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CONTROLLED-RELEASE FORMULATION
Field of the Invention
The present invention relates to controlled-release dosage formulations that
are useful for treating a wide variety of diseases or disorders associated
with
hepatitis C virus by inhibiting HCV protease (for example HCV NS3/NS4a serine
protease), and/or diseases or disorders associated with cathepsin activity and
inhibiting cathepsin activity.
BACKGROUND OF THE INVENTION
HCV has been implicated in cirrhosis of the liver and in induction of
hepatocellular carcinoma. The prognosis for patients suffering from HCV
infection is
currently poor. HCV infection is more difficult to treat than other forms of
hepatitis
due to the lack of immunity or remission associated with HCV infection.
Current data
indicates a less than 50% survival rate at four years post cirrhosis
diagnosis.
Patients diagnosed with localized resectable hepatocellular carcinoma have a
five-
year survival rate of 10-30%, whereas those with localized unresectable
hepatocellular carcinoma have a five-year survival rate of less than 1%.
Current therapies for hepatitis C include interferon-a (INF(,,) and
combination
therapy with ribavirin and interferon. See, e.g.. Beremguer et al. (1998)
Proc. Assoc.
Am. Physicians 110(2):98-112. These therapies suffer from a low sustained
response rate and frequent side effects. See, e.g., Hoofnagle et al. (1997) N.
Engl.
J. Med. 336:347. Currently, no vaccine is available for HCV infection.
Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus that has
been implicated as the major causative agent in non-A, non-B hepatitis
(NANBH),
particularly in blood-associated NANBH (BB-NANBH)(see, International Patent
Application Publication No. WO 89/04669 and European Patent Application
Publication No. EP 381 216). NANBH is to be distinguished from other types of
viral-
induced liver disease, such as hepatitis A virus (HAV), hepatitis B virus
(HBV), delta
hepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV), as
well
as from other forms of liver disease such as alcoholism and primary biliar
cirrhosis.
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Recently, an HCV protease necessary for polypeptide processing and viral
replication has been identified, cloned and expressed; (see, e.g., U.S. Patent
No.
5,712,145). This approximately 3000 amino acid polyprotein contains, from the
amino terminus to the carboxy terminus, a nucleocapsid protein (C), envelope
proteins (El and E2) and several non-structural proteins (NS1, 2, 3, 4a, 5a
and 5b).
NS3 is an approximately 68 kda protein, encoded by approximately 1893
nucleotides
of the HCV genome, and has two distinct domains: (a) a serine protease domain
consisting of approximately 200 of the N-terminal amino acids; and (b) an RNA-
dependent ATPase domain at the C-terminus of the protein. The NS3 protease is
considered a member of the chymotrypsin family because of similarities in
protein
sequence, overall three-dimensional structure and mechanism of catalysis.
Other
chymotrypsin-like enzymes are elastase, factor Xa, thrombin, trypsin, plasmin,
urokinase, tPA and PSA. The HCV NS3 serine protease is responsible for
proteolysis of the polypeptide (polyprotein) at the NS3/NS4a, NS4a/NS4b,
NS4b/NS5a and NS5a/NS5b junctions and is thus responsible for generating four
viral proteins during viral replication. This has made the HCV NS3 serine
protease
an attractive target for antiviral chemotherapy.
It has been determined that the NS4a protein, an approximately 6 kda
polypeptide, is a co-factor for the serine protease activity of NS3.
Autocleavage of
the NS3/NS4a junction by the NS3/NS4a serine protease occurs intramolecularly
(i.e., cis) while the other cleavage sites are processed intermolecularly
(i.e., trans).
Analysis of the natural cleavage sites for HCV protease revealed the
presence of cysteine at P1 and serine at P1' and that these residues are
strictly
conserved in the NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions. The
NS3/NS4a junction contains a threonine at P1 and a serine at P1'. The Cys->Thr
substitution at NS3/NS4a is postulated to account for the requirement of cis
rather
than trans processing at this junction. See, e ., Pizzi et al. (1994) Proc.
Natl. Acad.
Sci (USA) 91:888-892, Failla et al. (1996) Folding & Design 1:35-42. The
NS3/NS4a cleavage site is also more tolerant of mutagenesis than the other
sites.
See, e_gõ Kollykhalov et al. (1994) J. Virol. 68:7525-7533. It has also been
found
that acidic residues in the region upstream of the cleavage site are required
for
efficient cleavage. See; e.g.. Komoda et al. (1994) J. Virol. 68:7351-7357.
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Inhibitors of HCV protease that have been reported include antioxidants (see,
International Patent Application Publication No. WO 98/14181), certain
peptides and
peptide analogs (see, International Patent Application Publication No. WO
98/17679,
Landro et al. (1997) Biochem. 36:9340-9348, Ingallinella et al. (1998)
Biochem.
37:8906-8914, Llinas-Brunet et al. (1998) Bioorg. Med. Chem. Lett. 8:1713-
1718),
inhibitors based on the 70-amino acid polypeptide eglin c (Martin et al.
(1998)
Biochem. 37:11459-11468, inhibitors affinity selected from human pancreatic
secretory trypsin inhibitor (hPSTI-C3) and minibody repertoires (MBip) (Dimasi
et al.
(1997) J. Virol. 71:7461-7469), cVHE2 (a "camelized" variable domain antibody
fragment) (Martin et al.(1997) Protein Eng. 10:607-614), and a1-
antichymotrypsin
(ACT) (Elzouki et al.) (1997) J. Hepat. 27:42-28). A ribozyme designed to
selectively
destroy hepatitis C virus RNA has recently been disclosed (see, BioWorld Today
9 217 : 4 (November 10, 1998)).
Reference is also made to the PCT Publications, No. WO 98/17679,
published April 30, 1998 (Vertex Pharmaceuticals Incorporated); WO 98/22496,
published May 28, 1998 (F. Hoffmann-La Roche AG); and WO 99/07734, published
February 18, 1999 (Boehringer Ingelheim Canada Ltd.).
Pending and copending U. S. patent applications, Serial No. 60/194,607, filed
April 5, 2000, and Serial No. 60/198,204, filed April 19, 2000, Serial No.
60/220,110,
filed July 21, 2000, Serial No. 60/220,109, filed July 21, 2000, Serial No.
60/220,107,
filed July 21, 2000, Serial No. 60/254,869, filed December 12, 2000, Serial
No.
60/220,101, filed July 21, 2000, Serial No. 60/568,721 filed May 6, 2004, and
WO
2003/062265, disclose various types of peptides and/or other compounds as NS-3
serine protease inhibitors of hepatitis C virus.
There is a need for new treatments and therapies for HCV infection to treat,
prevent or ameliorate of one or more symptoms of hepatitis C, methods for
modulating the activity of serine proteases, particularly the HCV NS3/NS4a
serine
protease, and methods of modulating the processing of the HCV polypeptide
using
the compounds provided herein.
Another aspect of the present invention is directed to inhibiting cathepsin
activity. Cathepsins (Cats) belong to the papain superfamily of lysosomal
cysteine
proteases. Cathepsins are involved in the normal proteolysis and turnover of
target
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proteins and tissues as well as in initiating proteolytic cascades by
proenzyme
activation and in participating in MHC class II molecule expression. Baldwin
(1993)
Proc. Natl. Acad. Sci., 90: 6796-6800; Mixuochi (1994) Immunol. Left., 43:189-
193.
However, aberrant cathepsin expression has also been implicated in several
serious human disease states. Cathepsins have been shown to be abundantly
expressed in cancer cells, including breast, lung, prostate, glioblastoma and
head/neck cancer cells, (Kos et al. (1998) Oncol. Rep., 5:1349-1361; Yan et
al.
(1998) Biol. Chem., 379:113-123; Mort et al. (1997) Int. J Biochem. Cell
Biol., 29:
715-720; Friedrick et al. (1999) Eur. J Cancer, 35:138-144) and are associated
with
poor treatment outcome of patients with breast cancer, lung cancer, brain
tumor and
head/neck cancer. Kos et al, supra. Additionally, aberrant expression of
cathepsin is
evident in several inflammatory disease states, including rheumatoid arthritis
and
osteoarthritis. Keyszer (1995) Arthritis Rheum., 38:976-984.
The molecular mechanisms of cathepsin activity are not completely
understood. Recently, it was shown that forced expression of cathepsin B
rescued
cells from serum deprivation-induced apoptotic death (Shibata et al. (1998)
Biochem.
Biophys. Res. Commun., 251: 199-203) and that treatment of cells with
antisense
oligonucleotides of cathepsin B induced apoptosis. Isahara et at. (1999)
Neuroscience, 91:233-249. These reports suggest an anti-apoptotic role for the
cathepsins that is contrary to earlier reports that cathepsins are mediators
of
apoptosis. Roberts et al (1997) Gastroenterology, 113: 1714-1726; Jones et al.
(1998) Am. J Physiol., 275: G723-730.
Cathepsin K is a member of the family of enzymes which are part of the
papain superfamily of cysteine proteases. Cathepsins B, H, L, N and S have
been
described in the literature. Recently, cathepsin K polypeptide and the cDNA
encoding such polypeptide were disclosed in U.S. Pat. No. 5, 501,969 (called
cathepsin 0 therein). Cathepsin K has been recently expressed, purified, and
characterized. Bossard, M. J., et al., (1996) J Biol. Chem . 271, 12517-12524;
Drake,
F. H., et al., (1996) J. Biol. Chem. 271, 12511-12516; Bromme, D., et al.,
(1996) J.
Biol. Chem. 271, 2126-2132.
Cathepsin K has been variously denoted as cathepsin 0, cathepsin X or
cathepsin 02 in the literature. The designation cathepsin K is considered to
be the
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more appropriate one (name assigned by Nomenclature Committee of the
International Union of Biochemistry and Molecular Biology).
Cathepsins of the papain superfamily of cysteine proteases function in the
normal physiological process of protein degradation in animals, including
humans,
e.g., in the degradation of connective tissue. However, elevated levels of
these
enzymes in the body can result in pathological conditions leading to disease.
Thus,
cathepsins have been implicated in various disease states, including but not
limited
to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei
brucei,
and Crithidia fusiculata; as well as in schistosomiasis malaria, tumor
metastasis,
metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See
International Publication Number WO 94/04172, published on Mar. 3, 1994, and
references cited therein. See also European Patent Application EP 0 603 873
Al,
and references cited therein. Two bacterial cysteine proteases from P.
gingivallis ,
called gingipains, have been implicated in the pathogenesis of gingivitis.
Potempa,
J., et al. (1994) Perspectives in Drug Discovery and Design , 2, 445-458.
Cathepsin K is believed to play a causative role in diseases of excessive bone
or cartilage loss. Bone is composed of a protein matrix in which spindle- or
plate-
shaped crystals of hydroxyapatite are incorporated. Type I Collagen represents
the
major structural protein of bone comprising approximately 90% of the
structural
protein. The remaining 10% of matrix is composed of a number of non-
collagenous
proteins, including osteocalcin, proteoglycans, osteopontin, osteonectin,
thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes
remodeling at discrete foci throughout life. These foci, or remodeling units,
undergo a
cycle consisting of a bone resorption phase followed by a phase of bone
replacement. Bone resorption is carried out by osteoclasts, which are
multinuclear
cells of hematopoietic lineage. In several disease states, such as
osteoporosis and
Paget's disease, the normal balance between bone resorption and formation is
disrupted, and there is a net loss of bone at each cycle. Ultimately, this
leads to
weakening of the bone and may result in increased fracture risk with minimal
trauma.
The abundant selective expression of cathepsin K in osteoclasts strongly
suggests that this enzyme is essential for bone resorption. Thus, selective
inhibition
of cathepsin K may provide an effective treatment for diseases of excessive
bone
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loss, including, but not limited to, osteoporosis, gingival diseases such as
gingivitis
and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic
bone disease. Cathepsin K levels have also been demonstrated to be elevated in
chondroclasts of osteoarthritic synovium. Thus, selective inhibition of
cathepsin K
may also be useful for treating diseases of excessive cartilage or matrix
degradation,
including, but not limited to, osteoarthritis and rheumatoid arthritis.
Metastatic
neoplastic cells also typically express high levels of proteolytic enzymes
that
degrade the surrounding matrix. Thus, selective inhibition of cathepsin K may
also
be useful for treating certain neoplastic diseases.
There are reports in the literature of the expression of Cathepsin B and L
antigen and that activity is associated with early colorectal cancer
progression. Troy
et al., (2004) Eur J Cancer, 40(10):1610-6. The findings suggest that cysteine
proteases play an important role in colorectal cancer progression.
Cathepsin L has been shown to be an important protein mediating the
malignancy of gliomas and it has been suggested that its inhibition may
diminish
their invasion and lead to increased tumor cell apoptosis by reducing
apoptotic
threshold. Levicar et al., (2003) Cancer Gene Ther., 10(2): 141-51.
Katunama et al., (2002) Arch Biochem Biophys., 397(2):305-11 reports on
antihypercalcemic and antimetastatic effects of CLIK-148 in vivo, which is a
specific
inhibitor of cathepsin L. This reference also reports that CLIK-148 treatment
reduced
distant bone metastasis to the femur and tibia of melanoma A375 tumors
implanted
into the left ventricle of the heart.
Rousselet et al., (2004) Cancer Res., 64(1): 146-51 reports that anti-
cathepsin
L single chain variable fragment (ScFv) could be used to inhibit the
tumorigenic and
metastatic phenotype of human melanoma, depending on procathepsin L secretion,
and the possible use of anti-cathepsin L ScFv as a molecular tool in a
therapeutic
cellular approach.
Colella et al., (2003) Biotech Histochem., 78(2):101-8 reports that the
cysteine
proteinases cathepsin L and B participate in the invasive ability of the PC3
prostrate
cancer cell line, and the potential of using cystein protease inhibitiors such
as
cystatins as anti-metastatic agents.
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Krueger et al., (2001) Cancer Gene Ther., 8(7):522-8 reports that in human
osteosarcoma cell line MNNG/HOS, cathepsin L influences, cellular malignancy
by
promoting migration and basement membrane degradation..
Frohlich et al., (2204) Arch Dermatol Res., 295(10):411-21 reports that
cathepsins B and L are involved in invasion of basal cell carcinoma (BCC)
cells.
U.S. Provisional Patent Application Serial No. Not Yet Assigned, entitled
"Compounds for Inhibiting Cathepsin Activity", filed April 20, 2005, discloses
various
types of peptides and/or other compounds as inhibitors of cathepsin.
Cathepsins therefore are attractive targets for the discovery of novel
chemotherapeutics and methods of treatment effective against a variety of
diseases.
There is a need for compounds useful in the inhibition of cathepsin activity
and in the
treatment of these disorders.
Further, there is a need for controlled-release dosage formulations to
maintain
a minimum plasma concentration of such compounds to enhance treatment
efficacy.
SUMMARY OF THE INVENTION
The present invention provides a controlled-release dosage formulation for
modulating the activity of Hepatitis C virus (HCV) protease in a subject,
comprising
at least one HCV protease inhibitor and a controlled-release carrier to
control the
release of the at least one HCV protease inhibitor, comprising administering
to said
subject an effective amount of at least one HCV protease inhibitor compound of
various structural formulae set forth below. The HCV protease inhibitor
compounds
disclosed herein can also be cathepsin inhibitors.
The present invention further provides a method for modulating the activity of
Hepatitis C virus (HCV) protease in a subject, wherein the method comprises
administering to a subject in need of such treatment a dosage form containing
at
least one HCV protease inhibitor in a pharmaceutically effective amount
thereof
through a controlled-release formulation of at least one HCV protease
inhibitor
compound of various structural formulae set forth below.
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In one embodiment, the HCV protease inhibitor or cathepsin inhibitor is a
compound of structural Formula I
fA
M I
W
I R1
N
Rq.~
0
R2
3
Formula I
or a pharmaceutically acceptable salt, solvate or ester thereof;
wherein:
Y is selected from the group consisting of the following moieties: alkyl,
alkyl-aryl,
heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,
alkyloxy, alkyl-
aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy,
alkylamino,
arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and
heterocycloalkylamino, with the proviso that Y maybe optionally substituted
with X11
or X12;
X11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or
heteroarylalkyl, with the proviso that X11 may be additionally optionally
substituted
with X12;
X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,
arylamino,
alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,
carbalkoxy,
carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,
halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl
may be
additionally optionally substituted with moieties independently selected from
X12;
R1 is COR5 or B(OR)2, wherein R5 is H, OH, OR8, NR9R10, CF3, C2F51 C3F71
CF2R6,
R6, or COR7 wherein R7 is H, OH, OR8, CHR9R10, or NR9R10 , wherein R6, R8, R9
and R10 are independently selected from the group consisting of H, alkyl,
aryl,
heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl,
[CH(R1~)]pCOOR11, [CH(R1~)] pCONR12R1s, [CH(R1)]PSO2R11, [CH(R1 )]pCOR11,
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[CH(R")]PCH(OH)RCH(R" )CONHCH(R2' )COO R11,
CH(R")CONHCH(R2')CONR12R13, CH(R")CONHCH(R2' )R',
CH(R")CONHCH(R2')CONHCH(RT)COO R", CH(R")CONHCH(R2')CONHCH(R3')
CONR12R13, CH(R")CONHCH(R2' )CONHCH(R3') CONHCH(R4' )COO R",
CH(R")CONHCH(R2') CONHCH(R3')CONHCH(R4')CONR12R13, CH(R")CONHCH(R2'
)CONHCH(R3' )CONHCH(R4' )CONHCH(R5')COO R" and CH(R" )CONHCH(R2'
,
)CONHCH(R3 )CONHCH(R4')CONHCH(R5') CONR12R13, wherein R~~, R2', R3', R4'
R5' , R", R12, R13, and R' are independently selected from the group
consisting of H,
alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-
heteroaryl, aryl-alkyl
and heteroaralkyl;
Z is selected from 0, N, CH or CR;
W maybe present or absent, and if W is present, W is selected from C=O, C=S,
C(=N-CN), or SO2;
Q maybe present or absent, and when Q is present, Q is CH, N, P, (CH2)p,
(CHR)p ,
(CRR')p , 0, NR, S, or SO2; and when Q is absent, M may be present or absent;
when Q and M are absent, A is directly linked to L;
A is 0, CH2, (CHR) p,(CHR-CHR') p,(CRR') p, NR, S, SO2 or a bond;
E is CH, N, CR, or a double bond towards A, L or G;
G may be present or absent, and when G is present, G is (CH2)p, (CHR) p, or
(CRR')p; and when G is absent, J is present and E is directly connected to the
carbon atom in Formula I as G is linked to;
J maybe present or absent, and when J is present, J is (CHa)p, (CHR) p, or
(CRR')p,
SO2, NH, NR or 0; and when J is absent, G is present and E is directly linked
to N
shown in Formula I as linked to J;
L may be present or absent, and when L is present, L is CH, CR, 0, S or NR;
and
when L is absent, then M may be present or absent; and if M is present with L
being
absent, then M is directly and independently linked to E, and J is directly
and
independently linked to E;
M may be present or absent, and when M is present, M is 0, NR, S, SO2, (CH2)
p,
(CHR) p (CHR-CHR')P, or (CRR') P ;
p is a number from 0 to 6; and
R, R', R2, R3 and R4 are independently selected from the group consisting of
H; Cl-
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C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy,
aryloxy,
alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea,
ketone,
aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and
(heterocycloalkyl)alkyl,
wherein said cycloalkyl is made of three to eight carbon atoms, and zero to
six
oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of one to six
carbon
atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryl;
wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl,
cycloalkyl and
heterocycloalkyl moieties may be optionally and chemically-suitably
substituted, with
said term "substituted" referring to optional and chemically-suitable
substitution with
one or more moieties selected from the group consisting of alkyl, alkenyl,
alkynyl,
aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy,
aryloxy,
alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate, urea,
ketone,
aidehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl urea,
hydrazide,
and hydroxamate;
further wherein said unit N-C-G-E-L-J-N represents a five-membered or six-
membered cyclic ring structure with the proviso that when said unit N-C-G-E-L-
J-N
represents a five-membered cyclic ring structure, or when the bicyclic ring
structure
in Formula I comprising N, C, G, E, L, J, N, A, Q, and M represents a five-
membered
cyclic ring structure, then said five-membered cyclic ring structure lacks a
carbonyl
group as part of the cyclic ring.
In another embodiment, the inhibitor is a compound of Formula II:
P6 O P4 H O P2 H O
1V
X N N N Z~P
H O = H O O O
P5 P3 X1
Pla P1b
Formula II
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
ZisO,NHorNR12:
X is alkylsulfonyl, heterocyclylsulfonyl, heterocyclylalkylsulfonyl,
arylsulfonyl,
heteroaryisulfonyl, alkylcarbonyl, heterocyclylcarbonyl,
heterocyclylalkylcarbonyl,
arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, heterocyclyloxycarbonyl,
aryloxycarbonyl, heteroaryloxycarbonyl, alkyaminocarbonyl,
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heterocyclylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl
moiety,
with the proviso that X may be additionally optionally substituted with R12 or
R13;
Xl is H; Cl-C4 straight chain alkyl; Cl-C4 branched alkyl or ; CH2-aryl
(substituted or
unsubstituted);
R12 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or
heteroarylalkyl moiety, with the proviso that R12 may be additionally
optionally
substituted with R13
R13 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,
arylamino,
alkylsulfonyl, aryisulfonyl, alkylsulfonamido, aryisulfonamido, carboxy,
carbalkoxy,
carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,
halogen, cyano, or nitro moiety, with the proviso that the alkyl, alkoxy, and
aryl may
be additionally optionally substituted with moieties independently selected
from R13
P1 a, P1 b, P2, P3, P4, P5, and P6 are independently:
H; C1-C10 straight or branched chain alkyl; C2-C10 straight or branched
chain alkenyl;
C3-C8 cycloalkyl, C3-C8 heterocyclic; (cycloalkyl)alkyl or (heterocyclyl)alkyl
wherein said cycloalkyl is made up of 3 to 8 carbon atoms, and zero to 6
oxygen,
nitrogen, sulfur, or phosphorus atoms, and said alkyl is of I to 6 carbon
atoms;
aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein said alkyl is of 1 to
6
carbon atoms;
wherein said alkyl, alkenyl, cycloalkyl, heterocyclyl; (cycloalkyl)alkyl and
(heterocyclyl)alkyl moieties may be optionally substituted with R13, and
further
wherein said Pla and P1 b may optionally be joined to each other to form a
spirocyclic or spiroheterocyclic ring, with said spirocyclic or
spiroheterocyclic ring
containing zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and may
be
additionally optionally substituted with R13; and
P1' is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclyl-
alkyl, aryl, aryl-alkyl, heteroaryl, or heteroaryl-alkyl; with the proviso
that said P1' may
130 be additionally optionally substituted with R3.
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In another embodiment, the inhibitor is a compound of Formula III
N/ G
I N R'
R4~
R3 0 R2
Formula III
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
G, J and Y may be the same or different and are independently selected from
the
group consisting of the moieties: H, alkyl, alkyl-aryl, heteroalkyl,
heteroaryl, aryl-
heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,
heteroaryloxy,
heterocycloalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino,
arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, with
the
proviso that Y maybe additionally optionally substituted with X" or X12;
X" is selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl,
cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl,
heteroaryl,
alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that X" may be
additionally optionally substituted with X12;
X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,
arylamino,
alkylsulfonyl, arylsulfonyl, alkylsulfonamido, aryisulfonamido, carboxy,
carbalkoxy,
carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,
halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl
may be
additionally optionally substituted with moieties independently selected from
X12;
R' is COR5 or B(OR)2, wherein R5 is selected from the group consisting of H,
OH,
OR8, NR9R10, CF3, C2F5, C3F7, CF2R6, R6 and COR' wherein R' is selected from
the
group consisting of H, OH, OR8, CHR9R10, and NR9R'0 , wherein R6, R8, R9 and
Rlo
may be the same or different and are independently selected from the group
consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl,
arylalkyl,
heteroarylalkyl, CH(R1)COOR1',CH(R")CONR12R13,CH(R")CONHCH(R2)COOR",
CH(R1 )CONHCH(R2)CONR12R13,CH(R1)CONHCH(R2)R',CH(R' )CONHCH(R2 )CO
NHCH(R3)COOR",CH(Rl )CONHCH(R2)CONHCH(R3 )CONR12R13,
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CH(R' )CONHCH(R2 )CONHCH(R3 )CONHCH(R4 )COOR",CH(R')CONHCH(R2 )C
ONHCH(R3' )CONHCH(R4' )CONR12 R13,CH(R~ )CONHCH(R2 )CONHCH(R3'
)CONHC
H(R4 )CONHCH(R5)COOR",andCH(R')CONHCH(R2)CONHCH(R3 )CONHCH(R4 )
CONHCH(R5 ) CONR12R13, wherein R', R2, R3 , R4, R5 , R", R12, R13, and R' may
be the same or different and are independently selected from a group
consisting of
H, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, alkyl-
heteroaryl, aryi-alkyl
and heteroaralkyl;
Z is selected from 0, N, or CH;
W maybe present or absent, and if W is present, W is selected from C=O, C=S,
or
S02; and
R, R', R2, R3 and R4 are independently selected from the group consisting of
H; C1-
C10 alkyl; C2-C10 alkenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl, alkoxy,
aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate,
urea,
ketone, aldehyde, cyano, nitro; oxygen, nitrogen, sulfur, or phosphorus atoms
(with
said oxygen, nitrogen, sulfur, or phosphorus atoms numbering zero to six);
(cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made
of three
to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus
atoms,
and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl;
and alkyl-
heteroaryl;
wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl,
cycloalkyl and
heterocycloalkyl moieties may be optionally substituted, with said term
"substituted"
referring to optional and chemically-suitable substitution with one or more
moieties
selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl,
cycloalkyl,
heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio,
amino, amido,
ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro,
sulfonamide,
sulfoxide, sulfone, sulfonylurea, hydrazide, and hydroxamate.
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In another embodiment, the inhibitor is a compound of Formula IV
/Q
M I
\
\ E
w O \ O
N
R4/ Z
3 N O R2 R~
O
Formula IV
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
Y is selected from the group consisting of the following moieties: alkyl,
alkyl-aryl,
heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,
alkyloxy, alkyl-
aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy,
alkylamino,
arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and
heterocycloalkylamino, with the proviso that Y maybe optionally substituted
with X"
or X12;
X" is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or
heteroarylalkyl, with the proviso that X11 may be additionally optionally
substituted
with X12;
X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino,
arylamino,
alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxyl,
carbalkoxy,
carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,
halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy, and aryl
may be
additionally optionally substituted with moieties independently selected from
X12;
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R' is selected from the following structures:
N/ i 1 ~R11)k N~ (R11)k
~~
~
~ ~
-
N ~)k or N (Rl )k
\
~
wherein k is a number from 0 to 5, which can be the same or different, R"
denotes optional substituents, with each of said substituents being
independently
selected from the group consisting of alkyl, alkenyl, alkynyl, aryl,
cycloalkyl, alkyl-
aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, alkyloxy,
alkyl-aryloxy,
aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino,
arylamino,
alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,
heterocycloalkylamino,
hydroxy, thio, alkylthio, arylthio, amino, alkylsulfonyl, arylsulfonyl,
alkylsulfonamido,
aryisulfonamido, carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino,
alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, and nitro, with
the
proviso that R" (when R" # H) maybe optionally substituted with X" or X12;
Z is selected from 0, N, CH or CR;
W may be present or absent, and if W is present, W is selected from C=O, C=S,
C(=N-CN), or S(02);
Q may be present or absent, and when Q is present, Q is CH, N, P, (CH2)p,
(CHR)p,
(CRR')p , 0, N(R), S, or S(02); and when Q is absent, M may be present or
absent;
when Q and M are absent, A is directly linked to L;
A is 0, CH2, (CHR) p,(CHR-CHR') p,(CRR') p, N(R), S, S(02) or a bond;
E is CH, N, CR, or a double bond towards A, L or G;
G may be present or absent, and when G is present, G is (CH2)p, (CHR) p, or
(CRR')p; and when G is absent, J is present and E is directly connected to the
carbon atom in Formula I as G is linked to;
J may be present or absent, and when J is present, J is (CH2)p, (CHR) p, or
(CRR')p,
S(02), NH, N(R) or 0; and when J is absent, G is present and E is directly
linked to N
shown in Formula I as linked to J;
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L may be present or absent, and when L is present, L is CH, C(R), 0, S or
N(R); and
when L is absent, then M may be present or absent; and if M is present with L
being
absent, then M is directly and independently linked to E, and J is directly
and
independently linked to E;
M may be present or absent, and when M is present, M is 0, N(R), S, S(02),
(CH2)p,
(CHR) p (CHR-CHR')p, or (CRR') P ;
p is a number from 0 to 6; and
R, R', R2, R3 and R4 can be the same or different, each being independently
selected
from the group consisting of H; Cl-Clo alkyl; C2-Clo alkenyl; C3-C8
cycloalkyl; C3-C8
heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, ester,
carboxylic
acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen,
(cycloalkyl)alkyl and
(heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to eight
carbon
atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said
alkyl
is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-
heteroaryl;
wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl,
cycloalkyl and
heterocycloalkyl moieties may be optionally substituted, with said term
"substituted"
referring to substitution with one or more moieties which can be the same or
different, each being independently selected from the group consisting of
alkyl,
alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy,
thio, alkoxy,
aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic acid, carbamate,
urea,
ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl
urea,
hydrazide, and hydroxamate;
further wherein said unit N-C-G-E-L-J-N represents a five-membered cyclic ring
structure or six-membered cyclic ring structure with the proviso that when
said unit
N-C-G-E-L-J-N represents a five-membered cyclic ring structure, or when the
bicyclic
ring structure in Formula I comprising N, C, G, E, L, J, N, A, Q, and M
represents a
five-membered cyclic ring structure, then said five-membered cyclic ring
structure
lacks a carbonyl group as part of said five-membered cyclic ring.
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In another embodiment, the inhibitor is a compound of Formula V
M'
Ll H
N R
N ----Y y
O
/[D]
[XI
Formula V
or a pharmaceutically acceptable salt, solvate or ester of said compound
wherein:
(1) R' is -C(O)R5 or -B(OR)2;
-
(2) R5 is H, -OH, -OR8, -NR9R10, -C(O)OR8, -C(O)NR9R'0 , -CF31 -C2F5, C3F71
CF2R6, -R6, -C(O)R7 or NR7SO2R8;
(3) R7 is H, -OH, -ORg,or -CHR9R10;
(4) R6, R8, R9 and R10 are independently selected from the group consisting of
H:
alkyl, alkenyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, arylaikyl,
heteroarylalkyl, R14, -
CH(R")CH(R")C(O)OR",[CH(R")]pC(O)OR",-[CH(R")]PC(O)NR12R13,-[CH(R")]
pS(O2)R",-[CH(R")]pC(O)R11,-[CH(R1 )JpS(02)NR12R13, CH(R")C(O)N(H)CH(R2')(R'),
CH(R")CH(R")C(O)NR12R13, -CH(R")CH(R1')S(O2)R1', -
CH(R'')CH(R")S(O2)NR12R13, -CH(R")CH(R1')C(O)R'', -[CH(R1')]pCH(OH)R'1, -
CH(R" )C(O)N(H)CH(R2' )C(O)OR", C(O)N(H)CH(R2')C(O)OR",-
C(O)N(H)CH(R2')C(O)R'1,CH(R1')C(O)N(H)CH(R2') C(O)NR12R13,-
CH(R1')C(O)N(H)CH(R2')R',CH(R")C(O)N(H)CH(R2')C(O)N(H)
CH(R3')C(O)OR'1,CH(R")C(O)N(H)CH(R2')C(O)CH(R3')NR12R13,CH(R")C(O)N(H)CH
(R2')C(O)N(H)CH(R3')C(O)NR12R13,CH(R")C(O)N(H)CH(R2')C(O)N(H)CH(R3')C(O)N(
H)CH (R4)C(O)OR",
H(R'')C(O)N(H)CH(R2')C(O)N(H)CH(R3')C(O)N(H)CH(R4')C(O)NR12R13,
CH(R'')C(O)N(H)CH(R2'
)C(O)N(H)CH(R3')C(O)N(H)CH(R4')C(O)N(H)CH(R5')C(O)OR",
andCH(R")C(O)N(H)CH(R2')C(O)N(H)CH(R3')C(O)N(H)CH(R4')C(O)N(H)CH(R5')
C(O)NR12R13;
and R can be the same or different, each
wherein R~', R2' , R 3' , R4', R5', R~~, R12 13
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being independently selected from the group consisting of: H, halogen, alkyl,
aryl,
heteroalkyl, heteroaryl, cycloalkyl, alkoxy, aryloxy, alkenyl, alkynyl, alkyl-
aryl, alkyl-
heteroaryl, heterocycloalkyl, aryl-alkyl and heteroaralkyl;
or
R12 and R13 are linked together wherein the combination is cycloalkyl,
heterocycloalkyl, ary or heteroaryl;
R14 is present or not and if present is selected from the group consisting of:
H, alkyl,
aryl, heteroalkyl, heteroaryl, cycloalkyl, alkyl-aryl, allyl, alkyl-
heteroaryl, alkoxy, aryl-
alkyl, alkenyl, alkynyl and heteroaralkyl;
(5) R and R' are present or not and if present can be the same or different,
each
being independently selected from the group consisting of: H, OH, Cl-Clo
alkyl, C2-
CIo alkenyl, C3-C8 cycloalkyl, C3-C$ heterocycloalkyl, alkoxy, aryloxy,
alkylthio,
arylthio, alkylamino, arylamino, amino, amido, arylthioamino,
arylcarbonylamino,
arylaminocarboxy, alkylaminocarboxy, heteroalkyl, alkenyl, alkynyl,
(aryl)alkyl,
heteroarylalkyl, ester, carboxylic acid, carbamate, urea, ketone, aldehyde,
cyano,
nitro, halogen, (cycloalkyl)alkyl, aryl, heteroaryl, (alkyl)aryl,
alkylheteroaryl, alkyl-
heteroaryl and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of
three to
eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus
atoms,
and said alkyl is of one to six carbon atoms;
(6) L' is H, OH, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, or
heterocyclyl;
(7) M' is H, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, arylalkyl,
heterocyclyl or
an amino acid side chain;
or L' and M' are linked together to form a ring structure wherein the portion
of
structural Formula 1 represented by
M'
L'\ a
O 1
N I
0
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is represented by structural Formula 2:
Q__A
M I
\L/EG
(
J'N
O
Formula 2
wherein in Formula 2:
E is present or absent and if present is C, CH, N or C(R);
J is present or absent, and when J is present, J is (CH2)p, (CHR-CHR')p,
(CHR)p,
(CRR')p, S(02), N(H), N(R) or 0; when J is absent and G is present, L is
directly
linked to the nitrogen atom marked position 2;
p is a number from 0 to 6;
L is present or absent, and when L is present, L is C(H) or C(R); when L is
absent, M is present or absent; if M is present with L being absent, then M is
directly
and independently linked to E, and J is directly and independently linked to
E;
G is present or absent, and when G is present, G is (CH2)p, (CHR)p, (CHR-
CHR')p or (CRR')p; when G is absent, J is present and E is directly connected
to the
carbon atom marked position 1;
Q is present or absent, and when Q is present, Q is NR, PR, (CR=CR),
(CHOp, (CHR)P,(CRR')p ,(CHR-CHR')p, 0, NR, S, SO, or SO2; when Q is absent,
M is (i) either directly linked to A or (ii) an independent substituent on L,
said
independent substituent bing selected from -OR, -CH(R)(R'), S(O)0_2R or -NRR'
or
(iii) absent; when both Q and M are absent, A is either directly linked to L,
or A is an
independent substituent on E, said independent substituent bing selected from -
OR,
-CH(R)(R'), S(O)0_2R or -NRR' or A is absent;
A is present or absent and if present A is 0, O(R), (CHZ)p, (CHR)p , (CHR-
CHR')p,
(CRR')P, N(R), NRR', S, S(02), -OR, CH(R)(R') or NRR'; or A is linked to M to
form
an alicyclic, aliphatic or heteroalicyclic bridge;
M is present or absent, and when M is present, M is halogen, 0, OR, N(R), S,
S(O2),
(CH2)p, (CHR)p (CHR-CHR')p, or (CRR')p; or M is linked to A to form an
alicyclic,
aliphatic or heteroalicyclic bridge;
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(8) Z' is represented by the structural Formula 3:
YW i - -
R31
Formula 3
wherein in Formula 3, Y is selected from the group consisting of: H, aryl,
aikyl, alkyl-
aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,
alkyloxy,
alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, heteroalkyl-
heteroaryl,
heteroalkyl-heterocycloalkyl, cycloalkyloxy, alkylamino, arylamino, alkyl-
arylamino,
arylamino, heteroarylamino, cycloalkylamino and heterocycloalkylamino, and Y
is
unsubstituted or optionally substituted with one or two substituents which are
the
same or different and are independently selected from X" or X12;
X" is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or
heteroarylalkyl, and X" is unsubstituted or optionally substituted with one or
more of
X12 moieties which are the same or different and are independently selected;
X12 is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, thio,
alkylthio, arylthio,
amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,
arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkylcarbonyl,
arylcarbonyl,
heteroalkylcarbonyl, heteroarylcarbonyl, sulfonylurea, cycloalkylsulfonamido,
heteroaryl-cycloalkylsulfonamido, heteroaryl-sulfonamido, alkoxycarbonylamino,
alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, and said
alkyl,
alkoxy, and aryl are unsubstituted or optionally independently substituted
with one
or more moieties which are the same or different and are independently
selected
from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl,
aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl;
Z is 0, N, C(H) or C(R);
R31 is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-
heteroaryl, alkyl-
heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy,
heterocycloalkyloxy, heteroalkyl-heteroaryl, cycloalkyloxy, alkylamino,
arylamino,
alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino or
heterocycloalkylamino, and R31 is unsubstituted or optionally substituted with
one or
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two substituents which are the same or different and are independently
selected
from X13 or X14;
X13 is alkyl, alkenyl, alkynyl, cycloalkyl, 'cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or
heteroarylalkyl, and X13 is unsubstituted or optionally substituted with one
or more of
X14 moieties which are the same or different and are independently selected;
X14 is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, thio,
alkylthio, arylthio,
amino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido,
aryisulfonamido, carboxy, carbalkoxy, carboxamido, alkylcarbonyl,
arylcarbonyl,
heteroalkylcarbonyl, heteroarylcarbonyl, cycloalkylsulfonamido, heteroaryl-
cycloalkylsulfonamido, heteroarylsulfonamido, alkoxycarbonylamino,
alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, and said
alkyl,
alkoxy, and aryl are unsubstiuted or optionally independently substituted with
one or
more moieties which are the same or different and are independently selected
from
alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl, aryl,
alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl;
W may be present or absent, and if W is present, W is C(=0), C(=S), C(=N-
CN), or S(02);
(9) X is represented by structural Formula 4:
(O)e
11
- (CH)a- (C=C)b- (O)c - (S)d- (A)f -
R29 R3oR3o R29~
Formula 4
wherein in Formula 4, a is 2, 3, 4, 5, 6, 7, 8 or 9;
b, c, d, e and f are 0, 1,2,3,4or5;
AisC,N,SorO;
R29 and R29' are independently present or absent and if present can be the
same or
different, each being independently one or two substituents independently
selected
from the group consisting of: H, halo, alkyl, aryl, cycloalkyl,
cycloalkylamino,
cycloalkylaminocarbonyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl),
-
NH(cycloalkyl), -N(alkyl)2, carboxyl, C(O)O-alkyl, heteroaryl, aralkyl,
alkylaryl,
aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxyalkyl,
aryloxy,
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aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl,
alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,
heteroaryisulfinyl, arylthio,
heteroarylthio, aralkylthio, heteroaralkyithio, cycloalkenyl, heterocyclyl,
heterocyclenyl, YIY2N-aIkyl-, YlY2NC(O)- and YIY2NSO2-, wherein Y, and Y2 can
be
the same or different and are independently selected from the group consisting
of
hydrogen, alkyl, aryl, and aralkyl; or
R29 and R29' are linked together such that the combination is an aliphatic or
heteroaliphatic chain of 0 to 6 carbons;
R30 is present or absent and if present is one or two substituents
independently
selected from the group consisting of: H, alkyl, aryl, heteroaryl and
cylcoalkyl;
(10) D is represented by structural Formula 5:
(O)i
II
- (CH)g- (C)h - (N)j - (A)k- (C=C)1- (CH)m -
R3a R33 R34
Formula 5
wherein in Formula 5, R32, R33 and R34 are present or absent and if present
are
independently one or two substituents independently selected from the group
consisting of: H, halo, alkyl, aryl, cycloalkyl, cycloalkylamino, spiroalkyl,
cycloalkylaminocarbonyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl),
-
NH(cycloalkyl), -N(alkyl)2, carboxyl, -C(O)O-alkyl, heteroaryl, aralkyl,
alkylaryl,
aralkenyl, heteroaralkyl, alkylheteroaryl, heteroaralkenyl, hydroxyalkyl,
aryloxy,
aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl,
alkylsulfonyl,
arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl,
heteroaryisulfinyl, arylthio,
heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocyclyl,
heterocyclenyl, YjY2N-alkyl-, YlY2NC(O)- and YjY2NSO2-, wherein Y, and Y2 can
be
the same or different and are independently selected from the group consisting
of
hydrogen, alkyl, aryl, and aralkyl; or
R32 and R34 are linked together such that the combination forms a portion of a
cycloalkyl group;
g is 1, 2, 3, 4, 5, 6, 7, 8 or 9;
h, i, j, k, I and m are 0, 1, 2, 3, 4 or 5; and
A is C, N, S or O,
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(11) provided that when structural Formula 2:
~QIA
M I
\~/EG
\\J'
_ N
O
Formula 2
is
R W. R
O
O
N
O
and
W' is CH or N, both the following conditional exclusions (i) and (ii) apply:
conditional exclusion (i): Z' is not -NH-R36, wherein R36 is H, C6 or 10 aryl,
heteroaryl,
-C(O)-R37, -C(O)-OR37 or -C(O)-NHR37, wherein R37 is C1_6 alkyl or C3_6
cycloalkyl;
and
conditional exclusion (ii): R' is not -C(O)OH, a pharmaceutically acceptable
salt of -
C(O)OH, an ester of -C(O)OH or -C(O)NHR38 wherein R38 is selected from the
group consisting of Cl_$ alkyl, C3_6 cycloalkyl, C6 to 10 aryl or C7_16
aralkyl.
In another embodiment, the inhibitor is a compound of Formula VI
~Q---A
M
E
\L"- I G O
H
z N,, Pi
N _ R
Cap, W 0 ~F
R3 p F
Formula VI
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or a pharmaceutically acceptable salt, solvate or ester of said compound,
wherein:
Cap and P' are independently H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl,
aryl-
heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,
heteroaryloxy,
heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino,
arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy
or
heterocyclylamino, wherein each of said alkyl, alkyl-aryl, heteroalkyl,
heteroaryl, aryl-
heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,
heteroaryloxy,
heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino,
arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylalkyloxy
or
heterocyclylamino can be unsubstituted or optionally independently substituted
with
one or two substituents which can be the same or different and are
independently
selected from Xl and X2;
Xl is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclyialkyl,
aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino,
alkylheteroaryl,
or heteroarylalkyl, and Xl can be unsubstituted or optionally independently
substituted with one or more of X2 moieties which can be the same or different
and
are independently selected;
X2 is hydroxy, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino,
alkylamino,
arylamino, alkylsulfonyl, aryisulfonyl, alkylsulfonamido, aryisulfonamido,
carboxy,
carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,
arylureido, halogen, cyano, keto, ester or nitro, wherein each of said alkyl,
alkoxy,
and aryl can be unsubstituted or optionally independently substituted with one
or
more moieties which can be the same or different and are independently
selected
from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl,
aryl, alkylaryl, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino,
alkylheteroaryl
and heteroarylalkyl;
W may be present or absent, and when W is present W is C(=0), C(=S), C(=NH),
C(=N-OH), C(=N-CN), S(O) or S(02);
Q maybe present or absent, and when Q is present, Q is N(R), P(R), CR=CR',
(CH2)p, (CHR)p,(CRR')p ,(CHR-CHR')p, 0, S, S(O) or S(02); when Q is absent, M
is (i) either directly linked to A or (ii) M is an independent substituent on
L and A is an
independent substituent on E, with said independent substituent being selected
from
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-OR, -CH(R') , S(O)0_2R or -NRR'; when both Q and M are absent, A is either
directly linked to L, or A is an independent substituent on E, selected from -
OR,
CH(R)(R'), -S(O)0_2R or-NRR';
A is present or absent and if present A is -0-, -O(R) CH2-, -(CHR)p ,-(CHR-
CHR')p-, (CRR')p, N(R), NRR', S, or S(02), and when Q is absent, A is -OR, -
CH(R)(R') or -NRR' ; and when A is absent, either Q and E are connected by a
bond
or Q is an independent substituent on M;
E is present or absent and if present E is CH, N, C(R);
G may be present or absent, and when G is present, G is (CH2)p, (CHR)p, or
(CRR')p; when G is absent, J is present and E is directly connected to the
carbon
atom marked position 1;
J may be present or absent, and when J is present, J is (CH2)p, (CHR-CHR')p,
(CHR)p, (CRR')p, S(O2), N(H), N(R) or 0; when J is absent and G is present, L
is
directly linked to the nitrogen atom marked position 2;
L may be present or absent, and when L is present, L is CH, N, or CR; when
L is absent, M is present or absent; if M is present with L being absent, then
M is
directly and independently linked to E, and J is directly and independently
linked to
E;
M may be present or absent, and when M is present, M is 0, N(R), S, S(02),
(CH2)p,
(CHR)p, (CHR-CHR')p, or (CRR')p;
p is a number from 0 to 6;
R, R' and R3 can be the same or different, each being independently selected
from
the group consisting of: H, Cl-Clp alkyl, C2-CI0 alkenyl, C3-C8 cycloalkyl, C3-
C8
heterocyclyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido,
arylthioamino,
arylcarbonylamino, arylaminocarboxy, alkylaminocarboxy, heteroalkyl,
heteroalkenyl,
alkenyl, alkynyl, aryl-alkyl, heteroarylalkyl, ester, carboxylic acid,
carbamate, urea,
ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl, heteroaryl,
alkyl-aryl,
alkyiheteroaryl, alkyl-heteroaryl and (heterocyclyl)alkyl;
R and R' in (CRR') can be linked together such that the combination forms a
cycloalkyl or heterocyclyl moiety; and
R' is N(R) or O.
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In another embodiment, the inhibitor is a compound of Formula VII
/
N
V 1
R
~
O Formula VII
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein,
M is 0, N(H), or CH2;
n is 0-4;
H
N, õ~O 6
~
R1 is -OR6, -NR6R7 or R
where R6 and R7 can be the same or different, each being independently
selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
heteroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyi,
heterocyclylalkyl, hydroxyl, amino, arylamino and alkylamino;
R4 and R5 can be the same or different, each being independently selected from
the
group consisting of H, alkyl, aryl and cycloalkyl; or alternatively R4 and R5
together
X NH-~
form part of a cyclic 5- to 7- membered ring such that the moiety R4xR5 is
H
X NY
represented by )k where k is 0 to 2;
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X is selected from the group consisting of:
~S\
0 \S~ So P ~ 0 0
P2~ P2O \N~ N
I sy O
le
R6 O
CDs~I)p q
) p
/ N ~ N
O'S~\O, p'~0 O~S\O O
N) p
,">" and O
O
where p is 1 to 2, q is 1-3 and PZ is alkyl, aryl, heteroaryl, heteroalkyl,
cycloalkyl, dialkylamino, alkylamino, arylamino or cycloalkylamino;
and
R3 is selected from the group consisting of: aryl, heterocyclyi, heteroaryl,
r ""r
R$ N $ N R $ N
~ s ~ ~~ s
Y y R R Y Y R
R$
, '
/ R$ R$
R$ --~ ~ s J' s
~- Y R' 8, R' Y R
X
R8 ~ I R$ ~ I and R8 C
Z Z Z
where Y is 0, S or NH, and Z is CH or N, and the R 8 moieties can be the
same or different, each R 8 being independently selected from the group
consisting of
hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
hydroxyl,
amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and
alkyloxy.
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In another embodiment, the inhibitor is a compound of Formula VIII:
~
N
0
r\1' F~
. -~-~ HN
~ O O P,
Formula VIII
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein,
M is 0, N(H), or CH2;
H
VN, ~O
' 6
R' is -OR6, -NR6R7 or o R
where R6 and R' can be the same or different, each being independently
selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
heteroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl,
heterocyclylalkyl, hydroxyl, amino, arylamino and alkylamino;
P, is selected from the group consisting of alkyl, alkenyl, alkynyl,
cycloalkyl haloalkyl;
P3 is selected from the group consisting of alkyl, cycloalkyl, aryl and
cycloalkyl fused
with aryl;
R4 and R5 can be the same or different, each being independently selected from
the
group consisting of H, alkyl, aryl and cycloalkyl; or alternatively R4 and R5
together
X NH-~
form part of a cyclic 5- to 7- membered ring such that the moiety R4xR5 is
H
X ~,
represented by )k where k is 0 to 2;
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X is selected from the group consisting of:
0 >~/\
O
0 O 6/ \ p2 P~~ ~N NR R Nl~
O
R
0
S Np
CD J-) ~ ~ p ~N
O S-\O p'5~~O O~S-\O
o
and 0 0
where p is 1 to 2, q is I to 3 and P2 is alkyl, aryl, heteroaryl, heteroalkyl,
cycloalkyl, dialkylamino, alkylamino, arylamino or cycloalkylamino;
and
R3 is selected from the group consisting of: aryl, heterocyclyi, heteroaryl,
~ 1111\r
N R$ N /N ~N
~ s a
~ a R~,~ s
Y N Y R y R 1. R
R 8
R$ R8
NR$ )-
R8 Ra, VY Y R
X
R8 ~ I and R$ ,R8
z z
where Y is 0, S or NH, and Z is CH or N, and the R 8 moieties can be the same
or
different, each R8 being independently selected from the group consisting of
hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
hydroxyl,
amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and
alkyloxy.
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In another embodiment, the inhibitor is a compound of Formula IX:
~
'
O
1
R~ R
~~ HN
O O
n
Formula IX
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein,
M is 0, N(H), or CH2;
n is 0-4;
H
N, O
6
R1 is -OR6, -NR6R7 or o R
where R6 and R7 can be the same or different, each being independently
selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl,
heteroalkyl,
cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,
heterocyclyl,
heterocyclylalkyl, hydroxyl, amino, arylamino and alkylamino;
R4 and R5 can be the same or different, each being independently selected from
the
group consisting of H, alkyl, aryl and cycloalkyl; or alternatively R4 and R5
together
X NH-~
form part of a cyclic 5- to 7- membered ring such that the moiety R4xR5 is
H
X NY
represented by )k where k is 0 to 2;
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X is selected from the group consisting of:
\s~o 0s% P 0 \s\
Z
P PZ \N~~~
N NR6R~ N
O Re
Rs O
CD~s) pq )p
N N p ~N N
S,
0o~S~O~ p'O
0 i s ~ / )P q N~'~ .
and 0
0
where p is 1 to 2, q is 1 to 3 and P2 is alkyl, aryl, heteroaryl, heteroalkyl,
cycloalkyl, dialkylamino, alkylamino, arylamino or cycloalkylamino;
and
R3 is selected from the group consisting of: aryl, heterocyclyl, heteroaryl,
r
Rs ~ N N R8 N
~ Rs R8 ~ ~ s
Y N Y Y Y
R8 R
, ,
' t
~ R8 R8
Rs - s ~~
y R- s, Rr Y Y Rs
/
Rs Rs 'Z I and Rs ~ Z I
where Y is 0, S or NH, and Z is CH or N, and the R 8 moieties can be the
same or different, each R 8 being independently selected from the group
consisting of
hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl,
hydroxyl,
amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and
alkyloxy.
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In another embodiment, the inhibitor is a compound of Formula X:
M A
\_ / O
N R'
N
Y H O R2 O
O
O R3
Formula X
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR9R10, or CHR9R10, wherein R8, R9 and R10 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyl-, arylalkyl-,
and heteroarylalkyl;
A and M can be the same or different, each being independently selected from
R,
OR, NHR, NRR', SR, SO2R, and halo; or A and M are connected to each other such
that the moiety:
M\LE/A
sx
shown above in Formula I forms either a three, four, six, seven or eight-
membered
cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl,
or a
five to ten-membered heteroaryl;
E is C(H) or C(R);
L is C(H), C(R), CH2C(R), or C(R)CH2;
R, R', R2, and R3 can be the same or different, each being independently
selected
from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,
heteroalkyl-,
heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-,
aryl-alkyl-, and
heteroaryl-alkyl-; or alternately R and R' in NRR' are connected to each other
such
that NRR' forms a four to eight-membered heterocyclyl;
and Y is selected from the following moieties:
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0 R15 0"N R16
G-~
R15 17 R18 ~ ' R15 R
R 18 R17 R1518
O
R1~O~G_R1~N~G-~s R1~ S~N~G~~S ,
R17 R18 R16 R17 R18 R16 R17 R18
R16 R16 R15 R16 R15 R16
R15\ ~/G~~ i R15G~s O\ R16_NyJ_)~_G_j
O R17F218 R15-0"rN R17 R18 17R18 0 R17 R1a
wherein G is NH or 0; and R15, R'6, R17 and R 18 can be the same or different,
each
being independently selected from the group consisting of H, alkyl,
heteroalkyl,
alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl,
aryl, arylalkyl,
heteroaryl, and heteroarylalkyl, or alternately, R15 and R'6 are connected to
each
other to form a four to eight-membered cycloalkyl, heteroaryl or heterocyclyl
structure, and likewise, independently R17 and R"$ are connected to each other
to
form a three to eight-membered cycloalkyl or heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,
sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto,
carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,
alkylureido, arylureido, halo, cyano, and nitro.
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In one embodiment, the inhibitor is a compound of Formula XI:
M A
\L E / O
N R'
N
Y H
O R2 0
O
O R3
Formula Xi
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR9R10, or CHR9R10, wherein R8, R9 and Rl0 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyi-, arylalkyl-,
and heteroarylalkyl;
A and M can be the same or different, each being independently selected from
R,
NR9R10, SR, SO2R, and halo; or A and M are connected to each other (in other
words, A-E-L-M taken together) such that the moiety:
M
L A
sx
shown above in Formula I forms either a three, four, six, seven or eight-
membered
cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl,
or a
five to ten-membered heteroaryl;
E is C(H) or C(R);
L is C(H), C(R), CH2C(R), or C(R)CH2;
R, R', R2, and R3 can be the same or different, each being independently
selected
from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,
heteroalkyl-,
heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-,
aryi-alkyl-, and
heteroaryl-alkyl-; or alternately R and R' in NRR' are connected to each other
such
that NR9R10 forms a four to eight-membered heterocyclyl;
Y is selected from the following moieties:
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-35-
Y80 Y30 Y31
R19_I /G_~s R19 R19 G_~
R17nR1 s~ or X11 2
0-4 0-3
wherein Y30 and Y31are selected from
o~ ,o o~o ~ o ~ ~
Tl.N.SN.Hu'~ ' T~ ~N uH TA~~
N Ti N
T2 T3 T3 , T3 , T3
OII T4
T1. l~ '1-~ T o~N~A
T1~O~O
T2 T3
T T u ' 1 T3 U or
2 3
where u is a number 0-6;
X is selected from 0, NR15, NC(O)R16, S, S(O) and SO2;
G is NH or O; and
R15, R16, R17, R18, R19, T1, T2, T3 and T4 can be the same or different, each
being
independently selected from the group consisting of H, alkyl, heteroalkyl,
alkenyl,
heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,
arylalkyl,
heteroaryl, and heteroarylalkyl, or alternately, R17 and R18 are connected to
each
other to form a three to eight-membered cycloalkyl or heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,
sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto,
carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,
alkylureido, arylureido, halo, cyano, and nitro.
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In another embodiment, the inhibitor is a compound of Formula XII:
M A
\ L E / O
N R'
N
Y H O R2 O
O
O R3
Formula XII
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR9R10, or CHR9R'0, wherein R8, R9 and Rl0 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyl-, arylalkyl-,
and heteroarylalkyl;
A and M can be the same or different, each being independently selected from
R,
OR, NHR, NRR', SR, SO2R, and halo; or A and M are connected to each other such
that the moiety:
M A
LE/
shown above in Formula I forms either a three, four, six, seven or eight-
membered
cycloalkyl, a four to eight-membered heterocyclyi, a six to ten-membered aryl,
or a
five to ten-membered heteroaryl;
E is C(H) or C(R);
L is C(H), C(R), CH2C(R), or C(R)CH2;
R, R', R2, and R3 can be the same or different, each being independently
selected
from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,
heteroalkyl-,
heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-,
aryl-alkyl-, and
heteroaryl-alkyl-; or alternately R and R' in NRR' are connected to each other
such
that NRR' forms a four to eight-membered heterocyclyl;
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and Y is selected from the following moieties:
R16 0 R16 0 R16
R1151G/~/\G- ~s R15~G~G-~s R1~G~oG_~
R17 R18 R17 R18 R17 R18
0 R16
or R15NJ~O_~_KG_j
R19 R17 R18
wherein G is NH or 0; and R15, R16, R17, R18, and R19 can be the same or
different,
each being independently selected from the group consisting of H, alkyl,
heteroalkyl,
alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl,
aryl, arylalkyl,
heteroaryl, and heteroarylalkyl, or alternately, (i) either R15 and R16 are
connected to
each other to form a four to eight-membered cyclic structure, or R15 and R19
are
connected to each other to form a four to eight-membered cyclic structure, and
(ii)
likewise, independently, R17 and R18 are connected to each other to form a
three to
eight-membered cycloalkyl or heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,
sulfonamido, alkylsulfonamido, aryisulfonamido, alkyl, aryl, heteroaryl, keto,
carboxy,
carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,
arylureido, halo, cyano, and nitro.
