Title of Invention

A PHARMACEUTICAL FORMULATION FOR TREATING HCV INFECTION

Abstract Pharmaceutical formulations containing at least one compound of Formulae I-XXVI herein and at least one surfactant. Pharmaceutically acceptable carriers and excipients may also be included in the formulations. The formulations of the present invention are suited for use in single unit dosages.
Full Text

PHARMACEUTICAL FORMULATIONS AND METHODS OF
TREATMENT USING THE SAME
Field of the Invention
The present invention relates to pharmaceutical formulations that are useful for treating a wide variety of diseases or disorders associated with hepatitis C virus ("HCV") 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. Cun-ent data indicates a less than 50% survival rate at four years post cin-hosis 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 interi'eron-α (INFα) and combination therapy with ribavirin and interferon. See, e.g., Beremguer etal. (1998) Proc. Assoc. Am, Phvsicians 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. Cueeently. 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). particularty 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 vims (HDV). cytomegalovirus (CMV) and Epstein-Ban" virus (EBV), as well as from other forms of liver disease such as alcoholism and primary biiiar cirrhosis.

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 (E1 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 adds; 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/NS55 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 detemined that the NS4a protein, an approximately 6 kda polypeptide, is a co-factor for the serine protease activity of NS3. Autocleavage of the NS3/S4a junction by the NS3/NS4a serine protease occurs intramolecularty (i.e., cfs) while the other cleavage sites are processed intermolecuiarly (i.e., trans).
Analysis of the natural cleavage sites for HCV protease revealed the presence of cysteine at P1 and serine at PI' 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 PI and a serine at P1\ The Cys-j-Thr substitution at NS3/NS4a Is postulated to account for the requirement of cis rather than trans processing at this junction. See, e.g, Pizzi et al. (1994) Proc. Natl. Acad. Sci (USA) 91:888-892, Failia etal. (1996) Folding & Design 1:35-42. The NS3/NS4a cleavage site is also more tolerant of mutagenesis than the other sites. See, eg., Kollikhalov 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 deavage. See, e.g., Komoda et al. (1994) J. Virol 68:7351-7357.

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, Inqallinella et al. (1998) Biochem. 37:8906-8914, Llinas-Brunet et al. (1998) Bioorq. 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 Eno. 10:607-614). and al-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 POT Publications, No. WO 98/17679, published April 30, 1998 (Vertex Phamiaceuticals 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 viruis.
There is a need for new treatments and therapies for HCV Infection to treat or prevent or ameliorate of one or more symptoms of hepatitis C, methods for modulating the activity of serine proteases, particulariy 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

proteins and tissues as well as in initiating proteolytic cascades by proenzyme activation and in participating in MHC class 11 molecule expression. Baldwin (1993) Proc. Natl. Acad. Sci., 90: 6796-6800; Mixuochi (1994) Immunol. Lett., 43:183-193.
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 ceils 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 eariier 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 cDlsIA encoding such polypeptide were disclosed in U.S. Pat. No. 5, 501,969 (called cathepsin O 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. Blol Chem . 271, 2126-2132.

Cathepsin K has been variously denoted as cathepsin O, cathepsin X or cathepsin 02 in the literature. The designation cathepsin K is considered to be the 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 Internationa! Publication Number WO 94/04172, published on Mar. 3. 1994, and references cited therein. See also European Patent Application EP 0 603 873 A1, and references cited therein. Two bacterial cysteine proteases from P. gingivallis , called gingipains, have been implicated in the pathogenesis of gingivitis. Potempa, J., et a!. (1994) Perspectives in Drug Discovery and Design , 2, 445-458.
Cathepsin K is beiieved 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 canied out by osteoclasts, which are muttinuciear cells of hematopoietic lineage. In several disease states, such as osteoporosis and Pagets disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle. Uitimateiy, 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 loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Pagets 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 el 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 CL!K-148 in vlvo, 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 tnelanoma, depending on procathepsin L secretion, and the possible use of anti-cathepsin L ScFv as a molecular tool in a therapeutlc
cellular approach.

Colelia 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 PCS prostrate cancer cell line, and the potential of using cystein protease inhibitiors such as cystatins as anti-metastatic agents.
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..
Frohtich et al., (2204) Arch Dennatol Res.. 295(10);411-21 reports that cathepsins B and L are involved in invasion of basal celt carcinoma (BCC) cells..
U.S. Provisional Patent Application Serial No. Not Yet Assigned, entitled "Compounds for Inhibiting Cathepsin Activity", filed April 20, 2005, discloses venous 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 and associated formulations useful in the inhibition of cathepsin activity and in the treatment of these disorders.
There is a need for pharmacuetical formulations inlcuding inhibitors of HCV protease or cathepsin having good dissolution to facilitate absorption of the inhibitor.
SUMMARY OF THE INVENTION
The present invention provides phamiaceutical formulations comprising (i) at least one surfactant and (ii) at least one compound of Formulae l-XXVI.
In one embodiment, the compound is a compound of structural Formula I


Formula I
or a pharmaceuticaliy 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, cycloalkyi, alkyloxy, alkyl-
aryloxy, aryloxy, heteroaryioxy, heterocycloalkyioxy, cycloalkyloxy, alkylamino,
arylamino. alkyl-arylamino, ar^amino, heteroarylamino, cycloalkylamino and
heterocycloalkylamino, with the proviso that Y maybe optionally substituted v^rtth X"*^

X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino,
alkylsulfonyl, aryJsutfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonytamino, alkoxycarbonybxy. alki^ureido, arylureido, halogen, cyano. or nitro, wrth the proviso that said alkyl, alkoxy, and aryl may be


and heteroaralkyl;
Z is selected from O, N, CH or CR;
W maybe present or absent, and if W is present, W is selected from C=0. 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 , O, 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 O, 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 direcBy 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 (CH2)p. (CHR)p, or (CRR*)p,
SO2, NH, NR or O; 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, O, 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 O, NR. S, SO2, {CH2) p,
(CHR) p (CHR-CHR%, 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; C1-
C10 alkyl; C2-C10 alkenyl; C3-C6 cycloalkyi; C3-C6 heterocydoalkyi, alkoxy, aryloxy,
alkythio, arylthio, amino, amido, ester, carboxylic ackl, carbamate, urea, ketone,
aldehyde, cyano, nitro, halogen; (cycloalkyl)alkyl and (heterocydoalkyi)alkyl,
wherein said cycloalkyi is made of three to eight carbon atoms, and zero to six
oxygen, nitrogen, sulfurr, or phosphorus atoms, and said alkyl is of one to six carbon
atoms; aryl; heteroaryi; alkyl-aryl; and alkyl-heteroaryl;
wherein said alky1, heteroalkyi, alkenyl, heteroalkenyl, aryl, heteroaryi, cycloalkyi and
heterocydoalkyi moieties may be optionally and chemicaily-suitably substituted, with
said term "substituted" refening to optional and chemically-suitable substitution with


aldehyde, cyano. nitro, sulfonamido, sulfoxide, sulfone, suifonyl urea, hydrazide, and hydroxamate;
further wherein said unit N-C-G-E-L-J-N represents a five-membered or six-membered cyclic ring stnjcture 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 Fornriula 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


13
R is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio. amino, alkylamino, arylamino, alkylsulfonyi, arylsulfonyl, alkylsulfonamido, aryisulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycarbonyiamino, alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro moiety, with the proviso that the afkyi, alkoxy, and ary! may
be additionally optionally substituted with moieties independently selected from R . Pla, P1b, 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 cycloalkyi is made up of 3 to 8 carbon atoms, and zero to 6 oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl is of 1 to 6 carbon atoms;
aryl. heteroaryl, arylalkyl, or heteroarylalkyl, wherein said alkyl is of 1 to 6 carbon atoms;
wherein said alkyl, alkenyl, cycloalkyi, heterocyclyl; (cycioalkyl)alkyl and
13
(heterocyclyl)alkyl moieties may be optionally substituted with R , and further wherein said P1a and Pib 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 R ; and
PI' is H, alkyl, alkenyl. alkynyl, cycloalkyi, cycloalkyl-alkyl, heterocyclyl, heterocydyl-
alkyl. aryl, aryl-alkyl. heteroaryl, or heteroaryl-alkyl; with the proviso that said P1' may
be additionaKy opfionally substituted wiht R13 .
In another embodiment, the compound is a compound of 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, aikyl, alky!-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroary!, cycloalkyi, alkyloxy, alkyl-aryloxy, aryioxy. heteroaryloxy, heterocycioalkyloxy, cycloalkyloxy, alkylamino, arylamino, alkyi-arylamino. arylamino, heteroarylaniino, cycloalkylamino and heterocycloalkylamino, with the proviso that Y maybe additionally optionally substituted with X11 or X12
X11 is selected from the group consisting of alkyl, alkenyl. alkynyl, cycloalkyi. cycloalkyl-alkyl, heterocyclyl. heterocydyialkyl, aryl. alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that X11 may be additionally optionally substituted with X12;
X"^^ is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkylsulfonyl, arylsuffonyl, alkylsulfonamido, arylsulfonamido. carboxy, cart)alkoxy.


Z is selected from O, N, or CH;
W maybe present or absent, and tf W is present, W is selected from C=0. C=S, or
SO2; and
2 3 4
R, R', R , R and R are independently selected from the group consisting of H; CI-
C10 alky!; C2-C10 aikenyl; C3-C8 cycloalkyl; C3-C8 heterocycloalkyl. alkoxy,
aryloxy, aikylthio, 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 cydoalkyl is made of three
to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms,
and said alky! is of one to six carbon atoms; aryi; heteroaryl; alkyl-aryl; and alkyl-
heteroaryl;
wherein said alkyl, heteroalkyl, aikenyl, heteroalkenyl, aryl, heteroaryl, cydoalkyl 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 alkyt, aikenyl, alkynyl, aryt, aralkyi, cydoalkyl,
heterocydic. halogen, hydroxy', thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido,
ester, cariboxylic add, carbamate, urea, ketone, aldehyde, cyano. nitro, sulfonamide,
sulfoxide, sulfone, sulfonylurea. hydrazide. and hydroxamate.
In another embodiment, the compound is a compound of Formula IV

or a phamnaceutically acceptable salt, solvate or ester thereof; wherein:
Y is selected from the group consisting of the following moieties; alkyl, alkyl-aryl,
heteroalkyi, heteroaryl. aryl-heteroaryl, alkyl-heteroaryl, cydoalkyl, alkyloxy, alkyl-


X is hydroxy, aikoxy, aryloxy, thio, alkylthio, aryltiiio, amino, alkylamino. arylamino, alkylsuifonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxyl, carbaikoxy, carboxamido, alkoxycarbonyiamino, aikoxycarbonyloxy. alkylureido, arylureido, halogen, cyano, or nitro, with the proviso that said alky!, alkoxy, and aryl may be

alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino, hydroxy, thio, alkylthio, arylthio, amino, alkylsuifonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxyl, carbaikoxy, carboxamkJo. alkoxycarbonylamlno. alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, and nitro, with the proviso that R11 (when R12 = H) maybe optionally substituted with X11 or X12; Z is selected from O, N, CH or CR;

W may be present or absent, and if W is present, W is selected from C=0. 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 , O, 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 O, CH2. (CHR) p , (CHR-CHR^) p , (CRR) p, N(R), S, SCOz) or a bond;
E is CH. N. GR, 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 O; 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, C(R), O, 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 O, N(R), S, 8(02), (CH2)p,
(CHR) p (CHR-CHR*)p. or (CRR) p;
p is a number from 0 to 6; and
R, R\ R^. R^ and R^ can be the same or different each being independently selected
from the group consisting of H; C1-C10 alkyl; C2-C10 alkenyl; Ca-Ce cydoalkyi; C3-C8
heterocycloalkyi, aikoxy. aryloxy, alkylthio, arylthio, amino, amido, ester, carboxylic
acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl and
(hetenDcycloalkyl)alkyl, wherein said cycioalkyi is made of three to eight cart)on
atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyl
is of one to six carbon atoms; aryl; heteroar^i; alkyl-aryl; and alkyl-heteroaryl;
whK-ein said alkyl, heteroalk^, alkenyl, hetenoalkenyl, aryl, heteroaryl, cycioalkyi and
heterocycloalkyl moieties may be optionally substituted, witii said term "substituted"
referring to substitutfon wth one or more moieties which can be the same or
different, each being independentiy selected from the group consisting of alkyl,
alkenyl, alkynyl, aryl, aralkyl, cycbalkyl, heterocyclic, halogen, hydroxy', thio, aikoxy.

aryloxy, alkylthio, arylthio, amino, amido, ester, carboxyiic 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 Ihe 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 cydic ring.
In another embodiment, the compound is a compound of Formula V



R14 fs present or not and if present is selected from the group consisting of: H, alkyl, aryl, heteroalky!, heteroaryi, cycioaltcyl, alkyl-aryl, ally!, alkyt-heteroaryl, alkoxy, aryl-alkyl, alkenyl, alkynyl and heteroaralkyt;
(5) R and R' are present or not and if present can be the sanne or different, each being independently selected from the group consisting of: H, OH. C1-C10 alkyl, C2-C10alkenyl, C3-C6 cycloalkyl. C3-C6 hetenocycloalkyI, alkoxy, aryloxy. alkytthio^ arylthio, alkylamino, arylamino. amino, amido, arylthioamino, arylcarbonylamino, aryiaminocarboxy, alkylaminocarboxy, heteroalkyl, alkenyl, alkynyl, (aryl^lkyl, heteroaryialkyl, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen, (cycloalkyl)alkyl, aryl, heteroaryi^ (alkyl)aryl, alkylheteroaryl, alkyi-heteroaryi and (heterocycloalkyl)alkyl, wherein said cycloalkyl is made of three to


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 O; 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), (CH2)p. (CHR)p , (CRR')p , (CHR-CHR')p, O, 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


wherein in Formula 3, Y is selected from the group consisting of: H, aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryi, allcyl-heteroaryl, cycloalkyi, alkyloxy. alkyl-aryloxy. aryloxy, heteroar^oxy. heterocydoalkyioxy, heteroalkyl-heteroaryl, heteroalkyl-heterocycioalkyl, cydoalkyioxy, alkylamino, arylamino, alkyl-arylamino, aryiamino, heteroarylamino. cydoalkylamino and heterocycloalkylamino, and Y is unsubstituted or optionally substiturted with one or two substibjents which are the same or different and are independently selected from X11 or X12; X11 is alkyl, alkenyl, alkynyl, cydoalkyi, cydoalkyl-alkyl, heterocydy!, heterocydylalkyl, aryl, alkylaryl, aryialkyl, heteroaryl. aikylheteroaryl. or
heteroarylalkyl. and X is unsubstituted or optionally substituted with one or more of X12 oieties which are the same or different and are independently selected; X12 is hydroxy, aikoxy, alkyl, alkenyl. alkynyl, aryl, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino. alkylsulfonyl, arylsulfonyl, alkylsuffonamido, arylsulfonamido, carboxy, carbalkoxy, cartboxamido, alkylcarbonyl, arylcarbonyl. heteroa!kylcartbonyl, heteroarylcarbonyl, sulfonylurea, cydoalkylsulfonamido, heteroaryl-cycloalkylsuffonamido, heteroaryl-sulfonamido, alkoxycarbonylamino,

alkoxycarbonyloxy, aikylureido, 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, cydoalkyi, cycloalkyi-alkyi, heterocyclyl, heterocyciylalkyl, aryl, alkylaryl, arylalkyl. heteroaryl, alkylheteroaryl. or heteroarylalkyl;
Z is O.N.C(H)or C(R);
R31 is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyi, heteroaryl, aryl-heteroaryl, alkyl
heteroaryl, cydoalkyi, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy.
heterocycloalkyltoxy. heteroalkyl-heteroaryl, cycloalkyloxy, alkylamino. arylamino,
alkyl-aryiamino, arylamino, heteroarylamino, cycloalkylamino or
heterocycloalkyiamino. and R31 is unsubstituted or optionally substituted with one or two substituents which are the same or different and are Independently selected from X13 or X14
X13 Is alkyl, alkenyl, alkynyl, cydoalkyi. cycloalkyl-alkyl, heterocyclyl, heterocyclyialkyt, aryl, alkytaryl, 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,
arylsutfonamido, carboxy, carbalkoxy, carboxamido. alkylcarbonyl, arylcarbonyl,
heteroalkylcarbonyl, heteroarylcarbonyl, cycloalkylsulfonamido, heteroary!-
cycloalkylsulfonamido, heteroarylsulfbnamido, alkoxycarbonylamino,
alkoxycarbonyloxy, aikylureido, 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, cydoalkyi, cycloalkyl-alkyi, heterocyclyl, heterocydylalkyl, 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:


