) m/z 500.3; HRMS: calcd for C₂₅H₂₆ClN₃O₄S + H+, 500.14053; found (ESI-FTMS, [M+H]¹⁺), 500.14163. Example 8FFFFFFFFF; JV-(l.l-dimethyl-2-phenylethvD-iV²-r4-(1.3-thiazoI-2- yPhenzoyli-L-ot-glutamme

[0682] MS (ESI) m/z 4663; HRMS: calcd for C₂₅H₂₇N₃O₄S + H+, 466.17950; found (ESI-FTMS, [M+H]¹⁺), 466.18052.

Example 8GGGGGGGGG: iV-(l.l-dimethyl-2-phenylethyl)-N²-(5-phenvI-2-furoylV L-α-glutamine

[0683] MS (ESI) m/z 449.3; MS (ESI) m/z 897.6; MS (ESI) m/z 471.3; HRMS: calcd for C₂₆H₂₈N₂O₅ + H+, 449.20710; found (ESI-FTMS, [M+H]¹⁺), 449.20772.

Example 8HHHHHHHHH; iV-(l.l-dimethyl-2-phenylethvIViV²-r4-(5-formyl-2- thienvDbenzoyl] -L-α-glutamine

[0684] MS (ESI) m/z 493.3; MS (ESI) m/z 985.6; MS (ESI) m/z 515.3; HRMS: calcd for C₂₇H₂₈N₂O₅S + H+, 493.17917; found (ESI-FTMS, [M+H]¹⁺), 493.18011.

Example 8IIIHIIII: iV²-r4-(5-acetyl-2-thienvnbenzoyl]-N-(l.l-dimethyl-2- phenylethvD-L-α-glutamine

[0685] MS (ESI) m/z 507.3; MS (ESI) m/z 1013.7; MS (ESI) m/z 529.3; HRMS: calcd for C₂₈H₃₀N₂O₅S + H+, 507.19482; found (ESI-FTMS, [M+H]¹⁺), 507.19518.

Example 8.TJJJ.T.T.T.T.T: JV-r2-f4-chIorophenyl)-l.l-dimethylethyl]-iV²-[3-(5-chloro-2- thienvDbenzovϊl -L-α-glutamine

[0686] MS (ESI) m/z 533.3; MS (ESI) m/z 1065.5; MS (ESI) m/z 555.3; HRMS: calcd for C₂₆H₂₆Cl₂N₂O₄S + H+, 533.10631; found (ESI-FTMS, [M+H]¹⁺), 533.10835.

Example 8KKKKKKKKK: iV-[2-(4-chlorophenvn-l.l-dimethvIethvn-N²-r3-(2- thienyDbenzoyl] -L-α-glutamine

[0687] MS (ESI) m/z 499.3; MS (ESI) m/z 997.6; MS (ESI) m/z 521.3; HRMS: calcd for C₂₆H₂₇ClN₂O₄S + H+, 499.14528; found (ESI-FTMS, [M+H]¹⁺), 499.14679. Example 8LLLLLLLLL; iV-r2-(4-chlorophenyl)-l.l-dimethvIethvn-iV²-ir5-r4- chIorophenyl)-2-thienyllcarbonyl&gt;-L-α-glutamine

[0688] MS (ESI) m/z 533.3; MS (ESI) m/z 1065.5; MS (ESI) m/z 555.3; HRMS: calcd for C₂₆H₂₆Cl₂N₂O₄S + H+, 533.10631; found (ESI-FTMS, [M+H]¹⁺), 533.10784.

Example 8MMMMMMMMM; iV-r2-(4-chlorophenylVl.l-dimethvIethyl1-iV²-{r5-(4- fluorophenyl)-2-thienvncarbonyl&gt;-L-α-glutamine

[0689] MS (ESI) m/z 517.3; MS (ESI) m/z 539.3; MS (ESI) m/z 1033.6; HRMS: calcd for C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.13691.

Example 8NNNNNNNNN: iV²-[4-(5-bromo-2-thienvnbenzoyl]-iV-r2-(4- chIorophenyl)-l,l-dimethylethyl]-L-α-glutamine

[0690] MS (ESI) m/z 5112; MS (ESI) m/z 1153.4; HRMS: calcd for

C₂₆H₂₆BrClN₂O₄S + H+, 577.05579; found (ESI-FTMS, [M+H]¹⁺), 577.05597.

Example 8000000000: iV²-[4-(5-bromo-2-thienyl)benzoyl]-iV-(l.l-dimethvI-2- phenylethyl)-L-α-glutamine

[0691] MS (ESI) m/z 543.1; MS (ESI) m/z 1085.2; HRMS: calcd for

C₂₆H₂₇BrN₂O₄S + H+, 543.09477; found (ESI-FTMS, [M+H]¹⁺), 543.0965; HRMS: calcd for C₂₆H₂₇BrN₂O₄S + H+, 543.09477; found (ESI-FTMS, [M+H]¹⁺), 543.09494.

Example 8PPPPPPPPP: iV-fl.l-dimethyl-2-phenylethyl)-iV²-{[5-(4-fluorophenyl)-2- thienyl]carbonyl|-L-α-glutamϊne

[0692] MS (ESI) m/z 483.2; MS (ESI) m/z 965.4; MS (ESI) m/z 505.2; HRMS: calcd for C₂₆H₂₇FN₂O₄S + H+, 483.17483; found (ESI-FTMS, [M+H]¹⁺), 483.17634.

Example 8000000000: iV²-r3-(5-chloro-2-thienyl)benζoyl]-iV-(l,l-dimethyl-2- phenylethyl)-L-α-glutamine

[0693] MS (ESI) m/z 499.2; MS (ESI) m/z 997.3; MS (ESI) m/z 521.1; HRMS: calcd for C₂₆H₂₇ClN₂O₄S + H+, 499.14528; found (ESI-FTMS, [M+H]¹⁺), 499.14544. Example 8RRRRRRRRR; N-flΛ-dimethvI-2-phenylethylViV²-[3-(2- thienvDbenzoyli -L-α-glutamine

[0694] MS (ESI) m/z 465.2; MS (ESI) m/z 929 A; MS (ESI) m/z 487.2; HRMS: calcd for C₂₆H₂₈N₂O₄S + H+, 465.18425; found (ESI-FTMS, [M+H]¹⁺), 465.18439.

Example 8SSSSSSSSS: iV²-r(3'-chlorobiphenyl-4-vncarbonvIl-N-r2-(4-fluorophenvn-

1,1-dimethylethyll-L-q-glutamine

[0695] HRMS: calcd for C₂₈H₂₈ClFN₂O₄ + H+, 511.17944; found (ESI-FTMS,

[M+H]¹⁺), 511.17974.

Example 8TTTTTTTTT; iV²-r(4'-chIorobiphenyl-4-yl)carbonvn-N-r2-(4- fluorophenγl)-l,l-dimethylethyl]-L-α-glutamine

[0696] HRMS: calcd for C₂₈H₂₈ClFN₂O₄ + H+, 511.17944; found (ESI-FTMS,

[M+H]¹⁺), 511.17972.

Example 8UUUUUUUUU: N²4(4^fluorobiphenyl-4-ylkarbonyll-iV-[2-(4- fluorophenyl)-lΛ-dimethylethyl]-L-α-glutamine

[0697] HRMS: calcd for C₂₈H₂₈F₂N₂O₄ + H+, 495.20899; found (ESI-FTMS,

[MH-H]¹⁺), 495.20933.

Example 8VWVYWW: N²4(3'-fluorobiphenyl-4-ylkarbonyl]-iV-[2-(4- fluorophenyl)-l,l-dimethylethyl]-L-α-glutamine

[0698] HRMS : calcd for C₂₈H₂₈F₂N₂O₄ + H+, 495.20899; found (ESI-FTMS,

[M+H]¹⁺), 495.20937.

Example 8WWWWWWWWW: iV-r2-(4-chlorophenylVl.l-dimethylethyl]-iV²-r(3- phenyl-2-thienyl)carbonyl]-L-α-glutamine

[0699] HRMS: calcd for C₂₆H₂₇ClN₂O₄S + H+, 499.14528; found (ESI-FTMS,

[MH-H]¹⁺), 499.14664.

Example 8XXXXXXXXX: iV²-r(4'-chlorobiphenyl-4-vncarbonvn-iV-[2-(4- chlorophenyl)-l.l-dimethylethyl]-L-α-glutamine [0700] MS (ESI) m/z 527.3; MS (ESI) m/z 1053.7; MS (ESI) m/z 549.3; HRMS: calcd for C₂₈H₂₈Cl₂N₂O₄ + H+, 527.14989; found (ESI-FTMS, [M+H]¹⁺), 527.15049. [0701] HRMS : calcd for C₂₈H₂₈Cl₂N₂O₄ + H+, 527.14989; found (ESI-FTMS,

[M+H]¹⁺), 527.14931.

Example 8YYYYYYYYY; iV²-r(3'-chlorobiphenyl-4-yl)carbonvn-iV-r2-(4- chlorophenyl)-l,l-dimethylethyn-L-α-gIutamine

[0702] MS (ESI) m/z 527.3; MS (ESI) m/z 1053.7; MS (ESI) m/z 549.3; HRMS: calcd for C₂₈H₂₈Cl₂N₂O₄ + H+, 527.14989; found (ESI-FTMS, [MH-H]¹⁺), 527.15048.

Example 8ZZZZZZZZZ: iV-r2-(4-fluorophenvn-l.l-dimethylethyll-iV²-([5-(4- fluorophenyl)-2-thienyl1carbonγl|-L-α-glutamine

[0703] MS (ESI) m/z 501.3; MS (ESI) m/z 1001.6; MS (ESI) m/z 523.3; HRMS: calcd for C₂₆H₂₆F₂N₂O₄S + H+, 501.16541; found (ESI-FTMS, [M+H]¹⁺), 501.16642. [0704] MS (ESI) m/z 501.3; MS (ESI) m/z 1001.6; MS (ESI) m/z 523.3; HRMS: calcd for C₂₆H₂₆F₂N₂O₄S + H+, 501.16541; found (ESI-FTMS, [M+H]¹⁺), 501.16709.

Example 8AAAAAAAAAA: iV²-{[5-(4-chlorophenyl)-2-thienyl]carbonvU-iV-(l.l- dimethyl-2-phenylethyl)-L-α-glutamine

[0705] MS (ESI) m/z 499.1; MS (ESI) m/z 997.2; HRMS: calcd for

C₂₆H₂₇ClN₂O₄S + H+, 499.14528; found (ESI-FTMS, [M+H]¹⁺), 499.14552.

Example 8BBBBBBBBBB: iV-(l,l-dimethyl-2-phenylethyl)-iV²-[(3-phenyl-2- thienvDcarbonyl] -L-α-glutamine

[0706] MS (ESI) m/z 465.2; MS (ESI) m/z 929.4; MS (ESI) m/z 951.4; HRMS: calcd for C₂₆H₂₈N₂O₄S + H+, 465.18425; found (ESI-FTMS, [M+H]¹⁺), 465.18455.

Example 8CCCCCCCCCC: iV²-(4-bromobenζoyl)-iV-[2-(4-fluorophenylVlΛ- dimethylethyl]-L-α-glutamine

[0707] MS (ESI) m/z 479.3; MS (ESI) m/z 957.5; MS (ESI) m/z 501.2; HRMS: calcd for C₂₂H₂₄BrFN₂O₄ + H+, 479.09762; found (ESI-FTMS, [M+H]¹⁺), 479.0983. Example 8DDDDDDDDDD; iV-(l.l-dimethyl-2-phenylethvn-iV²-r(4' -fluorobiphenyl- 4-vDcarbonyn -L-α-glutamine

[0708] MS (ESI) m/z 4-173; MS (ESI) m/z 499.3; MS (ESI) m/z 953.7; HRMS: calcd for C₂₈H₂₉FN₂O₄ + H+, 477.21841; found (ESI-FTMS, [M+H]¹⁺), 477.21891.

Example 8EEEEEEEEEE; N-(l.l-dimethyl-2-phenylethyl)-iV²-r(3'-fluorobiphenvi-4- vDcarbonyli-L-α-glutamine

[0709] MS (ESI) m/z 477.3; MS (ESI) m/z 499.3; MS (ESI) m/z 953.7; HRMS: calcd for C₂₈H₂₉FN₂O₄ + H+, 477.21841; found (ESI-FTMS, [M+H]¹⁺), 477.21875.

Example 8FFFFFFFFFF; iV²-r4-(5-chloro-2-thienvI)benζovn-iV-r2-(4-fluorophenyl)- lΛ-dimethylethyl]-D-α-glutamine

[0710] MS (ESI) m/z 517.2; MS (ESI) m/z 539.2; MS (ESI) m/z 1033.5; HRMS: calcd for C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.1365.

Example δGGGGGGGGGGt ^-irθ-fS-chloro^-thienvDpyridin-a-yncarbonvn-iV- r2-(4-fluorophenyl)-l.l-dimethylethvn-L-α-glutamine

[0711] MS (ESI) m/z 518.2; HRMS: calcd for C₂₅H₂₅ClFN₃O₄S + H+, 518.13111; found (ESI-FTMS, [M+H]¹⁺), 518.13169.

Example 8HHHHHHHHHH; iV²-{[5-(4-chlorophenyl)-2-thienyl]carbonyll-iV-[2-(4- fluorophenyl)-l.l-dimethylethyl]-L-α-glutamϊne

[0712] MS (ESI) m/z 517.3; MS (ESI) m/z 539.3; MS (ESI) m/z 1033.6; HRMS: calcd for C₂₆H₂₆ClFN₂O₄S + H+, 517.13586; found (ESI-FTMS, [M+H]¹⁺), 517.1363.

Example iV²-{[5-(3.4-difluorophenyl)-2-thienvncarbonyll-iV-[2-(4- fluorophenvD-lΛ-dimethylethvn-L-α-glutamϊne

[0713] MS (ESI) m/z 519.3; MS (ESI) m/z 1037.7; MS (ESI) m/z 541.3; HRMS: calcd for C₂₆H₂₅F₃N₂O₄S + H+, 519.15599; found (ESI-FTMS, [M+H]¹⁺), 519.1568.

[0714] The following intermediates (R₁COOH in scheme 7) were prepared and used in the preparation of some of the compounds of Example 8: Example 8.TJ.T.T.T.T.T.TJ.T; 4-(2-thienvDbenzoic acid

<img file="EP1902014A2_D0067.tif" />

[0715] 4-iodobenzoic acid (3g, 12.1mmol), 2-thiopheneboronic acid (3.10g,

24.2mmol), and Pd(PPh₃)₄ (1.4g, 1.21mmol) were dissolved in DMF (75mL) in a 35OmL screw-cap pressure vessel. In a separate flask, K₂CO₃ (5.02g, 36.3mmol) was dissolved in H₂O (12mL) and was then added to the reaction. The flask was sealed, heated to 100⁰C and stirred overnight (17h).

[0716] The reaction was then diluted with H₂O (15OmL), placed in a sep. funnel, and IN NaOH was added to raise the pH to 10. The aqueous layer was washed with EtOAc (2x250mL). The aqueous layer was kept, activated charcoal was added, and the mixture heated and stirred. Celite was added, followed by the mixture being filtered through celite. The filtrate was then acidified with concentrated HCl. At pH 7 a tan solid starts to precipitate. The pH was lowered to 5 and the solid formed is filtered out. The solid was partially dissolved in a small amount of toluene, which was then removed to remove some of the water still present. This step was repeated, then the solid was dried under vacuum. Yield - 2.01g tan solid, 81%. MS (ESI) m/z 202.9; HRMS: calcd for C₁₁H₈O₂S + H+, 205.03178; found (ESI-FTMS, [M+H]¹⁺), 205.03127.