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In another embodiment, the inhibitor is a compound of Formula XIII:
M A
\ /
L E O
N R'
N
Y H O R2 O
O O 3
Formula XIII
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR R10, or CHR9R'0, wherein R8, R9 and R'0 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyl-, arylalkyl-,
and heteroarylalkyl;
A and M can be the same or different, each being independently selected from
R,
OR, NHR, NRR', SR, SO2R, and halo; or A and M are connected to each other (in
other words, A-E-L-M taken together) such that the moiety:
M\ / A
L-E
shown above in Formula I forms either a three, four, six, seven or eight-
membered
cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl,
or a
five to ten-membered heteroaryl;
E is C(H) or C(R);
L is C(H), C(R), CH2C(R), or C(R)CH2;
R, R', R2, and R3 can be the same or different, each being independently
selected
from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,
heteroalkyl-,
heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-,
aryl-alkyl-, and
heteroaryl-alkyl-; or alternately R and R' in NRR' are connected to each other
such
that NRR' forms a four to eight-membered heterocyclyl;
and Y is selected from the following moieties:
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R19 0 R19 oR19
R1~N~G,/ R15~N~G ~ R1~O~N~G,/
R17 R18 I R17 R18 I R17(~18
R16 ' R20 R20
O R19
15 0 0 R19 Q0 R19 ~ G
R~ .N G 155'N O R15 N~R17
N ~ R ~~ 18 20~ R18 R16 R20 R17 R18 , R20 R17 R R 0
O R19 O~ ~O R19
R15 __ N"ILI N G 15' S G
R N~
~ ~18 17 18
R16 R16 R17 R , R20 0 R R
00
R19 00 R19
R15~S~NGR1 ~NiSN
R17R18 or
R2o R16 ~ R17 R18
R20 O
wherein G is NH or 0, and R15, R1s, R17 , R18, R19 and R20 can be the same or
different, each being independently selected from the group consisting of H,
C1-C1o
alkyl, C1-C10 heteroalkyl, C2-C10 alkenyl, C2-C10 heteroalkenyl, C2-C10
alkynyl, C2-C1o
heteroalkynyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, aryl, heteroaryl, or
alternately: (i)
either R15 and R16 can be connected to each other to form a four to eight-
membered
cycloalkyl or heterocyclyl, or R15 and R19 are connected to each other to form
a five
to eight-membered cycloalkyl or heterocyclyl, or R15 and R20 are connected to
each
other to form a five to eight-membered cycloalkyl or heterocyclyl, and (ii)
likewise,
independently, R17 and R18 are connected to each other to form a three to
eight-
membered cycloalkyl or heterocyclyl,
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,
sulfonamido, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy,
carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido,
halo,
cyano, and nitro.
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In another embodiment, the inhibitor is a compound of Formula XIV:
M A
O
L
\ /
N R'
N IYY y
Y N 0 R2 O
O
O 3
Formula XIV
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR9R10, or CHR9R'0, wherein R8, R9 and Rl0 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
alkenyl-, alkynyl-, aryi-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyi-, arylalkyl-,
and heteroarylalkyl;
A and M can be the same or different, each being independently selected from
R,
OR, NHR, NRR', SR, SO2R, and halo;
or A and M are connected to each other such that the moiety:
M\ E/A
L
shown above in Formula I forms either a three, four, six, seven or eight-
membered
cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl,
or a
five to ten-membered heteroaryl;
E is C(H) or C(R);
L is C(H), C(R), CH2C(R), or C(R)CH2;
R, R', R2, and R3 can be the same or different, each being independently
selected
from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl,
alkynyl,
heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl,
or alternately R and R' in NRR' are connected to each other such that NRR'
forms a
four to eight-membered heterocyclyi;
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and Y is selected from the following moieties:
R15S~ R15S ~
x G R15S~
R17J'R18 O' R17R18 0 ~O R17R1s
R16 R16 R16
R15S~Gj , R1:S~GR1~S~G~j
R17 R18 0 R17 R18 ~Q R17 R18
R1 R16 017 1 s ' 15 R16 R17 18 R16 R1 R1 s
R R1\)~'~
R~ G~
S~G-~ S G-~ ~~S~O -
O
)1-2 )1-2 R16
, G-~s N, G ~ ~ s and ~N G
~ 5 ~ s ~ ' R15 i S ~ R I S~~ s~
R
R17 R18 O R17 R18 O R17 R wherein G is NH or 0; and R15, R16, R17 and R18 can
be the same or different, each
being independently selected from the group consisting of H, alkyl,
heteroalkyl,
alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyi,
aryl, and
heteroaryl, or alternately, (i) R15 and R16 are connected to each other to
form a four
to eight-membered cyclic structure, and (ii) likewise, independently R17 and
R18 are
connected to each other to form a three to eight-membered cycloalkyl or
heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,
sulfonamido, alkylsulfonamido, aryisulfonamido, alkyl, aryl, heteroaryl, keto,
carboxy,
carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido,
arylureido, halo, cyano, and nitro.
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In another embodiment, the inhibitor is a compound of Formula XV:
E J
O
N R'
R5 R4 N
G N O 2 0
Y Z O
O R3
Formula XV
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR9R10, or CHR9R" , wherein R8, R9 and R'0 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, cycloalkyl-, arylalkyl-, and
heteroarylalkyl;
E and J can be the same or different, each being independently selected from
the
group consisting of R, OR, NHR, NRR7, SR, halo, and S(02)R, or E and J can be
directly connected to each other to form either a three to eight-membered
cycloalkyl,
or a three to eight-membered heterocyclyl moiety;
Z is N(H), N(R), or 0, with the proviso that when Z is 0, G is present or
absent and if
G is present with Z being 0, then G is C(=0);
G maybe present or absent, and if G is present, G is C(=O) or S(02), and when
G is
absent, Z is directly connected to Y;
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Y is selected from the group consisting of:
R
R I ~N N~
N
N-N N-N N-NH , /~N '?zt H H
0 0
X HNA X
NH >j~-NH /-NH
p O O O
X=O,S, NH X=O,S, NH X=O,S, NH
R
HNrNN ~~
NN ~ N-NR , HNN_N , RNN=N
N 'N~ HN'N_ \N~ , \N~ ,
HN I x N
N 1=0-4 N N X= O, S, NH R
~ N
,
()~ N N ' N ,
N ~ N R N N N OR
p ~ O ~ (/ ~ O ~
/ '/
, X , xI~'
R e X=O,S,NH X=O,S,NH
~
ON O HN ~0
\
e :i~~ , I e I e /
~ O
N
R ~ H N N NH
N
0
N N
. ~ I ~~ , <I
~ ~
~ ~ ~ , ~ =
S X x
s
X=O,S,NH
-I ~ A~ J .iS ~
F3C , \,A~~ q\~ I / ~ and O q ~
A=O,NH
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R, R7, R2, R3, R4 and R5 can be the same or different, each being
independently
selected from the group consisting of H, alkyl-, alkenyl-, alkynyl-,
cycloalkyl-,
heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-,
(heterocyciyl)alkyl-,
aryl-alkyl-, and heteroaryl-alkyl-, wherein each of said heteroalkyl,
heteroaryl and
heterocyclyl independently has one to six oxygen, nitrogen, sulfur, or
phosphorus
atoms;
wherein each of said alkyl, heteroalkyl, alkenyl, alkynyl, aryl, heteroaryl,
cycloalkyl
and heterocyclyl moieties can be unsubstituted or optionally independently
substituted with one or more moieties selected from the group consisting of
alkyl,
alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, halo, hydroxy,
thio, alkoxy,
aryloxy, alkyithio, arylthio, amino, amido, ester, carboxylic acid, carbamate,
urea,
ketone, aldehyde, cyano, nitro, sulfonamido, sulfoxide, sulfone, sulfonyl
urea,
hydrazide, and hydroxamate.
In another embodiment, the inhibitor is a compound of Formula XVI:
R24 R23
R22
R25
N R'
C 'y O
N 1Y
Y H 0 2 O
O
0 R3
Formula XVI
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR9R10, or CHR9R'0, wherein R8, R9 and R10 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyl-, arylalkyl-,
and heteroarylalkyl, or alternately R9 and R"' in NR9R'0 are connected to each
other
such that NR9R10 forms a four to eight-membered heterocyclyl, and likewise
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independently alternately R9 and R10 in CHR9R10 are connected to each other
such
that CHR9R'0 forms a four to eight-membered cycloalkyl;
R 2 and R3 can be the same or different, each being independently selected
from the
group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,
heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl;
Y is selected from the following moieties:
R16 016 R17 R16 1,5 RO/~ ~~G\ R118
S 1
R~R18 R1:~G-
O R17 R18 R15 S G-~ O~ G
0 O R17 R1s 11
0
R16 GMN
12 )1_2 R16 0
R15 Neg\ GR15 NBS G~s R15 NsS~GR15~G~~
G R17 R18 O p R17 R18 0 p R17 R18 R17 R18 R151s
R17 R
R16 0 O O O O G~~ R16
R15 R15N ~J~/G S.
15' N
R15
R es R15~G
R17 R18 R17 R18 ' R19 R17 R18 ~ R2o R17 R1s O R17 R18
R16 R15 R16 R15 R16 R16
0 R16
~
R15 G~~ O1~1W7R18 G~,s' , R19~NIIlJ~/G_j R1~O~G_j, R15 O~G_/
R19 OM N R17 R18 O R17 R18 R17 R18 R17 R18
R16 0 R16
0 R1~ J~ R16 G R1N 0 O R1s G'~ R1~N~G~' R15~N/1 G,~
O O~ 1 ~ I 19 R17 R R1~7 R18
R17 R18 R19 R17 R18 R R20
1s R16
O R16 ~~ ~0 R16 O~SO R
R15O~N G~~,s 1 R 15 ~N1S"N R15/ i~G1s
R17 R R19 ~ ' R15 R~N 1s
~1s
18 / R2o I R17 R R20 R17 R 19~ O R17 R
R20
p 16 O G R16 O G
R15S\N R16
G~ R1\N~NG i R1\N~S"N~G18 ~N G-1
17 R18 R19 2!~O R17 R R15 R20R17 R18
R19AO R17 R18 R19 R20 R R
O
O)~N
R15.NR19 RzoR17 R18
wherein G is NH or O; and R15, R16, R17, R18, R19, R20, R21, R22, R23, R24 and
R25 can be the same or different, each being independently selected from the
group
consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,
heteroalkynyl,
cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or
alternately
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(i) R17 and R'$ are independently connected to each other to form a three to
eight-
membered cycloalkyl or heterocyclyl; (ii) likewise independently R15 and R19
are
connected to each other to form a four to eight-membered heterocyclyl; (iii)
likewise
independently R15 and R'6 are connected to each other to form a four to eight-
membered heterocyclyl; (iv) likewise independently R15 and R20 are connected
to
each other to form a four to eight-membered heterocyclyi; (v) likewise
independently
R22 and R23 are connected to each other to form a three to eight-membered
cycloalkyl or a four to eight-membered heterocyclyl; and (vi) likewise
independently
R24 and R25 are connected to each other to form a three to eight-membered
cycloalkyl or a four to eight-membered heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, aryisulfonyl,
sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto,
carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,
alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the inhibitor is a compound of Formula XVII:
M A
\ L E/ O
N R'
N
Y H
0 R2 0
O
O R3
Formula XVII
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R' is H, OR8, NR9R'0, or CHR9R10, wherein R8, R9 and R10 can be the same or
different, each being independently selected from the group consisting of H,
alkyl-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyl-, arylalkyl-,
and heteroarylalkyl;
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A and M can be the same or different, each being independently selected from
R,
OR, NHR, NRR', SR, SO2R, and halo; or A and M are connected to each other such
that the moiety:
M A
\L-E/
sx
shown above in Formula I forms either a three, four, six, seven or eight-
membered
cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl,
or a
five to ten-membered heteroaryl;
E is C(H) or C(R);
L is C(H), C(R), CH2C(R), or C(R)CH2;
R, R', R2, and R3 can be the same or different, each being independently
selected
from the group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-,
heteroalkyl-,
heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)aikyl-,
aryl-alkyl-, and
heteroaryl-alkyl-; or alternately R and R' in NRR' are connected to each other
such
that NRR' forms a four to eight-membered heterocyclyl;
Y is selected from the following moieties:
Y30 Y30 Y30
R19R19 R19 G~~
R X
171~R1s or 1 2
-4 0-3
wherein Y30 is selected from
0 0 0, s~0
T~. ):~ (~~s , ( SN N 0-2 u
T2 T3 T, T3
0 0
Nu
Ti
T3
where u is a number 0-1;
X is selected from 0, NR15, NC(O)R16, S, S(O) and SO2;
G is NH or O; and
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R15, R16, R17 , R18 , R19, Ti, T2, and T3 can be the same or different, each
being
independently selected from the group consisting of H, alkyl, heteroalkyl,
alkenyl,
heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl,
arylalkyl,
heteroaryl, and heteroarylalkyl, or alternately, R 17 and R 18 are connected
to each
other to form a three to eight-membered cycloalkyl or heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,
sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto,
carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,
alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the inhibitor is a compound of Formula XVIII:
M A
L E O
H (02)
N Y I N~SRs
H N I
Y N O R2 R9
O
0 R3
Formula XVIII
or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
R8 is selected from the group consisting of alkyl-, aryl-, heteroalkyl-,
heteroaryl-,
cycloalkyl-, heterocyclyl-, arylalkyl-, heteroarylalkyl-, and
heterocyclylalkyl;
R9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl
and
cycloalkyl;
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A and M can be the same or different, each being independently selected from
R,
OR, N(H)R, N(RR'), SR, S(02)R, and halo; or A and M are connected to each
other
(in other words, A-E-L-M taken together) such that the moiety:
M\ OA
L-E
-VL-L, sx
shown above in Formula I forms either a three, four, five, six, seven or eight-
membered cycloalkyl, a four to eight-membered heterocyclyl, a six to ten-
membered
aryl, or a five to ten-membered heteroaryl;
E is C(H) or C(R);
L is C(H), C(R), CH2C(R), or C(R)CH2;
R and R' can be the same or different, each being independently selected from
the
group consisting of H, alkyl-, alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-,
heterocyclyi-,
aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryi-alkyl-, and
heteroaryl-
alkyl-; or alternately R and R' in N(RR') are connected to each other such
that
N(RR') forms a four to eight-membered heterocyclyi;
R2 and R3 can be the same or different, each being independently selected from
the
group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,
heteroalkynyl, cycloalkyl, spiro-linked cycloalkyl, heterocyclyl, aryl,
arylalkyl,
heteroaryl, and heteroarylalkyl;
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Y is selected from the following moieties:
15 R16 R16 R17 R16 R17 R16
R ~S~G-~,,s ~R18 R1~ '\/~R1a R1: G~
O'''~ 18 R1 G- s" G-~
O R17 R n ~ O 's O 0 R17 R18
0
-2 )12 R16 p ~.OH
R15N;~S\ GR15'N;S G-~' R15'NiS\'~\ G~~s R15~G R16 Iv G,
O O R17 R1a O p R17 R18 O O R17R18 R17 R18 R15' ~
R17 R18
R16 0 p p
6
R G\~ R,5p ~
N G~ O'' AO R118
15 R17 R18 R17 R18 R19 R17 R18 R15/
R,5 2o Rt7 R'~ ' R15X'~l ~~
R 7 R
R16 R15 R16 R15 R16 R16 0 R16
R15 I G-~ p~G_/ R19'N~G,/ R1:O~G,/
O
R19pMN R17 R18 p R17 R18 0 R17 R18 R17 R18 R15
R17 R18
R16
0 R16
0 0 R16 R1:N~0 0 R16 R1R15~N~G~~s
R150~
R17 R18 R19 R17J'R1a R1s R17 R18 120 R17 R18
R
R16
O R16 0 0 R16 O\' 0 R16
R1\R\N S.N~R15~S\ IG'~ ' R1sN G~
J R17 R18 R9 Rfo R17 R18 Rzo R17 R18 R1s~0 R17 R1s
R2o
\ ,,0 R16 0 R16 G' O~ A R16 O
R15. S~N~G F''15,N1~ 35 R1~N~SN~G
~ R17 R1a 19 20 R17 R18 R19 ~ R17 R18 15 G
R19 p R R R20 0 R R20R17 R18
O
or ):~N
0
R15.NR19 R20R17 R18
wherein G is NH or 0; and R15, R16, R17, R'$, R19 and R20 can be the same or
different, each being independently selected from the group consisting of H,
alkyl,
heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,
heterocyclyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R17 and
R18 are
independently connected to each other to form a three to eight-membered
cycloalkyl
or heterocyclyl; (ii) likewise independently R15 and R19 are connected to each
other
to form a four to eight-membered heterocyclyi; (iii) likewise independently
R1*5 and
R16 are connected to each other to form a four to eight-membered heterocyclyl;
and
(iv) likewise independently R15 and R20 are connected to each other to form a
four to
eight-membered heterocyclyl;
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wherein each of said alkyl, aryl, heteroaryl, cycloalkyl, spiro-linked
cycloalkyl, and
heterocyclyl can be unsubstituted or optionally independently substituted with
one or
more moieties selected from the group consisting of hydroxy, alkoxy, aryloxy,
thio,
alkylthio, arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl,
arylsulfonyl,
sulfonamido, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonamido,
aryisulfonamido, keto,
carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,
alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the inhibitor is a compound of Formula XIX:
0
~_z
0
3Y 0
N R'
N
I
Y H 0 R2 O
O
O R3
Formula XIX
wherein:
Z is selected from the group consisting of a heterocyclyl moiety,
N(H)(alkyl), -N(alkyl)2, -N(H)(cycloalkyl), -N(cycloalkyl)2, -N(H)(aryl, -
N(aryl)2, -
N(H)(heterocyclyl), -N(heterocyclyl)2, -N(H)(heteroaryl), and -N(heteroaryl)2;
R' is H, OR8, NR9R10, or CHR9R'0, wherein R8, R9 and R'0 can be the same
or different, each being independently selected from the group consisting of
H, alkyl-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-,
heterocyclyl-, arylalkyl-,
and heteroarylalkyl, or alternately R9 and R10 in NR9R'0 are connected to each
other
such that NR9R10 forms a four to eight-membered heterocyclyl, and likewise
independently alternately R9 and R10 in CHR9R'0 are connected to each other
such
that CHR9R10 forms a four to eight-membered cycloalkyl;
R2 and R3 can be the same or different, each being independently selected from
the
group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl,
heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and
heteroarylalkyl;
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Y is selected from the following moieties:
R16 R16 R17 R16
15 R16 R1718 R151 1 ~R18 rj1\S G
15 R j
O SO ~?~R a\~ R00 G-~ ~ 17 R18
R R
0
) 12 )1 2 R16 0 R1s O6
N
R15 G~,s NBSS~G R15-
15 N,iS\ G~~s N;sS R15
F'
R o\O 17 R18 o O 17 R18 0O R17 R18 R17R18 R15XG,
R R R17 R18
R16 O O O O O R16
15 R15 G O R15I ~/G~
R15' R ~O G~ N~ R15-.N~G ' R17R1a R17 R18 R19 R17 R18 R2o R17 R1a R17nR18
R16 R15 R16 R15 R16 R16 0 R16
~ I ~ , R ~G~/ R.O~G~~. R15~O~G~~
R15 C O~G-19' N 15
R19 O,N N R17 R18 Q R17 R18 0 R17 R18 R17 R1s R17 R18
R16 0 R16
0 15
G R1~NO R16
~G,/ R \N G R15~N
0 R1~ J~ R16
O O~ 1a R1s R17 R1a I 19 R17 R18 I 2o R17R18
R17
R16 0 O R16 R16
R15 O R16 R O'g~ G~ /S N G~ , ~N
N N ~ R15 \ I~
R15 8 R18 R18
17 19~O R17
R17 R 18 R19 Rzo R17 R R~O R R
I
R2o
O
p O R16 R1 O R16 O~,O R 16 O
G~ ~N~G '~ R1NiS"
N~G 18
L G-1
R 15 R19~ R2o R17 R18, R19 /~ R17 R R15 RaoR 17 18
O R17 R1b R19 R 2 0
O
O)::~
~ N~G _/
R15NR19 R20R17 R18
wherein G is NH or 0; and R15, R16, R17, R18, R19, R20 and R21 can be the same
or
different, each being independently selected from the group consisting of H,
alkyl,
heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl,
heterocyclyl,
aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately (i) R17 and
R18 are
independently connected to each other to form a three to eight-membered
cycloalkyl
or heterocyclyl; (ii) likewise independently R15 and R19 are connected to each
other
to form a four to eight-membered heterocyclyl; (iii) likewise independently
R15 and
R16 are connected to each other to form a four to eight-membered heterocyclyl;
and
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(iv) likewise independently R15 and R20 are connected to each other to form a
four to
eight-membered heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl can
be
unsubstituted or optionally independently substituted with one or more
moieties
selected from the group consisting of hydroxy, alkoxy, aryloxy, thio,
alkylthio,
arylthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,
sulfonamido, alkyl, aryl, heteroaryl, alkylsulfonamido, aryisulfonamido, keto,
carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy,
alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the inhibitor is a compound of Formula XX
P6 P5 P4 P3 P2 P1
,R2
H 0 R5 Y 0 R3
N N NHN R~
B H 0 R4 N
~O
R6 H O
a b
Formula (XX)
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein: a is
0 or 1; b
is 0 or 1; Y is H or CI-6 alkyl;
B is H, an acyl derivative of formula R7-C(O)- or a sulfonyl of formula R7-S02
wherein
R7 is (i) Ci-1o alkyl optionally substituted with carboxyl, C1-6 alkanoyloxy
or C1-6
alkoxy;
(ii) C3_7 cycloalkyl optionally substituted with carboxyl, (C1-6
alkoxy)carbonyl or
phenylmethoxycarbonyl;
(iii) C6 or Clo aryl or C7-16 aralkyl optionally substituted with C1-6 alkyl,
hydroxy, or
amino optionally substituted with C1-6 alkyl; or
(iv) Het optionally substituted with C1-6 alkyl, hydroxy, amino optionally
substituted
with Cl-6 alkyl, or amido optionally substituted with C1-6 alkyl;
R6, when present, is Cl-6 alkyl substituted with carboxyl;
R5, when present, is C1-6 alkyl optionally substituted with carboxyl;
R4 is Cl-lo alkyl, C3-7 cycloalkyl or C4-10 (alkylcycloalkyl);
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R3 is Cl_lQ alkyl, C3_7 cycloalkyl or C4_10 (alkylcycloalkyl);
R2 is CH2-R20, NH-R20, 0-R20 or S-R20, wherein R20 is a saturated or
unsaturated C3_7
cycloalkyl or C4_10 (alkyl cycloalkyl) being optionally mono-, di- or tri-
substituted with
R21, or R20 is a C6 or Clo aryl or C7_16 aralkyl optionally mono-, di- or tri-
substituted
with R21,
or R20 is Het or (lower alkyl)-Het optionally mono-, di- or tri- substituted
with R21,
wherein each R21 is independently Cl_6 alkyl; C1_6alkoxy; amino optionally
mono- or
di-substituted with C1_6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; amido
optionally
mono-substituted with CI_6 alkyl, C6 or Clo aryl, C7_16 aralkyl, Het or (lower
alkyl)-Het;
carboxyl; carboxy(lower alkyl); C6 or Clo aryl, C7.16 aralkyl or Het, said
aryl, aralkyl or
Het being optionally substituted with R22;
wherein R22 is CI_6alkyl; C1_6 alkoxy; amino optionally mono- or di-
substituted with
C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; carboxyl; amide or (lower
alkyl)amide;
R, is C1_6 alkyl or C2_6 alkenyl optionally substituted with halogen; and
W is hydroxy or a N-substituted amino.
In the above-shown structure of the compound of Formula XX, the terms P6, P5,
P4, P3, P2 and P1 denote the respective amino acid moieties as is
conventionally
known to those skilled in the art.
In another embodiment, the inhibitor is a compound of Formula XXI
.R2
B, NN
Y Ipl (CHz)1-2
O NOH
H 0
Formula (XXI)
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
B is H, a C6 or CIo aryl, C7_16 aralkyl; Het or (lower alkyl)- Het, all of
which optionally
substituted with C1_6 alkyl; C1.6 alkoxy; C1_6 alkanoyl; hydroxy;
hydroxyalkyl; halo;
haloalkyl; nitro; cyano; cyanoalkyl; amino optionally substituted with C1_6
alkyl; amido;
or (lower alkyl)amide;
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or B is an acyl derivative of formula R4-C(O)-; a carboxyl of formula R4-0-
C(O)-; an
amide of formula R4-N(R5)-C(O)-; a thioamide of formula R4-N(R5)-C(S)-; or a
sulfonyl of formula R4-S02 wherein
R4 is (i) Cl_lo alkyl optionally substituted with carboxyl, C1_6 alkanoyl,
hydroxy,
CT_6 alkoxy, amino optionally mono- or di-substituted with C1_6 alkyl, amido,
or (lower
alkyl) amide;
(ii) C3_7 cycloalkyl, C3_7 cycloalkoxy, or C4_10 alkylcycloalkyl, all
optionally
substituted with hydroxy, carboxyl, (C1_6 alkoxy)carbonyl, amino optionally
mono- or
di-substituted with C1_6 alkyl, amido, or (lower alkyl) amide;
(iii) amino optionally mono- or di-substituted with C1_6 alkyl; amido; or
(lower
alkyl)amide;
(iv) C6 or CIo aryl or C7_16 aralkyl, all optionally substituted with Cl_ 6
alkyl,
hydroxy, amido, (lower alkyl)amide, or amino optionally mono- or di-
substituted with
C1_6 alkyl; or
(v) Het or (lower alkyl)-Het, both optionally substituted with C1_6 alkyl,
hydroxy,
amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with
C1_6
alkyl;
R5 is H or Cl.6 alkyl;
with the proviso that when R4 is an amide or a thioamide, R4 is not (ii) a
cycloalkoxy;
Y is H or CI_6 alkyl;
R3 is Cl_$ alkyl, C3_7 cycloalkyl, or C4_10 alkylcycloalkyl, all optionally
substituted with
hydroxy, CI_6 alkoxy, C1_6 thioalkyl, amido, (lower alkyl)amido, C6 or Clo
aryl, or C7_16
aralkyl;
R2 is CH2-R20, NH-R20, O-R20 or S-R20, wherein R20 is a saturated or
unsaturated C3_7
cycloalkyl or C4_10 (alkylcycloalkyl), all of which being optionally mono-, di-
or tri-
substituted with R21, or R20 is a C6 or Clo aryl or C7_14 aralkyl, all
optionally mono-, di-
or tri-substituted with R21,
or R20 is Het or (lower alkyl)-Het, both optionally mono-, di- or tri-
substituted with
R21,
wherein each R21 is independently C1_6 alkyl; C1_6 alkoxy; lower thioalkyl;
sulfonyl; NO2; OH; SH; halo; haloalkyl; amino optionally mono- or di-
substituted with
CI_6 alkyl, C6 or Clo aryl, C7_14 aralkyl, Het or (lower alkyl)-Het; amido
optionally
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mono-substituted with CI_6 alkyl, C6 or Clo aryl, C7_14 aralkyl, Het or (lower
alkyl)-Het;
carboxyl; carboxy(lower alkyl); C6 or Clo aryl, C7_14 aralkyl or Het, said
aryl, aralkyl or
Het being optionally substituted with R22;
wherein R22 is C1_6 alkyl; C3_7 cycloalkyl; Cl_6 alkoxy; amino optionally mono-
or di-substituted with Cl_6 alkyl; sulfonyl; (lower alkyl)sulfonyl; NO2; OH;
SH; halo;
haloalkyl; carboxyl; amide; (lower alkyl)amide; or Het optionally substituted
with Cl_6
alkyl;
R1 is H; C1_6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, or C2_6 alkynyl, all
optionally
substituted with halogen.
In another embodiment, the inhibitor is a compound of Formula XXII
R21 ~ R22
I R2
/
0
O N N q
O R'
3
R .
R4 (XXII)
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein
W is CH or N,
R21 is H, halo, C1-6 alkyl, C3_6 cycloalkyl, C1_6 haloalkyl, Cl_6 alkoxy, C3_6
cycloalkoxy,
hydroxy, or N(R23)2 , wherein each R23 is independently H, C1_6 alkyl or C3-6
cycloalkyl;
R22 is H, halo, C1-6 alkyl, C3_6 cycloalkyl, C1_6 haloalkyl, C1_6 thioalkyl,
C1_6 alkoxy, C3-6
cycloalkoxy, C2_7 alkoxyalkyl, C3-6 cycloalkyl, C6 or 10 aryl or Het, wherein
Het is a five-,
six-, or seven-membered saturated or unsaturated heterocycle containing from
one
to four heteroatoms selected from nitrogen, oxygen and sulfur;
said cycloalkyl, aryl or Het being substituted with R24 , wherein R24 is H,
halo, Cl_6
alkyl, C3_6 cycloalkyl, C1_6 alkoxy, C3-6 cycloalkoxy, NO2 , N(R25)2 , NH-C(O)-
R25 or
NH-C(O)-NH-R25 , wherein each R25 is independently: H, C1_6 alkyl or C3_6
cycloalkyl;
or R24 is NH-C(O)-OR26 wherein R26 is CI_6 alkyl or C3_6 cycloalkyl;
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R3 is hydroxy, NH2 , or a group of formula -NH-R31 , wherein R31 is C6 or 10
aryl,
heteroaryl, -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 , wherein R32 is C1_6 alkyl
or C3_6
cycloalkyl;
D is a 5 to 10-atom saturated or unsaturated alkylene chain optionally
containing one
to three heteroatoms independently selected from: 0, S, or N-R41 , wherein R41
is H,
C1.6 alkyl, C3_6 cycloalkyl or -C(O)-R42, wherein R42 is C1_6 alkyl, C3_6
cycloalkyl or C6
or 1o aryl; R4 is H or from one to three substituents at any carbon atom of
said chain
D, said substituent independently selected from the group consisting of: C1_6
alkyl,
C1_6 haloalkyl, C1_6 alkoxy, hydroxy, halo, amino, oxo, thio and C 1-6
thioalkyl, and
A is an amide of formula -C(O)-NH-R 5, wherein R 5 is selected from the group
consisting of: C1_$ alkyl, C3_6 cycloalkyl, C6 or 10 aryl and C7_16 aralkyl;
or A is a carboxylic acid.
In another embodiment, the inhibitor is a compound of Formula XXIII
R6 O O R1
R9-N.R7N, Rs N'R ~'R ~'N,R2
R$ O n R4 O O (XXIII)
a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R is a bond or difluoromethylene;
R' is hydrogen, optionally substituted aliphatic group, optionally substituted
cyclic
group or optionally substituted aromatic group;
R2 and R9 are each independently optionally substituted aliphatic group,
optionally
substituted cyclic group or optionally substituted aromatic group;
R3, R5 and R7 are each independently:
optionally substituted (1, 1- or 1,2-)cycloalkylene; or
optionally substituted (1,1- or 1,2-) heterocyclyiene; or
methylene or ethylene), substituted with one substituent selected from the
group consisting of an optionally substituted aliphatic group, an optionally
substituted
cyclic group or an optionally substituted aromatic group, and wherein the
methylene
or ethylene is further optionally substituted with an aliphatic group
substituent; or;
R4, R 6, R8 and R10 are each independently hydrogen or optionally substituted
aliphatic group;
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is substituted monocyclic azaheterocyclyl or optionally substituted
multicyclic azaheterocyclyi, or optionally substituted multicyclic
azaheterocyclenyl
wherein the unsaturatation is in the ring distal to the ring bearing the R9-L-
(N(R$)-R7-
C(O)-)õN(R6)-R5-C(O)-N moiety and to which the -C(O)-N(R4)-R3-C(O)C(O)NR2R'
moiety is attached; L is -C(O)-, -OC(O)-, -NR10C(O)-, -S(0)2-, or - NR'OS(0)2-
; and n
is0or1,
provided
when is substituted jqN, then L is -OC(O)- and R9 is optionally
substituted aliphatic; or at least one of R3, R5 and R7 is ethylene,
substituted with one
substituent selected from the group consisting of an optionally substituted
aliphatic
group, an optionally substituted cyclic group or an optionally substituted
aromatic
group and wherein the ethylene is further optionally substituted with an
aliphatic
group substituent; or R4 is optionally substituted aliphatic.
In another embodiment, the inhibitor is a compound of Formula (XXIV)
M
T,K,V--~yq?AI N
O L (XXIV)
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
W is:
O O O O O R2 O O
)><.\,R2 OR2 ~N. 2 MN' R2
I)L.1.,R2 R -B.
/~R2 ;~CF2R2 ; F F R2 ; 0 ; 0 ; 0 F F R2 ~ R';
0
ii
-P-(O)mR2 -p-()mR2 0
2 0 0 2 0 NR2
or -S-R
(O)mR ; (0)mR ; S-R , -S-R ; 2
mis0or1;
each R' is hydroxy, alkoxy, or aryloxy, or each R' is an oxygen atom and
together with the boron, to which they are each bound, form a 5-7 membered
ring,
wherein the ring atoms are carbon, nitrogen, or oxygen;
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each R2 is independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl,
heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyl, or two
R2 groups,
which are bound to the same nitrogen atom, form together with that nitrogen
atom, a
5-7 membered monocyclic heterocyclic ring system; wherein any R 2 carbon atom
is
optionally substituted with J;
J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy,
heterocyclyl, heterocyclyloxy, heterocyclylalkyl, keto, hydroxy, amino,
alkylamino,
alkanoylamino, aroylamino, aralkanoylamino, carboxy, carboxyalkyl,
carboxamidoalkyl, halo, cyano, nitro, formyl, acyl, sulfonyl, or sulfonamido
and is
optionally substituted with 1-3 Jl groups;
Jl is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy,
keto,
hydroxy, amino, alkanoylamino, aroylamino, carboxy, carboxyalkyl,
carboxamidoaikyl, halo, cyano, nitro, formyl, sulfonyl, or sulfonamido;
L is alkyl, alkenyl, or alkynyl, wherein any hydrogen is optionally
substituted
with halogen, and wherein any hydrogen or halogen atom bound to any terminal
carbon atom is optionally substituted with sulfhydryl or hydroxy;
A' is a bond;
R4 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl,
heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally
substituted with 1-
3 J groups;
R5 and R6 are independently hydrogen, alkyl, alkenyl, aryl, aralkyl,
aralkenyl,
cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl,
heteroaryl, or
heteroaralkyl, and is optionally substituted with 1-3 J groups;
X is a bond, -C(H)(R7)-, -0-, - S-, or -N(R8)-;
R7 is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl,
heterocyclylalkyl,
heteroaryl, or heteroaralkyl, and is optionally substititued with 1-3 J
groups;
R 8 is hydrogen alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl,
heteroaralkyl, aralkanoyl, heterocyclanoyl, heteroaralkanoyl, -C(O)R14, -
S02R14, or
carboxamido, and is optionally substititued with 1-3 J groups; or R 8 and Z,
together
with the atoms to which they are bound, form a nitrogen containing mono- or
bicyclic
ring system optionally substituted with 1-3 J groups;
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R14 is alkyl, aryl, aralkyl, heterocyclyl, heterocyclyalkyl, heteroaryl, or
heteroaralkyl;
Y is a bond, -CH2-, -C(O)-, -C(O)C(O)-, - S(O)-, -S(0)2-, or -S(O)(NR7)-,
wherein R7 is as defined above;
Z is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl,
heterocyclylalkyl, heteroaryl, heteroaralkyl, -OR2, or -N(R2)2, wherein any
carbon
atom is optionally substituted with J, wherein R2 is as defined above;
A2 is a bond or
0
-NH ?
R9
R9 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyi, heterocyclylalkyl,
heteroaryl,
heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally
substituted with 1-
3 J groups;
M is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl,
or heteroaralkyl, optionally substituted by 1-3 J groups, wherein any alkyl
carbon
atom may be replaced by a heteroatom;
V is a bond, -CH2-, -C(H)(R")-, -0-, -S-, or -N(Rll)-;
R' 1 is hydrogen or C1_3 alkyl;
K is a bond, -0-, -S-, -C(O)-, -S(O)-, -S(0)2-, or -S(O)(NR")-, wherein R" is
as
defined above;
T is -R12, -alkyl-R12, -alkenyl-R12, - alkynyl-R12, -OR12, -N(R12)2, -C(O)R12,
-
C(=NOaIkyl)R12, or
R15 H
K, N~R16 H o Rlo ,
R12 is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylidenyl,
or
heterocycloalkylidenyl, and is optionally substituted with 1-3 J groups, or a
first R12
and a second R12, together with the nitrogen to which they are bound, form a
mono-
or bicyclic ring system optionally substituted by 1-3 J groups;
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R10 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl,
heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally
substituted with 1-
3 hydrogens J groups;
R15 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl,
heteroaryl,
heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and is optionally
substituted with 1-
3 J groups; and
R16 is hydrogen, aikyl, aryl, heteroaryl, cycloalkyl, or heterocyclyl.
In another embodiment, the inhibitor is a compound of Formula XXV
H 0 R7 R6 0 R4 R3 0 R'
R9~H~N~H~N~H
R$ O R5 O R2 (XXV)
or a pharmaceutically acceptable salt, solvate or ester thereof;
wherein
E represents CHO or B(OH)2;
R' represents lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower
alkylthio-
lower alkyl, aryl-lower alkylthio-lower alkyl, aryl-lower alkyl,
heteroaryllower alkyl,
lower alkenyl or lower alkynyl;
R2 represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl, aryl-
lower
alkyl, aminocarbonyl-lower alkyl or lower cycloalkyl-lower alkyl; and
R3 represents hydrogen or lower alkyl;
or R2 and R3 together represent di- or trimethylene optionally substituted by
hydroxy;
R4 represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-lower alkyl,
carboxy-lower alkyl, aryllower alkyl, lower alkylthio-lower alkyl, cyano-lower
alkylthio-
lower alkyl, aryl-lower alkylthio-lower alkyl, lower alkenyl, aryl or lower
cycloalkyl;
R5 represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl,
aryl-
lower alkyl, aryl-lower alkylthio-Iower alkyl, cyano-lower alkylthio-lower
alkyl or lower
cycloalkyl;
R6 represents hydrogen or lower alkyl;
R7 represent lower alkyl, hydroxydower alkyl, carboxylower alkyl, aryl-iower
alkyl, lower cycloalkyl-lower alkyl or lower cycloalkyl;
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R$ represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl or aryl-
lower
alkyl; and
R9 represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl,
lower alkylsulphonyl, aryisulphonyl, lower alkoxycarbonyl or aryl-lower
alkoxycarbonyl.
In another embodiment, the inhibitor is a compound of Formula XXVI
P6 P5 P4 P3 P2 P1
O R5 Y O R3
H
N NY-1- N-L-TrW.N.Q -N) B H O R4 H O H
R6
a b
(XXV I )
or a pharmaceutically acceptable salt, solvate or ester thereof; wherein
B is an acyl derivative of formula RIj-C(O)- wherein Ril is CI-10 alkyl
optionally substituted with carboxyl; or RI, is C6 or CIo aryl or C7_16
aralkyl optionally
substituted with a CI_6 alkyl;
ais0or1;
R6, when present, is carboxy(lower)alkyl;
bis0or1;
R5, when present, is CI_6 alkyl, or carboxy(lower)alkyl;
Y is H or C1_6 alkyl;
R4 is CI_1o alkyl; C3_10 cycloalkyl;
R3 is C1-10 alkyl; C3_1o cycloalkyl;
W is a group of formula:
O
-N
R2
wherein R2 is CI_10 alkyl or C3_7 cycloalkyl optionally substituted with
carboxyl;
C6 or Clo aryl; or C7_16 aralkyl; or
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W is a group of formula:
O
\Y'
R2
wherein X is CH or N; and
R2' is C3_4 alkylene that joins X to form a 5- or 6-membered ring, said ring
optionally substituted with OH; SH; NH2; carboxyl; R12; OR12, SR12, NHR12 or
NR12R12' wherein R12 and R12' are independently:
cyclic C3_16 alkyl or acyclic C1_16 alkyl or cyclic C3_16 alkenyl or acyclic
C2_16
alkenyl, said alkyl or alkenyl optionally substituted with NH2, OH, SH, halo,
or
carboxyl; said alkyl or alkenyl optionally containing at least one heteroatom
selected
independently from the group consisting of: 0, S, and N; or
R12 and R12' are independently C6 or C10 aryl or C7_16 aralkyl optionally
substituted with C1_6 alkyl, NH2, OH, SH, halo, carboxyl or
carboxy(Iower)alkyl; said
aryl or aralkyl optionally containing at least one heteroatom selected
independently
from the group consisting of: 0, S, and N;
said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with
a
second 5-, 6-, or 7-membered ring to form a cyclic system or heterocycle, said
second ring being optionally substituted with NH2. OH, SH, halo, carboxyl or
carboxy(lower)alkyl; C6 or C10 aryl, or heterocycle; said second ring
optionally
containing at least one heteroatom selected independently from the group
consisting
of: 0, S, and N;
Q is a group of the formula:
R1
Z , R1s
i "
x
wherein Z is CH or N;
XisOorS;
R1 is H, C1_6 alkyl or C1_6 alkenyl both optionally substituted with thio or
halo;
and
when Z is CH, then R13 is H; CF3; CF2CF3; CH2-R14; CH(F)-R14; CF2-R14;
NR14R14'; S-R14; or CO-NH-R14 wherein R14 and R14' are independently hydrogen,
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cyclic C3_10 alkyl or acyclic C1_10 alkyl or cyclic C3_10 alkenyl or acyclic
C2_10 alkenyl,
said alkyl or alkenyl optionally substituted with NH2, OH, SH, halo or
carboxyl; said
alkyl or alkenyl optionally containing at least one heteroatom selected
independently
from the group consisting of: 0, S, and N; or
R14 and R14' are independently C6 or C10 aryl or C7_16 aralkyl optionally
substituted with C1_6 alkyl, NH2, OH, SH, halo, carboxyl or
carboxy(lower)alkyl or
substituted with a further C3_7 cycloalkyl, C6 or C10 aryl, or heterocycle;
said aryl or
aralkyl optionally containing at least one heteroatom selected independently
from the
group consisting of: 0, S, and N;
said cyclic alkyl, cyclic alkenyl, aryl or aralkyl being optionally fused with
a
second 5-, 6-, or 7-membered ring to form a cyclic system or heterocycle, said
second ring being optionally substituted with NH2, OH, SH, halo, carboxyl or
carboxy(lower)alkyl or substituted with a further C3_7 cycloalkyl, C6 or C10
aryl, or
heterocycle; said second ring optionally containing at least one heteroatom
selected
independently from the group consisting of: 0, S, and N;
or R14 and R14' are independently C1_4 alkyl which when joined together with N
form a 3 to 6-membered nitrogen-containing ring which is optionally fused with
a
further C3_7 cycloalkyl, C6 or C10 aryl or heterocycle;
with the proviso that when Z is CH, then R13 is not an a-amino acid or an
ester
thereof;
when Z is N, then R13 is H; carboxy; C1_6 alkyl optionally substituted with
carboxy; CH2-R14; CHR14R14'; CH(F)-R14; O-R14; NR14R14' or S-R14 wherein R14
and
R14' are as defined above; or
Q is a phosphonate group of the formula:
R1
R15
oR16
wherein R15 and R16 are independently C6.20 aryloxy; and R1 is as defined
above.
In the above-shown structure of the compound of Formula XXVI, the terms
P6, P5, P4, P3, P2 and P1 denote the respective amino acid moieties as is
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conventionally known to those skilled in the art. Thus, the actual structure
of the
compound of Formula XXVI is:
R5 i O R3
H O W-" Q
B H H N
R6 a O b R4 O
In another embodiment, the compound is selected from the group consisting
of:
"A'ZOF~ HgXCF6
o
O
K_) N Hp Q-13 G-i
~' = ~I ~/ o 0
N O a-s N ~N CFt
N
N~ O ' O
~ F1C % O
S
o~~~ 0 0/ YOCF~
ot at
H3c~Cit
7
s O Q~JLN
~
O
O NFI
N
O O 00 N N O QY N CF~
(1Y N
H
H3PX C=
\CF6
cFb "V-' cFt d
CH3 _ ~~~
H,O O n O ~ o
u \ / ~O O O
,-z
N ,' (~,N
O O O H3~ ~ N~ O O F~F.I '1
N
H~l I ~ ~ ~ o ~ ( o
Qt
cFb 0 F~
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~~CF6 7 qc
Y CH~
Yy
N
~ Z~LL p O N li
~
C~N-,-
O O N O O
O ~
~N N
N
~
/~
0 a-I Ft3c cvb
.CHa
OII ~
O N ~
N J ,N
N v ~'f(
~~ N~NNN O
O O "lO
O (~,N
N O-I~ ~
w N ~ 9 H O
O 0
O
/
CF6
FL,C\ CH~
o 'ICY
O
~~ = IIN p {3 W N CFL
O ~ O
~ Yy O ~ ~/~O O O ~
N O.b V~ IN ~ N
~ A y
H O!~ ~00 0
N N
s ~ ~ N
O/ O-~a O
~ ~
O
CF~ IN CH3 1 ''~6
O O
N
Qy,-)y
q~(l+~ N ~ o o
"'-
~N ~5 ~-N 0
p p ~ ~
F AO
H~=~ N ~
H3 N N
~o Q H
p dk~
~ i' d
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-67-
F~c c[t
clt o
0 N, 7
~ /N
NHP ~/~ O q{3 '~ ~
1 QY
N-b
~
O O CO O
N O N 0 CFb
H
~N O
~ O N
N qc clt o ~
~
H,
~ C C
i d\ I\
N 0 Q ; ~
~ N~L N,
1 Qy
N ' O 0 O 0-~oo 0 0
N
O CH3
Na ~C
qc
Fbo
a-~ 0
CF6
00 O
N
~ ~
O I O
N rf 1II(
~~~ C o 0 Hs~~~
~ '
\ ~0 0 O FbC ~O N
o~~~ ~ ,~~
~C \
~ ~
CF6
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-66-
Gt
IN a-~
C" F! ~
N ~~-a*4
~~~oy
o
o o ~ ; ~
~
R,CF~ o
o 0
N ~
%N' ~
~ '''' q ~ H N qN~=
\ NH
0 Clb
~
(=v' N,cFt
O O O 0
o H
IN CF~ H
~ 13 Ir
0 0
'43
o
Cit 0
o o RI -b
0
0 0 0
0 o H'0 Q-t 0 CF~
N ~ oo CF6
o I i N-'2
o 0 \
Q o 0 0
~ Nct o
o I
~ FbQl( O a CH3
~q-i cFb F' ,crkcF~ ~
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-69-
"~~,a~ ~at
</ ~1 I N nu ~C o
~a''~~f ~~' ~
~O I'O O 1-I~C O = O
O
~ .-~/ \ I
~ O O p
o q/ n1_~/ \~'
CF6
I-5 N ~j
Ilo
4C CF6
~~
O k
a ~ O \a~ N-6
O O
F~ ry 11 O
N CF~ O O
O O
N
~J~
FI~C{
~
O
H3C CF6 ~
o ~ ltc cFb CFL
N p
QY/N
N Clb N\~ O ~IIO
O
O IO p ~
C F 6
Ot
/
~CH2
A O ~ I-ra-b
N
a-~ O
C O O
F~C Cj-a 0 p
U N ~ YO
N ~ ~
N n F ~IY
Qi O ~ ~ N
FbC=,,(S=~ Q~:g at ~L1S'n
IbC ItC O O H' ~
CC~I~~'~ ~ F' ~
~~ 0
o QyN_)
Rc IN- Ry-~o o 0
Nc
~c 6~
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-70-
H CYp t p-tZ F~ccFb ~z
o O ~
/t~N O-3 N
~ = I( C, ~
~~0 0 0 N,~ O O
_ 1f O
4C q ~' O0 Ile
and
~a-b
o
N~N
O O O
PbNIN,~ O
or a pharmaceutically acceptable salt, solvate or ester thereof.
Methods of treating, preventing and/or ameliorating disorders associated with
HCV in a subject comprising administering to a subject in need of such
treatment an
effective amount of at least one of the "inventive compounds" are also
provided.
Methods of treating and/or reducing the signs and/or symptoms associated
with HCV in a subject comprising administering to a subject in need of such
treatment an effective amount of at least one of the inventive compounds are
also
provided.
Methods of treating a wide variety of diseases/disorders associated with
cathepsin activity and/or for inhibiting cathepsin activity in a subject
comprising
administering to a subject in need of such treatment an effective amount of at
least
one of the inventive compounds also are provided.
One example of such disorders is proliferative diseases, such as cancer,
autoimmune diseases, viral diseases, fungal diseases,
neurological/neurodegenerative disorders, arthritis, inflammation, anti-
proliferative
(e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease.
Many of
these diseases and disorders are listed in U.S. 6,413,974, the disclosure of
which is
incorporated herein.
CA 02611145 2007-11-29
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-71 -
Another example of a disease that can be treated by the present compounds
is an inflammatory disease, such as organ transplant rejection, graft v. host
disease,
arthritis, rheumatoid arthritis, inflammatory bowel disease, atopic
dermatitis,
psoriasis, asthma, allergies, multiple sclerosis, fixed drug eruptions,
cutaneous
delayed-type hypersentitivity responses, tuberculoid leprosy, type I diabetes,
and
viral meningitis.
Another example of a disease that can be treated by the present compounds
is a cardiovascular disease.
Another example of a disease that can be treated by the present compounds
is a central nervous system disease, such as depression, cognitive function
disease,
neurodegenerative disease such as Parkinson's disease, senile dementia such as
Alzheimer's disease, and psychosis of organic origin.
Other examples of diseases that can be treated by the present compounds
are diseases characterized by bone loss, such as osteoporosis; gingival
diseases,
such as gingivitis and periodontitis; and diseases characterized by excessive
cartilage or matrix degradation, such as osteoarthritis and rheumatoid
arthritis.
Other than in the operating examples, or where otherwise indicated, all
numbers expressing quantities of ingredients, reaction conditions, and so
forth used
in the specification and claims are to be understood as being modified in all
instances by the term "about."
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is further illustrated by the following drawings in which:
Fig. 1 is a graph of mean viral load measured over time with administration of
various doses and regimens of a compound of Formula Ia; and
Fig. 2 is a box plot showing serum levels of a compound of Formula Ia
measured on day 14 at various times when a compound of Formula Ia is
administered twice per day (bid, left box) and when a compound of Formula Ia
is
administered three times per day (tid, right box).
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to controlled-release dosage formulations
CA 02611145 2007-11-29
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-72-
and methods of treatment using the same. The formulations comprise at least
one
(one or more) compounds of Formulae I to XXVI as discussed above and a
controlled-release carrier. One of ordinary skill in the medicinal art will
readily
appreciate the potential advantages of controlled-release dosage formulations,
namely, enhanced delivery to the required site, delivery at the required rate,
fewer
administrations that increases patient compliance, reduced dangers of overdose
or
side effects; and also economic advantages by virtue of more efficient dosage,
at the
expense of possibly more complicated fabrication.
Suitable compounds of formula I are disclosed in PCT International
publication W003/062265 published July 31, 2003. Non-limiting examples of
certain
compounds disclosed in this publication include:
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-73-
Ph
O f~ =
O N 'I H O H p Me p p
R- ~/~N N N~ X t H O O O N p' 0 O H 0 Me vO~N~~N N~N NH2
O O H 0
O Me OO Me
(R = t-butyl, X = NH2)
(R = Isobutyl, X = NH2)
(R = t-butyl, X = OH)
(R = Trichloroethyl, X = OH)
c '
Me p S
Me p~
0 H u
~. 0 H 0
Me" pN~N p X Me
I N ~O1N~_ N N N~N X
0 _ 0 0 H O 0 O~ H 0
~
~ Me O Me
(X = OtBu) (X = OH)
(X = OH) (X = OtBu)
(X = NH2)
(X = NHMe)
(X = NMe2)
' ' ~
CI i H ~ S O p 0 CI ~( N~N N N
~N NHZ Me O pI' H O O
N N~N OH
HOOC O O O H Me/AH
O 0 O 0
Me O 0
Me O H
Me p N F F 0 0 I i M\ p~N~N N 0 N 'O
Me" _ ~ ~ p N N N~N OH Me/v p 0 O ~~H OH
O 0 0 H 0 Me 0
O Me
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-74-
~s s s
H H~~ Me~O~N~N N O N OH Me~NN~N N O N, x
pO 0 O H O OO 0 O H O
Me
(X = NH2)
(X = NMe2)
(X = NHMe)
(X = OH)
s
Me
0
e v O~ N~ N N N~ N NMe2 jAe H O ' H O H O
M
O O O H Me/I O N,,J J, N N-'-'N OH
Me M Me O 00 0 O H
(-~S
S S S I
~ O N~/' N N O N,J'~ OH ~ O N/- N N O N~ X
~
Me H Me O = N
O O H
O O~ Me O O 0 MeT Me 0
Me Me Me
~
Me ~ /
Me (X = OtBu)
Me (X = OH)
(X = NH2)
(X = NMe2)
Me Ph
Ac N Nl~N N 0
N~N X R~{N~!~N O N~N OH
H OO O O H O 10' O 0 O H O
Me Me
(X = OtBu) (R = t-butyl)
(X = OH) (R = Isobutyl)
(X = NH2)
(X = NMe2)
(X = NMeOMe)
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-75-
s s i~ ~s
H H O H O H O H 0 H 0
~OWNN N N~N NMe2 X NN N-'-J~ N NMeZ
Me M Me O O H O Me eMe 101 O H 0
Me Me
(X = Me, Y = CH2Me)
(X = OAc, Y = Me)
Me Me Me\,- Me
Me H O H O 0 O H 0 O
NN N N NMez
Me~O~N N N~N NMe2 Me~O ~ H
0 Me 0
O H 0 Me O/~Me O~ H 0
Me Me Me Me
Me
\., Me
Me
0 Me, O
Me" ' ONN ' N O N J~f NMe2 Me~O~{N' /~~N' [O N~N NMe2
Me O O O H 0 Me IO' _ Me 0 p H
Me~TMe O
Me Me Me
Me ~ e Me
O H 0 H O
Me~OUN~N N N~ (~ 0 / Me~O~(N~ ~ N~( N~N NMe2
O
'OI - O ~~o ~~N NMeZ IOI O O H
Me T Me H O
Me Me 0 0 Me
Me Me Me Me
H H 0 H O Me H j.~ O O
Me O
'/~NN N N~N NMe2 Me~O~(N'! N N N~N NMe2
TMe Me/I Me Me ~ O O H 0 'OI - 0 0 H 0
Me
Me Me
Me Me
H,CYM H~C,CFL
0 õ 0 0 ?H~
\/~Il~\
~ 0 N N q ~, ~ CFI, N H
(~ N~H N N,~a
~ IOI 0 0 0 O 0 0
OYNH 0\ 'NH
H,C~0 H,CxTIO'
F~C CH3
~C CH3
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-76-
EtOOC M ~Me
' Me \\ ; I
Me p 0 O N p ~H O H 0
~
Me~~( N'~ N N N~ NMe2 Me u= 0 N N N N NMeZ
'I 0 H
0 0 O H ' 0 pl
lrlJ Me Me 0
Me p \~Me
Me~~N" -N N 0 H~ Me Me p~N - N O H
N O 0
" N
N'-Jj~ N OMe
0 0 0 H NMe2 0 0
Me O Me H 0
>\, - ~Me
0
M Me O i
HN0
Me
Me p F p
Me~~N~N H 0 N O F N. X~N 0 N 0
H 0 0 O O ~ H NH2 HOOC O O 0 A H NH2
Me 0 O Me 0
OMe
0
HN, 0
l\
, Me H p =
Me HN,
H
11
H Me~N.-!- N N 0 H 0 Me~O~N N Y O N~ N NHZ
~ O ~
O O O 0 O H NH2
Me 0
Me 0
H \I ~I
N
N;S' S
~ 0
O
i O O
O /~ ~
Me ~ H 11 N~ - N N 0
H 0 l
Me~i N~ N N O H O ~ - NA
0 O p p NA N NH HOOC 0 O O p H ~NHZ
H Z Me 0
Me 0
itC~ H3 H'CCH'
' 0 O H3
F C~N N~q , CH3 C b~n NICH,
" IOI 0
O O O
O 0
O\ /NH OYNH CHZ
HC~~0" H" CO
H3C CH HzC CH3
a
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WO 2006/130607 PCT/US2006/020969
-77-
H3CVCH,
H3%,Ha I \ Q
NH, N= ~ II N O
Fy N C 0 \/\H N.
