FIELD OF THE INVENTION [2l This invention is directed generally to proteinase (also known as "protease") inhibitors, and, more particularly, to aromatic sulfone hydroxamates (also known as"aromatic sulfone hydroxamic acids") that, inter alia, inhibit matrix metalloproteinase (also known as"matrix metalloprotease"or"MMP") activity and/or aggrecanase activity. This invention also is directed to compositions of such inhibitors, intermediates for the syntheses of such inhibitors, methods for making such inhibitors, and methods for preventing or treating conditions associated with MMP activity and/or aggrecanase activity, particularly pathological conditions.

BACKGROUND OF THE INVENTION [3] Connective tissue is a required component of all mammals. It provides rigidity, differentiation, attachments, and, in some cases, elasticity. Connective tissue components include, for example, collagen, elastin, proteoglycans, fibronectin, and laminin. These biochemicals make up (or are components of) structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea, and vitreous humor.

[4] Under normal conditions, connective tissue turnover and/or repair processes are in equilibrium with connective tissue production. Degradation of connective tissue is carried out by the action of proteinases released from resident tissue cells and/or invading inflammatory or tumor cells.

[5] Matrix metalloproteinases, a family of zinc-dependent proteinases, make up a major class of enzymes involved in degrading connective tissue. Matrix metalloproteinases are divided into classes, with some members having several different

names in common use. Examples are: MMP-1 (also known as collagenase 1, fibroblast collagenase, or EC 3.4.24.3); MMP-2 (also known as gelatinase A, 72kDa gelatinase, basement membrane collagenase, or EC 3.4.24.24), MMP-3 (also known as stromelysin 1 or EC 3.4.24.17), proteoglycanase, MMP-7 (also known as matrilysin), MMP-8 (also known as collagenase II, neutrophil collagenase, or EC 3.4.24.34), MMP-9 (also known as gelatinase B, 92kDa gelatinase, or EC 3.4.24.35), MMP-10 (also known as stromelysin 2 or EC 3.4.24.22), MMP-1 I (also known as stromelysin 3), MMP-12 (also known as metalloelastase, human macrophage elastase or HME), MMP-13 (also known as collagenase 111), and MMP-14 (also known as MT1-MMP or membrane MMP). See, generally, Woessner, J. F.,"The Matrix Metalloprotease Family"in Matrix Metalloproteinases, pp. 1-14 (Edited by Parks, W. C. & Mecham, R. P., Academic Press, San Diego, CA 1998).

[6] Excessive breakdown of connective tissue by MMPs is a feature of many pathological conditions. Inhibition of MMPs therefore provides a control mechanism for tissue decomposition to prevent and/or treat these pathological conditions. Such pathological conditions generally include, for example, tissue destruction, fibrotic diseases, pathological matrix weakening, defective injury repair, cardiovascular diseases, pulmonary diseases, kidney diseases, liver diseases, ophthalmologic diseases, and diseases of the central nervous system. Specific examples of such conditions include, for example, rheumatoid arthritis, osteoarthritis, septic arthritis, multiple sclerosis, a decubitis ulcer, corneal ulceration, epidermal ulceration, gastric ulceration, tumor metastasis, tumor invasion, tumor angiogenesis, periodontal disease, liver cirrhosis, fibrotic lung disease, emphysema, otosclerosis, atherosclerosis, proteinuria, coronary thrombosis, dilated cardiomyopathy, congestive heart failure, aortic aneurysm, epidermolysis bullosa, bone disease, Alzheimer's disease, defective injury repair (e. g., weak repairs, adhesions such as post-surgical adhesions, and scarring), post-myocardial infarction, bone disease, and chronic obstructive pulmonary disease.

Matrix metalloproteinases also are involved in the biosynthesis of tumor necrosis factors (TNFs). Tumor necrosis factors are implicated in many pathological conditions. TNF-a, for example, is a cytokine that is presently thought to be produced initially as a 28 kD cell-associated molecule. It is released as an active, 17 kD form that can mediate a large number of deleterious effects in vitro and in vivo. TNF-a can cause

and/or contribute to the effects of inflammation (e. g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, fibrotic diseases, cancer, infectious diseases (e. g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, cardiovascular diseases (e. g., post-ischemic reperfusion injury and congestive heart failure), pulmonary diseases, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, and acute phase responses like those seen with infections and sepsis and during shock (e. g., septic shock and hemodynamic shock). Chronic release of active TNF-a can cause cachexia and anorexia. TNF-a also can be lethal.

[8] Inhibiting TNF (and related compounds) production and action is an important clinical disease treatment. Matrix metalloproteinase inhibition is one mechanism that can be used. MMP (e. g., collagenase, stromelysin, and gelatinase) inhibitors, for example, have been reported to inhibit TNF-a release. See, e. g., Gearing et al. Nature 376 555-557 (1994). See also, McGeehan et al. See also, Nature 376,558-561 (1994). MMP inhibitors also have been reported to inhibit TNF-a convertase, a metalloproteinase involved in forming active TNF-a. See, e. g., WIPO Int'l Pub. No. WO 94/24140. See also, WIPO Int'l Pub. No. WO 94/02466. See also, WIPO Int'l Pub. No.

WO 97/20824.

Matrix metalloproteinases also are involved in other biochemical processes in mammals. These include control of ovulation, post-partum uterine involution, possibly implantation, cleavage of APP ( (3-amyloid pxecursor protein) to the ainyloid plaque, and inactivation of (al-protease inhibitor (aI-PI). Inhibiting MMPs therefore may be a mechanism that may be used to control of fertility. In addition, increasing and maintaining the levels of an endogenous or administered serine protease inhibitor (e. g., al -PI) supports the treatment and prevention of pathological conditions such as emphysema, pulmonary diseases, inflammatory diseases, and diseases of aging (e. g., loss of skin or organ stretch and resiliency).

[10] Numerous metalloproteinase inhibitors are known. See, generally, Brown, P. D.,"Synthetic Inhibitors of Matrix Metalloproteinases,"in Matrix Metalloproteinases, pp. 243-61 (Edited by Parks, W. C. & Mecham, R. P., Academic Press, San Diego, CA 1998).

[11] Metalloproteinase inhibitors include, for example, natural biochemicals, such as tissue inhibitor of metalloproteinase (TIMP), a2-macroglobulin, and their analogs and derivatives. These are high-molecular-weight protein molecules that form inactive complexes with metalloproteinases.

[12] A number of smaller peptide-like compounds also have been reported to inhibit metalloproteinases. Mercaptoamide peptidyl derivatives, for example, have been reported to inhibit angiotensin converting enzyme (also known as ACE) in vitro and in vivo. ACE aids in the production of angiotensin II, a potent pressor substance in mammals. Inhibiting ACE leads to lowering of blood pressure.

[13] A wide variety of thiol compounds have been reported to inhibit MMPs.

See, e. g., W095/12389. See also, W096/11209. See also, U. S. Patent No. 4,595,700. See also, U. S. Patent No. 6.013,649.

[14] A wide variety of hydroxamate compounds also have been reported to inhibit MMPs. Such compounds reportedly include hydroxamates having a carbon backbone. See, e. g., WIPO Int'l Pub. No. WO 95/29892. See also, WIPO Int'l Pub. No.

WO 97/24117. See also, WIPO Int'l Pub. No. WO 97/49679. See also, European Patent No. EP 0 780 386. Such compounds also reportedly include hydroxamates having peptidyl backbones or peptidomimetic backbones. See, e. g, WIPO Int'l Pub. No. WO 90/05719. See also, WIPO Int'l Pub. No. WO 93/20047. See also, WIPO Int'l Pub. No.

WO 95/09841. See also, WIPO Int'l Pub. No. WO 96/06074. See also, Schwartz et al., Progr. Med. Chem., 29: 271-334 (1992). See also, Rasmussen et al., PharmacoL Ther., 75 (1) : 69-75 (1997). See also, Denis et al., Invest New Drugs, 15 (3): 175-185 (1997).

Various piperazinylsulfonylmethyl hydroxamates and piperidinylsulfonylinethyl hydroxamates have additionally been reported to inhibit MMPs. See, WIPO Int'l Pub. No.

WO 00/46221. And various aromatic sulfone hydroxamates have been reported to inhibit MMPs. See, WIPO Int'l Pub. No. WO 99/25687. See also, WIPO Int'l Pub. No. WO 00/50396. See also, WIPO Int'l Pub. No. WO 00/69821.

[15l It is often advantageous for an MMP inhibitor drug to target a certain MMP (s) over another MMP (s). For example, it is typically preferred to inhibit MMP-2, MMP-3, MMP-9, and/or MMP-13 (particularly MMP-13) when treating and/or preventing cancer, inhibiting of metastasis, and inhibiting angiogenesis. It also is typically preferred to inhibit MMP-13 when preventing and/or treating osteoarthritis. See, e. g., Mitchell et

al., J Clin. Invest., 97: 761-768 (1996). See also, Reboul et al., J Clin. Invest., 97: 2011-2019 (1996). Normally, however, it is preferred to use a drug that has little or no inhibitory effect on MMP-1 and MMP-14. This preference stems from the fact that both MMP-1 and MMP-14 are involved in several homeostatic processes, and inhibition of MMP-1 and/or MMP-14 consequently tends to interfere with such processes.

[16] Many known MMP inhibitors exhibit the same or similar inhibitory effects against each of the MMPs. For example, batimastat (a peptidomimetic hydroxamate) has been reported to exhibit ICso values of from about 1 to about 20 nM against each of MMP-1, MMP-2, MMP-3, MMP-7, and MMP-9. Marimastat (another peptidomimetic hydroxamate) has been reported to be another broad-spectrum MMP inhibitor with an enzyme inhibitory spectrum similar to batimastat, except that Marimastat reportedly exhibited an ICso value against MMP-3 of 230 nM. See Rasmussen et al., Pharmacol.

Ther., 75 (1) : 69-75 (1997).

[17] Meta analysis of data from Phase 1/11 studies using Marimastat in patients with advanced, rapidly progressive, treatment-refractory solid tumor cancers (colorectal, pancreatic, ovarian, and prostate) indicated a dose-related reduction in the rise of cancer-specific antigens used as surrogate markers for biological activity. Although Marimastat exhibited some measure of efficacy via these markers, toxic side effects reportedly were observed. The most common drug-related toxicity of Marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, and then spreading to the arms and shoulder. A short dosing holiday of 1-3 weeks followed by dosage reduction reportedly permits treatment to continue. See Rasmussen et al., Pharmacol. Ther., 75 (1) : 69-75 (1997). It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.

[18] Another enzyme implicated in pathological conditions associated with excessive degradation of connective tissue is aggrecanase, particularly aggrecanase-1 (also known as ADAMTS-4). Specifically, articular cartilage contains large amounts of the proteoglycan aggrecan. Proteoglycan aggrecan provides mechanical properties that help articular cartilage in withstanding compressive deformation during joint articulation. The loss of aggrecan fragments and their release into synovial fluid caused by proteolytic cleavages is a central pathophysiological event in osteoarthritis and rheumatoid arthritis.

It has been reported that two major cleavage sites exist in the proteolytically sensitive

interglobular domains at the N-terminal region of the aggrecan core protein. One of those sites has been reported to be cleaved by several matrix metalloproteases. The other site, however, has been reported to be cleaved by aggrecanase-1. Thus, inhibiting excessive aggrecanase activity provides an additional and/or alternative prevention or treatment method for inflammatory conditions. See generally, Tang, B. L.,"ADAMTS: A Novel Family of Extracellular Matrix Proteases,"Int'l Jouf°raal of Biochemistry & Cell Biology, 33, pp. 33-44 (2001). Such diseases reportedly include, for example, osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis. See, e. g., European Patent Application Publ. No. EP 1 081 137 Al.

[19] In addition to inflammatory conditions, there also is evidence that inhibiting aggrecanase may be used for preventing or treating cancer. For example, excessive levels of aggrecanase-1 reportedly have been observed with a ghoma cell line.

It also has been postulated that the enzymatic nature of aggrecanase and its similarities with the MMPs would support tumor invasion, metastasis, and angiogenesis. See Tang, Int'l Journal ofBiochemistry & Cell Biology, 33, pp. 33-44 (2001).

[20] Various hydroxamate compounds have been reported to inhibit aggrecanase-1. Such compounds include, for example, those described in European Patent Application Publ. No. EP 1 081 137 Al. Such compounds also include, for example, those described in WIPO PCT Int'l Publ. No. WO 00/09000. Such compounds further include, for example, those described in WIPO PCT Int'l Publ. No. WO 00/59874.

[21] In view of the importance of hydroxamate compounds in the prevention or treatment of several pathological conditions and the lack of enzyme specificity exhibited by two of the more potent MMP-inhibitor drugs that have been in clinical trials, there continues to be a need for hydroxamates having greater enzyme specificity (preferably toward MMP-2, MMP-9, MMP-13, and/or aggrecanase (particularly toward MMP-13 in some instances, toward both MMP-2 and MMP-9 in other instances, and aggrecanase in yet other instances), while exhibiting little or no inhibition of MMP-1 and/or MMP-14.

The following disclosure describes hydroxamate compounds that tend to exhibit such desirable activities.

SUMMARY OF THE INVENTION [22] This invention is directed to hydroxamate compounds (and salts thereof) that inhibit pathological protease activity (particularly compounds that inhibit MMP-2, MMP-9, MMP-13, and/or aggrecanase activity), while generally exhibiting relatively little or no inhibition against MMP-1 and MMP-14 activity. This invention also is directed to a method for inhibiting MMP activity and/or aggrecanase activity, particularly pathological MMP and/or aggrecanase activity. Such a method is particularly suitable to be used with mammals, such as humans, other primates (e. g., monkeys, chimpanzees. etc.), companion animals (e. g., dogs, cats, horses. etc.), farm animals (e. g., goats, sheep, pigs, cattle, etc.), laboratory animals (e. g., mice, rats, etc.), and wild and zoo animals (e. g., wolves, bears, deer, etc.).

[23] Briefly, therefore, the invention is directed in part to a compound or salt thereof. The compound has a structure corresponding to Formula I: I Here: A'is-H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl (thiocarbonyl), alkoxy (thiocarbonyl), carbocyclyl (thiocarbonyl), carbocyclylalkyl (thiocarbonyl), heterocyclyl (thiocarbonyl), heterocyclylalkyl (thiocarbonyl), carbocyclyloxy (thiocarbonyl), carbocyclylalkoxy (thiocarbonyl), or aminoalkyl (thiocarbonyl). Except where Al is - H, any member of this group optionally is substituted (i. e., it may be either unsubstituted or substituted).

A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members.

[24] In a preferred embodiment of the invention, X is-EJ-E2-E3-E4-E5. In this embodiment :

El is-O-,-S (O) 2-,-S (O)-,-S-,-N (Rl)-,-C (O)-N (R1)-, -N (Rl)-C (O)-, or -C(R1)(R2)-.

E2 forms a link of at least 2 carbon atoms between El and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E3 is -C(O)-, -O-(CO)-, -C(O)-O-, -C(NR3)-, -N(R4)-, -C(O)-N(R4)-, -N(R4)-C(O)-, -N(R4)-C(O)-N(R5)-, -S-, -S(O)-, -N(R4)-S(O)2-, -S(O2)-N(R4)-, -C(O)-N(R4)-N(R5)-C(O)-, -C(R4)(R6)-C(O)-, or-C (R7) (R)-.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

E5 is-H,-OH, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Except where E5 is except-H or-OH, any member of this group optionally is substituted. E5 is not-H when both E3 is-C (R7) (R8)- and E4 is a bond.

R'and W are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Ri nor R2 forms a ring structure with E2, E3, E4, or E5.

R3 is-H or-OH.

R4 and W are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except for-H, any member of this group optionally is substituted. Neither R4 nor R5 forms a ring structure with E2, E4, or E5.

R6 is-CN or-OH.

R7 is-H, halogen,-OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.

R8 is-OH or alkoxy. The alkoxy optionally is substituted.

[25] In another preferred embodiment of the invention, X is-El-E2-E3-E4-E5. In this embodiment: E1 is -O-, -S(O)2-, -S(O)-, -S-, -N(R1)-,-C(O)-N(R1)-, -N(R1)-C(O)-,or -C(R¹)(R²)-.

E2 forms a link of at least 2 carbon atoms between El and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E3 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted.

E4 is a bond, alkyl, alkenyl,-0-, or-N (R3)-. The alkyl and alkenyl optionally are substituted.

E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl optionally are substituted.

R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R'nor W forms a ring structure with E2, E3, E4, or E5.

R3 is-H or alkyl. The alkyl optionally is substituted.

[26] In another preferred embodiment of the invention, X is -E1-E2-C(E6)=C(E7)-E3-E4-E5. In this embodiment: E1 is -O-, -S(O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (R1)-, -N (Rl)-C (O)-, or -C(R1)(R2)-.

E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E4 is a bond or alkyl. The alkyl optionally is substituted.

Es is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

E6 is-H, halogen, or alkyl. The alkyl optionally is substituted.

E is-H, alkyl, alkenyl, alkynyl,-S (0) 2-R3, -NO2, -C (O)-N (R3) (R4), - (C) (OR3), carbocyclyl, carbocyclylalkyl, alkoxycarbocyclyl,-CN,-C=N-OH, or -C=NH. The alkyl, alkenyl, alkynyl, carbocyclyl, carbocycylalkyl, and alkoxycarbocyclyl optionally are substituted.

R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R'nor W forms a ring structure with E2, E4, E5, E6, or E7.

R3 and R4 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted.

[27] In another preferred embodiment of the invention, X is-El-E2-E3-E4-E5. In this embodiment: E1 is -O-, -S(O)2-, -S(O)-, -N(R3)-, -C(O)-N(R3)-, -N(R3)-C(O)-, or -C(R¹)(R²)-.

E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Except where the member is a bond, any member of such group optionally is substituted.

E3 is carbonylpyrrollidinyl. The carbonylpyrrollidinyl optionally is substituted.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally and substituted.

Es is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

Rl and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Rl nor R2 forms a ring structure with E, E, E, or E.

[28] In another preferred embodiment of the invention, X is-El-E2-E5. In this embodiment: El is-O-,-S (O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (Rl)-,-N (Rl)-C (O)-, or -C (RI) (R2) E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, and haloalkyl.

Es is alkyl, alkenyl, alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl optionally are substituted.

The alkyl, alkenyl, and alkynyl (a) contain at least 4 carbon atoms, and (b)

optionally are substituted with one or more substituents selected from the group consisting of-OH,-N02,-CN, and halogen.

R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Rl nor R2 forms a ring structure with Es.

[29] In another preferred embodiment of the invention, X is -E1-E2-E3-E4-E5. In this embodiment: El is-O-,-S (O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (R1)-, -N (Rl)-C (O)-, or -C(R1)(R2)-.

E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E3 is carbonylpiperidinyl. The carbonylpiperidinyl optionally is substituted.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

Es is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

Rl and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4, or E5.

[30] In another preferred embodiment of the invention, X is-El-E2-E5. h this embodiment: El is-O-,-S (O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (R1)-, -N (Rl)-C (O)-, or -C(R1)(R2)-.

E2 forms a link of at least 3 carbon atoms between El and Es. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

Es is optionally-substituted heterocyclyl, optionally-substituted fused-ring carbocyclyl, or substituted single-ring carbocyclyl.

R'and W are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Rl nor R2 forms a ring structure with E5.

[31] In another preferred embodiment of the invention, X is-El-E2-E5. In this embodiment: El is-O-,-S (O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (R1)-, -N (Rl)-C (O)-, or -C (RI) (R2) E2 forms a link of at least 4 carbon atoms between El and Es. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

Es is-OH or optionally-substituted carbocyclyl.

R'and W are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Rl nor R2 forms a ring structure with Es.

[32] In another preferred embodiment of the invention, X is -E1-E2-O-E4-E5. In this embodiment: E1 is -S(O)2-, -S(O)-, -N(R1)-, -C(O)-N(R1)-, -N(R1)-C(O)-, or-C (R1) (R2)- E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

Es is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

Ri and W are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R'nor W forms a ring structure with E2, E4, or Es.

[33] In another preferred embodiment of the invention, X is -O-E2-O-E5. In this embodiment: E2 comprises at least 3 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

Es is-H, alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxyalkyl. The alkyl, alkenyl, alkynyl, and alkoxyalkyl optionally are substituted with one or more substituents independently selected from the

group consisting of halogen,-OH,-N02, and-CN. the carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, and heterocyclylalkoxyalkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, -N (R3) (R4),-C (O) (R5),-S-R3,-S (O) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.

Rl and R2 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H., any member of this group optionally is substituted with one or more halogen.

R3 is-H, alkyl,-0-R4,-N (R4) (R5), carbocyclylalkyl, or heterocyclylalkyl.

The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.

R4 and Rs are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[34] In another preferred embodiment of the invention, X is-O-E2-O-E4-E5. In this embodiment: E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted. An atom in E2 optionally is bound to an atom in Es to form a ring.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

Es is : an optionally-substituted radical selected from the group consisting of alkenyl, alkynyl, alkoxy, alkoxyalkyl, fused-ring carbocyclyl, and heterocyclyl; single-ring carbocyclyl substituted with one or more substituents independently selected from the group consisting of - OH,-N02,-CN,-N (RS) (R6),-C (O) (R),-S-R5,-S (0) 2-R5

carbocyclyl, halocarbocyclyl, carbocyclylalkyl, halogen-substituted carbocyclylalkyl, heterocyclyl, haloheterocyclyl, heterocyclylalkyl, and halogen-substituted heterocyclylalkyl ; or single-ring carbocyclyl having multiple substitutions.

Rl and R2 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

R3 is-H, alkyl,-0-R4,-N (R4) (R5), carbocyclylalkyl, or heterocyclylalkyl.

The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.

R4 and Rs are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[35] In another preferred embodiment of the invention, X is-El-E2-S (O) 2-E4-E5.

In this embodiment: E'is-S (0) 2-,-S (O)-,-N (RI)-,-C (O)-N (R')-,-N (RI)-C (O)-, or-C (R1) (R2)-.

E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

Es is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

Rl and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Rl nor R2 forms a ring structure with E2, E4, or E5.

[361 In another preferred embodiment of the invention, X is-0-E2-S (O) 2-E4-E5.

In this embodiment: E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E4 is alkyl or alkenyl. The alkyl and alkenyl optionally are substituted.

E'is-H, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[37] In another preferred embodiment of the invention, X is-O-E2-S (O) 2-E5. In this embodiment: E2 comprises less than 5 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

Es is alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, or heterocyclyl.

Any member of this group optionally is substituted.

[38] In another preferred embodiment of the invention, X is-O-E2-S (O) 2-E5. In this embodiment: E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E5 is alkyl, alkenyl, alkynyl, alkoxyalkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[39] In another preferred embodiment of the invention, X is: In this embodiment: El-S (0) 2-,-S (O)-,-N (RI)-,-C (O)-N (RI)-,-N (Rl)-C (O)-, or-C (Ri) (R2)- E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E4 is a bond, alkyl, or alkenyl, The alkyl and alkenyl optionally are substituted.

Es is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

Rl and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Rl nor R2 forms a ring structure with E2, E4, or E5.

[40] In another preferred embodiment of the invention, X is:

In this embodiment: E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

Es is substituted carbocyclyl or optionally-substituted heterocyclyl. The carbocyclyl is substituted with: two or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl, -N(R3)(R4), -C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl ; or a substituent selected from the group consisting of halogen, - OH,-N02,-CN,-C (O)-O-R3,-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.

The heterocyclyl, on the other hand, optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, -NO2,-CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl,-N (R3) (R4),-C (O) (R),-S-R,-S (O) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.

R3 and R4 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

W is-H, alkyl,-0-R6,-N (R6) (R7), carbocyclylalkyl, or heterocyclylalkyl.

The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.

R6 and R7 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[41] In another preferred embodiment of the invention, X is-El-E2-E5. In this embodiment: El is-O-,-S (O) 2-,-S (O)-,-S-,-N (Rl)-,-C (O)-N (R1)-, -N (Ri)-C (O)-, or -C(R1)(R2)-.

E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of such group optionally is substituted.

Es is substituted heterocyclyl.

R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted.

Neither R1 nor R2 forms a ring structure with E5.