[0717] The following compounds were prepared according to the procedure similar to the one described in Example 8JJJJJJJJJJ, from appropriate commercially available reagents:

i: 5-(3-methoxyphenyl)thiophene-2-carboxylic acid

MS (ESI) m/z 233.1; HRMS: calcd for C₁₂H₁₀O₃S + H+, 235.04234; found (ESI- FTMS, [M+H]¹⁺), 235.04226; ii. 2,2'-bithiophene-5-carboxylic acid

MS (ESI) m/z 209.1; HRMS: calcd for C₉H₆O₂S₂ + H+, 210.98820; found (ESI- FTMS, [M+H]¹⁺), 210.98816;

Hi. 5-pyridin-4-ylthiophene-2-carboxylic acid

MS (ESI) m/z 206.1; HRMS: calcd for C₁₀H₇NO₂S + H+, 206.02703; found (ESI- FTMS, [M+H]¹⁺), 206.02691;

iv. 4-(5-chloro-2-thienyl)benzoic acid

H HRRMMSS:: ccaallccd for C₁₁H₇ClO₂S - H+, 236.97825; found (ESI-FTMS, [M-H]^1"), 236.97751;

v. 5-phenyl-2-furoic acid

HRMS: calcd for C₁₁H₈O₃ + H+, 189.05462; found (ESI-FTMS, [M+H]¹⁺), 189.05445;

vi. 4-(5-acetyl-2-thienyl)benzoic acid

MS (ESI) m/z 245.1; HRMS: calcd for C₁₃H₁₀O₃S + H+, 247.04234; found (ESI- FTMS, [MH-H]¹⁺), 247.04223;

vii. 3-(5-chloro-2-thienyl)benzoic acid

MS (ESI) m/z 237; HRMS: calcd for C₁₁H₇ClO₂S - H+, 236.97825; found (ESI- FTMS, [M-H]¹-), 236.97757;

viii. 3-(2-thienyl)benzoic acid

MS (ESI) m/z 203.1; HRMS: calcd for C₁₁H₈O₂S + H+, 205.03178; found (ESI- FTMS, [M+H]¹⁺), 205.03194;

ix. 5-(4-chlorophenyl)thiophene-2-carboxylic acid

MS (ESI) m/z 237; MS (ESI) m/z 283; MS (ESI) m/z 475.1; HRMS: calcd for C₁₁H₇ClO₂S - H+, 236.97825; found (ESI-FTMS, [M-H]^1"), 236.97825; x. S-phenylthiophene-l-carboxylic acid

MS (ESI) m/z 203.1; MS (ESI) m/z 249.1; HRMS: calcd for C₁₁H₈O₂S + H+, 205.03178; found (ESI-FTMS, [M+H]¹⁺), 205.03177;

xi. 4'-chlorobiphenyl-4-carboxyIic acid

MS (ESI) m/z 231.1; HRMS: calcd for C₁₃H₉ClO₂ - H+, 231.02183; found (ESI-

FTMS,

[M-H]^1"), 231.02129;

xii. 3'-chlorobiphenyl-4-carboxylic acid

MS (ESI) m/z 231.1; HRMS: calcd for C₁₃H₉ClO₂ - H+, 231.02183; found (ESI-

FTMS,

[M-H]^1"), 231.02128;

xiii. 5-(3,4-difluorophenyl)thiophene-2-carboxylic acid

MS (ESI) m/z 239; MS (ESI) m/z 285.1; MS (ESI) m/z 479.1; HRMS: calcd for C₁₁H₆F₂O₂S + H+, 241.01293; found (ESI-FTMS, [M+H]¹⁺), 241.01183;

xiv. 5-(2,4-difluorophenyl)thiophene-2-carboxylic acid

MS (ESI) m/z 239; MS (ESI) m/z 285; HRMS: calcd for C₁₁H₆F₂O₂S + H+, 241.01293; found (ESI-FTMS, [M+H]¹⁺), 241.01187;

xv. 4-phenoxybenzoic acid

MS (ESI) m/z 213.1; HRMS: calcd for C₁₃H₁₀O₃ + H+, 215.07027; found (ESI- FTMS, [M+H]¹⁺), 215.07029;

xvi. 4-(2,3-dihydro-l-benzofuran-6-yl)benzoic acid

MS (ESI) m/z 239.1; HRMS: calcd for C₁₅H₁₂O₃ - H+, 239.07137; found (ESI- FTMS, [M-H]^1"), 239.07131;

xvii. S-β-chloro^-fluorophenytythiophene-l-carboxylic acid MS (ESI) m/z 255.1; MS (ESI) m/z 511.2; HRMS: calcd for C₁₁H₆ClFO₂S - H+, 254.96883; found (ESI-FTMS, [M-H]^1"), 254.96892;

xviii. S-pyridin-S-ylthiophene-l-carboxylic acid

MS (ESI) m/z 206.1; HRMS: calcd for C₁₀H₇NO₂S + H+, 206.02703; found (ESI- FTMS, [M+H]¹⁺), 206.02708;

xix. 6-(5-chloro-2-thienyl)nicotinic acid

MS (ESI) m/z 238;

XX. 6-phenylnicotinic acid

MS (ESI) m/z 200.1; HRMS: calcd for C₁₂H₉NO₂ + H+, 200.07061; found (ESI- FTMS, [M+H]¹⁺), 200.07052;

xxi. 4-(l,3-thiaζol-2-yl)benζoic acid mp 235 - 237 ⁰C; MS (ESI) m/z 206; MS (ESI) m/z 204;

xxii. 4-(5-bromo-2-thienyl)benzoic acid

MS (ESI) m/z 281; MS (ESI) m/z 394.8;

xxiii. 5-(4-fluorophenyl)thiophene-2-carboxylic acid

MS (ES) m/z 221.0; MS (ES) m/z 443.0;

xxiv. 4-[5-(aminosulfonyl)-2-thienyl]benzoic acid

MS (ESI) m/z 282.1; MS (ESI) m/z 565.2;

XXV. 4-(5-cyano-2-thienyl)benzoic acid

MS (ESI) m/z 228.1;

xxvi. S'-fluorobiphenyM-carboxylic acid

MS (ESI) m/z 215.1; xxvii. 3',4'-difluorobiphenyI-4-carboxylic acid

MS (EST) m/z 233;

xxviii. 2',4'-difluorobiphenyl-4-carboxylic acid

MS (ESI) m/z 233.1;

xxix. 2',5'-difluorobiphenyl-4-carboxylic acid

MS (ESI) m/z 233.1;

XXX. 3',5'-difluorobiphenyl-4-carboxylic acid

MS (ESI) m/z 233.1;

xxxi. 2',6'-difluorobiphenyl-4-carboxylic acid

MS (ESI) m/z 233.1;

xxxii. 2',3'-difluorobiphenyl-4-carboxylic acid

MS (ESI) m/z 233;

xxxiii. 4-(5-methyl-2-thienyl)benzoic acid

MS (ESI) m/z 217.1; HRMS: calcd for C_J2H₁₀O₂S + H+, 219.04743; found (ESI- FTMS, [M+H]¹⁺), 219.04744;

xxxiv. 6-(3-methoxyphenyl)nicotinic acid

MS (ESI) m/z 230.1;

XXXV. 3-fluorobiphenyl-4-carboxyIic acid

MS (ESI) m/z 215.1; HRMS: calcd for C₁₃H₉FO₂ + H+, 217.06593; found (ESI- FTMS, [M+H]¹⁺), 217.06598. Scheme 8

<img file="EP1902014A2_D0068.tif" />

Example 9: JV²-(biphenyl-4-yIcarbonyl)-iV¹-r2-(4'-formylbiphenyl-4-yl)ethvn-L-α- glutamine

[0718] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-Λ/^rl-[2-(4'-formylbiphenyl-4- yl)ethyl] -L-α-glutaminate tert-butyl Λ^-CbiphenyM-ylcarbonyty-iV¹ - [2-(4-bromophenyl)ethyl] -L-α-glutaminate (333 mg, 0.59 mmol, 1 equiv.) was dissolved in DME (5 mL) and the mixture was added to 4- formylphenyl boronic acid (0.97 g, 0.65 mmol, 1.1 equiv.) and Pd(PPh₃)₄ (68 mg, 0.059 mmol, 0.1 equiv.) and stirred for 30 minutes prior to the addition of aq. K₂CO₃ (163 mg, 1.18 mmol, 2 equiv.) in 1 mL H₂O. The mixture was capped in a sealed vessel and stirred overnight at 80°C. The reaction was complete as determined by TLC. The mixture was filtered over celite, the solvent was removed, and the resulting tan solid was diluted with EtOAc (20 mL) and washed consecutively with H₂0, 10% HCl, brine, and dried over Na₂SO₄. The solid was purified by column chromatography (silica gel, 41% Acetone/Hexanes) to give 38 mg of tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4^l- formylbiphenyl-4-yl)ethyl]-L-α-glutaminate in 11% yield. MS (ESI) m/z 591.3; MS (ESI) m/z 1181.5; HRMS: calcd for C₃₇H₃₈N₂O₅ + H+, 591.28535; found (ESI-FTMS, [MH-H]¹⁺), 591.28473. [0719] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'-formylbiphenyl-4-yl)ethyl]-

L-α-glutamine tert-butyl iV²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4^l-formylbiphenyl-4-yl)ethyl]-L-α- glutaminate (100 mg, 0.17 mmol, 1 equiv.) was dissolved in CH₂Cl₂ (5 mL) and added to TFA (2 mL). The mixture was stirred at room temperature for 3 hrs. The reaction was complete as determined by TLC. Solvent was removed and the resulting solid was purified by preparative HPLC to give A/²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'- formylbiρhenyl-4-yl)ethyl]-L-α-glutamine in 89% yield (80 mg). MS (ESI) m/z 533.1; HRMS: calcd for C₃₃H₃₀N₂O₅ + H+, 535.22275; found (ESI-FTMS, [M+H]¹⁺), 535.22464.

Example 10;

[0720] The following compounds were prepared according to procedures similar to those described in Example 9.

Example IQA; A^-(biphenyl-4-ylcarbonyl)-iV¹-(2-r4'-(trifluoromethvI)biphenvI-4- yπethyl)-L-α-glutamine

[0721] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-{2-[4'-

(trifluoromethyl)biphenyl-4-yl] ethyl } -L-α-glutaminate

MS (ESI) m/z 631.2; MS (ESI) m/z 1261.4; MS (ESI) m/z 653.2; HRMS: calcd for

C₃₇H₃₇F₃N₂O₄ + H+, 631.27782; found (ESI-FTMS, [M+H]¹⁺), 631.27719.

[0722] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-{2-[4'-(trifluoromethyl)biphenyl-4- yl]ethyl } -L-α-glutamine

HRMS: calcd for C₃₃H₂₉F₃N₂O₄ + H+, 575.21522; found (ESI-FTMS, [M+H]¹⁺),

575.21548.

Example IQB; N²-(biphenyI-4-ylcarbonyl)-iV¹-[2-(4'-methoxybiphenyl-4-yl)ethvn-L- α-glutamine

[0723] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'-methoxybiphenyl-

4-yl)ethyl]-L-α-glutaminate

MS (ESI) m/z 593.3; MS (ESI) m/z 1185.5; HRMS: calcd for C₃₇H₄₀N₂O₅ + H+, 593.30100; found (ESI-FTMS, [M+H]¹⁺), 593.29946. [0724] Step B: iV²-(biphenyl-4-ylcarbonyl)-iV¹-[2-(4'-methoxybiρhenyl-4- yl)ethyl] -L-α-glutamine

HRMS: calcd for C₃₃H₃₂N₂O₅ + H+, 537.23840; found (ESI-FTMS, [M+H]¹⁺),

537.23906.

Example IQC: N²-(biphenyϊ-4-ylcarbonvI)-iV¹-(2-biphenyl-4-vIethyl)-L-α-gIutamine

[0725] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-(2-biρhenyl-4-ylethyl)-

L-α-glutaminate

MS (ESI) m/z 563.3; MS (ESI) m/z 1125.5; HRMS: calcd for C₃₆H₃₈N₂O₄ + H+,

563.29043; found (ESI-FTMS, [M+H]¹⁺), 563.28977.

[0726] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-(2-biphenyl-4-ylethyl)-L-α- glutamine

HRMS: calcd for C₃₂H₃₀N₂O₄ + H+, 507.22783; found (ESI-FTMS, [M+H]¹⁺),

507.22688.

Example IQD; JV²-(biphenyl-4-ylcarbonyl)-iV¹-(2-r4-(2-thienvI)phenvnethvI)-L-α- glutamine

[0727] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-{2-[4-(2- thienyl)phenyl]ethyl } -L-α-glutaminate

MS (ESI) m/z 569.2; MS (ESI) m/z 1137.4; HRMS: calcd for C₃₄H₃₆N₂O₄S + H+,

569.24685; found (ESI-FTMS, [M+H]¹⁺), 569.24702.

[0728] Step B: N²-(biρhenyl-4-ylcarbonyl)-N¹-{2-[4-(2-thienyl)ρhenyl]ethyl}-L- α-glutamine

MS (ESI) m/z 511.1; HRMS: calcd for C₃₀H₂₈N₂O₄S + H+, 513.18425; found (ESI-

FTMS, [M+H]¹⁺), 513.18417.

Example IQE: JV²-(biphenyl-4-ylcarbonvIViV¹-r2-(2'-ethoxybiphenyl-4-yl)ethvn-L-α- glutamine

[0729] MS (ESI) m/z 551.1; MS (ESI) m/z 1101.4; MS (ESI) m/z 573.1; HRMS: calcd for C₃₄H₃₄N₂O₅ + H+, 551.25405; found (ESI-FTMS, [M+H]¹⁺), 551.2538. Example IQF; JV²-(biphenyl-4-ylcarbonyl)-iV¹-r2-(4'-ethvnylbiphenyl-4-yl)ethvn-L-α- glutamine

[0730] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-A'^rl-[2-(4'-ethynylbiplienyl-4- yl)ethyl] -L-α-glutaminate

MS (ESI) m/z 587.3; MS (ESI) m/z 1173.5; HRMS: calcd for C₃₈H₃₈N₂O₄ + H+,

587.29043; found (ESI-FTMS, [M+H]¹⁺), 587.29016.

[0731] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'-ethynylbiρhenyl-4-yl)ethyl]-

L-α-glutamine

MS (ESI) m/z 529.2; HRMS: calcd for C₃₄H₃₀N₂O₄ + H+, 531.22783; found (ESI-FTMS,

[M+H]¹⁺), 531.22669.

Example IQG; JV²-(biphenyl-4-ylcarbonylViV¹-r2-(4-pyridin-2-vIphenyl)ethyl]-L-α- glutamine

[0732] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-pyridin-2- ylphenyl)ethyl]-L-α-glutaminate

MS (ESI) m/z 564.3; HRMS: calcd for C₃₅H₃₇N₃O₄ + H+, 564.28568; found (ESI-FTMS,

[M+H]¹⁺), 564.28472.

[0733] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4-pyridin-2-ylphenyl)ethyl]-L- α-glutamine

MS (ESI) m/z 508.2.

Example IQH; N²-(biphenvI-4-ylcarbonylV_J/V¹-r2-(4-pyridin-4-ylphenyl)ethvn-L-α- glutamme

[0734] Step A: tert-butyl Λ/²-(biphenyl-4-ylcarbonyl)-Λ/^rl-[2-(4-pyridin-4- ylphenyl)ethyl] -L-α-glutaminate

MS (ESI) m/z 564.2; HRMS: calcd for C₃₅H₃₇N₃O₄ + H+, 564.28568; found (ESI-FTMS,

[M+H]¹⁺), 564.28648.