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, cycloalkyiamino, cycloalkylaminocartx)nyl. cyano, hydroxy, alkoxy, alkylthio. amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxyl. C(0)0-aikyl, heteroaryl, aralkyl. alkylaryl, aralkenyl, heteroaralkyl, alkylheteroaryl. heteroaralkenyl, hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsuffonyl, heteroaryisutfonyl, alkyisulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocyciyl, heterocyclenyl, Yi Y2N-aIky!-, YiY2NC(0)- and Y1Y2NSO2-, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aTyl. and aralkyt; 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:


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. spiroaikyl, cycloalkylaminocarbonyl, cyano, hydroxy, alkoxy. alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxyl, -CiO)0-alkyl heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaratkyl, alkylheteroaryl, heteroaratkenyl. hydroxyalkyl, aryloxy. aralkoxy, acyl. aroyl, nitro. aryloxycarbonyl, aralkoxycarbonyl, alkylsutfonyi, aryisulfonyl, heteroarylsulfbnyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarytthio, aralkylthio, heteroaralkylthio, cycloalkenyl, hetsrocydyl, heterocydenyl, Yi Y2 N-alkyl-. Yi Y2NC(0)- and YiY2NSO2. wherein Y1 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;
gis1.2,3,4,5,6,7,8or9;
h, i, j. K 1 and m are 0,1,2, 3, 4 or 5; and •. A is C. N, S or O,
(11) provided that when structural Formula 2:
is


I
or a pharmaceutically acceptable sslt, solvate or ester of said compound, wherein: Cap and P' are independently H, alkyl, alkyl-aryl, heteroalkyI, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl. cycloalkyl. allcyloxy, alkyi-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamlno, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino, arlylaikyloxy or heterocyclylamino, wherein each of said allkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyk-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryioxy, heteroaryloxy, heterocyclyloxy, cycloalkyloxy. amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino, carboxyalkylamino. arlylaikyloxy or

heterocyctylamino can be unsubstituted or optionally independently substituted with one or two substituents which can be the same or different and are independently selected from X1 and X2',
X1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl. heterocyclyl. heterocyciylalkyl, aryl. alkylaryl, arylalkyl, arylheteroaryl. heteroaryl, heterocyclylamino, aikyiheteroaryl, or heteroarylalkyl, and X can be unsubstituted or optionally independently substituted with one or more of X2' moieties which can be the same or drfferent and are independently selected;
X2' is hydroxy, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amino, alkylamino, arylamino, alkyisulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido, aikoxycarbonylamlno, alkoxycarbonyloxy, alkyiureido. 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, cyctoafkyl-alkyl, heterocyclyl, heterocyciylalkyl, aryi, alkylaryl, arylalkyi, 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(0) 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, O, S. S(0) or S(O); 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 -OR, -CH(R') , S(0)o-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(0)o.2R or-NRR';
A is present or absent and if present A is -0-. -0(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(02), N(H), N(R) or O; 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 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, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cycloalkyl. C3-C8 heterocyclyl, alkoxy, aryloxy, alkylthio, arylthio, amino, amido, arylthioamino, arylcarbonyiamino, arylaminocarboxy, alkylaminocarboxy, heteroalkyl, heteroalkenyl, alkenyl, alkynyl, aryl-alkyl, heteroarylalkyl, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen, (cydoalkyl)alkyi, aryl, heteroaryl, alkyl-aryl, alkylheteroaryl, alkyl-heteroaryl and (heterocydyl)alkyi;
R and R' in (CRR') can be linked together such that the combination forms a cydoalkyl or heterocydyl moiety; and



where R6 and R7 can be the same or different, each being independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyi, cycloalkyl, cydoalkylalkyl, aryl, arylalkyi, 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, atkyi, aryi and cycloalkyl; or alternatively R4 and R5 together
form part of a cyclic 5- to 7- membered ring such that the moiety R4 R5 is



where Y is O, S or NH, and Z is CH or N, and the R8 moieties can be the same or different, each R8 being independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalikyl, aryl, heteroaryl. heterocyclyl. hydroxyl, amino, arylamino, aikylamino, diaikylamino, halo, alkylthio, arylthio and alkyloxy. In another embodiment, the compound is a compound of Formula VIII:

or a pharmaceutically acceptable salt, solvate or ester thereof, wherein.
M is O, N(H), or CH2;
H
R1 is -0R6 -NR6R^ or 6 ;
where R6 and R7 can be the same or different, each being independently selected from the group consisfing of hydrogen, alkyl. alkenyl. alkynyl, heteroalkyi, cycloalkyl, cycloalkylalkyi, aryl, arylalkyi, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl. hydroxyl, amino, arylamino and alkylamino; P1 is selected from the group consisting of alkyl. alkenyl, alkynyl, cycloalkyi haloalkyl;

P3 is selected from the group consisting of alkyl, cycloalkyl, aryi and cycioaikyi fused with aryl;
R4and 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
form part of a cyclic 5- to 7- membered ring such that the moiety R4 R5 is


different, each R8 being independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycioalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and .alkyjoxy. In another embodiment, the compound is a compound of Formula !X:

selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl. cydoalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyi, heterocyclyl, heterocydylalkyl. 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 altematively R4 and R5 together



where Y Is O, S or NH, and Z is CH or N, and the R^ moieties can be the same or different, each R8 being independently selected from the ggroup consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxyl, amino, arylamino, alkylamino, dialkylamino, halo, alkylthio, arylthio and alkyloxy. In another embodiment, the compound is a compound of Formula X:


or a pharmaceuticaliy acceptable salt, solvate or ester thereof, wherein: R1 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-, heterocydyl-, arylalkyl-.

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, alky!-, alkenyl-. alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyi-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocydyl)alkyl-, aryl-alkyi-, and heteroaryl-alkyl-; or altemately R and R' in NRR' are connected to each other such that NRR' fomis a four to eight-membered heterocydyl; and Y is selected from the following moieties:


wherein G is NH or O; and R15. R16, R17 and R18 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyl, aikenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl. heterocydyl, aryl, arylalkyi, heteroaryl. and heteroarylalkyl, or attemateiy, R15 and R16 are connected to each other to form a four to eight-membered cydoalkyl, heteroaryl or heterocydyl structure, and likewise, independently R17 and R18 are connected to each other to form a three to eight-membered cycloaiky! or heterocydyl;
wherein each of said alkyl, aryl. heteroaryl, cydoalkyl or heterocydyl 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, alkyisulfonamklo. arylsulfonamklo, keto, carboxy, carbalkoxy. carboxamido, alkoxycartjonylamino, alkoxycarbonyloxy, alkylureido. arylureido, halo, cyano, and nitro.
In one embodiment, tiie compound is a compound of Formula XI:


shown above in Formula 1 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-, heteroalkyi-,
heterocyclyl-. aryl-. heteroaryl-, (cycloalkyl)alkyl-. (heterocyclyl)alkyl-, aryt-alkyi-, and
heteroaryl-alkyi-; 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:



\where u is number 0-6; X is selected from O. NR15. NC(0)R16 S, S(0) 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, heteroallcyl, allkenyl. 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 cycloalkyt or heterocyclyl; wherein each of said alkyl, aryl, heteroaryl, cydoalkyi or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryioxy, thio, alkylthio, arylthio. amino, amido. alkylamino, arylamino. aikylsulfonyl, arylsulfonyl, sulfonamide, alkyl. aryl, heteroaryl, alkylsutfonamido, arylsulfbnamido, keto. carboxy, carbalkoxy, carboxamido. alkoxycarbonyiamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the compound is a compound of Fomiula XII:
01

R^ is H, 0R^ NR^R'^ or CHR^R^^, wherein R^ R^ and R'"° can be the same or different, each being independently selected from the group consisting of H, allcyl-, alkenyl-, alkynyl-, aryl-, heteroalkyi-. heteroaryl-, cycloalkyl-, heterocyclyl-. arylalkyi-, and heteroarylalkyi;
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:

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-, aikenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyctyl-, aryl-, heteroaryl-, (cycloalkyl)alkyi-, (heterocyclyl)alky[-, aryi-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:

wherein G is NH or O; and R15, R16, R17, R18 and R19 can be the same or different, each being independently selected from the group consisting of H, aikyl, heteroalkyl, aikenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl. arylalkyi, heteroaryl. and heteroarylalkyi, or altemately, (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, cycloalkyi 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. alkylsulfon^, aryisulfonyl, sulfonamklo, aikylsulfonamido, arylsulfonamido, alkyl, aryl, heteroaryl, keto. carboxy, carbalkoxy, carboxamido. alkoxycarbonylamino, alkoxycarbonyioxy, alkylureido, arvlureido. halo, cvano. and nrtro.
Formula XIII or a pharmaceutically acceptable salt, solvate or ester thereof; wherein: R1 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-, heteroalkyi-. heteroaryl-. cycloalkyi-, heterocyclyl-, arylalkyl-. and heteroarylalkyf;
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:

shown above in Formula 1 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, aikyl-, alkenyi-, alkynyl-, cycloalkyi-. heteroalkyi-,
heterocyclyl-. aryl-, heteroaryl-, (cycloalkyi)alkyl-, (heterocylyl)alkyl-, aryt-alkyi-, 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:


membered cycloalkyl or heterocyciyV.
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, alkylamlno, arylamino, atkylsulfonyl, arylsulfonyl, sulfonamido, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the compound is a compound of Formula XIV:

shown above in Formula I forms either a three, four, six, seven or eight-membered cycloalkyi, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl; E isC(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, heteroalkyi, aikenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately R and R1 in NRR' are connected to each other such that NRR' forms a four to eight-membered heterocyclyl;

wherein G is NH or O; and R15. R16. R17 and R18 can be the same or different, each being independently selected from the group consisting of H, alkyl. heteroalkyi, aikenyl, heteroalkenyl, alkynyl, heteroalkynyl, cydoalkyl, heferocydyl, aryl, and heteroaryl. or alternately, (i) R15 and R16 are connected to each other to form a four to eight-membered cydic structure, and (ii) likewise, independently R17 and R18 are connected to each other to form a three to eight-membered cydoalkyi or heterocydyl;
wherein each of said alkyl, aryl, heteroaryl, cydoalkyi or heterocydyl 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. alkyl. aryl, heteroaryl, keto, carboxy.

carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the compound is a compound of Fonnula XV:
Fomiula XV or a phanriaceutically acceptable salt, solvate or ester thereof; wherein: R1 is H, 0R6 NR9R10 or CHR9R10 wherein R6 R9 and R10 can be the same or different, each being independently selected from the group consisting of H, alkyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, cycloalkyl-, aryialkyi-, and heteroarylalkyl; E and J can be the same or different, each t)eing 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 O, with the proviso that when Z is O, G is present or absent arnl if G is present with Z being O, then G is C(=0);
G maybe present or absent, and if G is present G Is C(=0) or S(02). and when G is absent, Z is directly connected to Y;
Y is selected from the group consisting of:



R, R7, R2, R3, R4 and R5 can be the same or different, each being independently selected from the group consisting of H, alky!-, alkenyl-, alkynyl-, cycloalkyl-, heteroatkyl-, heterocyclyl-. aryl-, heteroaryi-. (cycloalkyl)alkyi-, (heterocyclyl)alkyl-, aryl-alkyi-, and heteroaryl-alkyi-. wherein each of said heteroalkyl, heteroaryi and heterocydyl independently has one to six oxygen, nitrogen, sulfur, or phosphorus atoms;
wherein each of said alkyl, heteroalkyi, alkenyl, alkynyl, aryl, heteroaryi, cycloalkyi and heterocydyl moieties can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyi. heterocydyl, halo, 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.
In another embodiment, the compound is a compourxi of Formula XVI:

or a pharmaceutically acceptable salt, solvate or ester thereof, wherein: R1 is H. 0R8 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-, heteroalkyi-, heteroaryi-. cydoalkyl-, heterocydyl-. arylalkyl-, and heteroarylalkyl, or alternately R9 and R10 in NR9R10 are connected to each other such that NR9R10forms a four to eight-membered heterocydyl, and likewise

independently alternately R9 and R10 in CHR9R10 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, heteroalkyi, alkenyl, heteroalkenyf, alkynyl, heteroalkynyl, cycloalkyi, heterocyclyl, aryl, arylaikyl. heteroaryl, and heteroarylalkyi; Y is selected from the following moieties:
wherein G is NH or O; and R'^ R^^ R^^ R'^ R^^ R^^, R^\ R^, R^. R^^ and R25 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyi, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyi, heterocyclyl. aryl, arylalkyi, heteroaryl, and heteroarylalkyi, or alternately


wherein each of said alkyl, aryl. heteroaryl, cycloalkyl or heterocydyl can be unsubstiturted 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 alkyisulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment, the compound is a compound of Formula XVII:


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:
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, alkyk, alkenyl-, alkynyl-, cycloalkyi-. heteroalkyl-,
heterocyclyl-, aryl-, heteroaryl-, (cycloa!kyl)a!kyl-, (heterocyclyl)alkyl-. aryl-alkyl-, and
heteroaryl-alky!-; 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:



heteroaryl, and heteroarylalkyl, or alternately, R17 and R18are connected to each other to form a three to eight-mennbered cycloalkyi or heterocydyl; wherein each of said alkyl, aryl, heteroaryl, cycloalkyi or heterocydyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, aryfthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, aikylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, aryiureido, halo, cyano, and nrtro.

or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
R8 is selected from the group consisting of alkyl-, aryl-, heteroalkyl-, heteroaryl-,
cycloalkyi-, heterocydyl-, arylalkyl-. heteroarylajkyl-, and heterocydylalkyl;
R9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and
cycloalkyl;
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:

shown above in Formula I forms either a three, four, five, six, seven or eight-membered cycbalkyl, a four to eight-membered heterocyclyl, a six to ten-membered aryl, or a five to ten-membered heteroaryi;
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-, cycloalkyi-. heteroalkyi-. heterocyclyl-, aryl-, heteroaryi-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, aryl-alkyl-, and heteroaryi-alkyl-; or alternately R and R' in N(RR') are connected to each other such that N(RR') forms a four to eight-membered heterocyclyl;
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, cycloalkyi. spiro-linked cycloalkyi, heterocyclyl, aryl. arylalkyi, heteroaryi, and heteroarylalkyl;
Y is selected from the following moieties;


different, each being independently selected from the group consisting of H, alkyl, heteroalkyl. alkenyl, heteroalkenyl. aikynyl. heteroalkynyl. cycloalkyl, heterocyclyi, aryl. arylalkyl, heteroaryl, and heteroarylaikyi, or alternately (i) R17 and R18 are independently connected to each other to form a three to eight-membered cycloallkyl or heterocyclyi; (ii) likewise independently R15 and R19 are connected to each other to fonn a four to elght-membered heterocyclyi; (iii) lilcewise independently R15 and R16 are connected to each other to form a four to eight-membered heterocyclyi; and (iv) likewise independently R15 and R2 are connected to each other to form a four to eight-membered heterocyclyi; wherein each of sakl alkyl. aryl, heteroaryl, cycloalkyi, 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, aikyi, alkenyl, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, csrboxy, carbalkoxy. carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro.
In another embodiment. the compound is a compound of Formula XIX:
wherein;
Z is selected from the group consisting of a heterocyclyl moiety,
N(H)(aIkyI), -N(alkyl)2. -N(H)(cycloalkyl), .N(cycloalkyl)2, -N(H)(aryl, -N{aryl)2. -N{H)(heterocycly!), -N(heterocyclyl)2, -N(H)(heteroaryl). and -N(heteroaryI)2;
R1 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, alky!-, alkenyl-, alkynyl-, aryl-. heteroalkyl-, heteroaryl", cycloalkyl-, heterocyclyl-, arylalkyi-, and heteroarylalkyl, or alternately R9 and R10 in NR9R10 are connected to each other such that NR9R10 forms a four to eight-membered heterocyclyl, and likewise independently alternately R9 and R10 in CHR9R10 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, heterocydyl, aryl, arylalkyl, hetenDaryl, and heteroarylalkyl;
Y is selected from the following moieties:


same or different, each being independently selected from the group consisting of H, alkyi, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroaikyl, cycloalkyl, heterocyclyl, aryl. arylalkyi, 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 (iv) likewise independently R15 and R2 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 unsubsiituted or. optionaliy independently substituted with one or more moieties selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkyithio, arylthio, amino, amido, alkylamino, arylamino, atkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl. heteroaryl, alkyisulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino. aikoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro. In ar
Formula XX or a pharmaceuticaliy acceptable salt, solvate or ester thereof; wherein: a is 0 or 1; b is 0 or 1; Y is H or C1-6 alky!;
B is H, an acyi derivative of formula R7-C(0)- or a sulfonyl of formula R7-SO2 wherein
R7 is (i) C1-10 alkyl optionally substituted with carboxyl, C1-6 alkanoyloxy or C1-6 alkoxy;
(ii) C3-7 cycloalkyi optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl or
phenylmethoxycarbonyl; (iii)C6 or C10 aryl or C7-16 aralkyi optionaliy substituted wth Ci^ alkyl, hydroxy, or
amino optionally substituted with C1-6 alkyl; or (Iv)Het optionally substituted with C1-6 alkyl, hydroxy, amino optionally substituted with C1-6 alkyl, or amido optionally substituted with C1-6 alkyl; R6. when present, is C1-6 alkyl substituted with carboxyl; R5. when present, is C1-6 alkyl optionally substituted with carboxyl; R4 is C1.10 alkyl, C3.7 cycloalkyi or C4-10 (alkylcycoalkyl); R3 is Cvio alkyl, C3-7 cycloalkyi or C4-10 (alkylcydoalkyl); R2 is CH2-R20, NH-R20, O-R20 or S-R20. wherein R20 is a saturated or unsaturated C3_7

cycloalkyl or C4_10 (alkyl cycloalkyi) being optionally mono-, di-or tri-substituted with
R21, or R20 is a C6 or C10 aryl or C7-16 aralkyi optionally mono-, di- or tri - substituted
with R21,
or R20 is Hat or (lower alkyl)-Het optionally mono-, di- or tri- substituted with R21,
wherein each R21 is independently C1-6 alkyl; C1-6alkoxy; amino optionally mono- or
di-substituted with C1-6 alkyl; sulfonyl; NO2; OH; SH; halo; haloalkyl; amido optionally
mono-substituted with C1-6 alkyl, C6 or C10 aryl, C7.-16 aralkyi, Het or (lower alkyl)-Het;
carboxyl; cart)oxy(lower alkyl); C5 or C10 aryl, C7-16 aralkyi or Het, said aryl, aralkyi or
Het being optionally substituted with R22;
wherein R22 is C1-6alkyi; 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;
R1 Is C1-6 alkyl or C2-6 alkenyl optionally substituted with halogen; and
W is hydroxy or a N-substituted amino.
In another embodiment, the compound is a compound of Formula XXI

Fonnula XXI or a pharmaceuticalty acceptable salt, solvate or ester thereoii wherein:
B is H, a C6 or C10 aryl, C7.16 aralkyi; Het or (lower alky!)- Het, all of which optionally substituted with C1-6 alkyl; C1-6 alkoxy; C1.6 alkanoyl; hydroxy; hydroxyalkyl; halo; haloalkyl; nitro; cyano; cyanoalkyi; amino optionally substituted with C1-6 alkyl; amido; or (lower alkyl)amide;
or B is an acyl derivative of formula R4-C(0)-; a carboxyl of formula R4-0-C(O)-; an amide of formula R4-N(R5)-C(0)-; a thioamide of formula R4-N(R5)-C(S)-; or a sulfonyl of formula R4-SO2 wherein

R4 is (i) C1-10 alkyl optionally substituted with carboxyi. C1-6 alkanoyl, hydroxy. C1-6 alkaxy, 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 alkylcycloaikyl. all optionally substituted with hydroxy, carboxyi, (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-substrtuted with C1-6 alkyl; amido; or (lower alkyl)amide;
(iv) C6 or C10 aryl or C7.16 araikyi, all optionally substituted with C1-6 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 C1-5 alkyl, hydroxy, amido, (lower alkyl) amide, or amino optionally mono- or di-substituted with C1-6 alkyl:
R5 is H or C1-6 alkyi;
with the proviso that when R4 is an amide or a thioamide, R4 is not (ii) a cycloalkoxy; Y is H or C1-6 alkyl;
R3 is C1-8 alkyl, C3.7 cycloalkyl, or C4-10 alkyicycloalkyl, all optionally substitued with hydroxy, C1_6 alkoxy, C1-6 thioalkyl. amido, (lower alkyI)amido, C6 or C10 aryl, or C7-16 araikyi;
R2 is CH2-R20, NH-R20. O-R20 or S-R20. wherein R20 is a saturated or unsaturated C3.7 cycloalkyl or C4-10 (alkyicycloalkyl). all of which being optionally mono-, di- or tri-substituted with R21, or R20 is a C6 or C1o aryl or C7-14 araikyi, all optionally mono-, dl-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; C1-5 alkoxy; lower thioalkyl;
sulfonyl; NO2; OH; SH; halo; haloalkyl; amino optionally mono- or di- substituted with C1-6 alkyl, C5 or C10 aryl, C7-14 araikyi, Het or (lower alkyl)-Het; amido optionally mono-substituted with C1-6 alkyl. C6 or C10 aryl, C7-14 araikyi, Het or (lower alkyI)-Het;


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, C1-6 alkoxy. C^ cycloalkoxy,
hydroxy, or N(R23)2 , wherein each R23 is independently H, C1-6 aikyl or C3-6
cycloalkyl;
R22 is H, halo, C1-6 alkyl. C3-6 cycbalkyl, C1-6 haloalkyi, C1-6 thioalkyl, C1-6 alkoxy, C3-5
cycloalkoxy, C2-7 alkoxyalkyi, 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, C1-6
alkyl. C3-6 cycloalkyl. C1-6 alkoxy. C3-6 cycloalkoxy, NO2 , N(R25)2 . NH-C(0)-R25 or
NH-C(0)-NH-R25, wherein each R25 is independently: H, C1-6 alkyl or C3.6 cycloalkyl;
or R24 is NH-C(0)-OR26 wherein R26 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: O, S, or N-R41, wherein R41 is H, C1-6 alkyl, C3.6 cycloalkyl or -C(0)-R42. wherein R42 is C1.6 alky!. C3.6 cycloalkyl or C6 or 10 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 alkyi, C1-6 haloalkyl, C1-5 alkoxy, hydroxy, halo, amino. 0x0, thio and C 1-6 thioalkyl, and A is an amide of formula -C{0)-NH-R 5 , wherein R 5 is selected from the group consisting of: C1-8 alkyl. C3-6 cycloalkyi, C6 or 10 aryl and C7.16 aralkyl; or A is a carboxylic acid.
In another embodiment, the compound is a compound of Fonnula XXIII

Formula XXIII
a pharmaceutically acceptable salt, solvate or ester thereof; wherein:
R0 !s a bond or difluonomethylene;
R1 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-) heterocyclylene; 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; on

R4, R 6, R8 and R10 are each independently hydrogen or optionally substituted aliphatic group;

wherein the unsaturatation is in the ring distal to the ring bearing the R9-L-(N(R8)-R7-C(0)-)nN(R6)-R5-C(O)N moiety and to which the -C(O)-N(R4)-R3-C(0)C(0)NR2R1 moiety is attached; L is -C(0)-, -00(0)-, -NR10C(0)-, -S(0)2-, or - NR10S(0)2-', and n
is 0 or 1,

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 compound is a compound of Formula XXIV



m is 0 or 1;
each R1 is hydroxy, alkoxy. or aryloxy, or each R1 is an oxygen atom and together with the boron, to which they are each bound, fonm a 5-7 membered ring, wherein the ring atoms are carbon, nitrogen, or oxygen;
each R2 is independently hydrogen, alkyi, alkenyl, aryl, aralkyl, aralikenyl, cycloalkyl, cycloalkylalkyl. cycloalkenyl. cycloalkenylalkyl. heterocydyl, heterocyciylalkyl, heterocyclylalkenyl, heteroaryi. or heteroaralkyl, or two R2 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a 5-7 membered monocyciic heterocyclic ring system; wherein any R2 carbon atom is optionally substituted with J;
J is alky!, aryl, aralkyl, aikoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocydyl, heterocyclyloxy, heterocyciylalkyl, keto. hydroxy, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carboxyalky[, carboxamidoalkyl, halo, cyano, nitro, formyl, acyl, sulfonyl. or sulfonamido and is optionally substituted with 1-3 J1 groups;
J1 is alkyl. aryi, aralkyl, aikoxy, aryloxy, heterocydyl, heterocydyloxy, keto, hydroxy, amino. alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoalkyi, halo, cyano, nitro, formyl, sulfonyl. or sulfonamido;
L is alkyl, alkenyl. or alkynyl, wherein any hydrogen is optionally substituted with halogen, and wherein any hydnogen or halogen atom bound to any terminal carbon atom is optionally substituted with sulfhydryl or hydroxy;
A1 is a bond;
R4 is alkyl, cydoalkyl, aryl, aralkyl, heterocydyl, heterocyciylalkyl, heteroaryi, heteroaralkyl, carboxyalkyi, orcarboxamidoalkyl. and is optionally substituted with 1-3 J groups;

R5 and R6 are independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cyclokyl, cycioalkyialkyl, cycloalkenyl, heterocyclyl heterocydylalkyl, 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. aralkyi, heterocydyl, heterocydylalkyl, heteroaryl, or heteroaralkyl. and is optionally substititued with 1-3 J groups;
R8 is hydrogen alkyl, aryl, aralkyi, heterocydyl, heterocydylalkyl, heteroaryl, heteroaralkyl. aralkanoyl. heterocyclanoyl, heteroaralkanoyl. -C(0)R14, -SO2R14. or carboxamido, and is optionally substititued with 1-3 J groups; or R8 and Z, together with the atoms to which they are bound, form a nitrogen containing mono- or bicyciic ring system optionally substituted with 1-3 J groups;
R14 is alkyl, aryl, aralkyi. heterocydyl. heterocyclyalkyl. heteroaryl, or heteroaralkyl;
Y is a bond, -CH2-, -C(0)-. -C(0)C(0)-, - S(0)-. -8(0)2-, or -S(0)(NR7)-, wherein R7 is as defined above;
Z is alkyl, aryl, aralkyi, cydoalkyl, cydoalkylalkyl, heterocydyl, heterocydylalkyl 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



R12 is hydrogen, aryl. heteroaryl, cyclaikyl, heterocyclyl. cycloalkylidenyl. or heterocycloaikylidenyl, 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;
R10 is alkyl. cydoaikyl, aryl. aralkyl, heterocyclyl, heterocyclylalkyl. heteroaryl, heteroaralkyl. carboxyalkyi. or carboxamidoalkly. and is optionally substituted with 1-3 hydrogens J groups;
R15 is alkyl, cydoaikyl, aryl, aralkyi, heterocydyl, heterocyclylalkyl. heteroaryl, heteroaralkyl, carboxyalkyi, or oarboxamidoalkyl, and is optionally substituted with 1-3 J groups; and
R16 is hydrogen, alkyl, aryl, heteroaryl, cydoaikyl, or heterocyclyl.
In another embodiment, the compound is a compound of Formula XXV

or a pharmaceutically acceptable salt solvate or ester thereoii wherein
E represents CHO or B(OH)2;
R1 represents lower alkyl, halo-lower alkyl, cyano-lower alkyl, lower alkylthio-lower alkyl, aryi-lower alkylthio-lower alkyl, aryl-lower alkyl, heteroaryllower alkyl, lower alkenyl or lower alkynyl;
R2represents lower alkyl, hydroxy-lower alkyl. carboxylower alkyl, aryl- lower alkyl, aminocarbonyl-lower alkyl or lower cydoalkyl-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 alky!, aryllower alkyl, lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-Iower alkyl. lower alkenyl, aryl or lower oycloalkyi;
R5 represents lower alkyl, hydroxy-lower alkyl, lower alkylthio-lower alkyl, aryl-iower alkyl, aryl-iower 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 cycioalkyl-iower alkyl or lower cycloalkyi;
R8 represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl or aryl-iower alkyl; and
R9 represents lower alkylcartxjnyl, carboxy-lower alkylcarbonyl. arylcarbonyl, lower alkylsulphonyl. arylsulphonyl, lower alkoxycarbonyl or aryl-iower alkoxycarbonyl.
in another embodiment, the compound is a compound of Formula XXV!
P6 P5 P4 P3 P2 P1





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)aIkyl or substituted with a further C3-7 cycioalkyl, C6 or C1o aryl, or heterocycle; said aryl or aralkyi optionally containing at least one heteroatom selected independently from the group consisting of. 0, S, and N;
said cyclic alkyl, cyclic alkenyl, aryl or aralkyi being optionally fused with a second 5-, 6-, or 7-membered ring to form a cyclic system or hetarocyce, said second ring being optionaliy 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 cycloalkyi, 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;



wherein R15 and R15 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 conventionally known to those skilled in the art. Thus, the actual structure of the compound of Formula XXVI is:







or a pharmaceutically acceptable salt, solvate or ester thereof.
The surfactant in the pharmaceutical formulations of the present invention enhances wetting of the present compounds by aqueous systems (as in a mammal) and improves the dissolution rate of the compounds to render a greater quantity of the compound available for absorption than is available in a formulation of the present compounds that does not include a surfactant Any phamnaceutically

acceptable surfactant that improves wetting of the present compounds may be used. Non-limiting examples of 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. Additional suitable surfactants are discussed later.
The pharmaceutical formulations of the present invention may be used In treating HCV and other diseases/disorders, including those associated with cathepsin activity and/or for inhibiting cathepsin activity in a subject 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.
Another example of a disease that can be treated using the pharmaceutical formulations of the present invention 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 using the pharmaceutical formulations of the present invention is a cardiovascular disease. Another example of a disease that can be treated using the pharmaceutical formulations of the present invention 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 using the pharmaceutical formulations of the present inventton 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 exampies, 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 ali instances by the term "about".

DETAILED DESCRIPTION
The present invention provides pharmaceutical formulations comprising at least one (one or more) compound of Formulae l-XXVl and at least one surfactant. Such formulations can be useful for inhibifing HCV protease and/or capthesin activity and have good dissolution characteristics to facilitate absorption of the compounds of Formulae l-XXVI.
Suitable compounds of formula I are disclosed in PCT International publication WO03/062265 published July 31. 2003. Non-limiting examples of certain compounds disclosed In this publication on include:





























































































































or a pharmaceutically acceptable salt, solvate or ester thereof.
In one embodiment, the HCV protease inhibitor is selected from the group consisting of
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

Formula lb Formula Ic
The chemical name of the compound of Formula Ic is (1R,2S,5S)-N-[(1S)-3-amino-1-
(cyclobutylmethyl)-2.3-dioxopropyl]-3-[(2S)-2-[II(1,1 -
dimethylethyl)amino]carbonyl]amino]-3,3-iimethyl-1-oxobutyl]-6,6-dimethyl-3-
azablcyoIo[3.1.0]hexane-2-carboxamide.
Processes for making compounds of Formula 1 are disclosed in U.S. Patent Publication Nos. 2005/0059648, 2005/0020689 and 2005/0059800, incorporated by

reference herein.
Non-limiting examples of suitable compounds of formula II and methods of making the same are disclosed in WO02/08256 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 WO02/08187 and in U.S. Patent Publication 2002/0160962 at page 3, paragraph 22 through page 132, incorporated herein by reference.
Non-iimiting examples of suitable compounds of formula IV and methods of making the same are disclosed in International Patent Publication WCX)3/062228 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-limiting 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 VIl-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 Vll disclosed in U.S. Patent Application Ser. No. 10/993,394 are:

























or a pharmaceutically acceptable salt, solvate or ester thereof.
Noniimiting examples of certain compounds of formula Vl!l disclosed in U.S. Patent Application Ser. No. 10/993,394 are:

^ (^ \V N " ■"■—^ \\ N "
or^ ^s / ci ^s /
°-/ /^K H Q^°J-0^ O./ ^ H ^ Qy' 3-OH

/
O^P H
o
■/ rj o ^ o^ ° )
/
O S / y 1 Q O


or a pharmaceutically acceptable salt, solvate or ester thereol
Nonlimrting examples of certain compounds of formula IX disclosed in U.S. Patent Application Ser. No. 10/993,394 are:

































































































































































































Compounds of formula XI are disclosed in U.S. Application Ser No. 11/065,509 filed Febnuary 24, 2005. The preparation of these compounds is

disclosed in the experimental section of this application set forth hereinbelow.
Non-limrting examples of certain compounds disclosed in U.S. Application
Ser. No. 11/065,509 are:






















or a pharmaceuticaily 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:






























Compounds of formula XIII 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:





























































































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 Appiicatron Ser. No. 11/054,673 are:















































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 hereinbeiow.
Non-limiting examples of certain compounds disclosed in U.S. Patent Application Ser. No. 11/007,910 are:













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








































or a pharmaceuticalty acceptable salt, solvate or ester hereof.
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.

