Title of Invention	PROTEASOME INHIBITORS AND METHODS OF USING THE SAME
Abstract	The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.

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WO 2006/086600 PCT/US2006/004664 PROTEASOME INHIBITORS AND METHODS OF USING THE SAME This application claims benefit of priority to U.S. Provisional Serial No. 60/652,370 filed on February 11,2005, which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION The present invention relates to boronic acid and boronic ester compounds useful as proteasome inhibitors and modulation of apoptosis. BACKGROUND OF THE INVENTION The proteasome, (also refered to as multicatalytic protease (MCP), multicatalytic proteinase, multicatalytic proteinase complex, multicatalytic endopeptidase complex, 20S, 26S, or ingensin) is a large, multiprotein complex present in both the cytoplasm and the nucleus of all eukaryotic cells. It is a highly conserved cellular structure that is responsible for the ATP-dependent proteolysis of most cellular proteins (Tanaka, Biochem Biophy. Res. Commun., 1998, 247, 537). The 26S proteasome consists of a 20S core catalytic complex that is capped at each end by a 19S regulatory subunit. The archaebacterial 20S proteasome contains fourteen copies of two distinct types of subunits, a and b, which form a cylindrical structure consisting of four stacked rings. The top and bottom rings contain seven:a-subunits each, while the inner rings contain seven b-subunits. The more complex eukaryotic 20S proteasome is composed of about 15 distinct 20-30 kDa subunits and is characterized by three major activities with respect to peptide substrates. For example, the proteasome displays tryptic-, chymotryptic-, and peptidylglutamyl peptide- hydrolytic activities (Rivett, Biochem. J., 1993, 291, 1 and Orlowski, Biochemistry, 1990, 29, 10289). Further, the proteasome has a unique active site mechanism which WO 2006/086600 PCT/US2006/004664 is believed to utilize a threonine residue as the catalytic nucleophile (Seemuller, et al., Science, 1995,268,579). The 26S proteasome is able to degrade proteins that have been marked by the addition of ubiquitin molecules. Typically, ubiquitin is attached to the e-amino groups of lysines in a multistep process utilizing ATP and El (ubiquitin activating) and E2 (ubiquitin-conjugating) enzymes. Multi-ubiquitinated substrate proteins are recognized by the 26S proteasome and are degraded. The multi-ubiquitin chains are generally released from the complex and ubiquitin is recycled (Goldberg, et al., Nature, 1992, 357, 375). Numerous regulatory proteins are substrates for ubiquitin dependent proteolysis. Many of these proteins function as regulators of physiological as well as pathophysiological cellular processes. Alterations in proteasome activity have been implicated in a number of pathologies including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, as well as occlusion/ischaemia reperfusion injuries, and aging of the central nervous system. The ubiquitin-proteasome pathway also plays a role in neoplastic growth. The regulated degradation of proteins such as cyclins, CDK2 inhibitors, and tumor suppressors is believed to be important in cell cycle progression and mitosis. A known substrate of the proteasome is the tumor suppressor p53 which is involved in several cellular processes (see, e.g., Ko, L. J. Genes Dev., 1996,10, 1054). Tumor suppressor p53 has been shown to induce apoptosis in several haematopoietic cell lines (Oren, M., Semin. Cancer Biol, 1994, 5, 221). Induction of p53 leads to cell growth arrest in the Gl phase of the cell cycle as well as cell death by apoptosis. Tumor suppressor p53 degradation is known to be carried out via the ubiquitin-proteasome pathway, and disrupting p53 degradation by inhibition of the proteasome is a possible mode of inducing apoptosis. The proteasome is also required for activation of the transcription factor NF- KB by degradation of its inhibitory protein, IKB (Palombella, et al., Cell, 1994, 78, 773). NF-KB has a role in maintaining cell viability through the transcription of 2 WO 2006/086600 PCT/US2006/004664 inhibitors of apoptosis. Blockade of NF-KB activity has been demonstrated to make cells more susceptible to apoptosis. Several inhibitors of the proteolytic activity of the proteasome have been reported. See, for example, Kisselev, et al., Chemistry & Biology, 2001, 8, 739. Lactacystin is a Streptomyces metabolite that specifically inhibits the proteolytic activity of the