H3 0 H3C CH,
H3C~ 0 0 0 O~NH CH
p~NH '
HN
H3C_ 0
FI,CJ~ICH,
aYci
HaCYCH, \ = FI
H3 ~ ~ IN NH
H3~N N~ N_ 0
CH O O
QQQ a TT
H,C~I I~ O O CH3 0 O,,~,NH
H3C/~I/~o
ONH CH, H,,C CHo~o
H,
Y
H,C' 'p
H,cJ~CH,
CH3
I \ = p 0 /
H3C~CH3
= H 0 H 0~ CH3 C~ =~N N~~ :
N N N~ H C
H3 N CH3 0 p ~NiCHj
H~C 0 O O O
CH,
H3C0 OY NH CH3
0 NH CH,
~ H3C O
H,C<~ H,C~
C CH3
H3Cv H3
H>cYCH,
0 ?Ha H 0 H\/ \ Hs
N N~ N~cHa N N N N~CH0 H, N
Haco 0 o p o 0 0 0 0
H,C
O'\'NH ~CH p' 'NH
YI yl' F F
H,C' 'O
d' H3C~j O
H'C CHa H3C I
CH3
H3CYC{3 I \ H3C\1/ CH3
H H p / T3 p Qll / ~H3
H-CH3 H, 0'~Yq
N, CH3
C 0 O O hi 0
HaC 0 0 0 Ha
O
O~NH CH3 O~NH CH,
~
C
f o
H,C H3 H,C~ \O
CH,
H,0 Gi, H3C~CH0 ~
0 H I/ H3 H3 NN N~q N\CH3
0
~~I N N N~ N,
CH' H3C O O O 0
p
~+~"'0 Y. 0 o~ Nri cH,
V ry H3 C NH
c
H,c ~ H3
H,C
v CH,
CICI
0
/-e y H,Cl~CH3 Q ~ ~ O N"~pHCHa ~ ~ N O N CH
0 O 0 0 CH, O li 0 a
O
O\ NH CHz O~\/ NH
F F
H3CV" F
>\ HC p
H3C CH3 CH3
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WO 2006/130607 PCT/US2006/020969
-78-
B~ B~ 9el H3 CYC{. r 0 O H~ CHa
"p ~3 ~ _ \l~1ll(~FV{ H ~H3
\-~ NJ'TI'(/tJ IV O H3C~-O O O
l\/1~J\
0 H
p p H'C CH~ H~ H
0\ /NH CH H
~il' z aCy' Q
H3~NH HpI
CH3
H~C CH3
H,CucH,
a ci \ /~y p
1Y, ~H
i0o O
H 0 0\/NH CH~
p O O
OY NH ~ INH
H~C~O
H3C CH3
H3C C
CI~CI F~
O O
/~-y1 0 ( 1 H H
CH / CFI~
''N' -X ' H N N ry 0u CH3 N,CH3
HaC 3 0 0 ~ CH ~ 0 1'OI O Fi O
H~CO 3
O\ /NH
O~NH ~CH YI
Z H" C~O
H3C~NH
~C CH3
H3C CH3
Ci\"/CI
BrBr
0
N N~CHz
/J--y, H O H p Ha HC CH~
HSN~T N N~N N, CH3 H~CO 0 0
H'Cp 0 t H 0 ONH CHz
~
H~C
O~NH NH
H3C
H~C~p
CH3
q G
~
HaCYCH3
o H ~b
NN N'~3 = II
00 0
p 0 0 O\ /NH CH~
OY NH CH3
H~ 0
~ro
H3C
HiC CH3
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WO 2006/130607 PCT/US2006/020969
-79-
H,C~CH~ I \
H3CVCH3
= R /
0
CNa N,,,, P o F6 N N aJ~
-~Y N
RC I 0 O H
H3C~CH, H~CO
CH3 O\ ' INH CH3
0\'NH CH il"
H3C~- Ylo Fl,CXNH
H3C CH3
H'C CH'
~6C CH, HCV CH,
H ilH,c CH3
N N l
5~ N~'O
=0
I 0 IOI 0 \ ' ~~0 0 0 \~
YINH
0 NH C b CHz
~C ~~ ~ ~C 0~
HC' 'C~ H3C CHa
H3CGi3 H,C CHa
~
0 -
a N'1--S=~ N clt
~
o o
\ OYNH
O NH
CHz 0
y
H3CXNH
H,C C
H3C CH3
H3OYCH3 H6Cv CH3 ~ N C~C~
a~a
H,C ~ ~ o 0
H,c~O H,c' ~c~
OY NH CH / I O~NH ICHz
H3Cx NH 2 \ H3C~NH
H,C
H3C CH3 CF~
H3CH3CV CH3
0 0
CH'~a N~O~ II a a~\I o 0
~ O 0 CH3
Ha 0 0 0 H3C 0
H,C
0\ /NH
CHZ ~I" 0\ /NH CH2
H,C~ INH HC~NH
H3C CH3 H~C
H6CYCF~
HaCCH, N ~ya
O 00 0 IIO
N Y N~ z
0 0 H ~NH ~CF~
0\ /NH CH3 ~ 0
~" "~ 3
~:r 0
H,C
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-80-
H,COF~ I \ HxOVO~
0 C C~
= I~ ~ / =N = N ~
~ H O I /
0 O a 0
0\ /NH ICHx ' /NH \CH
YI ~il' z
H3C~0 HN
H
~C pHx
clcl
= /--y o
H 0 H / 1 H H
~ N== N CHz ~NH
0 0 TIOIf \
~
HN y p 'CHZ 0Y NH - CHx
Z- NH HN):~F
cIYG Clcl
//- H 0 }{ H 0
H\ N O\n N N N\ 0~
H3C N' 0
1 0 0~ IaCJv 0 0 0 lp CH3
H3C0 CI, OY INH CH
O\~NH CH2
H3C~ INH x FI~C~ INH
HC C
HaC CH3 F~
CI\~,,CI HaCCH0
0 0
"" 1( b bI'l-fo~~ b p a 0
0 0 0 ~ 0 HCH3
0\ /NH CH 0\~NH CH
~il z I x
H3C~NH H3CNH
H3C CH3 H~C CH3
HyCCF~ FIxCCH,
I \
N H H /J-y1 H O H O /
N N 0 CH3 N~N
,Cr IXI
0 0 0 0 ~~ HC O O H
v YI H,C O
0\ /NH CH OYNH
~" x
H3C~NH FI~cX O
HxC CHz HaC CH~
HaCCH3 I \ N3CV~a
H\/\ p
r H H~ / N 0
/ NN tJ hl ~ N
0 0
~ 0 NH ~
Y CHx
F6C\i HC~(0
~C/~CH3 ~C \Cii,
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-81-
H~CX CH, HaCVCH3
p 0
CH
N~\/~ 0 ~ N a
N
1 p N 0
\N/0O
OO 0 0 ~ O~NH \C~ O~NH CH2
FI,CNH H,CXO
CH6 H,C CH3
H~C\,~ CFt CI~CI
0 0
C C~~N N~\IP O ~N N~/CHz
0
1 0 O
H,C~O 0
0\ /NH C~ HNyO CH
~ z
H3C~/ NH H3C~/ NH
'\ H3C I
~C CH, CH,
HzCyCHz HCCH3
0 ~{ O
N~{ N N'CH, N
0 0 0 0 0
OYNH
O\ /NH CH~
O ~il
H3C~O
CH3 C CH3
HaCVCH3 H3C,CIii
0 0
aw
CH
"I lf
O 0Y~~N__ 0\ /NH CH
~li' z
H,CXO HN
H3C CH3
HaC,,,~CH, H3CCHa
0 (J~y1 0
N N O '~ NCHz (~, N~/N
O O 0 TIOIf
1 0 TIOIf H3C
0 YINH CH3 0~/TINH CH
H,C CH3Y I a
0 H,CXO
CH, H~C CH,
H3C\x/CF~ CI\~ICI
0 0
N N 0 ~
FH3 NI N N N~~CHz
~Cx ~\ 0 0 HN
~C' YI p 0 0 O
6 I O\ 'NH CH'
0\ /NH CH, ~"
~IT'
H,C~/ NH \ H3C' /O
FI,C 'C 3 HaC~(CH3
CA 02611145 2007-11-29
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-82-
CI~G HaC~/CHz
, bj
~ p / I H,C 0 0
0
I'yC~ 0 O NH G{3
O NH CH3 N 0
H~C~O
~C CH3 CH3
CI~CI CI~CI
N N~~CH ~ N N 0
N~~ Hz
l z I I
0 0 O 0 0 O
"'0"'y~TTNH CH3 OYNH CH
z
/0 H3C~0
C1~ H3C CH3
\CH3
H,CyCH3 CICI
0 0
H H
~I- l~ N N~\CHz 11 N N~\ Hz
0 O
1 O 0 O O
O' NH HYIN O \
\~ CHz ~ CHz
f "7 H3C\ /NH
H,CJ~CH3
GCI H~CYCH3
0 O
N CH3
~ N,~CHz
0 0 H3C 3 O 0
~ O
0\ /NH \CH O\'NH ~
~li" z YI
HN
H3C'>~ 0
H3C CHs
~CCHz \ ~CUCt
I/ 0 H3C CH3
p '" ~I N N\/II\o \
H~ c H~ " i l a o 0 0 ~ i
H'c O 0
~ I
O\/NH CHz
O\ NH CH~ 'r
I H3C\ / IO
H' x
C CH'
CI-l,
H3C CHa
G\ ,G \ Y
0
N~N \ NN N~~~H2
N 0 0
H~CO O 0 0
FI~C
O NH CF6 Oy NH CH
z
H~C' /NH H O
H3C FIzC J'C ~ a
CA 02611145 2007-11-29
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-83-
H,C CH~ HaCX, CH,
0 O
N ~~ 0 CH3 ~~ N ~
OCH0 H C ~z M 101 CH~ CH3 HaC O O 0 0
a 0 C0 0
H3C 0 NH 'ONH ~2 y
~:
HN
H3C~NH
H~C CHa
HaC\.,CH3 CI\CI
0
JJJ-----yyy O
~N N~OCHZ - ~H H
N N O N~~CHz
0 0 0
O O
ONH
y ~
CHZ O"r NH ~
CH2
H3C~ ~0 H3C~O
HaC,d~CH3 H3C CH3
HaCCH3
CIV CI
0 CH3
~ N~N 0 N
N /~ N ~/CHz
~ 0 0 0 N 0
/ I O O
0\ /NH ~ \ v YI -
~7I' z HNYO CH
z
V\ /O NH
H~CnCH3
H3C\,~CH3 HzCX,' CH,
//--y1 0 (/-y1
H3C 0~\N~ /N CHz I/I N/
N N~~CHz -~y
H~C~O 0 0 l l IOI 0
~
H3C O~NH CH OYNH CH~
Z O
H3C~NH c~
CH3 CH,
H,CCH,
a a~/\N ~~ N X N 'CH
CFIa NI H O IOI O
O
FI~C' YI O OY NH CH3
0\ /NH CHZ
YI 0
F~C CF6 Cl~
H3Ca CI\ CI
0
N, N,_,--CHZ N.CH3
0 O 0 0
0
0\ /NH ~ Oy NH CHg
~ Z H3C' /O
HC NH ,d(
H,C CH3
H3C CH]
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-84-
H3CCH3 H3CCH,
CHz O
O 0 I II ~
0 0 0 0 0 HzC CF~
0 NH ~CHz v0 ~NH CH ~ z
H3C NH H~C 0
H3C~
CH3 H6Cc
G~CI H3CVCH3
0 0
N a ~~CHz ~a CHz
0-1 00 0 ~0 O 0
O~NH CH OY NH CHz
z
H3C0 H3C,~NH
H3C CH3 CFl3
H3CCH3 H3CCH3
~ 0 a~a N 0 0
y I ~- 0 O ~ CH3
0
~ 1 O 'fCH3
OyNH CH2 O\ /NH C~ CH3
H3C\ 0 H~N
HaCnCHs
H3C,~~CH3 H3C~CH3
0 H NHZ
a a~\~ AIN
(:~~ z H C CH3 N O
0 0 3 ~Y\ 0
F H3C I O
0-\ /NH F F Oy NH
INH NH
H3C-~
H3C CH3
H3C,CH3 H3C\~,CH3
0
H3 CH3~~ Na NHz
0 O I 0
H3C O O
\
CHz 0~ INH
H3C' /O
V NH
H3CJ~CH3
HaC\
,,CH3 G'G
O
O a NHz
~N N~\CHz N
0 0 0 0
~ CH3 O
Y O' NH
O
C~ H3C' /O
OH3 H3Cj~CH3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-85-
clxcl Brv6r
0 H 0
NN NHa ~N NHz
0 0 p 0 V
O' /YINH O\ /NH
H'cx~llp' ~~p"
~C cH3 C cH
H,C\~CH3 H,c' /CF6
p O
r~, ~N NHz NH2
0 O N 0 110 O
vOYYINH O\ /NH
H,C' /0 H,c' /~0
"
H,c/,I"~CH, HC/~I"~CH,
CIvCI H3CH3
0 0
yN YNHz [ ~ N NH
p V N z
a0 o i0l 0
0 NH
Y 0 NH
H,C~NH C CH3
H,C C ~ H C~O
CIG
CI,VCI
: :
QN NHz H 0
N N
NHz
H,C H, 0 ~ O
p ~ p
H3CO p
py NH OyNH
H,Cx NH ~1NH
H3C CH3
H3CICF~ CICI
0 O
N NHa ~N NHz
N II
' 0 O 0 O
I~C 0
Oy NH OY NH CH3
NH H3C~NH
H3C CH,
Cl~
cl CI~G
0
N H 0
, N NHz NH,
~0 0 O ~O O O
O~NH 'O'NH
~~u "p NH
~~ cl-I,
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-66-
Itc VCH3
HaCa
0
H 0 H
NH= NHZ
00 0 0 0 0
0\ /NH 0 NH
~ CH3Y
H3C 0 0
H'C CH3 H3C
Fi C~CFI
H~O
;- q 0
0 NHs
N NH~ N
C~ N O 0
H3 0 0
~ ONH
O~NH HC
0
H,C 0 ~
H~C~
F
F F F
F
CI,vCI
H3C~?3 O
NHi
0 N
(~~o NHZ H,C H,O O
H
0 ,C
O
O~NH
OY NH F F F
NH
H3C 0
H3C~
3
C~ CICI
H3C
~ 0
0
Z N. NHi N N NHZ
- O 0
O 0 O
O
0\ 'NH H3C ~ NH CH3
~" 3C
~~0 H3C
CF~ H3C
clyG H,c
0
H N
~ NHZ NHa
Cli~ N ~ 0 O
H,C 0 0 0
H3C 0 0\ /NH
OYNH 0~
H3CXNH aCH3
H3C G.{3 ~Cv ' H,CvC~
, O NF~
YNH, \ / N tJ
q)_) N
0 O O O
0
O~NH
0\ /NH
~" H~C~NH
H3C CH3
cj/NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-87-
HaCvH3 F~C
O
~ ~~ ON NHz YNFa
N T r~, N
p IOI p '~~O O O
OYNH O~YINH
O
Qc O
F~ a
GvG GxCI
0 0
\N~ NHZ
H'I C"y NHz
p p p H Cx ~0 0 O
O~NH ; ' '
0\ /NH CH3
~
NH
H3C~NH
H3C pH3
G~G H3CH3
//'--y1 H 0 /~ H p
~\N~ NHZ ~~ N NHz
~OllOlf y fty O
0\ 'NH CH3 0\ /NH
"
" ~
~C~~O 0
~C C~ ~ Ha
H~CuCF~ CI~CI
0 0
400 NHi 0 0 0
~NH
O
0\ 'NH CH,
~CVO H~~N"H
fl~ H,C
~p CH3 H3C
F~Cv~ C~ VCI
0 QD N' X b NHz NHZ
II H3 N
0 p O ~C
~1I' O O 0
O' /NH
0\ /NH
~NH ~C~'O~
~C CF~
~CvCFy
0 H3C,-~Il CH,
H O
~ NHa N NHz
0 0 0 H'C\ H'C\ 'N N ~ 0
O~NH H3 C~~Y y~O
yO CH~ ICH~ O 0
H~C CH
H,C
3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-88-
HsC~ ~ HC ~H3
F H
~ N NHz Hz
F
0 O 0 0
0\/NH O~H F F
F~C
~3C~c~ H3C -A-0
CH3 H3C CH3
H,C
0 H3c~ea
N
r 1 N l~ 2T0
H3CO NH
\ /
~1I' H3C O
H~NH O\ /NH
H3 CH, ~~~N"H
H3C CH3
H3P CK H3CCH3
0
l NHz
NH 0
0 O
H3C',~NYN 0
0
H ~ H
CH3 O 3C ~H H3
3
CH3
H3 v H3 CI'xCI
O
H NHz 0
N N
NHz
0 CH3 0
H,C 0 O
HCO
O\ /NH OY NH
NH H,C' /0
(\Itr\/1~_~Xj H,0 ~CH3
H3CvCH3 CIyCI
0 O
N NHx yN NHz
~ ~0 0 O O O O
0Y~YINH '~- 0 Y' -NH
H3C' /NH H,C ~INH
H,CxCH, H3 C~CH2
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-89-
G~G
G~G
0
NHz //-~' 0 NHz
\ ~/
N T"
0 Ipl 0
0 NH
~ 0NH
H3CXNH
NH
H3C CH3
H,CXCHJ CI~CI
N~ 0
0 ~ NHZ
"~~ z p
Oy NH
~NH
H3C~NH
v NH
H,C
CH3
FI~C\,CH3 HaC\,~CH3
0
j-~ NHz 0
(\/ . NH
Z
'7Q ~3 "" ~~H
Q Q
~c
OYNH
O~NH H,C
H3C0
H3CY NH H3C
CH3
HsC\_,CH3
H O
N N NHZ
QLO0
O
Oy NH CH3
H3C O
H3C~
H3C
O O'K
N O NLS N, N H O N~ N,
N
H
H
N~ 0 H 0 N~ 0 H 0
~O ~ = O ~p~ = O
0 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-90-
~\
O ~O
p
NJ- CHa Q Oia
O
O Ou
NH2 0
~ 'V\
O O O ~a
O 0 O
I \
!J~ O \ I ,O
Y C~-S
N CH 3 ,N
~ I 3
'7l: " ~ ~ H V
O 3/J\/~ O O
p "~
O O 0
0 O ~~N~ O ~ II IHz
O \
I /
I \ /
iS~O N
~
OFI, p 01~ HO" v ~' CHa
Hap~ ~f 7 O p 3 ~ O O
IOI ~ YW Ny~N~ O ~ ~ I~ ~Z
0 / p ON-~
p\~ 0
\
"Yo
IOI q.~3 ~
I V 3 ~ ~]
5CHO ,N N
O Q
II ~, 0
~
"V '
~ 0 0 z
o ~ o 0 0 O \ ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-91 -
Ci
/
\ ~O
N
O~
O O
00 n' ll
O \
0 I /
H3
/
\ I ~O
D'I
N
H3~ V CHO
O
0 eyNA
NH2
0 o
0
0~1
c
4 p
CH3 p . N
HaO)~
O ~ ~J
0 O 0
~ O
11 X /
IIp \ I ~O
~I
N
A
0 O
0 o nI ~
O n,\
~ I /
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-92-
~I
l'O
N
O
O
O ., II
U "'\~' NH2
O O
O
N
~ O
~ 3
H3 ~ _
O ~
o NHZ
O O 0
/
O
O~ O
" C
~
O
~
~s
C ~
\~~o
o%i
N
~ II CH3
H3C ~NV? JJ- O 0
0 0
O 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-93-
dcl-'
r>~O
i
~
I 3 0 N
0 ., 0~I~
oo
0 ~"~
I /
01 C
cl~
0
CH3-C"3
N
, ~
H3C p
O '
O NJ
C N'y NHZ
0 O
CI
N-f 0
N
CF~ 0 O-I3
~~ O O1'
O nL A
o 0 VVV ~~\NH2
~
CI
NyO
N
0 CH3
Ilar ~~ 0 0
O N
O fI y NF~
0 O
1/
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-94-
F~ O
N'/'o
I'IN(~
H C~ 'fyYJL O
Io CH3
l'If O
0 C 'V\
O O 0 NHz
H3 O
N'/.O
INf ~
~ ~ CH3
H ~ O
O O õ II
O O 0
as
(il
N
F-I
Fi~C,
P
O O
Ha~~CH N Y ! 'NHZ
\
/
O O
o
a
o'f~ N
3
H3C ~
C' fV~
~ NHz
~ O O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-95-
/ N
0
D'
N
CHO
0
0 - ~ ~
~ O ~ IulO ~z
/ I
/
\ ~ ~ g~0
D'I
i ~ 0 CHa
O 0
O
0 O IIO
~ \
/
/
\ I il0
cillS
/ F N
O q.L
\ O N~-
O p
, N J~~T
ai ~-/ NHz
O 00
H~
3 I
oy O
O Cl-I
\ II 3
O
0
OHO O N-,r " 'NH2
O 0 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-96-
I~
/
ci Nfo
C
O CH
3
0 0
o
CH ~ IV. _Yl't'Nu
O O
/
CH3
'7"
Cl 1
C N
O O
O
O q, ~ "'~-/\NHz
O O O
I /
O
CI C~S/=
C / ,N
NJ CH3
O O
OHO O/ n~/~
O õ II NHz
O O 0
("Y CI
/
N-r- O
HaC Q'(~ O
C
0
Q
N-Iz
O, .~ Vll\ ~~ \
0
/
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-97-
O_ ~
O OI~
H C~ n~ Mfl, N-{2
CH3 UU O O 0 0
CHs
H,c
CH
H3C
0 0
0 0 0
CH3
e~ I
~
~3
IQ 0 0
H~ X N,~ NHz
CHg Cl ' 0 0 0 0
CH3
H3C CI-6
0
Ha~ '~, N,~, NHZ
CN3 0 0 0
CF6
CH3
H U_/\
O
cH,
" II NHz
0 O
I~
O 0 0 ~
Ha,r~ CH
CH3 0 0 0 0
CF~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-98-
H3
cH, I \
CH 3 0 ,
H ~ e
~ NJlli OH
0 0 O 0
H3 OH3
0 0 e
H3Hti\~~ N,~ OH
CH3 0 0 0 0
CH3
~H I \
0 0 O /
H3~\ /~~ N~ CH
~CH3 0 0 0 0
"' 9
OH I \
O O 0 e
~ N,_~ OH
0 O O 0
CH3
H,C ~'CH' I\
ai3 0 o / CH3
11 -N,.vIXI' ~C
0O O O ~
CH3
0
0 ~- N 0 0 C1-t3
H3C~~ v ' N CH3
0 ~ O
O
0 ~C C~c
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-99-
0
~~-N O 0 t~b
N
H '}II{ N q.6
O O p ~ -
H3C 0 CH3
0
~ 0
~--N O 0 ~CH3
N
Ha~a,( : N CH3
00 O , -
H3C 0 O
CH3 0 N 0 0 /CH3
N
OO - H3C p O
~-N 0 N 0 CH3
0
O
p
N-,
~ H3C/\f CH$ic p
H3C
CH3
[H
p p j
Cii, V/\ O 0 0 j 0
a-+, OcH,
Q ~ p ~ ~
c~ N,
yI0 o p 0 "~
00 cH,
H,C ~
cH, I ,
CH
p p N,A 0
CH3 p p 0 C5~~,CH3 0
CH3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 100 -
H a-6
0 0
N~~
V,c~\~ ~ a,
ICi-f, 0 0 oHO-'~ 0
CH3
H CF~
~
~ Z) 0 0
~
~ v'~
H3C~ A O ~777 0
3 0 /
(1M 3
H3C CH3
O O
H3C~ YN,,K OH
O O O O
CH3
I \
~i IL 7 ~~3
N, CH3
H3~~ ~ ~
CH3 0 O O 0
CH3
1CH3
~ H
O 0 O (*{3
H~_~ \ YN, ~
~
I cl-~
CH3 0 O 0 0
CH3
C4-6
wt
1~H
0 0 0 ~ "
IyN-y ~~A N_~ N0C3-~
CH, 0 0 0 0
CF~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-101 -
HaL. C ~a I
CHa 0 H3 C O 0 ~ CHy
N, CHa
O O 0 0
CH3
H3
Ha C CH3H3 CH3 CHa
0 0
,,~/ ~~a
CHa 0 0 0 õ IIO / CH3
~ I
HaC' P~a0 HC cta
y
0 0 0 3
CH3
/ \
~
o ~
II I ~i
aYI 0
~ I
~ ,
3C
IpI p p
~ 7 V IV j~ ~
~3 p 0 p IOI ~
~I
0 0 ~ 0 0 ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 102 -
o
o 0 0 0
0
F'Qy,~,A N O
CH3 O O
~N O
H3C CH3
0 CFi,
~ o ~ -
r ~~ " N 0 0 0
', II
x 0
o o-
o 0
~ ~f-y r.~,
0 0 ~ ~
~~
>-? -k I / I
R,~k
0 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 103 -
~o~ II Ny"',,
0 0 0 0~
o o
N N,,, N L N O O O
O
ro o 0 0 0
~ I\
o-~ O O
N N*N,,, N
O 0O O
~ O O
~Nj~
N ~NN
O
~ ~~o o
rO ' N,~', N,
0 0 0 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 104 -
o
0 0 ~
-~N N.,
N
II I N II
O
O00
ci o ~ ',
ro '~II
0 0 o 0
Q-,
~-' '
o i o
-~
o -
~ ~ ~
0 o j 0 0
~ ~-
II~ I-k
0 0 0
o
roC ~ 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 105 -
Q
~o o XE
o
o 0
3 \
H3C. CH3 CH3 -11 '7 3 II oII
1,==/1' UJj~\ Y X "'r
7
0 O( C 0
CH3
~ \
~
N, \A,~ _~y II0
~
O O O
CH~ \
CcH
H3C~~ C CF6 C CH
CHO O ~ o 0
3
Hrõ~
CH6
HC ~ ,L
Nc~r
II 0 CH3
VJU\ CH
3
CH3 O o ( O 0
CH3
HC
CH
H 3 O~ N'v JOI(Iv C~
~ '~ 3
0
0 ~ 0 0
CH3
0 O O
N,
H I II : ~ cl~
CHi
3
CFIs 0 O ) O 0
1(CH3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 106 -
\
CHs Ha O
[~ p I~~3
~~ N, CF~
CHa 0 O j 0 0
1(CH3
I~
p-6 p O
~ CH
H I~ ~ K~lk N,
a~CIJ~' Y l~ CH3
CH3 0 p ~ 0 0
CF~
HaC~CKe
O O ~H3
H C N\CHa
' CIN' ~N N
H3C0 0 0
Oy IN
N
HC~~-
CHa
H;CvCHa
0 0 CHa
~ CI~ ~N N~N N,C~
FO 0 0 0
Oy N
HsC~
p
HSC
F F
F
HaCvCHa I ~
0 0 ~
CH3 N v 'N
I
Ha
QYN, Ha O 0 O
O\/N
H3 ~O"
H3C
F F
F
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-107-
H3C CH3
0 0
C N N Nj~O
p O
1 O
Oy N
H3Cx\ /0
H3CCH3
H3C~CH3
0 0 / CH3
F~
N N,,,)~N N\C
O O 0 0
ON
y F F F
H3C>r 0
H3C CH,
H3CX CH3
0
N O
N N
O 0 0 CH3
O\ /N CH CH3
~1I z
H3C N
H3C~H,
H3CvCH3
0 0 / H3
N N N v 'N N,CH
~ 3
0 0
H3C OvN F F
1 F
p
H3C:y
CH3
H,C~ ~ Q C~
N N N N " N JyN,Cft
H~C
H1C 0 0 0 O
OyN F F
~ C~p F
C
CF6
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 108 -
F~CCF~
O O
~N N v N
~O 0 O O V CH~
Oy N CH~ CH3
F~CO
F6C CI-~
F~CCH,
O O
N~I\NNj~ N
O O O O N/CH,
Oy N CH3 CH3
H3C~0
~C CH3
H.CCH, I /
O O
O O O' N~CH3
1
O' _N CH3 CH3
H,~ \IOY
Hs' "Ha
H3 C~CH3
F 0 0 j~
F ~N N N_OH0
~O 0 0
OY N
HI C_ /0
H3C~0H,
H3C~CN
Q O O Chy
CH3 ~N N\/ N N/~CF~
F~CO 0 0 0
O\ /N
H3C~~0"
v c
"~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 109 -
I~c~
0 o iH
N Nlfl'N NI CF~
00 0
0
IYN
O
HsC CH1
H3C"~CHa I
0 0 CH3
CH3~N Nv 'N N~CH3
H3C0 0 O 0
OY N
H3C_ N
H3C jIC~Ha
H3CvCH, ~
0 o ~ CH3
Ha
N NJ~N N\C
O O o 0
O\/N
~~N"
HaC CH3
itc~CH, Q : O O ?1-y
CH~ ~N Nv 'N N, CHs
F6C~0 0 O O
0 N
H3C y
I-I~C
F F
F
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 110 -
H3CVCH3 Q O 0 iH3
(~-Xo N N " N N~CHa
O O 0
O~~N
F~C y
0
C
F F
F
H3Cv H3 Q 0
0 iH3
H C CH II
3 N N~N N\CH3
H3C0 0
1 0 0
3
O\ /N
H3C ~N
H3',',Y
CH3
CICI I \
0 0
, Y,,k
~C CH3 ~( N N v N
H3CI0 IO' O
OYIN
H3C~0
"tc cf~
H,cCH3
'
C 0 O H3C CH3
C IC CH3 N~O
H 0I O
3 0
OYIN
~N
H~C
H3C CH3
H3C, CH0 0 0
H3N N~N " N
H3C
0 O O NCH3
H3C O I
O\ /N
H3C ~O"
H3C 'CH3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-111-
CIx CI
N NH2
CH3 N
H3C 0 0
H3C 0
0\/N
H3 ~0"
H3(, ~F
F F
CIvCI
O OII
N ?( N N CH3
N N
IOI O 0 CF~
O
O~N
H3C0
H3C CH3
CIV CI p O O CH3
I
CH3 N N v N N~CHa
~\ 0 O 0
H3C 0
0\ /N
H3 ~O"
Hs
CI\"CI
0 0
~N N v N NCH3
0 0 0 'CH3
Oy N
H3C\ /N
HaCj~CH3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 112 -
raci
0 0 I / CH3
CH3 ~N N " N N,
CH3
H3C 0 0 0
H3C 0
Oy N
H3XN
H3- CHa
H3CvCH3
0 N oSo
N
HaC CH3 ~
~C 0 IOI 0 v 'CH3
Oy N
H3C-K N
H3C CH3
H
O:~CH3
0 I
O CHa
N N NJN N\CH3
H CH3 ~
3C 0 O O 0
H3C
N
H3C" 1
cF6
H3C,"~ CH3
0
o0
~N N
N
0 0 0 )~ CH
3
0\/N
H3C ~IjO"
H3C 'CH3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 113 -
H3CX CH3
0 O / ~ H3
N Nj~ N N\CH3
O 0 0 0
O\ /N
H3C F
H3
F F
H3CIVPH3
0 0 ~ iH3
CH3N N N~N N\CH3
O O 0
O
0\ /N
H3C~ ~Q"
H3C ICH
H3CYCH3
0 OH
N NO\ CH3
N - CH3
O O O O CH3
Oy N CH3
H3C O
H3C CH3
Ci~Ci
0 0 CH3
CH3 N N N N~CH3
H3C Q Q 0
H3C
Oy N
H3C 0
H3C ~F
F/\F
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-114-
H3 \ CHa
x\
S
0 0 CHa
N N,_,~yN N N,,
CHa
O O O 0
Oy N
H3C 0
HaC/ CHa
H3C~CH3
0
N NHZ
CH3 N
O O
0
Oy N
H3C N
H3CCH3
HaC CHa
0'x\ I \
0 0 CHa
~N N N\CHa
O O O 0
O ~" \/N F F F
H3C O
HaC~a
HaC~C~ I \
H
3
N NJ~\
HO CH' I 3 ~j N C~
~CxY' 0 0 0 0
OYN
I-IaC~O
~C p~C C
F~
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- 115 -
H3C~ H3
0
N N NHZ
0 O O
OyN
~C N
~
H3C \ CHa
/x\
O
0 0 ~ C H~
N Nll~,N N\OH'
aO 0 O O
OY N
H3C 0
HaOY~F
F F
F~C" CH3
~
\
0 0 I~ CH3
N N~N NCH3
O 0 0 0
Oy N
H3 N
H3C CI-I,
H3CvCH3 I ~
0 0 / C H3
CH3 N N YN" -N N,, CH3
HC I
3
H,Cx .L~O O O O
OyIN
H3C-7~ N
H3C CH3
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- 116 -
H3Cv CH3
0
N NHZ
H3C CH3 N O O
H3C0
0 N
H3C y
N
H3Cv H3
0
N N YNH2
O O O
0 N
H3C 0
H3CvCH3
0
CH~N NHZ
H C 3
H3C~0 0 O
O N
H3C ~
~
H3Cv CH3
0
CHN NHZ
3 N
H3
H3C 0 0 O
Oy N
a N
c H3
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- 117 -
H3CvCH3
O O i H3
CH3 N ON" ~N N, CH3
HC
3 O O
H 0
Oy N
H3C-K N
H3C CH3
Br
H3C CH3
O
O 0 iH3
N N
N~N N'~
O O O
OyN
HC
H3C
CH3
FI3C\ ~CH3
1~ Q O i%
N
N NkN N,
CFI3
O p 0
FlC O N 0
~C ~ 0
H3C C%
N3Cy CH3
CH3
(N~y N NJ'N N\
O p 0
N ~
C~ O
H3 O 101
H3C CCH3
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-118-
a~v ci
0
CHN NHZ
3 N ~'I(
HaC 0 0
H3C 0
O~N
H3C /N
HaCd\CF~c Ha
CIx CI
0
~ /N NHz
CH3 N" l~'
H~C 'OI t
H3C 0
0
0\ /N
H,C ~
0 N
H3C CH3
CH3
H3C~CHa
0
N\ ~ N H HC CHa N " ~II(
3
H3C.~0 Q 0
0 y N
H3C N
HaC~Fia
H3C~CH3
0
N OH
O O y
0N F F
F
CH3
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- 119 -
HaCH3
0
C ~ N YNHa
~
HaCaCO 0 O
OIN
F
N
F+,(
F CH3
CIx CI
O
N N NHZ
0 0
O
0 O\ /N
H3C~C0 ~
N
H3C CH3
CH3
H3C CH3
O
0 0 ~ ~H3
N N-kN N~CH3
0 0 0
OY N
H3C 0
Hac~ a
H3c~ F6
0
H3C ~N NHZ
I-IaC 0 O 0
C~
O~N
HC\~ d
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-120-
H3C~CH3
0
N N NH2
O O 0
O~N
H3C
N
H3C' /CHa
0
H3C CHN NHZ
3 N
H3C 0 0 O
"CO N
H3C\ CHa
0
N NHZ
H3C N
HaC 0 0
H 3 C O
O"~( N
N
H3C~
H3C F
HaC\I,CH3
0
~N NHa
N
0 O
0
0 N
0
~
H3CN
0
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~tcF~
0
I\
/ H3
0 0
cT N N~N ?\C
H,
O 0 O
Oy N F
F F
H3 0
~
H3CvCH3
0 0
CH3 N N~N
H3 IIO 0
H3C 0
O\ N
H3C N
~
CivCi
0
N NH2
CH3 N
H3C 0 0
O
H 3
C
H3C' 0 Oy N
LN
H3C CH3
CH3
H3CCH3
0
CHN NHa
3
H3C 0 0
H3C O
ON
H3C N
H3C~
F F
F
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- 122 -
H3C CH3
4 I~
-V\
CH
~
~ I II N N-JN N\CH3
O 0 O 0
OyN F
F
H,C. .~<N
H3C CH3
H3C CH3
4N ~
0 0 CH3
H3C CH3 II N N~N N\CH3
0 0 0
H3C 0
0\/N
H3C\n'~0"
HaCCH3
F~C\ CH3
4~ ~ \
0 0 CH3
H3C ~~ N v 'N N,CH3 -Rl O 0 0 0
~
O~N
H5 C~O
H3c c
FF I \
0 0 CH3
CH3 ~IN N~N N~C~
'C~ .L\0 0 0 0
~C/ ~ '
0\/N
H3CX ~0"
HaC CH3
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FXF I \
0 0 CH3
CH3 ~N N " N N,CH3
HaC O 0 0
H3C
0\/N
H3C~1IN'
H3 C CH3
CH,
?r0
0 0 N N'-t~N 0 0 O H3CN, CH3
Oy N
H3C\ /0
H3Cj(CHa
H3C~( CHa
0 0 Ch~
CH, N v N N, CHa
N0 Qy0N
O O
Oy N
F6C~N
H3C C
",
0 0
N N~N N
?r0
O 0 O H3C' N., CH3
O~ N
H3 O
N" CF~
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\F
/
0 0
NNJ~N O
-ly
0 0 ~O HaCIN, CH3
Oy N
H3C j~\ /O
3CH,
F
I \
0 O
N NJ~N -ly O
O 0 0 H3C~N,
CH3
Oy N
H3C\ /O
H3CH3
H3Cv CH3 I \
0 0 / ~H3
N" N NJ~N N, CHa
IOI 0 0
0
OT N F F
H3C~/ 5
"'C~cF6
H3CV CH3 I \
0 0 / iH3
~ H,
C C ~N N~N NC~
O O O
H3C 0
0 N
N F F
H3C X I-I3C CI-~
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cH,
x ~\
0
0 0
N~Clt
"..'Y
N N~N
O O O O
O\/N F F
H3C~~jfO"
H3C CH3
F F
X
0 0
N NJ~N O
O O O H e N,, CH3
3
ON
y F F
H3C~0
H3C CH3
F F
X \
n jooY
II N NJ~N 0
0 O VCN
0 N
F F
H, IO
"~C~CF6
0 0
aN~N~N 0
HC CH N
H3C~0 0 ~O HsCC~
Oy N
H3C~O
H3C CHa
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-126-
~ I~
~
o O
N N~ O
N
H3C
~C ZN O O O HaCCF~
O~N
H3 O
F~C 'CH~
H'\/CHs
~
0 0
~N ON~N 0
H3C CH3 II
HaC O 0 H3CiN, CH3
OY N
II3C\ /O
H3Cj~CH3
H,C ,CH3
/~P\
0 0
C N N~N O
C ~ ~
~ O 0 HC' N~CH3
ON
y F F
H3C~/ O
"'C~cF~
H,ov N
0 0 cH,
C CH3 ~ ~N N~N N,C~
H~~C~ O OI" 0 0
O~IN
CH3
a N
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H3CvCH3
O
N NH2
H C CH3 N
H3C~0 O 0
ON F
HC y
N
I ~
0 0 ~ CH,
~N NAN N\C
0 0 ~
c0
H,C, o Oy N
N
~C~ C~
ti~C
H3CvCH3 I \
0 0 0 CH3
CH3 N~N N, C~
H3C' '~
~C'x~~' O 0 0 0
Oy N
F
H3 O
H3C
C"~
F6CvCHa p 0
O CH3
N N N ""J~N N
~CH3
0 0 0 0
0\/N
~" F
H3C' /0
H3C~C"H3
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-128-
H3C~CH3
O
N NHz
0 O
0-~Xo
0 N
H3C N F F
H3C~CH3
0
N NHZ
~C p 0 O
HsC C
0 N
H3C ~ F F
H3pCH,
0 o CH,
C ~ N N N~N CHa
~C ~p 0 p
O~N
F F
NN
C
H3C /CH3
Qx\ I ~
0 0 CH3
N N N~ I
H C N N, CH3
3
O 0 0 0
Oy N
H3C>/ O
H3C CH 3
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H o
N NH2
Y
CF3 Nu
I N N~O 0 O
O
I
~
or a pharmaceutically acceptable salt, solvate or ester thereof.
In one embodiment, the HCV protease inhibitor is selected from the group
consisting of
H O
N NH2
N
NuN~O O O
~ IOI =
Formula Ia
and pharmaceutically acceptable salts or solvates thereof.
The compound of formula Ia has recently been separated into its
isomer/diastereomers of Formulas lb and Ic. In one embodiment, the HCV
protease
inhibitor is selected from the group consisting of the compound of Formula Ic
and
pharmaceutically acceptable salts or solvates thereof as a potent inhibitor of
HCV
NS3 serine protease.
CH3\,,CH3 CH3\,,CH3
H O H O
OyL-NH2 QN\ yNH2
CH3 H3NUN~ 0 0 CH3 H~NUN~ O O
~ II O T II O ~
CH3 OCH CH H3 CH3 OCH ~HCHs
3 3
Formula lb Formula Ic
The chemical name of the compound of Formula Ic is (1 R,2S,5S)-N-[(1 S)-3-
amino-1-
(cyclobutylmethyl)-2,3-dioxopropyl]-3-[(2S)-2-[[[(1,1-
d imethylethyl)amino]carbonyl]amino]-3,3-dimethyl-1-oxobutyl]-6,6-d imethyl-3-
azabicyclo[3.1.0]hexane-2-carboxamide.
Processes for making compounds of Formula I are disclosed in U.S. Patent
Publication Nos. 2005/0059648, 2005/0020689 and 2005/0059800, incorporated by
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- 130 -
reference herein.
Non-limiting examples of suitable compounds of formula Il and methods of
making the same are disclosed in W002/08256 and in U.S. Patent No. 6,800,434,
at
col. 5 through col. 247, incorporated herein by reference.
Non-limiting examples of suitable compounds of formula III and methods of
making the same are disclosed in International Patent Publication W002/08187
and
in U.S. Patent Publication 2002/0160962 at page 3, paragraph 22 through page
132, incorporated herein by reference.
Non-limiting examples of suitable compounds of formula IV and methods of
making the same are disclosed in International Patent Publication W003/062228
and in U.S. Patent Publication 2003/0207861 at page 3, paragraph 25 through
page
26, incorporated herein by reference.
Non-limiting examples of suitable compounds of formula V and methods of
making the same are disclosed in U.S. Patent Application No. 10/948,367 filed
September 23, 2004, and the preparation of the compounds are detailed in the
experimental section of this application set forth hereinbelow.
Non-iimiting examples of suitable compounds of formula VI and methods of
making the same are disclosed in U.S. Patent Publication Ser. No. 2005/0085425
at
page 3, paragraph 0023 through page 139, incorporated herein by reference.
Compounds of formula VII-IX are disclosed in U.S. Patent Application Ser.
No. 10/993,394 filed November 19, 2004, and the preparation of the compounds
are
detailed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds of formula VII disclosed in U.S.
Patent Application Ser. No. 10/993,394 are:
o
0
q/,\D q/: N N N N NN
X O, S
O1
o j~l O o j-~ ,'o 0
O'g H~NHN OH O1'S~ N H'N~C OH
N N~O N ~N HN
O O;
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-131-
o
N H N \NN
S p S
O. p p O t~p O
H OH
H ~ HN OH O.,S N H ~p HN
p\~S~N NN
H O p
3
O /
0
H H
N N N
N NN
O, ~ p O \ o
O O
~~i ('~ H ~~( OH ,O H ~OH
H3C O~~S N N\IN~ HN OIS-N NN HN
CH3 (Or O_
/ O
O
q/:N q/:N H
NN \N~N
S p S
~ \r
O, p O p 0
~/~ O H OH
p'.S~ N H'N" ~ OH p'S\N N N HN
"'~r CS, NO N ,p O ,
O o
q/ N N\N ~ H
O \ S ~ p ~
' p p 'O
O H OH O.~S N N N N N HN OH
O~. // H ~
S Drl~-N,~ HN; C\S ~ p
N p ~ O~
N
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-132-
O
0
N N N \ / N
\N H
O, S Y
O O S /
O O
O H C~'~ O
NN~ HN OH N H N HN OH
~ g O
~ O ~O
/
/ 0
O
N H N N N
\ NY O \ s /
O O
o, / ,
S O ~ OH
/~\ ,,O O H H ' J~ OH NYN~ HN
N N N
O:tN~ ~O HN
O
O
/
0
\ / N N N N N N
\ ~ o, S r
0 \
o, o S ~-~ O
O
N H N OH O~. ,P H H N OH
HN S- N N~ HN
O lS\ 0 O
O
O/
-
q~\/ N N H \/ N N H
\ ~~N
o, S \r O' s
O O O
OH OH
O~N'N , O
O O HN N YN~ HN
O
O
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- 133 -
o
0 i
N N N N N N
p, S
O,
~ s
~/~ p O
H~ OH
H S N N'N ~HN OH O'S~ H
O
\p N' N O N Z ~p HN
~%
O/ O(
)N
N N N N
S
p, o s
o po
H -N ~ OH
N~ ~NNN N HN OH O.~ H
)SNThYNHN
p
\ ~ N N N N N N
p' S
O, S
O O
p N H N ' OH
H ~NN N N N HN OH 05NHN
Y N p p p
OO O
N N N N N~ N
S r p, \ S r
O,
O H O H /~ ,,O
I\ NN HN OH I\ NN ~~/~HN OH
F ~ 0 i ~ N / o~ p ~
I
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-134-
/ o
0
N
N N\ N N H
\
O, \ S O' O O
O H OH O, /~ N H HN OH
l~0 O
N N~ HN S i O NO
o O
/
0
N N -_
~ J ~ ~ 01, Ol 0 O 0
( O OH
O H '~ 'C
O H ' OH O~ // H N '~HN
~ S N N N HN SN ~N
O
~
/
O/ O
N ~ N
- ~ ~
~ j O,
O, O O O
O O H OH
OO N H OH O~~S N N N~ HN
N O N~O O O
CH3
O O
N
0 \ \N\~N
1 N\N
~ ~ S 01- S
O. O 0 ,_~ O O
i~HiN OH
O. 0 H f~ ~N' OH O-.S~ H H N
HN N
N N\
O O
CH3 0
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-135-
o 0(
q/,\ N N H ~N~ 'NN
O, S O S
O ~~p p O
O
O~. % H~N' ~ OH O. ~~ H H~N OH
H3CYS= N N HN S' N N~ HN
ICI-g O; O O O
N
~ \NN N
p S \\N~N
S
/~ O O 01.
O, "P H H'NJ~ OH p -~ p O
S'N NNZ HN O.S' N H'N~ OH
O O ' N N~ HN
p
/
0
/
O
\ / N N N
01. S N~NH
O O, S /
O
''S N N H " HN OH H H N" O OH
N O ~p N ~N\p HN
S O
\ ~ N N~ NY \ / N N H
~~NY
o, s / X
~ O O O1 S /
O p H ~ OH Q"t NNHOH
H~ N
N ~ O p
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-136-
o O
N N N N N N
- Y
O \ s ~ \ S /
O n ,O O O n ,p O
'l'r( .''J~( OH
N N~ HN OH O S:N~ HN
O O ~N3 O'
S
O
N N N N N H
S
\ S
Y
O, O O \r O, /
O.,o H OH 0 ~ p p
\S,N N 'N HN : N H~N' ~C OH
O O N
O O O HN
O/
O
N N N
X C
~- NN
O, S Y
~~ O p pl S /
O,S~ HN' OH O ~O O
N N N HN p';S N H~N' * OH
O p N N -N, HN
O
N N N N
X S / Y \N~~N
p p pl S /
O,
N OH ~O
N~N N~ HN O.~S~ N H~N' O OH
3 r ' O XN
N
yN~ HN O 0 ~ Z O
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-137-
o
0 ~
N NNY N N N
O, S \ g
/~ ,O ~ O
'l~( ~~~
N''N _-6 N N N HN OH 0~.0 N N'N N OH
p N N ~ , ~
o
0 0
N N N ~ N H
O, S ~ O, S
O O 0 O O O
N HN' OH N H~ OH
N~ HN HN
F i o; o,
~ o
0
N
N N N f\ \ N H
\~ N
X S p/ S
O O 0 p
N H~ OH O~SO N H~ OH
N, HN N N\~ HN
~ O
~
O O
qk\/: N N~ N ~ N N
O, S ! O, S/
O 0
HCN'~(p~OH
O~S0 N H~O~OH OI.S~ H
' N N~O HN c5i N oNC~"D
HN
"Dr S
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- 138 -
0 i o
N N~ N
O, \ / N N N
\r O, S /
p O
O ~~~O H OH
~ ~O ~ .S~ N H'N' ( H~N'
N N N~ HN N N HN
O p
O
O
q/:N q/::N
N~ N \ N~~' N H
~ p S ~
O,
p p p 0
~OH
O., OH ~ N H N <
S-N N 'N HN ~S N HN .
o
p
o
0 /
qD:N N H N N~ N
O, \ S / O g \r
/ ,,O O l p O
t OH ~
O\S N N~ HN p~'S N OH
HN
O O O
O pp
~
~ ~ N N\ N ~ ~ D N H
O, S / O, S \r
O
p, s H N OH O. "P H N OH
' 0 p O O
,
H N rp HN dNON
O p
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-139-
/
O ~
O
N H
N~N q/:N N N
O S S
~ O,
p p O r-~ O O
H3C p\S N N N HN OH O.SD N N
Y HjN OH
N yCf-13 "~ O~
o / 0 /
N NN NN
O \ S O S
O 0 O 0
OH
O~ ,~ T H~ OH O,.S,O
H N
-~ S- ~HN N HN
I I O
~ S N O = O Z
O
N H q/:N /
NN \N\N
S o, S
O 0 /~~~,, O O
OI~S~O H~ OH O=S N H~N~K OH
N ~ HN ' N I ~NO HN o;
I~ .N S
O
DN N H N H
NV _ N~N
O, S / pl S
O O O 0
~ OH O
0~ O N'N HN H~ OH
'~ O N ~N HN
O 1 O 0
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- 140 -
/
O
o
'- ~ N
H
N N N NS N\
\ S Ol
O
O, p O
p O O H~ OH
H N OH HN
N prN HN p O
O O
~ N N\ N N NN
O1 / O, S
O /~ O 0 p p O
p H~N/~( OH p~'S; H N OH
N HN N N~~ HN
O; ~ O
S
O O
~ N N N / N N H
p Y O Y
, i , S 1
C~p O p O
O.,S~ p H N OH H OH
N )_ HN N rN~~o
HN O
p
=
O O
N N~ N N N~ N
p Y Y
,
p o O, \ 0 1
O
o.' S~s H N OH O,s CrH N OH
N., N HN N ~ N~ HN
p 0 z
0
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- 141 -
0 0
\ N N\ N N N H
, r , N
S
O o S
p o ~ 0 o
NN CrN~_~o N HN OH O~S~ OH
~ HN
~ Z
YN~ N N~
p
DN ~NN N N
O, ~
p,
p p p
OH 00 p H 'N' ~( OH
OoOHN :N N N
~O
0 \ N N N N N
O, S O, S \r
O /~ O O O n,,O p
'I~( '~ OH
I\ ONN HN ,= OH ON~ HN '=
F / O O Z
O/
/
N N N N N H
C S ~~-N
O, X
O p ~ S
O
~ OH O
N O N Z ~ HN : N ~ O~ =, ~ p OH
r G
S,N O~HN Z and 5 or a pharmaceutically acceptable salt, solvate or ester
thereof.
Nonlimiting examples of certain compounds of formula VIII disclosed in U.S.
Patent Application Ser. No. 10/993,394 are:
CA 02611145 2007-11-29
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- 142 -
o
O ~
N N N _ N N~ N
, \ S ~
01. \ S O
p ~l p 0 ~p O
~ H~N/ OH O. s~ H OH
O.S' NN I HN S.N ~N~ HN
O ,i 0 O
--7\ ~
O p
N N NY N N N
X S _ \~-
l p p O
~ ~
S N :rN y N HN : OH O.~S~ N H~ OH
~O N ~N HN
CH
3 p '
0
O
N N,~ N
O, \ S / N N N
~ p O ~ S !
C/, o,
p, "p H C/L~- p
OH ~ O
f-3CS, i N O yN N p HN O~S~ N HN OH
~i I / I N Np HN
CH3
O p
N N N N N N
\ S ~
O, S O
p ,
O p ~p
O.,S N N c2HOH O.S~ N HHN OH
HN r N YN
O
lv) O
0 6
CA 02611145 2007-11-29
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-143-
/
0
\ / N N~ N N N H
0' ~ S S N
O o,
O O O
H N OH
S: H
H \\S N N~ HN OH ' O
o/
I I O -, N N~HN
~N O~ \ S o
0
/
0
O/
N N H
_ C S N \ / N N H
O' O O ~rN
H OH O S
O O
3 N NH 0
~ N
N ~N\ HN OH
O O ~
O/ O
N N H \ ~ N N~ H
\ S o
O, X S 0 NY O, O
/ O
O N N H HCN" O 0
OH N HNoOH
N~O HN~ ~
~ O
o
F'~F
q,\/DN
N H
N
O S Y O, S
X N\N \ \~No
0 O O / ~O O
H OH
N N'N N' OH N N N~ HN
~
o ~ - 0 _T\ 0
CA 02611145 2007-11-29
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- 144 -
/
/ O
o
N N H N NN
~ S N
O O \ o
p
O p p~. 0 H H~ N~
O . ~ S 0 N ~ N N roHN H
N ~ HN H ~YH
,0 1
o
0 0
N N~ N _" N
O \ S O, S /
~O 0
N
\ ' ~( O p
N:'N NN~ N~N NNN OH
HN H HN
O O O O
/
O /
O
N N N
N N N~
~s ~ s ~
o, o,
p o
~p O OH o H ~~ OH
O H
''N N C~ HN , I\ NN~~ HN
O O
0 6
o O/
q/:N N N N N N
~ S
Y O, S
O, /
~p O Q}-OH
O}1 NN N HN N\ HN
O O
F
\ / and
or a pharmaceutically acceptable sait, solvate or ester thereof.
Nonlimiting examples of certain compounds of formula IX disclosed in U.S.
Patent Application Ser. No. 10/993,394 are:
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-145-
O
0
~ N N
N N H
_ q/:N
O, S Y \ S N
O / , O ~
O. si H OH O O
S'N N~O HN I'S N N N N HN OH
O
O/
N N H
N H
O_ \
O \ S
/
C~i0 ~ S
O O O
O. ~C OH O. s~ H H~ OH
C N N~ HN / \~N NN HN
H3 q/,\::N O/
N N N H
~ S Y _\ \
N~N
O,
O O S
H3C ,S: N H'N OH O,s0 H ~O O
N N HN S, N H N OH
I O \ N o N~O HN
CH3
O
q N
N N / ~
~
S O
01.
o ~ s
H OH O. ~~ H ~S. N NN~ HN H OH
0
'S~N N HN
a O ~ ~ ~O
CA 02611145 2007-11-29
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-146-
/
o
0
N N H N H
\ ~'N \N~N~
01. S O S
p
0 '=0 O
~ 0 H '~( OH
p~'P H H~N' OH 0,1: N N HN
S NO N\~pHN, N O ~O
~N
O ~
O
q/:N NN N N N
~ S ~
O, pl
p p 0
~ OH O ~p
O\~ N N'N HN N H'N' OH
S ~~p N N HN
'.
O p
/
/ 0
O
N H N H
NS NY pl o I
p, p O
p p O N H~ OH
N H OH HN
N 'rN~O HN O Z O
O
O \ N N~ N N N N
~ Y 01. \ S
p' p / O
p p
O
~ OH O. /P H H~ OH
yN~ HN : ~S'N N~N~p HN
O O I IJ O
S
CA 02611145 2007-11-29
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- 147 -
o
0
N
N N~N ~ \N~N
p, ~ S r p1 S
O p ~)oO
p'Sp N H OH N H OH
~
N HN
N N~ HN N O
(:\j p
o
0/ o
N N H N N N
\ N
S \r p s
o,
o
O. ~0 H H~ OH OI.S~ H H~ OH
\\S.N N O p HN N N HN
p O
Ol O
N H / N
N N
NY
o, s i l s
p o o
O\ ~O H H OH O.S~ N H~ OH
NN N\ HN : N N ~N HN
p , O O
, O/
O
~
N N H \ ~ - N NN H
-_ ~ S Y p' '
rN ~ ~'
O, p O p O
~ OO N H N OH
N-N N N~ HN ' OH ~~ ~N ~ HN
p O
0
CA 02611145 2007-11-29
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-148-
0 0
_N N N N N~N
p S p' ~
S ~
~ O 0 ~O p
H
I\ NN~ HN OH NN~ HN OH
~ O _ p O
F
O O~
N N N N N N
~~-~
o 1'
S o Xs
p p O ~ 0
p H
H N OH O. ~P H OH
0 N~~O HN N N O N~ HN
/
0
qO
_N NN N
D
O S ~ NN
O 1~i O O, S /
N OH p
0 O
HN N HN OH
O p N HN
O ~ O .