Non-limiting examples of certain compounds disclosed in U.S. Patent Application Ser. No. 11/054,574 are:


or a pharmaceutically acceptable salt, solvate or ester thereof.
Compounds of formula XVIll 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:



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-limjting examples of certain compounds disclosed in U.S. Provisional Patent Application Ser. No. 60/573.191 are:



















or a pharmaceutically acceptabie 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 coi. 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 WOOO/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

Patent Publication WOOZ'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 present compounds (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 aiso include geometric isomers, e.g., when a double bond is present Polymorphous forms of the present compounds, whether crystalline or amorphous, also are contemplated as being part of this invention. The (+) isomers of the present compounds are preferred compounds used in the present Invention.
Unless othenwise 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.
It will be apparent to one skilled in the art that certain of the present compounds may exist in alternative tautomeric fomis. 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:


Prodnugs 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 Phamiaceutical Association and Pergamon Press. The temri "prodrug" means a compound (e.g. a drug precursor) that is transformed in vivo to yield a compound of Formula (!) or a pharmaceuticaliy 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, "Prodrugs 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 pharmaceuticaliy 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, (C1-C8)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, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycartonyloxy)ethyl having from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycartonyl)aminomethyl having from 3 to 9 carbon atoms. 1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl. 4-

crotonoiactonyl, gamma-butyro!acton-4-yl, di-N,N-(C1-C2)alkylamino(C2-i3)aIkyl (such asβ-dimethylaminoethyi). carbamoyl-(Ci-C2>alkyl, N,N-di (Ci-C2)alkylcarbamoyl-{C1-C2)a!kyl and piperidino-, pyrrolidine- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (1) 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, (CrC6)alkanoyloxymethyI, 1-((C1-C5)alkanoyloxy)ethyl. 1-methyl-1-((CrC6)alkanoyloxy)ethyl, (C-C5)alkoxycarbonyloxymethyI, N-(Ci-Ce)alkoxycarbonylaminomethyl, succinoyi, (C-i-C6)alkanoyt, a-amino(CrC4)alkanyl, arylacyl and α-aminoacyl, or a-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(0)(0H)2, -P(0)(0(CrC5)alkyI)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 (C1-C1)alky!. (C3-C7) cycioalkyi, benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl, —C{OH)C(0)OY1 wherein Y1 is H, (Ci-C6)alkyl or benzyl, —C(0Y2)Y3 wherein Y2 is (C1-C4) alkyi and Y3 is (Cr C6)alkyl, carboxy (C1-C6)alkyl, amino{C1-C4)alkyl or mono-N—or dl-N,N-(Cr C6)alkylaminoalkyl, —C(Y1-)Y3 wherein Y4 is H or methyl and Y5 is mono-N— or di-N,N-(C1-C6)a[kylamino morphotino, piperidin-1-yl or pyrrolidin-l-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 are incorporated in the crystal lattice 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 H2O.

0ns or more of the present compounds may aiso exist as, or optionaEty 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, MPS 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 l 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 used in 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 present compounds 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 fonmula I contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an ackiic 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 present compounds of the various formulae disclosed herein may be formed, for example, by reacting the present compounds 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 fomnation of pharmaceutically useful salts from basic (or acidic) pharmaceutical compounds are discussed, for

example, by S. Barge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, Intemational 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, Camilie G. Wermuth (Eds.), Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. 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-naph1halenesulfonates, nicotinates. nitrates, oxalates, pamoates, pectinates, persulfates, 3-phenylpropionates. phosphates, picrates, pivalates, propionates, salicylates, succinates, sulfates, sulfonates (such as those mentioned herein), tartarates, thiocyanates, toluenesuifonates (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-glucamldes, t-butyl amines, piperazine,
phenylcyclohexylamine, choline, tromethamine, and salts with amino adds such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyi 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 estenfication of the hydroxy groups, in which the non-carbonyi 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 othenwise specified, any alkyl moiety present preferably contains from 1 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 compounds of Formulae l-XXVI can exhibit HCV inhibitory activity and/or capthesin inhibitory activity- Pharmaceutical formulations containing these compounds can possess utility in treating hepatitis C and related disorders and/or capthesin-associated disorders and may be used by 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 formulatlons 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 a!. ("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., 1a, lb. 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 poiyprotein 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).
The formulations 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 Corporation, Madison, New Jersey) and Levovirin™ (from ICN Pharmaceuticals, Costa Mesa. California), VP 50406™ (from Viropharma, Incorporated, Exton, Pennsylvania). ISIS 14803™ (from ISIS Phamiaceuticals, Carisbad, California). Heptazyme™ (from Ribozyme Pharmaceuticals, Boulder, Colorado), VX 497™ (from Vertex Pharmaceuticals, Cambridge, Massachusetts), Thymosin™ (from SciClone Pharmaceuticals, San Mateo, California), Maxamine™ (Maxim Pharmaceuticals, San Diego, Califomia), 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 (Roferon™, from Hoffman La-Roche, Nutley,

New Jersey) in the form of pegylated interferon alpha-2a (e.g., as sold under the trade name pegasys™), interferon a!pha-2b (Intron™, from Schering-Plough Corporation) in the form of pegylated interferon aipha-2b (e.g.. as sold under the trade name PEG-intron™), interferon alpha-2c (Berofor Alpha™, from Boehringer Ingelheim, Ingelheim, Germany) or consensus interferon as defined by determination of a consensus sequence of naturally occurring interferon alphas (Infergen™, from Amgen, Thousand Oaks, California).
The formulations of the present invention 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 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-Piough 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 intramuscular injection at 3MIU(11.1 mcg/mL)rnW 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-Piough or COPEGUS ribavirin from Hoffmann-La Roche).
The formulations of the present invention comprise at least one compound of Formuiae l-XXVl, as defined above, together with one or more surfactant The formulation can further comprises one or more pharmaceutically acceptable adjuvants and optionally other therapeutic agents and phanmaceutically acceptable carrers and excipients. Each excipient must be acceptable in the sense of being compatible with the other ingredients of the fonnulation and not injurious to the mammal in need of treatment
In one embodiment, the adjuvant is at least one pharmaceutically acceptable 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", as used herein, refers to an adjuvant material that reduces the contact angle between the active drug component and the environment of its use in a mannma! and may also be referred to as a wetting agent. 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 by aqueous systems (as in a mammal) and improves the dissolution rate of the compounds to render a greater quantity of the compound available for absorption than is available in a formulation of the present compounds that does not include a surfactant. Any pharmaceutically acceptable surfactant that improves wetting of the present compounds may be used. Particulariy 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 glyco! 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 1 to about 5% by weight.
Acidifying agent refers to an adjuvant material that lowers the pH of the formulation. An acidic pH environment may improve the stability of the present compounds. Any pharmaceutically acceptable acidifying agent that improves stability of the present compounds may be used. Particularly suitable acidifying agents include tartaric add. ascorbic acid, citric acid, malic acid, lactic acid and succinic acid. In one 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 1 to 5% by weight.
Carrier refers to a substance that usually makes up the major portion of the composition or dosage form. Suitable carriers include celluloses such as microcrystalline cellulose; sugars such as lactose, sucrose, mannitol and sorbitol; and starches such as are derived from wheat, com, 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 50% 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 fonmulation. Binders add cohesive strength already available in the diluent or bulking agent. Suitable binders include sugars such as lactose, sucrose and com sweeteners; starches derived from wheat, com 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; poiyvinylpymolidone; 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 taic. The amount of giident 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 form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die 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 oieate, polyethylene glycols and d'l-ieucine. 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 indude 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 form. Such excipiente 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 forms. The bulk composition is material that has not yet been fomied 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, intravenously, subcutaneously, or transdermally. Preferably, the pharmaceutical formulation is in a unit dosage form. 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 forms are solids, gels, or fluids including elixirs, dispersible granules, syrups, suspensions. 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 forms suitable for oral administration. Other examples of phamaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.). Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. The formulations of the present invention may be produced via a dry blend processor a wet granulation process and filled or compressed into capsules or tablets.
Capsules (either solid-filled, semi-solid filled or liquid filled) 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 form containing the phanmaceutlcal formulation. The tablet can be prepared by compressin 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 hydrophiliic semi-soiid matrix.
Suppositories containing the formuiations 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 forms for sustained release 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 soiid form preparations which are intended to be converted, shortly before use, to liquid form preparations for eiher oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. Altematively, 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 transdemal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Broavaiiabillty 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 form as compared to a standard or control.
The present invention discloses methods for preparing the pharmaceutical formulations of the present invention. 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 mixture such as with a roller compactor, milling the compacted mixture, blending the milled material with any remaining excipients and filling the final blend into capsules.
In one embodiment, the pharmaceutical fonnulation of the present is administered orally and is in a unit dosage form. 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 1 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 form contains about 200 mg of the active compound. In another embodiment, the dosage fonn 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 following formulations exemplify some of the dosage forms of the present invention. In the formulation, the "Active Compound" designates any of the compounds of Formulae 1-XXVI, as defined above, or a pharmaceutically acceptable sale, solvate or ester thereof.

In one embodiment, the powdery Active Compound can be blended with some of the ingredients and compacted with a roller compactor to densify the powder. The resulting compact is miiied, and the milled compact is blended with the remaining ingredients and filled into a capsule or pressed into a tablet.


granules are milled and blended with the remaining ingredients and filled into a capsule or pressed into a tablet.
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-l ,2,3-ben20triazin-4(3H)-one EDCI: 1-(3-dimethylaminopropyI}-3-ethylcarbodiimlde hydrochloride NMM: N-Methylmorpholine ADDP: 1,1-(Azodicarbobyl)dipiperidine DEAD: Diethyiazodicarboxylate MeOH: Methanol EtOH: Ethano! Et20: Diethyl ether DMSO: Dimethylsulfoxide HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pyrroiidinophosphonium hexafluorophosphate DCM: Dichloromethane DCC: 1.3-Dicyclohexylcarbodiimide TEMPO: 2,2.6,6-Tetramethyl-1piperidinyloxy Phg: Phenylglycine Chg: Cyclohexyiglycine Bn: Benzyl Bzl: Benzyl Et: Ethyl Ph: Phenyl
iBoc: isobutoxycarbonyl iPr isopropyl

tBu or But terf-Butyl
Boc: tret-Butyloxycarbonyl
Cbz: Benzylioxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyi
MCPBA: 3-chloroperbenzoic acid.
Me: Methyl
HATU: 0-(7-azabenzotriazoI-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
DMAP: 4-N,N-Dimethylaminopyridine
Bop: Benzotriazol-1 -yl-oxy-tris(diniethylamino)hexafluorophosphate
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 under peptide coupling methodology (Louis A Carpino et al "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 P1-P' primary amide moiety afforded the hydroxyl amide 1.07. Oxidation (Moffatt, or Dess-Martin's) resulted in the target compound 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-BDC-P2-p3-acid 1.03 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 using
either formic acid or 4 M HOI in dioxane gave the formate or hydrochloride salt 1.13.
Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in the target
compound 1.14.


Method D
In yet another variation, the hydrochloride saft 1,13 was converted to the 4-
nitrophenyi carbamate 1.15 by reaction with 4-nitrophenyl chlorofomnate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice

Method E
in yet another variation, the dipeptide hydrochloride salt 1.04 was converted to the 4-nitropheny! carbamate as described above. Treatment with an amine (or amine hydrochloride salt) of choice provided the urea derivative 1.05. Hydrolysis and


The followinq 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-Hydroxy-1,2,3-benzotriazin-4(3H)-one
EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbod!imide hydrochloride
NMM: N-Methylmorpholine
ADDP: 1,1-(AzodicarbobyI)dipiperidine
DEAD; Diethylazodicarboxylate
MeOH: Methanol
EtOH: Ethanol
Et2O: Diethyl ether
DMSO: Dimethylsulfoxide
HOBt: N-Hydroxybenzotriazole

PyBrOP: Bromo-tris-pyrroiidinophosphonium hexafluorophosphate
DCM: Dichioromethane
DCC: 1,3-Dicyciohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-1-piperidinyloxy
Phg: Phenyiglycine
Chg: Cyclohexylglycine
Bn: Benzyl
Bzl: Benzyl
Et: Ethyl
Ph: Phenyl
iBoc: isobutoxycarbonyl
iPn isopropyl
tBu or But: tert-Butyl
Boc: tert-Butyloxycarbonyl
Cbz: Benzyloxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyl
Me: Methyl
HATU: 0-(7-azabenzotriazol-1--yl}-1,1,3,3-tetramethyiuronium hexafluorophosphate
DMAP: 4-N,N-Dinnethylaminopyridine
BOP: BenzotriazoM-y!-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 functionalrty 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 P1-P' primary amide moiety afforded the hydroxyl amide 1.07. Oxidation (Moffatt or related process - TT.Tidwetl, Synthesis, 1990. 857; or Dess-Martin's - J. Org. Cham., 1983, 48, 4155} resulted in the target compound 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.

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.
Method D
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-
nitrophenyl carbamate 1.15 by reaction with 4-nrtrophenyl chloroformate.


Method E
In yet another variation, the dipeptide hydrochloride salt 1.03 was converted to the 4-
nitrophenyi 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.
The following experimental section applies for the preparation of the compounds of Formula XIII:
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


Method B
Peptide coupling of the acid 1.06 with the appropriate P1-P' secondary amide moiety afforded the hydroxy1 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 1.17 with the appropriate P1-P' amide moiety afforded the hydroxy! 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.
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-nitrophenyl carbamate 1.15 by reaction with 4-nrtrophenyl chloroformate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice provided the target compound 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.
The foHowinq experimental section applies for the preparation of the compounds of Formula XtV:
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-ben20tria2in-4(3H)-one EDCI: 1-(3-dimethylaminopropyI}-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: Dichioromethane
DCC: 1,3-Dicyclohexylcarbodiimide
TEMPO: 2,2,6,6-Tetramethyl-1 -piperidinyloxy
Phg: Phenylglycine
Chg: Cyciohexylglycine
Bn: Benzy!
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: Cylcopentyidienyl
Ts: p-toluenesulfonyi
Me: Methyl
HATU: 0-(7-azabenzotriazol-1-yI)-1,1,3,3-tetramethyluronium hexafluorophosphate
DMAP; 4-N,N-Dimethylaminopyridine
BOP: BenzotriazoI-1-yl-oxy-tris(dimethylamino)hexafluorophosphate
PCC: Pyridiniumchlorochromate
KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimethyisilylamide)
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 P1-P' primary amide moiety afforded the hydroxy1 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.

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.



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 hydroxy! 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.

Method D
In yet another variation, the hydrochloride salt 1.13 was converted to the 4-nitrophenyi carbamate 1.15 by reaction with 4-nitrophenyl chioroformate. Subsequent treatment with an amine (or amine hydrochloride salt) of choice provided the target compound 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.
The following experimentat 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-l ,2,3-benzotriazin-4(3H>-one EDCI: 1-{3-dimethylaminopropyl>-3-ethylcarbodiimide hydrochloride NMM: N-Methylmorpholine ADDP: 1.1-(AzodicarbobyI)dipiperidine DEAD: Diethylazodicarboxylate MeOH: Methanol EtOH: Ethanol Et20: Diethyl ether

DMSO: Dimethyisuifoxide HOBt: N-Hydroxybenzotriazole
PyBrOP; Bromo-tris-pyrrolidinophosphonium hexafluorophosphate DCM: Dichioromethane DCC; 1,3-Dicydohexylcarbodiimide TEMPO: 2,2.6,6-Tetramethyl-1-prperidinyloxy Phg: Phenylglycine Chg: Cyclohexylglycine Bn: Benzyl Bzl: Benzyl Et; Ethyl Ph: Phenyl
iBoc: isobutoxycarbonyi iPr: isopropyl ^Bu or Bu^: tart-Butyl Boc: tert-Butyloxycarbonyl Cbz: Benzyloxycarbonyl Cp: Cylcopentyidienyi Ts: p-toluenesulfonyl Me: Methyl
HATU: 0-(7-azabenzotriazol-1 -yl)-1.1,3,3-tetramethyluronium hexafluorophosphate DMAP: 4-N,N-Dimethylaminopyridine
BOP: BenzotriazoH-yl-oxy-tris(dimethylanfiino)hexafluorophosphate PCC: Pyridiniumchlorochromate
KHMDS: Potassium Hexamethyldisilazide or Potassium bis(trimetiiylsilylamide) NaHMDS: Sodium Hexamethyldlsilazde or Sodium bis(trimethylsilylamide) LiHMDS: Lithium Hexamethyldisilazide or Lithium bls(trimethylsilyiamide) 10% Pd/C: 10% Palladium on carbon (by weight). Preparative Example 1:


A solution of pyrazinecarboxylic acid 1a (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 lb (1.2 eq, 6.03 g) was added in small portions. Then, N-methylmorphoiine (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 volatlles 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 1N 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 1c as a white solid. SteoB
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

reaction mixture was treated with 100 mL of aqueous 1N HC! 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
The amino ester 1e was prepared following the method of R. Zhang and J. S. Madalengoltia (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 HCl (4M HCI in dioxane was also employed for the deprotection).
(Note: In a variation of the reported synthesis, the sulfonium yiide was replaced with the corresponding phosphonium ylide). Step D

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^*0 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 1M HCI, saturated NaHCOa, brine, dried (MgS04), filtered and concentrated in vacuo ar>d purified by chromatography (SiOa, Acetone/Hexane 1:5) to yield 1g as a coloriess solid. StepE


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, 1h which was used without purification. Step F

A solution of acid 1d (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 1h (1.2 eq, 146 mg) was added. Then, N-methylmorphoiine (4 eq, 0.17 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 residue was chromatographed on silica gel (gradient: acetone/hexanes; 1:9 to 4:6) to afford the product II as a white solid.