proteasome complex (Fenteany, et al., Science, 1995, 268, 726). This molecule is capable of inhibiting the proliferation of several cell types (Fenteany, et al., Proc. Natl. Acad. Sci. USA, 1994, 91, 3358). It has been shown that lactacystin binds irreversibly, through its P-lactone moiety, to a threonine residue located at the amino terminus of the p~ subunit of the proteasome. Peptide aldehydes have been reported to inhibit the chymotrypsin-like activity associated with the proteasome (Vinitsky, et al., Biochemistry, 1992, 31, 9421; Tsubuki, et al., Biochem. Biophys. Res. Commun., 1993, 196, 1195; and Rock, et al., Cell, 1994, 78, 761). Dipeptidyl aldehyde inhibitors that have IC50 values in the 10- 100 nM range in vitro (Iqbal, M., et al., J. MedChem., 1995, 38, 2276) have also been reported. A series of similarly potent in vitro inhibitors from a.-ketocarbonyl and boronic ester derived dipeptides has also been reported (Iqbal, et al., Bioorg. Med. Chem. Lett., 1996, 6, 287, U.S. Pat. Nos. 5,614,649; 5,830,870; 5,990,083; 6,096,778; 6,310,057; U.S. Pat. App. Pub. No. 2001/0012854, and WO 99/30707). N-terminal peptidyl boronic ester and acid compounds have been reported previously (U.S. Pat. Nos. 4,499,082 and 4,537,773; WO 91/13904; Kettner, et al., J. Biol Chem., 1984, 259(24), 15106). These compounds are reported to be inhibitors of certain proteolytic enzymes. N-terminal tri-peptide boronic ester and acid compounds have been shown to inhibit the growth of cancer cells (U.S. Pat. No. 5,106,948). A broad class of N-terminal tri-peptide boronic ester and acid compounds and analogs thereof has been shown to inhibit renin (U.S. Pat. No. 5,169,841). Various inhibitors of the peptidase activities of the proteasome have also been reported. See, e.g., Dick, et al., Biochemistry, 1991, 30, 2725; Goldberg, et al., Nature, 1992, 357, 375; Goldberg, Eur. J. Biochem., 1992, 203, 9; Orlowski, Biochemistry, 1990, 29,10289; Rivett, et al, Archs. Biochem. Biophys., 1989,218, 1; 3 WO 2006/086600 PCT/US2006/004664 Rivett, et al., J. Biol. Chem., 1989, 264, 12215; Tanaka, et al., New Biol, 1992, 4, 1; Murakami, et al., Proc. Nad. Acad Sci. USA, 1986, 83, 7588; Li et al., Biochemistry, 1991, 30, 9709; Goldberg, Eur. J. Biochem., 1992, 203, 9; and Aoyagi, et al., Proteases and Biological Control, Cold Spring Harbor Laboratory Press (1975), pp. 429-454. Stein et al., U.S. patent application Ser. No. 08/212,909, filed March 15,1994, report peptide aldehydes useful for reducing in an animal both the rate of loss of muscle mass and the rate of intracellular protein breakdown. The compounds are also said to reduce the rate of degradation of p53 protein in an animal. Palombella, et al., WO 95/25533, report the use of peptide aldehydes to reduce the cellular content and activity of NF-KB in an animal by contacting cells of the animal with a peptide aldehyde inhibitor of proteasome function or ubiquitin conjugation. Goldberg and Rock, WO 94/17816, report the use of proteasome inhibitors to inhibit MHC-I antigen presentation. Stein, et al., U.S. Pat. No. 5,693,617 report peptidyl aldehyde compounds as proteasome inhibitors useful for reducing the rate of degradation of protein in an animal. Inhibition of the 26S and 20S proteasome by indanone derivatives and a method for inhibiting cell proliferation using indanone derivatives are reported by Lum et al., U.S. Pat. No. 5,834,487. Alpha-ketoamide compounds useful for treating disorders mediated by 20S proteasome in mammals are reported in Wang et al., U.S. Pat. No. 6,075,150. France, et al., WO 00/64863, report the use of 2,4-diamino-3-hydroxycarboxylic acid derivatives as proteasome inhibitors. Carboxylic acid derivatives as proteasome inhibitors are reported by Yamaguchi et al., EP 1166781. Ditzel, et al., EP 0 995 757 report bivalent inhibitors of the proteasome. 