/
O
0
N N N N N H
O' S ~ O S /
p p O ~p O
0
O\S i N HN : OH O,S N N N~ HN OH
~ _ O
CA 02611145 2007-11-29
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-149-
0 / o
N N H N NN
S p1 \ /
O, p p =~ O
p\~S0 N H ~ OH O~S~ NN NH (~N~~/~(i OH
HN
N HN
'CH3
/
O O/
N NyN q/:N N\ N
, p p O o
S' 'Y ~
H C ~ ~ H H~ OH pIl ,~ H H~NJ~( OH
y
3~S.N N N~ HN : SN N N HN
CH3 O o
O/ O
q/:N q~\/ N
NN \NN
g pl S /
O,
O O O
N(~N~1-~Cer OH
0 \~S N H~ OH O"S~ H
HN
i N~~ HN 0 \
CS, O
O OJ
N N H N N H
\Ny Y N
01. S / S
p p o
(
, s H ' OH O,,S~ N H N OH
oIS,N N N N HN : - N yNHN
O O -
L ~O ~
N
CA 02611145 2007-11-29
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- 150 -
0 1
0
N N N N N H
01, S /
O
p O O ~ O ' O
p N N N HN OH N H'N ON
N y-N
O ' O
O/
/
0 q/DN N N~ N \N~N
p, S
O1 ~ ~ p O O
p O H ~ OH
O N H~ OH NN~ HN
N yNO HN O O
O
O O
~
N
N N ~ ~ N N\\N
Y S
( O, O /
p, \ 0 O
0 ~
N H~ OH O.S0 N H~N" ~, ~C OH
HN N N\ HN
O p ~ V O O
S ~~r
O O
-_. ~--
N NN N N H
~r N
p, O O, O
S,O OH
~ dNN'1HN
CA 02611145 2007-11-29
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- 151 -
0 0
\ / N N N N \~ N N
~ - ~
o, s o, s
o 0 o
~50 N HN' OH O,S~ N HN OH
N N\HN N N ~NHN Co p -
O
N N~ N N N~ N
O, \ S / p, \ S /
p O p O
0 0 N H N OH 0 0 H HN OH
N N ~N\ S
HN Y N N N~ HN
O O
O s
\ /_N N~ N N N N
O, \ S / p, \ S /
OH H
' p (
OH
N''N N~ HN NN NyN \~'RHN H p Ipf
Ol O
N N
N N \N~rN
X S Y p, s Y
01. / p /
p O p QeO
H OH
NN~ HN OH NN~ HN
O O
F
CA 02611145 2007-11-29
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- 152 -
/
o
N o
N N N N
H
~YN
S
o,
o ' o
N N N HN pH O"S~ N N' OH
~p N
and
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula X are disclosed in U.S. Patent Application Ser. No.
11/065,572 filed February 24, 2005 and the preparation of the compounds are
detailed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Patent
Application Ser. No. 11/065,572 filed February 24, 2005 are:
v
O 0
N NH2 N N NH2
N
O O O O O O
p Oy NH OLJLNH
V
H H O
N N NH2 N N NH2
p O O p O O
p Oy NH p O\/NH
NH ~N(H
p I /
CA 02611145 2007-11-29
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- 153 -
H O H O
N N NH2 N N NH2
O O O O O O
O Oy NH O O (\/NH
NH N~ 'NH
~ /
CIcI
O H 0
N NH2 ~N NH2
N ~~0 O
O O O O NH
O O~NH 0 H
NH
H O H O
N N NH2 N N NH2
00 O 00 O
O Oy NH O O\/NH
~ 11 NH N' 'N(H
HO I ~ ~'-S
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-154-
'Y
o ' o
H
N NH2 ~N NH2
N
00 O 0o 0
O NH
O O\/NH 0 ~
N '((J5NH CI
cI V
H 0 H 0
N N NH2 N N NH2
O O V O O O
0 Oy NH 0 O \ /NH
N~ NH NH
S S
V
H O 0
N N NH2 N N NHZ
O O O O O O
O ONH 0 Oy NH
5NH
()-l) NH
CA 02611145 2007-11-29
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- 155 -
O
N N NH2 N O NH2
N3-'
00 O 0 O
o O'/NH
'( O Oy NH
5NH
~ j ~ NH
~ _S
CIcI
x
H O N 0
N
~'
N NH2 9--~-
oo
Nj~o O O
0
O ~ NH o O HNH I~
0
NH
H O H 0
N N NH2 N N NH
00 0 00 0
O ~NH F F o O~
NH NH
F O)JNH
CA 02611145 2007-11-29
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-156-
~ ~
O
O
N N
HZ NH
N 2
O 00 O
O Oy NH
O~NH
NH
NH
O
H O H O
N N NH2 N N NHZ
O O O 0 O O
Oy NH OH 0 O~/NH
NH 5.JLNH
O O 0
H H
H
N N N,-,,-,, N N NH2
O O O O O O
0 O (~/NH o Oy NH
'NH NH
CA 02611145 2007-11-29
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- 157 -
H O H O
N N NH N N NH
O O O O O O
O O\/NH O O ( ~/NH
O~NH ~" 'N
V-
O H O
H
N N NH2 N N NH2
00 O 00 O
O\/NH O O (~/NH
'N(H ~NH
O
O o
N NH2 N N NH2
N ~
Y I ~ 0 0
O O
O
O o O~NH O NH
'"H
NH
1/
CA 02611145 2007-11-29
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-158-
V V
0 H O
N N NH2 N N NH2
p0 O p0 O
p OVNH O'/NH
~N"H
V V
:-
0
N N NH2 N N O NH2
p O O
O O
0 O NH O
H OH
0
V-
H 0 O
N N NH2 N N NH2
p O p >p O O
0 p~/NH p Oy NN
'( NH
NH I
CA 02611145 2007-11-29
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- 159 -
CH O H O
N N NH2 N N NH2
pp p 00 O
O O~NH O ONH
NH 'N(H
O 0
N N NH2 CN3-y N NH
2
Op p O O
O Oy NH
0 O~NH
*NH H
~j}H
O 0
N N NH2 N N NH2
p0 p 00 O
O Oy NH O~NH
NH
NH
4Y6
0
CA 02611145 2007-11-29
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- 160 -
y V
O H H O
H N N N N NH2
N
0 O OO O
ONH II O NH
'N( H O y
NH
O
H O 0
N N YNH2 N N NH2
O O o O O
O ~ O~NH
0 O~NH
~ NH
~ NH ~
I ~N
F ~
V
0
N NH2 N H O N
N
O O O O O O
O O\/NH
'H O~NH
N( I I
NH
0
CA 02611145 2007-11-29
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-161-
~
H p H O
N N NH2 N N NH2
p O O p O O
O pYNH p Oy NH
NH NH
O
~ V
H p H O
N N NH2 N N NH2
p0 O p0 O
p Oy NH p O\/NH
~H
NH SI /
p O
N NHZ N N NH2
N
O O O
p p Oy NH
p O y NH O O
~ NH
~pIN NH ~ S
CA 02611145 2007-11-29
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-162-
V H O
O t N NHZ
N NH2 p O O
00 O oO\'NH
O O\/NH ~ NH
41) 'N(H CiI /
V- V
0
NH H 0
N H 2 N N NH
p0 p 00 O
O Oy NH O\~NH
NH '~"
NH
NCS
V,
H 0 H 0
N N NH2 N N NH2
00 O O
0 Oy NH Oy NH
cJt(NH ~ NH
N
0
CA 02611145 2007-11-29
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- 163 -
V
O O
N NN N NH2
N
O O
O O O 0
\/NH
0 NH 0 0 ~"
y NH
NH
O
Y6
v
O 0
N N NH2 N N
Op p 00 O
O O\/NH O O O'\/NH
cryH NH O p
N N NH2 N N NHZ
O 0 0
O o O
N NH O a 0 NH
y ~
V)y 0
0
CA 02611145 2007-11-29
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- 164 -
y
0 0
N N N N N NHZ
p p p p O O
0 OyNH F F 0 O\/NH
NH F fAN' 'H
V ~
H O H H 0
N N N~~\ N N NH2
00 o p0 O
0 OyNH 0 O NH
C
IH
jr) y
H
O ~ V
O p
N N NH2 N NH2
p O O p O O
0 O\/NH 0 Oy NH
'~ NH
N
CA 02611145 2007-11-29
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- 165 -
O
N N NH2 H 0 H
00
N
O O O
O
O O I NH 0 O y NH F F
F
NH
~ V
O O
N N NHZ N N NH2
O O O O O O
0 Oy NH 0 Oy NH
NH NH
I
N
H O H O
N N NH2 ~~N NH2
00 O ~"OYO O
N Oy NH 0 O \/NH
NH ~N(H
0 I
CA 02611145 2007-11-29
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-166-
~
O 0 N NH2 ~tHV H
N ~o o O
00 O
O NH F
O Oy NH 0 H F F
0 NH
NA
~ v
O O
N N NH2 N N N
O O O O O O
O Oy NH 0 O (~/NH
Br N~ NH 'NH
I / iN
H 0 H H 0
H
N N
N N N
O O 0 0 0
0
O O \/NH O Oy NH
(::ryH 'NH
CA 02611145 2007-11-29
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-167-
~ CIcI
0 ''
N N NH2 N O N
N ,,J~r,/z,,
00 O 00
0 0 O~NH O O\/NH
NH NH
V,
O O
N N Nc H NH2
O O O O O O
O Oy NH 0 Oy NH
NH NH
S
V-
H O H O
N N NH2 N N NH2
O O O O O O
O Oy NH F F 0 Oy NH
5NH F \ NH
I / I /
CA 02611145 2007-11-29
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- 168 -
V
H N O H H O
N N NH2
00 O pO O
0 Oy NH
O\/NH
NH ~"
NH
O
v
H O O
N N NHZ N NHZ
p O O p O O
p Oy NH p Oy NH
I N NH NH
V
0 H 0
H N N N~/\ C)H N,
N
O 0
1 1 y
p p 0 0
Oy NH p Oy NH
NH
NH
N ~
0 ~S
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-169-
V
H N O N H 0
N CN N NH2
O O O
O O O
ONH
NH O O\/NH
y
O
V V
H O H O H
N N NH2 ~N
OO O 00 O
O OVNH O OVNH
F F NH
NH
N
O
H 0 H " II N N~,~
N O O O
O O O 0 O O~NH
Ny NH NH
V---Y 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969 ~
O O H
N N N~ N N
00 O 00 O
O O'/NH Oy NH F ~.
'N~H NH F
O O
N N N~ N N NH
00 O 0 O O
O O ~~rNH O OvNH
'NH 1NH
V
H O 0 H
N N N,_,'-,, N N~/\
~
p
O O\~/NH F F O O~NH
'N~H F N\ NH
{ ,
CA 02611145 2007-11-29
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- 171 -
V
o 0
N N N NH2
N Q
00 O >1~00 O
~ /NH
O ONH / O O\
-N 'N( NH
NH
V
0 O
N N N N N N,
O O O O O O
O Oy NH O fL:L
y NH NH
H O H H O H
N N N~/\ N N N,
0 0 O >0 0 O
O Oy NH O Oy NH
NH NH
N
I
CA 02611145 2007-11-29
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- 172 -
V
H O H
N N
O O O
O OY NH
NH
V V
0 0
N N NH2 N NH2
N
00 O 00 O
O\\/NH O\ /NH
'N(H ~NH
N N
O OH
Y
H O H O
N N NH2 L N NH2
O O O 1~
O O V
>~,
Oy NH O\/NH I NH ,, 'N( H
O O O
&\o &\o
CA 02611145 2007-11-29
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-173-
~
H O
H O
N N NH2 N N NH2
O O O O O O
NH
ONH 0 XH
~- NH , O-~ ~
O O O
0 0
N N NH2 N NH
2
00 O N 0
~ 0
ONH
NH OyNH
,,.
O, ~O NH
~
O
X
H O H O
N N NH2 N N NH2
00 O j'~00 t 0
OY NH Oy NH
NH NH
O O
O
CA 02611145 2007-11-29
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- 174 -
V-
H O H H O
~/N N~~ N N NH2
I'~O~O O 00 O
O Oy NH O Oy NH
O NH io NH
H 0 0
N N NHa N N NH2
00 O O O O
Oy NH O\ /NH
XNH NH
O O 0 O
O O
N N NH2 cyNH2
00 V 00 V
QOYNH
NH
O
,, N
H ~ee, NH
~ ~
O O O O
CA 02611145 2007-11-29
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-175-
~
O H 0
N NH2 N N NH2
N
O ~0 0 O
O O OY NH
p O~NH
NH
O NH O O
H 0 H p
N N NH2 N N NH2 p0 0
p0 O
a' OyNH Oy NH
1NH ,, NH
~
010 p p
( \ &~o
H O DJ&JL1 O
N N NH2 N NH2
pp 0 ~~pO O
Oy NH OY NH
NH NH
O O O O
&\o
CA 02611145 2007-11-29
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- 176 -
Y X
H O 0
N N NH2 N N NH2
O O O O O O
Oy NH O \ /NH
NH 01, ~N"H
O O O1O
~
~ O VI-I
CICI V
:
H 0 H O
N N NHZ C~j N NH2
O O O O O O
OyNH Oy NH
-~ /NH NH
/O v-"'-O O O
H 0 H 0
N NH2 N N NH2
00 O 00 O
OiH NH ONH
, NH
KIJI-.O ~
~
O O O
~ /\
CA 02611145 2007-11-29
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-177-
~
H O O
N N NH2 N N NH2
0 O 0
0 ~ 0 O
NH
O~NH
NH
Ds,, NH
010 ~
O O
x O
N N NH2 H O
0 0 O N N 1INH2
Oy NH F O O O
F F
NH
4,, NH 0 Oy
~ :ONH
V-' F
O
c~LYo N NH2 N N NH2
OO O 00 O
Oy NH Oy NH
J=,, NH O,,, NH
~ ~
O O O O
CA 02611145 2007-11-29
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-178-
x CICI
O O
N NH2 N NH2
~N'
p 0 p p 0 O
Oy NH py~~NH
~' NH
NH
~~,
~
O O
O O
I \ ~
0
Y
0 H
N NH2 ~N NH2
N ~p p V
pp O
0 NH Oy NH
y NH
NH
O1O
p
H 0 0
N N
NH2 N N NH2
r _~
p0 O pO V
Oy NH p \ /NH
, NH F ~N"H
~ F
O O F O O
I \ ~
CA 02611145 2007-11-29
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- 179 -
V-
S~
H
0 O
CN N NH2 N N NH2
O 0 O ---0 0 O
O OyNH 0 OyO NH
INH O NH
x O
N NH2 H O
IN N NH2
O 0 O N
O O O
O NH
NH 0 O NH
, ~
~ NH
O O
Y CI~CI
~
H O H 0
N N N H 2 N N NHz
0 0 O O O O
Oy NH OyNH
NH 4/NH
O O 010
CA 02611145 2007-11-29
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-180-
N p NHZ V
N O
p p p c)NH2
O NH jO~O
1 O
NH p OyNH
~c I p NH
O O p X
p o
{ { NH2
~N
~N NH2
p 0 V
~~p 0 O p NH
p Oy NH ~
F~ , NH
p NH
F O O
O
V V
H O H O
N N NH2 N NH2
p0 O Np0 O
Oy NH O'~NH
0l,,, NH ~',, 'N( NH
~
O O O O
~ F
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 181 -
X
o H 0
N N NH2 N N NHa
p0 O p0 O
0 NH
NH NH
F F~
xY
010 O O
~ ~
i /
CI\/CI
H p Y
N N NH2 H O
p o O N N NH2
ONH p 0 O
NH
O O\/NH
1 O \N( NH
~
O O
~ CI~CI
~~ y
H O H 0
N N NH2
N N NH2
c~ '~ r
O O
p p
O O
OyNH O'~NH
,, NH I 'N( H
~ 0 0 0 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-182-
X
H O H O
N N NH2 CN3-y N NH2
O O O O O O
Oy NH 0 ( '~NH
NH 'N H
1O O 010
H O H 0
N N NH2 N N NH2
000
O O O O O
O~NH O~NH
F F
I NH NH
xo
O O O CICI
H O H 0
N N NHZ 'ND-Y N NH2
O O O >~io O O
Oy NH Oy NH
NH F -, NH
F F~
O O O O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 183 -
V cici
- H O N O NH2
N NHZ (:~, N o0
00
O NH Oy NH
O y NH
~O NH 010
V- V-
O 0
N NHZ N N NH2
00 O 00 O
O Oy NH O Oy NH
NH 0 NH
0 0
N NH2 N N NH2
CN~'y ~
O O O O O O
OyNH OyNH
NH
,
,, NH
O~O
~
O O
~ I ~ ,s'
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-184-
~
H O V
N NH H O
N NHZ
O 0 O N
O~NH O
~, O O
, NH 0 Oy NH
~ O NH
O O
I F
V ~
H
N NH2 N N NH2
\Yo O
N
00 0 o0 O
Oy NH
O Oy NH
NH
O NH
o O
~
CICI
0 O
~ N NH2 N N NHZ
OO O ~OO O
O~NH
O O~NH
~1 ,,, NH
NH
O~O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 185 -
H O H O
N N NH2 N N NHZ
O O 0 O 0
O
Oy NH O\/NH
FF NH 'N(H
F 0 0 ~
-~~N
O O
v
0
N N H O H
~N N
N Lyr0
00 O
0 ~00 O
0 NH ~ O NH
N
7H
0 0 I I
O~O
H O H V
N , H O H
O 0 0 N
0 NH O O O
NH 0 Oy NH
O NH
O O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-186-
x
H O H O
N N NHZ CN:'-y N NH2
O O O O O O
OyNH OyNH
NH
F
NH go
F F~
O O x
O H 0
N NH~ ~N NH2
N ~o ffo o
O O O OY NH
O~NH NH
- NH o, ~o
~
O 0--~
H O
N N NH2 O
H
O O O CN N NH2
Oy NH O O O
NH O O NH
010 H
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 187 -
x
H O H O
N N NH2 N N NH
O O O O O O
Oy NH Oy NH
NH NH NH
O~ olo
C IC I C IX C I
O
0
N N NH2
N N NH2
O O O O O O
Oy NH ONH
~~.,, NH
41, NH
O O ~
O O
I \ ~
ci~ci
Y
O 0
N NH N NH2
N 2 ~o 0 0
O O O 0 NH
NH
O y NH 10
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 188 -
cixci
0 v
N N NH2 N O NH
N 2
O O O O O O
Oy NH O Oy NH
, NH ~ cco)L~
O O V
o
N O
NH2
N ~o 0 0
0 0 O OyNH
O Oy NH NH
H Oo
40Y
&0
x x
NH2 NHa
(Yo
O O O O O
O~NH
O~NH
' NH 4NH
~ '
O~O
~
O O
~ I /
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-189-
X
o
N0 0 N NH N O O NH
2
0 NH 0
y O'~,,NH
0NH '(
NH
O 0 ~
~ 010
v x
0
N O N N N NH2
N ~O O O
O O O
0 NH O NH F F F
1., NH
O ,,,NH ~
O O
O
&~o
~ O V,
N NH2 H O
N N NH2
O O 0 N
O\/NH F F O O O
'N(H F O'\~. ONH
~ 'N(H
~ O
-- 0 \ O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 190 -
V-
N O N N 0 N
'
N ,
00 0 00 O
O OyNH O Oy NH
INH O 1) NH
x H O V-
N N NH2 H 0
H
0 0 O N N N
ONH O O
y O
NH O OyNH
'~1 -~O NH
0 0
O
~ V
0 H O
N NH2 N N NH2
~
00 0 00 O
O OyNH 0 O Y NH
NH H
O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-191 -
H O 0
N N NH2 CN N NH2
00 O OO O
ONH NH
4,NH
00
O NH
010
V N O NH2 N O N~ H
N
00 O 0o O
ONH OyNH
~ NH NH
O
O O
O
N O N ~N NH H N
~~ 0 O
~~0 O O
O NH OyNH
~,, INH
XH oõ
, O O
O O
~ I /
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 192 -
\y/ V
O
H
N N NHZ H 0 H
~0 O O N ,
O NH 0 0
O
NH O NH ~., Y
~ ,,, NH
O O ~
O O
H p O
CN N NH2 N N NH2
=. ~O O O ~~p 0 O ONH 0 O y NH
NH ~ 1 p NH
0
O O
~ x H O O
c).yJiyJ1yNH2
O O O O O O
Oy NH OyNH
41f" NH ,, NH
~
010 O O
6 6
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-193-
0
x
H O H
NH ~N NH2
N N 2 ~ 0o 0
O O O oy NH
OXH NH NH
xo
O O~
V
0
N N NHZ N rHV o N,
~
O O 0 ~~00 0
O Oy NH o oy NH
o NH
O NH
S
CI~CI
0 H 0
N NH2 N N NH2
00 O 0 V
O NH 41 Oy NH
, NH
NH
O O O
O ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-194-
~
0 0
,,,,-,,
0~1, N N NHZ N N NH
p0 O p0 O
p O~NH 0 O\/NH F F
O NH ~O 'N(H F
V u 0
IiN O H ~/N NH~
" \/\ N ~O O
O O >O
>O O NH
NH
O O HNH F F F F
O O1O
O
H
i N NH2 p
p 0 O N N NH2
ONH F O O O
F 0 pyNH
,O NH
~ p NH
O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 195 -
CI\/ CI CIV I
;
H p O
N N NHz CN 3 N NH2
p O O
p O V
>1
O~NH Oy NH
NH
NH
O O p
O
V
0
N N N 0
NH
N 2
O O O p O O
ONH p 0 /NH
NH ~N"H
~ O
O'O
V V
H p O
N N NH2 N N NH2
p p p p O O
pOyNH pO'~NH
/I O
NH p 11 NH
S
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-196-
Y
0 0
H
N NH2 N' N N
N
00 O oo O
ONH OyNH
0 Y FV ; INH
o NH F o~o
O H
H N 0 H N N N
N
I ~ , 00 O 00 O
1
Oy NH O~NH
Os,, NH
INH
-~oo
V
H O H H O
N N N N NH2
O O O O O o
O O~NH F F O o\~,NH
O NH F 0 NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-197-
CiXci
o O
N N NH2 N N NH2
O O O O O
O O\/NH Oy NH
O~ ~O NH NH
"v\~"
O O
V
0 O
N NH2 N NH2
~
00 O 00 O
O Oy NH o Oy NH
~ I O NH O :NH
S
0
H
O N NH2
N N NH2 OO
~
OO O Oy NH
O NH
0 y NH
I~ O N
O~, H O O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-198-
~
H O H O
N NH N NH
N3 - N
00 O 00 O
Oy NH O ( \~NH
NH 0~,,, 'N H
~
010 O O
y Y
0 0 H
N N N N,
O O O O O 0
Oy NH Oy NH
,O NH NH
O~ O ~O
V
O
N N N,/\ H 0
H
O O N N N-,-,~,
O 00 O
ONH
0 NH
,' NH O YH
O
O O
~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-199-
V V
O o
H H
N N NN N N
~
00 O 00 O
O
O~NH F F O O NH F
O NH F O NH F F
V O
H N 0 H 'N NH2
" "~
O 0 O ~O O O
~
0 Oy NH 0 O NH
NH ~/~O NH
I O
H O
N N NH2
H O
OO O N N NHZ
0 NH 0 0 0
NH 0 O NH
N
NH
O 0 O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-200-
X
O
O
N N N N
p O O p O O
Oy NH p\ /NH
NH ~N"H 010 O 1 p
V-1
y
H O H V
N N NN p N
O O N
O~NH p O O
NH 0 Oy NH
NH
X
OO
V ~
H O H O
N N NH2 yN NH2
p O O p O O
0 O\/NH 0 Oy NH
p NH '~ p NH
\% \% ,=
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-201-
ox
0 0
N NH2 N N
N y
O O O 00 O O
O NH
O\/NH I
, ~N" NH ~
010
O O
~
o
H
V- x
H O H N NHZ
9-y
N x0 0 0
O O O %NH
O OyNH ,,, NH
INH 0~0
H 0 H 0
QyN(NH2 N N NH2
O O O O O O
0 Oy NH OO~y NH
0= 0 NH I j 0 NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 202 -
v
V
O
N N N H O H
% N N N ,,
O O O
O O O
OyNH
INH 0 O\/NH F F
'I 'N(H F y O O
N NN N N
N
O O O >0 O O
-1 13
Oy NH ONH
NH
~ O,NH
O O ~O
V V
O H O H
N
N NH2
l
00 0 ~'f~00 0
0 O\/NH OyNH
\ 'N( H NH
O O , ~O
i~~ ~\%
O
+
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 203 -
v 0
H N 0 N N N
C:~
pO O
N O
O N~ Oy NH
OyNH p
I NH
NH F F F~
O O
O O ~
V
O p
N NH2 N N
O O O ~~~p O O
0 O\/NH p O~NH F N"H p NH F F
p '~
V x p H
H p H NN N"
QN p O O
>Y \p 0 0 OyNH F F
I
0 O (\/NH NH
'H O1O
6
0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 204 -
H O V-
N N NHa 0
0 0 0 N N NH2
O NH O O O
/
Y
~ I NH 0 O'\/NH
I O NH
0 O ~
V-
0 0
N N NN N NHZ
O O O O O O
O Oy NH F F O Oy NH
O NH O NH
0
N N NH2 N 0
NH
CN: 2
00 O O O
ONH O
y O~ NH
NH O
NH
0 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 205 -
CI\/CI
0 y
N NH~ N O N
N
00 O 00 O
O \/NH OyNH
'N( NH ~,,, INH
HO 0 HO~O
CI~CI
y
H O H O
N N NH2 N N NHZ
O O O O O O
Oy NH Oy NH
, NH NH
~
HO O HO O
CICI
H 0 H O
N N NH2 N N NH2
00 O 00 O
O O\/NH 0\/NH
HO 'N( H 'N( H
71
HO 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 206 -
V
0 O
N N NH2 N N NH2
O O O O O O
O Oy NH O Oy NH
HO NH HO NH
H 0 H O
N N NHZ N NH~
O O O O O O
O Oy NH 0 O\/NH
HO NH HO ~N(H
',.
H O H O
N N NH2 Q-y N NH2
00 O 00 O
O \/NH O O \/NH
O ~I" ~"
NH HO NH
HO
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-207-
v
H 0 H 0
N N NHZ C:~ N N NHZ
O O O O O O
Oy NH O O (~fNH
NH HO 'NH 18 HO O
~ v
H O O
N N NH2 N N
O O QTH
O Oy NH OyNH
HO NH INH
lHO O
V ~
N O
QL(NH2 N NHZ
~
OO O 0 O O
O~ ~O O OyNH O O NH cJNANH ~~/'
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 208 -
\y/ Y
O 0
H
N
N NHZ C N NH2
I r -"Y
-10 O V N
O O
O NH 0
H 0 NH
~., y
N~o ,, NH
N ~
N O
~ ( .
N O 0
NHZ N N NH2
N ~
O O O ~o O o
O~NH
O\/NH
NH
'( 4:~o
, NH ~ N O
H
N NHZ N N NH2
(Yo
O O O ~O O O
0 \'NH Oy NH
'~N" H 4111 NH
N ,, ~O N O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 209 -
H O
p p O O
$oo
Oy NH Oy NH
4'1, NH . NH
NO :~
N O
x
H p H O
N N NH2 N N NH2
p 0 0 p O 0
O\/NH Oy NH
,, 'N( H 4,, NH
~ ~
N ~ O ~ O
H O
NH2 NH2
V ~0 0 O
$000
O~NH ONH
NH NH
~s,,
~ NO
i p H
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-210-
~
O
H H
N O
N NH2 N N NHZ
p p O p O O
Oy NH Oy NH
= NH ~., NH
~
HN O rN O
I NVNJ
iiN
0
H 0
NH H
1;3--Ir 2 N N NH2
00 O p O O
O~NH 0 NH
J., NH
J~., NH
~
F I'N O ~
NJ HN O
x
H O H 0
N NH2 N N NH2
pp p ~00 O
Oy NH O~NH
NH ,,~'=,,, NH
4r,,
N~O
~
N 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-211 -
x
H O O
N N NH2 N N NHZ
O O O O O O
Oy NH O \/NH
~- NH 4, , 'N(H
4,
~
HN O ~
N O
H 0 0
N N NH2 N N NH2
-:~0 O O O O
~ O HNH O
0 NH
y
, NH
N O ~
I J HN O
F YS
H O H 0
N N NH2 N
N NHz
00 O 00 O
OY NH
O~NH
J=., NH
~~., NH
~O
N
H2N 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-212-
~
O / O
'
N NH2 N N NH2
00 O 00 O
-1
O ONH Oy NH
/ NH
N NH
CI /'N O
x
H O H O
N N NH2 N N NH2
0 0
0 O 0 O
Oy NH O O\/NH
4/1" NH G N 'N(H
H2N 0
O 0
N NH2 ~N NHZ
N
00 O 0 O
ONH
0 0 NH y
N,a NH
O
cy, EJINH
A
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-213-
CI~CI CI~CI
H O H O
N N NH2 N N NH2
O O O O O V
O\\~,NH Oy NH xo
'N( H HN cP
NH2
H O H NHz (0o
O
OyNH Oy NH
, NH NH
~
N O N O
O ~
x x
H O 0 H N N NH2 N N NH2
O O O 0 O O
Oy NH O NH F F
F
~=,, NH NH
~~
N O
0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-214-
X O
N NH2 H O
N N NH2
O O O N
ONH O O O
, NH 0 O'\/NH
~N ~p 'IN"H
~
y
N NHa
O Ncr
~
~ p p ~p O O
O~NH O \/NH
NH J~, 'N( H
HN~O N~O
J
H O H N
N NHZ
NH2 cYo
p p p ~p O V
3-y 1 -1
0 NH ONH
NH
rN .,
O HN~O
~
CI[: NJ
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-215-
X ~
O p
N N NH2 N N NH2
O O O O O O
O'NH O'NH
=, 'INH , 'N( H
~
N O N O
~
A
x x
O 0
N N NH2 N N NHz
p O V O O O
NH
OY NH OXH
, ~ ~p ~
N N O
x x
O p
N N NH2 N N NH2
p p p O O 0
~ OyNH O\\/NH F
I F
~. NH NH F
~N lo ,,
~
~-i 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-216-
~ ~
H O H 0
N N NH2 N N NH2
O O O O O O
Oy NH O~NH
NH
HN O N O
CI~C I
O O
N N NH2
QJLrNH2
00 O 00 O
0 NH
O\/NH
'( ~., NH
r,, NH
~ N O
O NN A I NY.
~
H O H O
N N NH2 N N NH2
O O O O O O
Oy NH O\ /NH
, NH , ~NH
~ ~
HN O ~ O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-217-
~ o V
N N NH2 N 0
NH
O Qy 2
000
O NH O O O
N 0 0 NH
y
O)51NH
HN O
N NH2 H O
N N NH2
O p V N
Oy NH O O O
~., NH O'\~, ONH
~ \N(
O H
N ~N
CI~CI x
H p N 0
NH2
N N NH2 N
9-y
O O O O O O
Oy NH ONH
NH
,,, NH
HN~O
~
HN O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-218-
O V
N H N 0
NH
O O O
O V
ONH O
y 0\/NH
, NH 0 '~"
~ NH
N ~N O S ~ H
x
H 0 H H 0
N N N N NH2
O O O O O O
O\/NH F F Oy NH F F
4, 'N(H F ~~,,, NH F
ON O N O
x
N O N N O
NH2
N ~/\ c I ~- y
0 0 0 -o 0 O
O~NH 0 NH
NH F F F NH
HNO
~ O ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-219-
V ~y!
H O N' o
N NH2 ~
N ~00 0
O O 0 OyNH
O NH ,,, INH
O O O
S,N NH NY N o
\% 1 I i N
~ x
O O N
N ~ N
N
N
~
o O
O O O
O NH
O NH ~
y 4, NH
~N, ~O
~'
~
H2N O
V
x
0 O
H H H
N N NH2 N N
O O V O O O
0 O~NH O~NH F F
F
NH s,, NH
S H ~
HzN 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 220 -
O 0
N N NN N NHZ
O O O 00 O
O\/NH O O\/NH
N 'N~H
'N( H ~JH
~i O O
x x
N O N O H
N N
N
O O O O 0 O
ONH F F F ONH
F F
, NH
NH F
HN O ~
i O
x ~
N O N H 0 H
N N N N,,/,
O 0 O O 0
O~NH
\ O\/NH
, NH '~"
~N~O , NH
~
N 0
OJ
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-221-
O V
N N NHZ O
0 0 O ~N NH~
0 NH ~~O 0 O
411, NHO O y NH
' N NH
HNO rH
~ I
~
H O H O
N N NH2 N N NH2
O O O O O O
O\/NH Oy NH
N ZNH NH
\ ~
17
0 v
H NH2 0
~N O N N NH2
O O O O O
O\/NH Oy NH
'N(H NH
~ / ~ + 0 H
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 222 -
v
H O H O
N N NH2 ~N NH~
00 O >~0o 0
O~NH Oy NH
NH
NH
S
yo
N N NH H 0
N NH2
O O O N
Oy NH O O O
NH Oy NH
NH
\
CH O
N N NH2 3-Y H 0
N NHZ
O O O H H CN O NH \ NyN~O O O
y ~ O
NH N
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 223 -
O p
N NH2 NN
C)-y N N
O p V O p p
O\/NH Oy NH I I
'N( H NH
OH
\ I ~ /
N 0 NH2 N O NH
2
N O
p p O O
O
O\/NH O\/NH
'N( H 'N( H
v
0 0
NHZ
N NH2
H H N ~o 0 0
N Ny N~p O O o~,NH
(Xjoj OH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-224-
X
0 0
N N NHZ N N
pO V >p0 O
Oy NH O\/NH I I
NH ~N(H
O-
y O Y
H O
N N NH2 N N NH2
p p O p 0
O
O \/NH ONH
~N" H y
I I
NH
N
H O
N NH2 H O
N N NH2
p 0
O p p N
O
O\/NH
~( O~NH
NH
NH
OH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-225-
~
O
N N NHZ H 0
O O N NH2
O NH O S H N O O
NH cr6 p O
=
~ OH O
~ /
Y.
O
H o
N NH2 ~N NHa
N ~O 0 O O 0 Oy NH
O\/NH NH
N 'N~H
~
~ /
OH
O ~ O
H NHZ
H H N N NHZ 0 0
NuO o 0yNH
S IOI INH
Ho
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 226 -
O V-
H NH2 H O
N p CN '-Y N NH2
p o p O O
Oy NH Oy NH
C NH NH
N
F F
y V
O p
yN NH2 N NH2
N
Oo O p
~ O O
ONH O NH
NH y
ZNH
OH
y
N O
NH2
N O O O N 0
NH
>1 O\/NH p O 0
~N"H O NH I I
NH
0-
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 227 -
Ys~ Y
H O H O
N N NH2 N N NH2
~00 O 00 O
~
O'NH Oy NH
N~ 'N(H N\ NH
_S S
CIXCI CI~CI
H O H O
cYL~NH2 N N NH2
~OO O OO O
~
Oy NH Oy NH
N, NH N\ NH
_S S
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 228 -
y
N NH2
H OYo
00 O
Oy NH
F
9 NH
F
~ /
y y
H O H O
N O O N O NH2 N OO N O NH2
~
O ( \~NH Oy NH
NH
N 'N H C~S
/~
V
H O
N N NH2
or O O O
O~r NH
NH
Compounds of formula XI are disclosed in U.S. Application Ser. No.
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 229 -
11/065,509 filed February 24, 2005. The preparation of these compounds is
disclosed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Application
Ser. No. 11/065,509 are:
v
H O
N N1: " NH2
OO
O\\/ NH
OS N 'IN"H
H
/\
v
H O
N N~NH2
OO ~O
OyNH
ocSNXNH
V
NH O H
I" yAy
C
N~
O O
O
O y NH
OõO
S'= N ,~XNH
v
H 0
NrJ~yNH2
0 O
O NH ~O
OSO
NH
I
7" N -::
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 230 -
V
H 0
~N~NH2
~ O O
O
NH
OO
y
,c(SNNH
V
H O
N N NH2
00 O
O Oy NH
F)AN NH
F ~
H 0
~N NH2
~~~0 O O
Oy NH
OõO
S'
~ NH
V
H 0 H
N
00 0
O Oy NH
õO
S
, N NH
Cys
CA 02611145 2007-11-29
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-231-
H O
N NH2
I'~ OO O
ONH
OO
,-~Sl N NH
V
H O H
~N N
I'~>0 O O
O O Oy NH
S
N
N H
H O H
NN
N
>1~0 O O
O~NH
OSO NH F F F
N
H O
N N NH2
O O O
O~NH
OSO NH
N
I
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 232 -
O H
N
N 11 O
O
O
O'~- NH
OSO
N NH
V
H 0
N NH2
>~i0 O O
ONH
0 0
y
YS', N DCH
I
V
H 0
N N NH2
O O
O
Oy NH
~SO NH
N
V
H 0
N N NH2
0 O O
O~NH
OSO NH
N
I
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 233 -
V
H 0 H
N N N
O O O
0 0 ONH
S I
N NH
H O
N NH2
O O O
0 NH
OS~
N NH
V
H 0 H
N
00 O
OO O---- NH
N NH
V
H O
~N NH
~ O O
O O Oy NH
N NH
G~
H O
NH
O O O
OY NH
OO
H
N
CJNN /
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 234 -
V
H O
~N~NH
-~0 O O
O NH
OO
S, N NH
N
V
O
~J&}NH2
0 0 \0O
OO OY NH
õ
SIN NH
V
H O
N,,ILyNH2
>~~o
O \---J~
O~ NH -O
O~,O
S,N NH
H O
N N NH
O O O
OY NH
N
OSO N H
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 235 -
O
H NH
N
p
N
O
O
O\/NH
O O \(
N NH
NNN H
O
H NH
N/ p
O
N -1 ,
O
p p Oy1NH
N~ N NH
H O
~N NH
p O O
ONH
OSO
N NH
U
0
H NH
N N
p
O
O
ONH
OO
N~S~ NH
N
I
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 236 -
~ I
O
)J1yNH
p
O
O
O~NH
Op
NN NH
~
0
N NH2
p
O
O
0 0 OyNH
~N N NH
H O
~N NH2
~
~~O O O
O O O NH ~
~'
~N H
S
H O
N,~YNH2
O O
O O O NH ~
S SN
H
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-237-
V
N 0 ~ NH
~~~ II
'"
O O \ O
OyNH
OSO NH
N
~ ~N I
V
O
N N NH
~
O O
O
-1
O 0 Oy NH
õ
S~
N DCH
,N
V ~
H O
N NH
O O O
O~NH
00
N H
o
N NH
O O O
Oy NH
0 O
N
N H
H O
9 ~
0 Y O N NH
O
O
OõO OY NH I I
S~N NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 238 -
O
N NH
CN --~ O
O
O
O O O'~- NH
~~ ee
N,S, N NH
V
H O
9--~- QNNH
O O O
-1 ~
qO~NH
O NH
o
N N NH
O O O
o o OY NH
N H
~N
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 239 -
V V
'~
H O Q D'~'I H O
~N NH N NH
O O O O O O
O NH O NH
~~
~S N NH ~ OSO N NH
N ~N
H O / H O
'
N NH NH
N N
O O O O
O NH O N H OO Y II O.~O Y
S.N NH S.N NH
H O
N NH
O O O
OyNH
~SO NH
, N
and
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XII are disclosed in U.S. Patent Application Ser. No.
11/065,531 filed February 24, 2005. The preparation of these compounds is
disclosed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Patent
Application Ser. No. 11/065,531 are:
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-240-
V
V p
p ~N NH
NHa
N '/ X .L~ O O
O O
~,o O\ /NH
OyNH ~I/
NH
O~H OH
HO
V V
O JJJ~~~ p
N NHa NHa
N N
O O O O
p
OyNH O\ /NH
\ ~ /NH \OaNH
V V
O 0
N NHa NHa
i~
1~ IOI O '/ O
O O
NH O\ 'NH
0)
NH
NH
HO HO
V
O 4
~
NHa NHa
N \
~ / N
O t
O O O
O
O~NH
O\ /NH
NH ~I/
, NH
p/JI
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-241-
~ V
q4. N NHZ N NHT
'I NI I7Ij
O O O
O Y \o
O'\ 'NH O_\ 'NH
~INH/ / \IIV
/
V V
/~'
' N NHZ \ / \ ~ ~N NHI
\ Irvl N' IXI
/ O O O
O O
O~\ 'NH O~\ 'NH
\lly \7lv F
XNH ~O~ ~v NH
,,,O ~
v
O O
Yy N N NHz
~
/\ O O O
O O
'I O
NH OvI\ /NH
NH NH/
OH
I I
V
O
NMZ NHz
N ;% I
yN
xvl ~\ O O
O O
O
ONH
O y NH
~NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 242 -
V V
H
C CO N NHx ~N NHx
TI If
O 1* O O
O
ONH O\ /NH
O O
NHx
N
O O N NHx
O N
O'\ 'NH 0 t
\llv O YI O
~ ~NH N
1~N
- ~
V
O O
l l N
\ / I(vl N~,~ ~N
O
O
O O
C4
ONH OY'\ 'NH I I
~ NH \IINH
O
V V
IIA, O
O O
O~Toyo N NO
O
O-\ 'NH O~' 'NH
\lly F \lly
F
~ NH \ NH
CrV
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-243-
V V
p p
H H H H
o IuOI o \/ ~
Oa4 N,~~
0
NH F
O\ 'NH Oy
\ly
NH V \ A
O VV
N NN NH2
Q Ixl/ O
N ;% I I '~~'~YI ~~~\' O //
O p
O
p~NH
O'T' NH
NH
V f
O O
V \O O
p /~ O X
NHi ' ~ .ry i~~p IOI p N p IOI O
OyNH OyNH
NH /NH
OI"
~p p \O" O
/~
O O
' ~ ~ NHz
I O O /%~ p O
\N/ Ifvl
'\X A\O O
/ vl \ pyNH
pyNH
NH NH
,
~ OV
O
\O~O OV
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 244 -
:i p
p
NH; NHI
~ II
O O
O NH
i ~ p o O
p NH
NH
Oo,. r/NH
\O~O V
p
O
/ /\\ NH
N NHZ
%% ' I p O
ONH
ONH
y
:r
~y NH \O O I
/~ O
/\~{ 0
' ~ NHZ
\N/ ~II/ \ /~ /IJ N V ~
~ N' ?II(
O p o
ONH
O
pNH
NH
J=õ /NH
O~ /JI
JI~ O"
I ~p~0
W ~
O
///------~~~ / O
[[[/// ~~,\\\ N NH2 (\ ' \~ IXI /q NH
\ ~
'' ~II( p
i ~ p O O
pNH
ONH
/NH
NH 'I"'==.(
::r O 1\ 0 O--O
Q 71
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-245-
O
NHa
O
~
ONH
NH
0_*,6
O
O
q NHa
q NHa yIl
~ ~ ~\ O O
O
O~NH
p NH
Y NH
O
I OL'/O ~ q" 'O
O
NHa
N
NHa / O O
IOI O O' 'NH
O \I~
O\ 'NH NH
~I/
~ NH
/ 'q O
~ q~p
NHa N
;
y
\'O O
~q q NHa
p' NH
~ O\ ~NH
\~INH/ j
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 246 -
V V
A p
\ O ' P1 NHa NHI
N/ t O 'y' IXOI t
O NH O O
NH/ ~ \IINyH
V V
p A. p
CN~yN NH2 NHa
O O \ / Irvl O
O i y O O
ONH O~INH
NH NH
y.,,.
p~
V " ' \ I N" 'O
H
V
p V
N NHa N p
N ~Ir,l/
O
> O O N'/\TII(/ \/ \
O O
pY NH O
0-
OyNH II
NH
NH
p
~
,--
V V
p \~ p
~ /NHa
-NHZ
IvOI O ' 1I.OI( O
O
axo
O\ 'NH O\ 'NH
\1I~/H ~
N \hIJyH
q q
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 247 -
~
V
'
// \ IN NH=
' J~ 'N
NH; O O
\N/ ~II,/ O
O '% ONH
O
O-\ /NH NH
NH
O \IY
M O O
HN" 'O
V V
O
N NH= 'N
N 1II,/
O O O O
O
/NH O~
~ \ 'NH I I
\IINyH \1INH
0 O\ y
H O" O-,
V
O O
N
NHZ ~ NHi
O O O
O O O
~N~ OyNH ~ O\ NH
NH ~-~ N \IINH
H
V V
O O
N N ~ NHa
O O O
O
NH
Oy NH I I ~ ~ Oy
q q
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-248-
V
/~\ p p
NHa \ / ~N NHa
\N/ Ivl " II
O O O O
O p
O NH ONH
O O
~ /fljl\ NH XH
O V
~ry NHa O
p O N \/ ~
O O
p' NH O
OyNH
NH ~ ~
~ NH
/\ V
o H NHa
N
~ (\ /\\TII(/ NHa
/ p
O
O O
O,,:,rNH
\ /NH
p O~I/
ll NH
V V
p O
Oy H NHa NHa
p
>,~ O p p
O~NH
NH ,........ NH
oV /! OV
HN,O HI" O
1
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-249-
OJ
NH
O
q N NH p O
N
O O p' NH
O _I/
\ 'NH NH
O \ly
NH
p
Oy p p
NHa NH ' x ~\ p O O
p~NH pNH
NH Y
NH
HN" O \NJO
J V
O p
N NHa NHa
O IOI O
O O
p' 'NH
O\~I'NH O \lly
~ NH Ll NH
A
/ 'H 0"~~ q \pa
p p
NHx q N V ~
I
I >~ J~ p p
o
>o p
O*:~NH
OyNH
NH y,,NH
/ OJ
of
i ~p Jq~p
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 250 -
V V
O O
NHZ ~q q /\
InOI O O
O O
ONH O' NH F F
0 0 F
NH ~ NH
V
/q
~
O O " O
94
O-\ /NH O-\ /NH
O \lI
V ~ ~1I/
\ ~ NH
H NH
V V
O O
O O
O O O
O\ /NH O\ NH
vINH/ ~ LL ~INH/
0"~
V
\ N
q N ~q
IOI 0 O O
O
O\ /NH Oõ\ 'NH
O \IY F F F \ '1 \IY
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-251-
V
V
O
N \/ ~
N Ny /\ \ O
N v \ i~~
O O I
pNH
O\ NH
H~ NH ~
HN~O
I
V p
N
N
N N N
O
O O
O OyNH
y Q O NH NH
/~ /~IJI\ NH
O
V V
O O
~ /N
O O '' ~O' t
O O
O\ /NH I I O\ /NH
\ \INYH \p ~INH/ -"x, -
H
V V
O O
p O t
p
TN - G~,
~ ~ O~\ 'NH I I O-\ MH
\~INH/ NH
q N ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 252 -
V V
O O
~
N N' N N'v\
N v \ N
O O O
O O
O\ /NH I I ~ ~ O\
'NH
~I/ ~INH/
NH
p ~ p O'~
V
0 0
O O O
yN C~ v \
O
O\ /NH Oy-\ 'NH I I
J~ N 11 ~INH/ \INH
V V
o O
O O O O
O O
~ N~ O\ 'NH o~\ 'NH I I
~INH NH
/
/ ~I
H H
V V
O O
( ~ b NH
V
~e~y QWNH
C\ I I
0 0 0 0
0 0
O OVNH I I OyNH I
/l-N NH /~\ HN ~/NH
ry O ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 253 -
V V rll
O / \ N O
\N~ ' ~
Ivl "
O NH
Y. ' QNH Ijli
\N/ O
O~NH p~NH I
p p
~II NH NH
HN O ol
0"~
V
V V
//'\ O p
' ~ 'N NH C l~ N NH
\ / IvOI O \ / IrvOl O
O p
OyNH OyNH I
/NH NH
HN O, HN
V
V V
p p
' l~ 'N INH C~N INH
N/ Ivl N
O O p
O
0~
OyNH
-\ 'NH I
O O p\lly
HN ~ NH HN NH
~
V V
v V
O p
\ ~ ~N INH NH
' ' IXI \N/ ~I I,/
O O O
O p
qyNH OyNH
/~\ ~/NH /\ ~/NH
V HN O HN V
I-I or a pharmaceutically acceptable salt, solvate or ester thereof.
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 254 -
Compounds of formula X111 are disclosed in U.S. Patent Application Ser. No.
11/065,647 filed February 24, 2005. The preparation of these compounds is
disclosed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Patent
Application Ser. No. 11/065,647 are:
H
0 O
~N NHZ
I N'
'-.J~ N x~0 O
N O 0 0 _Oy TNH
01 NH '~ N INH
O'S NH H~
l N-)(
x N
O N
~
9-
H O ~o o 0
~N NHZ OYNH F F F
~O 0 O NH
O NH N~
4~ NH ~s=o
N~ b
~ ~
x O ~ O
NN N~ ~N N~~
~OTO O 00 0
O NH O O ONH
O(' SNH (S: NH
~IN~ 'JNH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 255 -
u ~
H 0
H O
N~~ NH2
N 0 N N
~0 0 ~
0 NH ~O O O
Oy NH
NH 00
I
CN NH
s' 0 v ~
0
U ~
H O H O
~N N
N"
~0 O x~00 O
-1
O NH OyNH
O O
~SN NH ONH
U U
H 0
H 0 H
~N NH2 ~N~N N~
~0 0 O x~0 0 O
O NH
~. ~~ ~= O O O~'NH F F F
S NH S.N NH ~
H 0 H O
~ N
N~/~ NI N N
O
~O O x ~0 0 O
-1
O O 0 NH O 0 0 NH F F
~5. NH I=
S.N NH F
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 256 -
U U
' 0 ' o
N N NHZ Q N N ,-,-,,
p0 0 x~p0 0
0 O O~'N NH 0 O O'~TNH
~ONH ,N H
-~(
x
p H N o N
~ N ,~
~
p 0 0 00 0
O NH o~,NH
~. ~ y NH
NH 4
S 0
.N~
~ v
0 H H 0 H
H ~
N N N,~ ~ N,n
p0 0 p0 0
o~NH
p p O~ NH ~., NH
NH p p
v ~ N'SN-
v
N N~ ~N
0 H 0
H
H
I ~I O
p 0 O ~O o
0 NH
p ' ONH p O N H o
-T N"S=N-
u
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 257 -
x
H O H ~ O (
~N N\ N NH
N ~
0o
O 0 =~ o O
O NH O 00 NH
OõO
H o~
ONH ~I H
v
0
~N N' N O N,/\
p O
~O O O
ONH O NH
NH O~ e0
S.N NH
O O ~
,
C(N'S=~N~
\J H
V
0 x
, yH
O
' TI N N~ ;~-y N
0 O O O O O
~ O~1NH O O OyNH
NH
~ O O NH
N S=N/ v H
~ v
O 0
% NHZ
~N N ~N
~00 0 ~00 O
Oy NH OY NH
NH NH
~o ~o
NS=,N~ NS=,N~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 258 -
0 0
~N N ~N NH2
~O o O OL0 0 O
O O O NH
~' O O OyNH
ONH NH
v ~
0 0
N N N~ 0
0 0
0 0 0
0 NH
O ~o 00 NH NH
ONH N
S
o 0
9--t- N NH2 N N N
'v~~OO V ~O 0
O O 0~' TNH O O O~'NH
.,
~iS'N NH NH
H C~X N O N~/~ N O NHz H i~ O
0 O O
O
O 0 OyNH F F F O p O~NH
.
N NH
,.N~ NH ~
~
~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 259 -
O
H 0 H N NH2
~N N" =N O
O V jL OO
Oy NH O O OYNH
OõO
S. NH .S=N NH
U
O
H O H : ;= ~ NH2
coN NfO ~~ O O
OyNH ~ .O Oy NH
OõO
NH HN'S N NH
H 0 H N O NH2
'"
4( O O 'xi O O
O
~~ N N~~ I O
OyNH O O Ory TNH
NH
~J HN'S N NH
(S , ~~ ~
0 0 ~
\l/
INH N NH
N N O NO O
O O O II
Q O OY NH Q.O y NH
-N NH NN ~ NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 260 -
o
~N NHZ H 0
~oo o N NH
OY NH >1~0 0 0
N~ O O OYNH
lN s=o HN'S NH
S
v O N
~ ~ O
H NH
0 O O ~N
OyNH ~p O p
NH p p OYNH F F F
0
N-S=o N ~'S N NH s
v
H $oo0 O ~
ONH p O 0
~'' NH p p Oy NH
O
N s=o N'S NH
N
s
$000 o o
Oy NH >~Ap 0 p
-),NH 00 O~NH
lo
N~O ~N NH
SJ ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-261-
v ~ H o '-
N NHz N O N
~O TOf O ~ ,/~
ONH ~O O O
NH
~ NH 0.11
Oy
p N
N-H
o S.N~
~KI O
NHZ N NH
NoTOI to 1 ~l O
OY NH /~/~ 0
I O
NH O O Oy NH F F F
0
NS=O ~N NH
s
x ~
NH
N O O
N N O
\I "I iv
x0 0 O ~ O
' 7
O
OS~ OYNH O O yNH
\ ~ N NH N~S=N NH
O ~ ~
~
x v
O /- ~ O
H NN NH2 NN H
' .,~
x0 0 O ~ rol o
OSA O~TNH O~'NH
c ~ N NH o 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 262 -
x v
H p H N
~NN N~/~ "' TI ~~n
0o O
O,,Q O NH pO 0 O~,NH II
S Y ~,, NH
QNNH
~o N-S=0
S
N 0
,~
N N 0 N
fVp0 0 TOI O
O p /~
NH OY NH
S. pY NH
I N NH p
~ N-S=0
x v
N 0 N N O H
I , ~
LM pp 0 ~p O O
O/ NH Oy NH
O,,O
\ ~ SN NH ~,NHOO
~ N-S v
Cx
p x O H NN NH2 N N
xpO V pO O
p ,O O/~ NH ps OyNH
S N NH S ~N NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 263 -
V U
0 0 H
'NJ~N NHZ ~N N~~
~OO O CLIpO O
p p O NH p= ,O O NH
S NH 1 S* N NH
~ S
x
N O N N O
~~~
~pO O N OO O
p p O NH O=,~ O NH
c3:NH /j N H
S
~
. H p H 0
~N N,,~~, ~ NHZ
O ~pO O
0=9 O' NH p SD Oy NH
S ~ S N NH N NH
~ S ~
V
p ~~ o
~N NHZ NHz
NI
p0 O NH 00 0
O= ,O O NH OY
S H NHo
~~ N C O
v
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 264 -
O 0
N NF~
N
OLN
OO O O O
i
ONH OY NH
NH NH
CN 'S'O-A N_g'O-O
v v
~N 0 H J.~N N
N ~,/~ n NI ./\
p p 00 O
OY NH OYNH ~I
NH 4,. NH
CN SOO vN,gO
v
x
O 0
~~ NHZ ~N O NHZ
'" I~ O
O p p ~
~ O NH
p ,Q O NH ~
~/ S'N NH NHO
S' J ~/ vN, S.O
~
O O
N N,---,, NJ.~ N N,-,\
NO O 0 ~O O O
0, 0 OyNH (?,O OyNH ll
CNNH CN NH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 265 -
V ~
0 0
~N N~~ NN N~-,,
p O O OO O
0;0 O/ NH 00 O' N H
CNNH CNNH V ~
H O H O
N NHZ ~N NH2
O ~O O O
O,,Q O TNH 0.0 O NH
/ ~ S~N NH CNNH
~ ~ II
' 0
NH
H ~N NH2 N 0
OO O O O
p ~ O
p O NH OyNH
O N H
SCNNNH ~ ~
~
H 0 N N O NH2 -IC
,/,, ~
cL1- O ~
SO OyNH II p p O~NH
S~ N Oy NH
~N XNH
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-266-
/~~ ~ o
NJ~N NHZ N NH
~ O 0 O O
q,0 O NH
SCNNH y I 0 0 ~NH
N . NH
~N
~
O H O
N N
NH .I~.
p ~'p0 p
O NH
O ~
OYNH ~NH
p 0.~~ o
S.N NH N-S=o
S
~ H 0 N O
'I '
N NH N
p ~0 O O
>~io o'y TNH
O~NH qNH
0 N.v NH N~=o
s
U v
N 0 NH2 ~N o
H_j
N
CN O ~ 0 0
p o
0 O p OYNH O O H NH
/- N'S NH q o
~N~ Ns:0
b
s
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 267 -
H 0
O H
NH NIN N,~,,
0 O O
Oy NH II
0~O O O
~ 0 0 OY NH ~NHO
N.S N NH N ~.O
~ ~
N 0 NH2 H O
O QyNH2
*~o ~0 O
~N O O~NH N~ ,O OyNH
N NH ( ,N NH
~ ~
~
~ V
0
"' 1f N N~ N O N
~oo o N
0 NH O O O
qNH Hq =O Oy NH
N,s=o ~N NH
s
V
N 00 NH, H O
o N N
Oy NH O O O O
q NH H ~~ = O ~Oy NH
Q ; o N I
~, NH
d~
s
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 268 -
O H N O NH2
"I II N,/Q NO TI O
p O O >O
Hy :O O~NH ~ 00 O~NH
N-S
C N NH N,S=N NH
~ p ~ II
NN NHZ N O NH
p
~O TOf O
Oy NH O
NH ~ p p Oy NH
N_~:O N.N NH
I ~ J/
S
O d
~
0
N NH N H
NH
O O O
~O O.p O NH p
'
~OO O NH S, NH
1
N'SN NH ~N
~ ~
V V
'~ 'NJ~N NHZ
O O O O TOf O
O NH II O NH
NH O.. 0.,, NH
0
NS O 0
~NS=0
/ ~ / ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 269 -
~ V
Na ~a NHZ
x~oo to ~pO 0
0 O'~NH OYNH
NH 0NH
0
O
N S O N S=0
~ a a,~ V'~ p
N NJ~N NH
1f
oO 0
O~NH p 0 O
9=O O~NH
NH S
C O N NH
N S=0
x p
a
N NH 'I N'a
p p p '~p 0 O
q;0 OyNH o~TNH
N NH o , NH
O
N-S=O
V H p
NN NH ' ~N NrJ
pp p ~po 0
0 p NH I I p'yTN
N
NH q, O
NS.N~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 270 -
u V
0 0
N N N N N,_,,
00 O
pO O
cl,
9'O O '" O N
/~S ~-
( N N
v v N
Il O
N-S=0
V ~
O
N N 0 N
0 0 O N O
N
OO Oy N O
S O
r N N q"p O-)--N
v N S.NXN
0 ~
IN N~~ .. N N
p O O ~IV OO O
O~N
N OY N
p
41 , N
NS-0 C Q O
S ~ N-5
~N-
O v
NN N pO N O N
~O O
~ =O OyN OYN
~N N ~ NO
N=S=O
~N-
V v 0
~N N NN N~
~O O O OlOf O
~OyN Oy N
~~~N ~~ ~N
N S'O O
N~S-O
~N- S ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-271-
V
0
~ N
~ No N ~ ~N N
O O 0
o N QS0
O~N
NO \ ~ N N
'N S'o ~
UN-
v
o O
I =
N N N ~N N
lf ' 4
00 o OO O
o N 01\ o p' TN
N N-S N N
N0o
-'S' ~
UN-
v V
N N p
N N N
0 0 a 0 0 O
oN Q\ i10 O N
N N
CN S;o
N-
V
O
N y O
,N N
00 ~1SOO O
O N
/ / o O N
Y
~ ,.. N 31JN-
SN
KN-
CN 'o N N N N
on
00 O 00 O
O,S~ O~, N Q /~ OyN
S
CCNXN S I N-)(N
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-272-
~ ~ IJ
O /~ O
N N 'NJ~N N
O O O CO 101 O
SO O~N O/~ O~N 0 S
N
4 N- N S I N
G
O
~N N N N
0 ~0 0 0
O oO C\JX 0 0 O
//
0 N O N
S N N
N N
S
O O I
~N N N N N
OOO O O C~o O O
O /J O N /iO OyN
C ~ S~N-:~N N
~
N 0N,,
No N
O 00 ~f O y N o0
OS OyN N
CCN-~(N Ns:o
SI
v
O I 0
N N N
C\/1 s N 71 ~o 0 0
00 0 O N
q, /.,o O~N N
N N S:o
~ s~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 273 -
~ IJ V
o 0
~N N~ ~N N
00 0 0 cl,0 0 0
/N 0 N N CCN S~ O~N
S,
S N
v
V 0
0 ~N N
~N N O ~0 0 O
O ~0 0 O Ny N
N y N O
O
~ 0 v
N~'N N~~ O
N N
~0 O 0 _
O ~f V OO O
OyN 7 =. N c5JNYN F F F
O
V v
0 O
~N N cN)LN
0 O O 00 0
~0 ~
0 ~XNYN
ctYXNYN
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-274-
V U
o o
N N
~ ~ N N
O ~0 0 O ~0 0 O
Ny N N NY N
O O
v v
o o
N N ~
~ ~
N N
O ~0 0 O O ~0 0 O
N~NyN NYN
i O O
U Y ' Y N N ~N
x~0 0 O ~o 0 0
O N
O'~TN ~ N y F F F
O
O~N N ov ~
U U
O O
N N ~N
x~0 0 O ~0 0 O
O N
~ ONN OxN N
~
Ov v
-~(
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 275 -
v V
J~\ o " 0
N N N N
~OT0 0 OO O
O~N
N N
0 O
O ~ \ p b
v ~ V
= O 0
NN N~/~
vN N ~OO o
O ~0 0 O O~N
~rXNYN
~O O N
O 0
v ~
O O
N N ~,~ N N
N ~~ "' TI
~ 00 O o0 0
O / N Oy N
N N
O O
No
o ~ \
y O ~~ 0
~N N ~N N~~
~0 0 O ~0 0 O
0 N O~N
7'. N ~,. N
C O O
N4
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 276 -
~ v
O O
N NN N
~00 O ~OO O
OyN O~N
~'' IN N
0 0
No ~O
~ v
O 0
~N N ~N N
~0 0 0 ~O O O
OyN OyN
N ~''== IN
( O C O
~O
Y ~
O 0
N N N N,
N TI ttt~~l
00 O 00 O
OyN
OyN F F F N
T'==~ IN 0
O N
~O O Y/ \
V
O 0
~N N~~ N N
~00 O 00 O
OyN OyN
IN ~'''=/N
0
N4 N
L'O 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 277 -
v
N
O N ~ p ~N O N
N N
0 O 0 OyN
N Ny N -),,,.(N
o
O X
v
y ~IJ O
O N N
N N N N~
00 O
O 0 0 0
O N
5XNN O N O
CN
o
V
0 O
' '-/~I/~ ~,N N~/\ ~N N
\I ~ O
x~OO O
O ' 1 N p
N O N
~'
O N
O N
O
~ V
O II
LN N~ NO
N N
00 p N
0 O
ON O p
Y
-,~N OyN
O
N
0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 278-
v
0
O
O OO 0 O o
O N
QNN
c5NYN N
~N
O~
V
O 0
~ ~ N N N J L N,~
" fl O O
O ~ 0 O
N N ON O
N
~
~
~
O
V V
0 O
~N N 9-YN N
O ~00 O O ~00
1 O
N NyN N NyN
~ O I
T O
v V
O 0
~N N ~N N
O ~0 0 O O ~0 0 O
NY N Ny N
0 I 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 279 -
9~0 v v ON N,~ ~N N
O ~O0 0 ~O O O
l e N N~N
O
v v 0 ~NJN N~~ -.~ N N
O o TOf 0 0 ~N OO O
~ N N~N N ~LN N~N
~
v
= o O
~ N N N N N~
'" fl ~~ O O O
O 00 O O N
N N N N O.
p N:)
O
~
j-~ 0 O
N~/N N~ NN N~~
O f O TOf
ON O Oy N
N O NO N-:~N
fl
N O
0 0
V 4!