(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 1N 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 1j as a white solid.

A solution of acid Ik (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 ovemighL 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 1M 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 residue was chromatographed on silica gel (gradient: acetone/hexanes; 5:95 to 3:7) to afford the product 11 as a clear oil. Step I

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. Step J
A solution of aldehyde 1m (1,8 g) in 100 mL of dry dichloromethane was treated with isonitrile (1.1 eq, 680 mg) and acetic add (2 eq, 1.02 mL, d 1.0149). The mixture was stirred overnight. All the volatiles were removed under vacuum and
the residue was chromatographed on silica gel (gradient: ethy! acetate/hexanes; 2:8 to 6:4) to afford the product In as a white solid.

A solution of acetate In (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 1 h until all the starting material had t>een 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 1p as a white solid. Step L


The N-Boc protected amine 1p (1.5 g) was dissolved in 20 mL of 4M HCl in dioxane. The reaction mixture was stinted for about 1 h until all the starting material had been consumed. All the volatiles were removed under vacuum to afford the product 1q as a white solid. Step M

A solution of acid 1j (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 voiatiles 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 1N HCl (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 1r was used without further purification. Step N


A solution of alcohol 1r (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 1M sodium thiosuifate 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 1 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



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. Ail the volatiles were removed under vacuum and the residue was taken into 100 mL of ethyl acetate. The organic layer was washed with aqueous IN HCl (15 mL), aqueous saturated NaHCOS (15 mL), water (15 mL), brine (15 mL), dried over MgS04, filtered, and concentrated under reduced pressure to afford the desired product A1. No further purification was carried out for the product. Step 2

A solution of A1 (360 mg) in 20 mL of a 1:1 mixture of toluene/DMSO was treated with EDCI (1.3 g) and dichioroacetic 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 NaHCOs (15 mL), aqueous 1N HCl (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.


The N-Boc protected amine A2 was treated with 10 mL of formic acid. The resulting solution was stin-ed for 2 h. All the volatiles were removed under reduced pressure. No further purification was done for the product A3. Step 4

To a solution of the amine salt A3 in 1 mL of dry methylene chloride was added N-methyimorpholine (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 soln) 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 1N 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 C37H53N6O7 [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.

The foilowinq 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-Dimethy!formamide 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: Ethanoi Et20: Diethyl ether DMSO: Dimethylsulfoxide HOBt: N-Hydroxybenzotriazole
PyBrOP: Bromo-tris-pynrolidinophosphonium hexafluorophosphate DCM: Dichloromethane DCC: 1,3-Dicyclohexyicarbodiimide TEM PO: 2,2,6,6-Tetramethyl-1-piperidinyloxy Phg: Phenylglycine Chg: Cyclohexylglycine Bn: Benzyl Bzl: Benzyl Et: Ethyl Ph: Phenyl
iBoc: isobutoxycarbonyl iPn isopropyl tBu or But tert-Butyl Boc: tert-Butyloxycarbonyl

Cbz: Benzy'loxycarbonyl
Cp: Cylcopentyldienyl
Ts: p-toluenesulfonyl
Me: Methyl
HATU: 0-{7-azabenzotriazoI-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
DMAP: 4-N,N-DimethyIaminopyridine
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 beiow. 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 P1-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.


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.


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 hycochloride salt 1.13. Treatment with a suitable isocyanate (or isocyanate equivalent) resulted in the target compound 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.


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.

The following experimental section applies for the preparation of the
compounds of Formula XVIII:
Example 3 Preparation of Compound of Formula 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 mmo!). 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 1M H3PO4 and brine. Organic layer was dried over MgS04, filtered and concentrated to dryness. Residue was purified over silica gel using acetone-CH2Cl2 ( 1:9 to 1:1) to get 8.0 mg of product of formula 3 (6.5% 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
Stepl
I
To a stirred solution of the priline 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 reactfon flask was stored in the

freezer (-20°C), overnight (16 hr). The reaction mixture was diluted wiith dichloromethane (80 mL) and washed with saturated sodium bicarbonate solution (80 mL), 10% aq. citric acid solution (80 mL), brine (80 mL), dried (Na2S04). 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)+.

To a solution of the methyl ester 101a (1.21 g, 2.34 mmol) in THF (10 mL) and MeOH (5 mL) was added aq. 1M 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 materia! crashed out. This solid was filtered off, washed with water and dried in vacuo to afford 970 mg of 101b. LC-MS: 504.1 (M+H)",
The add 101b (503 mg, 1 mmol) was coupled with intermediate 13.06 (334 mg, 1.5 mmol) using essentially procedure described above (Step 1, preparation of 101a) to provide 101c which was used v^thout purification. MS: 672.37 (M+H)^ Step 4


To a solution of the hydroxy! 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 (Na2S04), 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)+.

Deprotection of the N-boc functionality of 101 d 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)+, Steps


To a solution of the amine salt 101e (60 mg, 0.1 mmol) in dichloromethane (2 mL) at 0°C was added DIPEA (0.05 mL, 0.3 mmol) followed by the isocyanate intemiediate 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 saturated ammonium chloride solution (20 mL), brine (20 mL), dried (Na2S04), 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 followinq experimental section applies for the preparation of the
compounds of Formulae la, 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-l ,2,3-benzotriazin-4 (3H)-one EDCl: 1-(3-dimethylaminopropyl)-3-ethylcarbodnmide hydrochloride NMM: N-Methylmorpholine MeOH: Methanol

EtOH: Ethanol
Et20: Diethyl ether
DMSO: Dimethylsulfoxide
K'BuO: Potassium tert-butoxide
DCM: Dichloromethane
Chg: Cyclohexylglycine
Bn: Benzyl
Et: Ethyl
Ph: Phenyl
iPr. isopropyl
tBu or But tert-Butyl
Boc: tert-Butyloxycarbonyl
Cbz: Benzyloxycarbonyl
HATU: 0-(7-azaben2otria2ol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate
BOP : Benzotriazol-yl-oxy-tris(dimethylamino)hexafluorophosphate
10% Pd/C: 10% Palladium on carbon (by weight).
Example:
Synthesis of (1R.5SVN-r3-Amino-1-(Cvclobutvlmethv!V2,3-Dioxopropvn-3-r2(S)-
III(1.1-Dimethviethyl)Amino1CarbonvnAmino1-3,3-Dimethvl-1-Oxobutvn-6.6-Dimethvl-
3-Azabicvclor3.1.01Hexan-2(SVCarboxamide (Structure la):


A stirred solution of the ketimime 1a' (50 g, 187.1 mmol, available from Aidrich Chemical Company, Milwaukee, Wisconsin) under N2 in dry THF (400 mL) was cooled to -78° C and treated with 1 M solution of K-^BuO (220 nnU 1-15 equiv.) in THF. The reaction mixture was wamied to 0°C mL) The resulting solution was stin-ed at room temperature for 5 h and extracted with Et2O (1 L). The aqueous layer was made basic to pH ~12-14 with aq. NaOH (50 %) and extracted with CH2C(2 (3x300 mL). The combined organic layers were dried (MgS04), filtered, and concentrated to give pure amine (lb', 18 g) as a colorless oil. Step 2.
A solution of the amine lb' (18g, 105.2 mmol) at 0° C in CH2CI2 (350 mL) was treated with di-tret-butyidicarbonate (23 g, 105,4 mmol) and stinred 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/H2O (200 ml, 1:1) and treated with LiOH.H20 (6.5 g, 158.5 mmo!) and stin-ed 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 CHaCl2. The combined organic layers were dried (MgS04), filtered, and concentrated in vacuo to yield 1c' as a coloriess viscous oil which was used for next step without any further purification. Step 3.


A solution of the acid 1c' (15.0 g, 62 mmol) in CH2CI2 (250 mL) was treated with BOP reagent (41.1 g, 93 mmo}}. N-methylmorpholine (27 mL), N,0-d!nnethyl hydroxylamine hydrochloride (9.07 g, 93 mmol) and stirred ovemight at rt. The reaction mixture was diluted with 1 N aq. HC! (250 mL), and the layers were separated and the aqueous layer was extracted with CH2CI2 (3x300 ml). The combined organic layers were dried (MgS04), filtered, concentrated in vacuo and purified by chromatography (Si02, EtOAc/Hex 2:3) to yield the amide 1d (15.0 g) as a coloriess solid. Step 4.
A solution of the amide 1d (15 g. 52.1 mmol) in dry THF (200 mL) was treated dropwise with a solution of LiAlH4 (1M, 93 mL, 93 mmol) at O°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 NaHGO3, brine, and dried (MgS04). The mixture was filtered and concentrated in vacuo to yield 1e as viscous colorless oil (14 g).

(MgS04), filtered, concentrated in vacuo and purified by chromatography (Si02, EtOAc/Hex 1:4) to yield 1f (10.3 g) as a colorless liquid as a mixture of diastereomers. Step 6.
Methanol saturated with HCI*, prepared by bubbling HCI gas to CH3OH (700 ml) at 0 °C, was treated with cyanohydrin If 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.
A solution of the amine hydrochloride 1g in CH2CI2 (200 mL) was treated with EtsN (45.0 mL, 315 mmol) and B0C2O (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 CH2Clz The combined organic layers wete dried (MgS04) filtered, concentrated in vacuo and purified by chromatography (EtOAc/Hex 1:4) to yield hydroxy ester 1h. Step 8.

A solution of methyl ester 1h (3g, 10.5 mmo!) in THF/H2O (1:1) was treated Willi 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 mmoi), 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 with aq. saturated NaHCOa. dried (MgS04) filtered concentrated in vacuo to obtain 1i, which was used as it is In the following steps. (Attematively 11 can aiso be obtained directly by the reaction of 1f (4.5 g, 17J mmol) with aq. H2O2 (10 mL), LiOH.H20 (820 mg, 20.8 mmol) at 0 °C in 50 mL of CH3OH for 0.5 h.)


A solution of Boc-tert-Lue 1k (Fluka, 5.0 g 21.6 mmoi) in dry CH2CI2/DMF (50 mL, 1:1) was cooled to 0° C and treated with the amine 11 (5.3 g. 25.7 mnriol), NMM (6.5 g, 64.8 mmol) and BOP reagent (11.6 g, 25.7 mmol). The reaction was stin"ed at rt. for 24 hrs, diluted with aq. HC! (1 M) and extracted with CH2CI2- The combined organic layers were washed with HCI (aq, 1 M), saturated NaHCO3, brine, dried (MgS04). filtered and concentrated in vacuo and purified by chromatography (Si02, acetone/hexane 1:5) to yield 1m as a colorless solid. Step 11.
A solution of methyl ester 1m (4.0 g, 10.46 mmoi) was dissolved in HC! (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 CH2CI2 (10 mL) was cooled to -78°C and treated with fert-butyl isocyanate (250 mg, 2.5 mmol) and stirred at rL overnight. The reaction mixture was concentrated in vacuo and the residue was diluted with aq. HCI (1M) and extracted with CH2CI2. The combined organic layers were washed with aq. HCI (1M), saturated NaHCO3 and brine. The organic layers were dried, filtered and concentrated in vacuo and the residue was purified by chromatography (SiO2. acetone/Hex 1:4) to yield In as a coloriess solid. Step 12.


A solution of methyl ester 1n (381 mg, 1.0 mmol) in THF/H2O (1:1,5 mL) was treated with L1OH.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.
A solution of acid (254.9 mg, 0.69 mmol) in DMF/CH2Cl2(1:1. 5.0 mL) was treated with amine 1j (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. 1M HCI and extracted with EtOAc, The combined organic layers were extracted with aq. NaHCO3, aq. HCI, brine, dried (MgS04) filtered, concentrated in vacuo to obtain I0 (470 mg) as a tan colored solid that was used in the next reaction without further purification. Step 13.

A solution of amide I0 (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 stin-ed 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

(MgS04), filtered, concentrated, in vacuo and purified by chromatography (Si02,
aceione/hexanes 3:7) to yield 1a as a coloriess solid.
Separation of the Compound of Fonmuia 1 into diastereomers of Formulas lb and Ic:

lb Ic
Preparative HPLC condition for separation
COLUMN USED: NORMAL PHASE YMC DIOL-NP COLUMN
120 A, S-10/20; 50 mm x 500 mm I.D/iength
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: 1 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 DM; 150 mm X 3 mm iength/l.D
SOLVENT A: Hexanes
SOLVENT B: To make 4 L of solvent (1.7 L Isopropanol + 300 mL of
CH3CN+ 2 L of CH2Cl2)
HPLC CONDITIONS: 8.5% of Solvent B/91.5% of Solvent A
FLOW: 0.7 mL/min
Rt Nonpolar isomer (compound lb) =13.2 min

Polar isomer (compound Ic) =16.1 min 2.5 mg of compound in 1 mL was used and 20µL was injected and analyzed with a U.V detector at =254 nm. Anafytical data for compounds 2 and 3. Compound 3 rPolar diastereomer]
1H NMR (d6-dmso. 500 MHz): D 8.26 (d, 1 H, J= 7.0 Hz), 8.00 (s, 1 H), 7.75 (s, 1 H), 5.96 (s, 1 H), 5.84 (d, 1 H, J=10 Hz). 4.96 (m. 1 H), 4.28 (s, 1H), 4.11 (d. 1 H, J=11 Hz), 3.94 (d, 1H, J=10 Hz), 3.73 (dd. 1 H, J= 10 & 5 Hz). 2.48 (m, 1 H), 1.95 (m, 2 H), 1.61 (m, 1 H), 1.59 (m, 1 H), 1.77(m, 1 H), 1.57 (m, 1 H), 1.74 (m. 2 H), 1.42 (dd, 1 H, J=7.5 & 5 Hz), 1.28 (d, 1 H, J=7.5 Hz), 1.17 (s, 9 H), 1.01 (s, 3 H), 0.90 (s, 9 H), 0.85 (s, 3 H). 13C NMR (d6-dmso, 125 MHζ: D 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 C27H46O5N5 [M+l]+ 520.3499; observed: 520.3505. Compound 2 [Non-polar diastereomer]
1H NMR (de-dmso, 500 MHz): D 8.15 (d, 1 H, J= 7.0 Hz), 7.95 (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, 1H),4-.13 (d, 1 H, J=11.0 Hz), 3.97 (d, 1H, J=1G 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, 1 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-dmso125 MHζ: 5 197.1, 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 G27H4BO5N5 [M+1]+ 520.3499; observed: 520.3514.
It will be appredated 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 artides) referred to in this application is incorporated in its entirety by reference for all purposes.