[42] In another preferred embodiment of the invention, X is -E1-E2-E5. In this embodiment : El is-O-,-S (O) 2-,-S (O)-,-N (RI)-,-C (O)-N (R')-,-N (RI)-C (O)-, or -C(R1)(R2)-.

E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of such group optionally is substituted. In addition, E2 comprises at least two carbon atoms.

Es is optionally-substituted heterocyclyl.

R'and W are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substitute.

Neither R1 nor R2 forms a ring structure with Es.

[43] In another preferred embodiment of the invention, X is-El-E2-E3-E4-E5. In this embodiment: El is-O-,-S (O) 2-,-S (O)-,-S-,-N (R1)-, -C (O)-N (R')-,-N (R1)-C (O)-, or -C(R1)(R2)-.

E is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of such group optionally is substituted.

E3 is -C(O)-, -O-(CO)-, -C(O)-O-, -C(NR3)-, -N(R4)-, -N(R4)-C(NR3)-, -C(NR3)-N(R4)-, -C(O)-N(R4)-, -N(R4)-C(O)-, -N(R4)-C(O)-N(R5)-, -S-, -S(O)-, -N(R4)-S(O)2-, -S(O)2-N(R4)-, -C(O)-N(R4)-N(R5)-C(O)-, -C(R4)(R6)-C(O)-, or -C(R7)(R8)-.

E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

Es is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl are: substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclylalkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclylalkyl ; and optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, alkyl, alkoxy, alkoxyalkyl,-N (R11)(R12), -C(O)(R13), -S-R11, -S(O)2-R11, carbocyclyl, carbocyclylalkyl, haloalkyl, haloalkoxy, halogen-substituted alkoxyalkyl, halocarbocyclyl, halogen-substituted carbocyclylalkyl, hydroxycarbocyclyl, and heteroaryl.

Rl and R2 are independently selected from the group consisting of-H and alkyl, wherein the alkyl optionally is substituted.

R3 is-H or-OH.

R4 and W are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl, wherein any member (except-H) of such group optionally is substituted.

R6 is-CN or-OH.

R7 is-H, halogen,-OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.

R8 is-OH or alkoxy. The alkoxy optionally is substituted.

Rl I and Rl2 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Any member (except-H) of such group optionally is substituted with one or more halogen.

R13 is-H, Cl-C8-alkyl,-O-R14,-N (R14) (Rls), carbocyclyl-Ci-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-Cl-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heterocyclyl-Ci-Cs-alkyl.

R14 and R15 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Any member (except-H) of such group optionally is substituted with one or more halogen.

Neither R1 nor R2 forms a ring structure with E, E3, E4, or Es.

Neither R4 nor Rs forms a ring structure with E2, E4, or E5.

1441 This invention also is directed, in part, to a method for preventing or treating a condition associated with pathological matrix metalloprotease activity in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition.

[45] This invention also is directed, in part, to a method for preventing or treating a pathological condition in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition. In this embodiment, the pathological condition comprises tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, a liver disease, an ophthalmologic disease, and a central nervous system disease.

146] This invention also is directed, in part, to a method for preventing or treating a pathological condition in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition. In this embodiment, the pathological condition comprises osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis,

atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermal ulceration, epidennolysis bullosa, aortic aneurysm, defective injury repair, an adhesion, scarring, congestive heart failure, post myocardial infarction, coronary thrombosis, emphysema, proteinuria, Alzheimer's disease, bone disease, and chronic obstructive pulmonary disease.

[47] This invention also is directed, in part, to a method for preventing or treating a condition associated with pathological TNF-a convertase activity in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition.

[48] This invention also is directed, in part, to a method for preventing or treating a condition associated with pathological aggrecanase activity in a mammal having the condition or predisposed to having the condition. The method comprises administering an above-described compound or a pharmaceutically acceptable salt thereof to the mammal in an amount that is therapeutically-effective to prevent or treat the condition.

[49] This invention also is directed, in part, to pharmaceutical compositions comprising a therapeutically-effective amount of an above-described compound or a pharmaceutically-acceptable salt thereof.

[50] This invention also is directed, in part, to a use of an above-described compound or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a condition associated with pathological matrix metalloprotease activity.

[51] This invention also is directed, in part, to a use of an above-described compound or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a condition associated with pathological TNF-a convertase activity.

[52] This invention also is directed, in part, to a use of an above-described compound or a pharmaceutically acceptable salt thereof to prepare a medicament for treating a condition associated with pathological aggrecanase activity.

[53] Further benefits of Applicants'invention will be apparent to one skilled in the art from reading this patent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [54] This detailed description of preferred embodiments is intended only to acquaint others skilled in the art with Applicants'invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This detailed description and its specific examples, while indicating preferred embodiments of this invention, are intended for purposes of illustration only. This invention, therefore, is not limited to the preferred embodiments described in this patent, and may be variously modified.

A. Compounds of This Invention [55] In accordance with this invention, it has been found that certain aromatic sulfone hydroxamates tend to be effective for inhibiting MMPs, particularly those associated with excessive (or otherwise pathological) breakdown of connective tissue.

Specifically, Applicants have found that these hydroxamates tend to be effective for inhibiting proteases (particularly MMP-2, MMP-9, MMP-13, other MMP's associated with pathological conditions, and/or aggrecanase) that are often particularly destructive to tissue if present or generated in abnormally excessive quantities or concentrations.

Moreover, Applicants have discovered that these hydroxamates tend to be selective toward inhibiting pathological protease activity, while avoiding excessive inhibition of other proteases (particularly MMP-1 and/or MMP-14) that are typically essential to normal bodily function (e. g., tissue turnover and repair).

A-1. Preferred Compound Structures [561 As noted above, the compound of this invention generally has a structure corresponding to Formula I :

[57] A1 is -H, alkylcarbonyl, alkoxycarbonyl, carbocyclylcarbonyl, carbocyclylalkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, aminoalkylcarbonyl, alkyl (thiocarbonyl), alkoxy (thiocarbonyl), carbocyclyl (thiocarbonyl), carbocyclylalkyl (thiocarbonyl), heterocyclyl (thiocarbonyl), heterocyclylalkyl (thiocarbonyl), carbocyclyloxy (thiocarbonyl), carbocyclylalkoxy (thiocarbonyl), or aminoalkyl (thiocarbonyl). Except where the member is-H, any member of this group optionally is substituted.

[58] In some preferred embodiments, Al is-H, Cl-C8-alkylcarbonyl, Cl-C8-alkoxycarbonyl, carbocyclylcarbonyl, carbocyclyl-C1-C8-alkylcarbonyl, heterocyclylcarbonyl, heterocyclyl-Ci-C8-alkylcarbonyl, carbocyclyloxycarbonyl, carbocyclyl-Cl-C8-alkoxycarbonyl, N (RA) (RB)-Cz-C8-alkylcarbonyl, Cl-Cg-alkyl (thiocarbonyl), Cl-C8-alkoxy (thiocarbonyl), carbocyclyl (thiocarbonyl), carbocyclyl-Cl-C8-alkyl (thiocarbonyl), heterocyclyl (thiocarbonyl), heterocyclyl-Cz-Cs-alkyl (thiocarbonyl), carbocyclyloxy (thiocarbonyl), carbocyclyl-Cz-Ca-alkoxy (thiocarbonyl), or N (RA) (RB)-Cl-C8-alkyl (thiocarbonyl). RA and RB are independently selected from the group consisting of-H, Cl-C8-alkyl, Cl-C8-alkoxycarbonyl, Cl-C8-alkylcarbonyl, carbocyclyl-Co-Cs-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.

[59] In generally more preferred embodiments, A1 is -H.

[60] A2 and A3, together with the carbon atom to which they are both attached, form an optionally-substituted heterocyclyl containing from 5 to 8 ring members (i. e., from 5 to 8 atoms are bound together to form the ring (or rings) of the heterocyclyl).

[61] In some preferred embodiments, A2 and A3, together with the carbon atom to which they both are attached, form an optionally-substituted heterocyclyl containing either 5 or 6 ring members.

[62] In some preferred embodiments, the compound corresponds in structure to one of the following formulas:

[63] A4 is-H, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonylalkylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkoxycarbonylalkylcarbonyl, alkylsulfonyl, alkyliminocarbonyl, alkenyl, alkynyl, alkoxyalkyl, alkylthioalkyl, alkylsulfonylalkyl, alkylsulfoxidoalkyl, alkylthioalkenyl, allcylsulfoxidoalkenyl, alkylsulfonylalkenyl, carbocyclyl, carbocyclylalkyl, carbocyclylalkoxyalkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl, carbocyclylthioalkyl, carbocyclylsulfoxidoalkyl, carbocyclylsulfonylalkyl, carbocyclylthioalkenyl, carbocyclylsulfoxidoalkenyl, carbocyclylsulfonylalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxyalkyl, heterocyclylcarbonyl, heterocyclylthioalkyl, heterocyclylsulfoxidoalkyl, heterocyclylsulfonylalkyl, heterocyclylthioalkenyl, heterocyclylsulfoxidoalkenyl, heterocyclylsulfonylalkenyl, heterocyclylsulfonyl, heterocyclyliminocarbonyl, heterocyclylalkylcarbonyl, heterocyclylcarbonylalkylcarbonyl, heterocyclylsulfonyl, heterocyclylcarbonylalkyl, aminoalkylcarbonyl, aminocarbonyl, aminocarbonylalkylcarbonyl, aminosulfonyl, aminosulfonylalkyl, aminoalkyl, aminocarbonylallcyl, or aminoalkylsulfonyl. Except where the member is-H, any member of this group optionally is substituted.

[64] In some preferred embodiments, A4 is-H, Cl-C8-alkyl, Cl-C$-alkylcarbonyl, Cl-Cs-alkylcarbonyl-Cl-C8-alkyl,

C1-C8-alkylcarbonyl-C1-C8-alkylcarbonyl, Cl-Cg-alkoxycarbonyl, C1-C8-alkoxycarbonyl-C1-C8-alkyl, C1-C8-alkoxycarbonyl-C1-C8-alkylcarbonyl, C1-C8-alkylsulfonyl, C1-C8-alkyliminocarbonyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkylthio-C1-C8-alkyl, C1-C8-alkylthio-C2-C8-alkenyl, Cl-C8-alkylsulfoxido-C1-C8-alkyl, Cl-C8-alkylsulfoxido-C2-C8-alkenyl, C1-C8-alkylsulfonyl-C1-C8-alkyl, C1-C8-alkylsulfonyl-C2-C8-alkenyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, carbocyclyl-C1-C8-alkoxy-Cl-C8-alkyl, carbocyclylcarbonyl, carbocyclylsulfonyl, carbocyclyliminocarbonyl, carbocyclyloxycarbonyl, carbocyclylthio-C1-C8-alkyl, carbocyclylthio-C2-C8-alkenyl, carbocyclylsulfoxido-C1-C8-alkyl, carbocyclylsulfoxido-C2-C8-alkenyl, carbocyclylsulfonyl-C1-C8-alkyl, carbocyclylsulfonyl-C2-C8-alkenyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkoxy-Cl-C8-alkyl, heterocyclylcarbonyl, heterocyclylthio-C1-C8-alkyl, heterocyclylsulfoxido-C1-C8-alkyl, heterocyclylsulfonyl-Cz-C8-alkyl, heterocyclylthio-C2-C8-alkenyl, heterocyclylsulfoxido-C2-C8-alkenyl, heterocyclylsulfonyl-C2-C8-alkenyl, heterocyclylsulfonyl, heterocyclyliminocarbonyl, heterocyclyl-C1-C8-alkylcarbonyl, heterocyclylcarbonyl-C1-C8-alkylcarbonyl, heterocyclylsulfonyl, heterocyclylcarbonyl-C1-C8-alkyl, N (RC) (RD)-C1-C8-alkylcarbonyl, N (RC) (RD)-carbonyl , N (RC) (RD)-carbonyl-C1-C8-alkylcarbonyl, N (RC) (RD)-sulfonyl, N (RC) (RD)-sulfonyl-C1-C8-alkyl, N (RC) (RD)-C1-C8-alkyl, N (RC) (RD)-carbonyl-C1-C8-alkyl, orN (RC) (RD)-Cl-C8-alkylsulfonyl. Any substitutable member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-CN,-C (O)-OH,-SH, -SO3H, and NO2.

[65] R and RD are independently selected from the group consisting of-H, -OH, C1-C8-alkyl, C1-C8-alkyl-carbonyl, C1-C8-alkoxy-C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-Cg-alkyl-thio-Cl-C$-alkyl, C1-C8-alkyl-sulfoxido-C1-C8-alkyl, C1-C8-alkyl-sulfonyl-C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, carbocyclylcarbonyl, carbocyclyl-C1-C8-alkoxy-C1-C8-alkyl, carbocyclylthio-C1-C8-alkyl, carbocyclylsulfoxido-Ci-C8-alkyl, carbocyclylsulfonyl-Cl-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, heterocyclyl-Cl-C8-alkoxy-Cl-Cs-alkyl, heterocyclylcarbonyl,

heterocyclylthio-Co-C8-alkyl,heterocyclylsulfoxido-Cl-C8-alk yl,<BR> <BR> <BR> <BR> <BR> heterocyclylsulfonyl-Cl-Cg-alkyl, aminocarbonyl-Cl-C8-alkyl, Cl-Cg-alkyloxycarbonylamino-Cl-Cg-alkyl, and amino-Cl-Cg-alkyl. Except where the member is-H or OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-CN, - C (O)-OH,-SH,-S03H, and N02. The nitrogen of the amino-Cl-C8-alkyl optionally is substituted with 1 or 2 substituents independently selected from the group consisting of Cl-C8-alkyl, Cl-C8-alkylcarbonyl, carbocyclyl, and carbocyclyl-Cl-C8-alkyl. No greater than one of RC or RD is-OH.

[66] In some preferred embodiments, A4 is-H, Cl-C6-alkyl (often preferably Cl-C4-alkyl, and more preferably ethyl), Cl-C6-alkoxy-Cl-C6-alkyl (often preferably Cl-C2-alkoxy-Cl-C3-alkyl, and more preferably methoxyethyl), carbocyclyl (often preferably C3-C6-cycloalkyl or phenyl, and more preferably cyclopropyl), carbocyclyl-Cl-C6-alkyl (often preferably C3-C6-cycloalkyl-Cl-C3-alkyl or phenyl-Cl-C3-alkyl, and more preferably cyclopropylmethyl or benzyl), Cl-C6-alkylsulfonyl (often preferably Cl-C2-alkylsulfonyl, and more preferably methylsulfonyl), C3-C6-alkenyl (often preferably C3-C4-alkenyl, and more preferably C3-alkenyl), C3-C6-alkynyl (often preferably C3-C4-alkynyl, and more preferably C3-alkynyl). Except where the member is-H, any member of these groups optionally is substituted with halogen, but more typically is preferably not substituted with halogen.

[67] In some preferred embodiments, A4 is-H, ethyl, methoxyethyl, cyclopropyl, cyclopropylmethyl, or benzyl.

[68] X may be selected from a wide range of substituents. The following discussion describes several specific preferred embodiments encompassing the substituents that Applicants have found to be generally preferred.

Preferred Embodiment No. 1 [69] In some embodiments of this invention, the compound has a structure corresponding to Formula II:

[701 A1, A2, and A3 are as defined above for Formula I.

[71] El is-O-,-S (O) 2-,-S (O)-,-N (R1)-, -C (O)-N (R')-,-N (R1)-C (O)-, or -C(R1)(R2)-. E1 alternatively may be-S-.

[72] E2 forms a link of at least 2 carbon atoms between E1 and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[73] In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or Cl-Clo-alkylcycloalkyl-Cl-Cio-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-Cl-C6-alkyl.

[74] In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.

[75] In some preferred embodiments, E2 is C2-C6-alkyl.

[76] In some preferred embodiments, E2 is C2-C6-alkyl.

[77] E3 is -C(O)-, -O-(CO)-, -C(O)-O-, -C(NR3)-, -N(R4)-, -C(O)-N(R4)-, -N(R4)-C(O)-, -N(R4)-C(O)-N(R5)-, -S-, -S(O)-, -N(R4)-S(O)2-, -S(O)2-N(R4)-, -C(O)-N(R4)-N(R5)-C(O)-, -C(R4)(R6)-C(O)-, or-C (R7) (R8)-- [78] E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[79] In some preferred embodiments, E4 is a bond, C1-C20-alkyl, or C2-C20-alkenyl. The C1-C20-alkyl andC2-C20-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl. This carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, -CN, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, halo-Cl-C8-alkyl, halo-Cl-C8-alkoxy, halogen-substituted

Cl-C8-alkoxy-Cl-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-Cl-C8-alkyl.

[80] In some preferred embodiments, E4 a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

The Cl-C3-alkyl, and C2-C3-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl.

This carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[81] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

[82] ES is-H,-OH, alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Except where ES is-H or-OH, any member of this group optionally is substituted. E5 is not-H when both E3 is-C (R7) (R8)-and E4 is a bond.

[83] In some preferred embodiments, E5 is-H,-OH, Cl-C2o-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, -N(R11)(R12), -C(O)(R13), -S-R11, -S(O)2-R11, carbocyclyl, carbocyclyl-C1-C8-alkyl, halo-C1-C8-alkyl, halo-C1-C8-alkoxy, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C8-alkyl. The carbocyclyl and heterocyclyl also optionally are substituted with one or more substituents independently selected from the group consisting of C1-C8-alkylcarbocyclyl, halogen-substituted Cl-C8-alkylcarbocyclyl, hydroxycarbocyclyl, and heterocyclyl.

[84] In some preferred embodiments, ES is-H,-OH, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl.

The Cl-Cs-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-Cg-alkoxy, and Cl-C$-alkoxy-Cl-Cg-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl,-N (Rll) (Rl2),-C (o) (Rl3),-S-Rll, -S (O) 2-Rll, carbocyclyl, carbocyclyl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-Cl-C6-alkyl, Cl-C6-alkylcarbocyclyl, halogen-substituted Cl-C6-alkylcarbocyclyl, hydroxycarbocyclyl, and heteroaryl.

[85] In some preferred embodiments, E5 is furanyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl, dihydropyranyl, pyridinyl, piperidinyl, diazinyl, piperazinyl, triazinyl, oxazinyl, isoxazinyl, oxathiazinyl, oxadiazinyl, morpholinyl, azepinyl, oxepinyl, thiepinyl, diazepinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, or acridinyl. Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, Cl-C6-alkyl, Cl-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, -N(R11)(R12), -C(O)(R13), -S-R11, -S(O)2-R11, aryl, aryl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Ci-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, haloaryl, and halogen-substituted aryl-Cl-C6-alkyl. Any member of such group also optionally is substituted with one or more substituent

independent selected from the group consisting of Cl-C6-alkylaryl, halogen-substituted Cl-C6-alkylaryl, hydroxyaryl, and heteroaryl.

[86] In some preferred embodiments, E5 is indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, or pyridofuranyl. Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl,-N (R11) (R12), -C(O)(R13), -S-R11, (-S(O)2-R11, aryl, aryl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, haloaryl, halogen-substituted aryl-Cl-C6-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of Cl-C6-alkylaryl, halogen-substituted Cl-C6-alkylaryl, hydroxyaryl, and heteroaryl.

[87] In some preferred embodiments, E5 is benzazinyl, benzofuranyl, or tetrahydroisoquinolinyl. Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, -N(R11)(R12), -C(O)(R13), - S-R",-S (0) 2-R", aryl, aryl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, haloaryl, and halogen-substituted aryl-Cl-C6-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of Cl-C6-alkylaryl, halogen- substituted Cl-C6-alkylaryl, hydroxyaryl, and heteroaryl.

[88] In some preferred embodiments, E5 is indolyl, benzoxazolyl, benzothienyl, benzothiazolyl, or pyridofuranyl. Such substituent any member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl,-N (R11)(R12), -C(O)(R13), -S-R11, -S(O)2-R11, aryl, aryl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted

Cl-C6-alkoxy-Cl-C6-alkyl, haloaryl, and halogen-substituted aryl-Ci-Ce-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of C1-C6-alkylaryl, halogen-substituted C1-C6-alkylaryl, hydroxyaryl, and heteroaryl.

[89] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Ri nor R2 forms a ring structure with E2, E', E, orE.

[90] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C8-alkyl, and halo-Cl-C$-alkyl.

[91] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-Cl-C6-alkyl.

[92] In some preferred embodiments, W and Ra are independently selected from the group consisting of-H, and Cl-C6-alkyl.

[93] R3 is-H or-OH.

[94] R4 and RS are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except for-H, any member of this group optionally is substituted. Neither R4 nor R5 forms a ring structure with E2, E4, or E5.

[95] In some preferred embodiments, R4 and R5 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-Cg-alkyl, heterocyclyl, and heterocyclyl-Cl-Cs-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

In some preferred embodiments, R4 and R5 are independently selected from the group consisting of-H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[97] R6 is-CN or-OH.

[98] R7 is-H, halogen,-OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.

[99] In some preferred embodiments, R7 is-H, halogen,-OH, Cl-C8-alkyl, Cl-C8-alkoxy, Cl-C8-alkoxy-Cl-C8-alkyl, halo-Cl-C8-alkyl, halo-Cl-C8-alkoxy, or halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.

[100] In some preferred embodiments, R7 is-H, halogen,-OH, C1-C6-alkyl, C1-C6-alkoxy,C1-C6-alkoxy-C1-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, or halogen-substituted C1-C6-alkoxy-C1-C6-alkyl.

[101] In some preferred embodiments, R7 is-H, halogen,-OH, C1-C6-alkyl, C1-C6-alkoxy, or C1-C6-alkoxy-C1-C6-alkyl.

[102] R8 is-OH or alkoxy. The alkoxy optionally is substituted.

[103] In some preferred embodiments, R8 is -OH, C1-C8-alkoxy, or halo-C1-C8-alkoxy.

[104] In some preferred embodiments, R8 is-OH, C1-C6-alkoxy, or halo-Cl-C6-alkoxy.

[1051 In some preferred embodiments, R8 is-OH or C1-C6-alkoxy.

R1 Rll and R12 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

1l07] In some preferred embodiments, R11 and R12 are independently selected from the group consisting of-H, C1-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-R, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[108] R13 is-H, C1-C8-alkyl, -O-R14, -N(R14)R15), carbocyclyl-C1-C8-alkyl, heterocyclyl-Cl-C8-alkyl, halo-Cl-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heterocyclyl-C1-C8-alkyl.

[109] In some preferred embodiments, R13 is-H, Cl-C6-alkyl,-0-R14, -N(R14)(R15), carbocyclyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halogen-substituted carbocyclyl-Cl-C6-alkyl, or halogen-substituted heterocyclyl-C1-C6-alkyl.

[110] In some preferred embodiments, R13 is-H, Cl-C6-alkyl,-O-Rl4, -N(R14)(R15), carbocyclyl-C1-C6-alkyl, or heterocyclyl-Cl-C6-alkyl.

[111] R14 and R15 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but typically is preferably not substituted with halogen.

[112] In some preferred embodiments, R14 and R15 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but typically is preferably not substituted with halogen.

Preferred Embodiment No. 1-a: E3 is -C(O)- [113] In some embodiments, E3 is -C(O)-.

[114] In some such embodiments, E5 is optionally-substituted carbocyclyl, and often preferably optionally-substituted cycloalkyl or optionally-substituted aryl.

[115] In some preferred embodiments, for example, ES is optionally-substituted phenyl. Such compounds include, for example:

Such compounds also include compounds wherein E5 is phenyl substituted with one or more substituents independently selected from the group consisting of aryl, haloaryl, aryl-Cl-C6-alkyl, and halogen-substituted aryl-Cl-C6-alkyl. Here, the phenyl also optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, Cl-C6-alkyl, Ci-Ce-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, -N(R11)(R12), -C(O)(R13), -S-R11, -S(O)2-R11, aryl, aryl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, haloaryl, halogen-substituted aryl-C1-C6-alkyl, C1-C6-alkylaryl, halogen-substituted Cl-C6-alkylaryl, hydroxyaryl, and heteroaryl. Such compounds include, for example: [116] In other preferred embodiments, E5 is optionally-substituted naphthalenyl.