O O
N.~/N N~~ ~N N
Tf ~
0 00 O
(tN Ny N I I O O~ N
ccN
-
:~
0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 280 -
O
x v
O O O
1;3-~-N N ~3...N N
O
O O N O O O O
>~~
N\ ~ N N N~N NYN
r~~ O
O
~ V o
0 N~N
N N N cl "rF
O y N F
O 0 O N
O ~
OyN N~
~ o
N~N
N~ I
O
V V
~
O
O
N N N N N
N
0 N 00 O O 00 O
CN O N F F F N~N NyN
O
v IJ v
O 0
N N N ~N
O 0 0 O ~OO O
N
N~N NyN NNy
~ r O
~
0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-281-
U V
0
/ O ~ 0 0 N
'~/N N 0
~
N
0 O O O Oy N
Nk N'~y Ny N N O
O
O ~ \
V ~
0
N 9N-Y NN
'V~OOO OO O
Oy N OY N
7''=.(N O =rN O
O~ O"~\Jl
V V
O 0
N N,,,-,,
';N~~ N N
~00 0 /x~OO O
OyN Oy~N"
N O IN O
N
0 0
9--~-N N N./,,,
I 'I I ~f
00 O x00 O
O'~,N
'I O~N N
O
J't=.(N 0
~
N O N~ \
~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 282 -
U v
O 0
~ J- ~ N N,,~ N N N./~
~/
00 0 O
O~ N
O N N N O
O N
N O b
O
V \-Z-
O 0
" N N NJ~~N N,/~
tJ~O~O' O OO O
O N
_I'~-.O~N N
O N 0
7( N
O ~
O
~\J ~ \
y
O " O
V
N N N N N
0o O N
O 00 O
O N N N~N Ny0 N
~-( O
0
~ v
N O
90 =
0 ~'I 0 ' N ~N N
o N
O~,N O ~O O O
N
qN O N A N N Y N
~~ O
O 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 283 -
V v ~
O O
~N N N N
~00 0 O '~~00 O
ONN NxN N'Y~N"
,'~y
N 0 O
O ~ \
v V
O 0
NN N ~N N
O O TOf O 0 ~O O t 0
NI ~N NYN N~N N O N
\/~ O ~~
v ~ x
O 0
N N ~N N~~
N
O ~00 O O 00 0
O' N
~NI N NoN N N
0
~
x v ~
/~ O O
N
'NJ~/ N N N
TOf 0
I '
~ O ~ N 0 x~0 0 O
O O
ON N O'kN N oN
O \/ ~
O O
v
N N,/~
N O0' ~O O O
ON ONN ONN N
~ O
O 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 284 -
V x
o 0
o ~N o ~ N N o o N O N
~oo
0 ON
N~N NyN F F F /j y
~ 0 O/~N IN
~
~3,NyLN V O I v 0
~,N)N
O
x N N O
~
U-T O O~N NYN
~~ O
x V
o 0
~N N' N N
TTTO~~ O ~
0 ~o O 0 O
o N oNN ~C O~'N
~o~ O\!N N
~\O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 285 -
U x 0
O J~.N
~N N ~ TI
~ 00 0
O 00 O 0 OyN
O~N~ Ny N ~N N
o O
9-N x O u O N QNN
~O O O 0 OO O
- 1 / Oy N ~ N~ N Ny N
O/ \N IN O
-\O
V ~ v
O
O IJ
cNAN ~N Y N
00 O
O 00 O 0 ~I~
N
~
O~N NyN o N
~~ O
V õ V
O ~IJ O
N N N N,~
~ 00 O
0 O 0 O ~ O N
ON N~N ~ ~N
~~ O ~
V
O o
N N,,,-,,,
0 N N
O
O cL0 0 O
O N ~0
N N O Oy N
N XN
0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 286 -
V o 0
N N
N N ~ O
N
rl-y
C~o O 00 O 0
O
~4NYN
N
O (~N X
O
V ~ v
O O ~
~N N ~N N
O ~0 0 O O ~0 0 O
N)~ N Ny N ~ N N N
~~0 0
V V
O O
~N N ~N N
O ~00 O 0 ~0 O
N~N Ny N N Ny N
0 O
V O 0 ~N N ~N N
O 00 O 00 O
~ ~
N Ny N 0 OYN
l J~ O ~ 1 N N
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 287 -
V O O ~
~N N ~N N
O ~0 0 O O ~ 0 O
O~N1N O O
O O ~
v v
N N N N N
O OL00 O O 00 O
(~N NyN F FF N N'irN
O ~ O
v v
O ~ z O ~N N \ tN N
O ~00 O 0 00 O
(~N Ny N N~' N
O O
_ v v
O O
N N N N
~
0 O 00 ON
O
N N
N NON ~Y.,Ty
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 288 -
y
Y~ ~
0 V
'NJ~ N N~~ - N N
0 O O
~ i N OyN N N N O
-~ N
O ~~ ~
O
v ~ v
O O
N N N ~N O N
O 0 0 0 O N ~O O
O N
N N N1
O ~~
~
0 0
V v
N N
~N N Q-Y
0 ~O
OO O ,0O~
O1N N NyN
~ O
V V
O O
~ N N 'NJ~~ N INf
0 ~O O O 0 ~O TOf O
O O
~N Ny N Ny N
v~ 9-YN N
1f
Q,N)N
0 00 O 0 00 O
ONYN 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 289 -
o x o ~
9N-Y N N x NN
p0 O p 00 O
O O
~ N O/~N
N N N N
0
v x ~
O
~N N
' N
N
N x0 O O
cL
0 0 0 O O O'~N
NYN N
-:N
0 O
v '~ 0
p N N N
N N N Tf
N TI 00 ~
p p p p O~,N
Ny N N
0
O N
~
" p 0 N N,,
~NJ~N N ~ ~o0 0
0 p Tpl p o N
O N N 0
N N
p~ N b
y
~
N N N N
~00 ~ ~00 O
O~N O~N F F F
N N
O 0
N
b 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 290 -
~ O O
~N N NN N
~OO O x~OO O
O~ N ON~,,.. N N
0 0
b . \
V /IJ ~ J
O I N N
~N N
~O O O ~O O O
O N ON II
N
O
O
N ~
\
~ V
0
/'}
~N N~/ 'NI~N
~OO O ~OTOI O
Oy N I I O N
N
O O
N
N
O
~! JI aa
N N 0
NN N
oro o ' I TI
o~,N O xO O O
N O/~N
C 11N N
N
b O
aYa V
O N
N N N N
TI 00
0
0 O O 0 OyN
N 0 N N N o
~
O 04
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-291-
~
0
N1J~~N ~N N~
O tOl to ~OO O
OyN O~ N
~,,..~N O ),,..( N O
O4 0-4
O O
~N N~~ ~N N~~
~00 O ~00 O
N Oy N I I
),,..(N O ,,..( N O
O-4 O-4
aa v
QN o
N rl o0
Oo -, O O~'N
O 0
OyN N
\ ) N N lN o
O
V ~
0
NN N N N~
C lOf o ~o lol ~
Oy N Oy N
O N O
0-4 N b
u v--\ O ~
N N N N
~00 0 ~OO O
Oy N ON
),,..(N O N O
04 lb
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 292 -
V
o O
tNJ~~N N N N
~OO O ~OO O
OyN N F FF ~O~ N N
I
O 0
N ~ \ N b
V
j~ O ~ O ~
~NJ~N N 1N N
~0101 '7 -00 O
OY N II oN
N
.~ O .~ O
s\ o\
~.N O
N_o~o" o N
O~N OO O
~=rN o --,/O Oy N
N N
0 0\ ~
O
0
0
~N N~ O
~00 0 C~X N N
OY N 0 O
~,..~N o O OY N
N
~N
0 0 \
tJ' O~
0
~ O
N N~ r
~ O
~oo o N N
~
O~,N ~OO O
N o O Oy N
N N
0 0 \ '~
O~
0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 293 -
~ 0 '
/~ IN
N N N N
I ',,,
xOO O O
O',yN 0 O
N ON
,.l ! O N
N
~'
O ~ \ N
0 O
~ X ~
~..J-,N N /~,,~ N N
NOIOi ~ V ~' O
O~N 00
N 0y N
O , N
Ol N
~
O 0
v
o Il '~ O ~
N N~ N N
N 00 O
O
O O O O O N
Ck y
N Ny N ~N N
O O
~
V O 0
N Nr N N
~ O
O O O 00
O C~o ~ O N
N Ny N i~\ /N N
0 O
'~
v O v O I
N N N N N
O 00 O 0 O O O
NY N OT4NYN O 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 294 -
V p p
N
N O N
N N N p
O O O
O ~O ~-~! O
Ny N N N
N \--~
~
0
V
N N
N p p QQN N
p ~ O O
O~N O O
N
\ N N O
y N
O
O ~
O
v
O < ~/N N
O O O p0 O
O ~O O N
CN Ny N ~_%~N N
~
~
V ~
0
p / ~N N
N N IN O N ~ O ~
p p O O N
N Ny o
p ~o
v "
0 0~
N N
~ ~7 p 0 N ON
O O " 0 O Co ~O N
NX NY N C';<N N
0 O
:
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 295 -
O O
N N <N~/N N
C~~~O~Of O OT O =
O OyN qN O~C_ J~~N N N
O~ 0~
p O
<N~/N N N N
00 f O O ClIX O O
O OyN OyN
C-~~N N ~N N
O~ O
V II V II
O O
N N N
O C~~x~OOf O O O
~ OyN
N OyN 1N N
N
'~ N~
O~ O
0 ~ o
-t~~
N N N lf N~N~j
C\J, , N C O o
',J[Y~' O O 0 O N
N O N N ),,,,(N o y ~>~ N
O~ O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 296 -
O O
N N N N
O0 0 O O ~0 0 O
O~ N ~j OyN
N N ~~ '~N N
~
O~ O~
V O O
~,I/N N N N
OC~~OOT O O~OO O
OyN OYN
>~N N ~~ N
~~0~ O~
O O
NN N N N~
O O TOf O O~O lOi O
N O N N O N N
N N J~N
~
O O
~
O O
' I 'N N ~N N
O '~00 O 0~00 O
~N ON~N" N ONN
~~<O O
~
~
O
~N N N N
~00 O O 'xi00 O
O 'Oy ~N OyN
N~N N~
Nr~'N N
O O~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 297 -
V ~ ~ J
N o ~N N
N Tf 0 0
~oO O o
O 0Y N
OY N
N
N~ N N fl o
O ~
S1% o II V o II
N N (:~~ N N o O O O O
OYN OY N
N N C~X\\~N N
O ~ o
NN N
OO O
OY N
~N N,
o
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XIV are disclosed in U.S. Patent Application Ser. No.
11/064,673 filed February 24, 2005. The preparation of these compounds is
disclosed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Patent
Application Ser. No. 11/064,673 are:
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 298 -
H O
~
N N NHZ
NyN~p O O
O ~
NH2
O H ~ N N no
OzS H H '" II H H N
0
uN~p O O S N ~ ~O O IOI O
X x
H 0 H N 0
NH2 QN N
N Nrj~r
S N~p p 0 S N~N O O
O O ~
II
\ / X
H O H
Q"r N O NHZ O2S H '" II N NH H N~p O 0
\S N~N O O O
~ O ~
O O
~N NH2 H H N OZS H N
S Ny Np O O y N~p O ~ O ~ O
X X
0 N p N~
QN
~
N N~\ paS H H
- S H N O 0 uN~p O 0
y p
~ II IOI ~ II
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 299 -
o
O
H 0 ~N NH2
S Q-~-N NH2 02S H H N
N''~'~O O O N0 O
~ ~
O
8
0~
O H O
S ~N NO S N N NH2
2
uN~O O O y, O O
IOI /C II O -T-
x x
O O
N
N NHZ N
~ O'S
H N H 0 0 N H H
u N
N~O O 0
S ~O y
IO~ O
H O H
/ I N NH2 N NH2
N O
~ Q--r O2S ~
H N 0 5NNL0 S y ~O O 0
O ~ O ~
N
H 0 H O
N NH2 02S N N NHz
N ~ H H
S N N~O O O N N~O O 0
O - O
~ O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-300-
~ o
H N NH2 ),jy O'S 9--l-N NH2 p2g H H N
N~p O YN~O O O
bNT
O
NN p QN ~~ N NH2
O,S 02S Q
NuN~p O O Ny N~p O O
IOi /C II 0
X x
I , 0
\I~/ H H / ~N Y NH2
'S ~N NH H
0 N
uO O O NyN~p
O I O O
I ~ O
I oN tNH2 H H O~ N NH2
2
~ ~O N N O O
O o =
0 O
N NH2 N
O N 02S H H N N
~ N N 0 O N~0 0
S u
/ IIO -T- 0 CF3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-301-
I j V
0 ~ H O H
N NH2 N Nv~
02S 02S H H N
N~O O O
N N O O NY
O O
X x
O
H
N 0
NH2 OaS N N N
02S N H H O
N NO O O bNYNO
O O -T-
~ / 0 O
2 S H N <N N N NH2
N
O 02S H H
uN~O O O NyN~O O O
IIO ~~ II 0
H N O N~\ ~ H O H
02S H H N O 02S '" ~~ N N~\
~N O
~O NyN~O O HO
OD
O O
~ x
N 0 N 0
~ NH 2
N
v 'v II 02S H H N
~\S N N O O N~O O O
02
~ 0
~C ~~
1~-
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 302 -
V
H
N HNH2 N N
0 Q--(
02S 2 S H NyN,,,~O O O bNyN0O 0
/r
V
H 0
0 N NH2
~,, N NH2 H H N
II N N O O
02S "'
~
N N O 02
O
9
H H
N NH2 N NH2
02S Q 02S H N H N~N, O O ~N~O 0 0
O O
0
H H N
H2
Q--r N
O2S N N02S H Ny N~O O O Ny N~O O 0
O 0 V N 0
NH2 O S N N N
N 2
y
~
H
QHH
N N 0
O O
OZ Ny y
1,-- 0 ~~ ~1
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 303 -
u
H O H 0
N H
N~N NH2
O2S H H N p2S H H N
N~N~p O 0 N~N~p O O
O O
V H O
H 0 N NHZ
- ' N NH2 2S N
02S ~ N N O O
Nu N O O 0 y
~O
II p p H O
O ~
N p2S ~N N~
H O H ~ H p H
02S H H O 0
O 0 NyN
Ny N~p
~
O 0 x x
p ~ N p N
N N NH2
02S 2S
H H
NyN~p O O O bNNxQOO
V
H 0 ~ p H
N N NH2 p2S H H ~ H H II
N NN 0 O O yN O 0
OZ 0 0
~' O II
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-304-
~\ x 0
H ~N NH2
/ ON O H
~N NH2
02S H (~ O O
N N~O O O 02 N~N~O
0 6 0-1'-- CF3
V
H 0 H + N 0
N~/\ H
N 02S N
O2S N~N N N O O
N N O O y
y O
O
O
~ N 0
NH2 N NH2
O2 S 02S
H H N
H " ii O
~NO O O 5NyN~O O
O O
O
H O H O
N NH2 N NH2
02S N O2S ~
~ H H
N~N~ O O NyN~O O 0
O O
V
H O H O
N N N NH2
'" II ,/\ 02S N
S H H H H
O O N~OO O
O2 0 - O o
O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-305-
O 0
H 02S N N O2S Q N NH2
NN~O O O NuN~ O O
yO ~ II IIO
x \
H O H O
T QN II N 02S N N
H ~
uN~O O 0 H N~ O
02s H
IIO ~ II O O
s
V
I o
H 0 H H
02S \ N N NH2 O2S H H N
Ny N~O O Ny N~O O O
O O /1\
V 0
\ I 0 Q,,rNNH N H 02S H Q N H N H O ~N,,/
N O 0 S yO
y O2 O /<
o~C
~
O.
0 H 0
O QN N NH2 02S H H N NH2
2 N
S N~O O
NuN O
~O 0 Ny
0 ~ 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 306 -
p O H N p N
N ~ ~
OzS H H Q--( OzS H N
Nu
O I N'p O O u NN~p O O
~ 'OI
V
~ H O H O
pzS ~N O S QN N NHz
H H z
~N~ O O yN~ O
_ O
p ~ II p ~
0
V
4 ~ O N ~ N 0
N NH2
OzS ~ II ~ OzS H H Q
N H O O Ny N O 0
O ~' II p
~ OH \/ V
X
H 0 H 0
N NH2 N NH2
y
OzS Q OzS H H Q--r
NN~p O O Ny N~ O O
u
II O
O O /~
Q ~ \ x
0 ~ O
N N
N NH2
02S~ OzS H H N
I N~p p uNO O O
Ny
O
0
/~ I /~ II
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 307 -
~ V
0 ~N 0
NH2
N
~ O NH2 O2S N
02S O ~ N N O O
N N~ y
~ : O
~ V
H 0 H N O N
~,
OZS
H ~ 02S H H
NyN~O O 0 yN~O O O
O ~ II O II
~ V V
I/ H 0 ~ H 0 H
N NH2 N N N,
O2S Q 02S H
NuN~O O O yN O O
IOI O
V
O
N N 0
O S H H N N N~ ~
-SO2 N 2
N~N, O O ~N~ O O
O
O O
V H O H H O H
N
N N,_,-~, r N
~ 02S
~SOZ N N H O 0 H N H N
N~00 O
y y
0 /~ 0
I ~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 308 -
/ , O
i~ ~
O H '~N NHa
O2S ~N ~ H H N
NyN~O O O O uN~O O O
O 2 IOI
~ V
H O H H O
N NH2
02S ~N N O2S H H N
N~N~O O NyN~O O O
O
O
0 \/
0
~ V / 02S ~N N~~~
X O NN~O O O
N NH2 y
O2S H H Q O
NyN~O O O ~
O
HO0
0
~N NH2
H O H -S02 H H ~
O2 S N N~l A}~ N N O O O
~O O O O =
H y ,
Ny N
O,~ 0
V Q
H O N NH2 NH2
H H i?
O O O NyNO
0 ~,<-
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 309 -
V
H p H Q ~N 0 N,p2S ~N NH H N
N H O O S NyN~p O O
~/~ O 02 p~ II
02S, O p
H H N H O H
~N N
~O N~p p p o N~N~p O 0
2
p
O O ~
V
V
O H H O H
N N Y N 02 S N
O2S ~ H H
N~p p p Nu
O N~p O y O
IOI
V
o V
0
I~ H H N N NH2 ~ N N NH2
N' ~ p O SO2
02S y vO N N~ O O
O p
0
V \/
~~
I O N /N ' N p H
N
02 s ~ 02S
~N O O NyN Q O O
0 ~~ II 0 ,,C CF3
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-310-
H
o CN o
NH2 N~SO2 H H
H H O
bNo S NO
O2 Y 0 O /I\
V
0
H O H lN NH2
~N /\ S02 H H N
N~O O O
H N~O O Ny
02 00X
= O O 8 ~ . O SO2 N
H H O NH2
N N ~
~ H H' O O
N N O O N~N v O
02 O = O ~
V V
0
H CN 0
NH2
OZS N N NH2 0H H N(
Ny NO 0 0 \ u~O O
O IOI X H 0 H H O H
N N~/\
N N N~\ \ SOZ N
S02 ~ H H
N H O 0 yNl-~O O O
0 /~ II 0
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-311-
V
V
0
NH2 ~\ SO~ ~N NH
2
\ SO2 H H Q-,Ir N 0
N N~O O O N N O O H
O 1r ~o O
O X V
~ N 0 N 0
S SO2 N~N N NHa
02 H
H
N O O N N t YO
y o O
O O
N3-,
V O'<
0 O
N N QN N NH2
-SH N -S0II
uN~O O 0 NyO N~O O
O O
V
0 ' H O H
NH2 ,, N
OZS H H -SOZ "' II
iN qy
uN~O 0 N
uN O 0
OI ~ I O I
O
V V
0 0
~N 0/\-S02 ~N NH2
4-S02 N N~ O 0 N~ O 0
O O
0 /< 1 I 0 K
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-312-
~
H o O H
2 H H N N Y NH2 ~ 9--rH N N
SO
~
~N~O O O NyN O O
O O
/N H O H
H 0 H
02S H H N N N,, SO2 Q N
N N~ 4- y O 0 u
N O O
O IOI
V
H O H H O H
N N QN
N N~H 2
0 SON~N~O O O
S0800
O 0 O =
\, / O
N H u
H 0
N N~ O 0 S02 Q N NH2
N y -r
.S ~ O N~ O O
O 0 CF3 y
O
V
O x
0
N NH2 H H
H H Q ~502 H H N ~
N N~ O O O 0
0,O u
~ = O N II N~O
O O
O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-313-
2 H O H
NH
SO2 N O,O 9--rN N
Ny N~O O O N Np O O
~
\ ~ O
O
~ H H 0,0 N O 0
NH2
O2 S N ~ H H 9--(
N N~O O 0 Ny N~O O O
oi~ 0
V 40,
N 0 H 0
~<p NH2
SO2 Q--( H H N
Ny N~O O O NuN O
O O O
V 0 X
H Y H O H
/--SOZ H H N N S02 H H N N
N
Ny N~O O O NH2 uN O O
O Ipl <
V V
0 p
H -SO2 ~N N~\ O Xso2
~ p Ny N~O O 0
O =
O
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-314-
ox
Q
H o ~
-~502 H H QN N NH2 QN
~ H O H
N O O ~ IH H
II u N~O
O O y
O ll<
X V
H O H 0p H O H
N
H N
~S02 H N N H O O
NyN, O O O NyNO
0 O
/
,X 0 ~H 0 H
N N O N N~/~
-S02 H H N H N
N 0 O~ N N0 0 O
o 0
\x/
O N 0 S02 H H N
Q N S02 ON
N 0 O H N~ 0 O
O II O II
X ~
0 0 H
S02 N N N~
Q
H H 2 ~
N N~O O O ~SO O 0
N~O
~ 6 y
I
O I
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-315-
clcl
eN N O N~ N N O N~
SO2
H H ~ H H
yNuN~O O O NuN~O O 0
IOI
IOI
0 6
C-CI
H O H p i? SOZ Y NO
IOI O /<
O
X
O ~ H
0 N N N~ ~o~ N N H
H
O O
N
N
y O y NO O O
O - O
6
H O H H 0 H
N
N N O N --( y
'" II ~ SOZ H H Q
~ j HO O O N N O O
~N~O y ~O
O6 O
CI~CI CI~CI
H O H N 0 N
xsoZ H N N SO2
N~ O O ~ O O
y O N O
0 X bNT
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-316-
~
0 o
QN N ~ ~N~N N o
H H O ~ H H' p O~~
O NyN~ O
p Ny
O N v 'O
/ -
O II a
X
H H O
~ Q,,rN N o *00 N N
~ H H ~
N O O o H H O O
y ~p NyN,,
O O -
6
V V H O H N O N
~ QN N H H QN
~ iy: H O O N N~ O O
Np~O ~ O
O ~p II
6
V V
N p N , N O N~
SO2 ~ SO2 ~
~
N~O O O
NN~p O O Ny
IOI - - X X
H 0 H H 0 H
N N N
SO2 ~ N " SO2 N ~
H
- p p N N
N~ ~O y ~
N O YO
O - 0
-
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-317-
i~
~ x
Q ,
H H O H
N N N +-qe Nf-{ N QN
NuN~ O NyN~ O a(o
V V
00 Q"rN N ~ N N,
H xc H H 0 H
H
N N 0 ~ H H O 0
u Ny N~
6 II
V
O N
N
H Q--(
H NN~~ H H
0 H 0
N~O O bNYN
II6F
F
X ;~
N
S02 QN N N ~L. SO2 ~
- / H H
H Jc H N 0
NuNO O 0 yO O 0
IO~ 6 O 6
X X
H H N 0 N
S02 ~N N~~ XSO2 H H ON
~ H H O O N N~ O 0
1~~ y
6 6 II
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-318-
V
X/ o
O p O H 0 C\H NN~~ H H N O ' 10(
H N O O 0 NyN~O
Y O -1"1-
~ / X
'~ H O H
O p H 0 H ~ O N,Y)yN~/\
N NT~/N H H N
~
~ H H ~ N 0
NuN~p 0 0 y o
N, 0--)
IOI _ O
-~ 6
\X/ V
H 0 H N 0 N
O~p N N,,,, '" II ~
~ ~ H
H S N HN~ p 0
NyN~p p 0 O~O ~ O
O
V V
0 H 0 H
~ QN N~~ N/-~,O ~N II N~~
S;p II H H
N~N~O 0 O~NyN~p O 0
O 6 O
ci~ci V
p
QN O S02 H H ~N\i ~ ~/N
S0i II ~J ~~ ~
N N~O 0 0 NuN~O 0 0
O IOI
I/ H O H Y H O H
Il N~N
O;S H~NN O .S~ H N
O N N~Op p~ N bo p~
O - O
6 6
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-319-
H3CCH3 F~ocF' H3cCH3
II
/-~ o 0
0
( \ N {I~I ~~ N' ! x~ 'N
C CH3 ~N/~/ uN CH3 II II C C~~N N
~C ~O 10~ IOI 0 O O ~C ~O O 0
0 N C~ OC/ IYN O N
~~ ~ ~
~ )
'/ O~
O-S\~ CH3 S CN BS~~/"C~
O/ I CH3 ~C.H3 1 (~.H3
C"~ C"3 and C"~ ; or a
pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XV are disclosed in U.S. Patent Application Ser. No.
11/007,910 filed December 9, 2004. The preparation of these compounds is
disclosed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Patent
Application Ser. No. 11/007,910 are:
o 0
0 H~N' ~/N~/ 0 HN~N N
IOI O
p0 ~ N' ~ N~O
Ny N N~O O N
C ~ \Y
N H O NJ H O~ II
0 v 0
N N N N\~
OII H~ 0 H~ V
CN }~N N'O O O ~N' N N 0 O
NJY 'H 0~ I I I NJ( H
v p v 0
O HN N O H~N N
N O 0 N~ O
N O
CN N O (N~N O
N/ H 0 N H O~
O 0
O H~/N H O H~N N
N N N~NO ~0 (N N IOI *CFOC~ _ O 2
H O
N 0 ~ CF3 N H
~ 0_T_
CA 02611145 2007-11-29
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-320-
N V
o N N o N
~~~
H ~~
O N ~ O N
O
CN~N NO O ~N~N N~O O O
N H N H O
v O
p N
p NO
H S.00o
i H p "~ N H O
N
0 0
HN N O HN N NV
0 N
&IHN N, pO O N~N NO O O
O~ N H p~
H p H 0
p H~/N NHp 0 H~N NHZ
CN~H N N~N O~O 0 N~ H N N O O
N O N O
O N N NH2 O N N NH2
II H H p H H 0
CN- N N~p p O N, N N~p O O
NJY 'H O~ I N H O~
v p 0
0 H N ~N N,,,~ ~ 0 H O N N~~
N II
'
N~N N O O (N~N N~O O
H H
N ~
p I- N O
O 0
N N N N N
0 H~ ~~ 0 q H
N~N N~O O O N~ N N~O 0
0
N H 0 ~ N H 0
II
CA 02611145 2007-11-29
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-321-
V U
N 0 N v' H N
S000 N N N rH O~ I'No H
N p H H 0 H
?N--~ O H ,/\ O N N~O OO
CN' ~ O O
N ~~( N O
H p NJ p~ I
0 O
H N H N N~~
O O N I'
CN~N N~O O O ~N' N N O O
H O INJ H O
N
v 0 0 H H O HN N,/~ 0 ~ H ~/
CN N N f O O O N N N O 0
J,/\ ,
N
N H O / H O
0 (/~ 0 N
H \ 1(N ~
~N N~ H
0 N ~ O N II
\ N NO O O \\ N NO O O
S H S H O
v
NO v 0 N
N ~ N
O H ~/~ p H N ,/
\ N. p p \ N N O
~H O O ~~-S H O =
s ~ 0 H O H
O <~_N N~~ O N
H"N
O~O O H
\ N N~f O O
\ N N
S H 0 S H 0
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- 322 -
N ~
0 N v' N o N
H H ,
0 ==, O N
\\ N N~O O O \ N N~O O O
S H O S S H O
N 0 N~ N 0 N
O H O H V
N
N~N NO O O : J H
O~
O 0
N NV 0 H~N NV
0
\\ N N~N OO O e\s N N ~O O O
S H O H O~
N O N N O N
0 H O O V O H N V
N N, o \\ N N"O O O
S O S H O
0 O
O H "' II N N 0 H~N N~~
eS N N~O p O ~~N N~p O O
H p (Ii\1N" p m
O O
O .N N~~~ O ~HNQ O
N~ I H O NI H O
v' O O
O HN N N O HNN
\~ N N~O p p N~N N~0 0 O
'XI _H O CS H p
I
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- 323 -
O H O H
O H NN N~~ O H~N N
N N~p 0~ N\ N N~0 0 O
N H O~ H O -
N
O O
O HN N O HNN N,
F~ N~ O O N IOI O
F H O ~~ H
F O N-NH O
O O
O N N~,-,, O N N,
O~N N__-I-O O O /"p''N N~O O O
H O H O .
qONN
N N N,~~
O ~H O H
O ~~~
0 O
9_,~_N N,,,-,,, O ~NH N
O
H
~HH N~O O O HH N, p O O
O p
H / O N N N~/\
II ~N O H O H
OHxH N~O O O " I N~N NO O O
O'~J O/T- H H O
O N O N
N N N, ~~~
,~ iSO N O O OS N NO O O
~\1S H p~ 0 iN H 0 -T-
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- 324 -
: O O
~N N~~ ~N N
\S N N~IV OO O N O6 N N~O O O
l H O \
~S H O
'x
vO H H O
~ N~~
N N OõO
N\ og N NO O O N~S.N N, O O O
/
\N-NH H 0 NH H O
H
N 0
N N O H
N ~~ O O N
Q. O " H H
HNN N S'N O N, O O O NS.H N~O O O
H NIH O _T_ _T_
and
H 0 H
~N N~~ H O H
OõO
~S ~ ~ N N N~
' N N 0 ~ Q o " H
O II
g' N NO O O
H I I/ H O
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XVI are disclosed in U.S. Patent Application Ser. No.
11/064,757 filed February 24, 2005. The preparation of these compounds is
disclosed in the experimental section of this application set forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Patent
Application Ser. No. 11/064,757 are:
H o o
N N~~ ~N N~
fV~O O O ~O O O
O\/NH OY NH
~~S N ~NH jS N NH
I '~( I
CA 02611145 2007-11-29
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-325-
N Do _;
O N N O N
~/\
IOI O >1~ O O
O O
0 O OY NH O~ O~ NH
S, H SeO NH
/
/~
H O O
' ~/N N,/~ ~N N
tV ~0 0 O 0
O = ~0
OY NH O\/NH II
O~SN NH ~SN N(H
~ H O ~ H 0
N/\'O ~II N NHz /\\\NO II/N NHZ
0 O 0 O
O\ /NH O~NH
0 jSN N~H 0>~N NH
N O N N O N
,~
IOI 0 fV 0 0
0 O
OY NH OY NH
jS N NH jS N NH
0 0
N N~~ N N
fV~ O ~O O 00 II O
OYNH OYNH
'S~N NH Oj~S N NH
O O 0
H N N N GLT0
l ~ 1 O
OY NH OY NH
jS N NH o S N NH
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- 326 -
H O H 0
N NHZ N NH2
O O O
O O 0
OyNH OY NH
jS N NH ~ S N NH
H N 0 N " II N O N
0 0 O O
C~xo O
Oy NH O\/NH
jS N NH ~S N N(H
~'T
C~Xo N~/\ N N~
0 \N~ O
0 0 IOI 0
0
O\/NH O\/NH
5S N N(H jS N N(H
H
0 0 H N N ~N N
fV O 0 O O
0 O
OY NH O\/NH I I
jS N NH O N N(H
'T
~ H O H 0
N NHZ N NHZ
lv lY ~\ O 0 0 0
0 0
0\/NH O\/NH
~ S N N(H ~~S N N(H
0
N O H N N~
IJ ~O 0 IJ0 O
O O
Oy NH OYNH
NH NH
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- 327 -
0 N N 0
~~ ~ N,~
N
O O O 0
>~iO >~~ O
Oy NH O\/NH
NH NH
Oe
H O N~ N O N
~ ,-,
>iO O O 0 0
O
O\'NH Oy NH II
Os O~NH
OO NH
H -- H
O O
N O \ ~ N NHa /\\\N/\_II,_ N NHZ
~O 0 OO 0
OY NH Oy NH
NH NH
OA~O~j
N 0 N N GYyv
~O O 0 0 O
O\/NH Oy NH
Ov NH
O
NH
x
H cTo O
y NH Oy NH
Oa o~NH Oe ~NH
O O
NN N~~ N N
G~X ~O O O O
O
~ Oy NH Oy NH II
0 NH Os O6NH
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- 328 -
~H 0 H O
N NH2 N NHZ
' x ~p O 0 0 O
~ O. NH ~ Oy NH
NH NH
Oa ~~ pAW
O
\N/~N O N~ N O N
II \ N "17
Op O pO O
0 NH O\ NH
NH ~ NH
0
v O
N \ N 0
\N/ ~ N 0
rI~lI N~/\
O O
O ~ pO O
~
O\'NH O. NH
~ ~NH NH
O
OSo p~~
0 0 H H H H
\N/~II N N,_,-\ N N
O O 00 II 0
ONH ~ Oy NH II
NH NH
06 pB~0
H 0 H O
C~ N NH2 N NHZ
O O O O
O v 7 p
O~NH O\ /NH
NH
N~H
Awb p
H II N p O
N H H
" ~/\ \ f~~ll N N~
00 0 N00 0
O O\/NH p O. NH
~"
NH NH
0
0
CA 02611145 2007-11-29
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-329-
H o p
H
N N, N N
~0 0 0 r1~0 O 0
0 Oy NH O 0\/NH
N NH ~N '~N"H
0~ O~
NO N N O N
~~ ,-
N
>t0 0 0 0 0 O
0 O\/NH O Oy NH
N N~H ~k N NH
0~ 0
N NHZ N NHZ
~H 0 ~H 0
~00 0 >1~00 0
0 py NH 0 Oy NH
~N N H N H
O~ 0
N O N N p N
~~~
n N' D
OO 0 00 O
0 Oy NH 0 pyNH
~xN NH N NH
O~ p
O 0 ~N N~~ N N
0 0 0 00 0
~ NI
0 Oy NH 0 0yNH '
N NH \xN NH
O~ p~
H O N N O N
~~
N n N'
OO O 00 O
0 oy NH 0 OyNH
N NH N NH
~ 0~
CA 02611145 2007-11-29
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- 330 -
H 0 O
CN)-~- N NH2 N NHZ
NI
0 p 0 O
0 O. NH OyNH
N NH 4N NH
O~ p~
H " II 0 O
N N N
00 0
0 O ~
0
O O\/NH 0 O\/NH
_-N ~N"H _-N N~H
0- p~
H O N N p
H
~~ N
~00 00 O O
p OyNH 0 O\/NH II
%~xN- INH 4N
~NH
b--
O n
N O N N p N
\NJ~~~
II N
pO p 00 O
0 Oy NH 0 Oy NH
N NH NH
N
X
0 0
\N/~H 0 N O
II N NHZ N NHZ
~00 O 00 O
0 OyNH 0 O~NH
%~xN INH N NH
O~ O)l
N
~ O N \ ~ N 0 N
~/\ V
N
>~io 0 0 0 0 O
O O NH OY NH
~ 'O ~ 0~ a0
,S i NH jS~NNH
CA 02611145 2007-11-29
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- 331 -
\
H N O N,\ N N O
N N~~
~ ~~ 00 0 00 0
0y NH 0 NH
O~ a0 I O~ i0 ~
.~~ ~I
/S N NH jS NH
N 0 H N O N
fV N
00 O 00 0
OY NH OY NH II
/S N NH jS O NH
'
~H 0 H O
N NH2 ~ N NH2
~00 0 / ~1 ~.Op O
0 NH 0 OY NH\
NH
NH
O
H O N~ N N~
II ~
00 0 00 O
OY NH OY NH
jS N NH NH
jS N
y \
N O N 0
Q-yo N N
~ lol 0 O O
0y NH 0YNH
%S ~ I O~ O
~i~ iNH
y =
0 H 0 H
~N N,--,,, N N,-,-,,,
~O IOI O 0 0 0
O NH 0y NH II
' i ~ 0\ i0
/S. i NH jS:N'TNH
CA 02611145 2007-11-29
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-332-
~~
0 0
~/N NH2 N NHZ
N' x~O O O 0 O
O NH O NH
o"o
is i OS i NH
O 0
~N N,~ N N
0 O 00 O
0 NH O NH
O~ "O ~ O O ~
jS~ i NH jS~ i NH
N 0 N~ N 0 N
,
O O O O
O p
O NH O NH
O\eO ~ 0 O ~
S-i NH NH
N 0 N H O .0 H
~~~ C~xo
O O O O
O\'NH O\'NH II
,S~ i N~H jS N~H
H 0 ~H O
N NHZ N NHp
00 O 0 O
O NH 0 NH
O~aO 0 O ~
jS~ i NH jS~ i NH
" II N 0 \NS O
0 0 0 ~O IOI O
OY NH O NH
NH NH
0
OAN
p~ o~
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 333 -
o N p
" II ~~ \ O~N N
N
00 0 ~pIO O
Oy NH Oy NH
~ NH NH
O~
NO N N p N
N~~
II N
00 O 00 0
~ Oly NH 0\/NH II
NH ~NH
0 p So~
y \ y '
O O
~H ~N
N NHZ N NHz
~0 0 O ~O 0 0
~ O\/NH 0\/NH
~NH ~ ~N"H
O S~~
y \ y \
p
N 0 N N N
~, /~
Op 0 00 O
0\'NH Oy NH
~N"H NH
0
N O H N O H
tJ ~ NI
00 O 00 O
0 NH Oy NH
0 O~NH 0 ONH
~
0 0
H H N N
~~
~ NI
00 O O O O
v y '
O\/NH
'~NH Oy NH
NH
OANO--6 p SkO
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
-334-
~
~H O H O
N NHp N NHZ
, x ~O 0 0 OO O
v ' v Y '
~ Oy INH ONH
NH NH
O
OS'
O p
ONN N~~ N N
Vi
0 O '
0 O
O\/NH ~ O\/NH
~N"H N(H
A'No
O
OS'
H
H
H " II N O N \ n '~ N O H
~~\ N1 II
0 0 O 0 0 O
~ Oy NH O. NH
NH /_\NH
00
H O N H p H
~~
~IVOO O 0O O
II
Oy NH ~ 0 NH
NH NH
OANO--6 p SO~
" II H 0 H 0
C~ 00 N O NH2 N NHZ
0 0 O
OY NH O\/NH
O o~NH oNH
N O H 0
N N,,V
>1~00 0 p p
O. NH 0 O. NH
INH ~N )~NH
O~ O
CA 02611145 2007-11-29
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-335-
H N 0 H H 0 H
N N,-,-,,,
>~i00 0 ~00 0
0 Oy NH 0 O\/NH
NH ~NH
O pl
/~ 0 p
' '/N N ~N N
NO~O 0 ~OO O
0 Oy NH O Oy NH
N NH %~kN NH
0~ p~
~H O ~H 0
N NH2 N NHZ
~0 0 0 ~0 0 0
0 ONH 0 NH
N NH 4NO-
F NH 0~ ~~\ O p
\N/~N N, - N N'~V7
O 00 0
II N
O O
O Oy NH 0 Oy NH
-XN NH %~xN NH
O~ p~
y ' y \
H O N H p N
~~ ,-,--
II n NI
00 0 00 0
0 O. NH 0 OYNH '
>N NH %/kN NH
O~ p~
y ' y \
O
N N,/~ N N,
IV~ 0 O 0
O
GTo
0 O~NH 0 OYNH
NH
%/,N- NH >Np
0
CA 02611145 2007-11-29
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- 336 -
N NHZ N NHa
~IH p IH O
00 O 00 O
0 OyINH 0 OyNH
N NH N NH
O~
H 0 N N 0
~~ N~
0 O 0 tV~00 O
0 Oy NH 0 O\/NH
~N NH 414 ~N"H
O~ p~
H 0 H H 0 N
~,-,-,,,
N T( N
00 O 00 0
0 Oy NH O Oy NH II
~N NH NH
O~ 0
N NN/~ Np N
N
O 0 O O
cTO
O O. NH 0 ONH
>CN NH >QNNH
0~
H 0 H O
?N-~-N NHZ N NHZ
0 O OO O
0 O\/NH 0 Oy NH
:~/N ~N"H %~,N- NH
\ O~ 0
H O N H 0 N
~~ ~~~
~OIO O ~Op O
SO. N Oy NH II O~NH II
NH o NH
\\O
CA 02611145 2007-11-29
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- 337 -
N
p N~~ ~N O
>1~0 0 0 >1~0 IOI 0
0 OY NH pyNH
N NH \ jS N NH '~( N 0 N H 0 H
~,/\
>~ip 0 0 >1~0 IOI O
O OY NH II p~AO QyNH II
OTH S NH
" O N~~, N 0
N
O 0 0 00 O
~
S
O I NH OY NH
~p\ s0 -I \ S i NH
N
H
O 0 ~/N N~~ N
~7 p0 0 00 jN-NH O~NH 11 ~,p O\/NH 110
CN NrH
0
O 0
NN N H N
p0 0 0 0
NO
S' p OyNH I O O OyNH I
H
J L J N H S N N H
~If I
0 0
H "O II N F~N~~ N~N
Np
I p O O F
p
O O Oy NH F Oy NH F
0S'N NH ~ NH
1 0
=.~Nv lfN \ ~N~N~/\
II ~~\ N
~O O F O O
p F
OY NH F 0NH F
03o NH \,SO NH
~ ~ ~
CA 02611145 2007-11-29
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- 338 -
o p
N N X N~~ ~N~N,
I F F
0 0 ~ IOI ~0 0 ~ p
O OY NH F OY NH F
OTH O~\St NH
(L_JN
/~ J\
O 0
" II ' ~ uN,/~/N,
O O FO /~/~O IOI lOl
\/ I NH F
OS~O O~ NH F p\ ~p O~
N "S" i NH
iN
O p
" II N~N~~ " II N~N
O 00 O 00 O
3NH ONH F~SO ONH FN NH
S
O J~ 0
"O II N~N~~ \ ~ uN~N,~
Np II
O p ~p
F F
0
\\~p Oy NH F OyNH F
S. 1 O~ m0
\ ~ N NH S~l N NH
0\ /\
N O H N p N
N/~~~ ~
I I N
00 O 00 0
Oy NH Oy NH
S N NH ~ NH
0
" II N O N,\ N 0 H
/\
O O O >1~0 IOI O
OY NH OY NH
~~ NH q~S-NH
N N
S
/\ /\
H O H H O H
N N~/~ N
00 O 00 0
0 O~ NH py NH
N
SO OTNH
N
CA 02611145 2007-11-29
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-339-
H o o
N N,/~ N N,/,,,
>~ipO O >Lyt OO 0
O~ NH O NH
~S~ NH O~sO O.
~ I S,i NH
iN
H /\ /\
0 O H ~/N N~/, N N~~
O NO~0 O p NOO O
~NH 11p ONH
NH ~ NH
O O
N H N~/, ~N N~~
00 0 00 O
~p NH p~ NH
NH N NH '~( N 0 0 H
~10 0 O N~ f V~O 0 N O
,
~NH O\/NH
~ S N NH ~ ~N"H
I 06,
O\ /\
~ N 0 N~ N 0 N
~7 ~/ N D
0 0 O 0 0 O
~ NH O~ NH
~ 'N NH -0.S N 1NH
S I '~( .'T
/\
N O N N 0 N
~V V
~ O O r1~0 O O
0 O NH NH
~jN ~ p~S NI ~
N N N
O O
N
0 O 0 p "
O ~p
NH NH
~m0 ~ O~mmO ~
C N NH -N,S,N NH
N I~( I
CA 02611145 2007-11-29
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-340-
~
0 0
H H
N N~ N N~
0 ~10 0 O O 0 O
~NH 11 0 0-YNH
NH NH
O
N O 0 N
N~ N ''~pO O ~IVp~p O V
op OYNH 0\/NH
I\~~ // NH \ \S N ~N"H
/\
H H
40000
ONH I Oy NH I
o S N NH ~ NH
H O N H 0 N
~/~ ,-,-z,
~00 p0 O 0
s O NHNH 0 OY NH I
~ NH
N -N
~
/\ /\
0
N O N~~ H N
' n~p0 O
40000
0 OY NH O~ 0
OH ONH
0
H
0
:" c H II N N,,,~ N N, -
p 0 0 00 0
N 'I
OY NH II O\'NH
o ~ NH O" ~O '(
N -N'S-N NH
\
H I
N 0
\ N O N~
~p0 0 00
N~\ C~co H
OyNH II ~p OyNH
I
N NH ~ N NH
S
CA 02611145 2007-11-29
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-341-
~
o p H \N/~N N~, N N,
II N
0-0 0 00 O
o; p OyNH 11 p p OyNH
N NH i'Sl~l N NH
/1I" I
H 0 0
,
~ O N N~~ N O N NH
O O O O
ONH II Oy NH
O ( ~
O S, N NH NH
6~
N O N H 0
,~ N
fJ O ~
O O N O O
O
O
O OY NH II O O ONH
\
~S, i NH
S~N NH
S
(::Z ~N 0
NH
,~
N, ~N 0
00 0
N
p0 0
0 OY NH II O O OY NH
N NH S; NH
O N
N O
O
Nq::L:00
OO OY NH II O OY NH
~ NH NH - N:S:N NH
N O H H 0 H
fV 0 0 0 N p O 0
OEN-H O OyNH II ~O ONH ~ ~ ~NH
S
0
N O N H 0 N
N ~~ N
O ~ O
0 O
O
o\. I p Oy NH I I O OYNH
~ O
N NH S,N NH
'~(
I
CA 02611145 2007-11-29
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-342-
H 0 p H ~~N N~~ N N~/~
fV~O~O O OO O
' I
OY NH I I vOyI NH
~ S N NH ~ NH
O~
N O N N O N
,_,,,,,
00 O 00 O
p~ s0 Oy' TNH I I p p OY NH
I
S, i NH NH
NH
O O
H
4 ~NN H NN
4;co OO O 0O
III O~NH II
p O~NH O
OTH iS\N NH
O p H N N~~ N NH
,
OO O C~co 1( O O
O\OO OY NH II O\sp OY NH
S~ i NH -i~S~ i NH
iN
O p H N N~~ N N
p 4~c O O O 0,1 ~O O O
/ O~NH II O OyNH II
~ N NH
S
O
N O N H O H
,~
00 O 00 O
0 p ONH I I p O OyNH I I
N NH N NH
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XVII are disclosed in U.S. Patent Application Ser. No.
11/064,574 filed February 24, 2005. The preparation of these compounds is
disclosed in the experimental section of this application set forth
hereinbelow.
CA 02611145 2007-11-29
WO 2006/130607 PCT/US2006/020969
- 343 -
Non-limiting examples of certain compounds disclosed in U.S. Patent
Application Ser. No. 11/064,574 are:
H3 C~CHa CHZ H~C,~,CH~ ~Hz
O
r~l ~N N N 0 N
O O O O
0 0 O~ N 0 O 0 N
ICH H C ~ I cH
N ~C
CH' H3C
~9CH31CH3
'6
HCH~ H,Cv H H3 C~CH3 Hx
0 I/I~
CCH3N N N' ~N N
V
0O O 0 O
0 0 OY N I 0 O OY N CH'
H3C N CH I
H3C N HC N N
CH3 H~C H'C CH CH
ja H3 3 HaC CH3H3
H3C~CH3 CH2 H3Cli H3 ICHz
I/I 0 I
N N N N
N CH N
~0 O O 0 0 0
0~gclj 0 OY N CH3 0 0 O~N
N H3C/~N N ICIH
Ha0 CCH
HaCCH3H' 3 H~C CH3H'
H3C~CHa H~C~CH3 H2
0 y 0
N ''' = N N
r l CH~ N ~/CH3 NI
0
1 0 O ' ~ 0 0 O
0 0 Oy N F F 0 0 'O'Y ~N"
F
H~C N H~C N
H3C ? HC
CH3 H3C C~ CH3 H3C CH~
H'C CHz NC' CH
H3C;H3 rHz H~C~ H3 ~H,
O IrJiT ~
~N, N N N
CH~ N CH3 N 0
O 0 0 0 0 (:~ 0 0 0\ /N CH3 O O O\ /N
YI y F F
H~C - N H~C I
N
H~C H~C -N
CH3 H3C CH9 CH3 NC CH
H~O CH' ~
H~C CH3
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H'C~ H3 H3C~CH~ Hx
N N ~N N
lI,CH, NI
O O _V C 0
O O ~~_0Y~~~N""" CH3 0 0 CY N CH3
HC - N H3C N N
I
v N _Z~'
CH3 H3C CH C4H~. CH
H C CH> > and CH3 3
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XVIII are disclosed in U.S. Provisional Patent
Application Ser. No. 60/605,234 filed August 27, 2004. The preparation of
these
compounds is disclosed in the experimental section of this application set
forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Provisional
Patent Application Ser. No. 60/605,234 are:
v v
H O O H O O
N O N NIS \ ~2~k N N~S ~
H ~HO O
H H HO O N,.
~ N N
~ ~
O O
v v
H O O H O O
11
O H H N N K HI~ I H N N H~~
~ O
1~ O O /// O N
N
~
1~ '~~
O = ~ O =
H O O 11
O O N HI01)
S Nu H
ON II ~O \
Cs O
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V U
H O O H O 0
0 N N N.S N N N.S
~
O H O N N
N 0 H O
y N = O \ II u ,. ~O
O O
v
H O O
0 N
H H N /O
Nu
O N
N II ~O O H
O
U
H O O
S
.
0 N H N O H O
~S N u ~O
n II
O O
and
V
H O O
0 N N N'S \
S H N O H O
Cy", 0N ~ ~O
O
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XIX are disclosed in U.S. Provisional Patent
Application Ser. No. 60/573,191 filed May 20, 2004. The preparation of these
compounds is disclosed in the experimental section of this application set
forth
hereinbelow.