CLAIMS
What is claimed is:
1. A pharmaceutical formulation comprising:
at least one surfactant; and
at least one compound selected from the group consisting of compounds of Formulae I to XXVI below:

or a phannaceutically acceptable salt, solvate or ester thereof,
wherein in Formula I above:
Y is selected from the group consisting of the following moieties: alkyl, alkyl-ary!,
heteroalkyl, heteroaryl, aryi-heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-
aryloxy, aryloxy, heteroaryloxy. heterocycloalkyloxy, cycloalkyioxy, alkylamino,
arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino and
hetetocycloalkylamino, with the proviso that Y maybe optionally substituted with X11
or X12
X11 is alkyl, alkenyl, alkynyl, cydoalkyi, cycloalkyl-alkyl, heterocyclyl,
heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or
heteroarylalkyl, 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, arylsulfonamido, carboxy, carbalkoxy, carboxamido, alkoxycart>onylamino, alkoxycarbonyioxy, alkylureido, arylureldo, 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, C2F5, C3F7. CF2R6,


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 (CH2)p, (CHR) p, or (CRR')p,
SO2, NH, MR or O; and when J is absent, G is present and E is directly linked to N
shown in Formula 1 as linked to J;
L may be present or absent, and when L is present, L is CH, CR, O, 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 O, NR, S, SO2, (CH2) p.


R. R', R2 R3 and R4 are independently selected from the group consisting of H; Ci-C10 alkyl; C2-C10 alkenyt; C3-C8 cycloalkyl; C3-C8 heterocycioalkyl, 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 phosphonjs atoms, and said alkyl is of one to six carbon atoms; aryl; heteroaryl; alkyl-aryl; and alkyl-heteroaryt;
wherein said alkyl, heteroaikyl. 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, 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 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;



halogen, cyano, or nitro moiety, with the proviso that the alkyl, alkoxy. and be additionally optionally substituted with moieties independently selected from P1a, P1b, P2, P3, P4, P5, and P6 are independently:
H; C1-C10 straight or branched chain alkyl; C2-C10 straight or chain alkenyl;
C3-C8 cycioalkyl. C3-C8 heterocyclic; (cycloaIky!)alky! or heterocyly)alkyl' wherein said cycioalkyl is made up of 3 to 8 carbon atoms, and zero to 6 oxyges nitrogen, sulfur, or phosphorus atoms, and said alkyl is of 1 to 6 carbon aioms
aryl, heteroaryl, arylalkyl, or heteroarylalkyl, wherein said alkyl is of 1 carbon atoms;
wherein said alkyl, alkenyl, cycioalkyl, heterocyclyl; (cycloalkv'i)aikyl and (heterocyclyl)alkyl moieties may be optionally substituted with R13 and further wherein said P1a and P1b may optionally be joined to each other to from spirocyclic or spiroheterocydic ring, with said spirocyciic or spiroheter

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-aikyi, heterocydyl, heterocydyl-
alkyl, aryl, aryl-alky!, heteroaryl. or heteroaryl-alkyl; with the proviso that said P1 may
13
be additionally optionally substituted with R ;

Fomiula ill or a pharmaceutically acceptable salt, solvate or ester thereof;
wherein in Formula Hi above:
G, J and Y may be the same or different and are independently seiected from the
group consisting of the moieties: H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, ary!-
heteroaryl, alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy, heterbaryloxy,
heterocycloalkyloxy. cydoalkyioxy, aikylamino. arylamino, alkyl-arylamino.
arylamino, heteroaryiamino, cydoalkylamino and heterocydoalkylamino, with the
11 12
proviso that Y maybe additionally optionally substituted with X or X ;
11 X is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl.
cydoalkyl-alky,, heterocydyl, heterocydylalkyl. aryl, alkylaryl. arylalky,, heteroaryl,
alkylheteroaryl, or heteroarylalkyl moiety, with the proviso that X11 may be
12
additionally optionally substituted with X ;
12
X is hydroxy, alkoxy, aryloxy, thio, alkylthlo, arylthio, amino, aikylamino, arylamino, alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido. alkoxycarbonyiamino, alkoxycarbonyloxy, alkylureido, arylurekio, halogen, cyano, or nitro, with the proviso that said alkyl. alkoxy, and aryl may be


4.'
2 3 4
R, R', R , R and R 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, sutfur, or phosphorus atoms numbering zero to six); (cycloalkyl)alkyl and (heterocycloalkyl)alkyl. wherein said cydoalkyl 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, hetaroalkenyl, aryl. heteroary. heterocycloalkyi moieties may be optionally substituted, with said term referring to optional and chemically-suitable substitutron with one or more: selected from the group consisting of alkyl, alkenyt, alkynyL ary!, aralkyl heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy. alkylthio, arylthio ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro sulfoxide, sulfone, sulfonylurea, hydrazide, and hydroxamate;

or a pharmaceutically acceptable salt, solvate or ester thereof;
wherein in Formula IV above:
Y is selected from the group consisting of the following moieties: alkyi. alKy\-aryl
heteroalkyi, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl, aikvioxy. coikyl-
aryloxy, aryloxy, heteroaryloxy, heterocycioalkyloxy. cycloalkyloxy, aikyiamino,
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-alkyi, heterocyclvL heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl. or
heteroarylalkyl, with the proviso that X may be additionally optionally substituted
with X12;
X12 is hydroxy, alkoxy, aryloxy. thio. alkylthio, arylthio, amino, aikyiamino, arvlamino.

alkyisuifonyl, arylsutfonyl, alkylsulfonamido, arylsulfonamido, carboxyl. carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbor.yloxy, alkylureido, arylureido. halogen, cyano, or nitro, with the proviso that said alkyl, alkoxy. and aryl may be additionally optionaity substituted with moieties independently selected from X12.,

wherein k is a number from 0 to 5, which can be the same or different, R11 denotes optional substituents, with each of said substituents t>eing independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, cycloalkyl, alky!-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, cycloalkyloxy, alkylamino, aryiamino, alkyl-arylamino,arylamino, heteroarylamino, cycloalkyiamino, heterocycioalkylamino, hydroxy, thio, alkylthio, arylthio, amino, alkyisuifonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido. carboxyl, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy. alkylureido, arylureido, halogen, cyano, and nitro, with the proviso that R11 (when R11= H) maybe optionally substituted with X11 or X12; 2 is selected from O, N, CH or CR;
W may be present or absent, and if W is present, W is selected from C=0, 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 , O, 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 O. CH2. (CHR)p , (CHR-CHR')p . (CRR')p, N(R), S, S(o2) 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 (GRR')p; and when G is absent, J is present and E is directly connected to the

selected from the group consisting of H; Ct-Cio alky!; Ca-C-jo aJkenyl; CS-CB cycloalkyl; C3-C8 heterocycloalkyl, alkoxy, aryloxy, alkylthio, arylthio. amino, amido, ester. cart)oxylic acid, carbamate, urea, ketone, aldehyde, cyano, nrtro, halogen, (cycloatkyl)alkyl and (heterocycloalkyl)alkyl, wherein said cycloaikyl is made of three to eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms, and said alkyi is of one to six carbon atoms; aryl; heteroaryl; alkyS-aryl; and alkyl-heteroaryi;
wherein said alkyl, heteroalkyl, alkenyl, heteroalkenyl. aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally substituted, with said term "substituted" referring to substltution 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, cydoalkyi. heterocydic. halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amino, amido. ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, suttonamido, sulfoade, sulfone, sulfonyl urea, hydrazide, and hydroxamate;
further wherein said unit N-C-G-E-L-J-N represents a five-membered cydic ring structure or six-membered cyclic ring structure with the proviso that when said unit N-C-G-E-L-J-N represents a ffve-membered cydic ring structure, or when the brcydic ring structure in Formula \ comprising N, C, G, E, L, J, N. A, Q, and M represents a ffve-membered cyclic ring structure, then said five-membered cydic ring structure





R12 and R13 are linked together wherein the combination is cycioalkyl, heterocycioalkyl. ary or heteroaryl;
R14 is present or not and if present is selected from the group consisting of: H, alkyl, aryl, heteroalkyl, heteroaryl. cycioalkyl. alky(-aryl, allyl, alkyl-heteroaryl, alkoxy, aryl-alkyl, alkenyl, alkynyl and heteroaralkyi;
(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, C1-C10 alkyl, C2-
C10 alkenyl, C3-C8 cycioalkyl, C3--C8 heterocycioalkyl, alkoxy, aryloxy. alkylthio.
arylthio, alkylamino, arylamino, amino, amido, arylthioamino, aryicarbonylamino,
aryiaminocarboxy, alkyiaminocarboxy, heteroaIkyl', alkenyl, alkynyl, (aryf)alkyl,
heteroarylalkyl, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano,
nitro, halogen, (cycloaIkyl)alkyl, aryl, heten3aryl, {alkyl)aryl, alkylheteroaryl, alkyl-
heteroaryl and (heterocycloalkyl)alkyl, wherein said cycioalkyl is made of three to
eight carbon atoms, and zero to six oxygen, nitrogen, sulfur, or phosphorus atoms,
and said alky! is of one to six carbon atoms;
(6) L' is H. OH, alkyl, heteroalkyi, aryl, heteroaryl. cycloalkyl, or heterocyclyl;
(7) M' is H, alkyl, heteroalkyi, aryl, heteroaryl, cycioalkyl, 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



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 O; 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), (CH2)p. (CHR)p. (CRR')p, (CHR-CHR')p, O, 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(0)o-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{0)o-2R or -NRR' or A is absent;



wherein in Formula 3, Y is selected from the group consisting of: H, aryl, alkyl, alkyi-aryl, heteroalkyl. heteroaryl. aryl-heteroaryl, alkyl-heteroaryl, cycloalkyt, alkyioxy, alkyl-aryioxy, aryloxy, heteroaryloxy, heterocycloalkyloxy, heteroalkyl-heteroaryl, heteroatkyl-heterocycloalkyl, cycloalkyloxy, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino. cycloalkylamino and heterocycloalkylamlno, and Y is unsubstituted or optionally substituted with one or two substituents which are the same or different and are independently selected from X11 or X12 X11 is alkyl, alkenyl, alkynyl. cycloalkyi, cydoalkyl-alkyl, heterocyclyl. heterocyciylalkyl, 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,cycIoaIkylsutfonamido,heteroaryl-
cycloalkylsulfonamido, heteroaryl-sulfonamido, alkoxycarbonylamino,
alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro, and sakl 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, cycloalkyi, cycloalkyl-alkyi, heterocyclyl, heterocydylalkyi, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl, or heteroarylalkyl;
Z is O. N,C(H)orC(R); R31 is H, hydroxyl, aryl, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkylheteroaryl, cycloalkyi, alkyloxy, alkyl-aryloxy. aryloxy, heteroaryloxy.

heterocycioalkyioxy, heteroalkyl-heteroaryl, cycloalkyioxy, alkylamino, arylamino,
aikyl-arylamino, arylamino, heteroarylamino, cycloalkylamino or
heterocycloalkyiamino, and R31 is unsubstituted or optionally substituted with one or two substituents which are the same or different and are Independently selected from X13 or X14;
X13 is alkyl, alkenyl, alkynyl, cycloalkyi, cydoalkyl-alkyl, heterocyclyl, heterocyclylalkyi, aryl. alkylaryl, arylalkyi, heteroaryl, alkylheteroaryl, or
13
heteroarylalkyl, and X 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, aryiamino, alkylsulfonyl, arylsulfonyi. alkylsulfonamido.
arylsulfonamido, carboxy, carbalkoxy, carboxamido. alkylcarbonyl, arylcarbonyl,
heteroalkylcarbonyl, heteroaryicarbonyl, cycloalkylsulfonamido, heteroaryl-
cycloalkylsulfonamido, heteroarylsulfonamido, alkoxycart>onylamino,
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 alkyi, alkenyl, alkyny[, cycioalkyl, cycioalkyl-aikyl, heterocydyl, heterocydylalkyl, aryl. alkylaryl, arylalkyi, heteroaryl, alkylheteroaryl, or heteroarylalkyl;
W may be present or absent, and If W is present, W is C(=0), C(==S), C(=N-


from the group consisting of: H. halo, alkyl, aryl, cycioalkyl, cycloatkylamino, cycloalkyiaminocarbonyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(a!kyl), -NH(cycloalkyl), -N(alky!)2, carboxyl, C(0)0-a!kyl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, alkylhetsroary!, heteroaralkenyl, hydroxyalkyl, aryloxy, aralkoxy, acyl, aroyi, n'rtro, aryyoxycarbonyl, aralkoxycarbonyl. alkyisulfonyl, arylsulfonyl, heteroarylsulfonyl. alkylsulfinyl, arylsulfinyl, heteroarylsuffinyl, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocydyl, heterocyclenyl. YiY2N-alkyl-, Y-tY2NC(0}- and Y1Y2NSO2-, wherein Yi 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 heteroaiiphatic 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 cylcoalkyi; (10) D is represented by structural 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, cycioalkyl, cycloalkylamino, spiroalkyi, cycloalkylaminocarbonyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalky!), -N(alkyl)2, carboxyl, -C(0)0-alkyl, heteroaryl, aralkyl, alkylaryl, aralkenyl, heteroaralkyl, aikylheteroaryl, heteroaralkenyl, hydroxyalkyl, aryloxy. aralkoxy, acyl, aroyl, nitro, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocydyl, heterocyclenyl, YiY2N-alkyl-, YiY2NC{0)- and Y1Y2NSO2-, wherein Yi and Y2 can be the same or different and are independently selected from the group consisting of





or a pharmaceutically acceptable salt, solvate or ester of said compound, wherein in Formula Vi above:
Cap and P' are independently H, alkyl, alkyl-aryl, heteroalkyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, oycloalkyl. alkyloxy, alkyl-aryloxy, aryioxy, heteroaryioxy, heterocyclyioxy, cycloalkyioxy, amino, alkylamino. aryiamino, alkyl-arylamino, arylamino. heteroarylamino, cydoalkylamino, carboxyalkylamino, arlylalkyloxy or heterocyclylamino, wherein each of said alkyl, alkyl-aryl, heteroalkyi, heteroaryl, aryl-heteroaryl, alkyf-heteroaryl, cycioalkyl, alkyloxy, alkyl-aryioxy, aryioxy, heteroarytoxy, heterocyclyloxy, cycloalkyioxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino, heteroarylamino, cydoalkylamino, carboxyalkylamino, arlyalky)oxy 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 X1 and X2;
X1 is aikyi. alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyc(yl, heterocycfylalkyl, aryl, alkylary!, arylalkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, or heteroarylalkyl, and X 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, aryioxy. thio, alkylthio, arylthio, amino, alkylamino. arylamino. alkylsulfonyl, arylsutfonyl, alkylsulfonamido, arylsulfonamido, 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


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 rf 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(02), N(H). N(R) or O; 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 O, 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, C1-C10 alkyl, C2-C10 alkenyl, C3-C8 cydoalkyl, C3-C8

heterocyclyl, alkoxy', aryloxy, alkylthio, arylthio, amino, amido, arylthioamino, arylcarbonylamino, aryiaminocarboxy, alkylaminocarboxy, heteroalkyl, heteroalkenyl, alkenyl, alkynyl, aryl-alkyi, heteroaryialkyl, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano, nitro, halogen, (cycloalky!)aIkyl, aryl, heteroaryl, alkyl-aryl, alkylheteroaryl, alkyl-heteroary! and (heterocyclyl)a!kyl;
R and R' in (CRR') can be linked together such that the combination fomns a cycloalkyi or heterocyciyl moiety; and

selected from the group consisting of hydrogen, alkyl. alkenyl, alkynyl, heteroalky,, cycloalkyi. cycloalkylalky,, aryl, arylalkyi, heteroaryl, heteroaryialkyi, heterocyciyl, 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 form part of a cyclic 5- to 7- membered ring such that the moiety R"^ R^ is
where Y is O, S or NH, and Z is CH or N, and the R8 moieties can be the same or different, each R8 being independently selected from the group consisting of

hydrogen, alkyl, heteroalkyl, cycloalkyi, aryl. heteroar^^l, heterocydyl, hydroxyl, amino, arylamino, alkylamino, dialkylamino. halo, alkyithio, aryithio and alkytoxy;
a
where R6 and R7 can be the same or different, each being independently selected from the group consisting of hydrogen, alkyl, alkeny!, alkynyl, heteroalkyl, cycloalkyi, cydoalkylalkyl, aryl, arylalkyl. heteroaryl, heteroarylalkyl, heterocycyl, heterocyclylalkyi, hydroxyl, amino, arylamino and alkylamino; P1 is selected from the group consisting of alkyl. alkenyl, alkynyl, cycloalkyi haloalkyi; P3 is selected from the group consisting of alkyl, cydoalkyl. aryl and cydoalkyl fused



where Y Is O, S or NH, and Z is CH or N, and the R8 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;