[0735] Step B: N²-(biρhenyl-4-ylcarbonyl)-iV¹-[2-(4-pyridin-4-ylphenyl)ethyl]-L- α-glutamine

MS (ESI) m/z 508.1; MS (ESI) m/z 275.1; HRMS: calcd for C₃₁H₂₉N₃O₄ + H+,

508.22308; found (ESI-FTMS, [M+H]¹⁺), 508.22403. Example 101: iV²-(biphenyl-4-ylcarbonyl)-iV¹-r2-(3-pyridin-2-ylphenyl)ethvn-L-α- glutamine

[0736] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(3-pyridin-2- ylphenyl)ethyl] -L-α-glutaminate

MS (ESI) m/z 564.3; HRMS: calcd for C₃₅H₃₇N₃O₄ + H+, 564.28568; found (ESI-FTMS,

[MH-H]¹⁺), 564.28531.

[0737] Step B: iV²-(biphenyl-4-ylcarbonyl)-N¹-[2-(3-pyridin-2-ylρhenyl)ethyl]-L- α-glutamine

MS (ESI) m/z 508.1; HRMS: calcd for C₃₁H₂₉N₃O₄ + H+, 508.22308; found (ESI-FTMS,

[M+H]¹⁺), 508.22432.

Example 10.T; iV²-(biphenyl-4-ylcarbonyl)-iV¹-r2-(4'-formylbiphenyl-3-yl)ethvn-L-α- glutamine

[0738] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'-formylbiρhenyl-3- yl)ethyl]-L-α-glutaminate

[0739] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'-formylbiphenyl-3-yl)ethyl]-

L-α-glutamine

MS (ESI) m/z 535.2; MS (ESI) m/z 1069.3; HRMS: calcd for C₃₃H₃₀N₂O₅ + H+,

535.22275; found (ESI-FTMS, [M+H]¹⁺), 535.22147.

Example IQK; JV²-(biphenvI-4-ylcarbonvI)-iV¹-{2-[4'-(trifluoromethyl)biphenyl-3- yl1ethyl)-L-α-glutamine

[0740] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-{2-[4'-

(trifluoromethyl)biphenyl-3-yl]ethyl } -L-α-glutaminate

HRMS: calcd for C₃₇H₃₇F₃N₂O₄ + H+, 631.27782; found (ESI-FTMS, [M+H]¹⁺),

631.27639.

[0741] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-{2-[4'-(trifluoromethyl)biphenyl-3- yl]ethyl } -L-α-glutamine

MS (ESI) m/z 575.2; HRMS: calcd for C₃₃H₂₉F₃N₂O₄ + H+, 575.21522; found (ESI-

FTMS, [M+H]¹⁺), 575.21382. 066

Example IQLt JV²-(biphenyl-4-ylcarbonyl)-iV^rl-r2-f4'-methoxybiphenyl-3-vDethvn-L- α-glutamine

[0742] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'-methoxybiphenyl-

3-yl)ethyl]-L-α-glutaminate

HRMS: calcd for C₃₇H₄₀N₂O₅ + H+, 593.30100; found (ESI-FTMS, [M+H]¹⁺),

593.29993.

[0743] Step B : N²-(biphenyl-4-ylcarbonyl)-N¹-[2-(4'-methoxybiphenyl-3- yl)ethyl]~L-α-glutamine

MS (ESI) m/z 537.2; HRMS: calcd for C₃₃H₃₂N₂O₅ + H+, 537.23840; found (ESI-FTMS,

[M+H]¹⁺), 537.23745.

Example IQM; A/^r2-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3-vinyIbenzyl)-L-α-glutamine

[0744] Step A: tert-butyl A/^r2-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3-vinylbenzyl)-L- α-glutaminate

Tert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-(3-iodobenzyl)-L-α-glutaminate was used as the starting material. MS (ESI) m/z 499.2; MS (ESI) m/z 997.4; HRMS: calcd for

C_3IH₃₄N₂O₄ + H+, 499.25913; found (ESI-FTMS, [M+H]¹⁺), 499.25906.

[0745] Step B: iV²-(l,r-biρhenyl-4-ylcarbonyl)-N¹-(3-vinylbenζyl)-L-α-glutamine

MS (ESI) m/z 443.2; MS (ESI) m/z 885.3; HRMS: calcd for C₂₇H₂₆N₂O₄ + H+,

443.19653; found (ESI-FTMS, [M+H]¹⁺), 443.19728.

Example ION; ^-(lΛ'-biphenyl^-ylcarbonyD-iV^O-thien^-ylbenzvD-L-α- glutamine

[0746] Step A: tert-butyl iV²-(l,l'-biρhenyl-4-ylcarbonyl)-iV¹-(3-thien-2-ylbenzyl)-

L-α-glutaminate

7ert-butyl N²-(l, r-biphenyl-4-ylcarbonyl)-N¹-(3-iodobenzyl)-L-α-glutaminate was used as the starting material. MS (ESI) m/z 555.2; MS (ESI) m/z 1109.3; HRMS: calcd for

C₃₃H₃₄N₂O₄S + H+, 555.23120; found (ESI-FTMS, [M+H]¹⁺), 555.23173.

[0747] Step B: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(3-thien-2-ylbenζyl)-L-α- glutamine

MS (ESI) m/z 499.1; HRMS: calcd for C₂₉H₂₆N₂O₄S + H+, 499.16860; found (ESI-

FTMS, [M+H]¹⁺), 499.16976. Example IQO: JV²-fbiphenyl-4-vIcarbonvn-iV¹-{r4'-(trifluoromethyl)biphenvI-3- ylimethyll-L-g-glutamine

[0748] Step A: tert-butyl ^-(biphenyl-Φ-ylcarbonyl^-t [4¹-

(trifluoromethyl)biphenyl-3-yl]methyl}-L-α-glutaminate rert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(3-iodobenzyl)-L-α-glutaininate was used as the starting material. MS (ESI) m/z 617.2; MS (ESI) m/z 1233.3; HRMS: calcd for

C₃₆H₃₅F₃N₂O₄ + H+, 617.26217; found (ESI-FTMS, [M+H]¹⁺), 617.26334.

[0749] Step B : iV²-(biphenyl-4-ylcarbonyl)-N¹- { [4'-(trifluoromethyl)biphenyl-3- yl]methyl } -L-α-glutamine

MS (ESI) m/z 559.1; MS (ESI) m/z 1119.1; HRMS: calcd for C₃₂H₂₇F₃N₂O₄ + H+,

561.19957; found (ESI-FTMS, [M+H]¹⁺), 561.2001.

Example IQP: N²-(biphenyl-4-ylcarbonvI)-iV¹-[(4'-ethvnylbiphenyl-3-yl)methyl1-L-α- glutamine

[0750] Step A: tert-butyl iV²-(biphenyl-4-ylcarbonyl)-iV¹-[(4'-ethynylbiphenyl-3- yl)methyl] -L-α-glutaminate rert-butyl N²-(l,r-biphenyl-4-ylcarbonyl)-iV¹-(3-iodobenzyl)-L-α-glutaminate was used as the starting material. MS (ESI) m/z 573.2; MS (ESI) m/z 1145.4; HRMS: calcd for

C₃₇H₃₆N₂O₄ + H+, 573.27478; found (ESI-FTMS, [M+H]¹⁺), 573.27518.

[0751] Step B: iV²-(biphenyl-4-ylcarbonyl)-N¹-[(4'-ethynylbiphenyl-3-yl)methyl]-

L-α-glutamine

MS (ESI) m/z 517.2; MS (ESI) m/z 1033.3; HRMS: calcd for C₃₃H₂₈N₂O₄ + H+,

517.21218; found (ESI-FTMS, [M+H]¹⁺), 517.2125.

Example IQQ; ^-(biphenyl^-ylcarbonvD-^-O-pyridin^-ylbenzyD-L-α-glutamine

[0752] Step A: tert-butyl N²-(biphenyl-4-ylcarbonyl)-N¹-(3-pyridin-2-ylbenzyl)-

L-α-glutaminate rert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(3-iodobenzyl)-L-α-glutaminate was used as the starting material. MS (ESI) m/z 550.2; HRMS: calcd for C₃₄H₃SN₃O₄ + H+,

550.27003; found (ESI-FTMS, [MH-H]¹⁺), 550.27066. [0753] Step B: N²-(biphenyl-4-ylcarbonyl)-N¹-(3-pyridin-2-ylbenzyl)-L-α- glutamine

MS (ESI) m/z 494.1; HRMS: calcd for C₃₀H₂₇N₃O₄ + H+, 494.20743; found (ESI-FTMS,

[M+H]¹⁺), 494.20803.

Example IQR: iV²-(l,l'-biphenyl-4-ylcarbonyl)-iV¹-(4-vinylbenzyl)-L-α-gIutamine

[0754] Step A: tert-butyl N²-(l,l'-biphenyl-4-ylcarbonyl)-N¹-(4-vinylbenzyl)-L- α-glutaminate

Tert-butyl N²-(l,l'-biρhenyl-4-ylcarbonyl)-N¹-(4-iodobenzyl)-L-α-glutaininate was used as the starting material. MS (ESI) m/z 499.2; MS (ESI) m/z 997.3; HRMS: calcd for

C_3JH₃₄N₂O₄ + H+, 499.25913; found (ESI-FTMS, [M+H]¹⁺), 499.25883.

[0755] Step B: N²-(l,r-biphenyl-4-ylcarbonyl)-N¹-(4-vinylbenzyl)-L-α-glutamine

MS (ESI) m/z 443.1; HRMS: calcd for C₂₇H₂₆N₂O₄ + H+, 443.19653; found (ESI-FTMS,

[M+H]¹⁺), 443.19697.

Scheme 9

K₂CO₃, <img file="EP1902014A2_D0069.tif" />

<img file="EP1902014A2_D0070.tif" />

27 26

Example 11; JV^rl-benzyl-iV²-(4-thien-2-vIbenzovI)-L-α-gIutamine

[0756] Step A: tert-butyl N¹-benzyl-N²-(4-bromobenzoyl)-L-α-glutaminate

A solution of 4-Amino-4-benzylcarbamoyl-butyric acid tert-butyl ester (6.39 g, 21.9 mmol, 1 equiv.) in DMF (18 mL) was added to 4-Bromobenzoic acid (4.39 g, 21.9 mmol, 1 equiv.) and PyBOP (14.7 g, 28.2 mmol, 1.2 equiv.) and the solution was stirred at room temperature under nitrogen. DIEA (4.58 mL, 26.3 mmol, 1.2 equiv.) was then added dropwise and the solution was stirred for 2 hrs. The reaction was complete as determined by TLC. The solution was diluted with EtOAc (250 mL) and washed consecutively with H₂0, 10% HCl, satd. NaHCO₃, brine, and dried over Na₂SO₄. After the solvent was evaporated, the crude residue was dissolved in ether and washed with aq. LiBr (2 x 250 mL) and dried over Na₂SO₄. A light tan solid was obtained, 8.94 g of tert-butyl N¹- benzyl-N²-(4-bromobenzoyl)-L-α-glutaminate in 86 % yield. MS (ESI) m/z 475.1; MS (ESI) m/z 949.2; HRMS: calcd for C₂₃H₂₇BrN₂O₄ + Na+, 497.10464; found (ESI_FTMS, [M+Na]¹⁺), 497.10542.

[0757] Step B: tert-butyl N¹-benzyl-iV²-(4-thien-2-ylbenzoyl)-L-α-glutaminate

Tert-butyl N¹-benzyl-N²-(4-bromobenzoyl)-L-a-glutaminate (200mg, 0.421mmol) was dissolved in toluene (4mL) under nitrogen. Copper iodide (16.0mg, 0.0841mmol), triphenylarsine (26.0mg, 0.0841mmol), and Pd(Cl)₂(PPh₃)₂ (59mg, 0.0841mmol) were then added as solids. The reaction mixture was then fitted with a condenser and heated to reflux (115⁰C), for 10 minutes. 2-(Tributylstannyl)-thiophene (267mL, 0.841mmol) was added and immediately the reaction went from orange to black. These are typical Stille reaction conditions. The reaction was monitored by TLC and was complete at 30 minutes. The reaction mixture was filtered through celite and the celite rinsed with MeOH (ImL). Solvent was removed and the remaining yellow residue was dissolved in a minimal amount of CH₂Cl₂. Hexanes were added, precipitating a white solid that was filtered, washed with hexanes, and then dried at reduced pressure. 140mg of tert-butyl N¹-benzyl-A/²-(4-thien-2-ylbenzoyl)-L-α-glutaminate, a white solid was obtained in 69% yield. MS (ESI) m/z 479.1; MS (ESI) m/z 957.3; HRMS: calcd for C₂₇H₃₀N₂O₄S + H+, 479.19990; found (ESI_FT, [M+H]¹⁺), 479.19826. [0758] Step C: N¹-benzyl-Λ/^r2-(4-thien-2-ylbenzoyl)-L-α-glutamine

Terr-butyl N¹-benzyl-N²-(4-thien-2-ylbenzoyl)-L-α-glutaminate (135mg, 0.282mmol) was dissolved in CH₂Cl₂ (1.5mL) under nitrogen. TFA was diluted in CH₂Cl₂ (2mL), and then added to the reaction. The reaction was monitored by TLC and was complete at 2 hrs. The solvent was removed and the remaining yellow residue was dissolved in toluene, which was then removed (2x) leaving an orange solid. The orange solid was taken up in acetone, and hexanes added, precipitating a pale orange solid. The solid was filtered, washed with hexanes, and dried at reduced pressure. The pale orange solid was run on a SiO₂ column, using 4%MeOH/CH₂Cl₂. The solvent was removed from the fractions yielding 79mg of N¹-benzyl-A/²-(4-thien-2-ylbenzoyl)-L-α-glutamine, a white solid, at 66% yield. MS (ESI) m/z 421.1; MS (ESI) m/z 843.3; HRMS: calcd for C₂₃H₂₂N₂O₄S + H+, 423.13730; found (ESI_FTMS, [M+H]¹⁺), 423.13742.

Example 12;

[0759] The following compounds were prepared according to procedures similar to those described in Example 11.

Example 12A; N¹-benzyl-N²-r4-(2-furyl)benzoyl1-L-α-glutamine

[0760] Step B: tert-butyl N¹-benzyl-N²-[4-(2-furyl)benzoyl]-L-α-glutaminate

MS (ESI) m/z 463.2; MS (ESI) m/z 925.3; HRMS: calcd for C₂₇H₃₀N₂O₅ + H+,

463.22275; found (ESI_FT, [M+H]¹⁺), 463.22159.

[0761] Step C: N¹-benzyl-N²-[4-(2-furyl)benzoyl]-L-α-glutamine

MS (ESI) m/z 407.1; MS (ESI) m/z 813.2; HRMS: calcd for C₂₃H₂₂N₂O₅ + H+,

407.16015; found (ESI_FTMS, [M+H]¹⁺), 407.16031.

Example 12B; N¹-benzyl-iV²-r(4'-ethvnyl-l,l'-biphenyl-4-vI)carbonvn-L-α-glutamine

[0762] Step B : tert-butyl N¹-benzyl-N²-[(4'-ethynyl- 1 , 1 -biphenyl-4-yl)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 497.3; MS (ESI) m/z 993.5; HRMS: calcd for C₃₁H₃₂N₂O₄ + H+,

497.24348; found (ESI_FTMS, [M+H]¹⁺), 497.24306.

[0763] Step C: N¹-benzyl-N²-[(4'-ethynyl-l,r-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI) m/z 439.2; MS (ESI) m/z 879.4; HRMS: calcd for C₂₇H₂₄N₂O₄ + H+,

441.18088; found (ESI_FT, [M+H]¹⁺), 441.18056.