Non-limiting examples of certain compounds disclosed in U.S. Provisional
Patent Application Ser. No. 60/573,191 are:
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Oy(~ OyN
0 - D
O ~ 0
N N~ N N
IV N D
O O O O
O O
OY NH O\ /NH
5NH jS N N~H
Oy N ) OyN b
0,, p,
cLgYw O 0 0 p O O O NH OY NH
O S N ~ p Ap
jS~NH
OyN b OyN b
Q 0,
O p
0 ~00 0
O O
O\/NH II
OY NH 0 p ~
O S N
~ OS~ i ~NH
OyN OyN b
01 p O, 0
N NH2 N NH2
CN3-y IO H n ~~ H
~x~ O O 0 0 O
- T
O NH 0 NH
O~ ~O ~ O O ~
jS~ i NH jS~NNH
OyN / ~ OyN ~ ~
0, - 0, -
O 0
N N
G.I~N 0 N O N~
OO p O
O_,~,NH OyNH
NH g NH
O
O~ p'a
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OY N ~ ~ oyN ~
0, - O,, -
O O
N N~- N N~,
(3~0 0 0 ~ x~fJ 00 0
0\/NH Oy NH
O/ O~/ NH O' s~NH
O
OyN OyN ~
~, O, -
O p
N N~/~ N N,
~0 0 O ' x 0 0 0
II
~ Oy NH Oy NH
NH NH
OS~ ~
O O
OYN 0y N ~ )
0, O, -
H O H 0
N NH2 N NHZ
00 O ' x 00 O
Oy NH p\/NH
NH '~N"H
Ak
0~ pe ~~
O,,
,~,N ~ ~ OY N
01, - O,
,/\ N N
'I " II N N ' I "O H 0 H
O 0 0 0 O
0 O\/NH 0 O\/NH
_-N ~H _-N N~H
O~ p~
OyN O~ N /
~ \
, N - O,, - H O N O N
~~~ ,
' I N
~00 0 0O 0
II
0 O\/NH 0 Oy NH
N N(H '~XN NH
O~ O~
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OY N Q~ OyN ~ ~
0, N - 011, - N
O N 0 N
/~~ 5
IJ ~O O O O
O p
p Oly NH O Oy NH
NH
4YN NH 4,14
O~ OyN ~ ~ OyN ~ ~
O - 0, -
O 0
N N N N
NO O O 'V 0 O
O NH O ~
~
N NH N NH
~
~
OyN ~ ~ OyN ~ ~
0, H - O O,, - H 0
N~-y N ~ NH2 N NHy
O O O
O ~O O
O Oy NH 0 O\/NH
NH i/N NH
~NO~ p~
O\/N / \ OYN
Q~, - O, -
O 0
G-I O N N~~ N N
0 O OO O 'v
O ONH O O\/NH
N N~H
4N0 N H
p~
OyN / ~ OyN
O ~ ~
, - , -
O Q 0
N N~~ N H N,/,,
fV ~ n N'
0 0 O 0 0 O
0 Oy NH O OyNH ' II
< NH ~~,N NH
O~ p~
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OyN ~ ~ O~N ~ ~
0, - O -
O /-~ p
G~~0 N N~~ \NI~N N~~~ (3~
p O O IOI O
O OYNH p OIYNH
~ NH
'
N~/ NH 4,0
p /JI,\ Oy N ~ ~ Oy N ~ ~
0, - O, -
// O p
G~x~ ' N N ' /~ N N
~O
O D ' x O O ~V/
O '~ p
O O\/ NH Oy NH
NH %~k NH
N
~x \\ j j O
O p
OyN b OyN ~ ~
O, . H O O,, -
H O
N NH2 GLI N NHZ
p p pO O
p O\/NH ONH
'I"
NH
NH 4,1
O pyN pYN ~ ~
0, 0, -
O p
Q-YN N~N N'
p p 0 O
~O ~Vi
p Oy NH 0\/NH
'(
)~NH NH
O*N p~
~ N
~ ~
, - O, -
O p
N N,,-,,, N N~,--
0 O fVp0 O
p Oy NH 0 y NH
~ I ~j0 II
N '' ~C//\N~NH
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OyN ~ OyN ~ ~
~ - O, N-
y 0 H
\N~ N ~~ ~~\
NN
N \
0 O O
O p
0 Oy NH O\/NH
'~N- NH ~N"H
OyN 6 OyN ~ ~
O, N 0 QYyv ~ N
II N
~0 0 0 ~ 0 O
O OYNH Oy NH
NH >N
~ NH
OyN b OyN ~ ~
-
~ . 0, H 0
Q~ N NH2 N NHZ
H O
>~iO 0 0 00 O
Oy NH O Oy NH
~NH ~N NH
~
OyN ~ O OyN ~
O, - 0 -
N N,/\ H H
\ N N
~ NI ~Vl
0 0 0 00 O
O 0y NH O 0yNH
NH NH
OyN ~ ~ OY N ~ ~
0, - 0, -
H O H O
~N N~~ ~N N,
~00 0 00 O
O OYNH O OyNH II
>N- NH NH
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OyN ~ ~ OyN ~ ~
O,, - O,, -
0 H /~ H 0
/~ N N~~ N N
~
~00 O ''x 00 O
O 'O"y ~N"H OyNH
NH NH
Oy N ~ ~ Oy N ~ ~
Q, - p,, -
O p
~ 0 N O N"V (:3~ N O N~
fV
O O O
~O OYNH 0 OYNH
N NH '~N NH
~ -:~
OyN b OyN ~ ~
O, O, -
N NH2 N NHZ
" II H p H 0
GLI 00 O 0 O
0 Oy NH 0 OYNH
NH >N- NH
OyN b OyN b
~ O
0, N 0 N , N p NV
~0 0 0 0 0
0 O\/NH 0 Oy NH
litINH NH
pyN b py(b
O,, N p, N
0 N 0 N
~~,~ .~~
~0 0 0 /x' I fV 00 0
OOy NH 00yNH~' II
H v )IINH
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ON / \ OyN / \
O,, N O,,
O p
N~~ N N~
>~iO0 0 >~iOO O
0 OY NH 0 O\/NH
V_~NH ~N"H
OyN / \ OyN / \
O, 0,
O 0
~N N ~N N'
~O 0 O ~0 O O Vi
0 pvNH 0 Oy NH
NH
IAIINH
OyN ~ ~ OyN ~ ~
O, p
N NHZ N NH2
" II H 0 ~H 0
O 0 0 ~O O 0
0 pyNH 0 pY NH
IH H
~-cP N O
p q
\ /N
5~" N
7I7I
\ / O O V
I 5 / '' x
IOI
O O O
N~
OyNH
~5~ N N O y
II 0 i3~ ~NN
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~ NHr
y p N
i"
O O O
O
O NH p ~NM
~~
\~~NH S\ ~NM
O IJI
N NHr N NH
O.IY NI
O O x h O O
O Iv\o
D~NN O~NH
O\/O
~ NH j\5o NH
I A ~~
o ~ ~ I Q p NH N NM
NI
O O O
O 7 O
NH 01,111, NH
S\N~NH S\ NN
N N~ p NHr O ~\ O
ly '_p
D\ 'NH F 0111, y NH
5\~~NH NH
F 5,\
NHx NH
Y
O o O O
O O
O_' 'NH ~ O~NH
\I~H NH
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~ \ / p
o o IJI
N NH N NX
\I NI
7 'O p
>( OYNH NH >( OyNH
OS~~ O O~NH
H H p 1I/J
NH N NH
\y' O \ O
O\/ NN II ~
~ NH x 5 ~
/p\O~
p
~N NH
0 0
0
~ Oy NH F
F
F
NH
or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula (XX) have been disclosed in U.S. Patent No.
6,767,991 at col. 3, line 48 through col. 147, incorporated herein by
reference.
Compounds of formula (XXI) have been disclosed in U.S. Patent Publication
Nos. 2002/0016442, 2002/0037998 and U.S. Patent Nos. 6,268,207, 6,323,180 at
col. 3, line 28 through col. 141, line 60, 6,329,379 at col. 3, line 28
through col. 147,
line 27, 6,329,417 at col. 3, line 25 through col. 147, line 30, 6,410,531 at
col. 3, line
28 through col. 141, 6,534,523 at col. 3, line 34 through col. 139, line 29,
and
6,420,380 at col. 3, line 28 through col. 141, line 65, each incorporated
herein by
reference.
Compounds of formula (XXII) have been disclosed in PCT International Patent
Publication W000/59929 published on October 12, 2000, U.S. Patent Publication
No. 2004/0002448 and U.S. Patent No. 6,608,027 at col. 4 through col. 137,
incorporated herein by reference.
Compounds of formula (XXIII) have been disclosed in PCT International
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Patent Publication W002/18369 published on March 7, 2002.
Compounds of formula (XXIV) have been disclosed U.S. Patent Publication
Nos. 2002/0032175, 2004/0266731 and U.S. Patent Nos. 6,265,380 at col. 3, line
35
through col. 121 and 6,617,309 at col. 3, line 40 through col. 121, each
incorporated
herein by reference.
Compounds of formula (XXV) have been disclosed U.S. Patent Nos.
5,866,684 at col. 1 through col. 72 and 6,018,020 at col. 1 through col. 73,
each
incorporated herein by reference.
Compounds of formula (XXVI) have been disclosed in U.S. Patent No.
6,143,715 at col. 3, line 6 through col. 62, line 20, incorporated herein by
reference.
Isomers of the various compounds of the present invention (where they exist),
including enantiomers, stereoisomers, rotamers, tautomers and racemates are
also
contemplated as being part of this invention. The invention includes d and I
isomers
in both pure form and in admixture, including racemic mixtures. Isomers can be
prepared using conventional techniques, either by reacting optically pure or
optically
enriched starting materials or by separating isomers of a compound of the
present
invention. Isomers may also include geometric isomers, e.g., when a double
bond is
present. Polymorphous forms of the compounds of the present invention, whether
crystalline or amorphous, also are contemplated as being part of this
invention. The
(+) isomers of the present compounds are preferred compounds of the present
invention.
Unless otherwise stated, structures depicted herein are also meant to include
compounds which differ only in the presence of one or more isotopically
enriched
atoms. For example, compounds having the present structures except for the
replacement of a hydrogen by a deuterium or tritium, or the replacement of a
carbon
by a 13C- or 14C-enriched carbon are also within the scope of this invention.
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It will be apparent to one skilled in the art that certain compounds of this
invention may exist in alternative tautomeric forms. All such tautomeric forms
of the
present compounds are within the scope of the invention. Unless otherwise
indicated, the representation of either tautomer is meant to include the
other. For
example, both isomers (1) and (2) are contemplated:
OH
N ~~ (1)
0
I I
(2) wherein R' is H or Cl_6 unsubstituted alkyl.
Prodrugs and solvates of the compounds of the invention are also
contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V.
Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium
Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche,
ed.,
American Pharmaceutical Association and Pergamon Press. The term "prodrug"
means a compound (e.g, a drug precursor) that is transformed in vivo to yield
a
compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or
solvate of
the compound. The transformation may occur by various mechanisms (e.g., by
metabolic or chemical processes), such as, for example, through hydrolysis in
blood.
A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella,
"Pro-
drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and
in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American
Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula (I) or a pharmaceutically acceptable
salt, hydrate or solvate of the compound contains a carboxylic acid functional
group,
a prodrug can comprise an ester formed by the replacement of the hydrogen atom
of
the acid group with a group such as, for example, (Cj-C$)alkyl, (C2-
C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-
methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,
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alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-
(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-
(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-
(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N-
(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-
crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CI-C2)alkylamino(C2-C3)alkyi
(such as /3-dimethylaminoethyl), carbamoyl-(CI-C2)alkyl, N,N-di (Cl-
C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-
C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group,
a
prodrug can be formed by the replacement of the hydrogen atom of the alcohol
group with a group such as, for example, (CI-C6)alkanoyloxymethyl, 1-((Cl-
C6)alkanoyloxy)ethyl, 1-methyl-l-((Cl-C6)alkanoyloxy)ethyl, (Cl-
C6)alkoxycarbonyloxymethyl, N-(Cl-C6)alkoxycarbonylaminomethyl, succinoyl, (Cl-
C6)alkanoyl, a-amino(Cj-C4)alkanyl, arylacyl and a-aminoacyl, or a-aminoacyl-a-
aminoacyl, where each a-aminoacyl group is independently selected from the
naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2 or
glycosyl (the
radical resulting from the removal of a hydroxyl group of the hemiacetal form
of a
carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a
prodrug can be formed by the replacement of a hydrogen atom in the amine group
with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl
where R
and R' are each independently (CI-Clo)alkyl, (C3-C7) cycloalkyl, benzyl, or R-
carbonyl is a natural a-aminoacyl or natural a-aminoacyl, -C(OH)C(O)OY'
wherein
Y' is H, (Cl-C6)alkyl or benzyl, -C(OY2)Y3 wherein Y2 is (Cl-C4) alkyl and Y3
is (Cl-
C6)alkyl, carboxy P-C6)alkyl, amino(CI-C4)alkyl or mono-N-or di-N,N-(Ci-
C6)alkylaminoalkyl, -C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N- or di-
N,N-(CI-C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the
like.
"Solvate" means a physical association of a compound of this invention with
one or more solvent molecules. This physical association involves varying
degrees
of ionic and covalent bonding, including hydrogen bonding. In certain
instances the
solvate will be capable of isolation, for example when one or more solvent
molecules
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are incorporated in the crystal laftice of the crystalline solid. "Solvate"
encompasses
both solution-phase and isolatable solvates. Non-limiting examples of suitable
solvates include ethanolates, methanolates, and the like. "Hydrate" is a
solvate
wherein the solvent molecule is H20.
One or more compounds of the invention may also exist as, or optionally
converted to, a solvate. Preparation of solvates is generally known. Thus, for
example, M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004)
describe the
preparation of the solvates of the antifungal fluconazole in ethyl acetate as
well as
from water. Similar preparations of solvates, hemisolvate, hydrates and the
like are
described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1), article 12
(2004);
and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-
limiting,
process involves dissolving a compound in desired amounts of the desired
solvent
(organic or water or mixtures thereof) at a higher than ambient temperature,
and
cooling the solution at a rate sufficient to form crystals which are then
isolated by
standard methods. Analytical techniques such as, for example I. R.
spectroscopy,
show the presence of the solvent (or water) in the crystals as a solvate (or
hydrate).
"Effective amount" or "therapeutically effective amount" is meant to describe
an amount of a compound or a composition of the present invention effective in
inhibiting HCV protease and/or cathepsins, and thus producing the desired
therapeutic, ameliorative, inhibitory or preventative effect in a suitable
subject.
The compounds of the present invention can form salts that are also within
the scope of this invention. Reference to a compound of the present invention
herein is understood to include reference to salts, esters and solvates
thereof, unless
otherwise indicated. The term "salt(s)", as employed herein, denotes acidic
salts
formed with inorganic and/or organic acids, as well as basic salts formed with
inorganic and/or organic bases. In addition, when a compound of formula I
contains
both a basic moiety, such as, but not limited to a pyridine or imidazole, and
an acidic
moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner
salts") may be
formed and are included within the term "salt(s)" as used herein.
Pharmaceutically
acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred,
although
other salts are also useful. Salts of the compounds of the various formulae of
the
present invention may be formed, for example, by reacting a compound of the
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-359-
present invention with an amount of acid or base, such as an equivalent
amount, in a
medium such as one in which the salt precipitates or in an aqueous medium
followed
by lyophilization. Acids (and bases) which are generally considered suitable
for the
formation of pharmaceutically useful salts from basic (or acidic)
pharmaceutical
compounds are discussed, for example, by S. Berge et al, Journal of
Pharmaceutical
Sciences (1977) 66(l) 1-19; P. Gould, International J. of Pharmaceutics (1986)
33
201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic
Press, New York; in The Orange Book (Food & Drug Administration, Washington,
D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.),
Handbook
of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'I. Union
of Pure
and Applied Chemistry, pp. 330-331. These disclosures are incorporated herein
by
reference thereto.
Exemplary, acid addition salts include acetates, adipates, alginates,
ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates, borates,
butyrates, citrates, camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates, dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,
glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides,
hydrobromides, hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,
methanesulfonates, methyl sulfates, 2-naphthalenesulfonates, nicotinates,
nitrates,
oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates, phosphates,
picrates, pivalates, propionates, salicylates, succinates, sulfates,
sulfonates (such as
those mentioned herein), tartarates, thiocyanates, toluenesulfonates (also
known as
tosylates,) undecanoates, and the like.
Exemplary basic salts include ammonium salts, alkali metal salts such as
sodium, lithium, and potassium salts, alkaline earth metal salts such as
calcium and
magnesium salts, aluminum salts, zinc salts, salts with organic bases (for
example,
organic amines) such as benzathines, diethylamine, dicyclohexylamines,
hydrabamines (formed with N,N-bis(dehydroabietyl) ethylenediamine), N-methyl-D-
glucamines, N-methyl-D-glucamides, t-butyl amines, piperazine,
phenylcyclohexylamine, choline, tromethamine, and salts with amino acids such
as
arginine, lysine and the like. Basic nitrogen-containing groups may be
quarternized
with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl
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chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl,
dibutyl, and
diamyl sulfates), long chain halides (e.g. decyl, lauryl, myristyl and stearyl
chlorides,
bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides),
and
others.
All such acid salts and base salts are intended to be pharmaceutically
acceptable salts within the scope of the invention. All acid and base salts,
as well as
esters and solvates, are considered equivalent to the free forms of the
corresponding
compounds for purposes of the invention.
Pharmaceutically acceptable esters of the present compounds include the
following groups: (1) carboxylic acid esters obtained by esterification of the
hydroxy
groups, in which the non-carbonyl moiety of the carboxylic acid portion of the
ester
grouping is selected from straight or branched chain alkyl (for example,
acetyl, n-
propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl),
aralkyl (for
example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for
example,
phenyl optionally substituted with, for example, halogen, C1_4alkyl, or
C1_4alkoxy or
amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example,
methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl);
(4)
phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate
esters
may be further esterified by, for example, a C1_20 alcohol or reactive
derivative
thereof, or by a 2,3-di (C6_24)acyl glycerol.
In such esters, unless otherwise specified, any alkyl moiety present
preferably
contains from I to 18 carbon atoms, particularly from 1 to 6 carbon atoms,
more
particularly from 1 to 4 carbon atoms. Any cycloalkyl moiety present in such
esters
preferably contains from 3 to 6 carbon atoms. Any aryl moiety present in such
esters
preferably comprises a phenyl group.
The present invention provides controlled-release pharmaceutical
formulations comprising the inventive peptides as an active ingredient and a
controlled-release carrier. Because of their HCV inhibitory activity, such
pharmaceutical compositions possess utility in treating hepatitis C and
related
disorders.
Another embodiment of the invention discloses the use of the pharmaceutical
formulations disclosed above for treatment of diseases such as, for example,
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hepatitis C and the like. The method comprises administering a therapeutically
effective amount of the inventive pharmaceutical formulation to a patient
having such
a disease or diseases and in need of such a treatment.
The pharmaceutical formulations of the present invention are suited for
treatment of infection by any of the genotypes of HCV. HCV types and subtypes
may differ in their antigenicity, level of viremia, severity of disease
produced, and
response to interferon therapy. (Holland, J. et al., "Hepatitis C genotyping
by direct
sequencing of the product from the Roche Amplicor Test: methodology and
application to a South Australian population," Pathology, 30:192-195, 1998).
The
nomenclature of Simmonds, P. et al. ("Classification of hepatitis C virus into
six
major genotypes and a series of subtypes by phylogenetic analysis of the NS-5
region," J. Gen. Virol., 74:2391-9, 1993) is widely used and classifies
isolates into six
major genotypes, 1 through 6, with two or more related subtypes, e.g., 1 a, I
b.
Additional genotypes 7-10 and 11 have been proposed, however the phylogenetic
basis on which this classification is based has been questioned, and thus
types 7, 8,
9 and 11 isolates have been reassigned as type 6, and type 10 isolates as type
3.
(Lamballerie, X. et al., "Classification of hepatitis C variants in six major
types based
on analysis of the envelope 1 and nonstructural 5B genome regions and complete
polyprotein sequences," J. Gen. Virol., 78:45-51, 1997). The major genotypes
have
been defined as having sequence similarities of between 55 and 72% (mean
64.5%),
and subtypes within types as having 75%-86% similarity (mean 80%) when
sequenced in the NS-5 region. (Simmonds, P. et al., "Identification of
genotypes of
hepatitis C by sequence comparisons in the core, El and NS-5 regions," J. Gen.
Virol., 75:1053-61, 1994).
In an alternative embodiment, the controlled-release formulations of the
present invention can be useful for inhibiting cathepsin activity, for example
for
treating cancer and other cathepsin-associated disorders as discussed below.
In yet another embodiment, the compounds of the invention may be used for
the treatment of HCV in humans in monotherapy mode or in a combination therapy
(e.g., dual combination, triple combination etc.) mode such as, for example,
in
combination with antiviral and/or immunomodulatory agents. Examples of such
antiviral and/or immunomodulatory agents include Ribavirin (from Schering-
Plough
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Corporation, Madison, New Jersey) and LevovirinTM (from ICN Pharmaceuticals,
Costa Mesa, California), VP 50406TM (from Viropharma, Incorporated, Exton,
Pennsylvania), ISIS 14803TM (from ISIS Pharmaceuticals, Carlsbad, California),
HeptazymeTM (from Ribozyme Pharmaceuticals, Boulder, Colorado), VX 497T"'
(from
Vertex Pharmaceuticals, Cambridge, Massachusetts), ThymosinTM (from SciClone
Pharmaceuticals, San Mateo, California), MaxamineTM (Maxim Pharmaceuticals,
San
Diego, California), mycophenolate mofetil (from Hoffman-LaRoche, Nutley, New
Jersey), interferon (such as, for example, interferon-alpha, PEG-interferon
alpha
conjugates) and the like. "PEG-interferon alpha conjugates" are interferon
alpha
molecules covalently attached to a PEG molecule. Illustrative PEG-interferon
alpha
conjugates include interferon alpha-2a (RoferonTM, from Hoffman La-Roche,
Nutley,
New Jersey) in the form of pegylated interferon alpha-2a (e.g., as sold under
the
trade name PegasysTM), interferon alpha-2b (lntronTM, from Schering-Plough
Corporation) in the form of pegylated interferon alpha-2b (e.g., as sold under
the
trade name PEG-IntronTM), interferon alpha-2c (Berofor AlphaTM, from
Boehringer
fngelheim, Ingelheim, Germany) or consensus interferon as defined by
determination
of a consensus sequence of naturally occurring interferon alphas (InfergenTM,
from
Amgen, Thousand Oaks, California).
The HCV protease inhibitor can be administered in combination with
interferon alpha, PEG-interferon alpha conjugates or consensus interferon
concurrently or consecutively at recommended dosages for the duration of HCV
treatment in accordance with the methods of the present invention. The
commercially available forms of interferon alpha include interferon alpha 2a
and
interferon alpha 2b and also pegylated forms of both aforementioned interferon
alphas. The recommended dosage of INTRON-A interferon alpha 2b (commercially
available from Schering-Plough Corp.) as administered by subcutaneous
injection at
3MIU(12 mcg)/0.5mL/TIW is for 24 weeks or 48 weeks for first time treatment.
The
recommended dosage of PEG-INTRON interferon alpha 2b pegylated (commercially
available from Schering-Plough Corp.) as administered by subcutaneous
injection at
1.5 mcg/kg/week, within a range of 40 to 150 mcg/week, is for at least 24
weeks.
The recommended dosage of ROFERON A inteferon alpha 2a (commercially
available from Hoffmann-La Roche) as administered by subcutaneous or
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intramuscular injection at 3MIU(11.1 mcg/mL)/TIW is for at least 48 to 52
weeks, or
alternatively 6MIU/TIW for 12 weeks followed by 3MIU/TIW for 36 weeks. The
recommended dosage of PEGASUS interferon alpha 2a pegylated (commercially
available from Hoffmann-La Roche) as administered by subcutaneous injection at
180mcg/1 mL or 180mcg/0.5mL is once a week for at least 24 weeks. The
recommended dosage of INFERGEN interferon alphacon-1 (commercially available
from Amgen) as administered by subcutaneous injection at 9mcg/TIW is for 24
weeks for first time treatment and up to 15 mcg/TIW for 24 weeks for non-
responsive
or relapse treatment. Optionally, Ribavirin, a synthetic nucleoside analogue
with
activity against a broad spectrum of viruses including HCV, can be included in
combination with the interferon and the HCV protease inhibitor. The
recommended
dosage of ribavirin is in a range from 600 to 1400 mg per day for at least 24
weeks
(commercially available as REBETOL ribavirin from Schering-Plough or COPEGUS
ribavirin from Hoffmann-La Roche).
In one embodiment, the compounds of the invention can be used to treat
cellular proliferation diseases. Such cellular proliferation disease states
which can
be treated by the compounds, compositions and methods provided herein include,
but are not limited to, cancer (further discussed below), hyperplasia, cardiac
hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft
rejection,
inflammatory bowel disease, immune disorders, inflammation, cellular
proliferation
induced after medical procedures, including, but not limited to, surgery,
angioplasty,
and the like. Treatment includes inhibiting cellular proliferation. It is
appreciated that
in some cases the cells may not be in a hyper- or hypoproliferation state
(abnormal
state) and still require treatment. For example, during wound healing, the
cells may
be proliferating "normally", but proliferation enhancement may be desired.
Thus, in
one embodiment, the invention herein includes application to cells or subjects
afflicted or subject to impending affliction with any one of these disorders
or states.
The methods provided herein are particularly useful for the treatment of
cancer including solid tumors such as skin, breast, brain, colon, gall
bladder, thyroid,
cervical carcinomas, testicular carcinomas, etc. More particularly, cancers
that may
be treated by the compounds, compositions and methods of the invention
include,
but are not limited to:
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Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma,
liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell,
undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar)
carcinoma,
bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma,
mesothelioma;
Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,
leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma),
pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma,
carcinoid
tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors,
Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma),
large
bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,
leiomyoma);
Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma),
lymphoma, leukemia), bladder and urethra (squamous cell carcinoma,
transitional
cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis
(seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma,
sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid
tumors,
lipoma);
Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,
hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous
histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum
cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma,
osteochronfroma (osteocartilaginous exostoses), benign chondroma,
chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis
deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain
(astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma),
glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma,
congenital
tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
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Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma,
pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous
cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma),
granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma,
malignant
teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma,
adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma,
squamous
cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes
(carcinoma);
Hematologic: blood (myeloid leukemia (acute and chronic), acute
lymphoblastic leukemia, acute and chronic lymphocytic leukemia,
myeloproliferative
diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-
Hodgkin's lymphoma (malignant lymphoma), B-cell lymphoma, T-cell lymphoma,
hairy cell lymphoma, Burkett's lymphoma, promyelocytic leukemia;
Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma,
Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma,
keloids,
psoriasis;
Adrenal glands: neuroblastoma; and
Other tumors: including xenoderoma pigmentosum, keratoctanthoma and
thyroid follicular cancer.
As used herein, treatment of cancer includes treatment of cancerous cells,
including cells afflicted by any one of the above-identified conditions.
The compounds of the present invention may also be useful in the
chemoprevention of cancer. Chemoprevention is defined as inhibiting the
development of invasive cancer by either blocking the initiating mutagenic
event or
by blocking the progression of pre-malignant cells that have already suffered
an
insult or inhibiting tumor relapse.
The compounds of the present invention may also be useful in inhibiting tumor
angiogenesis and metastasis.
The compounds of the present invention may also be useful as antifungal
agents, by modulating the activity of the fungal members of the bimC kinesin
subgroup, as is described in U.S. Patent 6,284,480.
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The present compounds are also useful in combination with one or more other
known therapeutic agents and anti-cancer agents. Combinations of the present
compounds with other anti-cancer or chemotherapeutic agents are within the
scope
of the invention. Examples of such agents can be found in Cancer Principles
and
Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition
(February
15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary
skill in the
art would be able to discern which combinations of agents would be useful
based on
the particular characteristics of the drugs and the cancer involved. Such anti-
cancer
agents include, but are not limited to, the following: estrogen receptor
modulators,
androgen receptor modulators, retinoid receptor modulators,
cytotoxic/cytostatic
agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-
CoA
reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell
proliferation
and survival signaling, apoptosis inducing agents and agents that interfere
with cell
cycle checkpoints. The present compounds are also useful when co-administered
with radiation therapy.
The phrase "estrogen receptor modulators" refers to compounds that interfere
with or inhibit the binding of estrogen to the receptor, regardless of
mechanism.
Examples of estrogen receptor modulators include, but are not limited to,
tamoxifen,
raloxifene, idoxifene, LY353381, LY117081, toremifene, fulvestrant, 4-[7-(2,2-
dimethyl-I-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-
benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-
dinitrophenyl-ydrazone, aid SH646.
The phrase "androgen receptor modulators" refers to compounds which
interfere or inhibit the binding of androgens to the receptor, regardless of
mechanism. Examples of androgen receptor modulators include finasteride and
other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole,
and
abiraterone acetate.
The phrase "retinoid receptor modulators" refers to compounds which
interfere or inhibit the binding of retinoids to the receptor, regardless of
mechanism.
Examples of such retinoid receptor modulators include bexarotene, tretinoin,
13-cis-
retinoic acid, 9-cis-retinoic acid, a difluoromethylornithine, ILX23-7553,
trans-N-(4'-
hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
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The phrase "cytotoxic/cytostatic agents" refer to compounds which cause cell
death or inhibit cell proliferation primarily by interfering directly with the
cell's
functioning or inhibit or interfere with cell mycosis, including alkylating
agents, tumor
necrosis factors, intercalators, hypoxia activatable compounds, microtubule
inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins,
inhibitors of
kinases involved in mitotic progression, antimetabolites; biological response
modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth
factors, monoclonal antibody targeted therapeutic agents, monoclonal antibody
therapeutics, topoisomerase inhibitors, proteasome inhibitors and ubiquitin
ligase
inhibitors.
Examples of cytotoxic agents include, but are not limited to, sertenef,
cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine,
prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin,
oxaliplatin,
temozolomide (TEMODARTM from Schering-Plough Corporation, Kenilworth, New
Jersey), cyclophosphamide, heptaplatin, estramustine, improsulfan tosilate,
trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin,
satraplatin,
profiromycin, cisplatin, doxorubicin, irofulven, dexifosfamide, cis-
aminedichloro(2-
methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans,
trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-
platinum(II)]bis[diamine(chloro)platinum(II)] tetrachloride,
diarizidinylspermine,
arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine,
zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,
pinafide,
valrubicin, amrubicin, antineoplaston, 3'-deansino-3'-morpholino-13-deoxo-10-
hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, 4-demethoxy-
3-deamino-3-aziridinyl-4-methylsulphonyl-daunombicin (see WO 00/50032),
methoxtrexate, gemcitabine, and mixture thereof .
An example of a hypoxia activatable compound is tirapazamine.
Examples of proteasome inhibitors include, but are not limited to, lactacystin
and bortezomib.
Examples of microtubule inhibitors/microtubule-stabilising agents include
paclitaxel, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-
norvincaleukoblastine,
docetaxel, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin,
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RPR109881, BMS184476, vinflunine, cryptophycin, 2,3,4,5,6-pentafluoro-N-(3-
fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N,N-dimethyl-
L-
valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, the
epothilones (see for example U.S. Patents 6,284,781 and 6,288,237) and
BMS188797.
Some examples of topoisomerase inhibitors are topotecan, hycaptamine,
irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo-benzylidene-chartreusin,
9-
methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, 1-
amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1 H,12H-
benzo[de]pyrano[3',4':b,7]-indolizino[1,2b]quinoline-10,13(9H,15H)dione,
lurtotecan,
7-[2-(N-isopropylamino) ethyl]-(20S)camptothecin, BNP1350, BNP11100, BN80915,
BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino-2'-
deoxy-etoposide, GL331, N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl-6H-
pyrido[4,3-b]carbazole-l-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-
(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy-3,5-dimethoxyphenyl]-
5,5a,6,8,8a,9-hexohydrofuro (3',4':6,7)naphtho(2,3-d)-1,3-dioxol-6-one, 2,3-
(methylenedioxy)-5- methyl-7-hyd roxy-8-methoxybenzo [c]-p hen a nth rid in iu
m, 6,9-
bis[(2-aminoethyi)amino] benzo[g]isoguinoline-5,10-dione, 5-(3-
aminopropylamino)-
7,1 0-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1 -de]acridin-6-
one,
N-[1 - [2-(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-
ylmethyl]formamide,N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-
(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one, dimesna,
and camptostar.
Other useful anti-cancer agents that can be used in combination with the
present compounds include thymidilate synthase inhibitors, such as 5-
fluorouracil.
In one embodiment, inhibitors of mitotic kinesins include, but are not limited
to, inhibitors of KSP, inhibitors of MKLPI, inhibitors of CENP-E, inhibitors
of MCAK,
inhibitors of Kif14, inhibitors of Mphosphl and inhibitors of Rab6-KIFL.
The phrase "inhibitors of kinases involved in mitotic progression" include,
but
are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like
kinases (PLK) (in
particular inhibitors of PLK-1), inhibitors of bub-1 and inhibitors of bub-R1.
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The phrase "antiproliferative agents" includes antisense RNA and DNA
oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,
and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,
doxifluridine,
trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate,
fosteabine
sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine,
nolatrexed,
pemetrexed, neizarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-
2'-
deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4-
dichlorophenyl)urea,
N6-[4-deoxy-4-[N2-[2(E),4(E)-tetradecad ienoyl]glycylamino]-L-glycero-B-L-
manno-
heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-
oxo-
4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1,4]thiazin-6-yl-(S)-ethyl]-2,5-
thienoyl-L-
glutamic acid, aminopterin, 5-flurouracil, alanosine, 11 -acetyl-8-
(carbamoyloxymethyl)-4-formyl-6-methoxy-1 4-oxa-1, 11 -diazatetracyclo(7.4.
1Ø0)-
tetrad eca-2,4,6-trie n-9-yi acetic acid ester, swainsonine, lometrexol,
dexrazoxane,
methioninase, 2'-cyano-2'-deoxy-N4-palmitoyl-l-B-D-arabino furanosyl cytosine
and
3-aminopyridine-2-carboxaldehyde thiosemicarbazone.
Examples of monoclonal antibody targeted therapeutic agents include those
therapeutic agents which have cytotoxic agents or radioisotopes attached to a
cancer cell specific or target cell specific monoclonal antibody. Examples
include
Bexxar.
Examples of monoclonal antibody therapeutics useful for treating cancer
include Erbitux (Cetuximab).
The phrase "HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-
3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that
may be used include but are not limited to lovastatin, simvastatin (ZOCOR ),
pravastatin (PRAVACHOL ), fluvastatin and atorvastatin (LIPITOR ; see U.S.
Patents 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structural
formulas of
these and additional HMG-CoA reductase inhibitors that may be used in the
instant
methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs",
Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patents 4,782,084 and
4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all
pharmaceutically acceptable lactone and open-acid forms (i.e., where the
lactone
ring is opened to form the free acid) as well as salt and ester forms of
compounds
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which have HMG-CoA reductase inhibitory activity, and therefore the use of
such
salts, esters, open acid and lactone forms is included in the scope of this
invention.
The phrase "prenyl-protein transferase inhibitor" refers to a compound which
inhibits any one or any combination of the prenyl-protein transferase enzymes,
including farnesyl-protein transferase (FPTase), geranylgeranyl-protein
transferase
type I(GGPTase-I), and geranylgeranyl-protein transferase type-II (GGPTase-II,
also
called Rab GGPTase).
Examples of prenyi-protein transferase inhibitors can be found in the
following
publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO
97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patents
5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European
Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ.
0
604181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO
95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152,
WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO
96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO
96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO
96/05169, WO 96/00736, U.S. Patent 5,571,792, WO 96/17861, WO 96/33159, WO
96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO
96/30363, WO 96/31111, WO 96/31477, WO 96/31478, WO 96/31501, WO
97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO
97/17070, WO 97/23478, WO 97/26246, WO, 97/30053, WO 97/44350, WO
98/02436, and U.S. Patent 5,532,359. For an example of the role of a prenyi-
protein
transferase inhibitor on angiogenesis see European of Cancer, Vol. 35, No. 9,
pp.1394-1401(1999).
Examples of farnesyl protein transferase inhibitors include SARASARTM(4-[2-
[4-[(11 R)-3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-
b]pyridin-
11-y1-]-1-piperidinyl]-2-oxoehtyl]-1-piperidinecarboxamide from Schering-
Plough
Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestra or R115777 from
Janssen Pharmaceuticals), L778,123 (a farnesyl protein transferase inhibitor
from
Merck & Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl
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protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals,
Princeton,
New Jersey).
The phrase "angiogenesis inhibitors" refers to compounds that inhibit the
formation of new blood vessels, regardless of mechanism. Examples of
angiogenesis inhibitors include, but are not limited to, tyrosine kinase
inhibitors, such
as inhibitors of the tyrosine kinase receptors FIt-1 (VEGFR1) and Flk-1/KDR
(VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet
derived
growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers,
interferon-
a (for example Intron and Peg-Intron), interleukin-12, pentosan polysulfate,
cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs)
like
aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like
celecoxib
and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982);
Arch.
Opthalmo%, Vol. 108, p.573 (1990); Anat. Rec., Vol. 238, p. 68 (1994); FEBS
Letters,
Vol. 372, p. 83 (1995); Clin. Orthop. Vol. 313, p. 76 (1995); J. Mol.
Endocrinol., Vol.
16, p.107 (1996); Jpn. J. Pharrnacol., Vol. 75, p.105 (1997); Cancer Res.,
Vol. 57,
p.1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mo% Med., Vol. 2, p. 715
(1998); J.
Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as
corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone,
methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4,
squalamine, 6-O-chloroacetyl-carbonyl)-fumagillol, thalidomide, angiostatin,
troponin-
1, angiotensin II antagonists (see Fernandez et al., J. Lab. Clin. Med.
105:141-145
(1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-
968
(October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO
00/61186).
Other therapeutic agents that modulate or inhibit angiogenesis and may also
be used in combination with the compounds of the instant invention include
agents
that modulate or inhibit the coagulation and fibrinolysis systems (see review
in Clin.
Chem. La. Med. 38:679-692 (2000)). Examples of such agents that modulate or
inhibit the coagulation and fibrinolysis pathways include, but are not limited
to,
heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins
and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin
activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101:329-354
(2001)).
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Examples of TAFia inhibitors have been described in PCT Publication WO
03/013,526.
The phrase "agents that interfere with cell cycle checkpoints" refers to
compounds that inhibit protein kinases that transduce cell cycle checkpoint
signals,
thereby sensitizing the cancer cell to DNA damaging agents. Such agents
include
inhibitors of ATR, ATM, the Chkl and Chk2 kinases and cdk and cdc kinase
inhibitors and are specifically exemplified by 7-hydroxystaurosporin,
flavopiridol,
CYC202 (Cyclacel) and BMS-387032.
The phrase "inhibitors of cell proliferation and survival signaling pathway"
refers to agents that inhibit cell surface receptors and signal transduction
cascades
downstream of those surface receptors. Such agents include inhibitors of EGFR
(for
example gefitinib and erlotinib), antibodies to EGFR (for example C225),
inhibitors of
ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine
receptors,
inhibitors of MET, inhibitors of P13K (for example LY294002), serine/threonine
kinases (including but not limited to inhibitors of Akt such as described in
WO
02/083064, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf
kinase (for example BAY-43-9006), inhibitors of MEEK (for example CI-1040 and
PD-098059), inhibitors of mTOR (for example Wyeth CCI-779), and inhibitors of
C-
abl kinase (for example GLEEVECTM , Novartis Pharmaceuticals). Such agents
include small molecule inhibitor compounds and antibody antagonists.
The phrase "apoptosis inducing agents" includes activators of TNF receptor
family members (including the TRAIL receptors).
The invention also encompasses combinations with NSAID's which are
selective COX-2 inhibitors. For purposes of this specification NSAID's which
are
selective inhibitors of COX-2 are defined as those which possess a specificity
for
inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of
IC50 for
COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays. Inhibitors
of
COX-2 that are particularly useful in the instant method of treatment are: 3-
phenyl-4-
(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4-
methylsulfonyl)phenyl-
2-(2-methyl-5 pyridinyl)pyridine; or a pharmaceutically acceptable salt
thereof.
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Compounds that have been described as specific inhibitors of COX-2 and are
therefore useful in the present invention include, but are not limited to,
parecoxib,
CELIEBREX and BEXTRA or a pharmaceutically acceptable salt thereof.
Other examples of angiogenesis inhibitors include, but are not limited to,
endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-
butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate,
acetyldinanaline, 5-
amino-1-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]methyl]-1 H-1,2,3-triazole-4-
carboxamide, CM101, squalamine, combretastatin, RPI4610, NX31838, sulfated
mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-
pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]-bis-(1,3-naphthalene
disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone
(SU5416).
As used above, "integrin blockers" refers to compounds which selectively
antagonize, inhibit or counteract binding of a physiological ligand to the
a,[33 integrin,
to compounds which selectively antagonize, inhibit or counteract binding of a
physiological ligand to the aV05 integrin, to compounds which antagonize,
inhibit or
counteract binding of a physiological ligand to both the aõR3 integrin and the
a,,R5
integrin, and to compounds which antagonize, inhibit or counteract the
activity of the
particular integrin(s) expressed on capillary endothelial cells. The term also
refers to
antagonists of the aõR6, a,R8, alk a41, a41, (41 and a44 integrins. The term
also
refers to antagonists of any combination of avR3, a45, avR6, a,Rs, a1Rl+ a201,
a41,
a6R, and a6R4 integrins.
Some examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-
5-methylisoxazol-4-carboxamide, 3-[(2,4-dimethylpyrrol-5-
yl)methylidenyl)indolin-2-
one,17-(allylamino)-17-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-
7-methoxy-6-[3-(4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-
bis(2-
methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11,12-hexahydro-10-
(hydroxymethyl)-10-hydroxy-9-methyl-9,12-epoxy-1 H-diindolo[1,2,3-fg:3',2',1'-
kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one, SH268, genistein, STI571, CEP2563,
4-(3-
chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethane sulfonate,
4-
(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-
hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, ST1571A, N-4-
chlorophenyl-4-(4-pyridylmethyl)-1- phthalazinamine, and EMD121974.
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Combinations with compounds other than anti-cancer compounds are also
encompassed in the instant methods. For example, combinations of the present
compounds with PPAR-y (i.e., PPAR-gamma) agonists and PPAR-S (i.e., PPAR-
delta) agonists are useful in the treatment of certain malingnancies. PPAR-y
and
PPAR-8 are the nuclear peroxisome proliferator-activated receptors y and S.
The
expression of PPAR-y on endothelial cells and its involvement in angiogenesis
has
been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31:909-
913; J.
Biol. Chem. 1999;274:9116-9121; Invest. Ophthalmol Vis. Sci. 2000; 41:2309-
2317).
More recently, PPAR-y agonists have been shown to inhibit the angiogenic
response
to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the
development
of retinal neovascularization in mice (Arch. Ophthamol. 2001; 119:709-717).
Examples of PPAR-y agonists and PPAR-y/a agonists include, but are not limited
to,
thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and
pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-
H039242,
JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NP0110, DRF4158,
NN622, G1262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1,2-
benzisoxazol-6-yl)oxy]-2-methylpropionic acid, and 2(R)-7-(3-(2-chIoro-4-(4-
fluorophenoxy) phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid.
In one embodiment, useful anti-cancer (also known as anti-neoplastic) agents
that can be used in combination with the present compounds include, but are
not
limited, to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil,
Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan,
Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine,
6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin,
leucovirin,
oxaliplatin (ELOXATINTM from Sanofi-Synthelabo Pharmaeuticals, France),
Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,
Daunorubicin, Doxorubicin, Epirubicin, ldarubicin, Mithramycin,
Deoxycoformycin,
Mitomycin-C, L-Asparaginase, Teniposide 17a-Ethinylestradiol,
Diethylstilbestrol,
Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate,
Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone,
Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone,
Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide,
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Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea,
Amsacrine,
Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole,
Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine,
doxorubicin
(adriamycin), cyclophosphamide (cytoxan), gemcitabine, interferons, pegylated
interferons, Erbitux and mixtures thereof.
Another embodiment of the present invention is the use of the present
compounds in combination with gene therapy for the treatment of cancer. For an
overview of genetic strategies to treating cancer, see Hall et al (Am J Hum
Genet
61:785-789,1997) and Kufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC
Decker,
Hamilton 2000). Gene therapy can be used to deliver any tumor suppressing
gene.
Examples of such genes include, but are not limited to, p53, which can be
delivered
via recombinant virus-mediated gene transfer (see U.S. Patent 6,069,134, for
example), a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA/uPAR
Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination
in Mice," Gene Therapy, August 1998;5(8):1105-13), and interferon gamma (J
lmmunol 2000;164:217-222).
The present compounds can also be administered in combination with one or
more inhibitor of inherent multidrug resistance (MDR), in particular MDR
associated
with high levels of expression of transporter proteins. Such MDR inhibitors
include
inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093,
R101922, VX853 and PSC833 (valspodar).
The present compounds can also be employed in conjunction with one or
more anti-emetic agents to treat nausea or emesis, including acute, delayed,
late-
phase, and anticipatory emesis, which may result from the use of a compound of
the
present invention, alone or with radiation therapy. For the prevention or
treatment of
emesis, a compound of the present invention may be used in conjunction with
one or
more other anti-emetic agents, especially neurokinin-1 receptor antagonists,
5HT3
receptor, antagonists, such as ondansetron, granisetron, tropisetron, and
zatisetron,
GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron
(dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or those
as
described in U.S. Patents 2,789,118, 2,990,401, 3,048,581, 3,126,375,
3,929,768,
3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the
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phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and
mesoridazine), metoclopramide or dronabino(. In one embodiment, an anti-emesis
agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor
antagonist
and a corticosteroid is administered as an adjuvant for the treatment or
prevention of
emesis that may result upon administration of the present compounds.
Examples of neurokinin-1 receptor antagonists that can be used in
conjunction with the present compounds are described in U.S. Patents
5,162,339,
5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833,
5,637,699, and 5,719,147, content of which are incorporated herein by
reference. In
an embodiment, the neurokinin-1 receptor antagonist for use in conjunction
with the
compounds of the present invention is selected from: 2-(R)-(1-(R)-(3,5-
bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1 H,4H-
1,2,4-
triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof,
which is
described in U.S. Patent 5,719,147.
A compound of the present invention may also be administered with one or
more immunologic-enhancing drug, such as for example, levamisole, isoprinosine
and Zadaxin.
Thus, the present invention encompasses the use of the present compounds
(for example, for treating or preventing cellular proliferative diseases) in
combination
with a second compound selected from: an estrogen receptor modulator, an
androgen receptor modulator, retinoid receptor modulator, a
cytotoxic/cytostatic
agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an
HMG-CoA
reductase inhibitor, an angiogenesis inhibitor, a PPAR-y agonist, a PPAR-S
agonist,
an inhibitor of inherent multidrug resistance, an anti-emetic agent, an
immunologic-
enhancing drug, an inhibitor of cell proliferation and survival signaling, an
agent that
interfers with a cell cycle checkpoint, and an apoptosis inducing agent.
In one embodiment, the present invention emcompasses the composition and
use of the present compounds in combination with a second compound selected
from: a cytostatic agent, a cytotoxic agent, taxanes, a topoisomerase II
inhibitor, a
topoisomerase I inhibitor, a tubulin interacting agent, hormonal agent, a
thymidilate
synthase inhibitors, anti-metabolites, an alkylating agent, a farnesyl protein
transferase inhibitor, a signal transduction inhibitor, an EGFR kinase
inhibitor, an
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antibody to EGFR, a C-abl kinase inhibitor, hormonal therapy combinations, and
aromatase combinations.
The term "treating cancer" or "treatment of cancer" refers to administration
to
a mammal afflicted with a cancerous condition and refers to an effect that
alleviates
the cancerous condition by killing the cancerous cells, but also to an effect
that
results in the inhibition of growth and/or metastasis of the cancer.
In one embodiment, the angiogenesis inhibitor to be used as the second
compound is selected from a tyrosine kinase inhibitor, an inhibitor of
epidermal-
derived growth factor, an inhibitor of fibroblast-derived growth factor, an
inhibitor of
platelet derived growth factor, an MW (matrix metalloprotease) inhibitor, an
integrin
blocker, interferon-a, interieukin-12, pentosan polysulfate, a cyclooxygenase
inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-(O-
chloroacetylcarbonyl)-fumagillol, thalidomide, angiostatin, troponin-1, or an
antibody
to VEGF. In an embodiment, the estrogen receptor modulator is tamoxifen or
raloxifene.
Also included in the present invention is a method of treating cancer
comprising administering a therapeutically effective amount of at least one
compound of the present invention in combination with radiation therapy and at
least
one compound selected from: an estrogen receptor modulator, an androgen
receptor
modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an
antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA
reductase
inhibitor, an angiogenesis inhibitor, a PPAR-y agonist, a PPAR-S agonist, an
inhibitor
of inherent multidrug resistance, an anti-emetic agent, an immunologic-
enhancing
drag, an inhibitor of cell proliferation and survival signaling, an agent that
interfers
with a cell cycle checkpoint, and an apoptosis inducing agent.
Yet another embodiment of the invention is a method of treating cancer
comprising administering a therapeutically effective amount of at least one
compound of the present invention in combination with paclitaxel or
trastuzumab.
The present invention also includes a pharmaceutical composition useful for
treating or preventing the various disease states mentioned herein cellular
proliferation diseases (such as cancer, hyperplasia, cardiac hypertrophy,
autoimmune diseases, fungal disorders, arthritis, graft rejection,
inflammatory bowel
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disease, immune disorders, inflammation, and cellular proliferation induced
after
medical procedures) that comprises a therapeutically effective amount of at
least one
compound of the present invention and at least one compound selected from: an
estrogen receptor modulator, an androgen receptor modulator, a retinoid
receptor
modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-
protein
transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis
inhibitor, a
PPAR-y agonist, a PPAR-b agonist, an inhibitor of cell proliferation and
survival
signaling, an agent that interfers with a cell cycle checkpoint, and an
apoptosis
inducing agent.
When the disease being treated by the cathepsin inhibitor compounds of the
present invention is inflammatory disease, an embodiment of the present
invention
comprises administering: (a) a therapeutically effective amount of at least
one
compound of the present cathepsin inhibitors (e.g., a compound according to
Formula I-XXVII) or a pharmaceutically acceptable salt, solvate or ester
thereof
concurrently or sequentially with (b) at least one medicament selected from
the
group consisting of: disease modifying antirheumatic drugs; nonsteroidal anti-
inflammatory drugs; COX-2 selective inhibitors; COX-1 inhibitors;
immunosuppressives (non-limiting examples include methotrexate, cyclosporin,
FK506); steroids; PDE IV inhibitors, anti-TNF-a compounds, TNF-alpha-
convertase
inhibitors, cytokine inhibitors, MMP inhibitors, glucocorticoids, chemokine
inhibitors,
CB2-selective inhibitors, p38 inhibitors, biological response modifiers;
anti-inflammatory agents and therapeutics.
Another embodiment of the present invention is directed to a method of
inhibiting or blocking T-cell mediated chemotaxis in a patient in need of such
treatment the method comprising administering to the patient a therapeutically
effective amount of at least one compound of the present cathepsin inhibitors
(e.g.,
a compound according to formula I-XXVII) or a pharmaceutically acceptable
salt,
solvate or ester thereof.
Another embodiment of this invention is directed to a method of treating
inflammatory bowel disease in a patient in need of such treatment comprising
administering to the patient a therapeutically effective amount of at least
one
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compound according to the present cathepsin inhibitors or a pharmaceutically
acceptable salt, solvate or ester thereof.
Another embodiment of this invention is directed to a method of treating or
preventing graft rejection in a patient in need of such treatment comprising
administering to the patient a therapeutically effective amount of at least
one
compound according to the present cathepsin inhibitors, or a pharmaceutically
acceptable salt, solvate or ester thereof.
Another embodiment of this invention is directed to a method comprising
administering to the patient a therapeutically effective amount of: (a) at
least one
compound according to the present cathepsin inhibitors, or a pharmaceutically
acceptable salt, solvate or ester thereof concurrently or sequentially with
(b) at least
one compound selected from the group consisting of: cyclosporine A, FK-506,
FTY720, beta-Interferon, rapamycin, mycophenolate, prednisolone, azathioprine,
cyclophosphamide and an antilymphocyte globulin.
Another embodiment of this invention is directed to a method of treating
multiple sclerosis in a patient in need of such treatment the method
comprising
administering to the patient a therapeutically effective amount of: (a) at
least one
compound according to the present cathepsin inhibitors, or a pharmaceutically
acceptable salt, solvate or ester thereof concurrently or sequentially with
(b) at least
one compound selected from the group consisting of: beta-interferon,
glatiramer
acetate, glucocorticoids, methotrexate, azothioprine, mitoxantrone, VLA-4
inhibitors
and/or CB2-selective inhibitors.
Another embodiment of this invention is directed to a method of treating
multiple sclerosis in a patient in need of such treatment the method
comprising
administering to the patient a therapeutically effective amount of: a) at
least one
compound according to the present cathepsin inhibitors, or a pharmaceutically
acceptable salt, solvate or ester thereof concurrently or sequentially with
(b) at least
one compound selected from the group consisting of: methotrexate, cyclosporin,
leflunimide, sulfasalazine, fl-methasone, fl-interferon, glatiramer acetate,
prednisone,
etonercept, and infliximab.
Another embodiment of this invention is directed to a method of treating
rheumatoid arthritis in a patient in need of such treatment the method
comprising
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administering to the patient a therapeutically effective amount of: (a) at
least one
compound according to the present cathepsin inhibitors or a pharmaceutically
acceptable salt, solvate or ester thereof concurrently or sequentially with
(b) at least
one compound selected from the group consisting of: COX-2 inhibitors, COX
inhibitors, immunosuppressives, steroids, PDE IV inhibitors, anti-TNF-a
compounds,
MMP inhibitors, glucocorticoids, chemokine inhibitors, CB2-selective
inhibitors,
caspase (ICE) inhibitors and other classes of compounds indicated for the
treatment
of rheumatoid arthritis.
Another embodiment of this invention is directed to a method of treating
psoriasis in a patient in need of such treatment the method comprising
administering
to the patient a therapeutically effective amount of: a) at least one compound
according to present cathepsin inhibitors, or a pharmaceutically acceptable
salt,
solvate or ester thereof concurrently or sequentially with (b) at least one
compound
selected from the group consisting of: immunosuppressives, steroids, and
anti-TNF-a compounds.
Another embodiment of this invention is directed to a method of treating a
disease selected from the group consisting of: inflammatory disease,
rheumatoid
arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection,
psoriasis,
fixed drug eruptions, cutaneous delayed-type hypersensitivity responses,
tuberculoid
leprosy, type I diabetes, viral meningitis and tumors in a patient in need of
such
treatment, such method comprising administering to the patient an effective
amount
of at least one compound according to present cathepsin inhibitors, or a
pharmaceutically acceptable salt, solvate or ester thereof.
Another embodiment of this invention is directed to a method of treating a
disease selected from the group consisting of inflammatory disease, rheumatoid
arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection,
psoriasis,
fixed drug eruptions, cutaneous delayed-type hypersensitivity responses,
tuberculoid
leprosy and cancer in a patient in need of such treatment, such method
comprising
administering to the patient an effective amount of at least one compound
according
to the present cathepsin inhibitors, or a pharmaceutically acceptable salt,
solvate or
ester thereof.
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Another embodiment of this invention is directed to a method of treating a
disease selected from the group consisting of inflammatory disease, rheumatoid
arthritis, multiple sclerosis, inflammatory bowel disease, graft rejection,
psoriasis,
fixed drug eruptions, cutaneous delayed-type hypersensitivity responses and
tuberculoid leprosy, type I diabetes, viral meningitis and cancer in a patient
in need
of such treatment, such method comprising administering to the patient an
effective
amount of (a) at least one compound according to the present cathepsin
inhibitors,
or a pharmaceutically acceptable salt, solvate or ester thereof concurrently
or
sequentially with (b) at least one medicament selected from the group
consisting of:
disease modifying antirheumatic drugs; nonsteroidal anti-inflammatory drugs;
COX-2
selective inhibitors; COX-1 inhibitors; immunosuppressives; steroids; PDE IV
inhibitors, anti-TNF-a compounds, MMP inhibitors, glucocorticoids, chemokine
inhibitors, CB2-selective inhibitors, biological response modifiers; anti-
inflammatory
agents and therapeutics.
When the present invention involves a method of treating a cardiovascular
disease, in addition to administering the cathepsin inhibitors of the present
invention,
the method further comprises administering to the subject in need one or more
pharmacological or therapeutic agents or drugs such as cholesterol
biosynthesis
inhibitors and/or lipid-lowering agents discussed below.
Non-limiting examples of cholesterol biosynthesis inhibitors for use in the
compositions, therapeutic combinations and methods of the present invention
include competitive inhibitors of HMG CoA reductase, the rate-limiting step in
cholesterol biosynthesis, squalene synthase inhibitors, squalene epoxidase
inhibitors
and mixtures thereof. Non-limiting examples of suitable HMG CoA reductase
inhibitors include statins such as lovastatin (for example MEVACORO which is
available from Merck & Co.), pravastatin (for example PRAVACHOLO which is
available from Bristol Meyers Squibb), fluvastatin, simvastatin (for example
ZOCORO which is available from Merck & Co.), atorvastatin, cerivastatin,
rosuvastatin, rivastatin (sodium 7-(4-fluorophenyl)-2,6-diisopropyl-5-
methoxymethylpyridin-3-yl)-3,5-dihydroxy-6-heptanoate, CI-981 and pitavastatin
(such as NK-104 of Negma Kowa of Japan); HMG CoA synthetase inhibitors, for
example L-659,699 ((E,E)-11-[3'R-(hydroxy-methyl)-4'-oxo-2'R-oxetanyl]-3,5,7R-
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trimethyl-2,4-undecadienoic acid); squalene synthesis inhibitors, for example
squalestatin 1; and squalene epoxidase inhibitors, for example, NB-598 ((E)-N-
ethyl-N-(6,6-dimethyl-2-hepten-4-ynyl)-3-[(3,3'-bithiophen-5-
yl)methoxy]benzene-
methanamine hydrochloride) and other sterol biosynthesis inhibitors such as
DMP-
565. Preferred HMG CoA reductase inhibitors include lovastatin, pravastatin
and
simvastatin.
