METHODS FOR PREPARING GLUTAMIC ACID DERIVATIVES
[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.
Cross Reference to Related Applications
[0003] This application claims the benefit of priority under 35 U.S.C. § 119(e) to
United States Patent Application Serial No. 60/726,441 filed on October 13, 2005 and is
hereby incorporated by reference in its entirety.
Field of the Invention
[0004] The present invention relates to novel methods for the preparation of
glutamic acid derivatives, which are useful as 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 super family 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 AD AMIS (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,Int JBiochem 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 Sci 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] The glutamic acid derivatives and the preparation thereof are disclosed in a
commonly assigned and co-pending United States patent application, Ser. No.
60/697,590, filed on July 11, 2005. There remains a need to find a more efficient method
suitable for commercial manufacturing of the glutamic acid derivatives.
Summary of the Invention
[0009] In one aspect, the invention provides novel methods as described in the
appended claims for preparing a compound of formula (I) and intermediates 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)nR11, -OH,
or
-O-(C1-C6) alkyl;
R5 is aryl, heteroaryl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-
aryl,
-S-heteroaryl, -NH-aryl, -NH-heteroaryl, -C(=O)-(C1-C6) alkyl, -C(=O)-
aryl,
-C(=O)-heteroaryl, -SO2-(C1-C6) alkyl, -SO2-aryl, -SO2-heteroaryl, -
SO2NH-aryl,
-SO2NH-heteroaryl, -NHSO2-(C1-C6) alkyl, -NHSO2-aryl, -NHSO2-
heteroaryl,
-NHC(=O)-aryl, -NHC(=O)-heteroaryl, -C(=O)NH-aryl, -C(=O)NH-
heteroaryl, (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl,
-NHC(=O)-(C1-C6) alkyl, -C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl,
-S-(C1-C6) cycloalkyl, -NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6)
cycloalkyl, or-C(=O)NH-(C1-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 is hydrogen, halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -
C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7,-CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8; (C1-C6) alkyl,
-O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6) alkyl, -NHC(=O)-(C1-C6)
alkyl,
-C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl, -S-(C1-C6) cycloalkyl,
-NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6) cycloalkyl,
-C(=O)NH-(C1-C6) cycloalkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7,
(C2-C6) alkynyl, (C2-C6) alkenyl, -O-(C1-C6) alkyl-cycloalkyl, -O-alkenyl,
-O-(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 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;
R12 is halogen,-CN, -OOF3, -CF3, -NO2,-OH,-SH,-NR7R8,-C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7, -CO2R7, -C(=O)R7, -SO2(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8, linear or branched or
cyclic (C1-C6) alkyl,-O-(C1-C6) alkyl,-S-(C1-C6) alkyl,-NH-(C1-C6)
alkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7, (C2-C6) alkynyl, (C2-
C6) alkenyl,
-O-(C1-C6) alkylcycloalkyl, -O-alkenyl, -O-(C1-C6) alkylaryl, aryl,
heteroaryl,
-(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-aryl, -S-
heteroaryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
alkenyl, or alkynyl optionally substituted with one or more of R13;
R13 is halogen, -O-(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 R15 together may form a five-
to seven-membered cyclic group containing up to 3 heteroatoms selected
from N, O, or S;
R16 is (C1-C6) alkyl; and
n is 0, 1, 2, 3, or 4.
[0010] In another aspect, the invention provides a compound of formula (I) and
intermediates thereof prepared by such novel methods.
Further Description of the Invention
Definitions
[0011] All recitations of a group, such as alkyl, are understood for the purposes of
this specification to encompass both substituted and unsubstituted forms.
[0012] 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: In one embodiment, an
alkyl is optionally substituted with one or more of the following groups: -V-halogen, -V-
(C1-C6)-alkyl,-V-(C2-C6)-alkenyl,
-V-(C2-C6)-alkynyl,-V-N(R')2, methylenedioxo, ethylenedioxo,-V-NHSO2R', -V-
NR'C(=O)R',
-V-NHCO2R', -V-NO2, -V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R',
-V-C(=O)N(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.
[0013] The number of carbon atoms 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.
[0014] 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 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: -V-halogen, -V-(C1-C6)-alkyl, -V-(C2-C6)-alkenyl,
-V-(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-C(=O)R', -V-CO2R',
-V-C(=O)N(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.
[0015] 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. In one embodiment, an alkynyl is optionally substituted with
one or more of the following groups: -V-halogen, -V-(C1-C6)-alkyl, -V-(C2-C6)-alkenyl, -
V-(C2-C6)-alkynyl,
-V-N(R')2, methylenedioxo, ethylenedioxo, -V-NHSO2R', -V-NR'C(=O)R', -V-
NHCO2R',