Formula IX or a pharmaceutically acceptable salt, solvate or ester thereof, wherein in Formula IX

where R6 and R7 can be the same or different, each being independently selected from the group consisting of hydrogen, alkyl, alkenyl. alkynyl, heteroalkyl, cydoalky,, cycloalkyialkyl, aryl, arylalkyi, heteroaryl, heteroarylalkl, heterocyclyl, heterocyclylalky,, 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 cydoalkyi; or alternatively R4 and R5 together



where Y is O, S or NH, and Z is CH or N, and the R8 moieties can be the same or different, each R8 being independently selected from the group consisting of hydrogen, alkyl, heteroaikyl, cycloallkyl. aryl. heteroaryl. heterocyclyl, hydroxy!, amino, arylamino. alkylamino, dialkylamino, halo, alkylthio, arylthio and alkyloxy;


or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein in Formula X above:
R1 is H, 0R8 NR9R10 or CHR9R10 wherein R8 R9 and R10 can be the same or
different, each being independently selected from the group consisting of H, alkyt-,
alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroary!-, cycioalkyi-, heterocyclyl-, arylalkyl-,
and heteroaryialkyl;
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:
shown above in Formula I forms either a three, four, six. seven or eight-membered
cycioalkyi, 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-, cycioalkyi-, heteroalkyl-
, heterocyclyl", aryl-, heteroaryl-, (cycloalkyl)alkyl-. (heterocydyl)alkyl-, aryl-alkyi-, and

heteroaryl-alkyi-; or alternately R and R' in NRR' are connected to each other such that NRR' forms a four to eight-membered heterocyclyl;

wherein G is NH or O; 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, heterocyclyl, aryl arylalkyl, heteroaryl, and heteroarylalkyl, or alternately, R15 and R16 are connected to each other to form a four to eight-membered cycloalkyl, heteroaryl or heterocyclyl structure, and likewise, independently R17' and R18 are connected to each other to form a three to eight-membered cycloalkyi or heterocyclyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyi 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, sulfonamide, alkyl. aryl, heteroaryl. alkylsulfonamido, arylsutfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamlno, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro;


or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula X!
above:
R1 is H, 0R8 NR9R10, or CHR9R10 wherein R8 R9 and R10 can be the same or
different, each being independently selected from the group consisting of H, alyl-,
alkeny!-, alkynyl-, aryl-, heteroalky!-, heteroaryl-, cycloalkyl-, heterocydyk, 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;
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-, heteroalkyi-
,heterocyclyI-, aryl-. heteroaryl-, {cydoaIkyi)alkyl-, (heterocyclyl)alky!-, aryl-alkyl-, and

heteroaryl-atkyl-; 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:
independently selected from the group consisting of H, alkyl, heteroaikyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, or alternately, R17 and R18 are connected to each other to fomri a three to eight-membered cycloalkyl or heterocyclyl; wherern each of said alkyl, aryl, heteroaryl, cycloalkyi or heterocyclyl can be unsubstltuted or optionally independently substituted with one or more moieties selected from the group consisting of. hydroxy, alkoxy, aryloxy, thio. alkylthio, arytthio, amino, amido, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfbnamido, alkyl, aryl, heteroaryl, alkylsutfonamido, aryisulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro;


or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula
XII above:
R1 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-, alkynyi-, aryl-, heteroalkyl-, heteroaryl-, cycioalkyl-, heterocydyl-, aryialky!-,
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:

shown above in Formula 1 forms either a three, four, six, seven or eight-membered
cycloalkyl. a four to eight-membered heterocydyl. a sbc 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-, cydoalkyl-. heteroalkyl-
,heterocydyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocydyl)alkyl-, aryl-alkyi-. and

heteraaryi-alkyl-; or a lternateiy R and R' in WRR are connected to each other such that NRR' forms a four to eight-membered heterocyciyl; and Y is selected from the following moieties:

wherein G is NH or O; 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, cydoalkyl, heterocyciyl, aryl, arylalkyi, 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 cydoalkyl or heterocyciyl;
wherein each of said alkyl, aryl, heteroaryl, cydoalkyl or heterocydyi 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, alkylamlno, arylamino. alkylsulfonyl, arylsulfonyl, sulfonamido. alkylsulfonamido, arylsulfonamido, alkyl, aryl, heteroaryl, keto, cart>oxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro;


or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formila
XIII above:
R1 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-,
aJkenyi-, alkyny!-, aryl-, heteroalky!-, heteroaryl-, cycioalkyl-, heterocyciyl-, aryialkyl-,
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.
shown above in Formula I forms either a three, four, six, seven or eight-membered
cycioalkyi, a four to eight-membered heterocyclyl, a six to ten-n>embered aryl. or a
five to ten-membered heteroaryl;
E is C(H)orC(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-, cycioalkyi-, 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;

membered cycloalkyi or heterocyclyl,
wherein each of said alkyl. aryl, heteroaryl. cycioalkyl or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkytthio, arylthio, amino, amido, alkylamino, arylamlno, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyisulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy. carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, aryureido, halo, cyano, and nitro;


or a pharmaceuticaliy acceptable salt, solvate or ester thereof; wherein in Formula
XIV above:
R1 is H, 0R8 NR9R10, or CHR9, R10 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-, cycioalkyl-, heterocyclyl-, arylalkyl-,
and heteroarylalkyt;
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:


heteroaryl, or alternately, (i) R"*^ and R**^ are connected to each other to fomr) 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, cycloalkyi or heterocyclyl can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkytthio, arylthio, amino, amido. alkylamino. arylamino. alkyisulfonyl, arylsulfonyl, sulfonamide, alkylsulfbnamido. arylsulfonamido, alkyl, aryl. heteroaryl, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro;
o. Formula XV

or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula
XV above:
R1 is H, 0R8 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-,
aryi-, heteroalkyl-, heteroaryl-, cycioalkyl-, cydoalkyl-, arylalkyl-, and heteroaryialkyl;
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 cydoalkyl,
or a three to eight-membered heterocyclyl moiety;
Z is N(H). N(R), or O, with the proviso that when Z is O, G is present or absent and if
G is present with Z being O, then G is C(=0);
G maybe present or absent, and if G is present, G is C(=0) or 8(02), and when G is
absent, Z is directly connected to Y;
Y is selected from the group consisting of:




R, R1, R2, R3, R4 and R5 can be the same or different, each being independently selected from the group consisting of H, alkyl-, alkeny!-, aikynyl-, cycloalkyi-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (Gyc!oalkyi)a!ky!-, (heterocycty!)alkyl-, aryl-alky!-, and heteroaryl-alkyK wherein each of said heteroalkyi, heteroaryl and heterocyclyl independently has one to six oxygen, nitrogen, sulfur, or phosphorus atoms;
wherein each of said alkyl, heteroalkyi, alkenyl, aikynyl, aryl, heteroaryl, cydoalkyl and heterocyclyl moieties can be unsubstituted or optionally independently substituted with one or more moieties selected from the group consisting of alkyl. alkenyl, aikynyl, aryl, aralkyl. cycloalkyl, heterocyclyl, halo, hydroxy, thio, alkoxy, aryloxy. alkylthio, aryithio, amino, amido, ester, carboxylic acid, carbamate, urea, ketone, aldehyde, cyano. nrtro, sulfonamido, sulfoxide, sulfone, sulfonyl urea, hydrazide, and hydroxamate;


alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloaiky!-, heterocydyl-. arylalkyL-, and heteroarylalkyL, or alternately R9and R10 in NR9R10 are connected to each other such that NR9R10 forms a four to eight-membered heterocyclyl, and likewise independently alternately R9 and R10 in CHR9R10 are connected to each other such that CHR9R10 forms a four to eight-membered cycloatkyi;
R2 and R3 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyi. alkenyl, heteroalke'iyi, alkynyl. heteroalkynyl, cycloaiky!. heterocyclyl, aryl, aryialkyi, heteroaryl, and heteroarylalkyi;


wherein G is NH or O; and R15 R16 R17 R18 R19 R20 R21 R22, R23, R24 and R25 can be the same or differeni, each being independently selected from the group consisting of H, alkyi, heteroaikyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl. heteroaryl, and heteroarylalkyi, 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; (iv) likewise independently R15 and R2 are connected to each other to form a four to eight-membered heterocyclyl; (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 heterocydyl; 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 heterocydyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl or heterocydyl 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, alkyisulfonyl, arylsulfonyl, sulfonamido, alkyi, aryl, heteroaryl, alkylsulfonamido, arylsulfonamido, keto, carboxy, carbalkoxy. carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido. arylureido, halo, cyano, and nitro;


Formula XVII or a pharmaceuticaliy acceptable salt, solvate or ester thereof; wherein in Formula XVII above;
R1 is H, 0R8 NR9R10. or CHR9R10. wherein R8 R9 and R10 can be the same or different each being independently selected from the group consisting of H, alkyi-, alkenyl-, alkynyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl-, and heteroarylalkyi;
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:

shown above in Formula I forms either a three, four, six. seven or eight-membered cycloalkyl, a four to eight-membered heterocydyl, a six to ten-membered aryl, or a five to ten-membered heteroaryl; E is C(H) or C(R);



independently selected from the group consisting of H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocydyl. 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, arylthlo. amino, amido, alkylamino. arylamino, alkylsulfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl. alkylsulfonamldo, arylsulfonamido, keto, cart)oxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano, and nitro;


or a pharmaceutically acceptable salt, solvate or ester thereof, wherein in Formula
XVIII above:
R8 is selected from the group consisting of alkyl-, aryl-, heteroalkyl-, heteroar>i-,
cycloalkyl-, heterocyclyl-, arylalkyi-, heteroarylalkyl-, and heterocyclylalkyl;
R9 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl and
cycloalkyl;
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:

shown above in Formula I forms either a three, four. five, sbc, seven or eight-membered cycloalkyi. 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-, cycloalkyi-, heteroalkyl-, heterocyclyl-. aryl-, heteroaryl-, (cyc!oalkyl)alkyl-, (heterocyclyl)alkyl- aryl-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 heterocyclyl;
r
R2 and R3 can be the same or different, each being independently selected from the group consisting of H, alkyl, heteroalkyi, alkenyl, heteroalkenyl, alkynyi, heteroalkynyl, cycloalkyl. spiro-linked cycloalkyl, heterocyclyl, aryl. arylalkyi, heteroaryl, and heteroarylalkyl;


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 fomn a four to eight-membered heterocydyl; (iii) likewise independently R15 and R16 are connected to each other to form a four to eight-membered heterocydyl; and (iv) likewise independently R15 and R20 are connected to each other to form a four to eight-membered heterocydyl;
wherein each of said alkyl, aryl, heteroaryl, cycloalkyl. spiro-linked cydoalkyl. and heterocydyl 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. arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamlno. alkoxycarbonyloxy. alkylureido, arylureido, halo, cyano, and nitro;

Formula XIX wherein in Formula XIX above: Z is selected from the group consisting of a heterocydyl moiety,
N(H)(aIky!), -N(alkyl)2, -N(H)(cydoalkyl), "N(cydoalkyl)2, -N(H){aryl. -N(aryl)2. -N(H)(heterocydyl), -N(heterocydyl)2, "N(H)(heteroaryl), and -N(heteroaryl)2;
R1 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-, heteroalkyi-, heteroaryl-, cycloalkyl-, heterocydyl-, arylalkyi-,

and heteroaryiaikyl, or alternately R9 and R10 in NR9R10 are connected to each other such that NR9R10 forms a four to eight-membered heterocyclyl, and likewise independently alternately R9 and R10 in CHR9R10 are connected to each other such that CHR9R10 forms a four to eight-membered cycloalkyt;
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 heteroaryiaikyi;


heteroalkyl, aikenyl, heteroalkenyl, aikynyl, heteroalkynyl, cycloalkyl. heterocyciyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyi, or alternately (i) R'17 and R18 are independently connected to each other to form a three to eight-membered cycloafkyi or heterocyclyl; (ii) likewise independently R15 and R19 are connected to each other to form a four to eight-membered heterocyclyi; (iii) likewise independently R15 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 heterocyciyi;
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, alkylsujfonyl, arylsulfonyl, sulfonamido, alkyl, aryl, heteroaryl, aikylsulfonamido. arylsulfonamido, keto, carboxy, carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido. arylureido, halo, cyano, and nitro;


alkoxv;
(ii) C3-7 cycloalkyl optionally substituted with carboxyl, (C1-6 alkoxy)carbonyl or phenylmethoxycarbonyl;
(iii) C6 or C10 aryl or C7.16 aralky! 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 C1-6 alkyl. or amido optionally substituted with C1-6 alkyl; Re, when present, is C1-6 alkyl substituted with carboxyl; R5, when present, is C1-6 alkyl optionally substituted witii carboxyl; R4 is C1-10 alkyl, C3-7 cycloalkyi or C4-10 (alkylcycloalkyl); R3 is C1-10 alkyl, C3-7 cycloalkyi or C4-10 (alkylcycloalkyl);
R2 is CH2-R20. NH-R20. O-R20 or S-R20, wherein R20 is a saturated or unsaturated C3-7 cycloalkyi or C4.10 (alkyl cycloalkyl) being optionally mono-, di- or tri-substituted with R21. or R20 is a Ce or C10 aryl or C7.16 aralkyi 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 C1-6 alky!; C1-6alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sutfonyl; NO2; OH; SH; halo; haloalkyl; amido optionally mono-substituted with C1-6 alkyl. C6 or C10 aryl, C7.16 aralkyi, Het or (lower alkyI)-Het; carboxyl; carboxy(lower alkyl); Ce or C10 aryl, C7-16 aralkyi or Het, said aryl, aralkyi or Het being optionally substituted with R22;
wherein R22 is C1-6alkyl; 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;
R1 is C1-6 alkyl or C2-6 alkenyl optionally substituted with halogen; and W is hydroxy or a N-substituted amino;
u. Fonmula XXI:


or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula
XXI above:
B is H, a C6 or C10 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; ammo optionally substituted with C1-6 alkyl; amido;
or (lower alkyl)amide;
or B is an acyl derivative of formula R4-C(0)-; a carixjxyl of formula R4-0-C(O)-; an
amide of formula R4-N(R5>-C(Oy, a thioamide of fonmula R4-N(R5>C(S)-; or a
sulfonyl of formula R4-SO2 wherein
R4 is (i) C1-6 alkyl optionally substituted with carboxyl, C1-6 alkanoyl, hydroxy, C1-6 alkoxy, amino optionally mono- or di-substituted with C1-6 alkyl, amido, or (lower alkyi) amide;
(ii) C3-7 cycloalky!, 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 alky!) amide;
(ill) amino optionally mono- or di-substituted with C1-6 alkyl; amido; or (lower a!kyl)amide;
(iv) C6 or C10 aryl or C7.16 aralkyl, all optionally substituted with C1-6 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-substrtuted with C1-6 alkyl;
R5 is H or C1-6 alkyl;
with the proviso that when R4 is an amide or a thioamide, R4 Is not (Ii) a cydoalkoxy; Y is H or C1-6 alkyl;


wherein each R21 is independently C1-6 alkyl; C1.6 alkoxy; lower thioalkyl; sulfonyl; NO2; OH; SH; halo; haioaikyl; amino optionally mono- or di- substituted with C1-6 alkyl, C6 or C10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het; amido optionally mono-substituted with C1-6 alkyl, C6 or C-10 aryl, C7-14 aralkyl, Het or (lower alkyl)-Het; carboxyl; carboxy(lower alkyl); C6 or C10 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; C1-6 alkoxy; amino optionally mono- or di-substituted with C1-6 alkyl; sulfonyl; (lower aIkyl)sulfonyl; NO2; OH; SH; halo; haioaikyl; carboxyl; amide; (lower alky[)amide; or Het optionally substituted with C1-5 alkyl;
R1 is H; C1-6 alkyl, C3-7 cycloalkyl, C2-6 alkenyl, or C2-6 alkynyl, all optionally substituted with halogen;


or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula
XXII above:
W is CH or N,
R-21 is H, haio, C1-6 alky!. C3-5 cycloalkyl, C1-5 haloalkyl. C1-6 alkoxy, C3-6 cycloalkoxy,
hydroxy, or N(R23)2 . wherein each R23 is independently H, C1-6 alkyl or C3-6
cydoalkyl;
R22 is H, halo. C1-6 alkyl, C3-6 cydoalkyl. C1-6 haloalkyl, C1-6 thioalkyl, C1-6 alkoxy, C3-6
cycloalkoxy. C2-7 alkoxyalkyl, C3-6 cydoalkyl, C6 or 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 cydoalkyl. aryl or Het being substituted with R24, wherein R24 is H, halo. C1-6
alkyl, C3-6 cydoalkyl, C1-6 alkoxy. C3-6 cydoalkoxy. NO2 , N(R^^}2 , NH-C(0)-R25 or
NH-C{0)-NH-R25, wherein each R25 is independently; H, C1-6 alkyl or C3-6 cydoalkyl;
or R24 is NH-C(0)-0R26 wherein R26 is C1-6 alkyl or C3-6 cydoalkyl;
R3 is hydroxy, NH2 , or a group of formula -NH-R31 , wherein R31 Is C6 or 10 aryl,
heteroaryl, -C(0)-R32 -C(0)-NHR32 or -C(0)-OR32 , wherein R32 is C1-6 alkyl or C3-6
cydoalkyl;
D is a 5 to 10-atom saturated or unsaturated alkyiene chain optionally containing one
to three heteroatoms independently selected from: O, S, or N-R41, wherein
R41 is H. C1-6 alkyl. C3-6cydoalkyl or -C(0)-R42, wherein R42 is C1-6 alkyl, C3-6 cydoalkyl or C6 or 10 aryl;
R4 is H or from one to three substituents at any carbon atom of said chain D, said substrtuent independently selected from the group consisting of: C1_6 alkyl. C1-6 haloalkyl, C1-6 alkoxy, hydroxy, halo, amino, 0x0, thio and C 1-6 thioalkyl, and A is an amide of fonnula -C(0}-NH-R 5 . wherein R 5 is selected from the group consisting of: C1-8 alkyl, C3-6 cydoalkyl, C6 or aryl and C7-16 aralkyl; or A is a carboxylic acid;