Such compounds include, for example: IIA-40 [117] In yet other preferred embodiments, E5 is optionally-substituted C5-C6-cycloallcyl. Such compounds include, for example: [118] In some preferred embodiments, E5 is-H,-OH, Cl-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cl-C6-alkoxy, or Cl-C6-alkoxy-Cl-C6-alkyl. The C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, and C1-C6-alkoxy-C1-C6-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. Such compounds include, for example:

Other such compounds include, for example: [119] In other preferred embodiments, E5 is optionally-substituted heterocyclyl.

In one such embodiment, ES is optionally-substituted thiophenyl. Such compounds include, for example:

Other such compounds include, for example:

IIA-52 Preferred Embodiment No. 1-b: E3 is -S- [120] In some embodiments, E3 is-S-.

[121] In some such embodiments, E5 is-H,-OH, Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, or Cl-C8-alkoxy-Cl-C8-alkyl. The Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, and-CN. Such compounds include, for example:

[122] In some preferred embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: [123] In some preferred embodiments, ES is optionally-substituted heterocyclyl.

In one such embodiment, ES is optionally-substituted pyrimidinyl. Such compounds include, for example:

In another such embodiment, E5 is optionally-substituted 2-fused-ring heterocyclyl. In some preferred embodiments, ES is optionally-substituted benzoxazolyl or optionally-substituted benzothiazolyl. Such compounds include, for example:

Other such compounds include, for example: Preferred Embodiment No. 1-c: E3 is -N(R4)-C(O)- [124] In some embodiments, E3 is-N (R4)-C(O)-.

[125] In some such embodiments, ES is optionally-substituted carbocyclyl. In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: Other such compounds include, for example: [126] In some preferred embodiments, ES is optionally-substituted naphthalenyl.

Such compounds include, for example: [127] In some preferred embodiments, E5 is optionally-substituted cycloalkyl.

Such compounds include, for example, fused-ring cycloalkyls. These compounds include, for example:

These compounds also include, for example: [128] In some preferred embodiments, ES is optionally-substituted C5-C6-cycloalkyl. These compounds include, for example:

[129] In some preferred embodiments, ES is optionally-substituted heterocyclyl.

In one such embodiment, E5 is an optionally-substituted heterocyclyl selected from the group consisting of pyridinyl, pyrrolyl, isopyrrolyl, oxazolyl, isoxazole, thiazolyl, furanyl, and morpholinyl. In another such embodiment, E5 is an optionally-substituted heterocyclyl selected from the group consisting of tetrazolyl, imidazolyl, and thienyl.

Compounds of these embodiments include, for example: Such compounds also include, for example: [1301 In some preferred embodiments, ES is optionally-substituted 2-fused-ring heterocyclyl. In some more preferred embodiments, ES is an optionally-substituted heterocyclyl selected from the group consisting of benzazinyl, benzofuranyl, tetrahydroisoquinolinyl or pyridofuranyl. In some other more preferred embodiments, E5 is an optionally-substituted heterocyclyl selected from the group consisting of indolyl, benzoxazolyl, benzothienyl, and benzothiazolyl. Compounds of such embodiments include, for example:

Other such compounds include, for example : [131] In some preferred embodiments, E5 is-OH, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, or Cl-C6-alkoxy-Cl-C6-alkyl. Except where the member is - OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, and-CN. Such compounds include, for example :

Preferred Embodiment No. 1-d: E3 is -C(O)-N(R4)- [132] In some embodiments, E3 is -C(O)-N(R4)-.

[133] In some such embodiments, for example, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl.

[134] In some preferred embodiments, ES is optionally-substituted phenyl. Such compounds include, for example: Other such compounds include, for example:

IID-16 [135] In some preferred embodiments, ES is optionally-substituted naphthalenyl.

These compounds include, for example: [136] In some preferred embodiments, E5 is-OH, Cl-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cl-C6-alkoxy, or Cl-C6-alkoxy-Cl-C6-alkyl. Except where the member is -OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. Such compounds include, for example: Preferred Embodiment No. 1-e: E3 is -N(R4)-C(O)-N(R5)- [137] In some embodiments, E3 is-N (R4)-C (O)-N (R5)-. In some such embodiments, for example, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

Preferred Embodiment No. 1-f: E3 is -S(O)2-N(R4)- [138] In some embodiments, E3 is-S (0) 2-N (R4)-.

[139] In some such embodiments, ES is optionally-substituted carbocyclyl. The carbocyclyl may be, for example, cycloalkyl. Such compounds include, for example: In some preferred embodiments, the carbocyclyl is aryl (preferably phenyl). Such compounds include, for example:

IIF-8 [140] In some preferred embodiments, ES is-H,-OH, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, Cl-C6-alkoxy, or Cl-C6-alkoxy-Cl-C6-alkyl. Except where the member is-H or-OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, - N02, and-CN. Such compounds include, for example: Preferred Embodiment No. 1-g: E3 is -N(R4)-S(O)2- [141] In some embodiments, E3 is-N (R4)-S (0) 2-. In some such embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: Other such compounds include, for example:

Preferred Embodiment No. 1-h: E3 is -C(O)-N(R4)-N(R5)-C(O)- [142] In some embodiments, E3 is-C (O)-N (R4)-N (R5)-C (O)-. In some such embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

Preferred Embodiment No. 1-i : E'is-C (R4) (R6)-C (O)- [143] In some embodiments, E3 is-C (R4) (R6)-C (O)-. In some such embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

Preferred Embodiment No. 1 j : E3 is-O-C (O)- [144] In some embodiments, E3 is-O-C (O)-. In some such embodiments, ES is optionally-substituted heterocyclyl. In some preferred embodiments, E5 is an optionally-substituted 2-fused-ring heterocyclyl. In some embodiments, for example, E5 is optionally-substituted tetrahydroisoquinolinyl. Such compounds include, for example:

Preferred Embodiment No. 1-k: E3 is -N(R4)- [145] In some embodiments, E3 is-N (R4)-. In some such embodiments, E5 is optionally-substituted heterocyclyl. In some preferred embodiments, E5 is optionally-substituted 2-fused-ring heterocyclyl. In some embodiments, for example, E5 is optionally-substituted benzoxazolyl, benzothiazolyl, or benzimidazolyl. Such compounds include, for example:

Preferred Embodiment No. 1-1 : E3 is-C (NR3)- [146] In some embodiments, E3 is -C(NR3)-. In some such embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: Preferred Embodiment No. 1-m: E3 is -C(R7)(R8)- [147] In some embodiments, E3 is-C (R7) (R8)-. In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: Preferred Embodiment No. 1-n: E3 is -N(R4)-C(NR3)- [148] In some embodiments, E3 is-N (R4)-CR3)-. In some such embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

Preferred Embodiment No. 2 [149] In some embodiments of this invention, the compound has a structure corresponding to Formula III: [150] Al, A2, and A3 are as defined above for Formula I.

[151] El is-O-,-S (O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (R1)-,-N (Rl)-C (O)-, or -C(R1)(R2)-. E1 alternatively may be-S-.

[152] E2 forms a link of at least 2 carbon atoms between El and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[153] In some preferred embodiments, E2 is C2-C2o-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-Cl-C6-alkyl.

[154] In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.

[155] In some preferred embodiments, E2 is C2-C5-alkyl optionally substituted with one or more halogen.

[156] In some preferred embodiments, E2 is C2-C5-alkyl.

[157] In some preferred embodiments, E2 is -(CH2)m-, wherein m is from 2 to 5.

[158] E3 is carbocyclyl or heterocyclyl. This carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted.

[159] In some preferred embodiments, E3 is carbocyclyl or heterocyclyl wherein the carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH, keto, Cl-C8-alkyl, Cl-C8-alkoxy, Cl-C8-alkoxy-Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-Cs-alkyl. Except where the substituent is halogen,-OH, or keto, any of these substituents optionally is substituted with one or more substituents independently selected from the group consisting of halogen, -OH, C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, C1-C8-alkylthio, halo-Cl-C8-alkyl, halo-Cl-C8-alkoxy, halo-Cl-C8-alkylthio, and halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.

[160] In some preferred embodiments, E3 is carbocyclyl or heterocyclyl wherein the carbocyclyl and heterocyclyl have 5 or 6 ring members and optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH, keto, Cl-C6-alkyl, C1-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the substituent is halogen,-OH, or keto, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, Cl-C6-alkyl, Ci-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylthio, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkylthio.

[161] E4 is a bond, alkyl, alkenyl,-0-, or-N (R3)-. The alkyl and alkenyl optionally are substituted.

[162] In some preferred embodiments, E4 is a bond,-O-,-N (R3)-, C1-C20-alkyl, or C2-C20-alkenyl. The C1-C20-alkyl and C2-C20-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl optionally substituted with one or more substituents independently selected

from the group consisting of halogen,-OH,-N02,-CN, C1-C8-alkyl, Cl-C8-alkoxy, Cl-C8-alkoxy-Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C$-alkyl, halo-Cl-C8-alkyl, halo-Cl-C8-alkoxy, halocarbocyclyl, halogen-substituted carbocyclyl-Cl-C8-alkyl, and halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.

[163] In some preferred embodiments, E4 is a bond,-O-,-N (R3)-, C1-C3-alkyl, or C2-C3-alkenyl. The Cl-C3-alkyl and C2-C3-alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, C1-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, halo-C1-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[164] In some preferred embodiments, E4 is a bond, -O-, -N(R3)-, C1-C3-alkyl, or C2-C3-alkenyl.

[165] In some preferred embodiments, E4 is a bond.

[166] E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl optionally are substituted. In some preferred embodiments, the carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, keto, Cl-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, -N(R6)(R7), -C(O)(R8), -S-R6, -S(O)2-R6, carbocyclyl, carbocyclyl-Cl-C8-alkyl, halo-Cl-C8-alkyl, halo-Cl-C$-alkoxy, halogen-substituted Cl-C8-alkoxy-Cl-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C8-alkyl. The carbocyclyl and heterocyclyl also optionally are substituted with one or more substituents independently selected from the group consisting of C2-C8-alkenyl and C2-C8-alkynyl.

[167] In some preferred embodiments, ES is pyridinyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, -N(R6)(R7), - C (O) (R8),-S-R6,-S (O) 2-R6, phenyl, phenyl-Cl-C6-alkyl, halo-C1-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halophenyl, and halogen-substituted phenyl-C1-C6-alkyl. The pyridinyl also is optionally substituted with

one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.

[168] In some preferred embodiments, Es is piperidinyl, piperazinyl, imidazolyl, furanyl, thienyl, pyrimidyl, benzodioxolyl, benzodioxanyl, benzofuryl, or benzothienyl.

Such substituent optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, C1-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl,-N (R6) (R7), -C (O) (R8),-S-R6,-S (O) 2-R6, phenyl, phenyl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-CI-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, halophenyl, and halogen-substituted phenyl-Cl-C6-alkyl. Such substituent also optionally is substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.

[169] In some preferred embodiments, ES is phenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-zalkyl, -N(R6)(R7), -C(O)(R8), -S-R6, -S(O)2-R6, phenyl, phenyl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halophenyl, and halogen-substituted phenyl-C1-C6-alkyl. The phenyl also is optionally substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.

[170] In some preferred embodiments, ES is naphthalenyl optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C6-alkyl, Cl-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, -N(R6)(R7), -C(O)(R8), -S-R6, -S(O)2-R6, phenyl, phenyl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halophenyl, and halogen-substituted phenyl-Cl-C6-alkyl. The naphthalenyl also is optionally substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl.

[171] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Rl nor R2 forms a ring structure with E2 E3 E4 orE5 [172] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, C1-C8-alkyl, and halo-Cl-C8-alkyl.

[173] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, C1-C6-alkyl, and halo-Cl-C6-alkyl.

[174] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and Cl-C6-alkyl.

[175] R3 is-H or alkyl. The alkyl optionally is substituted.

[176] In some preferred embodiments, R3 is-H, Cl-C8-alkyl, or halo-C1-C8-alkyl.

[177] In some preferred embodiments, R3 is-H, Cl-C6-alkyl, or halo-Cl-C6-alkyl.

[178] In some preferred embodiments, R3 is-H or Cl-C8-alkyl.

[179] R6 and R7 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, heterocyclyl-Cl-C$-alkyl, halo-Cl-C8-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-Cl-C8-alkyl, haloheterocyclyl, and halogen-substituted heterocyclyl-Cl-C8-alkyl.

[180] In some preferred embodiments, R6 and R7 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[181] R8 is-H, C1-C8-alkyl, -O-R9, -N (R9)(R10), carbocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-Cl-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heterocyclyl-C1-C8-alkyl.

[182] In some preferred embodiments, R8 is-H, C1-C6-alkyl, -O-R9, -N (R9) (Rio), carbocyclyl-Cl-C6-alkyl, heterocyclyl-Cl-C6-alkyl, halo-C1-C6-alkyl, halogen-substituted carbocyclyl-Cl-C6-alkyl, or halogen-substituted heterocyclyl-C1-C6-alkyl.

[183] In some preferred embodiments, R8 is-H, C1-C6-alkyl, -O-R9, -N (R9) (R10), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-C1-C6-alkyl.

[184] R9 and R10 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, halo-Cl-C8-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-C1-C8-alkyl, haloheterocyclyl, and halogen-substituted heterocyclyl-C1-C8-alkyl.

[185] In some preferred embodiments, R9 and Rl° are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, heterocyclyl-C1-C6-alkyl, halo-Cl-C6-alkyl, halocarbocyclyl,

halogen-substituted carbocyclyl-Cl-C6-alkyl, haloheterocyclyl, and halogen-substituted heterocyclyl-Cl-C6-alkyl.

[186] In some preferred embodiments, R9 and Rl° are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, and heterocyclyl, heterocyclyl-Cl-C6-alkyl.

Preferred Embodiment No. 2-a: E3 is optionally-substituted heterocyclyl [187] In some embodiments, E3 is optionally-substituted heterocyclyl.

[188] In some preferred embodiments E3 is an optionally-substituted heterocyclyl that contains only one heteroatom ring member. Examples of often suitable heterocyclyls include furanyl, tetrahydropyranyl, dihydrofuranyl, tetrahydrofuranyl, thiophenyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolyl, isopyrrolyl, pyrrolidinyl, pyridinyl, piperidinyl, pyranyl, dihydropyranyl, and tetrahydropyranyl.

[189] In some preferred embodiments, E3 is optionally-substituted pyridinyl. In some such embodiments, Es is optionally-substituted phenyl. Such compounds include, for example: IIIA-1 Such compounds also include, for example: IIIA-4 [190] In some preferred embodiments, E3 is an optionally-substituted heterocyclyl selected from the group consisting of : Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, Ci-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the substituent is halogen or -OH, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-C1-C6-alkyl, Cl-C6-alkylthio, halo-Ci-C6-alkyl, halo-C1-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and

halo-C1-C6-alkylthio. R14 is selected from the group consisting of halogen,-OH, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is halogen or-OH, any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, Cl-C6-alkyl, Cl-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, Cl-C6-alkylthio, halo-C1-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, and halo-C1-C6-alkylthio.

[191] In some preferred embodiments, E3 is optionally-substituted furanyl. In one such embodiment, for example, ES is optionally-substituted phenyl. Such compounds include, for example:

[192] In some preferred embodiments, E3 is optionally-substituted thienyl. In some such embodiments, ES is optionally-substituted phenyl. Such compounds include, for example : Such compounds also include, for example:

[193] In some preferred embodiments, E3 is optionally-substituted pyrrolidinyl.

In some such embodiments, for example, ES is optionally-substituted phenyl. Such compounds include, for example:

[1941 E3 also may be, for example, an optionally-substituted heterocyclyl that contains no greater and no less than two heteroatom ring members. Suitable heterocyclyls include, for example, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, dithiolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxathiolyl, oxathiolanyl, oxazolyl, isoxazolyl, oxazolidinyl, isoxazolidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazinyl, and morpholinyl.

[195] In some preferred embodiments, E3 is an optionally-substituted heterocyclyl selected from the group consisting of :

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, Cl-C6-alkyl,

Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the substituent is halogen or -OH, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, C1-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-CI-C6-alkyl, C1-C6-alkylthio, halo-Co-C6-alkyl, halo-Ci-Ce-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, and halo-Cl-C6-alkylthio. Such substituents also optionally are substituted with one or more substituents independently selected from the group consisting of C2-C6-alkenyl and C2-C6-alkynyl. R14 is as defined above where E3 contains only one heteroatom in its ring.

[196] In some particularly preferred embodiments, E3 is an optionally-substituted heterocyclyl selected from the group consisting of oxazolyl and isoxazolyl. In some such embodiment, for example, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

IIIA-21 [197] In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of pyrazolyl and isoimidazolyl. In some such embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

IIIA-26 [lssl In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of thiazolyl and isothiazolyl. In one such embodiment, for example, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: IIIA-27 [199] In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of pyrazolidinyl and imidazolidinyl. In some such embodiments, ES is optionally-substituted carbocyclyl. In some preferred embodiments, ES is optionally-substituted aryl, often preferably optionally-substituted phenyl. Such compounds include, for example: IIIA-28 IIIA-29 IIIA-32 IIIA-33 IIIA-34 In other preferred embodiments, Es is optionally substituted C5-C6-cycloalkyl. Such compounds include, for example:

[200] In some preferred embodiments, E3 is optionally-substituted oxazolidinyl.

In some such embodiments, ES is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

[201] E3 also may be, for example, an optionally-substituted heterocyclyl that contains no greater and no less than 3 heteroatom ring members. Often suitable heterocyclyls include, for example, oxadiazolyl, thiadiazolyl, and triazolyl. Here, the triazolyl optionally is substituted.

[202] In some preferred embodiments, E3 is an optionally-substituted heteroaryl selected from the group consisting of :

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, Cl-C6-alkyl, Cl-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the substituent is halogen or -OH, any substituent of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH, Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-C1-C6-alkyl, C1-C6-alkylthio, halo-C1-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, and halo-Cl-C6-alkylthio. R14 is as defined above for heterocyclyls containing 1 or 2 heteroatom ring members.

[203] In some preferred embodiments, E3 is oxadiazolyl.

[204] In some such embodiments, ES is optionally-substituted phenyl. Such compounds include, for example: IIIA-61 IIIA-62 IIIA-63 IIIA-64 Such compounds also include, for example: IIIA-123 [205] In other embodiments, E5 is optionally-substituted naphthalenyl. Such compounds include, for example: [206] In other embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: IIIA-126 [207] In yet other embodiments, E5 is optionally-substituted heterocyclyl. Such compounds include, for example: IIIA-128 IIIA-129

IIIA-130 Such compounds also include, for example: [208] E3 also may be, for example, an optionally-substituted heterocyclyl that contains at least 4 heteroatom ring members.

{209] In some preferred embodiments, E3 is selected from the group consisting of : In some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: IIIA-142 IIIA-144 IIIA-150 IIIA-151 In other such embodiments, Es is optionally-substituted heterocyclyl. Such compounds include, for example:

IIIA-152 IIIA-153 Preferred Embodiment No. 2-b : E3 is optiofzally substituted carbocyclyl [210] In some embodiments, E3 is an optionally-substituted carbocyclyl. E3 may be, for example, an optionally-substituted carbocyclyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, naphthalenyl, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl, fluoreneyl, decalinyl, and norpinanyl.

[211] In some preferred embodiments, E3 is optionally-substituted phenyl. In one such embodiment, for example, ES is optionally-substituted heterocyclyl.

[212] In some such embodiments, E5 is optionally-substituted heterocycloalkyl.

Examples of such compounds include, for example: IDB-3 [213] In other preferred embodiments, E5 is optionally-substituted, 5-member heteroaryl. Examples of such compounds include, for example: IIIB-4 IIIB-5 IIIB-8 IIIB-9 Such compounds also include, for example:

IIIB-10 [214] In other preferred embodiments, E5 is optionally-substituted, 6-member heteroaryl.

[215] In other preferred embodiments, ES is optionally-substituted pyridinyl.

Such compounds include, for example: IIIB-11 IIIB-12 IIIB-13 IIIB-14 IIIB-15 Such compounds also include, for example: IIIB-18 IIIB-19 IIIB-20 [216] In other preferred embodiments, Es is optionally-substituted pyrimidinyl.

Such compounds include, for example:

IIIB-21 [217] In other preferred embodiments, ES is optionally-substituted, multi-ring heterocyclyl. Such compounds include, for example: IIIB-22 IIIB-23 IIIB-26 [218] In some preferred embodiments, for example, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, [219] In some preferred embodiments, ES is optionally-substituted phenyl. Such compounds include, for example: IIIB-28 IIIB-27 IIIB-29 IIIB-30 IIIB-67 ITIB-68 IIIB-71 Other such compounds include, for example: IIIB-72 IIIB-73 IIIB-88 IIIB-89 IIIB-90 IIIB-91 IIIB-92 IIIB-93 IIIB-97 IIIB-98 [220] In other preferred embodiments, E5 is optionally-substituted naphthalenyl.

Such compounds include, for example: Preferred Embodiment No. 3 [2211 In some embodiments of this invention, the compound has a structure corresponding to Formula IV :

IV [2221 A1, A, and A3 are as defined above for Formula I.

[223] El is s -O-, -S (O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (R1)-, -N (Rl)-C (O)-, or -C(R1)(R2)-.

[2241 E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[225] In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[226] In some preferred embodiments, E2 is Cl-C6-alkyl, cycloalkyl, Ci-C6-alkylcycloalkyl, cycloalkyl-Cl-C6-alkyl, or Cl-C6-alkylcycloalkyl-Cl-C6-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C2-alkyl, and halo-C1-C2-alkyl.

[2271 In some preferred embodiments, E2 is Cl-C6-alkyl, cycloalkyl, Cl-C6-alkylcycloalkyl, cycloalkyl-Cl-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more Cl-C2-alkyl.

[228] E4 is a bond or alkyl. The alkyl optionally is substituted.

[229] In some preferred embodiments, E4 is a bond, C1-C20-alkyl, or halo-Cl-C2o-alkyl.

[230] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or halo-Cl-C3-alkyl.

[231] In some preferred embodiments, E is a bond or Cl-C3-alkyl.

[232] In some preferred embodiments, E4 is a bond.

[2331 ES is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[234] In some preferred embodiments, ES is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl.

The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, keto, Cl-Cg-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halo-Cl-Cs-alkoxy,-N (R7) (R8),-C (O) (R9), -S-R7, -S (O) 2-R, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C8-alkyl, and halogen-substituted C1-C8-alkoxy-C1-C8-alkyl.

[235] In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl.

The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-C$-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, keto, C1-C6-alkyl, halo-Ci-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halo-Cl-C6-alkoxy,-N (R7) (R8), -C (O) (R9),-S-R7,-S (O) 2-R7, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted C1-C6-alkoxy-C1-C6-alkyl.

[236] E6 is -H, halogen, or alkyl. The alkyl optionally is substituted.

[237] In some preferred embodiments, E6 is-H, halogen, or Cl-C8-alkyl. The Cl-Ce-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[238] In some preferred embodiments, E6 is-H, halogen, or Cl-C6-alkyl. The Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[239] E7 is -H, alkyl, alkenyl, alkynyl,-S (0) 2-R3, -NO2, -C (O)-N (R3)(R4), -(C)(OR3), carbocyclyl, carbocyclylalkyl, alkoxycarbocylcyl, -CN, -C=N-OH, or -C=NH.

The alkyl, alkenyl, alkynyl, carbocyclyl, carbocyclylalkyl, and alkoxycarbocyclyl optionally are substituted.

[240] In some preferred embodiments, E is-H, C1-C8-alkyl, C1-C8-alkenyl, C1-C8-alkynyl, -S (0) 2-R3,-NO2,-C (O)-N (R3) (R4), -(C)(OR3), carbocyclyl, carbocycyl-C1-C8-alkyl, C1-C8-alkoxycarbocyclyl, -CN, -C=N-OH, or-C=NH. The C1-C6-alkyl, C1-C8-alkenyl, C1-C8-alkynyl, carbocyclyl, carbocycyl-Cl-C8-alkyl, or Cl-Cg-alkoxycarbocyclyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[241] In some preferred embodiments, E is -H, C1-C6-alkyl, C1-C6-alkenyl, C1-C6-alkynyl, -S (0) 2-R3, -NO2, -C(O)-N(R3)(R4), -(C)(OR3), carbocyclyl, carbocycyl-C1-C6-alkyl C1-C6-alkoxycarbocyclyl, -CN, -C=N-OH, or-C=NH. The C1-C6-alkyl, Cl-C6-alkenyl, C1-C6alkynyl, carbocyclyl, carbocycyl-Cz-C6-alkyl, or Ci-C6-alkoxycarbocyclyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[242] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor Ra forms a ring structure with E2, E4,E5,E6, or E7.