-V-NO2, -V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0016] The term "cycloalkyl" refers to a monocyclic, bicyclic, tricyclic, fused,
bridged, or spiro monovalent saturated hydrocarbon ring system, wherein the carbon
atoms are located inside or outside of the ring system, e.g., of 3-15 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, cyclohexylmethyl,
cyclohexylethyl, 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, -V-(C1-C6)-alkyl, -V-(C2-C6)-alkenyl,
-V-(C2-C6)-alkynyl, -V-N(R')2, methylenedioxo, ethylenedioxo, -V-NHSO2R', -V-
NR'C(=O)R',
-V-NHCO2R', -V-NO2, -V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R',
-V-C(=O)N(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.
[0017] "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 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).
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. la one embodiment, a heteroaryl is optionally
substituted with one or more of the following groups: -V-halogen, -V-(C1-C6)-alkyl, -V-
(C2-C6)-alkenyl,
-V-(C2-C6)-alkynyl, -V-N(R')2, methylenedioxo, ethylenedioxo, -V-NHSO2R', -V-
NR'C(=O)R', -V-NHCO2R', -V-NO2, -V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -
V-CO2R',
-V-C(=O)N(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.
[0018] "Heterocycloalkyl" refers to a 5 to 7-membered saturated ring containing
carbon atoms and from 1 to 4 heteroatoms selected from N, O, and S. 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, -V-(C1-C6)-alkyl,
-V-(C2-C6)-alkenyl, -V-(C2-C6)-alkynyl, -V-N(R')2, methylenedioxo, ethylenedioxo,
-V-NHSO2R', -V-NR'C(=O)R', -V-NHCO2R', -V-NO2, -V-SO2N(R')2, -V-SO2R',-V-
OR',
-V-C(=O)R' -V-CO2R', -V-C(=O)N(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.
[0019] 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. In one embodiment,
an aryl group such as phenyl is optionally substituted with one or more of the following: -
V-halogen, -V-(C1-C6)-alkyl, -V-(C2-C6)-alkenyl, -V-(C2-C6)-alkynyl,
-V-N(R')2, methylenedioxo, ethylenedioxo, -V-NHSO2R', -V-NR'C(=O)R', -V-
NHCO2R',
-V-NO2, -V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0020] 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,-V-(C1-C6)-alkyl,
-V-(C2-C6)-alkenyl, -V-(C2-C6)-alkynyl, -V-N(R')2, methylenedioxo, ethylenedioxo,
-V-NHSO2R', -V-NR'C(=O)R', -V-NHCO2R', -V-NO2, -V-SO2(R')2, -V-SO2R', -V-
OR',
-V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0021] The term"biaryl" as used herein refers to two aryl groups connected at one
carbon site on each ring. In one embodiment, one or both aryl groups is independently
optionally substituted with one or more of the following groups: -V-halogen, -V-(C1-C6)-
alkyl,
-V-(C2-C6)-alkenyl, -V-(C2-C6)-alkynyl, -V-N(R')2, methylenedioxo, ethylenedioxo,
-V-NHSO2R', -V-NR'C(=O)R', -V-NHCO2R', -V-NO2, -V-SO2N(R'), -V-SO2R', -V-
OR',
-V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0022] 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, -V-(C1-C6)-alkyl, -V-(C2-C6)-alkenyl, -V-(C2-C6)-alkynyl, - V-N(R')2,
methylenedioxo, ethylenedioxo, -V-NHSO2R', -V-NR'C(=O)R', -V-NHCO2R', -V-NO2,
-V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0023] 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, -V-(C1-C6)-alkyl, -V-(C2-C6)-alkenyl, -
V-(C2-C6)-alkynyl, - V-N(R')2, methylenedioxo, ethylenedioxo, -V-NHSO2R', -V-
NR'C(=O)R', -V-NHCO2R', -V-NO2,
-V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0024] The term "bicyclic heteroaryl" as used herein refers to two fused cyclic
groups, wherem one or bom 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, -V-(C1-C6)-alkyl, -V-
(C2-C6)-alkenyl, -V-(C2-C6)-alkynyl,
- V-N(R')2, methylenedioxo, ethylenedioxo, -V-NHSO2R', -V-NR'C(=O)R', -V-
NHCO2R',
-V-NO2, -V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0025] 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, -V-(C1-C6)-alkyl, -V-
(C2-C6)-alkenyl, -V-(C1-C6)-alkynyl, - V-N(R')2, methylenedioxo, ethylenedioxo, -V-
NHSO2R', -V-NR'C(=O)R', -V-NHCO2R', -V-NO2,
-V-SO2N(R')2, -V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R', -V-C(=O)N(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] An optionally substituted moiety may be substituted with one or more
substituents, examples of which are as illustrated herem. In one embodiment, an
"optionally substituted" moiety is substituted with one or more of the following: -V-
halogen,
-V-(C1-C6)-alkyl, -V-(C2-C6)-alkenyl, -V-(C2-C6)-alkynyl, - V-N(R')2, methylenedioxo,
ethylenedioxo, -V-NHSO2R', -V-NR'C(=O)R', -V-NHCO2R', -V-NO2, -V-SO2N(R')2,
-V-SO2R', -V-OR', -V-C(=O)R', -V-CO2R', -V-C(=O)N(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.
[0027] 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-trifluorovinyl, 1,2-
dibromo ethane, 1,2 difluoro ethane, l-fluoro-2-bromo ethane, CF2F3, CF2CF2CF3, and
the like.
[0028] The term halogen includes bromine, chlorine, fluorine, and iodine.
[0029] 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.
[0030] 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, 1,1-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, Third Edition, John Wiley & Sons (1999).
[0031] 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. See, Greene and Wuts, Protecting Groups in Organic
Synthesis, Third Edition, John Wiley & Sons (1999).