2-Aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the 20S proteasome have been reported by Garcia- Echeverria, et al., Bioorg. Med. Chem. Lett., 2001,11, 1317. Some further proteasome inhibitors can contain boron moieties. For example, Drexler et al., WO 00/64467, report a method of selectively inducing apoptosis in activated endothelial cells or leukemic cells having a high expression level of c-myc by using tetrapeptidic boronate containing proteasome inhibitors. Furet et al., WO 4 WO 2006/086600 PCT/US2006/004664 02/096933 report 2-[[N-(2-amino-3-(heteroaryl or aryl)propionyl)aminoacyl]amino]alkylboronic acids and esters for the therapeutic treatment of proliferative diseases in warm-blooded animals. U.S. Pat. Nos. 6,083,903; 6,297,217; 5,780454; 6,066,730; 6,297,217; 6,548,668; U.S. Patent Application Pub. No. 2002/0173488; and WO 96/13266 report boronic ester and acid compounds and a method for reducing the rate of degradation of proteins. A method for inhibiting viral replication using certain boronic acids and esters is also reported in U.S. Pat. No. 6,465,433 and WO 01/02424. Pharmaceutically acceptable compositions of boronic acids and novel boronic acid anhydrides and boronate ester compounds are reported by Plamondon, et al., U.S. Patent Application Pub. No. 2002/0188100. A series of di- and tripeptidyl boronic acids are shown to be inhibitors of 20S and 26S proteasome in Gardner, et al., Biochem. J., 2000, 346,447. Other boron-containing peptidyl and related compounds are reported in U.S. Pat. Nos. 5,250,720; 5,242,904; 5,187,157; 5,159,060; 5,106,948; 4,963,655; 4,499,082; and WO 89/09225, WO/98/17679, WO 98/22496, WO 00/66557, WO 02/059130, WO 03/15706, WO 03/59898, WO 96/12499, WO 95/20603, WO 95/09838, WO 94/25051, WO 94/25049, WO 94/04653, WO 02/08187, EP 632026, and EP 354522. U.S. Pat. App. Ser. Nos. 10/918,664 and 10/918,610, the disclosures of each of which are incorporated herein by reference in their entireties, further report additional boron-containing peptidyl-like proteasome inhibitors. A great interest exists, as evidenced by the above references, in drugs which can modulate proteasome activity. For example, molecules capable of inhibiting proteasome activity can arrest or delay cancer progression by interfering with the ordered degradation of cell cycle proteins or tumor suppressors. Accordingly, there is an ongoing need for new and/or improved inhibitors of proteasome. SUMMARY OF THE INVENTION The present invention is directed to novel boronic acid and boronic ester compounds useful as proteasome inhibitors and modulation of apoptosis. The subject 5 WO 2006/086600 PCT7US2006/004664 invention also comprises methods for inhibition of multicatalytic protease ("MCP") associated with certain disorders, including the treatment of muscle wasting disorders. In one embodiment are provided compounds having Formula (I): wherein constituent members are defined infra, as well as preferred constituent members. In another embodiments, the present invention provides a compound which is a boronic anhydride of a compound of Formula (I), such as a cyclic boronic anhydride. In another embodiment the present invention provides a pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier. In another embodiment the present invention provides a method of inhibiting activity of proteasome comprising contacting a compound of Formula (I) with the proteasome. In another embodiment the present invention provides a method of treating cancer comprising administering to a mammal having or predisposed to the cancer a therapeutically effective amount of a compound of Formula (I). In another embodiment the present invention provides a method of treating cancer comprising administering to a mammal having or predisposed to the cancer a therapeutically effective amount of a compound of Formula (I), and wherein the cancer is selected from skin, prostate, colorectal, pancreas, kidney, ovary, mammary, liver, tongue, lung, and smooth muscle tissue. In another embodiment the present invention provides a method of treating cancer comprising administering to a mammal having or predisposed to the cancer a therapeutically effective amount of a compound of Formula (I), and wherein said 6 WO 2006/086600 PCT/US2006/004664 cancer is selected from leukemia, lymphoma, non-Hodgkin lymphoma, myeloma, and multiple myeloma. In another embodiment the present invention provides a method of treating cancer comprising administering to a mammal having or predisposed to the cancer a therapeutically effective amount of a compound of Formula (I) in combination with one or more antitumor or anticancer agent and/or radiotherapy. In another embodiment the present invention provides a method of inhibiting activity of transcription factor NF-KB comprising contacting IKB, the inhibitor of transcription factor NF-KB, with a compound of Formula (I). In another embodiment, the present invention provides a compound of Formula (I) for use in therapy. In another embodiment, the present invention provides use of a compound of Formula (I) for the manufacture of a medicament for the treatment of cancer. These and other features of the