Example 12C: JV¹-benzyl-iV²-(4-pyridin-3-vIbenzoyl)-L-α-gIutamine [0764] Step B: tert-butyl N¹-benzyl-N²-(4-pyridin-3-ylbenzoyl)-L-α-glutaminate

MS (ESI) m/z 474.2; HRMS: calcd for C₂₈H₃₁N₃O₄ + H+, 474.23873; found (ESI_FT,

[M-HH]¹⁺), 474.238741.

[0765] Step C: N¹-benzyl-N²-(4-pyridin-3-ylbenzoyl)-L-α-glutamine

MS (ESI) m/z 418.1; HRMS: calcd for C₂₄H₂₃N₃O₄ + H+, 418.17613; found (ESI_FT,

[M+H]¹⁺), 418.17555.

Example 12D: A/^rl-benzyl-iV²-[4-(1.3-thiazol-2-yl)benzovn-L-α-glutamine

[0766] Step B : tert-butyl N¹-benzyl-N²-[4-(l ,3-thiazol-2-yl)benzoyl]-L-α- glutaminate

MS (ESI) m/z 480.2; MS (ESI) m/z 959.2; HRMS: calcd for C₂₆H₂₉N₃O₄S + H+,

480.19515; found (ESI_FT, [M+H]¹⁺), 480.19659.

[0767] Step C: iV¹-benzyl-N²-[4-(l,3-thiazol-2-yl)benzoyl]-L-α-glutamine

MS (ESI) m/z 422.2; MS (ESI) m/z 845.3; HRMS: calcd for C₂₂H₂₁N₃O₄S + H+,

424.13255; found (ESI_FT, [M+H]¹⁺), 424.13204.

Example 12E: iV¹-benzyl-iV²-(4-pyridin-2-ylbenzoyl)-L-α-glutamine

[0768] Step B: ter?-butyl N¹-benzyl-N²-(4-pyridin-2-ylbenzoyl)-L-α-glutaminate

MS (ESI) m/z 474.2; HRMS: calcd for C₂₈H₃₁N₃O₄ + H+, 474.23873; found (ESI_FT,

[MH-H]¹⁺), 474.2401.

[0769] Step C: N¹-benzyl-Λ^r2-(4-pyridin-2-ylbenzoyl)-L-α-glutamine

MS (ESI) m/z 418.1; HRMS: calcd for C₂₄H₂₃N₃O₄ + H+, 418.17613; found (ESI_FT,

[M+H]¹⁺), 418.17517.

Example 12F: N-benzyl-N²-[4-(2-naphthyl)benzoyl]-L-α-glutamine

[0770] MS (ESI) m/z 467.2; MS (ESI) m/z 933.4; HRMS: calcd for C₂₉H₂₆N₂O₄ +

H+, 467.19653; found (ESI-FTMS, [M+H]¹⁺), 467.19661.

Example 12G; N-benzyl-N²-[4-(phenylethynyl)benzoyn-L-α-glutamine

[0771] MS (ESI) m/z 441.2; MS (ESI) m/z 881.4. Example 12H: N-benzvI-^-^-rfP-hvdroxy-gH-fluoren^-vDethvnvnbenzovπ-L-K- sslutamine

[0772] MS (ESI) m/z 543.1; MS (ESI) m/z 1087.2.

Example 121: N-benzyl-N²-{4-r(lEV3-oxo-3-phenylprop-l-en-l-vIlbenzoyll-L-α- glutamine

[0773] MS (ESl) m/z 471.2; MS (ESI) m/z 941.4.

Example 12.T: N²-{4-r(3-aminophenyl)ethvnvnbenzoyl|-N-benzyl-L-α-gltttamine

[0774] MS (ESI) m/z 456.1 ; MS (ESI) m/z 249.1.

Example 12K: N-benzyl-N²-[4-(3-hvdroxy-3,3-diphenylprop-l-vn-l-yl)benzoyn-L-α- glutamine

[0775] MS (ESI) m/z 545.1; MS (ESI) m/z 1091.2; MS (ESI) m/z 659.1.

Example 12L: N-benzyl-N²-{4-r(3-methoxyphenyl)ethvnyl1benzoyl)-L-α-sslutamine

[0776] MS (ESI) m/z 471.1 ; MS (ESI) m/z 941.2.

Example 13:

[0777] The following compounds were prepared according to procedures similar to those described in Example 11, except a Suzuki reaction was used at step B in place of a Stille reaction. Hydrolysis of the ester to the final product followed the same procedure as previously described.

Example 13A: N¹-benzyl-iV²-[(3' ,5'-dimethyl-l,l'-biphenyl-4-yl)carbonvn-L-α- glutamine

[0778] Step B: tert-butyl iV¹-benzyl-N²-[(3',5'-dimethyl-l,r-biphenyl-4- yl)carbonyl]-L-α-glutaminate

Tert-hutyl N¹-benzyl-N²-(4-bromobenzoyl)-L-α-glutaminate (350mg, 0.736mmol) was dissolved in DME, under nitrogen in a sealed vial. 3,5-Dimethylboronic acid (1 lOmg, 0.736mmol), and Pd(PPh₃)₄ (43mg, 0.037mmol) were added as solids, and the reaction heated to reflux for 10 minutes. At this point 2M K₂CO₃ (735mL, 1.47mmol) was added, the reaction vial was sealed, and the reaction heated to reflux and monitored by TLC. The reaction was complete at 2 hrs. The aqueous part of the reaction was removed via pipette. The reaction solution was then filtered through celite and the celite rinsed with MeOH. The solvent was removed, leaving a brown solid. The product was purified using a SiO₂ column and 33 %EtO Ac/Hex as the solvent. The product was obtained as a white solid, yielding 222mg at 60% yield. MS (ESI) m/z 501.3; MS (ESI) m/z 1001.6; HRMS: calcd for C₃₁H₃₆N₂O₄ + H+, 501.27478; found (ESI_FT, [MH-H]¹⁺), 501.27332. [0779] Step C: iV¹-benζyl-N²-[(3^l,5¹-dimethyl-l,r-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI_FT) m/z 445.21151; MS (ESI_FT) m/z 445.21219; HRMS: calcd for C₂₇H₂₈N₂O₄ + H+, 445.21218; found (ESI_FT, [M+H]¹⁺), 445.21151.

Example 13B: iV¹-benzyl-iV²-r(2'.5'-dimethyl-l.l'-biphenvI-4-yl)carbonyl]-L-α- glutamine

[0780] Step B: tert-butyl N¹-benzyl-N²-[(2',5'-dimethyl-l,r-biphenyl-4- yl)carbonyl] -L-α-glutaminate

MS (ESI) m/z 501.3; MS (ESI) m/z 1001.6; HRMS: calcd for C₃iH₃₆N₂O₄ + H+,

501.27478; found (ESI_FT, [M+H]¹⁺), 501.27441.

[0781] Step C: N¹-benzyl-N²-[(2',5'-dimethyl-l,r-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI) m/z 445.3; MS (ESI) m/z 889.5; HRMS: calcd for C₂₇H₂₈N₂O₄ + H+,

445.21218; found (ESI_FT, [M+H]¹⁺), 445.21172.

Example 13C: iV¹-benzvI-iV²-[(4'-ethyl-l,l'-biphenvI-4-vI)carbonyl]-L-a-gIutamine

[0782] Step B: tert-butyl N¹-benzyl-iV²-[(4¹-ethyl-l,r-biphenyl-4-yl)carbonyl]-L- α-glutaminate

MS (ESI) m/z 501.3; MS (ESI) m/z 1001.6; HRMS: calcd for C₃iH₃₆N₂O₄ + H+, 501.27478; found (ESI_FT, [M+H]¹⁺), 501.27326.

[0783] Step C: iV¹-benzyl-N²-[(4'-ethyl-l,l'-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESLFT) m/z 445.2115; MS (ESI_FT) m/z 445.21219; HRMS: calcd for C₂₇H₂₈N₂O₄ + H+, 445.21218; found (ESI_FT, [M+H]¹⁺), 445.2115. Example 13D; A^-benzyl-iV²-^' -ethoxy-1.1' -biDhenyl-4-ylkarbonyll-L-α-gIutamine

[0784] Step B: tert-butyl N¹-benzyl-N²-[(3'-ethoxy-l,r-biphenyl-4-yl)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 517.3; MS (ESI) m/z 1033.6; HRMS: calcd for C₃₁H₃₆N₂O₅ + H+,

517.26970; found (ESI_FT, [M+H]¹⁺), 517.26837.

[0785] Step C: N¹-benzyl-Λr²-[(3'-ethoxy-l,r-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI_FT) m/z 461.20568; MS (ESI_FT) m/z 461.2071; HRMS: calcd for C₂₇H₂₈N₂O₅

+ H+, 461.20710; found (ESI_FT, [M+H]¹⁺), 461.20568.

Example 13E: iV¹-benζyl-iV²-[(2'-ethoxy-l,l'-biphenyl-4-yl)carbonyl]-L-α-glutamine

[0786] Step B: tert-butyl N¹-benzyl-Λr²-[(2'-ethoxy-l,r-biphenyl-4-yl)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 517.3; MS (ESI) m/z 1033.5; HRMS: calcd for C₃₁H₃₆N₂O₅ + H+,

517.26970; found (ESI_FT, [M+H]¹⁺), 517.26833.

[0787] Step C: iV¹-benζyl-iV²-[(2'-ethoxy-l,l'-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI_FT) m/z 461.20572; MS (ESI_FT) m/z 461.2071; HRMS: calcd for C₂₇H₂₈N₂O₅

+ H+, 461.20710; found (ESI_FT, [M+H]¹⁺), 461.20572.

Example 13F; iV¹-benzyl-iV²-[(2\6'-dimethyl-l.l'-biphenyl-4-yl)carbonvn-L-α- glutamine

[0788] Step B: tert-butyl iV¹-benzyl-iV²-[(2',6'-dimethyl-l,l¹-biphenyl-4- yl)carbonyl]-L-α-glutaminate

MS (ESI_FT) m/z 501.27323; MS (ESI_FT) m/z 501.27479; HRMS: calcd for

C₃₁H₃₆N₂O₄ + H+, 501.27478; found (ESI_FT, [M+H]¹⁺), 501.27323.

[0789] Step C: N¹-benzyl-iV²-[(2',6'-dimethyl-l,l'-biphenyl-4-yl)carbonyl]-L-a- glutamine

MS (ESI_FT) m/z 445.21145; MS (ESI_FT) m/z 445.21219; HRMS: calcd for

C₂₇H₂₈N₂O₄ + H+, 445.21218; found (ESI_FT, [M+H]¹⁺), 445.21145. Example 13G: iV -benzyl-iV -r(4'-vinvI-l,l'-biphenvI-4-vI)carbonyl1-L-α-glutamine

[0790] Step B: tert-butyl N¹-benzyl-N²-[(4'-vinyl-l,l'-biρhenyl-4-yl)carbonyl]-L- α-glutaminate

MS (ESI) m/z 499.3; MS (ESI) m/z 997.5; HRMS: calcd for C₃₁H₃₄N₂O₄ + H+,

499.25913; found (ESI_FT, [M+H]¹⁺), 499.25855.

[0791] Step C: N¹-benzyl-iV²-[(4'-vinyl-l,r-biρhenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI) m/z 4432; MS (ESI) m/z 885.4; HRMS: calcd for C₂₇H₂₆N₂O₄ + H+,

443.19653; found (ESI-FTMS, [M+H]¹⁺), 443.19675.

Scheme 10

<img file="EP1902014A2_D0071.tif" />

Example 14: N¹-benzvI-7V²-r(4'-ethoxy-l,l'-biphenvI-4-yl)carbonvn-L-α-glutamine

[0792] Step A: tert-butyl N¹-benzyl-Λ/^r2-[(4'-hydroxy-l,r-biphenyl-4-yl)carbonyl]-

L-α-glutaminate

Tert-butyl Ν¹-benzyl-Ν²-(4-bromobenzoyl)-L-α-glutaminate (3.00g,6.31mmol) was dissolved in DME (4OmL), under nitrogen in a 75mL bomb flask. 4-

Hydroxyphenylboronic acid (871mg, 6.31mmol), and Pd(PPh₃)₄ (729mg, 0.631mmol) were added as solids, and the reaction heated to reflux for 30 minutes. At this point K₂CO₃ (1.74g, 12.6mmol) was dissolved in H₂O (8mL), and added to the reaction. The bomb flask was sealed and the reaction was heated to reflux, stirred overnight, and monitored by TLC. The reaction was complete after stirring overnight. The reaction mixture was filtered through celite and the celite rinsed with MeOH. The solvent was removed and the remaining solid was dissolved in EtOAc (20OmL) and then washed with 20OmL of 10% HCl (2x) and brine. The organic layer (top) was then dried (Na₂SO₄), filtered and concentrated, leaving a dark red oily solid. The product was purified using a SiO₂ column, and 40%Ace/Hex as the solvent. It would not dissolve in this solvent so it was dissolved in Acetone/MeOH (1:1) and dry mounted on the column. The product was obtained as the third spot of the column and as a yellow solid. Yield 1.9g of tert-butyl iV¹-benzyl-Λ/²-[(4'-hydroxy-l,r-biphenyl-4-yl)carbonyl]-L-α-glutaminate at 62% yield. MS (ESI) m/z 487.4; MS (ESI) m/z 533.5; MS (ESI) m/z 975.8; HRMS: calcd for C₂₉H₃₂N₂O₅ + H+, 489.23840; found (ESI_FTMS, [MH-H]¹⁺), 489.23862. [0793] Step B: tert-bwtyl N¹-benzyl-N²-[(4'-ethoxy-l,l'-biphenyl-4-yl)carbonyl]-

L-α-glutaminate

Tert-butyl N¹-benzyl-iV²-[(4'-hydroxy- 1 , 1 '-biphenyl-4-yl)carbonyl]-L-α-glutaminate (300mg, 0.614mmol) was dissolved in CH₃CN (7mL) in a sealed 2OmL vial. K₂CO₃ was added as a solid, the vial sealed and heated to 8O⁰C for 1 hour. Iodoethane (54mL, 0.675mmol) was added, the vial sealed and stirred at 8O⁰C overnight. The reaction was monitored by TLC and was complete after stirring overnight. The solvent was removed via nitrogen blower, and the remaining solid dissolved in CH₂Cl₂ (7mL) and washed with 10% HCl (7mL). The aqueous layer was decanted with a pipette, and the solvent was removed via nitrogen blower. The remaining solid was dissolved in DMSO (2mL) and purified on a Gilson HPLC. Yield: 123mg of tert-butyl iV¹-benzyl-N²-[(4'-ethoxy-l,r- biphenyl-4-yl)carbonyl]-L-α-glutaminate, a white solid at 39% yield. MS (ESI) m/z 517.2; MS (ESI) m/z 1033.4; HRMS: calcd for C₃₁H₃₆N₂O₅ + H+, 517.26970; found (ESI_FTMS, [M+H]¹⁺), 517.26801.

[0794] Step C: N¹-benzyl-N²-[(4^I-ethoxy-l,l'-biphenyl-4-yl)carbonyl]-L-α- glutamine The procedure used was similar to that described in Example 13. MS (ESI) m/z 461.2; MS (ESI) m/z 921.4; HRMS: calcd for C₂₇H₂₈N₂O₅ + H+, 461.20710; found (ESI_FTMS, [M+H]¹⁺), 461.20542.

Example 15:

[0795] The following compounds were prepared according to procedures similar to those described in Example 14.