[0032] 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, comeal 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.
[0033] 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.
[0034] 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.
[0035] 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, eamphorsulfonate, 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 Ms-(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.
[0036] 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.
[0037] 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 & Sons, pages 69-74 (1992).
[0038] The following abbreviations as used herein mean:
Ac is acetate;
ACN is acetonitrile;
Boc is t-butyl carbamate;
Bu is butyl;
DEA is diethylamine;
DIEA is diisopropylethylamine;
DME is dimethoxyethane;
DMF is dimethylformamide;
DMSO is dimethylsulfoxide;
Et is ethyl;
Fmoc is 9-fluorenylmethoxycarbonyl;
HPLC is high pressure liquid chromatography;
HRMS is high resolution mass spectrometry;
IPA is isopropyl alcohol;
LCMS is liquid chromatograph-mass spectrometry;
Me is methyl;
MS is mass spectrometry;
m/z is mass-to-charge ratio;
NMM is N-methylmorpholine;
NMR is nuclear magnetic resonance;
r.t is retention time;
TBME is t-butyl methyl ether;
TFA is trifluoroacetic acid; and
THF is tetrahydrofuran.
Compounds and Pharmaceutically Acceptable Salts of Compounds of the Invention
[0039] The compounds or pharmaceutically acceptable salts of compounds of the
present invention contain an asymmetric carbon atom and some of the compounds or
pharmaceutically acceptable salts of compounds of the invention can contain more than
one asymmetric centers or no asymmetric centers, and can thus give rise to optical
isomers, diastereomers and racemic mixtures. While depicted with or without respect to a
particular asymmetric center 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.
[0040] 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.
[0041] Prodrugs of the compounds or pharmaceutically acceptable salts of
compounds are also within the scope of the present invention.
Further Illustration of the Present Invention
[0042] For compounds of formulas (I) through (VII) and all reagents used in the
preparation thereof, and throughout the specification, the symbols are defined as follows
unless otherwise noted:
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 R5, the
substituents can be identical or different;
R2 is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -(CH2)nR11, -OH,
or
-O-(C1-C6) alkyl;
R5 is aryl, heteroaryl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-
aryl,
-S-heteroaryl, -NH-aryl, -NH-heteroaryl, -C(=O)-(C1-C6) alkyl, -C(=O)-
aryl,
-C(=O)-heteroaryl, -SO2-(C1-C6) alkyl, -SO2-aryl, -SO2-heteroaryl, -
SO2NH-aryl,
-SO2NH-heteroaryl, -NHSO2-(C1-C6) alkyl, -NHSO2-aryl, -NHSO2-
heteroaryl,
-NHC(=O)-aryl, -NHC(=O)-heteroaryl, -C(=O)NH-aryl, -C(=O)NH-
heteroaryl, (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl,
-NHC(=O)-(C1-C6) alkyl, -C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl,
-S-(C1-C6) cycloalkyl, -NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6)
cycloalkyl, or -C(=O)NH-(C1-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 is hydrogen, halogen, -CN, -OCF3, -CF3, -NO2 -OH, -SH, -NR7R8, -
C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7-CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8; (C1-C6) alkyl,
-O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6) alkyl, -NHC(=O)-(C1-C6)
alkyl,
-C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl, -S-(C1-C6) cycloalkyl,
-NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6) cycloalkyl,
-C(=O)NH-(C1-C6) cycloalkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7,
(C2-C6) alkynyl, (C2-C6) alkenyl, -O-(C1-C6) alkyl-cycloalkyl, -O-alkenyl,
-O-(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 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;
R12 is halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7-CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl,-SO2R7,-NR7SO2R8,-SO2NR7R8, linear or branched or
cyclic (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7, (C2-C6) alkynyl, (C2-
C6) alkenyl,
-O-(C1-C6) alkylcycloalkyl,-O-alkenyl,-O-(C1-C6) alkylaryl, aryl,
heteroaryl,
-(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-aryl, -S-
heteroaryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
alkenyl, or alkynyl optionally substituted with one or more of R13;
R13 is halogen, -O-(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 R15 together may form a five-
to seven-membered cyclic group containing up to 3 heteroatoms selected
from N,O, or S;
R16 is (C1-C6) alkyl;
PG1 is an amine protecting group;
PG2 is a carboxylic acid protecting group; and
n is 0, 1, 2, 3, or 4.
[0043] The compounds of formula (I) through (VII) include enantiomerically pure
compounds and/or sensitive protecting groups. Advantageously, the present invention
provides methods for preparing such compounds substantially free of their corresponding
opposite enantiomers and without disturbing the protecting groups when such groups are
needed.
[0044] In one embodiment, the present invention is directed to a method of
preparing a compound of formula (I):