[243] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C8-alkyl, and halo-C1-C8-alkyl.

[244] In some preferred embodiments, R and W are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-Ci-C6-alkyl.

[245] In some preferred embodiments, R and R are independently selected from the group consisting of-H and C1-C6-alkyl.

[246] R3 and R4 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted.

[247] In some preferred embodiments, R3 and R4 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C$-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[248] In some preferred embodiments, R3 and R4 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[249] R7 and R8 are independently selected from the group consisting of-H, Cl-Cg-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[250] In some preferred embodiments, R7 and R8 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[251] R9 is-H, C1-C8-alkyl, -O-R10, -N (R10) (Rl), carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-C8-alkyl. The Cl-C8-alkyl, carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[252] In some preferred embodiments, R9 is-H, Cl-C6-alkyl,-O-Rl°, -N (Rt°) (Rll), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The C1-C6-alkyl, carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[253] Rl° and Roll are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[254] In some preferred embodiments, Rlo and Rll are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[255] In some preferred embodiments, E5 is optionally-substituted carbocyclyl or optionally-substituted heterocyclyl. For example, in some such embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example: IV-1 IV-2 IV-4 IV-3

IV-19 [256] In some preferred embodiments, Es is C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, or Cl-C6-alkoxy-Cl-C6-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN.

[257] In some preferred embodiments, Es is optionally-substituted Cl-C6-alkyl, with the Cl-C6-alkyl often being more preferably unsubstituted. Such compounds include, for example:

IV-21 Preferred Embodiment No. 4 [258] In some embodiments of this invention, the compound has a structure corresponding to Formula V:

v [259] A1, A2, and A3 are as defined above for Formula I.

[260] El is-O-,-S (O) 2-,-S (O)-,-N (R3)-,-C (O)-N (R3)-, -N (R3)-C (O)-, or C(R1)(R2)-.

[261] E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Except where the member is a bond, any member of such group optionally is substituted.

[262] In some preferred embodiments, E2 is a bond, Cl-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-Ci-Clo-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl.

Any member of this group (except for the bond) optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-Cl-C6-alkyl.

[263] In some preferred embodiments, E2 is a bond, Cl-C6-alkyl, or halo-Cl-C6-alkyl.

[264] In some preferred embodiments E2 is a bond or Cl-C6-alkyl.

[265] E3 is carbonylpyrrollidinyl. The carbonylpyrrollidinyl optionally is substituted.

[266] In some preferred embodiments, E3 is carbonylpyrrollidinyl wherein the carbonylpyrrollidinyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[267] E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[268] In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or ahlo-C2-C20-alkenyl.

[269] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, halo-Cl-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[270] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

[271] In some preferred embodiments, E4 is a bond.

[272] ES is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[273] In some preferred embodiments, Es is C1-C20-alkyl, C2-C2o-alkenyl, C2-C20-alkynyl, Cl-C2o-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl.

The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, Cl-C8-alkoxy, halo-C1-C8-alkoxy,

Cl-C8-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C8-alkoxy-Cl-C8-alkyl,-N (R5)(R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C8-alkyl, and halogen-substituted carbocyclyl-Cl-C$-alkyl.

[274] In some preferred embodiments, E5 is Cl-C8-alkyl, C2-C8-alkenyl, C2-Cg-alkynyl, C1-C8-alkoxy, Cl-Cg-alkoxy-Cl-Cg-alkyl, carbocyclyl, or heterocyclyl.

The Cl-Cg-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, keto, C1-C6-alkyl, halo-Cl-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Ci-C6-alkyl,-N (R) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.

[275] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Ri nor R2 forms a ring structure with E2,E3,E4, or E5.

[276] In some preferred embodiments, Ri and R2 are independently selected from the group consisting of-H, Cl-Cg-alkyl, and halo-C1-C6-alkyl.

[277] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[278] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and Cl-C6-alkyl.

[279] RS and R6 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[280] In some preferred embodiments, RS and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-CI-C6-alkyl. Except where the member is-H, any member

of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[281] R7 is-H, Cl-Cg-alkyl,-O-R8,-N (R8) (R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-C8-alkyl. The Cl-C8-alkyl, carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-Cg-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[282] In some preferred embodiments, R7 is-H, Cl-C6-alkyl,-0-R8,-N (R8) (R9), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-CI-C6-alkyl, or heterocyclyl-CI-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[283] R8 and R9 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-allcyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[284] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[285] In some preferred embodiments, the compound has a structure corresponding to Formula V-A: V-A [286] In some preferred embodiments, ES is optionally-substituted carbocyclyl or optionally substituted heterocyclyl. For example, in some such embodiments, E5 is optionally substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

V-5 [287] In some preferred embodiments, ES is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: V-6 [288] In some preferred embodiments, E5 is Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, or Cl-C8-alkoxy-Cl-C8-alkyl. The C1-C8alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and Cl-Cs-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN.

[289] In some preferred embodiments, ES is optionally-substituted C1-C8-alkyl, with Cl-C8-alkyl often being more preferred. Such compounds include, for example:

Preferred Embodiment No. 5 [290] In some embodiments of this invention, the compound has a structure corresponding to Formula VI: VI [291] A1, A2, and A3 are as defined above for Formula I.

[292] E1 is -O-, -S(O) 2-,-S (O)-,-N (Rl)-,-C (O)-N (Rl)-,-N (R1)-C (O)-, or -C(R1)(R2)-.

[293] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, alkyl, and haloalkyl.

[294] In some preferred embodiments, E2 is Cl-C20-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or Cl-Clo-alkylcycloalkyl-Cl-Clo-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-Cl-C6-alkyl.

[295] In some preferred embodiments, E2 is Cl-C6-alkyl, cycloalkyl, C1-C6-alkylcycloalkyl, cycloalkyl-Cl-C6-alkyl, or Ci-C6-alkylcycloallcyl-Cl-C6-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C2-alkyl, and halo-C1-C2-alkyl.

[296] In some preferred embodiments, E2 is Cl-C6-alkyl, cycloalkyl, C1-C6-alkylcycloalkyl, cycloalkyl-Cl-C6-alkyl, or Cl-C6-alkylcycloalkyl-Cl-C6-alkyl. Any member of this group optionally is substituted with one or more Ci-C2-alkyl.

[297] ES is alkyl, alkenyl, alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. Here, the cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl optionally are substituted. The alkyl, alkenyl, and alkynyl (a) contain at least 4 carbon atoms, and (b) optionally are substituted with one or more substituents selected from the group consisting of-OH,-NO2,-CN, and halogen.

[298] In some preferred embodiments, Es is C4-C20-alkyl, C4-C20-alkenyl, C4-C20-alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. The C4-C2o-alkyl, C4-C20-alkenyl, and C4-C2o-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of -OH, -NO2, -CN, and halogen. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, -CN, keto, Ci-Cg-alkyl, halo-Cl-Cg-alkyl, C1-C8-alkoxy, halo-Cl-Cs-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted Cl-C8-alkoxy-Ci-Cs-alkyl,-N (RS) (R6), -C (O) (R7),-S-R,-S (0) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-CI-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.

[299] In some preferred embodiments, Es is C4-Cg-alkyl, C4-C8-alkenyl, C4-C8-alkynyl, cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, or cyclohexadienyl. The C4-C8-alkyl, C4-C8-alkenyl, and C4-C8-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of-OH,-N02,-CN, and halogen. The cycloalkyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, keto, C1-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-C1-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-CI-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[300] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither Ri nor R2 forms a ring structure with .

[301] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, C1-C8-alkyl, and halo-Cl-Cg-alkyl.

[302] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[303] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and Cl-C6-alkyl.

[304] Rs and R6 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Ci-Cs-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[305] In some preferred embodiments, Rs and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-CI-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[306] R7 is -H, C1-C8-alkyl, -O-R8, -N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-Cs-alkyl. The Cl-C8-alkyl, carbocyclyl-Co-C8-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[307] In some preferred embodiments, R7 is -H, C1-C6-alkyl, -O-R8, -N(R8)(R9), carbocyclyl-Cz-C6-alkyl, or heterocyclyl-Cz-C6-alkyl. The Cl-C6-alkyl, carbocyclyl-CI-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[308] R8 and R9 are independently selected from the group consisting of-H, Cl-Cg-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[309] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cz-C6-aLkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[310] In some preferred embodiments, ES is C4-C8-alkyl, C4-C8-alkenyl, or C4-C8-alkynyl. The C4-C8-alkyl, C4-C8-alkenyl, and C4-C8-alkynyl optionally are substituted with one or more substituents independently selected from the group consisting of-OH,-N02,-CN, and halogen. Such compounds include, for example: VI-1 VI-2 VI-3 VI-4

VI-5 [311] In some preferred embodiments, Es is optionally-substituted carbocyclyl.

In some such embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: In other such embodiments, ES is an optionally-substituted, partially-saturated carbocyclyl selected from the group consisting of cyclopentenyl, cyclopentadienyl, cyclohexenyl, and cyclohexadienyl. Such compounds include, for example:

Preferred Embodiment No. 6 [312] In some embodiments of this invention, the compound has a structure corresponding to Formula VII : VII [313] A1, A2, and A3 are as defined above for Formula I.

[314] El is-O-,-S (O) 2-,-S (O)-,-N (Ri)-,-C (O)-N (Rl)-,-N (RI)-C (O)-, or -C(R1)(R2)-.

[315] E2 is alkyl, cycloalkyl, alkylcycloalkyl, sycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[316] In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, Cl-yo-alkylcycloalkyl, cycloalkyl-Ci-Clo-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[317] In some preferred embodiments, E2 is Cl-C6-alkyl optionally substituted with one or more halogen.

[318] In some preferred embodiments, E2 is Cl-C6-alkyl.

[319] E3 is carbonylpiperidinyl. The carbonylpiperidinyl optionally is substituted.

[320] In some preferred embodiments, E3 is carbonylpiperidinyl wherein the carbonylpiperidinyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[321] In some preferred embodiments, the compound has a structure corresponding to one of the following formulas : VII-A VII-B [322] E is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[323] In some preferred embodiments, E4 is a bond, Cl-C2o-alkyl, halo-Cl-C2o-alkyl, C2-C2o-alkenyl, or halo-C2-C20-alkenyl.

[324] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, halo-Cz-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[325] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

[326] In some preferred embodiments, E4 is a bond.

[327] ES is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[328] In some preferred embodiments, ES is Cl-C2o-alkyl, C2-C20-alkenyl, C2-C20-alkynyl,C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl.

The C1-C20-alkyl, C2-C2o-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and Cl-C20-alkoxy-Ci-C2o-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, keto, Cl-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, -N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-C1-C8-alkyl.

[329] In some preferred embodiments, Es is C1-C8-alkyl, C2-Cg-alkenyl, C2-C8-alkynyl, Cl-C8-alkoxy, Cl-C8-alkoxy-Cl-C8-alkyl, carbocyclyl, or heterocyclyl.

Here, the Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and Cl-C6-alkoxy-Cl-C6-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, keto, Cl-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-C1-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cz-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[330] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E3, E4 or Es [3311 In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[332] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[333] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and C1-C6-alkyl.

[334] R and R6 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and

heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[335] In some preferred embodiments, Rs and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[336] R7 is-H, Cl-C6-alkyl,-0-R8,-N (R8) (R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The Cl-Cs-alkyl, carbocyclyl-Cz-C8-alkyl, or heterocyclyl-Cz-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[337] In some preferred embodiments, R7 is-H, Ci-C6-alkyl,-0-R8,-N (R8) (R9), carbocyclyl-Ci-C6-alkyl, or heterocyclyl-CI-C6-alkyl. The Cl-C6-alkyl, carbocyclyl-Cz-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[338] R8 and R9 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cz-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[339] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[340] In some preferred embodiments, Es is optionally-substituted carbocyclyl or optionally substituted heterocyclyl. In some such embodiments, Es is optionally-substituted aryl, often preferably optionally-substituted phenyl. Such compounds include, for example:

Preferred Embodiment No. 7 [341] In some embodiments of this invention, the compound has a structure corresponding to Formula VIII: VIII [342] A1, A2, and A3 are as defined above for Formula I.

[343] E1 is -O-, -S(O) 2-,-S (O)-,-N (R1)-,-C (O)-N (R')-,-N (RI)-C (O)-, or -C(R1)(R2)-.

[344] E2 forms a link of at least 3 carbon atoms between El and E5. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[345] In some preferred embodiments, E2 is C3-C20-alkyl, cycloalkyl, Cl-Clo-alkyl-cycloallcyl, cycloalkyl-Cl-Clo-alkyl, or Cl-Clo-alkyl-cycloalkyl-Cl-Cio-alkyl.

Any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[346] In some preferred embodiments, E is C3-C6-alkyl optionally substituted with one or more halogen.

[347] In some preferred embodiments, E2 is C3-C6-alkyl.

[348] Es is optionally-substituted heterocyclyl, optionally-substituted fused-ring carbocyclyl, or substituted single-ring carbocyclyl.

[349] In some preferred embodiments, Es is single-ring carbocyclyl, fused-ring carbocyclyl, or heterocyclyl.

[350] Here, the single-ring carbocyclyl is substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, keto, Cl-C8-alkyl, halo-C1-C8-alkyl, Cl-Cg-alkoxy, halo-Cl-Cg-alkoxy, Cl-C8-alkoxy-Cl-Cs-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, -N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cz-Ca-alkyl, halogen-substituted carbocyclyl-CI-C8-alkyl. The single-ring carbocyclyl also optionally is substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.

[351] In some preferred embodiments, the single-ring carbocyclyl is substituted with one or more substituents independently selected from the group consisting of and halogen,-OH,-N02,-CN, keto, Cl-C6-alkyl, halo-Ci-C6-alkyl, Ci-C6-alkoxy, halo-Ci-Ce-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, -N(R5)(R6), -C(O)(R7), -S-R5, -S(O)2-R5,carbocyclyl, halocarbocyclyl, carbocyclyl-CI-C6-alkyl, and halogen-substituted carbocyclyl-Cr-C6-alkyl. The single-ring carbocyclyl also optionally is substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-Cs-C6-cycloalkyl.

[352] The heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of and halogen, - OH,-N02,-CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, Cl-C8-alkoxy, halo-C1-C8-alkoxy, Cl-C8-alkoxy-Cl-Cs-alkyl, halogen-substituted Cl-Cs-alkoxy-Cl-Cs-alkyl,-N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-C1-C6-alkyl.

The heterocyclyl and fused-ring carbocyclyl also optionally are substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming Cs-C6-cycloalkyl or halo-C5-C6-cycloalkyl.

[353] In some preferred embodiments, the heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of and halogen,-OH,-N02,-CN, keto, Cl-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl,

halogen-substituted Ci-C6-alkoxy-Cl-C6-alkyl,-N (R5) (R6), -C (O) (R7)-S-R5,-S (O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-CI-C6-alkyl. The heterocyclyl and fused-ring carbocyclyl also optionally are substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.

[354] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5 [355] In some preferred embodiments, R and R2 are independently selected from the group consisting of-H, C1-C8-alkyl, and halo-C1-C8-alkyl.

[356] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

13571 In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and Cl-C6-alkyl.

[358] R5 and R6 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Ci-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[359] In some preferred embodiments, RS and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-CI-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[360] R7 is-H, Cl-C8-alkyl,-0-Rg,-N (R8) (R9), carbocyclyl-Cz-Ca-alkyl, or heterocyclyl-C1-C8-alkyl. The Cl-C8-alkyl, carbocyclyl-Cz-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[361] In some preferred embodiments, R7 is -H, C1-C6-alkyl, -O-R8, -N(R8)(R9), carbocyclyl-Cz-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl,

carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[362] R8 and R9 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-CI-Cs-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[363] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-CI-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[364] In some preferred embodiments, Es is a substituted single-ring carbocyclyl.

Es may be, for example a substituted single-ring carbocyclyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl.

[365] In some preferred embodiments, Es is substituted phenyl. Such compounds include, for example: Such compounds also include, for example:

VIII-14 [366] In some preferred embodiments, Es is optionally-substituted fused-ring carbocyclyl. Es may be, for example, optionally-substituted fused-ring carbocyclyl selected from the group consisting of naphthalenyl, tetrahydronaphthalenyl, indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl, fluoreneyl, decalinyl, and norpinanyl.

[367] In some preferred embodiments, Es is optionally-substituted naphthalenyl.

Such compounds include, for example:

VIII-17 [368] In some preferred embodiments, E is optionally-substituted, single-ring heterocyclyl.

[369] In some preferred embodiments, Es is an optionally-substituted pyridinyl.

Such compounds include, for example:

VIII-20 VIII-22 [370] In some preferred embodiments, Es is an optionally-substituted heterocyclyl selected from the group consisting of imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, and pyrazolidinyl. Such compounds include, for example: VIII-25 VIII-26 [371] In some preferred embodiments, Es is optionally-substituted fused-ring heterocyclyl. Es may be, for example, an optionally-substituted fused-ring heterocyclyl selected from the group consisting of indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl. Compounds wherein Es is an optionally-substituted fused-ring heterocyclyl include, for example: VIII-39 VIII-40 [372] In some preferred embodiments, Es is optionally-substituted tetrahydroisoquinolinyl. Such compounds include, for example:

VIII-49 [373] In some preferred embodiments, Es is heterocyclyl that is substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming Cs-C6-cycloalkyl or halo-Cs-C6-cycloalkyl. This heterocyclyl also optionally is substituted with one or more substituents independently selected from the group consisting of and halogen,-OH,-N02, - CN, keto, Cl-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (rus) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl. The heterocyclyl that is substituted may be, for example, selected from the group consisting of dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, dithiolyl, oxathiolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, oxathiolanyl, pyranyl, dihydropyranyl, piperidinyl, piperazinyl, and morpholinyl. Such compounds include, for example: VIII-50 Preferred Embodiment No. 8 [374] In some embodiments of this invention, the compound has a structure corresponding to Formula IX:

[375] A1, A2, and A3 are as defined above for Formula I.

[376] El is-O-,-S (0) 2-,-S (O)-,-N (Rl)-,-C (O)-N (Rl)-,-N (Rl)-C (O)-, or -C (R1) (R2)- [377] E2 forms a link of at least 4 carbon atoms between El and E5. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[378] In some preferred embodiments, E2 is C4-C20-alkyl, cycloalkyl, C1-C10alkyl-cycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkyl-cycloalkyl-C1-C10-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.

[379] In some preferred embodiments, E2 is C4-C6-alkyl optionally substituted with one or more halogen.

[380] In some preferred embodiments, E2 is C4-C6-alkyl.

[381] Es is-OH or optionally-substituted carbocyclyl.

[382] In some preferred embodiments, Es is-OH or carbocyclyl wherein the carbocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of and halogen,-OH,-N02,-CN, keto, C1-C8-alkyl, halo-Cl-C8-alkyl, Cl-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-aklkyl, -N (R) (R6),-C (O) (R7),-S-R5,-S (0) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C8-alkyl. The carbocyclyl also optionally is substituted with two Cl-Cs-alkyl or halo-Cl-C8-alkyl groups on the same atom that form a C5-C6-cycloalkyl or C5-C6-halocycloalkyl.

[383] In some preferred embodiments, Es is-OH or carbocyclyl wherein the carbocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of and halogen,-OH,-N02,-CN, keto, Cl-C6-alkyl,

halo-Cl-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, -N (rus) (R6),-C (O) (R7),-S-R5,-S (0) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Co-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[384] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E5.

[385] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, C1-C8-alkyl, and halo-C1-C8-alkyl.

[386] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-Cl-C6-alkyl.

[387] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and Cl-C6-alkyl.

[388] R5 and R6 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[389] In some preferred embodiments, R5 and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[390] R7 is-H, C1-C8-alkyl, -O-R8, -N (R8) (R9), carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-C8-alkyl. The Cl-Cs-alkyl, carbocyclyl-Cl-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[391] In some preferred embodiments, R7 is -H, C1-C6-alkyl, -O-R8, -N(R8)(R9), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[392] R8 and R are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[393] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen. Such compounds include, for example: [394] In some preferred embodiments, E5 is optionally-substituted carbocyclyl, often preferably optionally-substituted aryl, and more preferably optionally-substituted phenyl. Such compounds include, for example:

IX-3 [395] In some preferred embodiments, Es is-OH. Such compounds include, for example: Preferred Embodiment No. 9 [396] In some embodiments of this invention, the compound has a structure corresponding to Formula X:

x [397] A1, A2, and A3 are as defined above for Formula I.

[398] El is-S (0) 2-,-S (O)-,-N (RI)-,-C (O)-N (R1)-,-N (R1)-C (O)-, or-C (R') (R2)-.

[399] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[400] In some preferred embodiments, E2 is Cl-C20-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or Cl-Cio-alkylcycloalkyl-Cl-Clo-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, Cl-C6-halo-alkyl.

[401] In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.

[402] In some preferred embodiments, E2 is C2-C6-alkyl.

[403] E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[404] In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-Cl-C20-alkyl, C2-C2o-alkenyl, or halo-C2-C20-alkenyl.

[405] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[406] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

[407] ES is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[408] In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, Cl-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl.

The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, Cl-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, Cl-Cs-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted Cl-C8-alkoxy-Cl-Cs-alkyl,-N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-Cs-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.

[409] In some preferred embodiments, ES is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, carbocyclyl, or heterocyclyl.

The C1-C8-alkyl, C2-Cg-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of ahlogen, -OH, -NO2, -CN, keto, C1-C6-alkyl, halo-Cl-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (rus) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[410] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, orE.

[411] In some preferred embodiments, R'and R are independently selected from the group consisting of-H, Ci-Cs-alkyl, and halo-C1-C8-alkyl.

[412] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[413] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and C1-C6-alkyl.

[414] RS and R6 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-Cg-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may

be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[415] In some preferred embodiments, R5 and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[416] R7 is-H, C1-C6-alkyl, -O-R8, -N (R8) (R9), carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-C8-alkyl. The Cl-C8-alkyl, carbocyclyl-CI-C8-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[417] In some preferred embodiments, R is-H, C1-C6-alkyl, -O-R8, -N (R8) (R9), carbocyclyl-Cl-C6-alkyl, or heteroyclyl-C1-C6-alkyl. The C1-C6-alkyl, carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[418] R8 and R9 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[419] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[420] In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Ci-C8-alkoxy, or C1-C8-alkoxy-C1-C8-alkyl. The Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-C8-alkoxy, and Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of chalogen, -OH, -NO2, and-CN.

[421] In some preferred embodiments, E5 is Cl-C8-alkyl. Such compounds include, for example: Preferred Embodiment No. 10 [422] In some embodiments of this invention, the compound has a structure corresponding to Formula XI :

XI [423] A1, A2, and A3 are as defined above for Formula I.

[424] E2 comprises at least 3 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[425] In some preferred embodiments, E2 is C3-C20-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[426] In some preferred embodiments, E2 is C3-Clo-alkyl optionally is substituted with one or more halogen.

[427] In some preferred embodiments, E2 is C3-Clo-alkyl.

[428] In some preferred embodiments, E2 is C3-C5-alkyl.

[429] E5 is-H, alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, or heterocyclylalkoxyalkyl. The alkyl, alkenyl, alkynyl, and alkoxyalkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, and -CN. The carbocyclyl, carbocyclylalkoxyalkyl, heterocyclyl, heterocyclylalkyl, and

heterocyclylalkoxyalkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl,-N (R3) (R4), -C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.

[430] In some preferred embodiments, Es is-H, C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, carbocyclyl-Cl-Clo-alkoxy- Cl-Clo-alkyl, heterocyclyl, heterocyclyl-CI-Clo-alkyl, or heterocyclyl-Cl-Clo-alkoxy-Cl- Cio-alkyl. The C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy-C1-C20- alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl, carbocyclyl-Cl-Clo-alkoxy-Cl-Clo-alkyl, heterocyclyl, heterocyclyl-Cl-Clo-alkyl, and heterocyclyl-C1-C10-alkoxy-C1-C10-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, keto, Cl-C8-alkyl, halo-Cl-C8-alkyl, Cl-C8-alkoxy, halo-Cl-C$-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, -N (R3) (R4), -C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-Cs-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.