Example 15Ai JV¹ -benzyl-N²-r(4'-propoxy-l,l'-biphenyl-4-yl)carbonvn-L-α- glutamine

[0796] Step B: tert-butyl N¹-benzyl-A/²-[(4'-propoxy-l,r-biρhenyl-4-yl)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 531.3; MS (ESI) m/z 1061.4; HRMS: calcd for C₃₂H₃₈N₂O₅ + H+,

531.28535; found (ESI_FTMS, [M+H]¹⁺), 531.2844.

[0797] Step C: N¹-benzyl-iV²-[(4'-propoxy-l,r-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI) m/z 4152; MS (ESI) m/z 949.4; HRMS: calcd for C₂₈H₃₀N₂O₅ + H+,

475.22275; found (ESI_FTMS, [M+H]¹⁺), 475.22333.

Example 15B: JV¹-benzyl-N²-r(4'-butoxy-lΛ'-biphenyl-4-yl)carbonyl]-L-α-glutamine

[0798] Step B: tert-butyl N¹-benzyl-iV²-[(4'-butoxy-l,r-biphenyl-4-yl)carbonyl]-

L-α-glutaminate

MS (ESI) m/z 545.3; MS (ESI) m/z 1089.5; HRMS: calcd for C₃₃H₄₀N₂O₅ + H+,

545.30100; found (ESI_FTMS, [M+H]¹⁺), 545.30048.

[0799] Step C: iV¹-benzyl-iV²-[(4'-butoxy-l,r-biphenyl-4-yl)carbonyl]-L-α- glutamine

MS (ESI) m/z 489.3; MS (ESI) m/z 977 '.4; HRMS: calcd for C₂₉H₃₂N₂O₅ + H+,

489.23840; found (ESLFTMS, [M+H]¹⁺), 489.23871.

Example 15C: ^-benzyl-^-IR'-CcvclobutvImethoxy^-l.l'-biphenyl^-yncarbonyl}- L-α-glutamine [0800] Step B: tert-butyl <img file="EP1902014A2_D0072.tif" /> yl]carbonyl } -L-α-glutaminate

MS (ESI) m/z 557.3; MS (ESI) m/z 1113.4; HRMS: calcd for C₃₄H₄₀N₂O₅ + H+,

557.30100; found (ESI_FTMS, [M+H]¹⁺), 557.30064.

[0801] Step C: iV¹-benzyl-N²-{[4'-(cyclobutylmethoxy)-l,r-biphenyl-4- yl]carbonyl } -L-α-glutamine

MS (ESI) m/z 501.3; MS (ESI) m/z 1001.5; HRMS: calcd for C₃₀H₃₂N₂O₅ + H+,

501.23840; found (ESI_FTMS, [M+H]¹⁺), 501.23937.

Example lSDi ^-benzvI-^-l^'-Ccvclohexylmethoxy^-l.l'-biphenyl^-yllcarbonvU- L-α-glutamine

[0802] Step B: tert-butyl N¹ -benzyl-TV²- { [4'-(cyclohexylmethoxy)-l,r-biphenyl-4- yl]carbonyl } -L-α-glutaminate

MS (ESI) m/z 585.3; MS (ESI) m/z 1169.5; HRMS: calcd for C₃₆H₄₄N₂O₅ + H+,

585.33230; found (ESI_FTMS, [M+H]¹⁺), 585.33275.

[0803] Step C: N¹ -benzyl-TV²- { [4'-(cyclohexylmethoxy)- 1 , 1 '-biρhenyl-4- yl]carbonyl } -L-α-glutamine

MS (ESI) m/z 529.3; MS (ESI) m/z 1057.5; HRMS: calcd for C₃₂H₃₆N₂O₅ + H+,

529.26970; found (ESI_FTMS, [M+H]¹⁺), 529.27022.

Example 15E: iV²-{[4'-(aIIyloxy)-l.l'-biphenyl-4-vncarbonyll-iV¹-benzyl-L-α- glutamine

[0804] Step B: tert-butyl N²-{ [4'-(allyloxy)-l,l'-biphenyl-4-yl]carbonyl}-iV¹- benzyl-L-α-glutaminate

MS (ESI) m/z 529.2; MS (ESI) m/z 1057.4; HRMS: calcd for C₃₂H₃₆N₂O₅ + H+,

529.26970; found (ESI_FTMS, [M+H]¹⁺), 529.26804.

[0805] Step C: JV²-{ [4'-(allyloxy)-l,l'-biphenyl-4-yl]carbonyl}-N¹-benzyl-L-α- glutamine

Example 15F: iV¹-benzyl-iV²-((4' -r(3-methoxybenzvDoχv1 -1.1 ' -biphenyl-4- yl}carbonyl)-L-α-glutamine [0806] Step B: tert-butyl iV¹-benzyl-N²-({4'-[(3-methoxybenzyl)oxy]-l,l¹- biphenyl-4-yl } carbonyl)-L-α-glutaminate

MS (ESI) m/z 609.3; MS (ESI) m/z 1217.5; HRMS: calcd for C₃₇H₄₀N₂O₆ + H+,

609.29591; found (ESI-FTMS, [M+H]¹⁺), 609.29669.

[0807] Step C: iV¹-benzyl-N²-({4'-[(3-methoxybenzyl)oxy]-l,r-biphenyl-4- yl } carbonyl)-L-α-glutamine

MS (ESI) m/z 553.2; MS (ESI) m/z 1105.3; HRMS: calcd for C₃₃H₃₂N₂O₆ + H+,

553.23331; found (ESI-FTMS, [M+H]¹⁺), 553.23235.

Example 15G: iV¹-benzyl-iV²-α4'-r(3.5-dimethoxybenzyl)oxy]-l,l'-biphenyl-4- yUcarbonyI)-L-α-glutamine

[0808] Step B: tert-butyl iV¹-benzyl-N²-({4'-[(3,5-dimethoxybenzyl)oxy]-l,l'- biphenyl-4-yl } carbonyl)-L-α-glutaminate

MS (ESI) m/z 639.3; MS (ESI) m/z 1211 A; HRMS: calcd for C₃₈H₄₂N₂O₇ + H+,

639.30648; found (ESI-FTMS, [M+H]¹⁺), 639.30698.

[0809] Step C: N¹-benzyl-7V²-({4'-[(3,5-dimethoxybenzyl)oxy]-l,r-biphenyl-4- yl }carbonyl)-L-α-glutamine

MS (ESI) m/z 583.2; MS (ESI) m/z 1165.3; HRMS: calcd for C₃₄H₃₄N₂O₇ + H+,

583.24388; found (ESI-FTMS, [M+H]¹⁺), 583.2433.

Example 15H: _J/V¹-benzvI-iV²-{r4'-(2-naphthylmethoxyVl.l'-biphenyl-4-vncarbonvU-

L-α-glutamϊne

[0810] Step B : tert-butyl Λ^-benzyl-iV²- { [4'-(2-naρhthylmethoxy)- 1 , 1 '-biphenyl-

4-yl]carbonyl } -L-α-glutaminate

MS (ESI) m/z 629.3; HRMS: calcd for C₄₀H₄₀N₂O₅ + H+, 629.30100; found (ESI-FTMS,

[M+H]¹⁺), 629.30277. <img file="EP1902014A2_D0073.tif" /> yl]carbonyl}-L-α-glutamine

MS (ESI) m/z 571.3; HRMS: calcd for C₃₆H₃₂N₂O₅ + H+, 573.23840; found (ESI-FTMS,

[M+H]¹⁺), 573.23779. Example 151: N-benzyI-N²-({4'-r(3-fluorobenzvDoxy1biphenyI-4-yI}carbonyl)-L-α- glutamϊne

[0812] MS (ESI) m/z 541.1; MS (ESI) m/z 1081.2.

Example 15.T: N-benzvI-N²-{r4'-(benzyloxy)biphenyl-4-vncarbonyl)-L-α-gIutamine

[0813] MS (ESI) m/z 523.1; MS (ESI) m/z 1045.2.

[0814] The following compounds were prepared according to Scheme 10, Route

A:

Example 15K: N²-l[3'-(benzyloxy)biphenyl-4-vncarbonyl}-iV-(3.4.5- trimethoxybenzyl)-L-α-glutamine

[0815] MS (ESI) m/z 613.1; MS (ESI) m/z 1225.1; HRMS: calcd for C₃₅H₃₆N₂O₈

+ H+, 613.25444; found (ESI-FTMS, [M+H]¹⁺), 613.25451.

Example 15L: N²-α3'-[(3.5-dimethoxybenzyl)oxy1biphenyl-4-ylTcarbonyl)-N-(3.4.5- trimethoxybenzyl)-L-α-glutamine

[0816] MS (ESI) m/z 673.3; MS (ESI) m/z 1345.6; MS (ESI) m/z 690.4; HRMS: calcd for C₃₇H₄₀N₂O₁₀ + H+, 673.27557; found (ESI-FTMS, [M+H]¹⁺), 673.27431.

Example 15M: iV²-α3'-r(3-methoxybenζyl)oxy]biphenyl-4-yl&gt;carbonyl)-iV-(3.4.5- trimethoχybenzyI)-L-α-gIutamine

[0817] MS (ESI) m/z 643.3; MS (ESI) m/z 1285.6; HRMS: calcd for C₃₆H₃₈N₂O₉

+ H+, 643.26501; found (ESI-FTMS, [M+H]¹⁺), 643.26574.

Example 15N: iV²-((4' 4(3.5-dimethoxybenzvI)oxy]biphenyl-4-ylkarbonyl)-iV-[2-(4- fluorophenyI)-l,l-dimethyIethyl1-L-α-glutamine

[0818] MS (ESI) m/z 643.3; MS (ESI) m/z 1285.6; HRMS: calcd for C₃₇H₃₉FN₂O₇

+ H+, 643.28141; found (ESI-FTMS, [MH-H]¹⁺), 643.28187.

[0819] The following compounds were prepared according to Scheme 10, Route

B: Example 15O: JV²-r(4'-{r3,5-bis(trϊfluoromethyl)phenoxy1methvI&gt;biphenyl-4- yl)carbonvIl-iV-(l,l-diinethyl-2-phenylethyl)-L-α-gIutamiiie

[0820] Step A: tert-butyl N-(I , l-dimethyl-2-phenylethyl)-N²-[(4'-methylbiphenyl-

4-yl)carbonyl] -L-α-glutaminate tert-butyl iV¹-benzyl-N²-(4-bromobenzoyl)-L-α-glutaminate (1.0Og, 1.93mmol) was dissolved in DME (1OmL) under nitrogen and placed in a microwave vial. A- methylphenyl boronic acid (526mg, 3.87.mmol), and Pd(PPh₃)₄ (334mg, 0.290mmol) were added as solids prior to the addition of K₂CO₃ (800mg, 5.79mmol) dissolved in H₂O (2.3mL). The vial was sealed and heated to 80⁰C in a microwave for 20 minutes. The solvent was removed and the remaining yellow oil was dissolved in diethyl ether (125mL). The organics were washed consecutively with 10% HCl (125mL), water (125mL) and brine (125mL). The organic layer was dried with MgSO₄, filtered through celite and the solvent was removed. The sticky solid was purified using on a 4Og Combi flash column using an increasing gradient of EtO Ac/Hex as the solvent. The product was obtained as a light brown solid. Yield 792 mg of tert-butyl iV-(l,l-dimethyl-2- phenylethyl)-N²-[(4'-methylbiphenyl-4-yl)carbonyl]-L-α-glutaminate at 78% yield. MS (ESI) m/z 529.3; HRMS: calcd for C₃₃H₄₀N₂O₄ + H+, 529.30608; found (ESI-FTMS, [MH-H]¹⁺), 529.30594.

[0821] Step B: tert-butyl N²-{ [4'-(bromomethyl)biρhenyl-4-yl]carbonyl}-N-(l,l- dimethyl-2-phenylethyl)-L-α-glutaminate tert-butyl iV-(l,l-dimethyl-2-phenylethyl)-N²-[(4^l-methylbiphenyl-4-yl)carbonyl]-L-α- glutaminate (3.5g, 6.62mmol) was dissolved in CCl₄ (5OmL) along with N- Bromosuccinimide (2.36g, 13.2mmol) and benzoyl peroxide (321mg, 1.32mmol) in a 10OmL flask equipped with a reflux condenser. The reaction mixture stirred overnight at 7O⁰C. The solvent was removed and the residue was purified using a SiO2 column and 20%EtO Ac/Hex as the solvent giving a yellow solid. Yield 1.05g tert-butyl N²-{ [A'- (bromomethyl)biphenyl-4-yl]carbonyl } -N-(I , l-dimethyl-2-phenylethyl)-L-α-glutaminate at 57% yield. MS (ESI) m/z 607.1; HRMS: calcd for C₃₃H₃₉BrN₂O₄ + H+, 607.21660; found (ESI-FTMS, [M+H]¹⁺), 607.21591. [0822] Step C: tert-butyl N²-[(4'-{ [3,5- bisCtrifluoronietliy^phenoxylmethylJbiphenyl^- y^carbonyll-iV-Cl.l-dimethyl-l- phenylethyl)-L-α-glutaminate tert-butyl Λ/²-{[4'-(bromomethyl)biphenyl-4-yl]carbonyl}-N-(l,l-dimethyl-2- phenylethyl)-L-α-glutaminate (253mg,041mmol) 3,5-bis(trifluoromethyl)phenol (63μL,.42mmol) and K₂CO₃ (287mg, 2.08mmol) were all combined in a 1OmL vial. Acetonitrile (4mL) was added dissolving some of the solids upon heating to 8O⁰C. The reaction was monitored using TLC and MS. The reaction was stirred overnight (18h). The reaction was filtered using a fritted funnel and the solvent was removed. The filtrate was collected and the solvent was removed. The residue was purified using a SiO₂ column and 20%EtO Ac/Hex as the solvent giving a white solid. Yield 242mg of tert- butyl N²-[(4'-{ [3,5-bis(trifluoromethyl)phenoxy]methyl}biphenyl-4- yl)carbonyl]-N-(l,l- dimethyl-2-phenylethyl)-L-α-glutaminate at 77% yield. MS (ESI) m/z 151 A; HRMS: calcd for C₄₁H₄₂F₆N₂O₅ + H+, 757.30707; found (ESI-FTMS, [MH-H]¹⁺), 757.30532. [0823] Step D: N²-[(4'-{ [3,5-bis(trifluoromethyl)phenoxy]methyl}biphenyl-4- yl)carbonyl] -N-(1 , 1 -dimethyl-2-phenylethyl)-L-α-glutamine tert-butyl N²-[(4'-{ [3,5-bis(trifluoromethyl)phenoxy]methyl}biphenyl-4- yl)carbonyl]-N- (l,l-dimethyl-2-phenylethyl)-L-α-glutaminate (215mg,0.284mmol) was dissolved in CH₂Cl₂ (3mL) and stirred in a 1OmL flask. Trifluoroacetic acid (1.09mL, 14mmol) was added and the solution was stirred for 2 hours. The solvent was removed and the dried under vacuum. The resulting residue was purified using preparative HPLC (ACΝ/H₂O, 0.02% TFA). The main peak fractions were collected and after removal of solvent gave the product as a white solid. Yield of 104 mg of N²-[(4'-{ [3,5-bis(trifluoromethyl) phenoxy]methyl } biphenyl-4-yl)carbonyl]-N-( 1 , 1 -dimethyl-2-phenylethyl)-L-α- glutamine was obtained in 52% yield. MS (ESI) m/z 699.3; HRMS: calcd for C₃₇H₃₄F₆N₂O₅ + H+, 701.24447; found (ESI-FTMS, [M+H]¹⁺), 701.24429.