comprising:
a) treating a compound of formula (D),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IV);

b) treating the compound of formula (TV) with an amine having the formula of
HNR14R15 or a pharmaceutically acceptable salt thereof;
to give a compound of formula (V);

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI); and

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)C1 in the presence of a base to give a compound of formula (VH);
and

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VII), preferably via hydrolysis, to give the to compound of formula (I).
[0045] In another embodiment, the present invention is directed to a method for
preparing a compound of the formula (IV),

comprising treating a compound of formula (II),

with an alkyl chloroformate of formula (III) and a base,

to provide the compound of formula (IV).
[0046] In yet another embodiment, the present invention is directed to a method
for preparing a compound of formula (V),

comprising:
a) treating a compound of formula (II),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IV); and

b) treating the compound of formula (IV) with an amine having the formula of
HNR14R15 or a pharmaceutically acceptable salt thereof;
to give a compound of formula (V).
[0047] In yet another embodiment, the present invention is directed to a method
for preparing a compound of formula (VI),
comprising:
a) treating a compound of formula (II),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IV);

b) treating the compound of formula (IV) with an amine having the formula of
HNR14R15 or a pharmaceuticalry acceptable salt thereof;
to give a compound of formula (V); and

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI).
[0048] In yet another embodiment, the present invention is directed to a method
for preparing a compound of formula (VII),
comprising:
a) treating a compound of formula (II),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IV);

b) treating the compound of formula (IV) with an amine having the formula of
HNR14R15 or a pharmaceutically acceptable salt thereof;
to give a compound of formula (V);

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI); and

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)Cl in the presence of a base to give a compound of formula (VII).
[0049] In one further embodiment, the present invention is directed to a
compound of formula (IV),

wherein
R2 is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -(CH2)nR11, -OH,
or
-O-(C1-C6) alkyl;
R11 is aryl, heteroaryl, or cycloalkyl;
n is 0, 1, 2, 3, or 4;
R16 is (C1-C6) alkyl;
PG1 is an amine protecting group; and
PG2 is a carboxylic acid protecting group.
[0050] In another embodiment, the present invention is directed to a compound of
formula (IV), wherein R2 is hydrogen; and R16 is methyl, ethyl, propyl, isopropyl, butyl,
or isobutyl.
[0051] In yet another embodiment, the present invention is directed to a
compound of formula (IV), wherein R2 is hydrogen; R16 is methyl, ethyl, propyl,
isopropyl, butyl, or isobutyl; PG1 is Fmoc; and PG2 is f-butyl.
[0052] In one further embodiment, the present invention is directed to a
compound of formula (I),

prepared by the method comprising:
a) treating a compound of formula (II),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IV);

b) treating the compound of formula (IV) with an amine having the formula of
HNR14R15 or a pharmaceutically acceptable salt thereof;
to give a compound of formula (V);

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI); and

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)Cl in the presence of a base to give a compound of formula (VII);
and

e) deprotecting the carboxylic acid protecting group of the compound of f ormula
(VII), preferably via hydrolysis, to give the to compound of formula (I).
[0053] In one further embodiment, the present invention is directed to a
compound of formula (Ia):

prepared by the method comprising:
a) treating a compound of formula (IIa),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IVa);

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VIIa), preferably via hydrolysis, to give the to compound of formula (Ia).
[0054] In another embodiment, the present invention is directed to a method for
preparing a compound of formula (Ia),

comprising:
a) treating a compound of formula (IIa),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IVa);

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VIIa), preferably via hydrolysis, to give the to compound of formula (Ia).
[0055] In one further embodiment, the present invention is directed to a method for
preparing a compound of formula (I),

comprising:
a) treating a compound of formula (II),

with a chlorinating reagent such as oxalyl chloride or thionyl chloride, optionally
in the presence of a catalytic amount of DMF,
to provide a compound of the formula (IVb);

b) treating the compound of formula (IVb) with an amine having the formula of
HNR14R15 or a pharmaceuticaUy acceptable salt thereof;
to give a compound of formula (V);

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI);

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)Cl in the presence of a base to give a compound of formula (VII);
and

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI); and

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)Cl in the presence of a base to give a compound of formula (VII);
and

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VII), preferably via hydrolysis, to give the to compound of
formula (I).
Methods of Preparation
[0057] 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.
[0058] Scheme 1 demonstrates the synthesis of the compound of formula (I) from
the compound of formula (II). The compound of formula (II) can react with a (C1-C6)
alkyl chloroformate of formula (III) such as methyl chloroformate, ethyl chloroformate,
propyl chloroformate, isopropyl chloroformate, butyl chloroformate, isobutyl
chloroformate, followed by treatment with a base such as triethylamine,
diisopropylethylamine, pyridine, N-methyhnorpholine, sodium bicarbonate, or potassium
carbonate, to provide a compound of formula (IV). The compound of formula (TV) can
further react with an amine of formula HNR14R15 to afford a compound of formula (V).
Treatment of the compound of formula (V) with an amine base can cleave the amine
protecting group of PG1 to provide a compound of formula (VI). 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.
[0059] Coupling of the compound of formula (VI) with an acid of formula
R1COCl in the presence of a base affords a compound of formula (VII). The carboxylic
acid protecting group of the compound of formula (VII) can be cleaved via hydrolysis to
give the compound of formula (I). The hydrolysis step can be carried out using TFA,
NaOH, LiOH, potassium carbonate, or the like.
Scheme 1

[0060] Scheme 1a describes an alternative synthesis of the compound of formula
(V). Treatment of the compound of formula (II) with a chlorinating reagent, such as
oxalyl chloride, thionyl chloride, etc., and optionally in the presence of a catalytic amount
of DMF, provides an acid chloride of formula (IVb), which can be coupled with an amine
of formula HNR14R15, to give the compound of formula (V).
Scheme 1a

[0061] Scheme 2 further demonstrates the synthesis of a compound of formula
(Ia) from a compound of formula (IIa), using an analogous method as that is described in
Scheme 1. Alternatively, the compound of formula (Va) can be prepared from the
compound of formula (IIa) in accordance with Scheme 2a, which uses a similar method
as that of Scheme 1a.
Scheme 2