[431] In some preferred embodiments, E5 is -H, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-Cs-alkoxy-Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cl-Cg-alkoxy- C1-C8-alkyl, heterocyclyl, heterocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkoxy-C1- C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl, carbocyclyl-Cl-C8-alkoxy-Cl-C8-alkyl, heterocyclyl, heterocyclyl-Cl-C8-alkyl, and heterocyclyl-Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, -CN, keto, C1-C6-alkyl, halo-Ci-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R3) (R4), -C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.

[432] R1 and R2 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[433] In some preferred embodiments, Ri and R2 are independently selected from the group consisting of-H, Cl-Cg-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[4341 In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[435] R3 is-H, alkyl,-o-R4,-N (R4) (R5), carbocyclylalkyl, or heterocyclylalkyl.

The alkyl, carbocyclylalkyl, or heterocyclylalkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[436] In some preferred embodiments, R3 is-H, C1-C8-alkyl, -O-R4, -N (R4) (R5), carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-Cg-alkyl. The C1-C8-alkyl, carbocyclyl-Cl-Cs-alkyl, or heterocyclyl-Cl-Cs-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[437] In some preferred embodiments, R3 is-H, Cl-C6-alkyl,-0-R4,-N (R4) (R5), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The C1-C6-alkyl, carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[438] R4 and R5 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[439] In some preferred embodiments, R4 and RS are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member

of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[440] In some preferred embodiments, R4 and RS are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[441] In some preferred embodiments, E5 is-H, C1-C8-alkyl, C2-C8-alkenyl, C2-Cg-alkynyl, or Cl-C8-alkoxy-Cl-C8-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and -CN. Such compounds include, for example:

XI-7 XI-8 [442] In some preferred embodiments, ES is carbocyclyl, carbocyclyl-Cl-C8-alkoxy-Cl-C8-alkyl, heterocyclyl, heterocyclyl-Cl-C8-alkyl, or heterocyclyl-C1-C8-alkoxy-C1-C8-alkyl. the carbocyclyl,

carbocyclyl-Cl-C8-alkoxy-Cl-C8-alkyl, heterocyclyl, heterocyclyl-Cl-C8-alkyl, and heterocyclyl-Cl-Cg-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, keto, Ci-C6-alkyl, halo-C1-C6-alkyl, Ci-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R3) (R4), -C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.

[443] In some preferred embodiments, ES is optionally-substituted carbocyclyl.

[444] In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: XI-17 XI-18 [445] In some preferred embodiments, E5 is optionally-substituted naphthalenyl.

Such compounds include, for example:

XI-19 [446] In some preferred embodiments, ES is heterocyclyl or heterocyclyl-Cl-C8- alkyl. Such compounds include, for example:

Preferred Embodiment No. 11 [447] In some embodiments of this invention, the compound has a structure corresponding to Formula XII:

[448] A1, A2, and A3 are as defined above for Formula I.

[449] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted. An atom in E2 optionally is bound to an atom in Es to form a ring.

[450] In some preferred embodiments, E2 is Cl-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-CI-Clo-alkyl, or Cl-Clo-alkylcycloalkyl-Cl-Clo-alkyl.

Any member of this group optionally is substituted with one or more substituents selected from the group consisting of halogen, Cl-C6-alkyl, halo-Cl-C6-alkyl.

[451] In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.

[452] In some preferred embodiments, E2 is C2-C6-alkyl.

[453] E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[454] In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C20-alkenyl.

[455] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, halo-C1-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[456] In some preferred embodiments, E is a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

[457] In some preferred embodiments, E4 is methyl.

[458] In some preferred embodiments, E4 is a bond.

[459] ES is: an optionally-substituted radical selected from the group consisting of alkenyl, alkynyl, alkoxy, alkoxyalkyl, fused-ring carbocyclyl, and heterocyclyl; or single-ring carbocyclyl substituted with one or more substituents independently selected from the group consisting of-OH,-N02,-CN,-N [R5] (R6), -C (o) (R7),-S-R5,-S (O) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclylalkyl,

halogen-substituted carbocyclylalkyl, heterocyclyl, haloheterocyclyl, heterocyclylalkyl, and halogen-substituted heterocyclylalkyl ; or single-ring carbocyclyl having multiple substitutions.

[460] In some preferred embodiments, E5 is C2-C20-alkenyl, C2-C20-alkynyl, Cl-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, heterocyclyl, single-ring carbocyclyl, or fused-ring carbocyclyl. The C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, -CN, C1-C6-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted Cl-C8-alkoxy-Cl-C8-alkyl,-N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-Cz-Cs-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-Cl-C8-alkyl, and halogen-substituted heterocyclyl-C1-C8-alkyl. The single-ring carbocyclyl is either: substituted with one or more substituents independently selected from the group consisting of-OH,-N02,-CN,-N (R) (R6),-C (O) (R7),-S-R5,-S (O) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cz-Cs-alkyl, halogen-substituted carbocyclyl-CI-C8-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-Cg-alkyl, and halogen-substituted heterocyclyl-C1-C8-alkyl, or substituted with 2 or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, Cl-C8-alkoxy-Cl-C$-alkyl, halogen-substituted Cl-C8-alkoxy-Cl-Cs-alkyl,-N (R5) (R6),-C (O) (R7),-S-R5,-S (O) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, halogen-substituted carbocyclyl-Cz-C8-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C8-alkyl, and halogen-substituted heterocyclyl-C1-C8-alkyl.

[461] In some preferred embodiments, ES is C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, C1-C8-alkoxy-C2-C8-alkyl, heterocyclyl, single-ring carbocyclyl, or fused-ring carbocyclyl. The C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents

independently selected from the group consisting of halogen,-OH,-NO2, and-CN. The heterocyclyl and fused-ring carbocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, -CN, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C6-alkyl, halogen-substituted carbocyclyl-Cz-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-Cl-C6-alkyl, and halogen-substituted heterocyclyl-Cl-C6-alkyl. The single-ring carbocyclyl is either: substituted with one or more substituents independently selected from the group consisting of-OH,-N02,-CN,-N (rus) (R6),-C (O) (R7),-S-R5,-S (0) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, halogen-substituted carbocyclyl-Cl-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-Cl-C6-alkyl, and halogen-substituted heterocyclyl-Cz-C6-alkyl ; or substituted with 2 or more substituents independently selected from the group consisting of halogen -OH, -NO2, -CN, Ci-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-Ci-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R5) (R6),-C (O) (R7),-S-R5,-S (O) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, halogen-substituted carbocyclyl-Cl-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6-alkyl, and halogen-substituted heterocyclyl-Cl-C6-alkyl.

[462] R1 and R2 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[463] In some preferred embodiments, Ri and R2 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocylyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[464] In some preferred embodiments, Ri and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl,

heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[465] R3 is-H, alkyl,-0-R4,-N (R4) (R5), carbocyclylalkyl, or heterocyclylalkyl.

The alkyl, carbocyclylalkyl, or heterocyclylalkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[466] In some preferred embodiments, R3 is-H, C1-C8-alkyl, -O-R4, -N (R4) (R5), carbocyclyl-Cz-C8-alkyl, or heterocyclyl-Cz-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[467] In some preferred embodiments, R3 is-H, C1-C6-alkyl, -O-R4, -N (R4) (R5), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The Cl-C6-alkyl, carbocyclyl-Cz-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[468] R4 and RS are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[4691 In some preferred embodiments, R4 and RS are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[4701 In some preferred embodiments, R4 and R5 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-CI-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[471] In some preferred embodiments, E2 is bound to an atom of E5 to form a ring. Such compounds include, for example:

XII-1 [472] In some preferred embodiments, E2 is not bound to an atom of E5 to form a ring.

[47] In some such preferred embodiments, E5 is a single-ring carbocyclyl (preferably phenyl) substituted with one or more substituents independently selected from the group consisting of-OH,-N02,-CN,-N (R5) (R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, halogen-substituted carbocyclyl-CI-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-CI-C6-alkyl, and halogen-substituted heterocyclyl-Cz-C6-alkyl. Such compounds include, for example:

[474] In some preferred embodiments, ES is single-ring carbocyclyl (preferably phenyl) substituted with 2 or more substituents independently selected from the group consisting of halogen, -OH, -NO2, -CN, C1-C6-alkyl, halo-Cl-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, -N(R5)(R6), -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, halogen-substituted carbocyclyl-Cz-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-Cl-C6-alkyl, and halogen-substituted heterocyclyl-CI-C6-alkyl. Such compounds include, for example:

[475] In some preferred embodiments, E5 is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Ci-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R5) (R6),-C (O) (R7),-S-R5,-S (0) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cz-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, heterocyclyl, haloheterocyclyl, heterocyclyl-C1-C6-alkyl, and halogen-substituted heterocyclyl-Cl-C6-alkyl. Such compounds include, for example:

xi-po Preferred Embodiment No. 12 [476] In some embodiments of this invention, the compound has a structure corresponding to Formula XIII:

[477] Al, A2, and A3 are as defined above for Formula I.

[478] El is-S (0) 2-,-S (O)-,-N (R1)-, -C (O)-N (Rl)-,-N (R1)-C (O)-, or-C (Ri) (R2)-, [479] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[480] In some preferred embodiments, E2 is C-C20-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or Cl-Clo-alkylcycloalkyl-Cl-Clo-alkyl.

Any member of this group optionally is substituted with one or more substituents selected from the group consisting of halogen, Cl-C6-alkyl, and halo-Cl-C6-alkyl.

[481] In some preferred embodiments, E2 is Cl-C6-alkyl, cycloalkyl, Cl-C6-alkylcycloalkyl, cycloalkyl-Cz-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more halogen, although such substituent typically is preferably not substituted with halogen.

[482] E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[483] In some preferred embodiments, E4 is a bond, C1-C20-alkyl, halo-C1-C20-alkyl,C2-C20-alkenyl, or halo-C2-C20-alkenyl.

[484] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, halo-Cl-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[485] In some preferred embodiments, E4 is a bond, C1-C3-alkyl, or C2-C3-alkenyl.

[486] ES is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[487] In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl.

The Cl-C2o-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, Cl-C20-alkoxy, and Ci-C20-alkoxy-Cl-C2o-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, and-CN. The

carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, C1-C8-alkyl, halo-Cl-C8-alkyl, C1-C8-alkoxy, halo-Cl-C8-alkoxy,-N (rus) (R6),-C (O) (R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-Cs-alkyl, and halogen-substituted carbocyclyl-Cl-C8-alkyl.

[488] In some preferred embodiments, ES is Cl-Cs-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, Ci-C8-alkoxy-Cl-Cs-alkyl, carbocyclyl, or heterocyclyl.

The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, C1-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Ci-C6-alkyl, halo-Ci-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy,-N (rus) (R6) -C(O)(R7), -S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[489] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E, E, or E5, [490] In some preferred embodiments, Ri and R are independently selected from the group consisting of-H, Cl-C8-alkyl, and halo-Cl-C8-alkyl.

[491] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[492] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and Cl-C6-alkyl.

[493] R5 and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-Cs-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[494] In some preferred embodiments, R5 and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member

of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[495] R7 is-H, Cl-C6-alkyl,-0-Rg,-N (R8) (R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-C8-alkyl. The Cl-C8-alkyl, carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[496] In some preferred embodiments, R7 is-H, C1-C6-alkyl, -O-R8, -N (R) (R9), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The Ci-C6-alkyl, carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[497] R8 and R9 are independently selected from the group consisting of-H, Cl-Ca-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-Cg-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[498] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen. preferred Embodiment No. 13 [499] In some embodiments of this invention, the compound has a structure corresponding to Formula XIV: [500] A1, A2, and A3 are as defined above for Formula I.

[501] EZ is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[502] In some preferred embodiments, E2 is Cl-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or Cl-Clo-alkylcycloalkyl-Cl-Clo-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Ci-C6-alkyl, and halo-Cl-C6-alkyl.

[503] In some preferred embodiments, E2 is Cl-C6-alkyl optionally substituted with one or more halogen.

[504] In some preferred embodiments, E2 is C1-C6-alkyl.

[505] E4 is alkyl or alkenyl. The alkyl and alkenyl optionally are substituted.

[506] In some preferred embodiments, E4 is C1-C20-alkyl, halo-C1-C20-alkyl, C2-C20-alkenyl, or halo-C2-C2o-alkenyl.

[507] In some preferred embodiments, E4 is Cl-C3-alkyl, halo-Ci-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[508] In some preferred embodiments, E4 is C1-C3-alkyl or C2-C3-alkenyl.

[509] ES is-H, alkyl, alkenyl, alkynyl, alkoxy, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[510] In some preferred embodiments, Es is-H, Cl-C2o-alkyl, C2-C2o-alkenyl, C2-C2o-alkynyl, C1-C20-alkoxy, carbocyclyl, or heterocyclyl. The Cl-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH, - N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH, -NO2, -CN, C1-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, -N(R3)(R4), -C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.

[511] In some preferred embodiments, Es is-H, C1-C8-alkyl, C2-C8-alkenyl, C2-Cs-alkynyl, C1-C8-alkoxy, carbocyclyl, or heterocyclyl. The Cl-C$-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and Cl-C8-allcoxy optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH, - N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH, -NO2, -CN, -C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, -N(R3)(R4),

-C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[512] R3 and R4 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[513] In some preferred embodiments, R3 and R4 are independently selected from the group consisting of-H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[514] RS is-H, C1-C8-alkyl, -O-R6, -N (R6) (R7), carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-C8-alkyl. The C1-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[515] In some preferred embodiments, R5 is-H, C1-C6-alkyl, -O-R6, -N (R6) (R7), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The C1-C6-alkyl, carbocyclyl-Cl-C6-alkyl, or heterocyclyl-C1-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[516] R6 and R are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[517] In some preferred embodiments, R6 and R7 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[518] In some preferred embodiments, ES is-H, C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, or Cl-Cs-alkoxy. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and

Ci-C8-alkoxy optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, and-CN. In one such embodiment, ES is Cl-C8-alkyl optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. Such compounds include, for example: 1519] In some preferred embodiments, E5 is optionally-substituted carbocyclyl and optionally-substituted heterocyclyl.

[520] In some preferred embodiments, E5 is optionally-substituted aryl, often preferably optionally-substituted phenyl. Such compounds include, for example: XIV-2 XIV-3 Preferred Embodiment No. 14 [521] In some embodiments of this invention, the compound has a structure corresponding to Formula XV: XV [522] A1, A2, and A3 are as defined above for Formula I.

[523] E2 comprises less than 5 carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted, but preferably is not substituted.

[524] ES is alkyl, alkenyl, alkynyl, alkoxyalkyl, carbocyclyl, or heterocyclyl.

Any member of this group optionally is substituted.

[525] In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl,C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl. The C1-C20-alkyl,C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, keto, Cl-Cs-alkyl, halo-Cl-C8-alkyl, Cl-C8-alkoxy, halo-Cl-C8-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, -N(R3)(R4), -C(O)(R5), -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C8-alkyl, halogen-substituted carbocyclyl-Cl-C8-alkyl, Cl-C8-alkylcarbocyclyloxy, and halogen-substituted C1-C8-alkoxycarbocycloxy.

[526] In some preferred embodiments, E5 is Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-C8-alkoxy-Cl-C8-alkyl, carbocyclyl, or heterocyclyl. The C1-C8-alkyl, C2-8-alkenyl, C2-C8-alkynyl, andC1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, keto, Cl-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R3) (R4),-C (O) (R5),-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, C1-C6-alkylcarbocyclyloxy, and halogen-substituted C1-C6-alkylcarbocyclyloxy.

[527] R3 and R4 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and lieterocyclyl-Cl-Cg-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[528] In some preferred embodiments, R3 and R4 are independently selected from the group consisting of-H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member

of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[529] R5 is-H, C1-C8-alkyl, -O-R6, -N (R6) (R7), carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cl-Cg-alkyl. The Cl-Cg-alkyl, carbocyclyl-Cl-Cg-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[530] In some preferred embodiments, R5 is-H, C1-C6-alkyl, -O-R6, -N(R6)(R7), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The C1-C6-alkyl, carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[531] R6 and R7 are independently selected from the group consisting of-H, Cl-C$-alkyl, carbocyclyl, carbocyclyl-Cl-Cg-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[532] In some preferred embodiments, R6 and R7 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

15331 In some preferred embodiments, Eus is Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, or Cl-C8-alkoxy-Cl-Cg-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and - CN.

[534] In some preferred embodiments, ES is optionally-substituted carbocyclyl.

[535] In some preferred embodiments, E5 is optionally-substituted C5-C6-cycloalkyl. Such compounds include, for example: XV-1 XV-2 XV-3 [536] In some preferred embodiments, E5 is optionally-substituted phenyl. Such compounds include, for example: XV-4 XV-5

[537] In some preferred embodiments, E5 is optionally-substituted heterocyclyl.

[538] In some preferred embodiments, ES is optionally-substituted heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, and tetrahydroisoquinolinyl. Such compounds include, for example: XV-8 XV-9 XV-10 XV-11 XV-12 Preferred Embodiment No. 15 [539] In some embodiments of this invention, the compound has a structure corresponding to Formula XVI:

XVI [540] A1, A2, and A3 are as defined above for Formula I.

[541] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[542] In some preferred embodiments, E2 is Cl-C20-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or Cl-Clo-alkylcycloalkyl-Cl-Cio-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, halo-Ci-Ce-alkyl.

[543] In some preferred embodiments, E2 is Cl-C6-alkyl optionally substituted with one or more halogen.

[544] In some preferred embodiments, E2 is Cl-C6-alkyl.

[545] Es is alkyl, alkenyl, alkynyl, alkoxyalkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[546] In some preferred embodiments, ES is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy-C1-C20-alkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. The Cl-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The saturated carbocyclyl, partially saturated carbocyclyl, and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Ci-C6-alkyl, halo-C1-C6-alkyl, Ci-C8-alkoxy, halo-Cl-Cs-alkoxy, Cl-Cg-alkoxy-Cl-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl, -N(R3) (R4),-C (O) (RS),-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocylyl-C1-C6-alkyl, halogen-substituted carbocylyl-C1-C8-alkyl, Cl-Cg-alkylcarbocyclyloxy, and halogen-substituted Cl-C$-alkylcarbocyclyloxy.

[547] In some preferred embodiments, E5 is C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, Cl-C8-alkoxy-Cl-C8-alkyl, saturated carbocyclyl, partially saturated carbocyclyl, or heterocyclyl. The Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02, and-CN. The saturated carbocyclyl, partially saturated carbocyclyl, and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C6-alkyl, halo-Cl-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R3) (R4),-C (O) (RS),-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, halogen-substituted carbocyclyl-C1-C6-alkyl, Cl-C6-alkylcarbocyclyloxy, and halogen-substituted C1-C6-alkylcarbocyclyloxy.

[548] R3 and R4 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cl-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[549] In some preferred embodiments, R3 and R4 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-CI-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[550] R5 is s-H, C1-C8-alkyl,-O-R6,-N (R6) (R7), carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-Cg-alkyl. The Cl-C8-alkyl, carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[551] In some preferred embodiments, R5 is-H, C1-C6-alkyl, -O-R6,-N (R6) (R7), carbocyclyl-Cz-C6-alkyl, or heterocyclyl-CI-C6-alkyl. The Cl-C6-alkyl, carbocyclyl-Cz-C6-alkyl, or heterocyclyl-Cz-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[552] R6 and R7 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-Cz-C8-alkyl, heterocyclyl, and heterocyclyl-CI-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[553] In some preferred embodiments, R6 and R7 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[554] In some preferred embodiments, E5 is Cl-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, or Cl-C8-alkoxy-Cl-Cg-alkyl. The C1-C8-alkyl, C2-C8-alkenyl, C2-C8-alkynyl, and Cl-C8-alkoxy-Cl-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH,-NO2, and - CN.

[555] In some preferred embodiments, ES is optionally-substituted, partially-saturated carbocyclyl.

[556] In some preferred embodiments, ES is optionally-substituted, saturated carbocyclyl (preferably optionally-substituted C5-C6 cycloalkyl). Such compounds include, for example: XVI-1 XVI-2

XVI-3 [557] In some preferred embodiments, ES is optionally-substituted heterocyclyl.

Such compounds include, for example: XVI-8 Preferred Embodiment No. 16 [5581 In some embodiments of this invention, the compound has a structure corresponding to Formula XVII :

[559] A1, A2, and A3 are as defined above for Formula I.

[5601 E1 is -S(O)2-, -S(O)-, -N(R1)-, -C(O)-N(R1)-, -N(R1)-C(O)-, or-C (R1) (R2)-.

[561] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[562] In some preferred embodiments, E2 is Cl-C20-alkyl, cycloalkyl, Ci-Cio-alkylcycloalkyl, cycloalkyl-C1-Clo-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl.

Any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[563] In some preferred embodiments, E2 is Cl-C6-alkyl optionally substituted with one or more halogen.

[564] In some preferred embodiments, E2 is C1-C6-alkyl.

15651 E4 is a bond, alkyl, or alkenyl, The alkyl and alkenyl optionally are substituted.

[566] In some preferred embodiments, E4 is a bond, Cl-C2o-alkyl, halo-C1-C2o-alkyl, C2-C2o-alkenyl, or halo-C2-C20-alkenyl.

[567] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, halo-Cl-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[568] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

[569] Es is alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, carbocyclyl, or heterocyclyl. Any member of this group optionally is substituted.

[570] In some preferred embodiments, E5 is C1-C20-alkyl, C2-C20-alkenyl, C2-C20-alkynyl, C1-C20-alkoxy, C1-C20-alkoxy-C1-C20-alkyl, carbocyclyl, or heterocyclyl.

The C1-C20-alkyl, C2-C2o-alkenyl, C2-C2o-alkynyl, C1-C20-alkoxy, and C1-C20-alkoxy-C1-C20-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2, and-CN. The

carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH-NO2,-CN, Cl-C8-alkyl, halo-C1-C8-alkyl, Cl-Cg-alkoxy, halo-C1-C8-alkoxy, Ci-C8-alkoxy-Cl-C8-alkyl, halogen-substituted Cl-C8-alkoxy-Cl-C8-alkyl,-N (R5) (R6), -C(O)(R7),-S-R5,-S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C8-alkyl, and halogen-substituted carbocyclyl-Cl-C8-alkyl.

[571] In some preferred embodiments, ES is Cl-Cg-alkyl, C2-Cs-alkenyl, C2-C8-alkynyl, Cl-Cg-alkoxy, Cl-Cg-alkoxy-Cl-C8-alkyl, carbocyclyl, or heterocyclyl.

The Cl-C$-alkyl, C2-Cs-alkenyl, C2-C8-alkynyl, Cl-C8-alkoxy, and C1-C8-alkoxy-C1-C8-alkyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2, and-CN. The carbocyclyl and heterocyclyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, -OH, -NO2,-CN, C1-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-C1-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R) (R6), -C(O)(R7),-S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cz-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.

[572] R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted. Neither R1 nor R2 forms a ring structure with E2, E4, or E5.

[573] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-Cg-alkyl, and halo-C1-C8-alkyl.

[574] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, C1-C6-alkyl, and halo-Cl-C6-alkyl.

[575] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H and Cl-C6-alkyl.

[576] R5 and R6 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[577] In some preferred embodiments, Rs and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[578] R is-H, C1-C6-alkyl, -O-R8,-N (R8) (R9), carbocyclyl-Cl-C8-alkyl, or heterocyclyl-Cz-C8-alkyl. The Ci-Cs-alkyl, carbocyclyl-CI-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[579] In some preferred embodiments, R7 is-H, C1-C6-alkyl,-O-R8,-N(R8)(R9), carbocyclyl-Ci-C6-alkyl, or heterocyclyl-C1-C6-alkyl. The Cl-C6-alkyl, carbocyclyl-Ci-C6-alkyl, or heterocyclyl-Co-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[580] R8 and R9 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Ci-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[581] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

Preferred Embodiment No. 17 [582] In some embodiments of this invention, the compound has a structure corresponding to Formula XVII:

[583] A1, A2, and A3 are as defined above for Formula I.

[584] E2 is a bond, alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[585] In some preferred embodiments, E2 is a bond, C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl.

Any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

1586] In some preferred embodiments, E2 is a bond, Cl-C6-alkyl, or halo-Ci-C6-alkyl.

[5871 In some preferred embodiments, E2 is a bond or Cl-C6-alkyl.