[0824] The following compounds were prepared according to the procedure described above for example 150:

Example 15P; iV^r2-(l4'-r(1.3-benzodioxol-5-yloxy)methvnhiphenyl-4-vITcarbonyl)-N- (l,l-dimethyl-2-phenylethvI)-L-α-glutamine [0825] MS (ESI) m/z 609.3; MS (ESI) m/z 1217.6; HRMS: calcd for C₃₆H₃₆N₂O₇

+ H+, 609.25953; found (ESI-FTMS, [M+H]¹⁺), 609.26109.

Example 150 : iV²-({4' -r(3.5-dimethoxyphenoxy^')methvnbiphenyl-4-yl)carbonvI)-iV- (3-methylbenzyl)-L-α-glutamine

[0826] MS (ESI) m/z 595.4; HRMS: calcd for C₃₅H₃₆N₂O₇ + H+, 597.25953; found (ESI-FTMS, [MH-H]¹⁺), 597.25901.

Example 15R: iV²-({3'-[(3.5-dimethoxyphenoxy)methyl]biphenvI-4-yI}carbonyl)-iV- (3-methylbenzylVL-α-glutamine

[0827] MS (ESI) m/z 595.2; HRMS: calcd for C₃₅H₃₆N₂O₇ + H+, 597.25953; found (ESI-FTMS, [M+H]¹⁺), 597.2593.

Example 15S: iV²-r(3'-{[3.5-bis(trifluoromethyl)phenoxy1methvUbiphenyl-4- yl)carbonyl]-iV-(3-methyIbenζyl)-L-α-gIutainine

[0828] MS (ESI) m/z 671.2; MS (ESI) m/z 1343.7; HRMS: calcd for

C₃₅H₃₀F₆N₂O₅ + H+, 673.21317; found (ESI-FTMS, [M+H]¹⁺), 673.21279.

Example 15T; iV²-({3'-[(3-ethylphenoxy)methyl]biphenyl-4-ylkarbonyl)-iV-(3- methylbenζylVL-α-glutamine

[0829] MS (ESI) m/z 563.3; HRMS: calcd for C₃₅H₃₆N₂O₅ + H+, 565.26970; found (ESI-FTMS, [M+H]¹⁺), 565.26999.

[0830] The following compounds were prepared according to Scheme 10, Route

C:

Example 15U: iV-benzyl-iV²-{[4' -(biphenyl-3-ylmethoχy)biphenyl-4-yl]carbonyl}-L- α-glutamine

[0831] Step A: tβrt-butyl N¹-benzyl-N²-[(4'-hydroxy-l,r-biphenyl-4- yl)carbonyl]-L-α- glutaminate tert-butyl Λ/^rl-benzyl-Λ/^r2-(4-bromobenzoyl)-L-α-glutaminate (2.00g,4.21mmol) was dissolved in DME (2OmL) under nitrogen and placed in a 75mL flask. 4-Hydroxyphenyl boronic acid (638mg, 4.63.mmol), and Pd(PPh₃)₄ (729mg, 0.632mmol) were added as solids prior to the addition of K₂CO₃ (1.75g,12.6mmol) dissolved in H₂O (5mL). The flask was sealed and the reaction was heated to reflux, stirred for two days and monitored by TLC. The reaction mixture was filtered through celite and thne rinsed with MeOH. The solvent was removed and the resulting residue was purified using a SiO2 column and 33%EtOAc/Hex as the solvent. The product was obtained as a white solid. Yield: 514 mg of tert-butyl N¹-benzyl-N²-[(4'-hydroxy-l,r-biphenyl-4-yl)carbonyl]-L-α- glutaminate at 25% yield. MS (ESI) m/z 487.4; HRMS: calcd for C₂₉H₃₂N₂O₅ + H+, 489.23840; found (ESI_FTMS, [MH-H]¹⁺), 489.23862.

[0832] Step B: tert-butyl N-benzyl-N²-({4'-[(3-bromobenzyl)oxy]biphenyl-4- yl}carbonyl)-L-α-glutaminate

3,3-bromobenzylbromide and K₂CO₃ were all combined in a 2OmL vial. CH₃CN (6mL) was added, dissolving some of the solids upon heating to 8O⁰C. The reaction was monitored using TLC and MS. After 2 hours the reaction was complete. The resulting product quickly precipitated upon cooling of the CH₃CN. The reaction was filtered using a fritted funnel and the filtrate was collected and redissolved in warm CH₃CN. The solution was allowed to crystallize overnight in the freezer. The white solid was collected and washed with cold CH₃CN. Yield: 357mg of tert-butyl iV-benzyl-iV²-({4'-[(3- bromobenzyl)oxy]biphenyl-4-yl}carbonyl)-L-α-glutaminate at 57% yield. MS (ESI) m/z 657.2.

[0833] Step C: tert-butyl N-benzyl-iV²- { [4'-(biρhenyl-3-ylmethoxy)biρhenyl-4- yl]carbonyl } -L-α-glutaminate tβrt-butyl N-benzyl-N²-({4'-[(3-bromobenzyl)oxy]biphenyl-4-yl}carbonyl)-L-α- glutaminate (250mg, 0.38mmol) was dissolved in DME (5mL) under nitrogen in a 75mL bomb flask. Phenylboronic acid (51mg, 0.418mmol), and Pd(PPh₃)₄ (66mg,0.057mmol) were added as solids prior to the addition of K₂CO₃ (158mg,1.14mmol) dissolved in H₂O (1.5mL). The bomb flask was sealed and the reacton was heated to reflux, stirred two days and monitored by TLC. The reaction mixture was filtered through celite and the celite rinsed with MeOH. The solvent was removed and the resulting residue was purified using preparative HPLC. The product was obtained as a pale orange solid. Yield: 154 mg of tert-butyl iV-benzyl-iV²-{ [4'-(biphenyl-3-ylmethoxy)biphenyl-4- yl]carbonyl}-L-α-glutaminate at 60% yield. MS (ESI) m/z 655.5; HRMS: calcd for C₄₂H₄₂N₂O₅ + H+, 655.31665; found (ESI-FTMS, [MH-H]¹⁺), 655.31636. [0834] Step D: N-benzyl-iV²-{ [4'-(biphenyl-3-ylmethoxy)biphenyl-4- yl]carbonyl}-L-α- glutamine tert-bntyl N-benzyl-N²- { [4'-(biphenyl-3-ylmethoxy)biphenyl-4-yl]carbonyl } -L-α- glutaminate (130mg,0.199mmol) was dissolved in CH₂Cl₂ (3mL) and stirred in a 1OmL flask. Trifluoroacetic acid (765uL, lOmmol) was added and the solution was stirred for 2 hours. The solvent was removed and the dried under vacuum. The orange residue was dissolved in minimum acetone and precipitated with hexanes. Yield of 109 mg of N- benzyl-N²-{ [4'-(biphenyl-3-ylmethoxy)biphenyl-4-yl]carbonyl}-L-α- glutamine was obtained in 91% yield. MS (ESI) m/z 599.4; HRMS: calcd for C₃₈H₃₄N₂O₅ + H+, 599.25405; found (ESI-FTMS, [M+H]¹⁺), 599.25511.

Example 15V: iV-benzyl-N²-(|4'-[(3'-methoxybiphenyl-3-yl)methoxy]biphenyl-4- yltearbonyP-L-q-glutamine

[0835] MS (ESI) m/z 627.2; HRMS: calcd for C₃₉H₃₆N₂O₆ + H+, 629.26461; found (ESI-FTMS, [M+H]¹⁺), 629.26493.

Example 15W: iV-benzyl-N²-{r4'-(biphenyl-2-ylmethoxy)biphenyl-4-yl]carbonvII-L- α-glutamine

[0836] MS (ESI) m/z 597.3; HRMS: calcd for C₃₈H₃₄N₂O₅ + H+, 599.25405; found (ESI-FTMS, [M-HH]¹⁺), 599.25523.

Example 15X: iV^r-benzyl-N²-({4'-[(3'-methoxybiphenyl-2-yl)methoxy]biphenyl-4- yl}carbonyl)-L-α-glutamine

[0837] MS (ESI) m/z 627.3; HRMS: calcd for C₃₉H₃₆N₂O₆ + H+, 629.26461 ; found (ESI-FTMS, [MH-H]¹⁺), 629.26484.

Example 15Y: N²-({4'-r(3-tert-butylphenoxy)methyl]biphenvI-4-ylkarbonyl)-N-(l.l- dimethyl-2-phenylethyl)-L-α-glutamine

[0838] Tolyl-biphenylglutamate (Ig, 1.89mmol) was dissolved in CCl₄ (2OmL), in a 4OmL sealed vial. N-Bromosuccinimide (NBS) (673mg, 3.78mmol) and Benzoyl peroxide (92mg, 0.378mmol) were added. The reaction was heated to 7O⁰C, and stirred overnight. The reaction was cooled and the solvent removed. The remaining sticky orange solid was purified by silica column chromatography using 20%EtOAc/ Hexanes. 400mg of Bromo-tolyl-biphenylglutamate was obtained, as a pale yellow solid at 36% yield.

[0839] 3-t-Butylphenol (56mg, 0.374mmol) was dissolved in CH₃CN in a 20ml sealed vial and K₂CO₃ (258mg, 1.87mmol) was added. The reaction was heated to 8O⁰C and stirred for 30 minutes. The Bromo-tolyl-biphenylglutamate (250mg, 0.41 lmmol) was added and the reaction stirred at 8O⁰C overnight. The reaction was filtered, the solvent was removed and the remainder of the reaction was purified by silica column chromatography to give the title compound as a white solid was obtained in 87% yield. [0840] MS (ESI) m/z 621.2; MS (ESI) m/z 1241.4; HRMS: calcd for C₃₉H₄₄N₂O₅

+ H+, 621.33230; found (ESI-FTMS, [M+H]¹⁺), 621.33234.

[0841] The following compounds were prepared according to procedures similar to those described in Example 15 Y:

Example 15Z: N²-({4'-r(3,5-di-tert-butylphenoxy)methyl]biphenyI-4-vUcarbonyl)-N- (l,l-dimethyI-2-phenylethyl)-L-α-glutamine

[0842] MS (ESI) m/z 675.3; MS (ESI) m/z 1351.6; HRMS: calcd for C₄₃H₅₂N₂O₅

+ H+, 677.39490; found (ESI-FTMS, [M+H] ¹⁺), 677.39504.

Example 15AA; N-(lΛ-dimethvI-2-phenylethyl)-N²-({4'-r(3- ethylphenoxy)methynbiphenyI-4-yl|carbonyl)-L-α-glutamine

[0843] MS (ESI) m/z 593.2; MS (ESI) m/z 1185.4; HRMS: calcd for C₃₇H₄₀N₂O₅

+ H+, 593.30100; found (ESI-FTMS, [M+H]¹⁺), 593.30054.

Example 15BB: N-αΛ-dimethyl-2-phenylethyl)-N²-«4'-[(3- methoxyphenoxy)methyl]biphenyl-4-yl)carbonyl)-L-α-glutamine

[0844] MS (ESI) m/z 595.3; MS (ESI) m/z 1189.6; HRMS: calcd for C₃₆H₃₈N₂O₆

+ H+, 595.28026; found (ESI-FTMS, [M+H]¹⁺), 595.28031. Example 16; N²-[(3'-ethoxybiphenyl-4-yl)carbonvn-N-(3.4,5-trimethoxybenzvϊ)-L-α- glutamine

[0845] The title compound was prepared according to procedures similar to those described in Examples 7 and 11. MS (ESI) m/z 551.2; MS (ESI) m/z 1101.4; MS (ESI) m/z 573.2; HRMS: calcd for C₃₀H₃₄N₂O₈ + H+, 551.23879; found (ESI-FTMS, [MH-H]¹⁺), 551.23735.

[0846] The following compounds were prepared according to procedures similar to those described in Example 16.

Example 17A: N²-r(2'-ethoxybiphenyl-4-vIkarbonyll-N-(3.,4.,5-trimethoxybenzyl)-L- α-glutamine

[0847] MS (ESI) m/z 551.2; MS (ESI) m/z 1101.4; MS (ESI) m/z 573.2; HRMS: calcd for C₃₀H₃₄N₂O₈ + H+, 551.23879; found (ESI-FTMS, [M+H]¹⁺), 551.23739.

Example 17B: N²-[(4'-methoχybiphenyl-4-yl)carbonyn-N-(3,4,5-trimethoxybenzyl)- L-ct-glutamine

[0848] MS (ESI) m/z 537.2; MS (ESI) m/z 1073.4; MS (ESI) m/z 559.2; HRMS: calcd for C₂₉H₃₂N₂O₈ + H+, 537.22314; found (ESI-FTMS, [M+H]¹⁺), 537.22188.

Example 17C; N²-[(3'-methoxybiphenyI-4-yI)carbonyn-N-(3,4,5-trimethoxybenzyl)- L-α-glutamϊne

[0849] HRMS : calcd for C₂₉H₃₂N₂O₈ + H+, 537.22314; found (ESI-FTMS,

[M+H]¹⁺), 537.22188.

Example 17D; 4'-|[(αS)-3-carboχy-l-{[(3.4,5- trimethoxybenzyl)amino]carbonyI}propyl)amino1carbonyl&gt;biphenyl-3-carboxyIic acid

[0850] MS (ESI) m/z 551.1; MS (ESI) m/z 1101.3; MS (ESI) m/z 573.1; HRMS: calcd for C₂₉H₃₀N₂O₉ + H+, 551.20241; found (ESI-FTMS, [M+H]¹⁺), 551.2008. Example 17E: N²-r(4'-ethvIbiphenyl-4-vI)carbonyl1-N-(3,4.5-trimethoxybenzvI)-L-α- glutamine

[0851] MS (ESI) m/z 535.2; MS (ESI) m/z 1069.4; HRMS: calcd for C₃₀H₃₄N₂O₇

+ H+, 535.24388; found (ESI-FTMS, [M+H]¹⁺), 535.2425.

Example 17F: N²-r(3'.4'-dimethoxybiphenvI-4-vncarbonvn-N-(3.4.5- trimethoxybenzvI)-L-α-glutamine

[0852] MS (ESI) m/z 567.2; MS (ESI) m/z 1133.5; MS (ESI) m/z 589.2; HRMS: calcd for C₃₀H₃₄N₂O₉ + H+, 567.23371; found (ESI-FTMS, [M+H]¹⁺), 567.23327.

Example 17G: N²-r(2'.4'-dimethoxybiphenyl-4-yl)carbonyll-N-(3.4.5- trimethoxybenzyl)-L-α-glutamine

[0853] MS (ESI) m/z 567.2; MS (ESI) m/z 1133.5; HRMS: calcd for C₃₀H₃₄N₂O₉

+ H+, 567.23371; found (ESI-FTMS, [M+H]¹⁺), 567.23397.

Example 17H; N-(3.4.5-trimethoxybenzvn-N²-r(3'.4'.5'-trimethoxybiphenyl-4- yl)carbonyl]-L-α-glutamine

[0854] MS (ESI) m/z 597.2; MS (ESI) m/z 1193.4; HRMS: calcd for C₃₁H₃₆N₂O₁₀

+ H+, 597.24427; found (ESI-FTMS, [M+H]¹⁺), 597.24385.

Example 171; N-(l.l-dimethyl-2-phenylethyl)-N²-r(3'-methoχybiphenyl-4- yl)carbonyl]-L-α-glutamine

[0855] MS (ESI) m/z 489.2; MS (ESI) m/z 977.4; MS (ESI) m/z 511.2; HRMS: calcd for C₂₉H₃₂N₂O₅ + H+, 489.23840; found (ESI-FTMS, [MH-H]¹⁺), 489.2373.