[0062] One of ordinary skill in the art will recognize that Schemes 1, 1a, 2, and 2a
can be adapted to produce other compounds and pharmaceutically acceptable salts of
compounds according to the present invention.
Examples
Scheme 3

[0063] Compound 1 [2(S)-(9H-Fluoren-9-ylmethoxycarbonylamino)-pentanedioic
acid 5-tert-butyl ester] (161 g) was suspended in toluene (1 L). Iso-Butyl chloroformate
(59.5 g), N-methylmorpholine (91.7 g) and 2-(4-Fluoro-phenyl)-1,1-dimethyl-ethylamine
(88.7 g as hydrochloride salt) were added sequentially at 5 to 15 °C. After the reaction
was completed in about 1 h, toluene solution was washed with water, treated with
diethylamine (66.2 g) and stirred at ambient temperature until deprotection was complete
(2 to 12 h). The product was extracted with 2N hydrochloric acid and by-products were
removed by extraction with heptane. The resulting aqueous solution was treated with
potassium carbonate and extracted with t-butyl methyl ether (TBME) to afford
Compound 4 as a solution in TBME.
[0064] Alterative Synthesis of Compound 4: Compound 1 [2(S)-(9H-Fluoren-9-
ylmethoxycarbonylamino)-pentanedioic acid 5-tert-butyl ester] (1 g, 2.3 mmol) was
combined with THF (5 mL) and 1 drop of DMF and cooled to 0 C. Oxalyl chloride
(0.328 g, 2.5 mmol) was added and the solution was stirred for about 30 min. before it
was concentrated to form foam. The resulting foam was dissolved in THF and 2-(4-
Fluoro-phenyl)-1,1-dimethyl-ethylamine (0.864 g, 4.6 mmol) was added. After the
reaction was completed as determined by HPLC, Compound 4 was isolated following
regular aqueous work-up.
Example 2: Preparation of 4(5)-[(Biphenyl-4-carbonyl)-amino]-4-[2-(4-fluoro-
phenyl)-1,1-dimethyl-ethylcarbamoyl]-butyric acid tert-butyl ester (Compound 5)

[0065] To me TBME solution of Compound 4 (561 g, strength 20%) were added
triethylamine (64.6 g) and biphenyl carbonyl chloride (58.9 g, dissolved in THF) at 15 to
35 °C. After the reaction was completed (1 to 18 h), the reaction mixture was washed
with diluted HCl solution, sodium bicarbonate solution and water, concentrated, and
Compound 5 was precipitated from the IPA/water mixture as white crystals (131 g, 77%
yield). NMR data: 1.35 - s, 6H, CH3; 1.40 - s, 9H, CH3; 2.10 - m, 2H, CH2; 2.20-2.30 -
m, 2H, CH2, 2.90-3.10 - m, 2H, CH2; 4.50 - m, 1H, CH; 6.80-7.80 - m, 13H, Ph; 7.90 -
d, 1H, NH.
Example 3: Preparation of 4(5)-[(Biphenyl-4-carbonyl)-amino]-4-[2-(4-fluoro-
phenyl)-1,1-dimethyl-ethylcarbamoyl]-butyric acid (Compound 6)

[0066] To a suspension of Compound 5 (100 g) in toluene (325 ml) were added
trifluoroacetic acid (TFA, 313 g) at 5 to 20 °C. The resulting solution was stirred at
ambient temperature until the reaction was completed (4 to 6 h). TFA was removed by
vacuum distillation, the solution diluted with ethyl acetate, washed with aqueous
potassium acetate, and crystallization was affected by adding heptane to afford
Compound 6 as white solid (82.7 g, yield 92%; Purity - 99.8% (HPLC area %); Strength
- 98.0%; ee - 99.0%). NMR data: 1.37,1.45 - s, 6H, CH3; 2.10 - m, 2H, CH2; 2.35-2.60
- m, 2H, CH2; 2.80-3.10 - d, 2H, CH2; 4.80 - q, 1H, CH; 6.80-7.80 - m, 13H, Ph; 7.90 -
s, 2H, NH.
[0067] While particular embodiments of the present invention have been
illustrated and described, it would be obvious to those skilled in the art that various other
changes and modifications can be made without departing from the spirit and scope of the
invention. It is therefore intended to cover in the appended claims all such changes and
modifications that are within the scope of this invention.
CLAIMS
What is claimed is:
1. A method for preparing a compound of the formula (TV),

wherein
R2 is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -(CH2)nR11, -OH,
or
-O-(C1-C6) alkyl;
R11 is aryl; heteroaryl, or cycloalkyl;
n is 0, 1, 2, 3, or 4;
R16 is (C1-C6) alkyl;
PG1 is an amine protecting group; and
PG2 is a carboxylic acid protecting group,
comprising treating a compound of formula (II),

wherein R2, PG1 and PG2 are defined as herein above,
with an alkyl chloroformate of formula (ID) and a base,