Formula XXII!
a pharmaceuticaliy acceptable salt, solvate or ester thereof; wherein in Formula XXIII
above:
R° is a bond or difluoromethylene;
R1 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-) heterocyclylene; 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; on
R4, R 6, R8 and R10 are each independently hydrogen or optionally substituted
aliphatic group;
substituted monocyclic azaheterocyclyl or optionally substituted multlcyclic azaheterocyclyl, or optionally substituted multicyclic azaheterocyclenyl wherein the unsaturatation is in the ring distal to the ring bearing the R9L-(N(R8)-R7-C(0)-)nN(R6)-R5-C(0)-N moiety and to which the -C(0)-N(R4)-R3-C(0)C{0)NR2R1 moiety is attached; L is -C(O) -0C(0)-, -NR10C(0)-. -S{0)2-. or - NR10S(0)2-; and n is 0 or 1, provided


group and wherein the ethyiene is further optionally substituted with an aliphatic group substituent; or R4 is optionally substituted aliphatic;

each R1 is hydroxy, alkoxy, or aryloxy, or each R1 is an oxygen atonn and together with the boron, to which they are each bound, form a 5-7 mennbered ring, wherein the ring atoms are carbon, nitrogen, or oxygen;
each R2 is independently hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyi, cycloalkenyl, cycloalkenylalkyl. heterocyclyl. heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroaralkyi, 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 R2 carbon atom is optionally substituted with J;
J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyi, cycloalkoxy, heterocyclyl, heterocydyloxy, heterocyclylalkyi, keto. hydroxy, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carboxyalkyl, carboxamidoalkyl, halo, cyano, nitro, formyl, acyl, sulfonyl, or sulfbnamido and is optionally substituted with 1-3 J1 groups;

J1 is alkyl, aryl. araikyl, aikoxy, aryloxy, heterocyciyl, heterocyclyloxy, keto, hydroxy, amino, alkanoylamino, aroylamino, carboxy, carboxyalkyl, carboxamidoaikyl, halo, cyano, nitro, formyi, suifonyl, 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;
A1 is a bond;
R4 is alkyl, cycloalky1, aryl, aralkyi, heterocyciyi, heterocyclylalkyl. heteroaryl. heteroaralkyl, carboxyalkyi, or carboxamidoaikyi, and is optionally substituted with 1-3 J groups;
R5 and R6 are independently hydrogen, alkyl, alkenyl, aryl. aralkyi, aralkenyl. cycioalkyl, cycioalkylalkyl. cycloalkenyl, heterocyciyi, heterocyclyalkyl, 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, aralkyi, heterocyciyi, heterocyclylalkyl. heteroaryl, or heteroaralkyl, and is optionally substititued with 1-3 J groups;
R8 is hydrogen alkyl, aryl, aralkyi,' heterocyciyi, heterocyclylalkyl, heteroaryl, heteroaralkyl, aralkanoyl, heterocyclanoyi, heteroaralkanoyl. -C(0)R14, -S02R14, or carboxamido, and is optionally substititued with 1-3 J groups; or R8 and Z, together with the atorns to which they are bound, form a nitrogen containing mono- or bicyclic ring system optionally substituted with 1-3 J groups;


R9 is alkyl. cycloalkyl, aryl, aralkyi, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaraikyl, carboxyalkyl, or carboxamidoalkyi, and is optionally substituted with 1-3 J groups;
M is alkyl, cycloalkyl, aryl, aralkyl, iieterocyclyl, heterocydylalky!, heteroaryl, or heteroaralkyi, optionally substituted by 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom;

heterocycioalkyiidenyl, 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;
R10 is alkyl. cycloalkyl, aryl, aralkyl, heterocycly1, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyi, or carboxamidoalky1, and is optionally substituted with 1-3 hydrogens J groups;
R15 is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, carboxyalkyi, or carboxamidoalkyi, and is optionally substituted with 1-3 J groups; and
R16 is hydrogen, alkyl, aryl, heteroaryl, cycloalkiy, or heterocydyl;


wherein [n Formula XVII above:
E represents CHO or B(OH)Z;
R1 represents lower alkyl, haio-lower alkyl. cyano-lower alkyl, lower alkylthio-iower alky!, aryl-lower alkylthio-lower alkyl. aryl-lower alkyl, heteroaryllower alkyl, lower aikenyl or lower atkynyl;
R2 represents lower alkyl, hydroxy-lower alkyl, carboxylower aikyl. aryl- lower alkyi, aminocarbonyl-lower alkyl or lower cycloalkyl-lower alkyl; and
R3 represents hydrogen or lower alkyl;
or R2 and R3 together represent di- or trimettiylene optionally substituted by hydroxy;
R4 represents lower alkyl, hydroxy-lower alkyl, lower cycloalkyl-iower alkyl, carboxy-lower alkyl, aryllower alkyl. lower alkylthio-lower alkyl. cyano-lower alkylthio-lower alkyl, aryl-lower alkylthio-lower alkyl, lower aikenyl, aryl or lower cydoaikyi;
R^ represents lower alkyl, hydroxy-lower alkyl, lower alkylrhio-lower alkyl, aryllower alkyl. aryl-lower alkylthio-lower alkyl, cyano-lower alkylthio-lower alkyl or lower cydoaikyi;
R6 represents hydrogen or lower alkyl;
R7 represent lower alkyl, hydroxydower alkyl, carboxylower alkyl, aryl-iower alkyl, lower cycloalkyi-lower alkyl or lower cydoaikyi;
R8 represents lower alkyl, hydroxy-lower alkyl, carboxylower alkyl or aryl-lower alkyl; and
R9 represents lower alkylcarbonyl, carboxy-lower alkylcarbonyl, arylcarbonyl, lower alkylsulphonyl. arylsulphonyl, lower alkoxycarbonyl or aryl-lower alkoxycarbonyl; and


XXVI above
B is an acyl derivative of formula R11-C(0)- wherein R11 is Cl-10 alkyl optionally substituted with carboxyi; or R11 is C6 or C1o aryl or C7-16 aralkyi optionally substituted with a C-1-6alkyl;
a is 0 or 1;
R6, when present, is carboxy(lower)alkyl;
b is 0 or 1;
R5, when present, is C1-6 alkyl. or carboxy(lower)alkyl;
Y is H or C1-6 alkyI;
R4 is C1-6 alkyl; C3.10 cycloalkyl;
R3 is Cl-10 alkyl; C3.10 cycloalkyi;
W is a group of formula:

cyclic C3-16 alkyl or acyclic Cvi6 alkyl or cyclic C3.16 alkenyl or acyclic C2.16 alkenyl, said alkyl or alkenyl optionally substituted with NH2, OH, SH, halo, or carboxyi; said alkyl or alkenyl optionally containing at least one heteroatom selected independently fronn the group consisting of: 0, S, and N; or
R12 and R12 are independently Cg or Cio aryl or C7-16 aralkyi optionally substituted with C1.6 alkyl, NH2, OH. SH, halo, carboxyi or carboxy(lower)alkyl; said aryl or aralkyi optionally containing at least one hetenDatom selected independently from the group consisting of: 0, S. and N;

said cyclic alky!, cyclic alkenyi, aryl or aratky! being optionaliy fused with a second 5-, 6-, or 7-rnembered ring to form a cyclic system or heterocycle. said second ring being optionaliy substituted with NH2. OH, SH. halo, carboxyl or carboxy(lower)alkyl; C6 or C10 aryl, or heterocyde; said second ring optionally containing at least one heteroatom selected independently from the group consisting of: 0, S. and N;

X is 0 or S;
R1 is H, C1-6 alkyi 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)-Ri4; CF2-R14; NR14R14'; S-R14; or CO-NH-R14 wherein R-14 and R14' are independently hydrogen, cyclic C3_1o alkyi or acyclic C1.10 alkyl or cyclic C3.10 alkenyl or acyclic C2-10 alkenyl, said alky! or alkenyl optionaliy 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 airalkyi optionaliy substituted with C1-6 alkyl. NH2. OH, SH, halo, carboxyl or carboxy(lower)a!kyl or substituted with a further C3.7 cydoalkyl, C6 or C10 aryl, or heterocyde; said aryl or aralkyi optionally containing at least one heteroatom selected independently from the group consisting of: 0, S, and N;
said cyclic alkyl, cyclic alkenyl, aryl or aralkyi being optionally fused with a second 5-, 6-, or 7-membered ring to form a cyclic system or heterocyde, said second ring being optionally substituted with NH2, OH, SH, halo, carboxyl or carboxy(lower)alkyl or substituted with a further C3.7 cydoalkyl, C6 or C10 aryl, or hetenocycle; 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 ary1 or heterocycle;
with the proviso that when Z is CH, then R13 is not an α-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:






or a pharmaceuticaliy acceptable salt, solvate or ester thereof.
3. The pharmaceutical formulation of claim 1 wherein said at least one
compound is selected from the group consisting of:


and pharmaceutically acceptable salts or solvates thereof.
5. The pharmaceutical formulation of claim 1 wherein said at least one
surfactant is selected from the group consisting of sodium lauryl sulfate, stearic acid,
monoethanolamine, docusate sodium, poloxamer, tecithin, sorbltan fatty acid esters,
polyoxyethylene sorbltan fatty acid esters, ethoxylated aliphatic alcohols, propylene
glycol monocaprylate. glycerol monostearate, medium chain triglycerides,
polyoxyethylene alkyl ethers, and polyoxyethylene stearates.
6. The pharmaceutical formulation of claim 5 wherein said at least one
surfactant comprises sodium lauryl sulfate.
7. The pharmaceutical formulation of claim 5 wherein said at least one
surfactant comprises polyoxyethylene sorbitan fatty acid esters.

8.. Ths pharmaceutica! formulation of claim 5 wherein said at least one surfactant comprises PEG-1-PEG-9-lauryl glycol ether.
The pharmaceutical formulation of claims 1 further comprising at least one pharmaceuticaliy acceptable excipient.
The pharmaceutical formulation of claim 9 wherein said at least one pharmaceuticaliy acceptable excipient is selected from the group consisting of a binder, a glident, a lubricant, a diluent, and a disintegrant
The pharmaceutical formulation of claim 1 wherein said formulation is in the form of a capsule, a tablet, a gel, a suppository, a powder, or a fluid.
The pharmaceutical formulation of claim 11 wherein said formulation is in capsule form.
The pharmaceutical formulation of claim 1 wherein said at least one surfactant is present in an amount of about 0.1 to about 10% by weight.
The pharmaceutical formulation of claim 1 wherein said at least one surfectant is present in an amount of about 1 to about 5% by weight
15- The pharmaceutical formulation of claim 1 wherein said at least one compound is present in an amount of about 50 to about 1000 mg.
16. The phamiaceutical formulation of claim 1 wherein said at least one
compound is present in an amount of about 200 to about 800 mg.
17, A unrt dosage form of a phamiaceutical formulation of any one of
claims 1-10,13,14,15 and 16, wherein said compound is present in an amount of
about 50 to about 1000 mg.

18. The unit dosage form of claim 16 wherein said at least one compound
is present in an amount of about 50 to about 800 mg.
19. The unit dosage form of claim 17 wherein said at least one compound
is present in an amount of about 50 to about 600 mg,
20. The unit dosage form of claim 17 wherein said at least one compound
is present in an amount of about 50 to about 400 mg.
21. The unit dosage form of claim 17 wherein said at least one compound
is present in an amount of about 50 to about 200 mg.
The unit dosage form of daim 17 wherein said form is a capsule, a tablet, a geU a suppository, a powder, or a fluid.
The unit dosage form of daim 17 wherein said form is a capsule.
24. A method of treating HCV infection comprising administering an
effective amount of the pharmceutical formulation of any of daims 1-3 to a subject in
need of such treatment.
25. A method of treating a capthesin-associated disorder comprising
administering an effective amount of the pharmceutical formulation of any of daims
1-3 to a subject in need of such treatment
Dated this 3 day of December 2007


Documents:

5546-CHENP-2007 CORRESPONDENCE OTHERS 13-05-2011.pdf

5546-CHENP-2007 AMENDED PAGES OF SPECIFICATION 30-01-2012.pdf

5546-CHENP-2007 AMENDED PAGES OF SPECIFICATION 1 30-01-2012.pdf

5546-CHENP-2007 AMENDED PAGES OF SPECIFICATION 2 30-01-2012.pdf

5546-CHENP-2007 AMENDED PAGES OF SPECIFICATION 3 30-01-2012.pdf

5546-CHENP-2007 AMENDED CLAIMS 12-03-2012.pdf

5546-CHENP-2007 AMENDED CLAIMS 30-01-2012.pdf

5546-CHENP-2007 FORM-3 30-01-2012.pdf

5546-CHENP-2007 OTHER PATENT DOCUMENT 30-01-2012.pdf

5546-CHENP-2007 POWER OF ATTORNEY 30-01-2012.pdf

5546-CHENP-2007 CORRESPONDENCE OTHERS 06-03-2012.pdf

5546-CHENP-2007 CORRESPONDENCE OTHERS 12-03-2012.pdf

5546-CHENP-2007 CORRESPONDENCE OTHERS 04-04-2012.pdf

5546-CHENP-2007 CORRESPONDENCE OTHERS 30-03-2012.pdf

5546-CHENP-2007 EXAMINATION REPORT REPLY RECEIVED 30-01-2012.pdf

5546-chenp-2007-abstract.pdf

5546-chenp-2007-assignement.pdf

5546-chenp-2007-claims.pdf

5546-chenp-2007-correspondnece-others.pdf

5546-chenp-2007-description(complete) 1.pdf

5546-chenp-2007-description(complete) 2.pdf

5546-chenp-2007-form 1.pdf

5546-chenp-2007-form 18.pdf

5546-chenp-2007-form 26.pdf

5546-chenp-2007-form 3.pdf

5546-chenp-2007-form 5.pdf

5546-chenp-2007-pct.pdf


Patent Number 254362
Indian Patent Application Number 5546/CHENP/2007
PG Journal Number 44/2012
Publication Date 02-Nov-2012
Grant Date 29-Oct-2012
Date of Filing 03-Dec-2007
Name of Patentee SCHERING CORPORATION
Applicant Address PATENT DEPARTMENT K-6-1 1990, 2000 GALLOPING HILL ROAD, KENILWORTH, NEW JERSEY 07033-0530, USA
Inventors:
# Inventor's Name Inventor's Address
1 MALCOLM, BRUCE, A 344 POLI WOODS, PAOLI, PA 19301, USA
2 BRADLEY, PRUDENCE, K 375 LINCOLN AVENUE EAST, CRANFORD, NEW JERSEY 07016, USA
3 PAVLOVSKY, ANASTASIA 14 PIGEON HILL ROAD, MORRIS PLAINS, NEW JERSEY 07950, USA
4 CHO, WING-KEE, PHILIP RD, #4, 12 DANA COURT, PRINCETON, NJ 08540, USA
5 QIU, ZHIHUI 138 BONNEY COURT, BRIDGEWATER, NEW JERSEY 08807, USA
PCT International Classification Number A61K 31/454
PCT International Application Number PCT/US06/21003
PCT International Filing date 2006-05-31
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/686,945 2005-06-02 U.S.A.