Example 17.T: N²-[(3'.4'-dimethoxybiphenyl-4-yl)carbonyll-N-(l.l-dimethyl-2- phenylethvD-L-α-glutamine

[0856] MS (ESI) m/z 519.2; MS (ESI) m/z 1037.5; HRMS: calcd for C₃₀H₃₄N₂O₆

+ H+, 519.24896; found (ESI-FTMS, [M+H]¹⁺), 519.248971. Example 17K; N-(l.l-dimethvI-2-phenylethvn-N²-r(2'-ethoxybiphenyl-4- yDcarbonyli-L-g-glutamine

[0857] MS (ESI) m/z 503.2; MS (ESI) m/z 1005.5; HRMS: calcd for C₃₀H₃₄N₂O₅

+ H+, 503.25405; found (ESI-FTMS, [M+H]¹⁺), 503.25421.

Example 17L: N-fl.l-dimethyl-2-phenylethvIVN²-r(3'-fluoro-4'-methylbiphenyl-4- yI)carbonyIl-L-α-glutamϊne

[0858] MS (ESI) m/z 491.2; MS (ESI) m/z 981.5; HRMS: calcd for C₂₉H₃₁FN₂O₄

+ H+, 491.23406; found (ESI-FTMS, [M+H]¹⁺), 491.23402.

Example 17M: 4-[(4'-Methoxy-3'-methyI-biphenyl-4-carbonyl)-aminol-4-(3,4,5- trimethoxy-benzylcarbamoyD-butyric acid

[0859] MS (ESI) m/z 551.2; MS (ESI) m/z 1101.5; MS (ESI) m/z 1123.5.

Example 17N: 4-(4-Benzo[l_&lt;3]dioxol-5-yI-benzoylamino)-4-(3,4,5-trimethoxy- benzylcarbamovD-butyric acid

[0860] MS (ESI) m/z 551.2; MS (ESI) m/z 1101.4.

Example 17O; N-(l-adamantylmethyl)-N²-[(4'-hydroxybiphenvI-4-yl)carbonyl]-L-α- glutamine

[0861] MS (ESI) m/z 491.4; MS (ESI) m/z 981.7; HRMS: calcd for C₂₉H₃₄N₂O₅ +

H+, 491.25405; found (ESI-FTMS, [M+H]¹⁺), 491.25465.

Example 17P: N²-[4-(1.3-benzodioxol-5-yl)benzovI]-N-(l.l-dimethyl-2-phenyIethyl)- L-α-glutamine

[0862] MS (ESI) m/z 503.2; MS (ESI) m/z 1005.4; MS (ESI) m/z 525.2; HRMS: calcd for C₂₉H₃₀N₂O₆ + H+, 503.21766; found (ESI-FTMS, [M+H]¹⁺), 503.21771.

Example 170: N²-[(2',4'-dimethoxybiphenyl-4-ylkarbonyl]-N-(l.l-dimethyl-2- phenylethyl)-L-α-glutamine

[0863] MS (ESI) m/z 519.2; MS (ESI) m/z 1037.5; MS (ESI) m/z 541.2; HRMS: calcd for C₃₀H₃₄N₂O₆ + H+, 519.24896; found (ESI-FTMS, [M+H]¹⁺), 519.24917. Example 17R: N²-r(3'-fluoro-4'-methylbiphenvI-4-yl)carbonvn-N-(3.4.5- trimethoxybenzyl)-L-α-glutamine

[0864] MS (ESI) m/z 539.3; MS (ESI) m/z 1077.6; MS (ESI) m/z 561.3; HRMS: calcd for C₂₉H₃₁FN₂O₇ + H+, 539.21881; found (ESI-FTMS, [M+H]¹⁺), 539.2182.

Example 17S; N²-r(4'-sec-butylbiphenyl-4-ylkarbonvn-N-(l.l-dimethvI-2- phenvIethyl)-L-α-glutamine

[0865] MS (ESI) m/z 515.4; MS (ESI) m/z 1029.9; HRMS: calcd for C₃₂H₃₈N₂O₄

+ H+, 515.29043; found (ESI-FTMS, [MH-H]¹⁺), 515.29203.

Example 17T: N-α,l-dimethyl-2-phenvIethyl)-N²-[(4'-isopropylbiphenyl-4- yl)carbonyl]-L-α-glutamine

[0866] MS (ESI) m/z 501.4; MS (ESI) m/z 1001.8; HRMS: calcd for C₃₁H₃₆N₂O₄

+ H+, 501.27478; found (ESI-FTMS, [M-HH]¹⁺), 501.27468.

Example 17U: N-α.l-dimethyl-2-phenylethyl)-N²-(l.l':4'.l"-terphenyl-4- ylcarbonyD-L-α-glutamine

[0867] MS (ESI) m/z 535.4; MS (ESI) m/z 1069.8; HRMS: calcd for C₃₄H₃₄N₂O₄

+ H+, 535.25913; found (ESI-FTMS, [M+H]¹⁺), 535.26044.

Example 17V; N²4(4'-hvdroxybiphenyl-4Λi)carbonyl1-N-(3A54rimethoxybenzyl)- L-α-glutamine

[0868] MS (ESI) m/z 521.3; MS (ESI) m/z 1043.7; HRMS: calcd for C₂₈H₃₀N₂O₈

+ H+, 523.20749; found (ESI-FTMS, [M+H]¹⁺), 523.20878.

Example 17W; N-d-adamantylmethyD-^-dS'-rCdimethylamino^carbonylibiphenyl- 4-yUcarbonyl)-L-α-glutamine

[0869] MS (ESI) m/z 546.4; MS (ESI) m/z 1091.9; HRMS: calcd for C₃₂H₃₉N₃O₅

+ H+, 546.29625; found (ESI-FTMS, [M+H]¹⁺), 546.29678. Example 17X; N-(l-adamantvImethyl)-N²-r(3'.5'-dimethvIbiphenyl-4-ylkarbonyll- L-α-glutamine

[0870] MS (ESI) m/z 503.4; MS (ESI) m/z 1005.8; HRMS: calcd for C₃₁H₃₈N₂O₄

+ H+, 503.29043; found (ESI-FTMS, [M+H]¹⁺), 503.29107.

Example 17Y; N-r2-(4-fluorophenyl)-l.l-dimethylethvn-N²-r(3'-methylbiphenyl-4- yDcarbonyli-L-q-glutamine

[0871] MS (ESI) m/z 491.4; MS (ESI) m/z 981.7; MS (ESI) m/z 513.3; HRMS: calcd for C₂₉H₃₁FN₂O₄ + H+, 491.23406; found (ESI-FTMS, [M+H]¹⁺), 491.23228.

Example 17Z: N -r(3'-isopropylbiphenyl-4-yl)carbonyl]-N-(3,4,5-trimethoxybenzyl)- L-oc-glutamine

[0872] MS (ESI) m/z 549.4; MS (ESI) m/z 1097.9; HRMS: calcd for C₃₁H₃₆N₂O₇

+ H+, 549.25953; found (ESI-FTMS, [M+H]¹⁺), 549.26013.

Example 17 AA: N²-[(4'-isopropylbiphenyl-4-yl)carbonyll-N-(3A5- trimethoxybenzvD-L-α-glutamine

[0873] MS (ESI) m/z 549.4; MS (ESI) m/z 1097.9; HRMS: calcd for C₃₁H₃₆N₂O₇

+ H+, 549.25953; found (ESI-FTMS, [M+H]¹⁺), 549.26066.

Example 17BB: N-(l-adamantylmethyl)-N²-[4-(l-benzofuran-5-yl)benzoyn-L-α- glutamine

[0874] MS (ESI) m/z 515.4; MS (ESI) m/z 1029.9; HRMS: calcd for C₃₁H₃₄N₂O₅

+ H+, 515.25405; found (ESI-FTMS, [M+H]¹⁺), 515.25447.

Example 17CC: N-(l-adamantylmethyn-N²-r4-(lH-indol-5-vDbenzoyl]-L-α- glutamine

[0875] MS (ESI) m/z 514.4; MS (ESI) m/z 1027.7; HRMS : calcd for C₃₁H₃₅N₃O₄

+ H+, 514.27003; found (ESI-FTMS, [M+H]¹⁺), 514.27038.

Example 17DD: N²-[(3'-ethoxybiphenyl-4-yl)carbonyll-N-r2-f4-fluorophenyl)-l,l- dimethylethyl]-L-α-glutamine [0876] MS (ESI) m/z 521.4; MS (ESI) m/z 1041.7; HRMS: calcd for

C₃₀H₃₃FN₂O₅ + H+, 521.24463; found (ESI-FTMS, [M+H]¹⁺), 521.24248.

Example 17EE: N-r2-r4-fluorophenylVl.l-dimethvIethvn-N²-r(3'-methoxybiDhenvI- 4-yl)carbonyl1 -L-α-glutamine

[0877] MS (ESI) m/z 507.3; MS (ESI) m/z 1013.7; HRMS: calcd for

C₂₉H_3IFN₂O₅ + H+, 507.22898; found (ESI-FTMS, [M+H]¹⁺), 507.22717.

Example 17FF: N-[2-(4-fluorophenvn-l.l-dimethylethvn-N²-[(3'-isopropylbiphenyl- 4-yl)carbonyl1 -L-cc-glutamine

[0878] MS (ESI) m/z 519.4; MS (ESI) m/z 1037.7; HRMS: calcd for

C₃₁H₃₅FN₂O₄ + H+, 519.26536; found (ESI-FTMS, [M+H]¹⁺), 519.26474.

Example 17GG: N²-r(3'-fluoro-4'-methvIbiphenyl-4-ylkarbonyl]-N-[2-(4- fluorophenylVlΛ-dimethylethyl]-L-α-glutamine

[0879] MS (ESI) m/z 509.3; MS (ESI) m/z 1017.7; HRMS: calcd for

C₂₉H₃₀F₂N₂O₄ + H+, 509.22464; found (ESI-FTMS, [M+H]¹⁺), 509.22537.

Example 17HH: N-[2-(4-fluorophenyl)-l.l-dimethylethyl]-N²-[(4'-isobutvIbiphenyl- 4-yDcarbonyπ -L-α-glutamine

[0880] MS (ESI) m/z 533.4; MS (ESI) m/z 1065.8; HRMS: calcd for

C₃₂H₃₇FN₂O₄ + H+, 533.28101; found (ESI-FTMS, [M+H]¹⁺), 533.28214.

Example 17II: N²-(l.l':4'.l"-terphenyl-4-ylcarbonyl)-N-(3.4.5-trimethoxybenzvn-L- α-glutamine

[0881] MS (ESI) m/z 581.2; MS (ESI) m/z 1163.4; HRMS: calcd for C₃₄H₃₄N₂O₇

+ H+, 583.24388; found (ESI-FTMS, [M+H]¹⁺), 583.24414.

Example 17.T.T: N-benzyl-N²-{ [3' -(hydroxymethyI)biphenyl-4-yl]carbonyl)-L-α- glutamine

[0882] MS (ESI) m/z 445.1 ; MS (ESI) m/z 891.2. Example 17KK; N-(3,4.5-trimethoxybenzyl)-N²-r(2'.4'.6'-trimethylbiphenyl-4- vDcarbonyl] -L-α-glutamine

[0883] HRMS: calcd for C₃₁H₃₆N₂O₇ + H+, 549.25953; found (ESI-FTMS,

[M+H]¹⁺), 549.25817.

Example 17LL: N-(l.l-dimethyl-2-phenylethylVN²-r(4'-hvdroxybiphenyl-4- yDcarbonyll-L-a-glutamine

[0884] MS (ESI) m/z 475.2; MS (ESI) m/z 949.4; HRMS: calcd for C₂₈H₃₀N₂O₅ +

H+, 475.22275; found (ESI-FTMS, [M+H]¹⁺), 475.22358.

Example 17MM: N-(l.l-dimethyl-2-phenylethyl)-N²-r(3'-ethoxybiphenyl-4- yl)carbonyl]-L-α-glutamine

[0885] MS (ESI) m/z 503.2; MS (ESI) m/z 1005.3; MS (ESI) m/z 525.1; HRMS: calcd for C₃₀H₃₄N₂O₅ + H+, 503.25405; found (ESI-FTMS, [M+H]¹⁺), 503.25252.

Example 17NN: N²-r4-(1.3-benzodioxol-5-yl)benzovn-N-(3-methvIbenzylVL-α- glutamine

[0886] MS (ESI) m/z 475.1; MS (ESI) m/z 949.2; HRMS: calcd for C₂₇H₂₆N₂O₆ +

H+, 475.18636; found (ESI-FTMS, [M+H]¹⁺), 475.1872.

Example 17OO: N-[2-(4-fluorophenyl)-l.l-dimethylethyl]-N²-[(4'-hvdroxybiphenyl- 4-yl)carbonvπ-L-α-gmtamine

[0887] MS (ESI) m/z 493.2; MS (ESI) m/z 985.4; HRMS: calcd for C₂₈H₂₉FN₂O₅

+ H+, 493.21333; found (ESI-FTMS, [M+H]¹⁺), 493.21327.

Example 17PP: N²-[4-(1.3-benzodioxol-5-vI)benzoyl]-N-[2-(4-fluorophenyl)-l,l- dimethylethyll -L-α-glutamine

[0888] (1): MS (ESI) m/z 521.1; MS (ESI) m/z 1041.3; HRMS: calcd for

C₂₉H₂₉FN₂O₆ + H+, 521.20824; found (ESI-FTMS, [M+H]¹⁺), 521.20872; (2): MS (ESI) m/z 521.2; MS (ESI) m/z 1041.3. Example 17QQ: N-benzyl-N²-{4-r(4-hvdroxycvcIohexyl)ethvnvnbenzovU-L-α- glutamine

[0889] MS (ESI) m/z 463.1 ; MS (ESI) m/z 925.3.

Example 17RR: N²-r(3'-hvdroxybiphenyl-4-vIkarbonvn-N-(3.4.5-trimethoxybenzyl)- L-α-glutamine

[0890] HRMS: calcd for C₂₈H₃₀N₂O₈ + H+, 523.20749; found (ESI-FTMS,

[M+H]¹⁺), 523.20809.

Example 17SS : N-(lΛ-dimethvI-2-phenylethyn-N²-l [4' -(hvdroxymethvDbiphenyI-4- yLlcarbonvU-L-α-glutamine

[0891] MS (ESI) m/z 487.1 ; MS (ESI) m/z 975.2; HRMS: calcd for C₂₉H₃₂N₂O₅ +

H+, 489.23840; found (ESI-FTMS, [M+H]¹⁺), 489.2389.

Example 17TT: N-(l.l-dimethyl-2-phenylethyl)-N²-[(4'-methylbiphenyl-4- yl)carbonyl1-L-α-glutamine

[0892] MS (ESI) m/z 473.1; MS (ESI) m/z 945.3; HRMS: calcd for C₂₉H₃₂N₂O₄ +

H+, 473.24348; found (ESI-FTMS, [M+H]¹⁺), 473.24409.

Example 17UU: N-[2-(4-fluorophenvD-l.l-dimethylethvn-N²-[(3'-hvdroxybiphenvI- 4-yl)carbonyl1-L-α-glutamine

[0893] MS (ESI) m/z 493.2; MS (ESI) m/z 985.4.

Example 17W: N¹-benzyl-N²-(4-pyridin-4-ylbenzoyI)-L-α-glutamϊne

[0894] MS (ESI) m/z 418.2; HRMS: calcd for C₂₄H₂₃N₃O₄ + H+, 418.17613; found (ESI_FT, [M+H]¹⁺), 418.17461.

Example 17WW: ^-benzvI-^-dΛ'-biphenyl-S-ylcarbonvD-L-α-glutamine

[0895] MS (ESI) m/z 417.1; MS (ESI) m/z 833.1; HRMS: calcd for C₂₅H₂₄N₂O₄ +

H+, 417.18088; found (ESI-FTMS, [M+H]¹⁺), 417.18049.