[588] In some preferred embodiments, E2 is a bond.

[589] E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[5901 In some preferred embodiments, E4 is a bond, Cl-C20-alkyl, halo-C1-C20-alkyl, C2-C2o-alkenyl, or halo-C2-C20-alkenyl.

[5911 In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, halo-Cl-C3-alkyl, C2-C3-alkenyl, or halo-C2-C3-alkenyl.

[592] In some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or C2-C3-alkenyl.

[593] In some preferred embodiments, E4 is a bond.

[594] Es is optionally-substituted heterocyclyl or substituted carbocyclyl.

[595] The ES heterocyclyl optionally is substituted with one or more substituents independently selected from the group consisting of halogen, -OH,-NO2,-CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl,-N (R3) (R4), -C (O) (R5),-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.

[596] In some preferred embodiments, Es is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Ci-C8-alkyl, halo-Cl-C8-alkyl, Cl-C8-alkoxy, halo-C1-C8-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-Cg-alkoxy-Cl-C6-alkyl,-N (R3) (R4),-C (O) (RS),-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Ci-C6-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.

[597] In some preferred embodiments, Es is heterocyclyl optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, Ci-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-C1-C6-alkoxy. Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R3) (R4),-C (O) (RS),-S-R3,-S (O) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.

[598] The Es carbocyclyl is substituted with: 2 or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, alkyl, haloalkyl, alkoxy, haloalkoxy, alkoxyalkyl, halogen-substituted alkoxyalkyl,-N (R3) (R4), - C (O) (RS),-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl ; or a substituent selected from the group consisting of halogen,-OH, -NO2, -CN, -C(O)-O-R3, -S-R3, -S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclylalkyl, and halogen-substituted carbocyclylalkyl.

[599] In some preferred embodiments, Es is carbocyclyl substituted with: 2 or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C8-alkyl, halo-C1-C8-alkyl, C1-C8-alkoxy, halo-C1-C8-alkoxy, Cl-Cs-alkoxy-Cl-C$-alkyl, halogen-substituted Cl-C8-alkoxy-Cl-C8-alkyl,-N (R3) (R4),-C (O) (R5), -S-R3,-S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-C1-C8-alkyl, and halogen-substituted carbocyclyl-C1-C8-alkyl, or

a substituent selected from the group consisting of halogen,-OH, - N02,-CN,-C (O)-O-R3,-S-R3,-S (0) 2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C8-alkyl, and halogen-substituted carbocyclyl-Cl-C8-alkyl.

[600] In some preferred embodiments, Es is carbocyclyl substituted with: 2 or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, Cl-C6-alkyl, halo-Cl-C6-alkyl, Cl-C6-alkoxy, halo-C1-C6-alkoxy, Cl-C6-alkoxy-C1-C6-alkyl, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R3) (R4),-C (O) (R5), -S-R3,-S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-Cz-C6-alkyl, or a substituent selected from the group consisting of halogen,-OH, -NO2, -CN,-C(O)-O-R3,-S-R3,-S(O)2-R3, carbocyclyl, halocarbocyclyl, carbocyclyl-Co-C6-alkyl, and halogen-substituted carbocyclyl-C1-C6-alkyl.

[601] R3 and R4 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[602] In some preferred embodiments, R3 and R4 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[603] In some preferred embodiments, R3 and W are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Cl-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[604] Rs is-H, alkyl,-0-R6,-N (R6) (R7), carbocyclylalkyl, or heterocyclylalkyl.

The alkyl, carbocyclyalkyl, or heterocyclylalkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[605] In some preferred embodiments, R5 is-H, C1-C8-alkyl, -O-R6,-N (R6) (R7), carbocyclyl-C1-C8-alkyl, or heterocyclyl-C1-C8-alkyl. The Cl-C8-alkyl,

carbocyclyl-Cz-C8-alkyl, or heterocyclyl-C1-C8-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[606] In some preferred embodiments, Rs is-H, C1-C6-alkyl, -O-R6,-N(R6)R(7), carbocyclyl-Cl-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The C1-C6-alkyl, carbocyclyl-Cz-C6-alkyl, or heterocyclyl-Cz-C6-alkyl may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[607] R6 and R are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[608] In some preferred embodiments, R6 and R7 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-Cg-alkyl, heterocyclyl, and heterocyclyl-Co-C8-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[609] In some preferred embodiments, R6 and R7 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-Co-C6-alkyl, heterocyclyl, and heterocyclyl-CI-C6-alkyl. Except where the member is-H, any member of this group may be substituted with one or more halogen, but more typically is preferably not substituted with halogen.

[610] In some preferred embodiments, ES is optionally-substituted heterocyclyl.

[611] In some preferred embodiments, Es is substituted carbocyclyl (preferably substituted phenyl). Such compounds include, for example: XVIII-3 Preferred Embodiment No. 18 [612] In some embodiments of this invention, the compound has a structure corresponding to Formula XVIII:

XIX [613] A1, A2 and A3 are as defined above for Formula I.

[614] El is-O-,-S (O) 2-,-S (O)-,-S-,-N (Rl)-,-C (O)-N (Rl)-,-N (Rl)-C (O)-, or -C(R1)(R2)-.

[615] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[616] In some preferred embodiments, E2 is Cl-C20-alkyl, cycloalkyl, Cl-Clo-alkyl-cycloalkyl, cycloalkyl-C1-Clo-alkyl, or Cl-Clo-alkyl-cycloalkyl-Cl-Clo-alkyl.

Any member of this group optionally is substituted with one or more halogen.

[617] In some preferred embodiments, E2 is C1-C6-alkyl. The alkyl optionally is substituted with one or more halogen.

[618] E5 is substituted heterocyclyl.

[619] In some preferred embodiments, ES is heterocyclyl that is: substituted with one or more substituents independently selected from the group consisting of halogen, -OH,-NO2,-CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, Cl-C8-alkoxy, halo-C1-C8-alkoxy, Cl-C8-alkoxy-Cl-C8-alkyl, halogen-substituted C1-C8-alkoxy-C1-C8-alkyl,

-N(R5)(R6),-C(O)(R7),-S-R5,-S(O)2-R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-Cl-C6-alkyl, and/or substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cyclaolkyl.

[620] In some preferred embodiments, E5 is heterocyclyl that is: substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, keto, Cl-C6-alkyl, halo-Ci-C6-alkyl, Cl-C6-alkoxy, halo-Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halogen-substituted C1-C6-alkoxy-C1-C6-alkyl, -N (R) (R6),-C (O) (R7),-S-R5,-S (O) 2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl, and/or substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.

[6211 R1 and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted.

[622] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C8-alkyl, and halo-C1-C8-alkyl.

[623] R3 and R4 are independently selected from the group consisting of-H, C1-C8-alkyl, Cl-C8-alkoxycarbonyl, C1-C8-alkylcarbonyl, carbocyclyl-C1-C8-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.

[624] R5 and R6 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[625] In some preferred embodiments, R5 and R6 are independently selected from the group consisting of-H, C1-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[6261 R7 is -H, C1-C8-alkyl, -O-R8, -N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-Cl-Cg-alkyl. The alkyl, carbocyclylalkyl, or heterocyclylalkyl may be substituted with one or more halogen.

[627] In some preferred embodiments, R7 is -H, C1-C6-alkyl, -O-R8,-N(R8)(R9), carbocyclyl-Cz-C6-alkyl, or heterocyclyl-Cl-C6-alkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.

[628] R and R9 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-CI-C8-alkyl, heterocyclyl, and heterocyclyl-Cz-C8-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[629] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-CI-C6-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[630] Compounds of this embodiment include, for example: XIX-3 XIX-4 Preferred Embodiment No. 19 [631] In some embodiments of this invention, the compound has a structure corresponding to Formula XIX:

[632] A1, A2, and A3 are as defined above for Formula I.

[633] E1 is -O-, -S(O) 2-,-S (O)-,-N (R1)-, -C (O)-N (R')-,-N (R1)-C (O)-, or -C (R') (W)-.

[634] E2 comprises at least two carbon atoms. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[635] In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, Cl-Clo-alkyl-cycloalkyl, cycloalkyl-Cl-Clo-alkyl, or Cl-Clo-alkyl-cycloalkyl-Cl-Clo-alkyl.

Any member of this group optionally is substituted with one or more halogen.

[636] In some preferred embodiments, E2 is C2-C6-alkyl. The alkyl may optionally be substituted with one or more halogen.

[637] Es is optionally-substituted heterocyclyl.

[638] In some preferred embodiments, Es is heterocyclyl that is: optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, keto, C1-C8-alkyl, halo-C1-C8-alkyl, Cl-C8-alkoxy, halo-C1-C8-alkoxy, Cl-C8-alkoxy-Cl-C8-alkyl, halogen-substituted Cl-Cg-alkoxy-Cl-C8-alkyl,-N (R) (R6),-C (O) (R7),-S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, and carbocyclyl-Cz-C6-alkyl, and/or optionally substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming C5-C6-cycloalkyl or halo-C5-C6-cycloalkyl.

[639] In some preferred embodiments, Es is heterocyclyl that is: optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH,-NO2,-CN, keto, Cl-C6-alkyl, halo-C1-C6-alkyl, Cl-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkyl,

halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl,-N (R) (R6),-C(O)(R7),-S-R5, -S(O)2-R5, carbocyclyl, halocarbocyclyl, carbocyclyl-Cl-C6-alkyl, and halogen-substituted carbocyclyl-CI-C6-alkyl, and optionally substituted on the same atom with two substituents independently selected from the group consisting of alkyl and haloalkyl, the two substituents together forming Cs-C6-cycloalkyl or halo-C5-C6-cycloalkyl.

[640] Rl and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted.

[641] In some preferred embodiments, Rl and R2 are independently selected from the group consisting of-H, C1-C8-alkyl, and halo-C1-C8-alkyl.

[642] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[643] R3 and R are independently selected from the group consisting of-H, C1-C8-alkyl, Cl-C8-alkoxycarbonyl, Cl-C8-alkylcarbonyl, carbocyclyl-CI-C8-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.

[644] Rs and R6 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-Cz-Cs-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[645] In some preferred embodiments, R5 and R6 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[646] R7 is -H, C1-C8-alkyl,-O-R8,-N(R8)(R9), carbocyclyl-C1-C8-alkyl, or heterocyclyl-CI-C8-alkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.

[647] In some preferred embodiments, R7 is-H, Cl-C6-alkyl,-0-R8,-N (R8) (R9), carbocyclyl-C1-C6-alkyl, or heterocyclyl-Cz-C6-alkyl. The alkyl, carbocyclylalkyl, and heterocyclylalkyl optionally are substituted with one or more halogen.

[648] R8 and R9 are independently selected from the group consisting of-H, C1-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and

heterocyclyl-Cz-C8-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[649] In some preferred embodiments, R8 and R9 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cz-C6-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[650] Some particularly preferred compounds include: XX-1 XX-2 Preferred Embodiment No. 20 [651] In some embodiments of this invention, the compound has a structure corresponding to Formula XX: XXI [652] A1, A, and A3 are as defined above for Formula I.

[653] E1 is -O-, -S(O)2-, -S(O)-, -S-, -N(R1)-, -C(O)-N(R1)-, -N(R1)-C(O)-, or -C (R') (R2)-.

[654] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[655] In some preferred embodiments, E2 is C2-C2o-alkyl, cycloalkyl, Cl-Clo-alkylcycloalkyl, cycloalkyl-Cl-Clo-alkyl, or Ci-Clo-alkylcycloalkyl-Cl-Cio-alkyl.

Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, Cl-C6-alkyl, and halo-C1-C6-alkyl.

[656] In some preferred embodiments, E2 is C2-C6-alkyl. The alkyl may optionally be substituted with one or more halogen.

[657] E3 is -C(O)-,-O-(CO)-,-C(O)-O-, -C(NR3)-, -N(R4)-, -N(R4)-C(NR3)-, -C(NR3)-N(R4)-,-C(O)-N(R4)-,-N(R4)-C(O)-, -N(R4)-C(O)-N(R5)-, -S-, -S(O)-, -N(R4)-S(O) 2-,-S (O) 2-N (R4)-,-C (O)-N (R4)-N (R5)-C (O)-,-C (R4) (R6)-C (O)-, or -C (R7) (R8)-.

[658] E4 is a bond, alkyl, or alkenyl. The alkyl and alkenyl optionally are substituted.

[659] In some preferred embodiments, E4 is a bond, C1-C20-alkyl, or C2-C20-alkenyl. The alkyl and alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen, and carbocyclyl.

The carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, C1-C8-alkyl, Cl-Cs-alkoxy, Cl-Cs-alkoxy-Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-Cg-alkyl, halo-C1-C8-alkyl, halo-Cz-C8-alkoxy, halogen-substituted Cl-C8-alkoxy-Cl-C8-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-C1-C8-alkyl.

[660] k some preferred embodiments, E4 is a bond, Cl-C3-alkyl, or C2-C3-alkenyl. The alkyl and alkenyl optionally are substituted with one or more substituents independently selected from the group consisting of halogen and carbocyclyl.

The carbocyclyl, in turn, optionally is substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-N02,-CN, C1-C6-alkyl, Ci-Ce-alkoxy, C1-C6-alkoxy-C1-C6-alkyl, carbocyclyl, carbocyclyl-Cz-C6-alkyl, halo-Cl-C6-alkyl, halo-Cz-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halocarbocyclyl, and halogen-substituted carbocyclyl-Cl-C6-alkyl.

[661] Es is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl are: substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclylalkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclylalkyl, and

optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, alkyl, alkoxy, alkoxyalkyl, -N(R11)(R12),-C(O)(R13),-S-R11,-S(O)2-R11, carbocyclyl, carbocyclylalkyl, haloalkyl, haloalkoxy, halogen-substituted alkoxyalkyl, halocarbocyclyl, halogen-substituted carbocyclylalkyl, hydroxycarbocyclyl, and heteroaryl.

[662] In some preferred embodiments, E5 is carbocyclyl or heterocyclyl. The carbocyclyl and heterocyclyl are: substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclyl-C1-C8-alkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclyl-Cl-C8-alkyl, and optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, Cl-Cg-alkyl, Cl-Cg-alkoxy, Cl-C8-alkoxy-Ci-C8-alkyl,-N (R11)(R12),-C(O)(R13),-S-R11,-S(O)2-R11, carbocyclyl, carbocyclyl-Cz-C8-alkyl, halo-C1-C8-alkyl, halo-Cz-C8-alkoxy, halogen-substituted Ci-Cg-alkoxy-Cl-C8-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-Cl-C8-alkyl, hydroxycarbocyclyl, and heteroaryl.

[663] In some preferred embodiments, ES is carbocyclyl or heterocyclyl, wherein the carbocyclyl and heterocyclyl are: substituted with a substituent selected from the group consisting of optionally-substituted carbocyclyl, optionally-substituted carbocyclyl-C1-C6-alkyl, optionally-substituted heterocyclyl, and optionally-substituted heterocyclyl-Cz-C6-alkyl, and optionally substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-NO2,-CN, Ci-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-C1-C6-alkyl,-N (RI (R12),-C(O)(R13),-S-R11,-S(O)2-R11, carbocyclyl, carbocyclyl-Cl-C6-alkyl, halo-Cl-C6-alkyl, halo-Cl-C6-alkoxy, halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl, halocarbocyclyl, halogen-substituted carbocyclyl-Ci-C6-alkyl, hydroxycarbocyclyl, and heteroaryl.

[664] Rl and R2 are independently selected from the group consisting of-H and alkyl. The alkyl optionally is substituted.

[665] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, C1-C8-alkyl, and halo-Cl-C8-alkyl.

[666] In some preferred embodiments, R1 and R2 are independently selected from the group consisting of-H, C1-C6-alkyl, and halo-Ci-Ce-alkyl.

R3 is -H or-OH.

[668] R4 and R5 are independently selected from the group consisting of-H, alkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl. Except where the member is-H, any member of this group optionally is substituted.

[669] In some preferred embodiments, R4 and R5 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-C1-C8-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[670] In some preferred embodiments, R4 and RS are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-allcyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[671] R6 is-CN or-OH.

[672] R7 is-H, halogen,-OH, alkyl, alkoxy, or alkoxyalkyl. The alkyl, alkoxy, and alkoxyalkyl optionally are substituted.

[673] In some preferred embodiments, R7 is-H, halogen,-OH, C1-C8-alkyl, Ci-Cg-alkoxy, C1-C8-alkoxy-C1-C8-alkyl, halo-Cz-C8-alkyl, halo-Cl-Ca-alkoxy, or halogen-substituted Cl-C8-alkoxy-Cl-Cg-alkyl.

[674] In some preferred embodiments, R7 is-H, halogen,-OH, Cl-C6-alkyl, Cl-C6-alkoxy, Cl-C6-alkoxy-Cl-C6-alkyl, halo-Cz-C6-alkyl, halo-Cl-C6-alkoxy, or halogen-substituted Cl-C6-alkoxy-Cl-C6-alkyl.

[675] R8 is-OH or alkoxy. The alkoxy optionally is substituted.

[676] In some preferred embodiments, R8 is-OH, Cl-C8-alkoxy, or halo-C1-C8-alkoxy.

[677] In some preferred embodiments, R8 is-OH, Cl-C6-alkoxy, or halo-C1-C6-alkoxy.

[678] R9 and Rl° are independently selected from the group consisting of-H, C1-C8-alkyl, Cl-C8-alkoxycarbonyl, Cl-Cs-alkylcarbonyl, carbocyclyl-C1-Cs-alkyl, and carbocyclyl-C1-C8-alkoxycarbonyl.

[679] R"and R"are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cz-C8-alkyl, heterocyclyl, and heterocyclyl-Ci-Cg-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[680] In some preferred embodiments, R11 and R12 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-C1-C8-alkyl, heterocyclyl, and heterocyclyl-CI-C8-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[6811 In some preferred embodiments, Rll and Rl2 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-C1-C6-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[682] R13 is-H, C1-C8-alkyl, -O-R14, -N(R14)(R15), carbocyclyl-C1-C8-alkyl, heterocyclyl-C1-C8-alkyl, halo-Cz-C8-alkyl, halogen-substituted carbocyclyl-C1-C8-alkyl, or halogen-substituted heteroyclyl-C1-C8-alkyl.

[683] In some preferred embodiments, R13 is of-H, Cl-C6-alkyl,-O-R14, -N(R14)(R15), carbocyclyl-C1-C6-alkyl, heterocyclyl-C1-C6-alkyl, halo-C1-C6-alkyl, halogen-substituted carbocyclyl-Cz-C6-alkyl, or halogen-substituted heterocyclyl-C1-C6-alkyl.

[684] R14 and Rl5 are independently selected from the group consisting of-H, Cl-C8-alkyl, carbocyclyl, carbocyclyl-Cz-C8-alkyl, heterocyclyl, and heterocyclyl-Cl-Cg-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

[685] In some preferred embodiments, R14 and Rl5 are independently selected from the group consisting of-H, Cl-C6-alkyl, carbocyclyl, carbocyclyl-C1-C6-alkyl, heterocyclyl, and heterocyclyl-Cl-C6-alkyl. Except where the member is-H, any member of this group optionally is substituted with one or more halogen.

Some preferred compounds include, for example:

XXI-1 A-2. Preferred Selectivities [686] The hydroxamate compound or salt preferably has an inhibitory activity against MMP-1 or MMP-14 that is substantially less than its inhibitory activity against MMP-2, MMP-9, or MMP-13. In other words, the hydroxamate compound or salt preferably has an in inhibition constant (Ks) against at least one of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times its inhibition constant (s) against at least one of MMP-1 and MMP-14. The inhibition constant of a compound or salt thereof may be determined using an in vitro inhibition assay, such as the K ; assay described below in Examples 55-89.

[687] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki (s) against one or both of MMP-1 and MMP-14.

[688] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-9 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki (s) against one or both of MMP-1 and MMP-14.

[689] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki (s) against one or both of MMP-1 and MMP-14. It is believed

that such a selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.

[690] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki's against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki (s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.

1691] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki's against all of MMP-2, MMP-9, and MMP-13 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki (s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.

[692] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki's against both MMP-1 and MMP-14.

[693] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-9 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki's against both MMP-1 and MMP-14.

[694] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has a Ki against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki's against both MMP-1 and MMP-14. It is believed that such a

selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.

[695] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki's against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki's against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.

[696] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has Ki's against all of MMP-2, MMP-9, and MMP-3 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its Ki's against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.

The activity and selectivity of a hydroxamate compound or salt may alternatively be determined using an in vitro ICso assay, such as the IC50 assay described below in Examples 55-89. In that instance, the hydroxamate compound or salt preferably has an ICso value against at least one of MMP-2, MMP-9, and MMP-13 that is no greater than about 0.1 times its ICso value (s) against at least one of MMP-1 and MMP-14.

[698] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an ICso value against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso value (s) against one or both of MMP-1 and MMP-14.

[699] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an ICso value against MMP-9 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no

greater than about 0.00001) times its ICso value (s) against one or both of MMP-1 and MMP-14.

[700] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an IC50 value against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso value (s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.

[701] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has ICso values against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso value (s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.

[702] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has ICso values against all of MMP-2, MMP-9, and MMP-13 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso value (s) against one or both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.

[703] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an ICso value against MMP-2 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso values against both MMP-1 and MMP-14.

[704] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an ICso value against MMP-9 that is no greater than about 0.1 (more

preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso values against both MMP-1 and MMP-14.

[705] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has an ICso value against MMP-13 that is no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its IC50 values against both MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, a cardiovascular condition or arthritis.

[706] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has ICso values against both MMP-2 and MMP-9 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso values against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, or an ophthalmologic condition.

[707] In some particularly preferred embodiments, the hydroxamate compound or salt preferably has ICso values against all of MMP-2, MMP-9, and MMP-3 that are no greater than about 0.1 (more preferably no greater than about 0.01, even more preferably no greater than about 0.001, still more preferably no greater than about 0.0001, and still even more preferably no greater than about 0.00001) times its ICso values against both of MMP-1 and MMP-14. It is believed that such a selectivity profile is often particularly preferred when preventing or treating, for example, cancer, a cardiovascular condition, arthritis, or an ophthalmologic condition.

B. Salts of the Compounds of this Invention [708] The compounds of this invention can be used in the form of salts derived from inorganic or organic acids. Depending on the particular compound, a salt of the compound may be advantageous due to one or more of the salt's physical properties, such as enhanced pharmaceutical stability in differing temperatures and humidities, or a

desirable solubility in water or oil. In some instances, a salt of a compound also may be used as an aid in the isolation, purification, and/or resolution of the compound.

[709] Where a salt is intended to be administered to a patient (as opposed to, for example, being used in an in vitro context), the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include salts commonly used to form alkali metal salts and to form addition salts of free acids or free bases. In general, these salts typically may be prepared by conventional means with a compound of this invention by reacting, for example, the appropriate acid or base with the compound.

[710] Pharmaceutically-acceptable acid addition salts of the compounds of this invention may be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic acid, hydroionic, nitric, carbonic, sulfuric, and phosphoric acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclyl, carboxylic, and sulfonic classes of organic acids. Specific examples of suitable organic acids include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid, mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, dodecylsulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

[711] Pharmaceutically-acceptable base addition salts of the compounds of this invention include, for example, metallic salts and organic salts. Preferred metallic salts include alkali metal (group la) salts, alkaline earth metal (group IIa) salts, and other physiological acceptable metal salts. Such salts may be made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc. Preferred organic salts can be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Basic nitrogen-containing groups can be

quaternized with agents such as lower alkyl (Cl-C6) halides (e. g., methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides), dialkyl sulfates (e. g., dimethyl, diethyl, dibuytl, 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.

[712] Particularly preferred salts of the compounds of this invention include hydrochloric acid (HC1) salts and trifluoroacetate (CF3COOH or TFA) salts.