compounds will be set forth in expanded form as the disclosure continues. DETAILED DESCRIPTION The present invention provides, inter alia, compounds that can inhibit proteasome activity and be used for the treatment of diseases or disorders related to proteasome activity. Compounds of the invention include compounds of Formula (I): or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; 7 WO 2006/086600 PCT/US2006/004664 RB is, independently, H, C1-4alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3 or-CHaNR1aR1; Hy is a 5- or 6- membered heterocyclic group optionally fused with an aryl or heteroaryl group, wherein said 5- or 6-membered heterocyclic group contains at least one ring-forming N atom, and wherein said Hy is optionally substituted by 1,2 or 3 R4; R1 is H, C1-10 alkyl, carbocyclyl, heterocyclyl, C1-10 alkyl-C(=O)-, C2-10 alkenyl-C(=O)-, C2-10 alkynyl-C(=O)-, carbocyclyl-C(=O)-, heterocyclyl-C(=O)-, carbocyclylalkyl-C(=O)-, heterocyclylalkyl-C(=0)-, C1-10 alkyl-S(=O)2-, carbocyclyl- S(=O)2-, heterocyclyl-S(=O)2-, carbocyclylalkyl-S(=O)2-, heterocyclylalkyl-S(=O)2-, C1-C10 alkyl-NHC(=O)-, carbocyclyl-NHC(=O)-, heterocyclyl-NHC(=O)-, carbocyclylalkyl-NHC(=0)-, heterocyclylalkyl-NHC(=O)-, C1-C10 alkyl-OC(=O)-, carbocyclyl-OC(=O)-,heterocyclyl-OC(=O)-, carbocyclylalkyl-OC(=0)-, heterocyclylalkyl-OC(=O)-, C1-10 alkyl-NH-C(=O)-NHS(=O)2-, carbocyclyl-NH- C(=O)-NHS(=O)2-, heterocyclyl-NH-C(=O)-NHS(=O)2-5 C1-10 alkyl-S(=O)2-NH- C(O)-, carbocyclyl-S(=O)2-NH-C(=O)-, heterocyclyl-S(=O)2-NH-C(=O)-, or an amino protecting group; wherein R1 is optionally substituted with 1, 2 or 3 substituents selected from C1-6 alkyl, C2-6 alkenyl, C2_6 alkynyl, F, Cl, Br, I, C1-4 haloalkyl, -NH2, -NHR2, -N(R2)2, -N3, -NO2, -CN, -CNO, -CNS, -C(=O)OR2, - C(=O)R2, -OC(=O)R2, -N(R2)C(=O)R2, -N(R2)C(=O)OR2, -C(=O)N(R2)2, ureido, - OR2, -SR2, -S(=O)-(C1-6 alkyl), -S(=O)2-(C1-6 alkyl), -S(=O)-aryl, -S(=O)2-aryl, - S(=O)2-N(R2)2; carbocyclyl optionally substituted witli 1,2, 3,4 or 5 R3; and heterocyclyl optionally substituted with 1, 2, 3,4, or 5 R3; Rla is H; or Rla and R1 together with the N atom to which they are attached form a 4-, 5-, 6- or 7-memebered heterocyclyl group optionally substituted with 1, 2, or 3 R3; R2 is, independently, H or C1-6 alkyl; alternatively, two R2 may be combined, together with the N atom to which they are attached, to form a 5-, 6- or 7-membered heterocyclic group; 8 WO 2006/086600 PCT/US2006/004664 R3 is, independently, selected from C1-4alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(=O)-, alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl- OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(=O)O, (alkyl-O)r-alkyl,'HO-(alkyl-O)r- alkyl-, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(=O)-, alkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-; R4 is, independently, selected from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, - OR4a, -SR4a, -CN, halo, haloalkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHC(=O)O-alkyl, - NHC(=O)alkyl, -COOH, -C(=O)O-alkyl, -C(=O)alkyl, -C(O)H, -S(=O)-alkyl, - S(=O)2-alkyl, -S(=O)-atyl, -S(=O)2-aryl, carbocyclyl optionally substituted with 1,2 or 3 R5, and heterocyclyl optionally substituted with 1, 2 or 3 R5; R4a is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, carbocyclyl or heterocyclyl; R5 is, independently, selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl- OC(=O)-, alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl-OC(=O)NH-, alkyl- C(=O)NH-, alkyl-C(=O)O-, (ilkyl-O)r-alkyl,HO-(alkyl-O)r-alkyl-OH, -SH, -CN, - N3, -CNO, -CNS, alkyl-S(=O)-, aIkyI-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-; 9 with the proviso that when Z is -CH(OH)CH3 and Q is WO 2006/086600 PCT/US2006/004664 In some embodiments, Q is boronic acid (B(OH)2) or a cyclic boronic ester wherein said cyclic boronic ester contains from 6 to 10 carbon atoms and contains at least one cycloalkyl moiety. In some embodiments, Q is B(OH)2 or pinanediol boronic ester. In some embodiments, Q is pinanediol boronic ester. In some embodiments, Z is -CH(OH)CH3. In some embodiments, Z is -CH2NRlaR1. In some embodiments, Z is -CH2NHR1. In some embodiments, Z is -CH2NHR1 and R1 is carbocyclyl-C(=O)- or carbocyclyl-S(=O)2-, each optionally substituted with 1,2 or 3 substituents selected from C1-16 alkyl, C2-6 alkenyl, C2-6 alkynyl, F, Cl, Br, I, C1-4 haloalkyl, -NH2, -NHR2, - N(R2)2, -N3, -NO2, -CN, -CNO, -CNS, -C(=O)OR2, -C(=O)R2, -OC(=O)R2, - N(R2)C(=O)R2, -N(R2)C(=O)OR2, -C(=O)N(R2)2, ureido, -OR2, -SR2, -S(=O)-(C1-6 