wherein R16 is as defined as herein above.
2. The method of claim 1, wherein R16 is methyl, ethyl, propyl, isopropyl, butyl, or
isobutyl.
3. The method of claim 1, wherein R16 is methyl, or isobutyl; PG1 is Fmoc; and said base
is triethylamine, diisopropylethylamine, pyridine, N-methyhnorpholine, sodium
bicarbonate, sodium carbonate, potassium bicarbonate, or potassium carbonate.
4. The method of claim 1, further comprising treating the compound of formula (IV)
with an amine having the formula of HNR14R15 or a pharmaceutically acceptable
salt thereof, wherein
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 R15
together may form a five- to seven-membered cyclic group
containing up to 3 heteroatoms selected from N, O, or S;
R12 is halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7, -CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8, linear or branched or
cyclic (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7, (C2-C6) alkynyl, (C2-
C6) alkenyl,
-O-(C1-C6) alkylcycloalkyl, -O-alkenyl, -O-(C1-C6) alkylaryl, aryl,
heteroaryl,
-(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-aryl, -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 may form a five- to seven-
membered cyclic group containing up to 3 heteroatoms selected
from N,O, or S;
R13 is halogen, -O-(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, 1, 2, 3, or 4;
to give a compound of formula (V),

wherein R2, PG1, and PG2 are defined as in claim 1; and R14 and R15 are defined as
herein above.
5. The method of claim 4, wherein R16 is methyl, ethyl, propyl, isopropyl, butyl, or
isobutyl.
6. The method of claim 4, wherein R16 is methyl, or isobutyl; PG1 is Fmoc; and said base
is triethylamine, diisopropylethylamine, pyridine, N-methyhnorpholine, sodium
bicarbonate, sodium carbonate, potassium bicarbonate, or potassium carbonate.
7. The method of claim 4, further comprising a cleavage of the amine protecting group
of the compound of formula (V) to give a compound of formula (VI),

wherein R2, PG2, R14 and R15 are defined as in claim 4.
8. The method of claim 7, wherein said cleavage of the amine protecting group is
achieved by using an amine.
9. The method of claim 7, further comprising treating the compound of formula (VI)
with an acid chloride having the formula of R1C(=O)Cl in the presence of a base,
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;
R5 is aryl, heteroaryl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-
aryl,
-S-heteroaryl, -NH-aryl, -NH-heteroaryl, -C(=O)-(C1-C6) alkyl, -C(=O)-
aryl,
-C(=O)-heteroaryl, -SO2-(C1-C6) alkyl, -SO2-aryl, -SO2-heteroaryl, -
SO2NH-aryl,
-SO2NH-heteroaryl, -NHSO2-(C1-C6) alkyl, -NHSO2-aryl, -NHSO2-
heteroaryl,
-NHC(=O)-aryl, -NHC(=O)-heteroaryl, -C(=O)NH-aryl, -C(=O)NH-
heteroaryl, (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl,
-NHC(=O)-(C1-C6) alkyl, -C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl,
-S-(C1-C6) cycloalkyl, -NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6)
cycloalkyl, or-C(=O)NH-(C1-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 is hydrogen, halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -
C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7,-CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8; (C1-C6) alkyl,
-O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6) alkyl, -NHC(=O)-(C1-C6)
alkyl,
-C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl, -S-(C1-C6) cycloalkyl,
-NH-(C1-C6) cycloalkyl,-NHC(=O)-(C1-C6) cycloalkyl,
-C(=O)NH-(C1-C6) cycloalkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7,
(C2-C6) alkynyl, (C2-C6) alkenyl, -O-(C1-C6) alkyl-cycloalkyl, -O-alkenyl,
-O-(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; and
R7, R8, and R13 are defined as in claim 4;
to provide a compound of formula (VII),

wherein R1 is defined as herein above; and R2, PG2, R14 and R15 are defined as in
claim 7.
10. The method of claim 9, further comprising cleaving the carboxylic acid protecting
group of the compound of formula (VII) to provide a compound of formula (I).

wherein R1, R2, R14 and R15 are defined as in claim 9.
11. A compound of formula (IV),

wherein
R2 is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -(CH2)nR11, -OH,
or
-O-(C1-C6) alkyl;
R11 is aryl, heteroaryl, or cycloalkyl;
n is 0, 1, 2, 3, or 4;
R16 is (C1-C6) alkyl;
PG1 is an amine protecting group; and
PG2 is a carboxylic acid protecting group.
12. The compound of claim 11, wherein R2 is hydrogen; and R16 is methyl, ethyl, propyl,
isopropyl, butyl, or isobutyl.
13. The compound of claim 12, wherein PG1 is Fmoc, and PG2 is t-butyl.
14. A compound of formula (I),

prepared by the method comprising:
a) treating a compound of formula (II),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IV);

b) treating the compound of formula (IV) with an amine having the formula of
HNR14R15 or a pharmaceutically acceptable salt thereof;
to give a compound of formula (V);

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI);

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)Cl in the presence of a base to give a compound of formula (VII);
and