Example 17XX: ^-benzyl-^-O-thien^-ylbenzovD-L-α-glutamine [0896] MS (ESI) m/z 423.1; MS (ESI) m/z 845; HRMS: calcd for C₂₃H₂₂N₂O₄S +

H+, 423.13730; found (ESI-FTMS, [M+H]¹⁺), 423.1383.

Example 17YY: N¹-benzyl-N²-r(3-chloro-l.l'-biphenvI-4-yl)carbonyll-L-α-gIutamine

[0897] MS (ESI) m/z 451.1; MS (ESI) m/z 901; HRMS: calcd for C₂₅H₂₃ClN₂O₄

+ H+, 451.14191; found (ESI-FTMS, [MH-H]¹⁺), 451.1417.

Example 17ZZ: N^benzyl-^-rO-fluoro-l.l'-biphenvI^-vDcarbonvn-L-α-glutamϊne

[0898] HRMS: calcd for C₂₅H₂₃FN₂O₄ + H+, 435.17146; found (ESI-FTMS,

[M+H]¹⁺), 435.17091.

Example 17AAA: N¹-benzvI-N²-[(2.6-dimethoxy-l.l'-biphenyl-4-yl)carbonyl1-L-α- glutamine

[0899] HRMS: calcd for C₂₇H₂₈N₂O₆ + H+, 477.20201; found (ESI-FTMS,

[M+H]¹⁺), 477.20098.

Example 17BBB: N²-(l.l'-biphenyl-4-ylcarbonyl)-N¹-(4-methoxy-l.l'-biphenyl-3-yl)- L-α-glutamine

[0900] MS (ESI) m/z 509.2; MS (ESI) m/z 1017.2; HRMS: calcd for C₃₁H₂₈N₂O₅

+ H+, 509.20710; found (ESI-FTMS, [M+H]¹⁺), 509.20875.

Example 18: N²-α4'-[(3.5-dimethoxybenzyl)oxy1biphenyl-4-yl&gt;carbonyl)-N-(3.4.5- trimethoxybenzvI)-L-α-glutamine

[0901] MS (ESI) m/z 673.4; MS (ESI) m/z 1345.9; HRMS: calcd for C₃₇H₄₀N₂O₁₀

+ H+, 673.27557; found (ESI-FTMS, [MH-H]¹⁺), 673.27498.

Example 19:

[0902] The following compounds were prepared according to procedures similar to those described in Example 18.

Example 19A: N-(l-adamantylmethyl)-N²-({4'-[(3-methoxybenzyl)oxy1biphenyl-4- ylkarbonyl)-L-α-glutamine [0903] MS (ESI) m/z 611.5; MS (ESI) m/z 1222; HRMS: calcd for C₃₇H₄₂N₂O₆ +

H+, 611.31156; found (ESI-FTMS, [M+H]¹⁺)₅ 611.31164.

Example 19B: N-(l-adamantylmethylVN²-(l4'-r(3.5-dimethoxybenzvI)oxy1biphenvI-

4-yl}earbonyl)-L-oc-ghitamine

[0904] MS (ESD m/z 641.5; MS (ESI) m/z 1282; HRMS: calcd for C₃₈H₄₄N₂O₇ +

H+, 641.32213; found (ESI-FTMS, [M+H]¹⁺), 641.32171.

Example 19C: N²-({4'-[(3.5-dimethoxybenzvI)oxy1biphenyl-4-yl&gt;carbonyl)-N-(l,l- dimethyl-2-phenylethyl)-L-α-glutamine

[0905] MS (ESI) m/z 625.5; MS (ESI) m/z 1249.9; HRMS: calcd for C₃₇H₄₀N₂O₇

+ H+, 625.29083; found (ESI-FTMS, [M+H]¹⁺), 625.2906.

Example 19D: N²-f 14' 4f 3.5-dimethylbenzyl)oxy1biphenyl-4-yllearbonyIVN-(3 A5- trimethoxybenzylVL-α-glutamine

[0906] MS (ESI) m/z 641.5; MS (ESI) m/z 1282.

Example 19E: N²-[(4'-{r3,5-bis(trifluoromethyl)benzyl]oχy}biphenyl-4-yI)carbonvn- N-(3,4,5-trimethoxybenzyl)-L-α-gIutamine

[0907] MS (ESD m/z 749.5; MS (ESD m/z 771.5; HRMS: calcd for

C₃₇H₃₄F₆N₂O₈ + H+, 749.22921; found (ESI-FTMS, [M+H]¹⁺), 749.2297.

Example 19F: N-(l,l-dimethyl-2-phenylethylVN²-({4'-F(3- methoxybenzyI)oxy1biphenyl-4-ylicarbonyl)-L-α-glutamine

[0908] MS (ESD m/z 595.3; MS (ESD m/z 1189.5; HRMS: calcd for C₃₆H₃₈N₂O₆

+ H+, 595.28026; found (ESI-FTMS, [M+H]¹⁺), 595.28185.

Example 19G: N²-((4' -[f3.5-dimethoxybenzyl)oxy1biphenyl-4-ylkarboπyl)-N-(6- hydroxyhexylVL-α-glutamine

[0909] MS (ESD m/z 591.2; HRMS: calcd for C₃₃H₄₀N₂O₈ + H+, 593.28574; found (ESI-FTMS, [M+H]¹⁺), 593.28726. Example 19H; N²-α4'-r(3-methoxybenzvnoxy1biphenyl-4-vIkarbonvn-N-(3,4,5- trimethoxybenzylVL-α-glutamine

[0910] MS (ESI-FTMS) m/z 643.26499; MS (ESI-FTMS) m/z 643.26501 ;

HRMS: calcd for C₃₆H₃₈N₂O₉ + H+, 643.26501; found (ESI-FTMS, [M+H]¹⁺),

643.26499.

Scheme 11

<img file="EP1902014A2_D0074.tif" />

R₁₃-B(OH)₂

Pd(PPh₃)₄, K₂CO₃₁ DME

<img file="EP1902014A2_D0075.tif" />

35

Example 20: ^-benzyl-^-CS-phenyl^-furovD-L-α-glutamine [0911] Step A: tert-butyl N¹-benzyl-N²-(5-bromo-2-furoyl)-L-a-glutaminate

Tert-butyl Ν^benzyl-L-α-glutaminate (2.33g, 7.98mmol) was dissolved in DMF (7mL) under nitrogen. 5-Bromofuroic acid (1.52g, 7.98mmol) was added, followed by addition of PyBOP (5.0Og, 9.6mmol). Finally, DIEA (1.67mL, 9.6mmol) was added dropwise over 5 minutes via addition funnel. The reaction was monitored by TLC and stirred overnight. The solution was diluted with EtOAc (250 mL), washed consecutively with H₂0, 10% HCl, saturated NaHCO₃, brine, and then dried over Na₂SO₄. After solvent was evaporated, the crude residue was dissolved in ether and washed with aq. LiBr (2 x 250 mL) and dried over Na₂SO₄. Ether was removed, leaving an oil which was further purified on a SiO₂ column using 33%-40%EtOAc/Hex as the solvent. The product was the third spot off the column and a sticky orange solid. Yield 1.60g of tert-butyl N¹- benzyl-iV -(5-bromo-2-furoyl)-L-α-glutaminate at 43% yield.

[0912] Step B: tert-butyl N¹-benzyl-N²-(5-phenyl-2-furoyl)-L-α-glutaminate

HRMS: calcd for C₂₇H₃₀N₂O₅ + Na+, 485.20469; found (ESI_FTMS, [M+Na]¹⁺),

485.20466.

[0913] Step C: N¹-benzyl-iV²-(5-ρhenyl-2-furoyl)-L-α-glutamine

HRMS: calcd for C₂₃H₂₂N₂O₅ + H+, 407.16015; found (ESI_FTMS, [M+H]¹⁺),

407.15841.

Example 21:

[0914] The following compounds were prepared according to procedures similar to those described in Example 20.

Example 21A: N -benzyl-iV -[5-(3-ethoxyphenyl)-2-furoyl]-L-α-glutamine

[0915] Step B: tert-butyl ^-benzyl-^-tS-P-ethoxyphenyl^-furoylJ-L-a- glutaminate

HRMS: calcd for C₂₉H₃₄N₂O₆ + H+, 507.24896; found (ESI_FTMS, [M+H]¹⁺),

507.24894.

[0916] Step C: N¹-benzyl-N²-[5-(3-ethoxyρhenyl)-2-furoyl]-L-α-glutamine

HRMS: calcd for C₂₅H₂₆N₂O₆ + H+, 451.18636; found (ESI_FTMS, [M+H]¹⁺),

451.18545.

Example 21B: iV¹-benzyl-iV²-[5-(3.5-dimethylphenylV2-furoyl]-L-α-glutamine

[0917] Step B: tert-butyl N¹-benzyl-N²-[5-(3,5-dimethylphenyl)-2-furoyl]-L-α- glutaminate

HRMS: calcd for C₂₉H₃₄N₂O₅ + H+, 491.25405; found (ESI_FTMS, [M+H]¹⁺), 491.2538.

[0918] Step C: N¹-benzyl-N²-[5-(3,5-dime%lphenyl)-2-furoyl]-L-α-glutamine

HRMS: calcd for C₂₅H₂₆N₂O₅ + H+, 435.19145; found (ESI_FTMS, [M+H]¹⁺),

435.19034.

Example 21C: iV¹-benzyl-iV²-(2.2'-bifuran-5-vIcarbonyl)-L-α-glutamine [0919] Step B : tert-butyl N¹-benzyl-N²-(2,2'-bifuran-5-ylcarbonyl)-L-α- glutaminate

HRMS: calcd for C₂₅H₂₈N₂O₆ + H+, 453.20201; found (ESI_FTMS, [M+H]¹⁺),

453.20173.

[0920] Step C: N¹-benzyl-N²-(2,2'-bifuran-5-ylcarbonyl)-L-α-glutamine

HRMS: calcd for C₂₁H₂₀N₂O₆ + H+, 397.13941; found (ESI_FTMS, [M+H]¹⁺),

397.13777.

Example 21D: JV^benzyl-ivVs^hien^-yl^-furoylVL-α-glutamine

[0921] Step B : tert-butyl N¹-benzyl-N²-(5-thien-2-yl-2-furoyl)-L-α-glutaminate

HRMS: calcd for C₂₅H₂₈N₂O₅S + H+, 469.17917; found (ESI_FTMS, [MH-H]¹⁺),

469.1789.

[0922] Step C: N¹-benzyl-N²-(5-thien-2-yl-2-furoyl)-L-α-glutamine

HRMS: calcd for C₂₁H₂₀N₂O₅S + H+, 413.11657; found (ESI_FTMS, [M+H]¹⁺),

413.11511.

Scheme 12

<img file="EP1902014A2_D0076.tif" />

37 38

Example 22:

[0923] The following compounds were prepared according to procedures similar to those described in Example 20.

Example 22A; iV¹-benzyl-iV²-[(6-phenylpyridin-3-yl)carbonyl1-L-α-glutamine

[0924] Step A: tert-butyl N^benzyl-N^Kό-bromopyridin-S-ytycarbonylJ-L-α- glutaminate

MS (ESl) m/z 476.1; MS (ESI) m/z 951.1; HRMS: calcd for C₂₂H₂₆BrN₃O₄ + H+,

476.11794; found (ESI-FTMS, [M+H]¹⁺), 476.11935. [0925] Step B: tert-butyl i^-benzyl-Λ^-Kό-phenylpyridin-S-y^carbonylJ-L-α- glutaminate

MS (ESI) m/z 4:14.2; HRMS: calcd for C₂₈H₃₁N₃O₄ + H+, 474.23873; found (ESI-FTMS,

[M+H]¹⁺), 474.23861.

[0926] Step C: N¹-benzyl-N²-[(6-phenylpyridin-3-yl)carbonyl]-L-α-glutamine

MS (ESI) m/z 418.1; HRMS: calcd for C₂₄H₂₃N₃O₄ + H+, 418.17613; found (ESI-FTMS,

[M+H]¹⁺), 418.17674.

Example 22B; N -(3-methoxybenzyl)-iV -[(6-phenvIpyridin-3-yl)carbonyl]-L-α- glutamine

[0927] Step A: tert-butyl N²-[(6-bromopyridin-3-yl)carbonyl]-iV¹-(3- methoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 506.1; MS (ESI) m/z 1011.1; HRMS: calcd for C₂₃H₂₈BrN₃O₅ + H+,

506.12851; found (ESI-FTMS, [M+H]¹⁺), 506.12839.

[0928] Step B: tert-butyl N¹-(3-methoxybenzyl)-N²-[(6-phenylpyridin-3- yl)carbonyl] -L-α-glutaminate

MS (ESI) m/z 504.2; HRMS: calcd for C₂₉H₃₃N₃O₅ + H+, 504.24930; found (ESI-FTMS,

[M+H]¹⁺), 504.24835.

[0929] Step C: N¹-(3-methoxybenzyl)-N²-[(6-ρhenylpyridin-3-yl)carbonyl]-L-α- glutamine

MS (ESI) m/z 448.1; HRMS: calcd for C₂₅H₂₅N₃O₅ + H+, 448.18670; found (ESI-FTMS,

[M+H]¹⁺), 448.18686.

Example 22C; iV²-r(2.2'-dimethvI-l.l'-biphenyl-4-vncarbonyl]-iV¹-(3- methoxybenzyl)-L-α-glutamine

[0930] Step B: tert-butyl iV²-[(2,2'-dimethyl-l,r-biphenyl-4-yl)carbonyl]-iV¹-(3- methoxybenzyl)-L-α-glutaminate

MS (ESI) m/z 531.3; MS (ESI) m/z 1061.4; HRMS: calcd for C₃₂H₃₈N₂O₅ + H+,

531.28535; found (ESI_FTMS, [M+H]¹⁺), 531.2855.

[0931] Step C: iV²-[(2,2'-dimethyl-l,r-biphenyl-4-yl)carbonyl]-N¹-(3- methoxybenzyl)-L-α-glutamine HRMS: calcd for C₂₈H₃₀N₂O₅ + H+, 475.22275; found (ESI_FTMS, [MH-H]¹⁺), 475.22271.

Example 22D; N²-(4-bromobenzoyl)-N-(3.4.5-trimethoxybenzyl)-L-α-gIutamine

[0932] MS (ESI) m/z 507; MS (ESI) m/z 1015.1; HRMS: calcd for C₂₂H₂₅BrN₂O₇

+ H+, 509.09179; found (ESI-FTMS, [M+H]¹⁺), 509.09078.

Example 22E: N²-(4-bromobenzoyl)-N-(l,l-dimethvI-2-phenylethyl)-L-α-glutamine

[0933] MS (ESI) m/z 461.1; MS (ESI) m/z 921.2; HRMS: calcd for

C₂₂H₂₅BrN₂O₄ + H+, 461.10705; found (ESI-FTMS, [M+H]¹⁺), 461.10805.

Example 22F: N-(l-adamantylmethyl)-N²-(4-bromobenzoyl)-L-α-gIutamine [0934] MS (ESI) m/z 477.3; MS (ESI) m/z 953.5; HRMS: calcd for

C₂₃H₂₉BrN₂O₄ + H+, 477.13835; found (ESI-FTMS, [M+H]¹⁺), 477.13801.

Example 22G: N²-(4-bromobenzoyl)-N-(3-methyIbenzylVL-α-glutamine

[0935] MS (ESI-FTMS) m/z 433.07562; MS (ESI-FTMS) m/z 433.07575;

HRMS: calcd for C₂₀H₂₁BrN₂O₄ + H+, 433.07575; found (ESI-FTMS, [M+H]¹⁺), 433.07562.

Scheme 13

<img file="EP1902014A2_D0077.tif" />