alkyl), -S(=O)2-(C1-6 alkyl), -S(=O)-aryl, -S(=O)2-aryl, -S(=O)2-N(R2)2; carbocyclyl optionally substituted with 1,2, 3,4 or 5 R3; and heterocyclyl optionally substituted with 1,2, 3, 4, or 5 R3. In some embodiments, Z is -CH2NHR1 and R1 is aryl-C(=O)- or aryl-S(=O)2- , each optionally substituted with 1,2 or 3 substituents selected from C1-6 alkyl, F, Cl, Br, I, C1-4 haloalkyl, carbocyclyl optionally substituted with 1, 2, 3, 4 or 5 R3 and heterocyclyl optionally substituted with 1,2, 3,4, or 5 R3. In some embodiments, Z is -CH2NHR1 and R1 is phenyl-C(=O)- or phenyl- S(=O)2-, each optionally substituted with C1-4 alkyl, F, Cl, Br, I, or aryl. In some embodiments, R1 is aryl-C(=O)- or aryl-S(=O)2-, each optionally substituted with 1, 2 or 3 substituents selected from C1-6 alkyl, F, Cl, Br, I, C1-4 haloalkyl, carbocyclyl optionally substituted with 1,2, 3,4 or 5 R3 and heterocyclyl optionally substituted with 1,2, 3,4, or 5 R3. In some embodiments, R1 is aryl-C(=O)- optionally substituted with 1,2 or 3 substituents selected from C1-6 alkyl, F, Cl, Br, I, and C1-4 haloalkyl. In some embodiments, R1 is phenyl-C(=O)- optionally substituted with 1,2 or 3 substituents selected from C1-6 alkyl, F, Cl, Br, I, and C1-4 haloalkyl. 10 WO 2006/086600 PCT/US2006/004664 In some embodiments, R1 is -CO-(4-methyIphenyl). In some embodiments, R1 is optionally substituted with 1 or 2 substituents. In some embodiments, R1 is optionally substituted with 1 substituent. In some embodiments, R1 is substituted with 1 substituent. In some embodiments, R1 is substituted with C1-6alkyl. In some embodiments, R1 is substituted with methyl. In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1,2 or 3 R4. In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, each optionally substituted by 1, 2 or 3 R4. In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, each optionally substituted by 1 or 2 C1-8 alkyl, carbocyclyl optionally substituted with 1, 2 or 3 R5, or heterocyclyl optionally substituted with 1,2 or 3 R5. In some embodiments, Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, each optionally substituted by 1 or 2 methyl, ethyl, propyl, butyl, aryl optionally substituted with 1,2 or 3 R5, or heteroaryl optionally substituted with 1,2 or 3 R5. In some embodiments, Hy is pyridyl, pyrimidinyl, pyrazinyl, thiazolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, or indolyl, each optionally substituted by 1 or 2 methyl, ethyl, propyl, butyl, aryl optionally substituted with 1,2 or 3 R5, or heteroaryl optionally substituted with 1,2 or 3 R5. In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R4, unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R4, pyridin-4- yl optionally substituted by 1 or 2 R4, N-oxo-pyridinyl optionally substituted by 1 or 2 R4, pyrimidinyl optionally substituted by 1 or 2 R4, imidazolyl optionally substituted by 1 or 2 R4, thiazolyl optionally substituted by 1 or 2 R4, oxazolyl optionally 11 WO 2006/086600 PCT/US2006/004664 substituted by 1 or 2 R4, pyrrolyl optionally substituted by I or 2 R4, pyrazolyl optionally substituted by 1 or 2 R4, quinolinyl optionally substituted by 1 or 2 R4, isoquinolinyl optionally substituted by 1 or 2 R4, quinoxalinyl optionally substituted by 1 or 2 R4, indolyl optionally substituted by 1 or 2 R4, quinazolinyl optionally substituted by 1 or 2 R4, benzoimidazolyl optionally substituted by 1 or 2 R4, benzothiazolyl optionally substituted by 1 or 2 R4, or benzoxazolyl optionally substituted by 1 or 2 R4. In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R4, unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R4, pyridin-4- yl optionally substituted by 1 or 2 R4, N-oxo-pyridinyl optionally substituted by 1 or 2 R4, pyrimidinyl optionally substituted by 1 or 2 R4, imidazolyl optionally substituted by 1 or 2 R , thiazolyl optionally substituted by 1 or 2 R4, oxazolyl optionally substituted by 1 or 2 R4, pyrrolyl optionally substituted by 1 or 2 R4, pyrazolyl optionally substituted by 1 or 2 R4, quinolinyl optionally substituted by 1 or 2 R4, isoquinolinyl optionally substituted by 1 or 2 R4, quinoxalinyl optionally substituted by 1 or 2 R4, indolyl optionally substituted by 1 or 2 R4, quinazolinyl optionally substituted by 1 or 2 R4, benzoimidazolyl optionally substituted by 1 or 2 R4, benzothiazolyl optionally substituted by 1 or 2 R4, or benzoxazolyl optionally substituted by 1 or 2 R4, wherein R4 is C1-6alkyl, aryl or