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VII) to give the to compound of formula (I),
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)nR11, -OH,
or
-O-(C1-C6) alkyl;
R5 is aryl, heteroaryl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-
aryl,
-S-heteroaryl, -NH-aryl, -NH-heteroaryl, -C(=O)-(C1-C6) alkyl, -C(=O)-
aryl,
-C(=O)-heteroaryl, -SO2-(C1-C6) alkyl, -SO2-aryl, -SO2-heteroaryl, -
SO2NH-aryl,
-SO2NH-heteroaryl, -NHSO2-(C1-C6) alkyl, -NHSO2-aryl, -NHSO2-
heteroaryl,
-NHC(=O)-aryl, -NHC(=O)-heteroaryl, -C(=O)NH-aryl, -C(=O)NH-
heteroaryl, (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl,
-NHC(=O)-(C1-C6) alkyl, -C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl,
-S-(C1-C6) cycloalkyl, -NH-(C1-C6)v cycloalkyl, -NHC(=O)-(C1-C6)
cycloalkyl, or -C(=O)NH-(C1-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 is hydrogen, halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -
C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7,-CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8; (C1-C6) alkyl,
-O-(C1-C6) alkyl, -S-v alkyl, -NH-(C1-C6) alkyl, -NHC(=O)-(C1-C6)
alkyl,
-C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl, -S-(C1-C6) cycloalkyl,
-NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6) cycloalkyl,
-C(=O)NH-(C1-C6) cycloalkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7,
(C1-C6) alkynyl, (C2-C6) alkenyl, -O-(C1-C6) alkyl-cycloalkyl, -O-alkenyl,
-O-(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 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;
R12 is halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7, -CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8, linear or branched or
cyclic (C1-C6) alkyl,-O- (C1-C6) alkyl,-S-(C1-C6) alkyl,-NH-(C1-C6)
alkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7, (C2-C6) alkynyl, (C2-
C6) alkenyl,
-O-(C1-C6) alkylcycloalkyl,-O-alkenyl, -O-(C1-C6) alkylaryl, aryl,
heteroaryl,
-(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-aryl, -S-
heteroaryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
alkenyl, or alkynyl optionally substituted with one or more of R13;
R13 is halogen, -O-(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 R15 together may form a five-
to seven-membered cyclic group containing up to 3 heteroatoms selected
from N, O,or S;
R16 is (C1-C6) alkyl;
PG1 is an amine protecting group;
PG2 is a carboxylic acid protecting group; and
n is 0, 1, 2, 3, or 4.
15. A compound of formula (Ia),

prepared by the method comprising:
a) treating a compound of formula (IIa),

with an alkyl chloroformate of formula (III) and a base,

to provide a compound of the formula (IVa);

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VIIa) to give the to compound of formula (Ia),
wherein:
PG1 is an amine protecting group;
PG2 is a carboxylic acid protecting group; and
R16 is (C1-C6) alkyl.
16. The compound of claim 15, wherein R16 is methyl, or isobutyl; PG1 is Fmoc; PG2 is
(C1-C4) alkyl; and said base is triethylamine, diisopropylethylamine, pyridine, N-
methylmorpholine, sodium bicarbonate, sodium carbonate, potassium bicarbonate,
or potassium carbonate.
17. A method for preparing a compound of formula (Ia),

with an alkyl chloroformate of formula (III) and a base,

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VIIa) to give the to compound of formula (Ia),
wherein:
PG1 is an amine protecting group;
PG2 is a carboxylic acid protecting group; and
R16 is (C1-C6) alkyl.
18. A method for preparing a compound of formula (I),

comprising:
a) treating a compound of formula (II),

with oxalyl chloride or thionyl chloride, optionally in the presence of a catalytic
amount of DMF,
to provide a compound of the formula (IVb);

b) treating the compound of formula (IVb) with an amine having the formula of
HNR14R15 or a pharmaceutically acceptable salt thereof;
to give a compound of formula (V);

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI);

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)Cl in the presence of a base to give a compound of formula (VII);
and

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VII) to give the to compound of formula (I),
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)nR11, -OH,
or
-O-(C1-C6) alkyl;
R5 is aryl, heteroaryl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-
aryl,
-S-heteroaryl, -NH-aryl, -NH-heteroaryl, -C(=O)-(C1-C6) alkyl, -C(=O)-
aryl,
-C(=O)-heteroaryl, -SO2-(C1-C6) alkyl, -SO2-aryl, -SO2-heteroaryl, -
SO2NH-aryl,
-SO2NH-heteroaryl, -NHSO2-(C1-C6) alkyl, -NHSO2-aryl, -NHSO2-
heteroaryl,
-NHC(=O)-aryl, -NHC(=O)-heteroaryl, -C(=O)NH-aryl, -C(=O)NH-
heteroaryl, (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl,
-NHC(=O)-(C1-C6) alkyl, -C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl,
-S-(C1-C6) cycloalkyl, -NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6)
cycloalkyl, or -C(=O)NH-(C1-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 is hydrogen, halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -
C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7,-CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8; (C1-C6) alkyl,
-O-(C1-C6) alkyl, -S-(C1-C6) alkyl -NH-(C1-C6) alkyl, -NHC(=O)-(C1-C6)
alkyl,
-C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl, -S-(C1-C6) cycloalkyl,
-NH-(C1-C6) cycloalkyl,-NHC(=O)-(C1-C6) cycloalkyl,
-C(=O)NH-(C1-C6) cycloalkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7,
(C2-C6) alkynyl, (C2-C6) alkenyl, -O-(C1-C6) alkyl-cycloalkyl, -O-alkenyl,
-O-(C1-C6) alkyl substituted with aryl, aryl, heteroaryl, -(CH2)naryl,
-(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 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;
R12 is halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7, -CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8, linear or branched or
cyclic (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7, (C2-C6) alkynyl, (C2-
C6) alkenyl,
-O-(C1-C6) alkylcycloalkyl, -O-alkenyl, -O-(C1-C6) alkylaryl, aryl,
heteroaryl,
-(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-aryl, -S-
heteroaryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
alkenyl, or alkynyl optionally substituted with one or more of R13;
R13 is halogen, -O-(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 R15 together may form a five-
to seven-membered cyclic group containing up to 3 heteroatoms selected
from N, O, or S;
R16 is (C1-C6) alkyl;
PG1 is an amine protecting group;
PG2 is a carboxylic acid protecting group; and
n is 0, 1, 2, 3, or 4.
19. A compound of formula (I),

prepared by the method comprising:
a) treating a compound of formula (II).