C. Preventing or Treating Conditions Using the Conipounds and Salts of this Invention [713] One embodiment of this invention is directed to a process for preventing or treating a pathological condition associated with MMP activity in a mammal (e. g., a human, companion animal, farm animal, laboratory animal, zoo animal, or wild animal) having or disposed to having such a condition. Such a condition may be, for example, tissue destruction, a fibrotic disease, pathological matrix weakening, defective injury repair, a cardiovascular disease, a pulmonary disease, a kidney disease, a liver disease, an ophthalmologic disease, or a central nervous system disease. Specific examples of such conditions include osteoarthritis, rheumatoid arthritis, septic arthritis, tumor invasion, tumor metastasis, tumor angiogenesis, a decubitis ulcer, a gastric ulcer, a corneal ulcer, periodontal disease, liver cirrhosis, fibrotic lung disease, otosclerosis, atherosclerosis, multiple sclerosis, dilated cardiomyopathy, epidermal ulceration, epidermolysis bullosa, aortic aneurysm, weak injury repair, an adhesion, scarring, congestive heart failure, post myocardial infarction, coronary thrombosis, emphysema, proteinuria, bone disease, chronic obstructive pulmonary diseases, and Alzheimer's disease.

[714] In some particularly preferred embodiments, the condition comprises arthritis.

[715] In some particularly preferred embodiments, the condition comprises tumor invasion, tumor metastasis, or tumor angiogenesis.

[716] In some particularly preferred embodiments, the condition comprises periodontal disease.

[717] In some particularly preferred embodiments, the condition comprises atherosclerosis.

[718] In some particularly preferred embodiments, the condition comprises multiple sclerosis.

[719] In some particularly preferred embodiments, the condition comprises dilated cardiomyopathy.

[720] In some particularly preferred embodiments, the condition comprises post myocardial infarction.

[721] In some particularly preferred embodiments, the condition comprises congestive heart failure.

[722] Ill some particularly preferred embodiments, the condition comprises chronic obstructive pulmonary disease.

[723] The condition may alternatively (or additionally) be associated with TNF-a convertase activity. Examples of such a condition include inflammation (e. g., rheumatoid arthritis), autoimmune disease, graft rejection, multiple sclerosis, a fibrotic disease, cancer, an infectious disease (e. g., malaria, mycobacterial infection, meningitis, etc.), fever, psoriasis, a cardiovascular disease (e. g., post-ischemic reperfusion injury and congestive heart failure), a pulmonary disease, hemorrhage, coagulation, hyperoxic alveolar injury, radiation damage, acute phase responses like those seen with infections and sepsis and during shock (e. g., septic shock, hemodynamic shock, etc.), cachexia, and anorexia.

[724] The condition may alternatively (or additionally) be associated with aggrecanase activity. Examples of such a condition include inflammation diseases (e. g., osteoarthritis, rheumatoid arthritis, joint injury, reactive arthritis, acute pyrophosphate arthritis, and psoriatic arthritis) and cancer.

[725] In this patent, the phrase"preventing a condition"means reducing the risk of (or delaying) the onset of the condition in a mammal that does not have the condition, but is predisposed to having the condition. In contrast, the phrase"treating a condition" means ameliorating, suppressing, or eradicating an existing condition. The pathological condition may be (a) the result of pathological MMP activity itself, and/or (b) affected by MMP activity (e. g., diseases associated with TNF-a).

[726] A wide variety of methods may be used alone or in combination to administer the hydroxamates and salt thereof described above. For example, the hydroxamates or salts thereof may be administered orally, parenterally, by inhalation spray, rectally, or topically.

[727] Typically, a compound (or pharmaceutically acceptable salt thereof) described in this patent is administered in an amount effective to inhibit a target MMP (s).

The target MMP is/are typically MMP-2, MMP-9, and/or MMP-13, with MMP-13 often being a particularly preferred target. The preferred total daily dose of the hydroxamate or salt thereof (administered in single or divided doses) is typically from about 0.001 to about 100 mg/kg, more preferably from about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i. e., mg hydroxamate or salt thereof per kg body weight). Dosage unit compositions can contain such amounts or submultiples thereof to make up the daily dose. In many instances, the administration of the compound or salt will be repeated a plurality of times. Multiple doses per day typically may be used to increase the total daily dose, if desired.

[728] Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations, such as the activity, efficacy, pharmacokinetic, and toxicology profiles of the particular hydroxamate or salt thereof employed; whether a drug delivery system is utilized; and whether the hydroxamate or salt thereof is administered as part of a drug combination. Thus, the dosage regimen actually employed can vary widely, and, therefore, can deviate from the preferred dosage regimen set forth above.

D. Pharmaceutical Compositions Containing the Coinpounds and Salts of tllis Invention [729] This invention also is directed to pharmaceutical compositions comprising a hydroxamate or salt thereof described above, and to methods for making pharmaceutical compositions (or medicaments) comprising a hydroxamate or salt thereof described above.

[730] The preferred composition depends on the method of administration, and typically comprises one or more conventional pharmaceutically acceptable carriers, adjuvants, and/or vehicles. Formulation of drugs is generally discussed in, for example, Hoover, John E., Remiiigtotis Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975). See also, Liberman, H. A. See also, Laclunan, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N. Y., 1980).

1731] Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such solid dosage forms, the hydroxamates or

salts thereof are ordinarily combined with one or more adjuvants. If administered per os, the hydroxamates or salts thereof can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain a controlled-release formulation, as can be provided in a dispersion of the hydroxamate or salt thereof in hydroxypropylmethyl cellulose. In the case of capsules, tablets, and pills, the dosage forms also can comprise buffering agents, such as sodium citrate, or magnesium or calcium carbonate or bicarbonate. Tablets and pills additionally can be prepared with enteric coatings.

[732] Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art (e. g., water). Such compositions also can comprise adjuvants, such as wetting, emulsifying, suspending, flavoring (e. g., sweetening), and/or perfuming agents.

[733]"Parenteral administration"includes subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, and infusion. Injectable preparations (e. g., sterile injectable aqueous or oleaginous suspensions) can be formulated according to the known art using suitable dispersing, wetting agents, and/or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e. g., synthetic mono- or diglycerides), fatty acids (e. g., oleic acid), dimethyl acetamide, surfactants (e. g., ionic and non-ionic detergents), and/or polyethylene glycols.

[734] Formulations for parenteral administration may, for example, be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The hydroxamates or salts thereof can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, com oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers.

[735] Suppositories for rectal administration can be prepared by, for example, mixing the drug with a suitable nonirritating excipient that is solid at ordinary temperatures, but liquid at the rectal temperature and will therefore melt in the rectum to

release the drug. Suitable excipients include, for example, such as cocoa butter; synthetic mono-, di-, or triglycerides ; fatty acids; and/or polyethylene glycols [736]"Topical administration"includes the use of transdermal administration, such as transdermal patches or iontophoresis devices.

[737] Other adjuvants and modes of administration well-known in the pharmaceutical art may also be used.

E. Definitions [738] The term"alkyl" (alone or in combination with another term (s)) means a straight-or branched-chain saturated hydrocarbyl typically containing from 1 to about 20 carbon atoms, more typically from 1 to about 8 carbon atoms, and even more typically from 1 to about 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, and the like.

[739] The term"alkenyl" (alone or in combination with another term (s)) means a straight-or branched-chain hydrocarbyl containing one or more double bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethenyl (vinyl); 2-propenyl; 3-propenyl; 1,4-pentadienyl; 1,4-butadienyl; 1-butenyl ; 2-butenyl; 3-butenyl; decenyl; and the like.

The term"alkynyl" (alone or in combination with another term (s)) means a straight-or branched-chain hydrocarbyl containing one or more triple bonds and typically from 2 to about 20 carbon atoms, more typically from about 2 to about 8 carbon atoms, and even more typically from about 2 to about 6 carbon atoms. Examples of such substituents include ethynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.

[741] The term"carbocyclyl" (alone or in combination with another term (s)) means a saturated cyclic (i. e.,"cycloalkyl"), partially saturated cyclic, or aryl hydrocarbyl containing from 3 to 14 carbon ring atoms ("ring atoms"are the atoms bound together to form the ring or rings of a cyclic group). A carbocyclyl may be a single ring, which typically contains from 3 to 6 ring atoms. Examples of such single-ring carbocyclyls include cyclopropanyl, cyclobutanyl, cyclopentyl, cyclopentenyl, cyclopentadienyl,

cyclohexyl, cyclohexenyl, cyclohexadienyl, and phenyl. A carbocyclyl alternatively may be 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalenyl (also known as"tetralinyl"), indenyl, isoindenyl, indanyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as"phenalenyl"), fluoreneyl, decalinyl, and norpinanyl.

[742l The term"cycloalkyl" (alone or in combination with another term (s)) means a saturated cyclic hydrocarbyl containing from 3 to 14 carbon ring atoms. A cycloalkyl may be a single carbon ring, which typically contains from 3 to 6 carbon ring atoms. Examples of single-ring cycloalkyls include cyclopropyl (or"cyclopropanyl"), cyclobutyl (or"cyclobutanyl"), cyclopentyl (or"cyclopentanyl"), and cyclohexyl (or "cyclohexanyl"). A cycloalkyl alternatively may be 2 or 3 carbon rings fused together, such as, decalinyl or norpinanyl.

[743] The term"aryl" (alone or in combination with another term (s)) means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms. Examples of aryls include phenyl, naphthalenyl, and indenyl.

[744] In some instances, the number of carbon atoms in a hydrocarbyl (e. g., alkyl, alkenyl, alkynyl, or cycloalkyl) is indicated by the prefix"Cx-Cy-", wherein x is the minimum and y is the maximum number of carbon atoms in the substituent. Thus, for example,"Cl-C6-alkyl"refers to an alkyl containing from 1 to 6 carbon atoms. Illustrating further, C3-C6-cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.

[745] The term"hydrogen" (alone or in combination with another term (s)) means a hydrogen radical, and may be depicted as-H.

[746] The term"hydroxy" (alone or in combination with another term (s)) means -OH.

[747] The term"nitro" (alone or in combination with another term (s)) means -NO2.

[748] The term"cyano" (alone or in combination with another term (s)) means - CN, which also may be depicted as: [749] The term"keto" (alone or in combination with another term (s)) means an oxo radical, and may be depicted as =O.

[750] The term"carboxy" (alone or in combination with another term (s)) means -C (O)-OH, which also may be depicted as:

[751] The term"amino" (alone or in combination with another term (s)) means - NH2. The term"monosubstituted amino" (alone or in combination with another term (s)) means an amino wherein one of the hydrogen radicals is replaced by a non-hydrogen substituent. The term"disubstituted amino" (alone or in combination with another term (s)) means an amino wherein both of the hydrogen atoms are replaced by non-hydrogen substituents, which may be identical or different.

[752] The term"halogen" (alone or in combination with another term (s)) means a fluorine radical (which may be depicted as-F), chlorine radical (which may be depicted as - Cl), bromine radical (which may be depicted as-Br), or iodine radical (which may be depicted as-I). Typically, a fluorine radical or chlorine radical is preferred, with a fluorine radical often being particularly preferred.

[753] If a substituent is described as being"substituted", a non-hydrogen radical is in the place of a hydrogen radical on a carbon or nitrogen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one non- hydrogen radical is in the place of a hydrogen radical on the alkyl substituent. To illustrate, monofluoroalkyl is alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be recognized that if there are more than one substitutions on a substituent, each non-hydrogen radical may be identical or different (unless otherwise stated).

[754] If a substituent is described as being"optionally substituted", the substituent may be either (1) substituted, or (2) not substituted.

[755] This specification uses the terms"substituent"and"radical" interchangeably.

[756] The prefix"halo"indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, haloalkyl means an alkyl wherein at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1, 1, 1-trifluoroethyl, and the like.

Illustrating further,"haloalkoxy"means an alkoxy wherein at least one hydrogen radical is replaced by a halogen radical. Examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as"perfluoromethyoxy"), 1, l, 1,-trifluoroethoxy, and the like. It should be recognized that if a substituent is substituted by more than one halogen radical, those halogen radicals may be identical or different (unless stated otherwise).

[757] The prefix"perhalo"indicates that every hydrogen radical on the substituent to which the prefix is attached is replaced with independently selected halogen radicals, i. e., each hydrogen radical on the substituent is replaced with a halogen radical.

If all the halogen radicals are identical, the prefix typically will identify the halogen radical. Thus, for example, the term"perfluoro"means that every hydrogen radical on the substituent to which the prefix is attached is substituted with a fluorine radical. To illustrate, the term"perfluoroalkyl"means an alkyl wherein a fluorine radical is in the place of each hydrogen radical. Examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluorobutyl, perfluoroisopropyl, perfluorododecyl, perfluorodecyl, and the like. To illustrate further, the term"perfluoroalkoxy"means an alkoxy wherein each hydrogen radical is replaced with a fluorine radical. Examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF3), perfluorobutoxy, perfluoroisopropoxy, perfluorododecoxy, perfluorodecoxy, and the like.

[758l The term"carbonyl" (alone or in combination with another term (s)) means -C (O)-, which also may be depicted as: This term also is intended to encompass a hydrated carbonyl substituent, i. e.,-C (OH) 2-.

The term"aminocarbonyl" (alone or in combination with another term (s)) means-C (O)-NH2, which also may be depicted as:

[760] The term"oxy" (alone or in combination with another term (s)) means an ether substituent, and may be depicted as-O-.

1761] The term"alkoxy" (alone or in combination with another term (s)) means an alkylether, i. e.,-O-alkyl. Examples of such a substituent include methoxy (-O-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[7621 The term"alkylcarbonyl" (alone or in combination with another term (s)) means-C (O)-alkyl. For example,"ethylcarbonyl"may be depicted as:

[763] The term"aminoalkylcarbonyl" (alone or in combination with another term (s)) means-C (O)-alkyl-NH2. For example,"aminomethylcarbonyl"may be depicted as: [764] The term"alkoxycarbonyl" (alone or in combination with another term (s)) means-C (O)-O-alkyl. For example,"ethoxycarbonyl"may be depicted as:

[765] The term"carbocyclylcarbonyl" (alone or in combination with another term (s)) means-C (O)-carbocyclyl. For example,"phenylcarbonyl"may be depicted as:

Similarly, the term"heterocyclylcarbonyl" (alone or in combination with another term (s)) means-C (O)-heterocyclyl.

[766] The term"carbocyclylalkylcarbonyl" (alone or in combination with another term (s)) means-C (O)-alkyl-carbocyclyl. For example,"phenylethylcarbonyl"may be depicted as:

Similarly, the term"heterocyclylalkylcarbonyl" (alone or in combination with another term (s)) means-C (O)-alkyl-heterocyclyl.

[767] The term"carbocyclyloxycarbonyl" (alone or in combination with another tenn (s)) means-C (O)-O-carbocyclyl. For example,"phenyloxycarbonyl"may be depicted as:

[768] The term"carbocyclylalkoxycarbonyl" (alone or in combination with another term (s)) means-C (O)-O-alkyl-carbocyclyl. For example,"phenylethoxycarbonyl" may be depicted as:

[769] The term"thio"or"thia" (alone or in combination with another term (s)) means a thiaether, i. e., an ether substituent wherein a divalent sulfur atom is in the place of the ether oxygen atom. Such a substituent may be depicted as-S-. This, for example, "alkyl-thio-alkyl"means alkyl-S-alkyl.

[770] The term"thiol"or"sulfhydryl" (alone or in combination with another term (s)) means a sulfhydryl, and may be depicted as-SH.

[771] The term" (thiocarbonyl)" (alone or in combination with another term (s)) means a carbonyl wherein the oxygen atom has been replaced with a sulfur. Such a substituent may be depicted as-C (S)-, and also may be depicted as: [772] The term"alkyl (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-alkyl. For example,"ethyl (thiocarbonyl)" may be depicted as: [773] The term"alkoxy (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-O-alkyl. For example,"ethoxy (thiocarbonyl)" may be depicted as: [774] The tenn"carbocyclyl (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-carbocyclyl. For example,"phenyl (thiocarbonyl)" may be depictedas:

Similarly, the term"heterocyclyl (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-heterocyclyl.

[775] The term"carbocyclylalkyl (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-alkyl-carbocyclyl. For example, "phenylethyl (thiocarbonyl)" may be depicted as:

Similarly, the term"heterocyclylalkyl (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-alkyl-heterocyclyl.

[776] The term"carbocyclyloxy (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-O-carbocyclyl. For example,"phenyloxy (thiocarbonyl)" may be depicted as:

[777] The term"carbocyclylalkoxy (thiocarbonyl)" (alone or in combination with another term (s)) means-C (S)-O-alkyl-carbocyclyl. For example, "phenylethoxy (thiocarbonyl)" may be depicted as: [778] The term"sulfonyl" (alone or in combination with another term (s)) means - S (0) 2-, which also may be depicted as: Thus, for example,"alkyl-sulfonyl-alkyl"means alkyl-S (O) 2-alkyl.

The term"aminosulfonyl" (alone or in combination with another term (s)) means-S (O) 2-NH2, which also may be depicted as:

[780] The term"sulfoxido" (alone or in combination with another tenn (s)) means - S (0)-, which also may be depicted as: Thus, for example,"alkyl-sulfoxido-alkyl"means alkyl-S (O)-alkyl.

[781] The term"heterocyclyl" (alone or in combination with another term (s)) means a saturated (i. e.,"heterocycloalkyl"), partially saturated, or aryl (i. e.,"heteroaryl") ring structure containing a total of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i. e., oxygen, nitrogen, or sulfur), with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.

[782] A heterocyclyl may be a single ring, which typically contains from 3 to 7 ring atoms, more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples of single-ring heterocyclyls include furanyl, dihydrofurnayl, tetradydrofurnayl, thiophenyl (also known as"thiofuranyl"), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as"azoximyl"), 1,2,5-oxadiazolyl (also known as"furazanyl"), or 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl or 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl, or 1,3,4-dioxazolyl), oxathiazolyl, oxathiolyl, oxathiolanyl, pyranyl (including 1,2-pyranyl or 1,4-pyranyl), dihydropyranyl, pyridinyl (also known as"azinyl"), piperidinyl, diazinyl (including pyridazinyl (also

known as"1,2-diazinyl"), pyrimidinyl (also known as"1,3-diazinyl"), or pyrazinyl (also known as"1,4-diazinyl")), piperazinyl, triazinyl (including s-triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known 1,2,4-triazinyl), and v-triazinyl (also known as "1,2,3-triazinyl")), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as"pentoxazolyl"), 1,2,6-oxazinyl, or 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl or p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl or 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl.

[783] A heterocyclyl alternatively may be 2 or 3 rings fused together, such as, for example, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl (including pyrido [3,4-b]-pyridinyl, pyrido [3,2-b]-pyridinyl, or pyrido [4,3-b]-pyridinyl), and pteridinyl. Other examples of fused-ring heterocyclyls include benzo-fused heterocyclyls, such as indolyl, isoindolyl (also known as "isobenzazolyl"or"pseudoisoindolyl"), indoleninyl (also known as"pseudoindolyl"), isoindazolyl (also known as"benzpyrazolyl"), benzazinyl (including quinolinyl (also known as"1-benzazinyl") or isoquinolinyl (also known as"2-benzazinyl")), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl (including cinnolinyl (also known as "1,2-benzodiazinyl") or quinazolinyl (also known as"1,3-benzodiazinyl")), benzopyranyl (including"chromanyl"or"isochromanyl"), benzothiopyranyl (also known as "thiochromanyl"), benzoxazolyl, indoxazinyl (also known as"benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as"benzothiophenyl", "thionaphthenyl", or"benzothiofuranyl"), isobenzothienyl (also known as "isobenzothiophenyl","isothionaphthenyl", or"isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,1-benzoxazinyl, or 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,2-benzisoxazinyl or 1,4-benzisoxazinyl), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, and acridinyl.

[784] The term"2-fused'ring"heterocyclyl (alone or in combination with another term (s)) means a saturated, partially saturated, or aryl heterocyclyl containing 2 fused rings. Examples of 2-fused-ring heterocyclyls include indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinyl, pteridinyl,

indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl, benzisoxazinyl, and tetrahydroisoquinolinyl.

[785] The term"heteroaryl" (alone or in combination with another term (s)) means an aromatic heterocyclyl containing from 5 to 14 ring atoms. A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, pyrazyl, pyrimidinyl, and pyridazinyl ; 5-membered ring substituents such as 1,3,5-, 1,2,4- or 1,2,3-tiiazinyl, imidazyl, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl ; 6/5-membered fused ring substituents such as benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fused rings such as 1,2-, 1,4-, 2,3-and 2,1-benzopyronyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, and 1,4-benzoxazinyl.

[786] A carbocyclyl or heterocyclyl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen, hydroxy, carboxy, keto, alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl (also known as "alkanoyl"), aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, arylalkoxycarbonyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkoxy, cycloalkylalkoxyalkyl, and cycloalkylalkoxycarbonyl.

More typically, a carbocyclyl or heterocyclyl may optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen,-OH,-C (O)-OH, keto, Cl-C6-alkyl, Cl-C6-alkoxy, C1-C6-alkoxy-Cl-C6-alkyl, C,-C6-alkylcarbonyl, aryl, aryl-Cl-C6-alkyl, aryl-Ci-C6-alkoxy, <BR> <BR> <BR> aryl-Cl-C6-alkoxy-Cl-C6-alkyl, aryl-Cl-C6-alkoxycarbonyl, cycloalkyl,<BR> <BR> <BR> <BR> <BR> cycloalkyl-Ci-C6-alkyl, cycloalkyl-CI-C6-alkoxy, cycloalkyl-Cz-C6-alkoxy-CI-C6-alkyl, and cycloalkyl-Cl-C6-alkoxycarbonyl. The alkyl, alkoxy, alkoxyalkyl, alkylcarbonyl, aryl, arylalkyl, arylalkoxy, arylalkoxyalkyl, or arylalkoxycarbonyl substituent (s) may further be substituted with, for example, one or more halogen. The aryls or cycloalkyls are typically single-ring substituents containing from 3 to 6 ring atoms, and more typically from 5 to 6 ring atoms.

[787] An aryl or heteroaryl can optionally be substituted with, for example, one or more substituents independently selected from the group consisting of halogen,-OH, -CN, -NO2, -SH, -C(O)-OH, amino, aminocarbonyl, aminoalkyl, alkyl, alkylthio, carboxyalkylthio, alkylcarbonyl, alkylcarbonyloxy, alkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkoxy, alkoxyalkylthio, alkoxycarbonylalkylthio, carboxyalkoxy, alkoxycarbonylalkoxy, carbocyclyl, carbocyclylalkyl, carbocyclyloxy, carbocyclylthio, carbocyclylalkylthio, carbocyclylamino, carbocyclylalkylamino, carbocyclylcarbonylamino, carbocyclylcarbonyl, carbocyclyalkyl, carbonyl, carbocyclylcarbonyloxy, carbocyclyloxycarbonyl, carbocyclylalkoxycarbonyl, carbocyclyloxyalkoxycarbocyclyl, carbocyclylthioalkylthiocarbocyclyl, carbocyclylthioalkoxycarbocyclyl, carbocyclyloxyalkylthiocarbocyclyl, heterocyclyl, heterocyclylalkyl, heterocyclyloxy, heterocyclylthio, heterocyclylalkylthio, heterocyclylamino, heterocyclylalkylamino, heterocyclylcarbonylamino, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, heterocyclyloxycarbonyl, heterocyclylcarbonyloxy, heterocyclylalkoxycarbonyl, heterocyclyloxyalkoxyheterocyclyl, heterocyclylthioalkylthioheterocyclyl, heterocyclylthioalkoxyheterocyclyl, and heterocyclyloxyalkylthioheterocyclyl. More typically, an aryl or heteroaryl may, for example, optionally be substituted with one or more substituents independently selected from the group consisting of halogen,-OH,-CN, - N02,-SH,-C (O)-OH, amino, aminocarbonyl, amino-Cl-C6-alkyl, Cl-C6-alkyl, C1-C6-alkylthio, carboxy-CI-C6-alkylthio, Cl-C6-alkylcarbonyl, Cl-C6-alkylcarbonyloxy, Cl-C6-alkoxy, Cl-C6-alkoxy-C1-C6-alkyl, Cl-C6-alkoxycarbonyl, Cl-C6-alkoxycarbonyl-C1-C6-alkoxy,Cl-C6-alkoxy-C1-C6-alkylth io, Cl-C6-alkoxycarbonyl-C1-C6-alkylthio, carboxy-C1-C6-alkoxy, Cl-C6-alkoxycarbonyl-Cl-C6-alkoxy, aryl, aryl-Cl-C6-alkyl, aryloxy, arylthio, aryl-Cl-C6-alkylthio, arylamino, aryl-Cl-C6-alkylamino, arylcarbonylamino, arylcarbonyl, aryl-Cl-C6-alkylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, aryl-Cl-C6-alkoxycarbonyl, aryloxy-Cz-C6-alkoxyaryl, arylthio-Cz-C6-alkylthioaryl, arylthio-C1-C6-alkoxyaryl, aryloxy-Cl-C6-alkylthioaryl, cycloalkyl, cycloalkyl-Cl-C6-alkyl, cycloalkyloxy, cycloalkylthio, cycloalkyl-Cl-C6-alkylthio, cycloalkylamino, cycloalkyl-Cl-C6-alkylamino, cycloalkylcarbonylamino, cycloalkylcarbonyl, cycloalkyl-Cl-C6-alkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyloxycarbonyl,

cycloalkyl-Cl-C6-alkoxycarbonyl, heteroaryl, heteroaryl-Cl-C6-alkyl, heteroaryloxy, heteroarylthio, heteroaryl-Cl-C6-alkylthio, heteroarylamino, heteroaryl-Cl-C6-alkylamino, heteroarylcarbonylamino, heteroarylcarbonyl, heteroaryl-Cl-C6-alkylcarbonyl, heteroaryloxycarbonyl, heteroarylcarbonyloxy, and heteroaryl-Cl-C6-alkoxycarbonyl.