heterocyclyl. In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R4, unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R4, pyridin-4- yl optionally substituted by 1 or 2 R4, N-oxo-pyridinyl optionally substituted by 1 or 2 R4, pyrimidinyl optionally substituted by 1 or 2 R4, imidazolyl optionally substituted by 1 or 2 R4, thiazolyl optionally substituted by 1 or 2 R4, pyrazolyl optionally substituted by 1 or 2 R4, quinolinyl optionally substituted by 1 or 2 R4, isoquinolinyl optionally substituted by 1 or 2 R4, quinoxalinyl optionally substituted by 1 or 2 R4, or indolyl optionally substituted by 1 or 2 R4. In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R4, unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R4, pyridin-4- yl optionally substituted by 1 or 2 R4, N-oxo-pyridinyl optionally substituted by 1 or 2 12 WO 2006/086600 PCT/US2006/004664 R4, pyrimidinyl optionally substituted by 1 or 2 R4, imidazolyl optionally substituted by 1 or 2 R4, thiazolyl optionally substituted by 1 or 2 R4, pyrazolyl optionally substituted by 1 or 2 R4, quinolinyl optionally substituted by 1 or 2 R4, isoquinolinyl optionally substituted by 1 or 2 R4, quinoxalinyl optionally substituted by 1 or 2 R4, or indolyl optionally substituted by 1 or 2 R4, wherein R4 is C1-6 alkyl, aryl or heterocyclyl. In some embodiments, Hy is pyrazine substituted by at least 1 or 2 R4, unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R4, pyridin-4- yl optionally substituted by 1 or 2 R4, pyrimidinyl optionally substituted by 1 or 2 R4, imidazolyl optionally substituted by 1 or 2 R4, thiazolyl optionally substituted by 1 or 2 R4, pyrazolyl optionally substituted by 1 or 2 R4, quinolinyl optionally substituted by 1 or 2 R4, isoquinolinyl optionally substituted by 1 or 2 R4, quinoxalinyl optionally substituted by 1 or 2 R4, or indolyl optionally substituted by 1 or 2 R4, wherein R4 is C1-6 alkyl, aryl or heterocyclyl. 13 In some embodiments, Hy is selected from: WO 2006/086600 PCT/US2006/004664 In some embodiments, Rla is H. In some embodiments, RB is H. In some embodiments, R4 is unsubstituted. In some embodiments, R is methyl, ethyl, propyl, butyl, aryl optionally substituted with 1,2 or 3 R5, or heteroaryl optionally substituted with 1, 2 or 3 R5. In some embodiments, R4 is C1-6alkyl, aryl or heterocyclyl. In some embodiments, R4 is methyl, butyl, phenyl, thienyl, or morpholino. In some embodiments: 14 WO 2006/086600 PCT/US2006/004664 Z is -CH(OH)CH3; and Hy is a 5- or 6- membered heterocyclic group optionally fused with an aryl or heteroaryl group, wherein said 5- or 6-membered heterocyclic group contains at least one ring-forming N atom, and wherein said Hy is optionally substituted by 1,2 or 3 R4. In some embodiments: Zis-CH(OH)CH3;and Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1,2 or 3 R4. In some embodiments,: Z is-CH2NHR1; Hy is a 5- or 6- membered heterocyclic group optionally fused with an aryl or heteroaryl group, wherein said 5- or 6-membered heterocyclic group contains at least one ring-forming N atom, and wherein said Hy is optionally substituted by 1, 2 or 3 R4; and R1 is carbocyclyl-C(=O)- or carbocyclyl-S(=O)2-5 each optionally substituted with 1,2 or 3 substituents selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, F, Cl, Br, I, C1-4 haloalkyl, -NH2, -NHR2, -N(R2)2, -N3, -NO2, -CN, -CNO, -CNS, - C(=O)OR2, -C(=O)R2, -OC(=O)R2, -N(R2)C(=O)R2, -N(R2)C(=O)OR2, - C(=O)N(R2)2, ureido, -OR2, -SR2, -S(=O)-(C1-6 alkyl), -S(=O)2-(C1-6 alkyl), -S(=O)- aryl, -S(=O)2-aryl, -S(=O)2-N(R2)2; carbocyclyl optionally substituted with 1,2, 3, 4 or 5 R3; and heterocyclyl optionally substituted with 1, 2, 3,4, or 5 R3. In some embodiments: Zis-CH2NHR1; 15 WO 2006/086600 PCT/US2006/004664 Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1, 2 or 3 R4; and Rl is carbocyclyl-C(=O)- or carbocyclyl-S(=O)2-, each optionally substituted with 1, 2 or 3 substituents selected from C1-6 alkyl, F, Cl, Br, I, C1-4 haloalkyl, carbocyclyl optionally substituted with 1,2, 3,4 or 5 R3, and heterocyclyl optionally substituted with 1,2, 3, 4, or 5 R3. In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3 or -CH2NHR1; Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1, 2 or 3 R4; R1 is carbocyclyl-C(=O)- or heterocyclyl-C(=O)-, each optionally substituted withl, 2 or 3 R3; R3 is, independently, selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(=O)-, alkyl-C(-O)-, aryl-0C(O)-, alkyl-OC(=O)NH-, aryl- OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(=O)O-, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(=O)-, alkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-; R4 