In another embodiment, the method of treatment comprises administering the
present cathepsin inhibitors in combination with one or more cardiovascular
agents
and one or more cholesterol biosynthesis inhibitors.
In another alternative embodiment, the method treatment of the present
invention can further comprise administering nicotinic acid (niacin) and/or
derivatives
thereof coadministered with or in combination with the cardiovascular agent(s)
and
sterol absorption inhibitor(s) discussed above.
As used herein, "nicotinic acid derivative" means a compound comprising a
pyridine-3-carboxylate structure or a pyrazine-2-carboxylate structure,
including acid
forms, salts, esters, zwitterions and tautomers, where available. Examples of
nicotinic acid derivatives include niceritrol, nicofuranose and acipimox (5-
methyl
pyrazine-2-carboxylic acid 4-oxide). Nicotinic acid and its derivatives
inhibit hepatic
production of VLDL and its metabolite LDL and increases HDL and apo A-1
levels.
An example of a suitable nicotinic acid product is NIASPAN (niacin extended-
release tablets) which are available from Kos.
In another alternative embodiment, the method of treatment of the present
invention can further comprise administering one or more AcylCoA:Cholesterol 0-
acyltransferase ("ACAT") Inhibitors, which can reduce LDL and VLDL levels,
coadministered with or in combination with the cardiovascular agent(s) and
sterol
absorption inhibitor(s) discussed above. ACAT is an enzyme responsible for
esterifying excess intracellular cholesterol and may reduce the synthesis of
VLDL,
which is a product of cholesterol esterification, and overproduction of apo B-
100-
containing lipoproteins.
Non-limiting examples of useful ACAT inhibitors include avasimibe ([[2,4,6-
tris(1-methylethyl)phenyl]acetyl]sulfamic acid, 2,6-bis(1-methylethyl)phenyl
ester,
formerly known as CI-1011), HL-004, lecimibide (DuP-128) and CL-277082 (N-(2,4-
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difluorophenyl)-N-[[4-(2,2-dimethylpropyl)phenyl]methyl]-N-heptylurea). See P.
Chang et al., "Current, New and Future Treatments in Dyslipidaemia and
Atherosclerosis", Drugs 2000 JuI;60(1); 55-93, which is incorporated by
reference
herein.
In another alternative embodiment, the method of treatment of the present
invention can further comprise administering probucol or derivatives thereof
(such as
AGI-1067 and other derivatives disclosed in U.S. Patents Nos. 6,121,319 and
6,147,250), which can reduce LDL levels, coadministered with or in combination
with
the cardiovascular agent(s) and sterol absorption inhibitor(s) discussed
above.
In another alternative embodiment, the method of treatment of the present
invention can further comprise administering fish oil, which contains Omega 3
fatty
acids (3-PUFA), which can reduce VLDL and triglyceride levels, coadministered
with
or in combination with the cardiovascular agent(s) and sterol absorption
inhibitor(s)
discussed above. Generally, a total daily dosage of fish oil or Omega 3 fatty
acids
can range from about I to about 30 grams per day in single or 2-4 divided
doses.
In another alternative embodiment, the method of treatment of the present
invention can further comprise administering natural water soluble fibers,
such as
psyllium, guar, oat and pectin, which can reduce cholesterol levels,
coadministered
with or in combination with the cardiovascular agent(s) and sterol absorption
inhibitor(s) discussed above. Generally, a total daily dosage of natural water
soluble
fibers can range from about 0.1 to about 10 grams per day in single or 2-4
divided
doses.
In another alternative embodiment, the method of treatment of the present
invention can further comprise administering plant sterols, plant stanols
and/or fatty
acid esters of plant stanols, such as sitostanol ester used in BENECOL
margarine,
which can reduce cholesterol levels, coadministered with or in combination
with the
cardiovascular agent(s) and sterol absorption inhibitor(s) discussed above.
Generally, a total daily dosage of plant sterols, plant stanols and/or fatty
acid esters
of plant stanols can range from about 0.5 to about 20 grams per day in single
or 2-4
divided doses.
In another alternative embodiment, the method of treatment of the present-
invention can further comprise administering antioxidants, such as probucol,
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tocopherol, ascorbic acid, P-carotene and selenium, or vitamins such as
vitamin B6
or vitamin B12, coadministered with or in combination with the cardiovascular
agent(s) and sterol absorption inhibitor(s) discussed above. Generally, a
total daily
dosage of antioxidants or vitamins can range from about 0.05 to about 10 grams
per
day in single or 2-4 divided doses.
In another alternative embodiment, the method of treatment of the present
invention can further comprise administering one or more bile acid
sequestrants
(insoluble anion exchange resins), coadministered with or in combination with
the
cardiovascular agents and sterol absorption inhibitor(s) discussed above.
Bile acid sequestrants bind bile acids in the intestine, interrupting the
enterohepatic circulation of bile acids and causing an increase in the faecal
excretion
of steroids. Use of bile acid sequestrants is desirable because of their non-
systemic
mode of action. Bile acid sequestrants can lower intrahepatic cholesterol and
promote the synthesis of apo B/E (LDL) receptors which bind LDL from plasma to
further reduce cholesterol levels in the blood.
Non-limiting examples of suitable bile acid sequestrants include
cholestyramine (a styrene-divinylbenzene copolymer containing quaternary
ammonium cationic groups capable of binding bile acids, such as QUESTRAN or
QUESTRAN LIGHT cholestyramine which are available from Bristol-Myers
Squibb), colestipol (a copolymer of diethylenetriamine and 1-chloro-2,3-
epoxypropane, such as COLESTID tablets which are available from Pharmacia),
colesevelam hydrochloride (such as WelChol Tablets (poly(allylamine
hydrochloride) cross-linked with epichlorohydrin and alkylated with 1-
bromodecane
and (6-bromohexyl)-trimethylammonium bromide) which are available from
Sankyo),
water soluble derivatives such as 3,3-ioene, N-(cycloalkyl) alkylamines and
poliglusam, insoluble quaternized polystyrenes, saponins and mixtures thereof.
Other useful bile acid sequestrants are disclosed in PCT Patent Applications
Nos.
WO 97/11345 and WO 98/57652, and U.S. Patents Nos. 3,692,895 and 5,703,188
which are incorporated herein by reference. Suitable inorganic cholesterol
sequestrants include bismuth salicylate plus montmorillonite clay, aluminum
hydroxide and calcium carbonate antacids.
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Also useful with the present invention are methods of treatment that can
further comprise administering at least one (one or more) activators for
peroxisome
proliferator-activated receptors (PPAR). These activators act as agonists for
the
peroxisome proliferator-activated receptors. Three subtypes of PPAR have been
identified, and these are designated as peroxisome proliferator-activated
receptor
alpha (PPARa), peroxisome proliferator-activated receptor gamma (PPARy) and
peroxisome proliferator-activated receptor delta (PPARcS). It should be noted
that
PPARd is also referred to in the literature as PPARa and as NUCI, and each of
these names refers to the same receptor.
PPARa regulates the metabolism of lipids. PPARa is activated by fibrates
and a number of medium and long-chain fatty acids, and it is involved in
stimulating
fl-oxidation of fatty acids. The PPARy receptor subtypes are involved in
activating
the program of adipocyte differentiation and are not involved in stimulating
peroxisome proliferation in the liver. PPARd has been identified as being
useful in
increasing high density lipoprotein (HDL) levels in humans. See, e.g., WO
97/28149.
PPARa activator compounds are useful for, among other things, lowering
triglycerides, moderately lowering LDL levels and increasing HDL levels.
Useful
examples of PPARa activators include the fibrates discussed above.
Other exampies of PPARa activators useful with the practice of the present
invention include suitable fluorophenyl compounds as disclosed in U.S. No.
6,028,109 which is incorporated herein by reference; certain substituted
phenylpropionic compounds as disclosed in WO 00/75103 which is incorporated
herein by reference; and PPARa activator compounds as disclosed in WO 98/43081
which is incorporated herein by reference.
Non-limiting examples of PPARy activator include suitable derivatives of
glitazones or thiazolidinediones, such as, troglitazone (such as REZULIN
troglitazone (-5-[[4-[3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1 -
benzopyran-2-
yl)methoxy]phenyl] methyl]-2,4-thiazolidinedione) commercially available from
Parke-
Davis); rosiglitazone (such as AVANDIA rosiglitazone maleate (-5-[[4-[2-
(methyl-2-
pyridinylamino)ethoxy] phenyl] methyl]-2,4-thiazolidinedione, (Z)
-2-butenedioate) (1:1) commercially available from SmithKline Beecham) and
pioglitazone (such as ACTOSTM pioglitazone hydrochloride (5-[[4-[2-(5-ethyl-2-
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pyridinyl)ethoxy]phenyl]methyl]-2,4-] thiazolidinedione monohydrochloride)
commercially available from Takeda Pharmaceuticals). Other useful
thiazolidinediones include ciglitazone, englitazone, darglitazone and BRL
49653 as
disclosed in WO 98/05331 which is incorporated herein by reference; PPARy
activator compounds disclosed in WO 00/76488 which is incorporated herein by
reference; and PPARy activator compounds disclosed in U.S. Patent No.
5,994,554
which is incorporated herein by reference.
Other useful classes of PPARy activator compounds include certain
acetylphenois as disclosed in U.S. Patent No. 5,859,051 which is incorporated
herein by reference; certain quinoline phenyl compounds as disclosed in WO
99/20275 which is incorporated herein by reference; aryl compounds as
disclosed by
WO 99/38845 which is incorporated herein by reference; certain 1,4-
disubstituted
phenyl compounds as disclosed in WO 00/63161; certain aryl compounds as
disclosed in WO 01/00579 which is incorporated herein by reference; benzoic
acid
compounds as disclosed in WO 01/12612 & WO 01/12187 which are incorporated
herein by reference; and substituted 4-hydroxy-phenylalconic acid compounds as
disclosed in WO 97/31907 which is incorporated herein by reference.
PPARa compounds are useful for, among other things, lowering triglyceride
levels or raising HDL levels. Non-limiting examples of PPARa activators
include
suitable thiazole and oxazole derivates, such as C.A.S. Registry No. 317318-32-
4,
as disclosed in WO 01/00603 which is incorporated herein by reference);
certain
fluoro, chloro or thio phenoxy phenylacetic acids as disclosed in WO 97/28149
which
is incorporated herein by reference; suitable non-(3-oxidizable fatty acid
analogues
as disclosed in U.S. Patent No. 5,093,365 which is incorporated herein by
reference;
and PPARa compounds as disclosed in WO 99/04815 which is incorporated herein
by reference.
Moreover, compounds that have multiple functionality for activating various
combinations of PPARa, PPARy and PPARd are also useful with the practice of
the
present invention. Non-limiting examples include certain substituted aryl
compounds
as disclosed in U.S. Patent No. 6,248,781; WO 00/23416; WO 00/23415; WO
00/23425; WO 00/23445; WO 00/23451; and WO 00/63153, all of which are
incorporated herein by reference, are described as being useful PPARa and/or
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PPARy activator compounds. Other non-limiting examples of useful PPARa and/or
PPARy activator compounds include activator compounds as disclosed in WO
97/25042 which is incorporated herein by reference; activator compounds as
disclosed in WO 00/63190 which is incorporated herein by reference; activator
compounds as disclosed in WO 01/21181 which is incorporated herein by
reference;
biaryl-oxa(thia)zole compounds as disclosed in WO 01/16120 which is
incorporated
herein by reference; compounds as disclosed in WO 00/63196 and WO 00/63209
which are incorporated herein by reference; substituted 5-aryl-2,4-
thiazolidinediones
compounds as disclosed in U.S. Patent No. 6,008,237 which is incorporated
herein
by reference; arylthiazolidinedione and aryloxazolidinedione compounds as
disclosed in WO 00/78312 and WO 00/78313G which are incorporated herein by
reference; GW2331 or (2-(4-[difluorophenyl]-1 heptylureido)ethyl]phenoxy)-2-
methylbutyric compounds as disclosed in WO 98/05331 which is incorporated
herein
by reference; aryl compounds as disclosed in U.S. Patent No. 6,166,049 which
is
incorporated herein by reference; oxazole compounds as disclosed in WO
01/17994
which is incorporated herein by reference; and dithiolane compounds as
disclosed in
WO 01/25225 and WO 01/25226 which are incorporated herein by reference.
Other useful PPAR activator compounds include substituted
benzylthiazolidine-2,4-dione compounds as disclosed in WO 01/14349, WO
01/14350 and WO/01/04351 which are incorporated herein by reference;
mercaptocarboxylic compounds as disclosed in WO 00/50392 which is incorporated
herein by reference; ascofuranone compounds as disclosed in WO 00/53563 which
is incorporated herein by reference; carboxylic compounds as disclosed in WO
99/46232 which is incorporated herein by reference; compounds as disclosed in
WO
99/12534 which is incorporated herein by reference; benzene compounds as
disclosed in WO 99/15520 which is incorporated herein by reference; o-
anisamide
compounds as disclosed in WO 01/21578 which is incorporated herein by
reference;
and PPAR activator compounds as disclosed in WO 01/40192 which is incorporated
herein by reference.
Also useful with the present invention are methods of treatment which further
comprise administering hormone replacement agents and compositions. Useful
hormone agents and compositions for hormone replacement therapy of the present
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invention include androgens, estrogens, progestins, their pharmaceutically
acceptable salts and derivatives. Combinations of these agents and
compositions
are also useful.
The cathepsin inhibitors of the present invention are useful in the treatment
of
central nervous system diseases such as depression, cognitive function
diseases
and neurodegenerative diseases such as Parkinson's disease, senile dementia as
in
Alzheimer's disease, and psychoses of organic origin. In particular, the
cathepsin
inhibitors of the present invention can improve motor-impairment due to
neurodegenerative diseases such as Parkinson's disease.
The other agents known to be useful in the treatment of Parkinson's disease
which can be administered in combination with the cathepsin inhibitors of the
present
invention include: L-DOPA; dopaminergic agonists such as quinpirole,
ropinirole,
pramipexole, pergolide and bromocriptine; MAO-B inhibitors such as deprenyl
and
selegiline; DOPA decarboxylase inhibitors such as carbidopa and benserazide;
and
COMT inhibitors such as toicapone and entacapone.
A preferred dosage for the administration of a compound of the present
invention is about 0.001 to 500 mg/kg of body weight/day of a compound of the
present invention or a pharmaceutically acceptable salt or ester thereof. An
especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a
compound of the present invention or a pharmaceutically acceptable salt or
ester
thereof.
The phrases "effective amount" and "therapeutically effective amount" mean
that amount of a compound of the present invention, and other pharmacological
or
therapeutic agents described herein, that will elicit a biological or medical
response
of a tissue, a system, or a subject (e.g., animal or human) that is being
sought by the
administrator (such as a researcher, doctor or veterinarian) which includes
alleviation
of the symptoms of the condition or disease being treated and the prevention,
slowing or halting of progression of one or more of the presently claimed
diseases.
The formulations or compositions, combinations and treatments of the present
invention can be administered by any suitable means which produce contact of
these
compounds with the site of action in the body of, for example, a mammal or
human.
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For administration of pharmaceutically acceptable salts of the above
compounds, the weights indicated above refer to the weight of the acid
equivalent or
the base equivalent of the therapeutic compound derived from the salt.
As described above, this invention includes combinations comprising an
amount of at least one compound of the presently claimed methods or a
pharmaceutically acceptable salt or ester thereof, and an amount of one or
more
additional therapeutic agents listed above (administered together or
sequentially)
wherein the amounts of the compounds/ treatments result in desired therapeutic
effect.
When administering a combination therapy to a patient in need of such
administration, the therapeutic agents in the combination, or a pharmaceutical
composition or compositions comprising the therapeutic agents, may be
administered in any order such as, for example, sequentially, concurrently,
together,
simultaneously and the like. The amounts of the various actives in such
combination
therapy may be different amounts (different dosage amounts) or same amounts
(same dosage amounts). Thus, for illustration purposes, a compound of the
present
invention and an additional therapeutic agent may be present in fixed amounts
(dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the
like).
If formulated as a fixed dose, such combination products employ the
compounds of this invention within the dosage range described herein and the
other
pharmaceutically active agent or treatment within its dosage range. Compounds
of
the present invention may also be administered sequentially with known
therapeutic
agents when a combination formulation is inappropriate. The invention is not
limited
in the sequence of administration; compounds of the present invention may be
administered either prior to or after administration of the known therapeutic
agent.
Such techniques are within the skills of persons skilled in the art as well as
attending
physicians. I
The pharmacological properties of the compounds of this invention may be
confirmed by a number of pharmacological assays for measuring HCV viral
activity
or cathepsin activity, such as are well know to those skilled in the art.
The compositions of the present invention comprise at least one compound of
Formulae I to XXVI, as defined above, together with one or more acceptable
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controlled-release carriers, other adjuvants or vehicles thereof and
optionally other
therapeutic agents. Each carrier, adjuvant or vehicle must be acceptable in
the
sense of being compatible with the other ingredients of the composition and
not
injurious to the mammal in need of treatment.
The compositions of the present invention are formulated with one or more
controlled-release carriers to provide the rate controlled-release of any one
or more
of the components or active ingredients to optimize the therapeutic effects,
i.e. HCV
inhibitory activity and the like. Suitable dosage formulations for sustained
release
include, inter alia, layered tablets containing layers of varying
disintegration rates or
controlled release polymeric matrices impregnated with the active components
and
shaped in tablet form or capsules containing such impregnated or encapsulated
porous polymeric matrices.
Controlled-release is a term known in the medicinal art and is typically used
interchangeably with delayed release, slow release, controlled availability,
slow
acting, extended release, and metered release. Controlled-release is generally
defined as the release of an agent from a dosage formulation slowly over a
period of
time, such as over hours or days. In the present invention, controlled-release
is
further defined as administering a predetermined dose of at least one of the
compounds of Formulae I to XXVI over a predetermined period of time.
The present invention discloses dosage formulations and methods of using
the same in which a predetermined dose of at least one of the compounds of
Formulae I to XXVI is administered to maintain a suitable therapeutically
efficacious
trough level Cmin plasma concentration of said one compound throughout the
dosing interval. Preferably, in an embodiment, the present invention discloses
dosage formulations and methods of using the same in which a predetermined
dose
of at least one of the compounds of Formulae I to XXVI is administered to
maintain
the average Cmin plasma concentration of the at least one HCV protease
inhibitor at
or above about 10ng/ml. However, in other embodiments, the average Cmin plasma
concentration of the at least one protease inhibitor may be maintained at or
above 50
ng/ml, 100ng/mI, 150ng/ml or 200ng, ml. Cmin is generally defined as the
minimum
concentration of drug in plasma to obtain a predetermined intensity of
response.
Cmin is a measure of the concentration of drug in blood/plasma and is
typically
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quantified at a time when the drug concentration will be near its lowest
level, i.e.
before the next predetermined dose of the drug. The controlled-release dosage
formulation and method are intended to treat, prevent, and/or ameliorate
disorders
associated with HCV. The controlled-release dosage formulation and method are
further intended to treat and/or reduce the signs and/or symptoms associated
with
HCV.
The rate of dissolution of the formulation can range suitably to generally
allow
the dissolution of from about 5 % of the drug in the first 6 hours to about
80% of the
drug in the first 6 hours, preferably from about 20 % of the drug in the first
6 hours to
about 50% of the drug in the first 6 hours. Dissolution can be determined
according
to standard USP procedures well known to those skilled in the art. A non-
limiting
example of a suitable procedure for determining dissolution is described in
the
following table:
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(50 mg) Dissolution Procedure
Apparatus USP Apparatus 2 (Paddles)
Dissolution 0.5% SDS in phosphate buffer, pH 6.8, 500 mL for 50
Medium mg strength
Temperature 37 C
Detection HPLC with UV detector at 220 nm wavelength
The controlled-release dosage formulation has at least one dosage unit, but
may contain a plurality of dosage units, ranging from 2-100 dosage units. An
oral
dosage formulation may be provided, such as one of the following: tablets,
capsules, or caplets. A transdermal treatment via a medicated patch may also
be
used as the controlled-release dosage formulation.
The controlled-release dosage formulation contains from about I mg to about
3000mg of at least one HCV protease inhibitor from Formulae I to XXVI
discussed
herein. The dosage formulation may be administered once a day, twice a day,
three
times a day, four times a day, or more frequently. In one non-limiting
embodiment,
400mg of the HCV protease inhibitor is administered three times a day.
However,
the dosing schedule may be at from about 100mg a day, 100mg twice a day, 200mg
twice a day, 400mg twice a day, 600mg twice a day, or 600mg three times a day.
Also, as discussed herein, the amount and frequency of administration of the
formulations of the present invention will be regulated according to the
judgment of
the attending clinician considering such factors as age, condition and size of
the
patient as well as severity of the symptoms being treated. A typical
recommended
daily dosage regimen for oral administration can range from about 50 mg/day to
about 3000 mg/day, in two to four divided doses.
The quantity of active compound in a unit dose of preparation may be varied
or adjusted from about I mg to about 1000 mg, or from about 50 mg to about 800
mg, or from about 50 mg to about 600 mg, or from about 50 mg to about 400 mg,
or
from about 50 mg to about 200 mg according to the particular application. In
one
embodiment, the dosage formulation contains about 200 mg of the active
compound.
The controlled-release dosage formulation may be administered at a time of
day to coincide with the circadian rhythm of the subject being treated.
Circadian
rhythms are endogenous oscillations that occur with a periodicity of about 24
hours,
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and are synchronized according to internal biologic clocks related to the
sleep-wake
cycle. The controlled-release dosage formulation thus may be administered in
one
or more discrete dosages over a twenty-four hour time interval in an
asymmetric
pattern as to dosage amount and/or timing of dosage, wherein the at least one
HCV
protease inhibitor is selected from the group consisting of compounds of
Formulae I-
XXVI, as described above.
Studies of viral activity in HCV infected patients indicate that viral
activity and
resulting viral load are influenced by the circadian rhythm of the patient. As
shown in
Fig. 1, in patients treated with compound Ia of the present invention the
decline in
viral load is cyclical, with the viral load declining during cell division in
the liver, and
increasing at times when no cell division is occurring. During cell division
the virus is
unable to replicate, and the viral load declines. Thus, in one aspect of the
invention,
the one or more discrete dosages are adjusted in amount to provide a highest
dose
or doses at a time or times corresponding to the time interval when
replication of the
hepatitis-C virus is highest.
It has been determined that metabolism of compounds of the present invention
is also affected by the patient's circadian rhythm. As shown in Fig. 2 (right
hand
box), plasma levels of the drug are highest in the morning, when measured 8
hours
after the previous dose and before the morning dose is administered. Plasma
levels
8 hours after the morning dose are much lower, suggesting that metabolism of
the
drug is faster during the day than at night.
Accordingly, in another aspect of the present invention, the one or more
discrete dosages are adjusted in amount to provide a highest dose or doses at
a
time or times corresponding to the time interval when metabolism of the
protease
inhibitor is highest. In a preferred embodiment, the one or more discrete
dosages is
three doses, administered as one dose of 300 mg., one dose of 400 mg., and one
dose of 500 mg., each dose administered every 8 hours, wherein the 500 mg.
dose
is administered at a time corresponding to the time interval of highest
replication of
the hepatitis-C virus and/or highest metabolism of the protease inhibitor. It
may also
be desirable to provide different patterns of dosage, such as, but not limited
to 200,
300, 700; or 200, 200, 300, 500; 200, 200, 200, 600, or other combinations,
depending on considerations such as the length of time that highest viral
replication
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is occurring, metabolism of the protease inhibitor and the highest tolerated
dose.
One skilled in the art can determine the appropriate number of doses and dose
amounts without undue experimentation.
Alternatively, and in additional embodiments, the one or more discrete
dosages is administered in equal dose amounts but staggered as to timing of
administration, to accommodate fluctuations in viral load and/or drug
metabolism.
For example, if the total desired dose over 24 hours is 1200 mg., it can be
administered as a 300 mg/dose, at 8 am, 12 noon, 4 pm, and 8 pm, with a 12-
hour
interval between the evening dose and the morning dose. This example is non-
limiting, and one skilled in the art can easily determine the appropriate
number of
doses and the timing of administration. In a preferred embodiment, the one or
more
discrete dosages is at least three doses in equal amounts, administered at
unequal
time intervals in twenty-four hours. The time intervals of dosage are adjusted
to
provide administration of one or more doses at a time or times corresponding
to the
time interval of highest replication of the hepatitis-C virus, or they can be
adjusted to
provide administration of one or more doses at a time or times corresponding
to the
time interval of highest metabolism of the protease inhibitor.
As will be understood by one skilled in the art, both the amount of dosage
given over a 24-hour period and the timing of administration can be varied in
an
asymmetric pattern. The asymmetric pattern of dose amount or timing of dosage
is
adjusted to accommodate variations in viral replication and/or metabolism of
the
protease inhibitor influenced by the patient's circadian rhythm.
Further, as discussed herein, the controlled-release dosage formulation may
be administered concurrently or sequentially as combination therapy with at
least
one of an antiviral agent and/or at least one of an immunomodulatory agent
that are
different from the HCV protease inhibitors disclosed in Formulae I to XXVI.
Further,
the different antiviral agent(s) and/or the immunomodulatory agent(s) may be
contained within the controlled-release dosage formulation with the HCV
protease
inhibitors disclosed in Formulae I to XXVI. As discussed herein, the
controlled-
release dosage formulation may contain at least one anti-cancer agent or may
be
administered concurrently or sequentially with at least one anti-cancer agent.
In the pharmaceutical compositions and methods of the present invention, the
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active ingredients will typically be administered in admixture with suitable
carrier
materials suitably selected with respect to the intended form of
administration, i.e.
oral tablets, capsules (either solid-filled, semi-solid filled or liquid
filled), powders for
constitution, oral gels, elixirs, dispersible granules, syrups, suspensions,
and the like,
and consistent with conventional pharmaceutical practices. For example, for
oral
administration in the form of tablets or capsules, the active drug component
may be
combined with any oral non-toxic pharmaceutically acceptable inert carrier,
such as
lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate,
calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like.
Moreover,
when desired or needed, suitable binders, lubricants, disintegrating agents
and
coloring agents may also be incorporated in the mixture. Powders and tablets
may
be comprised of from about 5 to about 95 percent inventive composition.
Suitable controlled-release carrier forms include general types now known or
heretofore developed in the art. Examples include and are incorporated herein
by
reference, but are not limited to, hydrophilic polymers as disclosed in U.S.
Patent
Application Publication No. 2004/0156899, multi-layer release beads as
disclosed in
U.S. Patent No. 6,673,367, controlled-release beads as disclosed in U.S.
Patent No.
6,770,295, coated tablets as disclosed in U.S. Patent Nos. 4,990,535 and
5,100,675,
matrix core tablets as disclosed in U.S. Patent No. 5,314,697, bilayer tablets
as
disclosed in WO 01/45676, controlled-release beads as disclosed in U.S. Patent
No.
6,630,162, and osmotic dosage formulations as disclosed in U.S. Patent Nos.
4,777,049, 4,851,229, and 5,178,867.
In one non-limiting embodiment, the controlled-release carrier is a swellable
polymer. The swellable polymer is a biocompatible or bioerodible, hydrophilic
polymer, preferably a cellulosic polymer. The term "hydrophilic" is generally
defined
in terms of a partition coefficient P, which is the ratio of the equilibrium
concentration
of a compound in an organic phase to that in an aqueous phase. A hydrophilic
compound has a P value less than 1.0, typically less than about 0.5, where P
is the
partition coefficient of the compound between octanol and water. Hydrophilic
polymeric carriers are thus compatible with aqueous fluids such as those
present in
the human body.
The term "polymer" as used herein refers to a molecule containing a plurality
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of covalently attached monomer units, and includes branched, dendrimeric and
star
polymers as well as linear polymers. The term also includes both homopolymers
and
copolymers, e.g., random copolymers, block copolymers and graft copolymers, as
well as uncrosslinked polymers and slightly to moderately to substantially
crosslinked
polymers.
The terms "swellable" and "bioerodible" (or simply "erodible") are used to
refer
to the preferred polymers herein, with "swellable" polymers being those that
are
capable of absorbing water and physically swelling as a result, with the
extent to
which a polymer can swell being determined by the degree of crosslinking, and
"bioerodible" or "erodible" polymers referring to polymers that slowly
dissolve and/or
gradually hydrolyze in an aqueous fluid, and/or that physically erodes as a
result of
movement within the stomach or gastrointestinal tract.
Polymers suitable for use in the present invention are those that both swell
upon absorption of gastric fluid and gradually erode over a time period of
hours.
Erosion initiates simultaneously with the swelling process, upon contact of
the
surface of the dosage formulation with gastric fluid. Erosion reflects the
dissolution
of the polymer beyond the polymer gel-solution interface where the polymer has
become sufficiently dilute that it can be transported away from the dosage
formulation by diffusion or convection. This may also depend on the
hydrodynamic
and mechanical forces present in the gastrointestinal tract during the
digestive
process. While swelling and erosion occur at the same time, it is preferred
herein
that drug release should be erosion-controlled, meaning that the selected
polymer
should be such that complete drug release occurs primarily as a result of
erosion
rather than swelling and dissolution. However, swelling should take place at a
rate
that is sufficiently fast to allow the tablet to be retained in the stomach.
At minimum,
for an erosional gastric retentive dosage formulation, there should be an
extended
period during which the dosage formulation maintains its size before it is
diminished
by erosion.
Suitable polymers for use in the present dosage formulations may be linear,
branched, dendrimeric, or star polymers, and include synthetic hydrophilic
polymers
as well as semi-synthetic and naturally occurring hydrophilic polymers. The
polymers may be homopolymers or copolymers, if copolymers, either random
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copolymers, block copolymers or graft copolymers. Synthetic hydrophilic
polymers
useful herein include, but are not limited to:
polyalkylene oxides, particularly poly(ethylene oxide), polyethylene glycol
and
poly(ethylene oxide)-poly(propylene oxide) copolymers;
cellulosic polymers;
acrylic acid and methacrylic acid polymers, copolymers and esters thereof,
preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl
acrylate,
methyl methacrylate, ethyl methacrylate, and copolymers thereof, with each
other or
with additional acrylate species such as aminoethyl acrylate;
maleic anhydride copolymers;
polymaleic acid;
poly(acrylamides) such as polyacrylamide per se, poly(methacrylamide),
poly(dimethylacrylamide), and poly(N-isopropyl-acrylamide);
poly(olefinic alcohol) such as poly(vinyl alcohol);
poly(N-vinyl lactams) such as poly(vinyl pyrrolidone), poly(N-vinyl
caprolactam), and copolymers thereof;
polyols such as glycerol, polyglycerol (particularly highly branched
polyglycerol), propylene glycol and trimethylene glycol substituted with one
or more
polyalkylene oxides, e.g., mono-, di- and tri-polyoxyethylated glycerol, mono-
and di-
polyoxyethylated propylene glycol, and mono- and di-polyoxyethylated
trimethylene
glycol;
polyoxyethylated sorbitol and polyoxyethylated glucose;
polyoxazolines, including poly(methyloxazoline) and poly(ethyloxazoline);
polyvinylamines;
polyvinylacetates, including polyvinylacetate per se as well as ethylene-vinyl
acetate copolymers, polyvinyl acetate phthalate, and the like;
polyimines, such as polyethyleneimine;
starch and starch-based polymers;
polyurethane hydrogels;
chitosan;
polysaccharide gums;
zein; and
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shellac, ammoniated shellac, shellac-acetyl alcohol, and shellac n-butyl
stearate.
The term "cellulosic polymer" is used herein to denote a linear polymer of
anhydroglucose. Cellulosic polymers that can be used advantageously in the
present dosage formulations include, without limitation,
hydroxymethylcellulose,
hydroxypropylcellulose, hyd roxyethylcellu lose, hydroxypropyl
methylcellulose,
methylcellulose, ethylcellulose, cellulose acetate, cellulose acetate
phthalate,
cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate,
hydroxypropylcellulose phthalate, cellulose hexahydrophthalate, cellulose
acetate
hexahydrophthalate, carboxymethylcellulose, carboxymethylcellulose sodium, and
microcrystalline cellulose. Preferred cellulosic polymers are alkyl-
substituted
cellulosic polymers that ultimately dissolve in the GI tract in a predictably
delayed
manner. Preferred alkyl-substituted cellulose derivatives are those
substituted with
alkyl groups of 1 to 3 carbon atoms each. Examples are methylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropyl methylcellulose, and carboxymethylcellulose and mixtures
thereof. In
terms of their viscosities, one class of preferred alkyl-substituted
celluloses includes
those whose viscosity is within the range of about 50 to about 110,000
centipoise as
a 2% aqueous solution at 20 C. Another class includes those whose viscosity is
within the range of about 800 to about 6,000 centipoise as a 1% aqueous
solution at
20 C. Particularly preferred alkyl-substituted celluloses are
hydroxyethylcellulose and
hydroxypropylmethylcellulose. A presently preferred hyd roxyethyicell u lose
is
NATRASOL 250HX NF (National Formulary), available from Aqualon Company,
Wilmington, Del., USA.
Suitable polymers also include naturally occurring hydrophilic polymers such
as, by way of example, proteins such as collagen, fibronectin, albumins,
globulins,
fibrinogen, fibrin and thrombin; aminated polysaccharides, particularly the
glycosaminoglycans, e.g., hyaluronic acid, chitin, chondroitin sulfate A, B,
or C,
keratin sulfate, keratosulfate and heparin; guar gum; xanthan gum; carageenan;
alginates; pectin; and activated polysaccharides such as dextran and starches.
The aforementioned list of polymers is not exhaustive, and a variety of other
synthetic hydrophilic polymers may be used, as will be appreciated by those
skilled
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in the art.
The polymer may include biodegradable segments and blocks, either
distributed throughout the polymer's molecular structure or present as a
single block,
as in a block copolymer. Biodegradable segments are those that degrade so as
to
break covalent bonds. Typically, biodegradable segments are segments that are
hydrolyzed in the presence of water. Biodegradable segments may be composed of
small molecular segments such as ester linkages, anhydride linkages, ortho
ester
linkages, ortho carbonate linkages, amide linkages, phosphonate linkages, etc.
Any polymer or polymers of the matrix may also be crosslinked, with the
degree of crosslinking directly affecting the rate of polymer swelling as well
as the
erosion rate. That is, a polymer having a higher degree of crosslinking will
exhibit
less swelling and slower erosion than a polymer having a lower degree of
crosslinking. Crosslinked polymers may be prepared using the above-mentioned
exemplary polymers using conventional crosslinking procedures (e.g., chemical
crosslinking with an added crosslinking agent, photolytically induced
crosslinking,
etc.), or the polymers may be obtained commercially in crosslinked form.
The water-swellable polymers can be used individually or in combination.
Certain combinations will often provide a more controlled release of the drug
than
their components when used individually. Examples include, but are not limited
to,
the following: a cellulosic. polymer combined with a gum, such as
hydroxyethylcellulose or hydroxypropylcellulose combined with xanthan gum; a
polyalkylene oxide combined with a gum, such as poly(ethylene oxide) combined
with xanthan gum; and a polyalkylene oxide combined with a cellulosic polymer,
such as poly(ethylene oxide) combined with hydroxyethylcellulose or
hydroxypropylcellulose.
Combinations of different poly(ethylene oxide)s are also contemplated, with
polymers of different molecular weights contributing to different dosage
formulation
characteristics. For example, a very high molecular weight poly(ethylene
oxide)
such as Polyox 303 (with a number average molecular weight of 7 million) or
Polyox Coag (with a number average molecular weight of 5 million) may be used
to
significantly enhance diffusion relative to disintegration release by
providing high
swelling as well as tablet integrity. Incorporating a lower molecular weight
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poly(ethylene oxide) such as Polyox WSR N-60K (number average molecular
weight approximately 2 million) with Polyox 303 and/or Polyox Coag increases
disintegration rate relative to diffusion rate, as the lower molecular weight
polymer
reduces swelling and acts as an effective tablet disintegrant. Incorporating
an even
lower molecular weight poly(ethylene oxide) such as Polyox WSR N-80 (number
average molecular weight approximately 200,000) further increases
disintegration
rate.
The hydrophilicity and water swellability of these polymers cause the drug-
containing matrices to swell in size in the gastric cavity due to ingress of
water in
order to achieve a size that will be retained in the stomach when introduced
during
the fed mode. These qualities also cause the matrices to become slippery,
which
provides resistance to peristalsis and further promotes their retention in the
stomach.
The release rate of a drug from the matrix is primarily dependent upon the
rate of
water imbibition and the rate at which the drug dissolves and diffuses from
the
swollen polymer, which in turn is related to the solubility and dissolution
rate of the
drug, the drug particle size and the drug concentration in the matrix.
The amount of polymer relative to the drug can vary, depending on the drug
release rate desired and on the polymer, its molecular weight, and excipients
that
may be present in the formulation. The amount of polymer will be sufficient
however
to retain at least about 40% of the drug within the matrix one hour after
ingestion (or
immersion in the gastric fluid). Preferably, the amount of polymer is such
that at
least 50% of the drug remains in the matrix one hour after ingestion. More
preferably, at least 60%, and most preferably at least 80%, of the drug
remains in the
matrix one hour after ingestion. In all cases, however, substantially all of
the drug will
be released from the matrix within about eight hours, and preferably within
about six
hours, after ingestion, "substantially all" meaning at least 85%, preferably
at least
90%.
Higher molecular weight polymers may be preferred to provide a desired
extended release profile using the present dosage formulations. Suitable
molecular
weights are generally in the range of about 5,000 to about 20,000,000. For
sparingly
soluble drugs, the polymers have molecular weights preferably in the range of
about
5,000 to about 8,000,000, more preferably in the range of about 10,000 to
about
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5,000,000. For water-soluble drugs, the polymers preferably have molecular
weights
of at least about 10,000, but the molecular weight used will vary with the
selected
polymer. For example, for hydroxypropyl methyicellulose, the minimum molecular
weight may be as low as 10,000, while for poly(ethylene oxide)s the molecular
weight may be far higher, on the order of 2,000,000 or more.
The swellable polymer used as the controlled-release dosage formulation
carrier is preferably present in an amount to obtain a weight gain level of
the dosage
formulation from about 1 to 90 percent, or about 2 to 50 percent, or more
preferably
about 2 to 25 percent. The swellable polymer used as the controlled-release
dosage
formulation carrier is also preferably present at from about 1 to 99 weight
percent
(wt.%), or about 2 to 98 weight percent (wt.%), or more preferably about 20 to
90
weight percent (wt.%).
The formulations of the present invention comprise at least one HCV protease
inhibitor, as defined above, together with one or more pharmaceutically
acceptable
adjuvants and optionally other therapeutic agents and pharmaceutically
acceptable
carriers and excipients. Each excipient must be acceptable in the sense of
being
compatible with the other ingredients of the formulation and not injurious to
the
mammal in need of treatment.
In yet another embodiment, the present invention discloses methods for
preparing the pharmaceutical formulations of the present invention. In the
pharmaceutical formulations, the HCV protease inhibitor will typically be
administered in admixture with suitable carrier materials suitably selected
with
respect to the intended form of administration, i.e. oral tablets, capsules
(either
solid-filled, semi-solid filled or liquid filled), powders for constitution,
oral gels, elixirs,
dispersible granules, syrups, suspensions, and the like, and consistent with
conventional pharmaceutical practices. For example, for oral administration in
the
form of tablets or capsules, the active drug component may be combined with
any
oral non-toxic pharmaceutically acceptable inert carrier, such as lactose,
starch,
sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate,
talc,
mannitol, ethyl alcohol (liquid forms) and the like. Powders and tablets may
be
comprised of from about 5 to about 95 percent of the HCV protease inhibitor.
In one embodiment, the adjuvant is at least one pharmaceutically acceptable
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surfactant or at least one acidifying agent or both. When desired or needed,
suitable
carriers and other excipients (such as binders, glidents, lubricants, and
disintegrants)
may also be incorporated in the formulation. These adjuvants, carriers and
excipients as well as others are described hereinafter.
Surfactant refers to an adjuvant material that reduces the contact angle of
the
active drug component and may also be referred to as a wetting agent.
Typically,
the present HCV protease inhibitors have relatively low solubilities in
aqueous
systems (as in a mammalian body), such as less than 1 mg/ml. For example, the
solubility of a compound of Formula 1 a in water is about 0.6 mg/mI. Treatment
of
diseases requiring high dosages of the present compounds, such as HCV, is
enhanced by improving the absorption rate of the compounds thereby improving
the
extent of absorption of the compounds in a mammal. The surfactant in the
pharmaceutical formulations of the present invention enhances wetting of the
present compounds and improves the dissolution rate of the compounds to render
a
greater quantity of the compounds available for absorption than is available
in a
formulation of the present corripounds that does not include a surfactant. Any
pharmaceutically acceptable surfactant that improves wetting of the present
compounds may be used. Particularly suitable surfactants include sodium lauryl
sulfate, stearic acid, monoethanolamine, docusate sodium, sorbitan fatty acid
esters,
polyoxyethylene sorbitan fatty acid esters, ethoxylated aliphatic alcohols,
propylene
glycol monocaprylate, glycerol monostearate, medium chain triglycerides,
polyoxyethylene alkyl ethers, and polyoxyethylene stearates. In one
embodiment,
the surfactant is sodium lauryl sulfate. In another embodiment, the surfactant
is a
polyoxyethylene sorbitan fatty acid ester. In yet another embodiment, the
surfactant
is PEG-1-PEG-9-lauryl glycol ether. These surfactants may be used alone in or
combination in the pharmaceutical formulations of the present invention in a
total
amount of about 0.1 to about 10% by weight or about I to about 5% by weight.
Acidifying agent refers to an adjuvant material that lowers the pH of the
formulation. The present compounds are known to generally be most stable at
acidic pH. Any pharmaceutically acceptable acidifying agent that improves
wetting
of the present compounds may be used. Particularly suitable acidifying agents
include tartaric acid, ascorbic acid, citric acid, malic acid and succinic
acid. In one
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embodiment, the acidifying agent is tartaric acid. These acidifying agents may
be
used alone in or combination in the pharmaceutical formulations of the present
invention in a total amount of about 0.1 to about 10% by weight or about I to
5% by
weight.
Carrier refers to a substance that usually makes up the major portion of the
composition or dosage formulation. Suitable carriers include celluloses such
as
microcrystalline cellulose; sugars such as lactose, sucrose, mannitol and
sorbitol;
and starches derived from wheat, corn, rice and potato. The amount of carrier
in the
formulation can range from about 10 to about 90% by weight of the total
formulation,
or about 25 to about 75% by weight, or about 30 to about 60% by weight, or
about
12 to about 60% by weight. In one embodiment, the carrier is microcrystalline
cellulose.
Binders refers to substances that bind or "glue" powders together and make
them cohesive by forming granules, thus serving as the "adhesive" in the
formulation. Binders add cohesive strength already available in the diluent or
bulking
agent. Suitable binders include sugars such as lactose, sucrose and corn
sweeteners; starches derived from wheat, corn rice and potato; natural gums
such
as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic
acid,
sodium alginate and ammonium calcium alginate; cellulosic materials such as
methylcellulose and sodium carboxymethylcellulose and
hydroxypropylmethylcellulose; polyvinylpyrrolidone; polyethylene glycol; waxes
and
inorganics such as magnesium aluminum silicate. The amount of binder in the
formulation can range from about 10 to about 90% by weight of the total
formulation,
or about 25 to about 75% by weight, or about 30 to about 60% by weight, or
about
12 to about 60% by weight. In one embodiment, the binder is anhydrous lactose.
Glidents refers to material that prevents caking and improves the flow
characteristics of granulations, so that flow is smooth and uniform. Suitable
glidents
include silicon dioxide and talc. The amount of glident in the formulation can
range
from about 0.1 % to about 5% by weight of the total formulation, or from about
0.5 to
about 3% by weight.
Lubricants are substances added to the dosage formulation to enable the
tablet, granules, etc. after it has been compressed, to release from the mold
or die
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by reducing friction or wear. Suitable lubricants include metallic stearates
such as
magnesium stearate, calcium stearate or potassium stearate; stearic acid; high
melting point waxes; and water soluble lubricants such as boric acid sodium
chloride,
sodium benzoate, sodium acetate, sodium chloride sodium oleate, polyethylene
glycols and d'i-leucine. Lubricants are usually added at the very last step
before
compression, since they must be present on the surfaces of the granules and in
between them and the parts of the tablet press. The amount of lubricant in the
formulation can range from about 0.1 to about 10% by weight of the
formulation, or
from about 0.5 to about 5% by weight.
Disintegrant refers to materials added to the formulation to help it break
apart
(disintegrate) and release the drug. Suitable disintegrants include starches;
"cold
water soluble" modified starches such as sodium carboxymethyl starch; natural
and
synthetic gums such as locust bean, karaya, guar gum, tragacanth and agar;
cellulose derivatives such as methylcellulose and sodium
carboxymethylcellulose;
microcrystalline celluloses and cross-linked microcrystalline celluloses such
as
sodium croscarmellose; alginates such as alginic acid and sodium alginate;
clays
such as bentonites; and effervescent mixtures. The amount of disintegrant in
the
composition can range from about 2 to about 15% by weight of the formulation,
or
from about 2 to about 10% by weight.
Coloring agents provide coloration to the formulation or the dosage
formulation. Such excipients can include food grade dyes and food grade dyes
adsorbed onto a suitable adsorbent such as clay or aluminum oxide. The amount
of
the coloring agent can vary from about 0.1 to about 5% by weight of the
formulation,
or from about 0.1 to about 1%.
Sweetening agents, flavoring agents, stabilizers, antioxidants and
preservatives may also be included where appropriate.
The term pharmaceutical formulation encompasses both the bulk formulation
and individual unit dosage formulations. The bulk composition is material that
has
not yet been formed into individual dosage units. An illustrative dosage unit
is an
oral dosage unit such as tablets, capsules and the like.
The formulations of the present invention may be administered orally or
transdermally. Preferably, the pharmaceutical formulation is in a unit dosage
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formulation. In such form, the preparation is subdivided into suitably sized
unit
doses containing appropriate quantities of the active components, e.g., an
effective
amount to achieve the desired purpose. Suitable unit dosage formulations are
solids, gels, or fluids. Solid form preparations include powders, tablets,
dispersible
granules, capsules, cachets and suppositories.
The powders, tablets and capsules may be comprised of from about 5 to
about 95 percent active ingredient. Tablets, powders, cachets and capsules can
be
used as solid dosage formulations suitable for oral administration. Other
examples of
pharmaceutically acceptable carriers and methods of manufacture for various
compositions may be found in A. Gennaro (ed.), Remington's Pharmaceutical
Sciences, 13t" Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
Capsules are special - containers or enclosures, often made of methyl
cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or
containing
the pharmaceutical formulation. Hard shell capsules are typically made of
blends of
relatively high gel strength bone and pork skin gelatins. The capsule itself
may
contain small amounts of dyes, opaquing agents, plasticizers and
preservatives.
Tablet refers to a compressed or molded solid dosage formulation containing
the pharmaceutical formulation. The tablet can be prepared by compression of
mixtures or granulations obtained by wet granulation, dry granulation or by
compaction.
A gel, such as an oral gel refers to the formulations dispersed or solubilized
in
a hydrophillic semi-solid matrix.
Suppositories containing the formulations of the present invention may be
prepared by melting a low melting wax such as a mixture of fatty acid
glycerides
such as cocoa butter, and dispersing the components of the formulations
homogeneously therein by stirring or similar mixing. The molten homogeneous
mixture is then poured into convenient sized molds, allowed to cool and
thereby
solidify.
Additionally, the compositions of the present invention may be formulated in
sustained release form to provide the rate controlled release of any one or
more of
the components or active ingredients to optimize the therapeutic effects, i.e.
HCV
inhibitory activity and the like. Suitable dosage formulations for sustained
release
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include layered tablets containing layers of varying disintegration rates or
controlled
release polymeric matrices impregnated with the active components and shaped
in
tablet form or capsules containing such impregnated or encapsulated porous
polymeric matrices.
Fluid forms may be liquids including solutions, suspensions and emulsions
containing the formulations. Non-limiting examples include water or water-
propylene
glycol solutions for parenteral injections or addition of sweeteners and
pacifiers for
oral solutions, suspensions and emulsions. Liquid form preparations may also
include solutions for intranasal administration.
Also included are aerosol preparations of the present invention that are
suitable for inhalation. Aerosols may include solutions and solids in powder
form,
which may be in combination with a pharmaceutically acceptable carrier such as
inert compressed gas, e.g. nitrogen.
Also included are solid form preparations which are intended to be converted,
shortly before use, to liquid form preparations for either oral or parenteral
administration. Such liquid forms include solutions, suspensions and
emulsions.
Alternatively, the formulations of the present invention may be prepared in
powder
blends that can be suspended in water or juices.
Transdermal formulations may take the form of creams, lotions, aerosols
and/or emulsions and can be included in a transdermal patch of the matrix or
reservoir type as are conventional in the art for this purpose.
Bioavailability refers to the rate and extent to which the active drug
ingredient
or therapeutic moiety is absorbed into the systemic circulation from an
administered
dosage formulation as compared to a standard or control.
Conventional methods for preparing tablets and capsules are known. Such
methods include dry methods such as direct compression and compression of
granulation produced by compaction, or wet methods or other special
procedures. In
one embodiment, a capsule containing the pharmaceutical formulation of the
present
invention is produced by blending the active drug component with some
excipients,
compacting the mixing such as with a roller compactor, milling the compact,
blending
the milled material with any remaining excipients and filling the final blend
into
capsules.
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In one embodiment, the pharmaceutical formulation of the present is
administered orally and is in a unit dosage formulation. In such form, the
preparation
is subdivided into suitably sized unit doses containing appropriate quantities
of the
active component, e.g., an effective amount to achieve the desired purpose.
The amount and frequency of administration of the formulations of the present
invention will be regulated according to the judgment of the attending
clinician
considering such factors as age, condition and size of the patient as well as
severity
of the symptoms being treated. A typical recommended daily dosage regimen for
oral administration can range from about 50 mg/day to about 3000 mg/day, in
two to
four divided doses.
The quantity of active compound in a unit dose of preparation may be varied
or adjusted from about I mg to about 1000 mg, or from about 50 mg to about 800
mg, or from about 50 mg to about 600 mg, or from about 50 mg to about 400 mg,
or
from about 50 mg to about 200 mg according to the particular application. In
one
embodiment, the dosage formulation contains about 200 mg of the active
compound.
The actual dosage employed may be varied depending upon the
requirements of the patient and the severity of the condition being treated.
Determination of the proper dosage regimen for a particular situation is
within the
skill of the art. For convenience, the total daily dosage may be divided and
administered in portions during the day as required.
The amount of drug released over time by the controlled-release carrier is
tested by any of the standardized USP Dissolution Tests in vitro. It is
desirable to
administer the dosage formulation twice a day and to have a relatively
constant
release of HCV protease inhibitor over a 12 hour period.
The following formulation exemplifies some of the dosage formulations of the
present invention. In the formulation, the "Active Compound" designates any of
the
compounds of Formulae I-XXVI, as defined above, or a pharmaceutically
acceptable
sale, solvate or ester thereof.
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Hypothetical Example
Tablet
Ingredient Amount
Active Compound 200-500 mg
Swellable Polymer 2-75 %
Microcrystalline cellulose 0-60 wt.%
Lactose 0-60 wt.%
Sodium lauryl sulfate 0-10 wt.%
Tartaric acid 0-10 wt.%
Silicon dioxide 0-3 wt.%
Magnesium stearate 1-10 wt.%
TOTAL TABLET WEIGHT 300-1000 mg
The powdery Active Compound is blended with some of the ingredients and
compacted with a roller compactor to densify the powder. The resulting compact
is
milled, blended with the remaining ingredients and filled into the capsule.
The following experimental section applies for the preparation of the
compounds of Formula XI:
Abbreviations which are used in the descriptions of the schemes, preparations
and the examples that follow are:
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
EtOAc: Ethyl acetate
AcOH: Acetic acid
HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
NMM: N-Methylmorpholine
ADDP: 1,1'-(Azodicarbobyl)dipiperidine
DEAD: Diethylazodicarboxylate
MeOH: Methanol
EtOH: Ethanol
Et2O: Diethyl ether
DMSO: Dimethylsulfoxide
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HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate
DCM: Dichloromethane
DCC: 1,3-Dicyclohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy
Phg: Phenylglycine
Chg: Cyclohexylglycine
Bn: Benzyl
Bzl: Benzyl
Et: Ethyl
Ph: Phenyl
iBoc: isobutoxycarbonyl
iPr: isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
Cbz: Benzyloxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyl
MCPBA: 3-chloroperbenzoic acid.
Me: Methyl
HATU: O-(7-azabenzotriazol-l-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
DMAP: 4-N,N-Dimethylaminopyridine
Bop: B enzotriazol- 1 -yl-oxy-tris (d i methyla m i no)h exafl uoro p hosp
hate
PCC: Pyridiniumchlorochromate
Other abbreviations are commonly used abbreviations Such as according to
the guidelines published by Journal of Organic Chemistry.
General Schemes for Preparation of Target Compounds
Compounds of the present invention were synthesized using the general schemes
(Methods A-E) described below.
Method A
Deprotection of the N-Boc functionality of 1.01 under acidic conditions
provided the
hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine
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under peptide coupling methodology (Louis A Carpino et a/. "Preparation of
uronium
and immonium salts for peptide coupling", WO 2002094822, pp. 76) to afford
1.03.
N-Boc deprotection followed by treatment with appropriate isocyanate gave the
urea
1.05. Hydrolysis of the methyl ester provided the acid 1.06. Peptide coupling
of the
acid 1.06 with the appropriate Pj-P' primary amide moiety afforded the
hydroxyl
amide 1.07. Oxidation (Moffatt, or Dess-Martin's) resulted in the target
compound
1.08.
v _ v
v ~OCH3
~OCH3 COZCH3 ~ O N, 0
O O O H.HCI ~ y
1.02 1.03
1.01
v v
N OCH3 1OCH3 H HCI.HZN, 0 N N,~N 0
O CaP, Y _ 01,05
O
1.04
V v
OH
N OH N NHZ
Cap'NUN~ O0 Cap'NUN 00 O
IO' ~ O
I I
1.07
1.06 v
0
N -Y N NHZ
-~ Cap'NyNl-O 0 0
O ~
1.08
Method B
Peptide coupling of the acid 1.06 with the appropriate PI-P' secondary amide
moiety
afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's)
resulted in
the target compound 1.10.
Method C
In another variation, peptide coupling of the N-Boc-P2-P3-acid 1.03 with the
appropriate Pj-P' amide moiety afforded the hydroxyl amide 1.11. Oxidation
(Moffatt
or Dess-Martin's) resulted in the keto-amide 1.12. Deprotection of the N-Boc
using
either formic acid or 4 M HCI in dioxane gave the formate or hydrochloride
salt 1.13.
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Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in
the target
compound 1.14.
v v
H OH H
H '" II OH H~N N.P1
~OUN~O O OUNIV O O
IOI 1.17 IOI
1.11
V S_%
O O
H ~N N,P1 .~/N N.P,
I OUN~O O O X.H2NN O O
\/ O
/~I I _T_
1.12 1.13 X= HCI or HCOOH
U
H O H
"cap-NCO" N N,P1
or Ca 'N N~O O O
equivalent p y
0 1.14
Method D
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-
nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate.
Subsequent treatment with an amine (or amine hydrochloride salt) of choice
provided the target compound 1.14.
V
v o 0
N N N.P1 N N,P1
HCI.H2N~0 O 0 ~ puN~O O O
O~N I / IOI =
_T_
1.13 1.15
v
H O H
~N N.P,
"cap-NH2"
Ca 'N~NO O O
P
O z
-1'--
1.14
Method E
In yet another variation, the dipeptide hydrochloride salt 1.04 was converted
to the 4-
nitrophenyl carbamate as described above. Treatment with an amine (or amine
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hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis
and
further elaboration as described in Methods A/B provided the target compounds
1.14.
v V
N OCH3 N OCH3
HCI.H2N,-~O 0 ~ O N~O O
= ~ =
1.04 02N (~ O 1.16
V v
H O H
cap -NH2" N OCH3 as above N N N,P,
N N~
Cap'NyN~O O (Method A) Cap y O O O
O O
1.05 1.14
The following experimental section applies for the preparation of the
compounds of Formula XII:
Abbreviations which are used in the descriptions of the schemes, preparations
and
the examples that follow are:
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
EtOAc: Ethyl acetate
AcOH: Acetic acid
HOOBt: 3-Hyd roxy-1,2,3-benzotriazin-4(3 H )-one
EDCI: 1 -(3-d imethyl ami n opropyl)-3-ethyl ca rbod i i mid e hydrochloride
NMM: N-Methylmorpholine
ADDP: 1,1'-(Azodicarbobyl)dipiperidine
DEAD: Diethylazodicarboxylate
MeOH: Methanol
EtOH: Ethanol
Et20: Diethyl ether
DMSO: Dimethylsulfoxide
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HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate
DCM: Dichloromethane
DCC: 1,3-Dicyclohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-l-piperidinyloxy
Phg: Phenylglycine
Chg: Cyclohexylglycine
Bn: Benzyl
Bzl: Benzyl
Et: Ethyl
Ph: Phenyl
iBoc: isobutoxycarbonyl
iPr: isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
Cbz: Benzyloxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyl
Me: Methyl
HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
DMAP: 4-N,N-Dimethylaminopyridine
BOP: Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate
PCC: Pyridiniumchlorochromate
General Schemes for Preparation of Target Compounds
Compounds of the present invention were synthesized using the general
schemes (Methods A-E) described below.