with oxalyl chloride or thionyl chloride, optionally in the presence of a catalytic
amount of DMF,
to provide a compound of the formula (IVb);

b) treating the compound of formula (IVb) with an amine having the formula of
HNR14R15 or a pharmaceutically acceptable salt thereof;
to give a compound of formula (V);

c) deprotecting the amine protecting group of the compound of formula (V) to
give a compound of formula (VI);

d) treating the compound of formula (VI) with an acid chloride having the formula
R1C(=O)Cl in the presence of a base to give a compound of formula (VII);
and

e) deprotecting the carboxylic acid protecting group of the compound of formula
(VII) to give the to compound of formula (I),
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 R5, the
substituents can be identical or different;
R2 is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, -(CH2)nR11, -OH,
or
-O-(C1-C6) alkyl;
R5 is aryl, heteroaryl, -(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-
aryl,
-S-heteroaryl, -NH-aryl, -NH-heteroaryl, -C(=O)-(C1-C6) alkyl, -C(=O)-
aryl,
-C(=O)-heteroaryl, -SO2-(C1-C6) alkyl, -SO2-aryl, -SO2-heteroaryl, -
SO2NH-aryl,
-SO2NH-heteroaryl, -NHSO2-(C1-C6) alkyl, -NHSO2-aryl, -NHSO2-
heteroaryl,
-NHC(=O)-aryl, -NHC(=O)-heteroaryl, -C(=O)NH-aryl, -C(=O)NH-
heteroaryl, (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl,
-NHC(=O)-(C1-C6) alkyl, -C(=O)NH-(C1-C6) alkyl, -O-(C1-C6) cycloalkyl,
-S-(C1-C6) cycloalkyl, -NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6)
cycloalkyl, or-C(=O)NH-(C1-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 is hydrogen, halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -
C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7,-CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8; (C1-C6) alkyl,
-O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6) alkyl, -NHC(=O)-(C1-C6)
alkyl,
-C(=O)NH-(C1-C6) alkyl,-O-(C1-C6) cycloalkyl,-S-(C1-C6) cycloalkyl,
-NH-(C1-C6) cycloalkyl, -NHC(=O)-(C1-C6) cycloalkyl,
-C(=O)NH-(C1-C6) cycloalkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7,
(C2-C6) alkynyl, (C2-C6) alkenyl, -O-(C1-C6) alkyl-cycloalkyl, -O-alkenyl,
-O-(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; R11 is aryl, heteroaryl, or
cycloalkyl;
R7 and R8 are each independently hydrogen, (C1-C6) alkyl, aryl, heteroaryl,
(C2-C5) alkenyl, (C2-C6) alkynyl, cycloalkyl, -(CH2)n-aryl, or -(CH2)n-
heteroaryl; or R7 and R8 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;
R12 is halogen, -CN, -OCF3, -CF3, -NO2, -OH, -SH, -NR7R8, -C(=O)NR7R8,
-NR8C(=O)R7, -NR8CO2R7, -CO2R7, -C(=O)R7, -SO2-(C1-C6) alkyl, -SO2-
aryl,
-SO2-heteroaryl, -SO2R7, -NR7SO2R8, -SO2NR7R8, linear or branched or
cyclic (C1-C6) alkyl, -O-(C1-C6) alkyl, -S-(C1-C6) alkyl, -NH-(C1-C6)
alkyl, heterocycloalkyl, -(C1-C6) alkyl-OR7, (C2-C6) alkynyl, (C2-
C6) alkenyl,
-O-(C1-C6) alkylcycloalkyl, -O-alkenyl, -O-(C1-C6) alkylaryl, aryl,
heteroaryl,
-(CH2)n-aryl, -(CH2)n-heteroaryl, -O-aryl, -O-heteroaryl, -S-aryl, -S-
heteroaryl, each alkyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl,
alkenyl, or alkynyl optionally substituted with one or more of R13;
R13 is halogen, -O-(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-heterdaryl; and
R14 and R15 are each independently hydrogen, (C1-C6) alkyl, aryl, heteroaryl,
(C1-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 R15 together may form a five-
to seven-membered cyclic group containing up to 3 heteroatoms selected
fromN, O, or S;
PG1 is an amine protecting group;
PG2 is a carboxylic acid protecting group; and
n is 0, 1, 2, 3, or 4.
20. The compound of claim 19, wherein:
R1 is biphenyl 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;
R14 is hydrogen; and
R15 is (C1-C6) alkyl optionally substituted with one or more R12.

The present invention relates to novel methods for the preparation of glutamic acid derivatives and intermediates
thereof, and such compounds prepared by the novel methods.