is, independently, selected from C1-6 alkyl, aryl and heterocyclyl; 16 WO 2006/086600 PCT/US2006/004664 with the proviso that when Z is -CH(OH)CH3 and Q is In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3 or -CH2NHR1; Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1, 2 or 3 C1-6 alkyl, aryl or heterocyclyl; R1 is carbocyclyl-C(=0)- or heterocyclyl-C(=O)-, each optionally substituted withl, 2 or 3 R3; R3 is, independently, selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(=O)-; alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl- 17 WO 2006/086600 PCT/US2006/004664 OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(=O)O-, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(=O)-, alkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-; R4 is, independently, selected from C1-6alkyl, aryl and heterocyclyl; with the proviso that when Z is -CH(OH)CH3 and Q is In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3 or -CH2NHR1; Hy is pyridyl, N-oxopyridyl, pyrimidinyl, pyrazinyl, imidazolyl, thiazolyl, oxazolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indolyl, quinazolinyl, benzoimidazolyl, benzothiazolyl, or benzoxazolyl, each optionally substituted by 1,2 or 3 C l-6 alkyl, phenyl, thienyl or morpholino; R! is carbocyclyl-C(=O)- or heterocyclyl-C(=O)-, each optionally substituted with 1,2 or 3 R3; 18 WO 2006/086600 PCT/US2006/004664 R3 is, independently, selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(=O)-, alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl- OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(=O)O-, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(=O)-, alkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-; R4 is, independently, selected from C1-6 alkyl, aryl and heterocyclyl; with the proviso that when Z is -CH(OH)CH3 and Q is In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3 or -CH2NHR1; Hy is selected from 19 20 WO 2006/086600 PCT/US2006/004664 WO 2006/086600 PCT/US2006/004664 R1 is carbocyclyl-C(=O)- or heterocyclyl-C(=O)-, each optionally substituted with 1, 2 or 3 R3; and R3 is, independently, selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, aIkyl-OC(=O)-5 alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl- OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(=O)O-, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(=O)-, alkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-. In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3 or -CH2NHR1; Hy is selected from 21 22 WO 2006/086600 PCT/US2006/004664 WO 2006/086600 PCT/US2006/004664 In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(OH)2 or pinanediol boronic ester; Z is -CH(OH)CH3 or-CH2NHR]; 23 By is selected from WO 2006/086600 PCT/US2006/004664 In some embodiments, compounds of the invention include compounds of Formula (I) or phannaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; 24 WO 2006/086600 PCT/US2006/004664 Z is -CH(OH)CH3; Hy is a 5- or 6- membered heterocyclic group optionally fused with an aryl or heteroaryl group, wherein said 5- or 6-membered heterocyclic group contains at least one ring-forming N atom, and wherein said Hy is optionally substituted by 1,2 or 3 R4; R4 is, independently, selected from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, - OR4a, -SR43, -CN, halo, haloalkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHC(=O)O-aIkyl, - NHC(=O)alkyl, -COOH, -C(=O)O-alkyl, -C(=O)alkyl, -C(O)H, -S(=O)-alkyl, - S(=O)2-alkyl, -S(=O)-aryl, -S(=O)2-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R5, and heterocyclyl optionally substituted with 1, 2 or 3 R5; R4a is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, carbocyclyl or heterocyclyl; R5 is, independently, selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylambo, carboxyl, alkyl-0C(=O)-, alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl- OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(=O)O-, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(=O)-, alkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-; 25 with the proviso that when Q is WO 2006/086600 PCT/US2006/004664 In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3; Hy is pyrazine substituted by at least 1 or 2 R4, unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R4, pyridin-4-yl optionally substituted by 1 or 2 R4, N-oxo-pyridinyl optionally substituted by 1 or 2 R4, pyrimidinyl