Method A:
Deprotection of the N-Boc functionality of 1.01 under acidic conditions
provided the
hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine
under peptide coupling methodology to afford 1.03. N-Boc deprotection followed
by
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treatment with appropriate isocyanate gave the urea 1.05. Hydrolysis of the
methyl
ester provided the acid 1.06. Peptide coupling of the acid 1.06 with the
appropriate
Pj-P' primary amide moiety afforded the hydroxyl amide 1.07. Oxidation
(Moffatt or
related process - T.T.Tidwell, Synthesis, 1990, 857; or Dess-Martin's - J.
Org.
Chem., 1983, 48, 4155) resulted in the target compound 1.08.
V V
v
OCH3
OCH3 ~CO2CH3 H N
N O N O
>~ O~O O H.HCI O
1.02 ~ 1.03
1.01
U V
N OCH3 N OCH3
HCI.H2N0 Ca
p NNO 0
II
~ O ~
1.04 1.05
v V
OH
Q0OH NH2
Cap Cap Nu
I I N~O O O
O O
I I
1.07
1.06 v
H O
N NH2
9-Y
Cap' NyNO O O
O
1.08
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Method B
Peptide coupling of the acid 1.06 with the appropriate P1-P' secondary amide
moiety
afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's)
resulted in
the target compound 1.10.
V U
H OH H
N N
N N
Cap'yNv 'O O Cap'NUN~O O O
O/~. 1.06 v O/T. 1.09
H O H
N N
N
CaP'NyN~O 0 0
O
1.10
Method C
In another variation, peptide coupling of the N-Boc-P2-P3-acid 1.17 with the
appropriate P1-P' amide moiety afforded the hydroxyl amide 1.11. Oxidation
(Moffatt
or Dess-Martin's) resulted in the keto amide 1.12. Deprotection of the N-Boc
functionality gave the hydrochloride salt 1.13. Treatment with a suitable
isocyanate
(or isocyanate equivalent) resulted in the target compound 1.14.
V V
v ; H OH H
H 9N ---j- OH H ~N N.P1
~OyN~O O -- f V O O
O 1.17 O
\ / 1.11 V \ /
v H O H H O H
N' ~y N N,P, (N;)'.y N N,P,
OyNJ,,O 0 O HCI.H2N O O
O
1.12 1.13
V
H O H
cap-NCO" N N.P1
or ~N N~ IOI O
equivalent Cap y O
O ~ 1.14
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Method D
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-
nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate.
Subsequent treatment with an amine (or amine hydrochloride salt) of choice
provided the target compound 1.14.
V
.. ~ :; o
/
N N.P, N N,P,
9--
HCI.H2NO~O 0 ~ O N~N O O
0
O
O~N I / -T,
1.13 \ / 1.15
V H O H
oap-NH2" H N N N.P
Cap' NyN,,,-O O O
O
1.14
Method E
In yet another variation, the dipeptide hydrochloride salt 1.03 was converted
to the 4-
nitrophenyl carbamate as described above. Treatment with an amine (or amine
hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis
and
further elaboration as described in Methods A/B provided the target compounds
1.14.
V V
9 /OCH3 OCH3
~ H ~
HCI.H2N~0 0 ~ Oy N~O 0
1.04 02N I~ O 1.16
V V
H O H
bap-NH2" ~OCH3 as above ~N N=P1
(Method A)
Cap'NYNO O Cap'NYN O O
O 0
1.05 1.14
The following experimental section applies for the preparation of the
compounds of Formula XIII:
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Abbreviations which are used in the descriptions of the schemes, preparations
and
the examples that follow are:
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
EtOAc: Ethyl acetate
AcOH: Acetic acid
HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
NMM: N-Methylmorpholine
ADDP: 1,1'-(Azodicarbobyl)dipiperidine
DEAD: Diethylazodicarboxylate
DIAD: Diisopropylazodicarboxylate
MeOH: Methanol
EtOH: Ethanol
Et20: Diethyl ether
DMSO: Dimethylsulfoxide
HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate
DCM: Dichloromethane
DCC: 1,3-Dicyclohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy
Phg: Phenylglycine
Chg: Cyclohexylglycine
Bn: Benzyl
Bz: Benzyl
Et: Ethyl
Ph: Phenyl
iBoc: isobutoxycarbonyl
iPr: isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
Cbz: Benzyloxycarbonyl
Cp: Cylcopentyldienyl
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Ts: p-toluenesulfonyl
Me: Methyl
Ms or Mesyl: Methane sulfonyl
HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
DMAP: 4-N,N-Dimethylaminopyridine
Bop: Benzotriazol-l-yl-oxy-tris(dimethylamino)hexafluorophosphate
PCC: Pyridiniumchlorochromate
DIBAL-H: diisopropyl aluminum hydride
rt or RT: Room temperature
quant.: Quantitative yield
h or hr: hour
min: minute
TFA: Trifluoroacetic acid
General Schemes for Preparation of Target Compounds
Compounds of the present invention were synthesized using the general
schemes (Methods A-E) described below.
Method A
Deprotection of the N-Boc functionality of 1.01 under acidic conditions
provided the
hydrochloride salt 1.02 which was subsequently coupled with N-Boc-tert-leucine
under peptide coupling methodology to afford 1.03. N-Boc deprotection followed
by
treatment with appropriate isocyanate gave the urea 1.05. Hydrolysis of the
methyl
ester provided the acid 1.06. Peptide coupling of the acid 1.06 with the
appropriate
Pj-P' primary amide moiety afforded the hydroxyl amide 1.07. Oxidation
(Moffatt or
related process - T.T.Tidwell, Synthesis, 1990, 857; or Dess-Martin's
periodinane (J.
Org. Chem., 1983, 48, 4155) resulted in the target compound 1.08.
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U V
V
OCH3
OCH3 ~C02CH3 N
~ ~ O N~00
H
O O O H.HCI O
1.02 -j- 1.03
1.01
V V
~OCH3 N OCH3
HCI.H2N0 Cap 'NN~O 0
~ O ~
1.04 1.05
V v
OH
OH N NH2
-- ~
Cap'NyN~O 0 Cap'NUNO
I O O
O O
~ I
1.06 V 1.07
H 0
~N NH2
~ Cap NyN~O O O
0
~
1.08
Method B
Peptide coupling of the acid 1.06 with the appropriate PI-P' secondary amide
moiety
afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's)
resulted in
the target compound 1.10.
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V V
H OH H
OH N N,
N N
Cap'NyN '~ 'O O Cap NuN~O 0 0
1.09
O 1.06 v 0
H O H
N N N
Cap'Ny N~O 0 0
O
1.10
Method C
In another variation, peptide coupling of the N-Boc-P2-P3-acid 1.17 with the
appropriate Pj-P' amide moiety afforded the hydroxyl amide 1.11. Oxidation
(Moffatt
or Dess-Martin's) resulted in the keto amide 1.12. Deprotection of the N-Boc
functionality gave the hydrochloride salt 1.13. Treatment with a suitable
isocyanate
(or isocyanate equivalent) resulted in the target compound 1.14.
V V
; v H OH H
H .. ~OH H '" If N N1P'
\ /OyN~O O ~OUN~O O O
/ll O ~ 1.17 40I
\ / 1.11 \ /
V H O H V H O H
~N N,P1 N,P,
Ou~O O O ---- HCI.H2N~fV OO O
~ IOI
1.12 \ / 1.13
V H O H
"cap-NCO" ~N N.P,
or Cap N N~O O O
equivalent y
O m 1.14
Method D I
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-
nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate.
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Subsequent treatment with an amine (or amine hydrochloride salt) of choice
provided the target compound 1.14.
V V
H O H H O H
(N N.P1 ~N N.P,
HCI.H2N~N O~O 0 OuN~O O O
O2N IOI rn
I
1.13 \ / 1.15
V H O H
"cap-NH2" H H ~N N.P.
Cap'NyN~O O O
O -T-
1.14
Method E
In yet another variation, the dipeptide hydrochloride salt 1.03 was converted
to the 4-
nitrophenyl carbamate as described above. Treatment with an amine (or amine
'hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis
and
further elaboration as described in Methods A/B provided the target compounds
1.14.
V V
c)..OCH3 HCI.H2N~O 0 ~ OyN~N O O
1.04 O2N I~ O-T- 1.16
V V
H O H
"cap-NH2" OCH3 as above H HN N,p,
Cap'Ny N~O O (Method A) Cap NYN~O O O
I 1.05 1.14
O O
The following experimental section applies for the preparation of the
compounds of Formula XIV:
For the procedures described below, the following abbreviations are used:
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
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EtOAc: Ethyl acetate
AcOH: Acetic acid
HOOBt: 3-Hyd roxy-1,2,3-benzotriazin-4(3H)-one
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
NMM: N-Methylmorpholine
ADDP: 1,1'-(Azodicarbobyl)dipiperidine
DEAD: Diethylazodicarboxylate
MeOH: Methanol
EtOH: Ethanol
Et20: Diethyl ether
DMSO: Dimethylsulfoxide
HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate
DCM: Dichloromethane
DCC: 1,3-Dicyclohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-l-piperidinyloxy
Phg: Phenylglycine
Chg: Cyclohexylglycine
Bn: Benzyl
Bzl: Benzyl
Et: Ethyl
Ph: Phenyl
DMF-DMA: N,N-Dimethylformamide-dimethylacetal
iBoc: isobutoxycarbonyl
iPr: isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
Cbz: Benzyloxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyl
Me: Methyl
HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
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DMAP: 4-N,N-Dimethylaminopyridine
BOP : Benzotriazol- 1 -yl-oxy-tris (d i methyl am in o)h exafl uo ro phosp
hate
PCC: Pyridiniumchlorochromate
KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimethylsilylamide)
NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide)
LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide)
10% Pd/C: 10% Palladium on carbon (by weight).
TG: Thioglycerol
General Schemes for Preparation of Target Compounds
Compounds of the present invention were synthesized using the general
schemes (Methods A-E) described below.
Method A
Deprotection of the N-Boc functionality of 1.01 under acidic conditions
provided the hydrochloride salt 1.02 which was subsequently coupled with N-Boc-
tert-leucine under peptide coupling methodology to afford 1.03. N-Boc
deprotection
followed by treatment with appropriate isocyanate gave the urea 1.05.
Hydrolysis of
the methyl ester provided the acid 1.06. Peptide coupling of the acid 1.06
with the
appropriate Pj-P' primary amide moiety afforded the hydroxyl amide 1.07.
Oxidation
(Moffatt oxidation or related process - see, T. T. Tidwell, Synthesis, 1990,
857), or
Dess-Martin Periodinane - J. Org. Chem., (1983) 48, 4155) resulted in the
target
compound 1.08.
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V v
V
~OCH3
~OCH3 CO2CH3 ~
H
>~O,JO 0 H.HCI O ~ N 0 0
1.02 1.03
1.01
U V
N OCH3 ~OCH3
HCI.HaN~ 0 H N O
O Cap' 0
~
O 05
m ~
I1.04
V V
v v OH
OH ~N NH2
Cap'NUN~N 0O Cap'NN~IV 0
O I O O
I O -T-
1.06 \/ 1.07
~/ H 0
N~ -N NH2
-~ Cap NyNO O O
O ~
1.08
Method B
Peptide coupling of the acid 1.06 with the appropriate P1-P' secondary amide
moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's)
resulted in the target compound 1.10.
V V
v H OH H
9-YOH N
Cap'NyN~O 0 CaP'NyN OO 0
0 1.06 O 1.09
H O H
N N~~
N
CaP'Ny NO 0 0
0
1.10
-T-
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Method C
In another variation, peptide coupling of the N-Boc-P2-P3-acid 1.17 with the
appropriate P1-P' amide moiety afforded the hydroxyl amide 1.11. Oxidation
(Moffatt
or Dess-Martin Periodinane) resulted in the keto amide 1.12. Deprotection of
the N-
Boc functionality gave the hydrochloride salt 1.13. Treatment with a suitable
isocyanate (or isocyanate equivalent) resulted in the target compound 1.14.
V V
H OH H
H QOH H N N.P.
:~,OUN~O O OUN~ O O O
IOI 1.17 IOI -T-
1.11
~
v O
v
H ,P,
N O N,P, N N
\/OyN~O O O HCI.HZN~O O O
/I~ O -T-
1.12 v 1.13
9N H O H
~~cap-NCO~. N N,P.
or Cap N H N~O IOI O
equivalent y
o 1.14
Method D
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-
nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate.
Subsequent treatment with an amine (or amine hydrochloride salt) of choice
provided the target compound 1.14.
~/
. o 0
~N N,P N N,
H P'
HCI.H2NO O O N~O O O
-T, O2N O
1.13 \ ~ 1.15
V
H O H
"cap NH2" H H '" II N N.P1
N O O
'N~ O
CaP
O
1.14
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Method E
In yet another variation, the dipeptide hydrochloride salt 1.03 was converted
to
the 4-nitrophenyl carbamate as described above. Treatment with an amine (or
amine
hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis
and
further elaboration as described in Methods A/B provided the target compounds
1.14.
V V
~).OCH3 (OCH3
HCI.H2N~O O OuN~N O O
1.04 02N I~ IOI 1.16
V V
H O H
"cap-NH2" H HOCH3 asabove H H~N N,p1
N N O (Method A) N N O O
Cap'~O Cap' y O
O ~ O m
1.05 I 1.14
The following experimental section applies for the preparation of the
compounds of Formula XV:
For the procedures described below, the following abbreviations are used:
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
EtOAc: Ethyl acetate
AcOH: Acetic acid
HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
NMM: N-Methylmorpholine
ADDP: 1,1'-(Azodicarbobyl)dipiperidine
DEAD: Diethylazodicarboxylate
MeOH: Methanol
EtOH: Ethanol
Et20: Diethyl ether
DMSO: Dimethylsulfoxide
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HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate
DCM: Dichloromethane
DCC: 1,3-Dicyclohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-l-piperidinyloxy
Phg: Phenylglycine
Chg: Cyclohexylglycine
Bn: Benzyl
Bzl: Benzyl
Et: Ethyl
Ph: Phenyl
iBoc: isobutoxycarbonyl
iPr: isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
Cbz: Benzyloxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyl
Me: Methyl
HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
DMAP: 4-N,N-Dimethylaminopyridine
BOP : Benzotriazol-l-yl-oxy-tris(dimethylamino)hexafluorophosphate
PCC: Pyridiniumchlorochromate
KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimethylsilylamide)
NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide)
LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide)
10% Pd/C: 10% Palladium on carbon (by weight).
Preparative Example 1:
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H O
NjyH
N
0 N
H
N N N~OO
H
C ~ O = ~
Step A
O O
(NOH + CIO OMe I N N OMe
H3N
+O O ~ H
1c
1a 1b
A solution of pyrazinecarboxylic acid 1 a (3 g) in 150 mL of dry
dichloromethane and 150 mL of dry DMF was stirred at 0 C and treated with HATU
(1.4 eq, 6.03 g). L-cyclohexylglycine hydrochloride 1 b(1.2 eq, 6.03 g) was
added in
small portions. Then, N-methylmorpholine (4 eq, 10 mL, d 0.920) was added
dropwise. The reaction mixture was gradually warmed to room temperature and
stirred for 20 h. All the volatiles were removed under vacuum and the residue
was
dissolved in 500 mL of ethyl acetate. The organic layer was washed with water
(100
mL), aqueous 1 N HCI (100 mL), aqueous saturated sodium bicarbonate solution
(100 mL), and brine (100 mL). The organic layer was dried over magnesium
sulfate,
filtered and concentrated under reduced pressure. The residue was
chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to
afford the
product 1 c as a white solid.
Step B
0 0
N\ N OMe N\ OH
C~ H O CN H O
N
1 1d
A solution of methyl ester 1c (6.5 g) in 270 mL of a 1:1:1 mixture of
THF/MeOH/water was cooled to 0 C and treated with lithium hydroxide
monohydrate (2.5 eq, 2.45 g). The mixture was stirred and monitored by TLC
(acetone/hexanes; 2:8). When all the starting material had been consumed, the
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reaction mixture was treated with 100 mL of aqueous 1 N HCI and the mixture
was
concentrated on the rotavap. Dichloromethane (250 mL) was added and layers
separated. The aqueous layer was extracted with dichloromethane (3 x 80 mL).
The
combined organic layers were dried over magnesium sulfate, filtered, and
concentrated to afford the product 1d as a white solid.
Step C
H3C ~CH3
C)CO2CH3
N
H.HCI
le
The amino ester 1e was prepared following the method of R. Zhang and J. S.
Madalengoitia (J. Org. Chem. 1999, 64, 330), with the exception that the Boc
group
was cleaved by the reaction of the Boc-protected amino acid with methanolic
HCI
(4M HCI in dioxane was also employed for the deprotection).
(Note: In a variation of the reported synthesis, the sulfonium ylide was
replaced with
the corresponding phosphonium ylide).
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Step D
O
BocHNI-A OCH3
OCH3 + OH ~ Q
H H2CI BocHN~0 O
2 O
1e 1f ~ I-g
A solution of Boc-tert-Leu 1f (Fluka, 5.0 g, 21.6 mmol) in dry CH2CI2/DMF (50
mL, 1:1 ) was cooled to 0 C and treated with the amine hydrochloride 1e (5.3
g, 25.7
mmol), NMM (6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol). The
reaction
was stirred at rt. for 24h, diluted with aqueous HCI (1 M) and extracted with
CH2CI2.
The combined organic layers were washed with aqueous 1 M HCI, saturated
NaHCO3, brine, dried (MgSO4), filtered and concentrated in vacuo and purified
by
chromatography (Si02, Acetone/Hexane 1:5) to yield I g as a colorless solid.
Step E
CL,OCH3 ~ /OCH3
BocHN~O O HCI.H2N"'t"O
0
1h
A solution of methyl ester 1g (4.0 g, 10.46 mmol) was dissolved in 4M HCI in
dioxane and stirred at rt. for 3 h. The reaction mixture was concentrated in
vacuo to
obtain the amine hydrochloride salt, 1 h which was used without purification.
Step F
OCH
O 3 O H ~OMe
~NH OH + HCI.HZN~O IOI -' N~ H N~O O
N O C O
1d 1h N
A solution of acid Id (100 mg) in 5 mL of dry dichloromethane and 5 mL of dry
DMF
was stirred at 0 C and treated with HATU (1.4 eq, 202 mg). The amine
hydrochloride
1 h(1.2 eq, 146 mg) was added. Then, N-methylmorpholine (4 eq, 0.17 mL, d
0.920)
was also added. The reaction mixture was stirred at 0 C overnight. All the
volatiles
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were removed under vacuum and the residue was dissolved in 80 mL of ethyl
acetate. The organic layer was washed with water (10 mL), aqueous I N HCI (10
mL), aqueous saturated sodium bicarbonate solution (10 mL), and brine (10 mL).
The organic layer was dried over magnesium sulfate, filtered and concentrated
under
reduced pressure. The residue was chromatographed on silica gel (gradient:
acetone/hexanes; 1:9 to 4:6) to afford the product 1 i as a white solid.
OMe OH
O ~ O N
N N N~O O N N N O
C H C H
N O-T- 1i N O~ ~!
A solution of methyl ester 1 i(180 mg) in 9 mL of a 1:1:1 mixture of
THF/MeOH/water was cooled to 0 C and treated with lithium hydroxide
monohydrate
(2.5 eq, 35 mg). The mixture was stirred and monitored by TLC
(acetone/hexanes;
3:7). When all the starting material had been consumed, the reaction mixture
was
treated with 50 mL of aqueous I N HCI and the mixture was concentrated on the
rotavap. Dichloromethane (80 mL) was added and layers separated. The aqueous
layer was extracted with dichloromethane (3 x 50 mL). The combined organic
layers
were dried over magnesium sulfate, filtered, and concentrated to afford the
product
lj as a white solid.
Step H
0 0
/~ OyN v _OH O~N'_'N'O~
I O O
1k ) 1I ~
A solution of acid 1 k (2 g) in 100 mL of dry dichloromethane and 5 mL of DMF
was treated with N,O-dimethylhydroxylamine hydrochloride (1.1 eq, 986 mg), BOP
reagent (1.1 eq, 4.47 g), and N-methylmorpholine (3.3 eq, 3.3 mL, d 0.920) in
that
order. The mixture was heated to 50 C overnight. The reaction mixture was
concentrated to half its volume and diluted with 400 mL of ethyl acetate. The
organic
layer was washed with water (80 mL), aqueous 1 M HCI (80 mL), aqueous
saturated
sodium bicarbonate solution (80 mL), and brine (80 mL). The organic layer was
dried
over magnesium sulfate, filtered, and concentrated under reduced pressure. The
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residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to
3:7)
to afford the product 1 I as a clear oil.
Step I
0 p
H OyN"'~'N'o" OyN v _H
0 ~ - ~
11 ~ 1m)
A solution of amide 11 (2.2 g) in 100 mL of dry THF was cooled to C. Lithium
aluminum hydride solution (1.3 eq) was added dropwise. The cooling bath was
removed after 5 min and the mixture was allowed to reach room temperature. TLC
analysis (ethyl acetate/hexanes; 2:8) showed that all the starting material
had been
consumed. The excess LAH was carefully quenched by addition of drops of
aqueous
saturated sodium hydrogen sulfate. The mixture was diluted with 200 mL of
ether
and aqueous saturated sodium hydrogen sulfate was added in small portions
until a
white solid precipitated. The mixture was filtered thru celite and the
filtrate was
washed with 50 mL of brine. The organic layer was dried over magnesium
sulfate,
filtered and concentrated. The residue was chromatographed on silica gel
(gradient:
ethyl acetate/hexanes; 5:95 to 4:6) to afford the aldehyde product 1m as a
colorless
oil.
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StepJ
0 o1y
H'-A 0
~ O~N H OYN~N
~I( O O O '-V
1m)
1n
A solution of aidehyde Im (1.8 g) in 100 mL of dry dichloromethane was
treated with isonitrile (1.1 eq, 680 mg) and acetic acid (2 eq, 1.02 mL, d
1.0149).
The mixture was stirred overnight. AII the volatiles were removed under vacuum
and
the residue was chromatographed on silica gel (gradient: ethyl
acetate/hexanes; 2:8
to 6:4) to afford the product 1 n as a white solid.
Step K
OH
O~.( N'/ O~~ N N N
II _ II O O
O O
1n ip
A solution of acetate 1n (1.6 g) in 60 mL of a 1:1:1 mixture of
THF/MeOH/water was treated with lithium hydroxide monohydrate and stirred for
approximately I h until all the starting material had been consumed as
determined
by TLC analysis (ethyl acetate/hexanes; 1:1). The volatiles were removed in
rotavap
and the residue was diluted with dichloromethane (150 mL). The layers were
separated and the aqueous layer was diluted with 30 mL of aqueous saturated
sodium bicarbonate solution and extracted with dichloromethane (3 x 80 mL).
The
combined organic layers were dried over magnesium sulfate, filtered and
concentrated to afford the product 1 p as a white solid.
Step L
OH G) O OH H
Ou N N CI H3N~N',
II Y
o ob o
~~
The N-Boc protected amine 1 p(1.5 g) was dissolved in 20 mL of 4M HCI in
dioxane. The reaction mixture was stirred for about I h until all the starting
material
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had been consumed. All the volatiles were removed under vacuum to afford the
product lq as a white solid.
Step M
+O OH H
HsN: N~ H OH H
OH e O O ~N N
~
N\ H N~N 0 Cl 1 I N N N'O 0 0
C~ 0 H O -f- 1r
N ~ ~ N
A solution of acid 1 j(50 mg) in 2 mL of dry dichloromethane and 2 mL of dry
DMF was stirred at 0 C and treated with HATU (1.4 eq, 52 mg). The amine
hydrochloride 1q (1.2 eq, 26 mg) was added. Then, N-methylmorpholine (4 eq,
0.042
mL, d 0.920) was also added. The reaction mixture was stirred at 0 C
overnight. All
the volatiles were removed under vacuum and the residue was dissolved in 80 mL
of
ethyl acetate. The organic layer was washed with water (10 mL), aqueous IN HCI
(10 mL), aqueous saturated sodium bicarbonate solution (10 mL), and brine (10
mL).
The organic layer was dried over magnesium sulfate, filtered and concentrated
under
reduced pressure. The product 1 r was used without further purification.
Step N
OH 0
O N N~N~ O H N_,YN
H
CN~N N~O O O N~IN N~O O O
O O
N ~ 1r N
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A solution of alcohol 1 r(65 mg) in 5 mL of dry dichloromethane was treated
with Dess-Martin periodinane (3 eq, 121 mg). Reaction mixture was stirred at
room
temperature for 45 min. The mixture was treated with aqueous 1 M sodium
thiosulfate
solution (10 mL) and aqueous saturated sodium bicarbonate solution (10 mL) and
stirred for 15 min. The mixture was extracted with dichloromethane (3 x 20
mL). The
combined organic layers were dried over magnesium sulfate, filtered, and
concentrated. The residue was chromatographed on silica gel (gradient:
acetone/hexanes; 2:8 to 5:5) to afford the product I as a white solid.
One skilled in the art would understand that other suitable compounds of
Formula XV can be prepared in a similar manner to that disclosed above.
The following experimental section applies for the preparation of the
compounds of Formula XVI:
Preparative Example A
0
H
N NH2
O O
O
O Oy N H
N NH
O
A
Step 1
OH OH
OH HCI.H2N NHa N NH
~ 2
~N~ O + O ~N O O
Boc O Boc O
? A1
A solution of acid 1 (255 mg) in 5 mL of dry dichloromethane and 5 mL of dry
DMF
was stirred at 0 C and treated with HATU (368 mg). The amine hydrochloride 2
(201
mg) was added followed by addition of N-methylmorpholine (0.42 mL). The
reaction
mixture was gradually warmed to room temperature and stirred overnight. All
the
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volatiles were removed under vacuum and the residue was taken into 100 mL of
ethyl acetate. The organic layer was washed with aqueous 1 N HCI (15 mL),
aqueous
saturated NaHCO3 (15 mL), water (15 mL), brine (15 mL), dried over MgSO4,
filtered, and concentrated under reduced pressure to afford the desired
product Al.
No further purification was carried out for the product.
Step 2
H OH H O
CN~~ N NH2 N N NH2
Boc N--~O O O Boc N~O O O
Al --T"- A2
A solution of Al (360 mg) in 20 mL of a 1:1 mixture of toluene/DMSO was
treated
with EDCI (1.3 g) and dichloroacetic acid (0.42 mL, d 1.563). Reaction mixture
was
stirred at room temperature for about 3 h. The reaction mixture was diluted
with
dichloromethane (100 mL) and washed with aqueous saturated NaHCO3 (15 mL),
aqueous 1 N HCI (15 mL), and brine (15 mL). The organic layer was dried over
magnesium sulfate, filtrated, and concentrated under reduced pressure. The
residue
was chromatographed on silica gel (gradient: acetone/hexanes; 2:8 to 5:5) to
afford
the product A2 in 84% yield.
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Step 3
p o O
N NH2 HCOO ~ C)jLNH2
H CN' P-11- O O
H3N~p O
Boc N0 ,~O 0
A2 A3
The N-Boc protected amine A2 was treated with 10 mL of formic acid. The
resulting
solution was stirred for 2 h. All the volatiles were removed under reduced
pressure.
No further purification was done for the product A3.
Step 4
H ~
O ~ N o
NH2
O Q-y
HCOO N
NH2 >~~O O O
O+ ~ =
H3N~0 O O -= O ONH
~ ~ N NH
A3 A
O
To a solution of the amine salt A3 in I mL of dry methylene chloride was added
N-
methylmorpholine (0.037 mL, d 0.920). The resulting solution was cooled in an
ice-
water bath and a solution of isocyanate in toluene (2.5 mL of a 0.135M soin)
was
slowly added. The mixture was stirred for 2 h (temp 0 to 25 C). The reaction
mixture
was diluted with 60 mL of dichloromethane and washed with 15 mL of aqueous 1 N
HCI. Aqueous layer was back extracted with dichloromethane (2 x 20 mL).
Combined organic layers were dried over magnesium sulfate, filtered and
concentrated under reduced pressure. The residue was chromatographed on Silica
gel (gradient: acetone/hexanes; 1:9 to 6:4) to give the product A (15 mg) as a
white
solid in 20% yield. HRMS (FAB) calcd for C37H53N607 [M+H] 693.3976; found
693.3987.
One skilled in the art would understand that other suitable compounds of
Formula XVI can be prepared in a similar manner to that disclosed above.
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The following experimental section applies for the preparation of the
compounds of Formula XVII:
Abbreviations which are used in the descriptions of the schemes, preparations
and the examples that follow are:
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
EtOAc: Ethyl acetate
AcOH: Acetic acid
HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
NMM: N-Methylmorpholine
ADDP: 1,1'-(Azodicarbobyl)dipiperidine
DEAD: Diethylazodicarboxylate
MeOH: Methanol
EtOH: Ethanol
Et20: Diethyl ether
DMSO: Dimethylsulfoxide
HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pyrrolidinophosphonium hexafluorophosphate
DCM: Dichloromethane
DCC: 1,3-Dicyclohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy
Phg: Phenylglycine
Chg: Cyclohexylglycine
Bn: Benzyl
Bzl: Benzyl
Et: Ethyl
Ph: Phenyl
iBoc: isobutoxycarbonyl
iPr: isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
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Cbz: Benzyloxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyl
Me: Methyl
HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
DMAP: 4-N,N-Dimethylaminopyridine
BOP : Benzotriazol-1-yl-oxy-tris(dimethylamino)hexafluorophosphate
PCC: Pyridiniumchlorochromate
KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimethylsilylamide)
NaHMDS: Sodium Hexamethyldisilazide or Sodium bis(trimethylsilylamide)
LiHMDS: Lithium Hexamethyldisilazide or Lithium bis(trimethylsilylamide)
10% Pd/C: 10% Palladium on carbon (by weight).
TG: Thioglycerol
General Schemes for Preparation of Target Compounds
Compounds of the present invention were synthesized using the general
schemes (Methods A-E) described below.
Method A
Deprotection of the N-Boc functionality of 1.01 under acidic conditions
provided the hydrochloride salt 1.02 which was subsequently coupled with N-Boc-
tert-leucine under peptide coupling methodology to afford 1.03. N-Boc
deprotection
followed by treatment with appropriate isocyanate gave the urea 1.05.
Hydrolysis of
the methyl ester provided the acid 1.06. Peptide coupling of the acid 1.06
with the
appropriate Pj-P' primary amide moiety afforded the hydroxyl amide 1.07.
Oxidation
(Moffatt oxidation or related process - see, T. T. Tidwell, Synthesis, 1990,
857), or
Dess-Martin Periodinane - J. Org. Chem., (1983) 48, 4155) resulted in the
target
compound 1.08.
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V V
V
OCH3
c3OCH3 ~CO2CH3 H >~O-J--O O H.HCI O O N O 0
1.01 1.02 1.03
V V
N OCH3 --~ N OCH3
H H ~
HCI.H2N~ O N N O
O Cap' y 01.05
1.04
V V
' v OH
~OH ~ ~ H
NH2
H H H H N T(
Cap'NyN~O O Cap'NUN~O O O
O IOI ~
1.06 V 1.07
H O
N NH2
-' Ca 'NyN~O O O
p
O m
I 1.08
Method B
Peptide coupling of the acid 1.06 with the appropriate P1-P' secondary amide
moiety afforded the hydroxyl amide 1.09. Oxidation (Moffatt or Dess-Martin's)
resulted in the target compound 1.10.
V V
H OH H
~OH N N~
H N N H H H N
Cap' ~ _~O 0 Cap'Ny N 0 0
O 1.06 O 1.09
H O H
N N
N
Cap'NyN 0 0
0
-1,1- 1.10
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Method C
In another variation, peptide coupling of the N-Boc-P2-P3-acid 1.17 with the
appropriate P1-P' amide moiety afforded the hydroxyl amide 1.11. Oxidation
(Moffatt
or Dess-Martin Periodinane) resulted in the keto amide 1.12. Deprotection of
the N-
Boc functionality gave the hydrochloride salt 1.13. Treatment with a suitable
isocyanate (or isocyanate equivalent) resulted in the target compound 1.14.
V V
H OH H
H QOH H N N,P,
\/OUN~O O \ /OyN~O O O
/TI IOI 1.17 ~I( 0
1.11
V V
H O H H O H
H ~ N N,P1 N N,P1
XI I/OUN~N OO O HCI.H2N~0 O O
OI -T-
1.12 v 1.13
H O H
'.oap-NCO" ~N N.P1
or Cap'NYN~O O O
equivalent
O 1.14
Method D
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-
nitrophenyl carbamate 1.15 by reaction with 4-nitrophenyl chloroformate.
Subsequent treatment with an amine (or amine hydrochloride salt) of choice
provided the target compound 1.14.
V V
H 0 H H 0 H
N N.P1 N N.P,
HCI.H2N~IV 0~0 0 -~ ~ Ou
O I N~O O 0
OzN I / I I
1.13 \ / 1.15
V O
õcap-NH2" N N N,P1
Cap NuNO
I 0 O
O
I
1.14
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Method E
In yet another variation, the dipeptide hydrochloride salt 1.03 was converted
to
the 4-nitrophenyl carbamate as described above. Treatment with an amine (or
amine
hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis
and
further elaboration as described in Methods A/B provided the target compounds
1.14.
v V
= N OCH3 ~/OCH3
H N ~O
HCI.H2N0 OuN
1.04 02N 10' /rl 1.16
V V
H O H
OCH3 as above ~N N'p,
cap-NHN ' H H~
(Method A) N O O
O
Cap'N~N~O O Cap' '~ N
O m O
I _ I 1.14
1.05
The following experimental section applies for the preparation of the
compounds of Formula XVIII:
Example 3 Preparation of Compound of Formula 3
CH31,-1CH3 H3Cl--,CH3
O O
ii
OH O O H S
H 0 CIH.H2N Ig H H OH 8-
Nu N } N ii Nu N~O
II O ~HO II =
O = ~ O
CH CHCH3
1.06 1.09 3
To a cooled solution (0 C) of the intermediates 1.06 (75.0 mg, 0.2 mmol) and
1.09 (100.0 mg, 0.36 mmol) in DMF (5.0 mL) was added HATU (Aldrich, 76.05 mg,
0.20 mmol), followed by DIPEA (0.102 mL, 6 mmol). The reaction mixture was
stirred for two days then warmed up to room temperature, diluted with ethyl
acetate
(40.0 mL), washed with 5% KH2PO4 containing 0.05 vol. of 1 M H3P04 and brine.
Organic layer was dried over MgSO4, filtered and concentrated to dryness.
Residue
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was purified over silica gel using acetone-CH2CI2 ( 1:9 to 1:1) to get 8.0 mg
of
product of formula 3(6.5 lo yield) ; LCMS :(590.1).
One skilled in the art would understand that other suitable compounds of
Formula XVIII can be prepared in a similar manner to that disclosed above.
The following experimental section applies for the preparation of the
compounds of Formula XIX:
Synthesis of Preparative Examples
Synthesis of Example 101
St ep1
~
O
N
O
tBocHN~O O
HCI. H 0 1.01 101a
To a stirred solution of the proline derivative 1.01 (3.66 mmol, prepared as
described
above) in dichloromethane (20 mL) and DMF (15 mL) at 0 C was added L-boc-tert-
leucine (930 mg, 4.03 mmol), DIPEA (2.02 mL, 10.98 mmol) and HATU (1.8 g, 4.76
mmol). After 15 minutes at that temperature, the reaction flask was stored in
the
freezer (-20 C), overnight (16 hr). The reaction mixture was diluted with
dichloromethane (80 mL) and washed with saturated sodium bicarbonate solution
(80 mL), 10% aq. citric acid solution (80 mL), brine (80 mL), dried (Na2SO4),
filtered
and concentrated. The crude material was purified by silica chromatography
using
25/75 to 50/50 EtOAc/hexanes to provide 1.77 g of the required material, 101a.
LC-
MS: 518.1 (M+H)+.
Step 2
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ON \ f O~\ N \ /
N O~ ~~. N OH
tBocHN~O 0 tBocHN~O O
101a 101b
To a solution of the methyl ester 101 a(1.21 g, 2.34 mmol) in THF (10 mL) and
MeOH (5 mL) was added aq. IM LiOH solution (5 mL). The reaction mixture was
stirred at RT for 4 h. It was then concentrated, diluted with water (50 mL)
and
acidified with solid citric acid (pH approximately 3) when white solid
material crashed
out. This solid was fiifiered off, washed with water and dried in vacuo to
afford 970
mg of 101 b. LC-MS: 504.1 (M+H)+.
Step 3
O N \ / O N \ / ,
O~-
OH
N OH
CN 3--~r N
N
tBocHNO O tBocHN O O
101 b
101c
The acid 101 b(503 mg, 1 mmol) was coupled with intermediate 13.06 (334 mg,
1.5
mmol) using essentially procedure described above (Step 1, preparation of 101
a) to
provide 101c which was used without purification. MS: 672.37 (M+H)+.
Step 4
O\\~N \ l O\\ N \ /
O/ O~"
N OH N N O N
--~
C 3-~r
N N
tBocHNIO O O tBocHNIO 0 0
101c 101d
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To a solution of the hydroxyl compound 101c from above in dichloromethane (15
mL) was added Dess-Martin's periodinane (848 mg, 2 mmol) and the reaction
mixture was stirred at RT for 5 h. At this time, the reaction mixture was
diluted with
dichloromethane (30 mL) and washed with 1:1 mixture of aq. 10% sodium
thiosulfate
solution and saturated sodium bicarbonate solution (2 x 25 mL each), brine (50
mL),
dried (Na2SO4), filtered and concentrated. The crude material was purified by
silica
chromatography using 15/85 to 50/50 acetone/hexanes to provide 410 mg of the
required material, 101d. LC-MS: 670.2 (M+H)+.
Step 5
O~N \ / O~N
0 0
N O N N O N
tBocHN O
~
N O ~ HCI.H2N N
~ O O
101d 101e
Deprotection of the N-boc functionality of 101d to provide the required
material 101e
was carried out as described for intermediate 1.01, Step 3 (reaction time = 2
h). LC-
MS: 570.1 (M+H)+.
Step 6
o~ Q
N
O
O
H H
N N
O N
101e csl SI O N N~O O O
~ --- c 15 /"~ 101
To a solution of the amine salt 101e (60 mg, 0.1 mmol) in dichloromethane (2
mL) at
0 C was added DIPEA (0.06 mL, 0.3 mmol) followed by the isocyanate
intermediate
65.01 (0.25 M solution in toluene, 0.8 mL, 0.2 mmol). After 15 minutes at that
temperature, the reaction flask was stored in the freezer (-20 C), overnight
(16 hr).
The reaction mixture was diluted with dichloromethane (20 mL) and washed with
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saturated ammonium chloride solution (20 mL), brine (20 mL), dried (Na2SO4),
filtered and concentrated. The crude material was purified by silica
chromatography
using 15/85 to 50/50 acetone/hexanes to provide the required compound 101 (53
mg); LC-MS: 872.2 (M+H)}.
One skilled in the art would understand that other suitable compounds of
Formula XIX can be prepared in a similar manner to that disclosed above.
The following experimental section applies for the preparation of the
compounds of Formulae Ia, lb and Ic:
Abbreviations:
Abbreviations which are used in the descriptions of the schemes, preparations
and the examples that follow are:
THF: Tetrahydrofuran
DMF: N,N-Dimethylformamide
EtOAc: Ethyl acetate
AcOH: Acetic acid
HOOBt: 3-Hydroxy-1,2,3-benzotriazin-4(3H)-one
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
NMM: N-Methylmorpholine
MeOH: Methanol
EtOH: Ethanol
Et20: Diethyl ether
DMSO: Dimethylsulfoxide
KtBuO: Potassium tert-butoxide
DCM: Dichloromethane
Chg: Cyclohexylglycine
Bn: Benzyl
Et: Ethyl
Ph: Phenyl
iPr: isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
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Cbz: Benzyloxycarbonyl
HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium
hexafluorophosphate
BOP : Benzotriazol-l-yl-oxy-tris(dimethylamino)hexafluorophosphate
10% Pd/C: 10% Palladium on carbon (by weight).
Example:
Synthesis of (1 R5S)-N-[3-Amino-1-(Cyclobutylmethyl)-2,3-Dioxopropyll-3-[2(S)-
I[[(1 1-Dimethylethyl)Amino]CarbonYlAminol-3,3-Dimethyl-l-Oxobutyll-6,6-
Dimethyl-
3-Azabicyclo[3.1.01Hexan-2(S)-Carboxamide (Structure la):
CH3,"/CH3
H O
N NH2
CH3CH3N N O O
~y
CH3 OCH~CH3
3 CH3 la
Step 1.
O O
N CIH3N
OC2H5 OCZH5
~ - -
\
1a' 1b'
A stirred solution of the ketimime 1 a' (50 g, 187.1 mmol, available from
Aldrich Chemical Company, Milwaukee, Wisconsin) under N2 in dry THF (400 mL)
was cooled to -78 C and treated with 1 M solution of I<-tBuO (220 mL, 1.15
equiv.)
in THF. The reaction mixture was warmed to 00 C and stirred for 1 h and
treated with
bromomethylcyclobutane (28 mL, 249 mmol). The reaction mixture was stirred at
room temperature for 48 h and concentrated in vacuo. The residue was dissolved
in
Et20 (300 mL) and treated with aq. HCI (2 M, 300 mL) The resulting solution
was
stirred at room temperature for 5 h and extracted with Et20 (1 L). The aqueous
layer
was made basic to pH -12-14 with aq. NaOH (50 %) and extracted with CH2CI2
(3x300 mL). The combined organic layers were dried (MgSO4), filtered, and
concentrated to give pure amine (1 b', 18 g) as a colorless oil.
Step 2.
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O O
CiH3N OC2H5 BocHN OH
1 b' 1 c'
A solution of the amine I b' (18g, 105.2 mmol) at 00 C in CH2CI2 (350 mL) was
treated with di-tert-butyldicarbonate (23 g, 105.4 mmol) and stirred at rt.
for 12 h.
After the completion of the reaction (TLC), the reaction mixture was
concentrated in
vacuo and the residue was dissolved in THF/H20 (200 ml, 1:1) and treated with
LiOH=H20 (6.5 g, 158.5 mmol) and stirred at room temperature for 3 h. The
reaction
mixture was concentrated and the basic aqueous layer was extracted with Et20.
The
aqueous layer was acidified with conc. HCI to pH-1-2 and extracted with
CH2CI2.
The combined organic layers were dried (MgSO4), filtered, and concentrated in
vacuo to yield 1c' as a colorless viscous oil which was used for next step
without any
further purification.
Step 3.
O O
BocHN OH BocHN N,OMe
Me
1c' 1d
A solution of the acid 1c' (15.0 g, 62 mmol) in CH2CI2 (250 mL) was treated
with BOP reagent (41.1 g, 93 mmol), N-methylmorpholine (27 mL), N,O-dimethyl
hydroxylamine hydrochloride (9.07 g, 93 mmol) and stirred overnight at rt. The
reaction mixture was diluted with 1 N aq. HCI (250 mL), and the layers were
separated and the aqueous layer was extracted with CH2CI2 (3x300 ml). The
combined organic layers were dried (MgSO4), filtered, concentrated in vacuo
and
purified by chromatography (Si02, EtOAc/Hex 2:3) to yield the amide 1d (15.0
g) as
a colorless solid.
Step 4.
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0 0
BocHN N'OMe BocHN H
i
Me \
1d lLeJ
A solution of the amide 1d (15 g, 52.1 mmol) in dry THF (200 mL) was treated
dropwise with a solution of LiAIH4 (1 M, 93 mL, 93 mmol) at 0 C. The reaction
mixture
was stirred at room temperature for 1 h and carefully quenched at 0 C with a
solution of KHSO4 (10% aq.) and stirred for 0.5 h. The reaction mixture was
diluted
with aq. HCI (1 M, 150 mL) and extracted with CH2CI2 (3x200 mL), The combined
organic layers were washed with aq. HCI (1 M), saturated NaHCO3, brine, and
dried
(MgSO4). The mixture was filtered and concentrated in vacuo to yield le as
viscous
colorless oil (14 g).
Step 5.
O OH
BocHN H BocHN CN
'b
1e 1f
A solution of the aidehyde le (14 g, 61.6 mmol) in CH2CI2 (50 mL), was
treated with Et3N (10.73 mL, 74.4 mmol), and acetone cyanohydrin (10.86 g,
127.57
mmol) and stirred at room temperature for 24 hrs. The reaction mixture was
concentrated in vacuo and diluted with aq. HCI (1 M, 200 mL) and extracted
into
CH2CI2 (3x200 mL). The combined organic layer were washed with H20, brine,
dried
(MgSO4), filtered, concentrated in vacuo and purified by chromatography (Si02,
EtOAc/Hex 1:4) to yield If (10.3 g) as a colorless liquid as a mixture of
diastereomers.
Step 6.
OH + OH
BocHN CN CIH3N OCH3
If Ig
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Methanol saturated with HCI*, prepared by bubbling HCI gas to CH3OH (700
mi) at 0 C, was treated with cyanohydrin 1f and heated to reflux for 24 h. The
reaction was concentrated in vacuo to yield 1g, which was used in the next
step
without purification.
* Alternatively 6M HCI prepared by addition of AcCI to dry methanol can also
be
used.
Step 7.
_ OH OH
+ BocHN OCH3
CIH3N
OCH3 y-ly
TI-Y
O O
1g 1h
A solution of the amine hydrochloride 1g in CH2CI2 (200 mL) was treated with
Et3N (45.0 mL, 315 mmol) and Boc2O (45.7g, 209 mmol) at
-78 C. The reaction mixture was then stirred at room temperature overnight and
diluted with HCI (2 M, 200 mL) and extracted into CH2CI2. The combined organic
layers were dried (MgSO4) filtered, concentrated in vacuo and purified by
chromatography (EtOAc/Hex 1:4) to yield hydroxy ester I h.
Step 8.
OH OH
BocHN OCH3 BocHN NH2
O
1h 1i
A solution of methyl ester 1 h (3g, 10.5 mmol) in THF/H20 (1:1) was treated
with LiOH=H20 (645 mg, 15.75 mmol) and stirred at rt. for 2 h. The reaction
mixture
was acidified with aq HCI (1 M, 15 mL) and concentrated in vacuo. The residue
was
dried in vacuum.
A solution of the acid in CH2CI2 (50 mL) and DMF (25 mL) was treated with
NH4CI (2.94 g, 5.5 mmol), EDCI (3.15 g, 16.5 mmol), HOOBt (2.69 g, 16.5 mmol),
and NMM (4.4 g, 44 mmol). The reaction mixture was stirred at room temperature
for
3 d. The solvents were removed under vacuo and the residue was diluted with
aq.
HCI (250 mL) and extracted with CH2CI2. The combined organic layers were
washed
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with aq. saturated NaHCO3, dried (MgSO4) filtered concentrated in vacuo to
obtain
1 i, which was used as it is in the following steps. (Alternatively 1 i can
also be
obtained directly by the reaction of If (4.5 g, 17.7 mmol) with aq. H202 (10
mL),
LiOH9H20 (820 mg, 20.8 mmol) at 0 C in 50 mL of CH3OH for 0.5 h.)
Step 9.
OH + OH
BocHN NH2 CIH3N NH2
Y-, Y
11)r
'
O O
1i 11
A solution of 1 i obtained in the previous step was dissolved in 4 N HCI in
dioxane and stirred at rt. for 2 h. The reaction mixture was concentrated in
vacuo to
give Ij as a solid, which was used without further purification.
Step 10.
CH3,_,,CH3
0 CH3-,/CH3
BocHNI-AOH OCH3
_ --~ N II
+ ~ OCH3 O
CH3 NCH3 H BocHN
s 2CI O
1k 11 CH3 H3 CH31m
The amino ester 11 was prepared following the method of R. Zhang and J. S.
Madalengoitia (J. Org. Chem. 1999, 64, 330), with the exception that the Boc
group
was cleaved by the reaction of the Boc-protected amino acid with methanolic
HCI.
A solution of Boc-tert-Lue 1k (Fluka, 5.0 g 21.6 mmol) in dry CH2CI2/DMF (50
mL, 1:1) was cooled to 00 C and treated with the amine 11 (5.3 g, 25.7 mmol),
NMM
(6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol). The reaction was
stirred at
rt. for 24 hrs, diluted with aq. HCI (1 M) and extracted with CH2CI2. The
combined
organic layers were washed with HCI (aq, 1 M), saturated NaHCO3, brine, dried
(MgSO4), filtered and concentrated in vacuo and purified by chromatography
(Si02,
acetone/hexane 1:5) to yield 1 m as a colorless solid.
Step 11.
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CH3,,,CH3 CH3,,,,,CH3
~OCH3 OCH3
BocHN~O 0 NN O
IOI
CH3 CHCH3 CH3 C 3H3
3
Im 1n
A solution of methyl ester 1 m (4.0 g, 10.46 mmol) was dissolved in HCI (4 M
solution in dioxane) and stirred at rt. for 3 h. The reaction mixture was
concentrated
in vacuo to obtain the amine hydrochloride salt used in the next step without
further
purification.
A solution of the amine hydrochloride salt (397 mg, 1.24 mmol) in CH2Cl2 (10
mL) was cooled to -78 C and treated with tert-butyl isocyanate (250 mg, 2.5
mmol)
and stirred at rt. overnight. The reaction mixture was concentrated in vacuo
and the
residue was diluted with aq. HCI (1 M) and extracted with CH2CI2. The combined
organic layers were washed with aq. HCI (1 M), saturated NaHCO3 and brine. The
organic layers were dried, filtered and concentrated in vacuo and the residue
was
purified by chromatography (Si02, acetone/Hex 1:4) to yield In as a colorless
solid.
Step 12.
CH3,_,CH3 CH3._,CH3
OH
H
Q-.-(OCH3 QN NH2
Nu
O O
I N O ~-" ~~ N O
I = y
O
CH3 H3 H3 OCH3CH3 H3
In lo
A solution of methyl ester In (381 mg, 1.0 mmol) in THF/H2O (1:1, 5 mL) was
treated with LiOH=H20 (62 mg, 1.5 mmol) and stirred at rt. for 3 h. The
reaction
mixture was acidified with aq. HCI and concentrated in vacuo to obtain the
free acid.
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A solution of acid (254.9 mg, 0.69 mmol) in DMF/CH2CI2 (1:1, 5.0 mL) was
treated with amine 1 j(159 mg, 0.763 mmol), EDCI (199 mg, 1.04 mmol), HOOBt
(169.5 mg, 1.04 mmol) and NMM (280 mg, 2.77 mmol) at -20 C. The reaction
mixture was stirred at -20 C for 48 h and concentrated in vacuo. The residue
was
diluted with aq. 1 M HCI and extracted with EtOAc, The combined organic layers
were extracted with aq. NaHCO3, aq. HCI, brine, dried (MgSO4) filtered,
concentrated in vacuo to obtain 1o (470 mg) as a tan colored solid that was
used in
the next reaction without further purification.
Step 13.
CH3,_,CH3 CH3,-,,CH3
H OH H 0
N
NH2
~ /N NH2 Q
N N'/ ~' O - H NO
y = ~y
OCH3 HCH3 OCH3 HCH3
3 3
lo 1a
A solution of amide 1 o(470 mg, 0.9 mmol) in toluene and DMSO (1:1 20 mL)
at 0 C was treated with EDCI (1.72 g, 9.0 mmol) and dichloroacetic acid (0.37
mL,
4.5 mmol) and stirred at 0 C for 4 hrs. The reaction mixture was diluted with
CH2CI2,
and washed with saturated NaHCO3, and brine. The organic layer was dried
(MgSO4), filtered, concentrated, in vacuo and purified by chromatography
(Si02,
acetone/hexanes 3:7) to yield 1a as a colorless solid.
Separation of the Compound of Formula I into diastereomers of Formulas lb and
Ic:
CH3~CH3 CH3I/CH3
H 0 H
N N NH2 N N\ ~ NH2
CH3tijiNyN~ CH3\~/NyN O
O T O
CH3 OCH C 3Hs CH3 OCH C 3Hs
lb Ic
Preparative HPLC condition for separation
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COLUMN USED: NORMAL PHASE YMC DIOL-NP COLUMN
120 A, S-10/20; 50 mm x 500 mm I.D/length
SOLVENT A: Hexanes
SOLVENT B: To make 4 L of solvent (1.7 L Isopropanol + 300 mL of
CH3CN+ 2 L of CH2CI2)
HPLC CONDITIONS: 12% of Solvent B/88% of Solvent A
FLOW: 120 mL/min
Procedure: I g of compound 1a was dissolved in 10 mL of CH2CI2/25 mL of
Hexanes
and injected into the column. It was eluted with 120 mL/min and two peaks were
independently collected and concentrated. The solid residue was further dried
in high
vacuum and analyzed by analytical HPLC. Since the polar (second isomer)
contained 2.6% of nonpolar diastereomer (First isomer), it was purified once
more to
isolate the pure diastereomers.
Analytical conditions for analysis of diastereomeric purity
COLUMN USED: NORMAL PHASE YMC DIOL-NP COLUMN
200 A, S-5 ~M; 150 mm x 3 mm length/I.D
SOLVENT A: Hexanes
SOLVENT B: To make 4 L of solvent (1.7 L Isopropanol + 300 mL of
CH3CN+ 2 L of CH2CI2)
HPLC CONDITIONS: 8.5% of Solvent B/91.5% of Solvent A
FLOW: 0.7 mL/min
Rt Nonpolar isomer (compound Ib) =13.2 min
Polar isomer (compound Ic) =16.1 min
2.5 mg of compound in 1 mL was used and 20 L was injected and analyzed with a
U.V detector at a,=254 nm.
Analytical data for compounds 2 and 3.
Compound 3 [Polar diastereomerl
'H NMR (d6-dmso, 500 MHz): 8 8.26 (d, 1 H, J= 7.0 Hz), 8.00 (s, 1 H), 7.75 (s,
I H),
5.96 (s, 1 H), 5.84 (d, I H, J=10 Hz), 4.96 (m, I H), 4.28 (s, 1 H), 4.11 (d,
1 H, J=11
Hz), 3.94 (d, 1 H, J=10 Hz), 3.73 (dd, 1 H, J= 10 & 5 Hz), 2.48 (m, I H), 1.95
(m, 2
H), 1.61 (m, I H), 1.59 (m, I H), 1.77(m, 1 H), 1.57 (m, I H), 1.74 (m, 2 H),
1.42 (dd,
I H, J=7.5 & 5 Hz), 1.28 (d, I H, J=7.5 Hz), 1.17 (s, 9 H), 1.01 (s, 3 H),
0.90 (s, 9 H),
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0.85 (s, 3 H). 13C NMR (d6-dmso, 125 MHz): S 197.8, 170.9, 170.8, 162.8,
157.4,
59.1, 56.8, 51.8, 48.9, 47.4, 36.7, 34.0, 32.0, 30.6, 29.1, 27.8, 27.3, 27.1,
26.4, 26.1,
18.5, 17.7, 12.5. MS [FAB] 520 (55), 421 (100), 308 (75), 213 (90). HRMS calcd
for
C27H4605N5 [M+1]+ 520.3499; observed: 520.3505.
Compound 2 [Non-polar diastereomer]
'I-i NMR (d6-dmso, 500 MHz): S 8.15 (d, 1 H, J= 7.0 Hz), 7.96 (s, 1 H), 7.74
(s, 1 H),
5.96 (s, 1 H), 5.86 (d, 1 H, J=10 Hz), 4.85 (m, 1 H), 4.27 (s, 1 H), 4.13 (d,
I H, J=11.0
Hz), 3.97 (d, 1 H, J=10 Hz), 3.76 (dd, 1 H, J= 10 & 5 Hz), 2.36 (m, 1 H), 1.97
(m, 2
H), 1.60 (m, 2 H), 1.78 (m, 1 H), 1.64 (m, 1 H), 1.75 (m, 2 H), 1.44 (dd, 1 H,
J=7.5 &
5 Hz), 1.27 (d, I H, J=7.5 Hz), 1.17 (s, 9 H), 1.00 (s, 3 H), 0.89 (s, 9 H),
0.82 (s, 3 H).
13C NMR (d6-dmsol25 MHz): S 197.1, 171.1, 170.7, 163.0, 157.3, 59.4, 56.9,
52.1,
48.9, 47.4, 36.6, 34.0, 32.1, 30.5, 29.1, 27.9, 27.4, 26.8, 26.4, 26.1, 18.5,
17.8, 12.4.
MS [FAB] 520 (40), 421 (100), 308 (60), 213 (65). HRMS calcd. for C27H4605N5
[M+1 ]+ 520.3499; observed: 520.3514.
It will be appreciated by those skilled in the art that changes could be made
to
the embodiments described above without departing from the broad inventive
concept thereof. It is understood, therefore, that this invention is not
limited to the
particular embodiments disclosed, but it is intended to cover modifications
that are
within the spirit and scope of the invention, as defined by the appended
claims.
Each document (including granted patents, published patent applications, and
nonpatent publications such as journal articles) referred to in this
application is
incorporated in its entirety by reference for all purposes.