optionally substituted by 1 or 2 R4, imidazolyl optionally substituted by 1 or 2 R4, thiazolyl optionally substituted by 1 or 2 R4, oxazolyl optionally substituted by 1 or 2 R , pyrrolyl optionally substituted by 1 or 2 R4, pyrazolyl optionally substituted by 1 or 2 R4, quinolinyl optionally substituted by 1 or 2 R4, isoquinolinyl optionally substituted by 1 or 2 R4, quinoxalinyl optionally substituted by 1 or 2 R4, indolyl optionally substituted by 1 or 2 R4, quinazolinyl optionally substituted by 1 or 2 R4, benzoimidazolyl optionally substituted by 1 or 2 R4, benzothiazolyl optionally substituted by 1 or 2 R4, or benzoxazolyl optionally substituted by 1 or 2 R4; R4 is, independently, selected from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, - OR4a, -SR4a, -CN, halo, haloalkyl, -NH2, -NH(alkyl), -N(alkyl)2, -NHC(=O)O-alkyl, - NHC(=O)alkyl, -COOH, -C(=O)O-aIkyI, -C(=O)alkyI, -C(O)H, -S(=O)-alkyl, - S(=O)2-alkyl, -S(=O)-aryl, -S(=O)2-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R5, and heterocyclyl optionally substituted with 1,2 or 3 R5; R4a is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, carbocyclyl or heterocyclyl; and R5 is, independently, selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(=O)-, alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl- 26 WO 2006/086600 PCT/US2006/004664 OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(=O)O, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(K))-, alkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-. In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3; Hy is pyrazine substituted by at least 1 or 2 R4, unsubstituted pyridin-2yl, pyridin-3-yl optionally substituted by 1 or 2 R4, pyridin-4-yl optionally substituted by 1 or 2 R4, N-oxo-pyridinyl optionally substituted by 1 or 2 R4, pyrimidinyl optionally substituted by 1 or 2 R4, imidazolyl optionally substituted by 1 or 2 R4, thiazolyl optionally substituted by 1 or 2 R4, pyrazolyl optionally substituted by 1 or 2 R4, quinolinyl optionally substituted by 1 or 2 R4, isoquinolinyl optionally substituted by 1 or 2 R4, quinoxalinyl optionally substituted by 1 or 2 R4, or indolyl optionally substituted by 1 or 2 R4; R4 is, independently, selected from C1-20 alkyl, C2-20 alkenyl, C2-20 alkynyl, - OR4a, -SR4a, -CN, halo, haloalkyl, -NH2, -NH(alkyl), -N(alkyl>2, -NHC(=O)O-alkyl, - NHC(=O)alkyl, -COOH, -C(=O)O-alkyl, -C(=O)alkyl, -C(O)H, -S(=O)-alkyl, - S(=O)2-aIkyl, -S(=O)-aryl, -S(=O)2-aryl, carbocyclyl optionally substituted with 1, 2 or 3 R5, and heterocyclyl optionally substituted with 1,2 or 3 R5; R4a is H, C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, carbocyclyl or heterocyclyl; and R5 is, independently, selected from C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, phenyl, halo, haloalkyl, alkoxy, thialkoxy, amino, alkylamino, dialkylamino, carboxyl, alkyl-OC(=O)-, alkyl-C(=O)-, aryl-OC(=O)-, alkyl-OC(=O)NH-, aryl- 27 WO 2006/086600 PCT/US2006/004664 OC(=O)NH-, alkyl-C(=O)NH-, alkyl-C(O)0-, -OH, -SH, -CN, -N3, -CNO, -CNS, alkyl-S(=O)-, aIkyl-S(=O)2-, H2NS(=O)-, and H2NS(=O)2-. In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; RB is, independently, H, C1-4 alkyl, cycloalkyl, cycloalkylalkyl, aryl, or aralkyl; Z is -CH(OH)CH3; and 28 Hy is selected from WO 2006/086600 PCT/US2006/004664 29 In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(OH)2 or pinanediol boronic ester; Z is -CH(OH)CH3; and Hy is selected from WO 2006/086600 PCT/US2006/004664 In some embodiments, compounds of the invention include compounds of Formula (I) or pharmaceutically acceptable salt forms thereof, wherein: Q is -B(ORB)2, boronic acid, or a cyclic boronic ester wherein said cyclic boronic ester contains from 2 to 20 carbon atoms, and, optionally, a heteroatom which can be N, S, or O; 30 The present invention provides boronic acid compounds, boronic esters, and compositions thereof that can modulate apoptosis such as by inhibition of proteasome activity. The compounds and compositions can be used in methods of inducing apoptosis and treating diseases such as cancer and other disorders associated directly or indirectly with proteasome activity.

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02726-kolnp-2007-abstract.pdf

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2726-KOLNP-2007-(23-07-2012)-ANNEXURE TO FORM 3.pdf

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2726-KOLNP-2007-(23-07-2012)-PETITION UNDER RULE 137.pdf

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