Here, one or more hydrogen bound to a carbon in any such substituent may, for example, optionally be replaced with halogen. hi addition, the cycloalkyl, aryl, and heteroaryl are typically single-ring substituents containing 3 to 6 ring atoms, and more typically 5 or 6 ring atoms.

[788] A prefix attached to a multi-component substituent only applies to the first component. To illustrate, the term"alkylcycloalkyl"contains two components: alkyl and cycloalkyl. Thus, the Cl-C6-prefix on Cl-C6-alkylcycloalkyl means that the alkyl component of the alkylcycloalkyl contains from 1 to 6 carbon atoms; the Cl-C6-prefix does not describe the cycloalkyl component. To illustrate further, the prefix"halo"on haloalkoxyalkyl indicates that only the alkoxy component of the alkoxyalkyl substituent is substituted with one or more halogen radicals. If halogen substitution may alternatively or additionally occur on the alkyl component, the substituent would instead be described as "halogen-substituted alkoxyalkyl"rather than"haloalkoxyalkyl."And finally, if the halogen substitution may only occur on the alkyl component, the substituent would instead be described as"alkoxyhaloalkyl." [789] If substituents are described as being"independently selected"from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent (s).

[790] When words are used to describe a substituent, the rightmost-described component of the substituent is the component that has the free valence. To illustrate, benzene substituted with methoxyethyl has the following structure: As can be seen, the ethyl is bound to the benzene, and the methoxy is the component of the substituent that is the component furthest from the benzene. As further illustration, benzene substituted with cyclohexanylthiobutoxy has the following structure :

[791] When words are used to describe a linking element between two other elements of a depicted chemical structure, the rightmost-described component of the substituent is the component that is bound to the left element in the depicted structure. To illustrate, if the chemical structure is X-L-Y and L is described as methylcyclohexanylethyl, then the chemical would be X-ethyl-cyclohexanyl-methyl-Y.

[792] When a chemical formula is used to describe a substituent, the dash on the left side of the formula indicates the portion of the substituent that has the free valence.

To illustrate, benzene substituted with-C (O)-OH has the following structure: [793] When a chemical formula is used to describe a linking element between two other elements of a depicted chemical structure, the leftmost dash of the substituent indicates the portion of the substituent that is bound to the left element in the depicted structure. The rightmost dash, on the other hand, indicates the portion of the substituent that is bound to the right element in the depicted structure. To illustrate, if the depicted chemical structure is X-L-Y and L is described as-C (O)-N (H)-, then the chemical would be: [794] The term"pharmaceutically acceptable"is used adjectivally in this patent to mean that the modified noun is appropriate for use as a pharmaceutical product or as a part of a pharmaceutical product.

[795] With reference to the use of the words"comprise"or"comprises"or "comprising"in this patent (including the claims), Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they are

to be interpreted inclusively, rather than exclusively, and that Applicants intend each of those words to be so interpreted in construing this patent, including the claims below.

F. Conipound Preparation [796] The detailed examples below illustrate preparation of compounds and salts of this invention. Other compounds and salts of this invention may be prepared using the methods illustrated in these examples (either alone or in combination with techniques generally known in the art). Such known techniques include, for example, those disclosed in Int'l Publ. No. WO 99/25687 (PCT Patent Application No. PCT/US98/23242 published on May 27,1999) (incorporated herein by reference). Such known techniques also include, for example, those disclosed in Int'l Publ. No. WO 00/50396 (PCT Patent Application No. PCT/USOO/02518 published on August 31,2000) (incorporated herein by reference). Such known techniques further include, for example, those disclosed in Int'l Publ. No. WO 00/69821 (PCT Patent Application No. PCT/US00/06719 published on November 23,2000) (incorporated herein by reference).

EXAMPLES [797] The following examples are merely illustrative, and not limiting to the remainder of this disclosure in any way.

[798] Example 1. Preparation of 4- [ [4- (3-aminopropoxy)- phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid 1, 1-dimethylethyl ester, monohydrochloride.

[799] Part A. To a solution of t-butylchloroacetate (67 g, 0.44 mol) and 4- fluorothiophenol (50 g, 0.40 mol) in N, N-dimethylformamide (1 L) was added potassium carbonate (62 g, 0.45 mol), followed by dimethylaminopyridine (2 g, 0.02 mol). The mixture was stirred at ambient temperature overnight under nitrogen. Once HPLC showed that the reaction was complete, the mixture was poured into stirring 10% aqueous HC1 (1

L) and extracted with ethyl acetate (4x). The combined organic layers were washed with water (2x), dried over magnesium sulfate, filtered, and concentrated in vacuum to afford 112 g (100+% crude yield) of a brown oil. 1H NMR confirmed the desired sulfide with no disulfide formation. This material was used without further purification.

[800] Part B. To a solution of the product from Part A (approximately 108g, 0.45 mol) in tetrahydrofuran (400 ml) was added water (700 ml), followed by Oxone (600 g, 0.98 mol). The reaction mixture was stirred overnight. Once HPLC showed completion, the reaction mixture was filtered to remove excess Ozone, and the mother liquor was then extracted with ethyl acetate (3x). The combined organic layers were washed with water (2x), dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 78.3 g (64% crude yield) of a yellow oil. Both 19F and lH NMR were consistent with the desired sulfone with no starting material remaining. This material was used without further purification.

[801] Part C. To a solution of the product from Part B (78 g, 0.28 mol) in N, N- dimethylacetamide (300 ml) was added potassium carbonate (86 g, 0.62 mol). After stirring for 5 min, 2,2'- (dibromoethyl) ether (79 g, 0.34 mol) was added, followed by 4- dimethylaminopyridine (1.7 g, 0.014 mol) and tetrabutylammonium bromide (4.5 g, 0.14 mol). The reaction mixture was stirred overnight via a mechanical stirrer. Once HPLC showed completion, the reaction mixture was slowly dumped into stirring 10% aqueous HC1 (1 L). The resulting yellow solid was collected and washed with hexanes to afford 84 g (86%) of a yellow solid. 1H NMR confirmed the desired product.

[802] Part D. To a solution of the product from Part C (19.8 g, 57.5 mmol) and t-butyl-N- (3-hydroxypropyl) carbamate (11.1 g, 63.3 mmol) in anhydrous N, N- dimethylformamide (300 mL) at 0°C was added sodium hydride (2.8 g, 69.0 mmol; 60% dispersion in mineral oil). After 18 hr, the reaction was quenched with water and concentrated in vacuo. The oily residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated, and the organic layer was washed with brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo. The oily residue was taken up in acetonitrile and again concentrated in vacuo. The resulting solid was triturated with diethyl ether, and 15.3 g (53%) of the pure desired product was collected as a white powder. ESMS m/z = 522 [M+Na] +. The filtrate

contained 11.6 g of material which was shown by HPLC to be 55% product. This material could be purified by flash chromatography to obtain more material if desired.

[803] Part E. The product from Part D (15.3 g, 30. 6 mmol) was taken up in 4N HC1 in dioxane (17 mL). After 1 hr, HPLC indicated incomplete reaction, so additional 4N HC1 in dioxane (2 mL) was added. After 20 min, the reaction mixture was slowly added to rapidly stirring diethyl ether (400 mL). The resulting oily solid was rinsed with more diethyl ether then dissolved in acetonitrile and concentrated in vacuo. 12.3 g (92%) of the desired hydrochloride salt was obtained as a white solid. ESMS m/z = 400 [M+H] +.

[804] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-A. Such compounds include, for example, those summarized in Table 1.

Table 1 Ex # structure n T < ESMS m/z 3C, CH3 0 0 0 1 CH3 CH3 428 (M+H] + H3C HCI O'NHZ C 0 HgC CH3 3 H3C CH3 0 0 0 0 CH3 H 422 [M+Na] + H3C °4) > CH3 J oY CH3 4 CH3 0 0 0 0 H CH3 422 [M+Na] + hic HOY Roc CHg Ex # structure n Y Y ESMS m/z 3C, g3 0 0 0 0 H H 408 [M+Na] + hic H3 /\O NH "0" 6 CH3 0 0 0 2 H H 414 (M+H] + \ HCl Ho /\orcS a Cl 0 [805] Example 7. Preparation of tetrahydro-4- [ [4- [ [5- (methoxy- <BR> <BR> methylamino)-5-oxopentyl] oxy] phenyl] sulfonyl]-N-(tetrahydro-2H-pyran-2-yl) oxy]- 2H-pyran-4-carboxamide

[806] Part A. To a solution of 5-benzyloxy-1-pentanol (32.6 g, 168 mmol) in anhydrous N, N-dimethylformamide (150 mL) at 0°C was added sodium hydride (7.7 g, 192 mmol, 60% dispersion in mineral oil). After 15 min, the reaction mixture was allowed to warm to 20°C, and then re-cooled to 0°C. A solution of 4- [ (4- fluorophenyl) sulfonyl] tetraliydro-2H-pyran-4-carboxylic acid, 1, 1-dimethylethyl ester (55.1 g, 160 mmol, as prepared in Example 1, Part C) in anhydrous N, N- dimethylformamide (100 mL) was added, and the cooling bath removed. After 4 hr, the reaction was concentrated in vacuo. The oily residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated, and the aqueous layer was back extracted with ethyl acetate (2X). The combined extracts were washed with 5% potassium hydrogensulfate, water, and brine (3X); dried over magnesium sulfate; filtered ; and concentrated in vacuo. The resulting opaque oil solidified upon standing, and was subsequently purified by column chromatography using 10-20% ethyl acetate/hexanes to afford 67.6 g (81%) of the desired product as a white solid. ESMS m/z = 541 [M+Na] +.

[8071 Part B. The product from Part A (20.0 g, 38.6 mmol) was dissolved in tetrahydrofuran (80 mL) in a small Fisher/Porter bottle. After purging with a stream of

nitrogen for 5 min, the reaction was charged with 5% palladium on carbon catalyst (4.0 g, Degussa ElOI NO/W, 50% water) and pressurized to roughly-80 psi with hydrogen.

After 1.5 hr, hydrogen uptake had ceased and HPLC analysis indicated the reaction was complete. The reaction was filtered through a bed of celite and the filtrate was concentrated to yield 17.2 g (100%) of the desired alcohol as a viscous oil. This material was used without further purification.

[808] Part C. The product from Part B (16.5 g, 38.6 mmol) was dissolved in acetonitrile (80 mL). The reaction mixture was treated with carbon tetrachloride (80 mL), water (120 mL), then sodium periodate (24.7 g, 115.7 mmol), and finally ruthenium trichloride (180 mg, 0.9 mmol). After 1 hr, HPLC analysis indicated that the reaction was complete. The reaction mixture was diluted with methylene chloride (300 mL), and the solids were removed by gravity filtration. The layers were separated, and the aqueous layer was extracted with methylene chloride (3X). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a blue solid.

This was redissolved in tetrahydrofuran, slurried with activated carbon, filtered, and concentrated in vacuo to yield 17.1 g (100%) of an off-white solid. lHNMR was consistent with the desired product. This material was used without further purification.

[809] Part D. To a solution of the product from Part C (17.1 g, 38.6 mmol) in N, N-dimethylformamide (160 ml) was added 1-hydroxybenzotriazole (7.8g, 57.9 mmol), and then 143-dimethyaminopropyl)-3-ethylcarbodiirnide hydrochloride (10.3 g, 54.0 mmol). After 1.5 hr, N, O-dimethylhydroxylamine HC1 (11.3 g, 115.7 mmol) and triethylamine (32.2 ml, 231.4 mmol) were added. The reaction mixture was left stirring at ambient temperature overnight. The mixture was concentrated, and the residue partitioned between ethyl acetate and saturated sodium bicarbonate solution. The aqueous layer was back extracted with ethyl acetate (2X), and the combined organic layers were washed with 5% potassium hydrogensulfate solution, water, and brine (3X), then dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude solid was purified by column chromatography using 50% ethyl acetate/hexanes, and 14.7 g (79%) of the desired weinreb amide was obtained as an off-white solid. ESMS m/z = 508 [M+Na] +.

[810] Part E. The product from Part D (6.24 g, 12.85 mmol) was taken up in neat trifluoroacetic acid (50 mL). After 1. 5 hr, the trifluoroacetic acid was removed in vacuo at 50°C to give the free acid as a syrupy oil. ESMS m/z = 430 [M+H] +. To a

solution of this material in anhydrous N, N-dimethylformamide (25 mL) was added 1- hydroxybenzotriazole (2.14 g, 15.88 mmol), tetrahydropyranhydroxylamine (4.64 g, 39.72 mmol), and triethylamine (5.5 mL, 39.72 mmol), followed by 1- (3-dimethyaminopropyl)- 3-ethylcarbodiimide hydrochloride (3.35 g, 15.83 mmol). The reaction mixture was heated at 40°C for 3.5 hr, and then cooled to ambient temperature and stirred overnight.

The reaction mixture was concentrated in vacuo at 60°C. The residue was taken up in ethyl acetate, washed with saturated sodium bicarbonate solution (2X) and brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo to give 8 g of a syrup.

The crude material was purified by flash chromatography using 50-100% ethyl acetate/hexanes to give the title compound as a white solid. ESMS m/z = 529 [M+H] +.

HRMS calculated for C24H36N209S : 529.2220 [M+H] +, found: 529.2210.

[811] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-B. Such compounds include, for example, the compound summarized in Table 2.

EX-B Table 2 Ex structure n Calcd Observed # Mass Mass 8 oo 0 518. 2172 518.2176 CN I O O H Chug I 9 0 o o 1532. 2329 532.2307 0, v ° Wo gNso, CH3 0 O [812] Example 10: Preparation of tetrahydro-4-[[4-[3-[(methyl- sulfonyl)oxy]propoxy]phenyl)sulfonyl]-N-[(tetrahydro-2H pyran-2-yl)oxy]-2H-pyran- 4-carboxamide

[813] Part A. To a solution of 4- [ (4-fluorophenyl) sulfonyl]-tetrahydro-2H- pyran-4-carboxylic acid, 1, 1-dimethylethyl ester (5.0 g, 14.5 mmol, as prepared in Example 1, Part C) and 3-benzyloxy-1-propanol (2.3 mL, 14.5 mmol) in N, N- dimethylformamide (50 mL) at 0°C was added NaH (696 mg, 17.4 mmol, 60% dispersion in mineral oil). The solution was stirred at ambient temperature for 5 lir. The reaction was quenched with water, and then partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 7.89 g (quantitative yield) of the benzyl ether as a yellow oil. (ESMS m/z = 435 [M-tBu] +.

[814] Part B. The benzyl ether of Part A (4.39 g, 8.94 mmol) was hydrolized in 1: 1 trifluoroacetic acid: methylene chloride (50 mL). The solution was concentrated in vacuo to provide 3.69 g (950) of the free acid as a crude white solid. ESMS m/z = 452 [M+NH4] +. This material was used without purification.

[815] Part C. To a solution of the crude acid of Part B (3.60 g, 8.29 mmol) in N, N-dimethylformamide (40 mL) was added 1-hydroxybenzotriazole (1.34 g, 9.95 mmol), triethylamine (3.5 mL, 24.9 mmol), and tetrahydropyranhydroxylamine (2.91 g, 24.9 mmol). After 30 min, 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (2.23 g, 11.6 mmol) was added. The solution was stirred for 18 hr at ambient temperature.

The solution was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution and brine, and then dried over sodium sulfate. Purification by flash chromatography using ethyl acetate/hexanes provided 3.71 g (84 0) of the protected hydroxamate as a crude oil.

ESMS m/z = 551 (M+NH4) +. HRMS calculated for C27H35NO8S NH4 : 551.2427 (M+NH4)''. Found: 551.2418.

[816] Part D. The benzyl ether of Part C (3.52 g, 6.6 mmol) was hydrogenated over 10% palladium/carbon (3.31g) in methanol with ammonium formate (2.5 g, 39. 6

mmol) as the hydrogen source added in 3 portions and heated at reflux. The solution was filtered through celite and concentrated in vacuo to provided 2.89 g (98 %) of the alcohol as a colorless oil. ESMS m/z = 442 [M-H] +. This material was used without purification.

[817] Part E. To a solution of the protected hydroxamate of Part D (2.57 g, 5.8 mmol) in methylene chloride (25 mL) was added triethylamine (2.5 mL, 18. 8 mmol). The solution was cooled to 0°C, and methylsulfonyl chloride (1.25 mL, 16.0 mmol) was added.

After 18 hr, the reaction was washed with water, 10% citric acid, 5% sodium bicarbonate solution, and brine, and then dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexanes) provided the title compound as a colorless oil (1.48 g, 49 0). ESMS m/z = 544 (M+Na) +. HRMS calculated for C2lH3lNO1oS2 NH4 : 539.1733 (M+NH4) +.

Found: 539.1709.

[818] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-C. Such compounds include, for example, the compounds summarized in Table 3.

EX-C Table 3 Ex structure n Calcd Observed # Mass Mass 11 0 oso 1 525.1517 525.1561 0 N// O fez po 12 0 NX 3 558. 1444 558.1429 W ol N /i 0 0 zozo 13 o 4 572. 16 572. 1583 O. N s W \ % O'N'ho or""c [819] Example 14. Preparation of (tetrahydro-4- [ (4- (2- propenyloxy) phenyl] sulfonyl]-N- [(tetrahydro-2H-pyran-2-yl) oxy]-2H-pyran-4- carboxamide

[820] Part A. To a solution of sodium (8. 97 g, 390 mmol) in methanol (1 L) at 0°C were added 4-fluorothiophenol (50 g, 390 mmol) and methyl chloroacetate (34.2 mL, 390 mmol). After stirring at ambient temperature for 4 hr, the solution was filtered to remove salts, and the filtrate was concentrated in vacuo to provide 75.85 g (970) for the desired sulfide as a colorless oil.

[821] Part B. To a solution of the product from Part A (75.85 g, 380 mmol) in methanol (1 L) and water (100 mL) was added OxoneTM (720 g, 1.17 mmol). After 2 hr, the reaction mixture was filtered to remove the excess salts, and the filtrate was concentrated in vacuo. The resulting residue was dissolved in ethyl acetate and washed with water, saturated sodium bicarbonate solution, and brine, and then dried over magnesium sulfate. Concentrating in vacuo provided 82.74 g (94%) of the desired sulfone as a white solid.

[822] Part C. To a solution of the product from Part B (28. 5 g, 123 mmol) in N, N-dimethylacetamide (200 mL) were added potassium carbonate (37.3 g, 270 mmol), bis- (2-bromoethylether (19.3 mL, 147 mmol), 4-dimethylaminopyridine (750 mg, 6 mmol), and tetrabutylammonium bromide (1.98 g, 6 mmol). The resulting solution was stirred at ambient temperature for 72 lir, and then poured into 1 N HC1 (300 mL). The resulting precipitate was collected by vacuum filtration. Recrystallization using ethyl acetate/hexanes provided 28. 74 g (77%) of the tetrahydropyran product as a beige solid.

[823] Part D. To a solution of the product from Part C (8. 0 g, 26.5 mmol) in tetrahydrofuran (250 mL) was added potassium trimethylsilonate (10.2 g, 79.5 mmol).

After 1.5 hr, the reaction mixture was quenched with water, acidified to pH 2.5, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 5.78 g (76%) of the desired acid salt as a white solid.

[824] Part E. To a solution of the product from Part D (5.4 g, 18.7 mmol) in N, N-dimethylformamide (35 mL) were added 1-hydroxybenzotriazole (3.04 g, 22.5 mmol), N-methylmorpholine (6.2 mL, 56.2 mmol), tetrahydropyranhydroxylamine (6.8 g, 58.1 mmol) and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0 g, 26.2 mmol). After stirring for 3 hr at ambient temperature, the solution was concentrated in vacuo, and the residue partitioned between ethyl acetate and water. The organic layer was washed with 5% aqueous potassium hydrogen sulfate, water, saturated sodium bicarbonate solution, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo to provide 6.34 g (87%) of the THP protected hydroxamate as a white solid.

[825] Part F. To a solution of the product from Part E (1.0 g, 2.58 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (0.89 g, 6.45 mmol) and allyl alcohol (0.35 mL, 12.9 mmol). The mixture was heated to 110°C for 72 hr. Additional allyl alcohol (0. 88 mL, 13 mmol) and cesium carbonate (2.1 g, 6.45 mmol) were added, and the mixture heated at 120°C for 6 hr. After cooling to ambient temperature, the mixture was diluted with water (50 mL), and the pH adjusted to 8-9 with 1 N HC1. The aqueous layer was extracted with ethyl acetate. The organic layer was washed brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification via flash column chromatography with 15% ethyl acetate/hexanes yielded 0.67 g of pure title compound as a white solid. ESMS m/z = 426 [M+H] +.

[826] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-D. Such compounds include, for example, the compounds summarized in Table 4.

EX-D Table 4 Ex. Structure n ESMS m/z # 15 0 oxo 2 440 [M+H] + w kO H .. t CH2 16 0 o o 3 454 [M+H] + O. S 'TT r 1 I I I 0" [827] Example 17. Preparation of tetrahydro-N-hydroxy-4-[[4-[3-[(4- methoxybenzoyl) amino] propoxy] phenyl] sulfonyl]-2H-pyran-4-carboxamide

[828] Part A. To a solution of 4-[[4-(3-aminopropoxy)-phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid 1, 1-dimethylethyl ester, monohydrochloride (507 mg, 1.27 mmol, prepared as in Example 1) in anhydrous N, N-dimethylformamide (5 mL) at ambient temperature was added triethylamine (215 uL, 1.54 mmol), followed immediately by panisoyl chloride (260 mg, 1.52 mmol). After 1 hr, the reaction mixture was quenched with water (-2 mL) and concentrated in vacuo at 60°C. The crude residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow oil. The crude product was partially purified by flash chromatography using 80% ethyl acetate/hexanes to provide 225 mg (33%) of the desired acylated product as a clear, colorless oil. ESMS m/z = 556 [M+Na] +. This material was used without further purification.

[829] Part B. The product from Part A (225 mg, 82% purity by HPLC) was taken up in neat trifluoroacetic acid (1 mL). After 3 hr, the trifluoroacetic acid was removed in vacuo at 50°C to give the free acid as a colorless oil. ESMS m/z = 478 [M+H] +. To a solution of this material in anhydrous N, N dimethylformamide (2 mL) was added 1-hyrdoxybenzotriazole (72 mg, 0.53 mmol), N-methylmorpholine (100 uL, 0.91

mmol) and tetrahydropyranhydroxylamine (78 mg, 0.67 mmol), followed by 1- (3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (119 mg, 0.62 mmol). The reaction mixture was stirred at ambient temperature for 72 hr, and then concentrated in vacuo at 60°C. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution and brine (2X), dried over sodium sulfate, filtered, and concentrated in vacuo to give 255 mg of the desired THP protected hydroxamate as a colorless oil. ESMS m/z = 599 [M+Na] +. HRMS calculated for C2gH36N209S : 577.2220 [M+H] +, fouid : 577.2215.

[830] Part C. The product from Part B (255 mg, 88% purity by HPLC) was dissolved in 4N HC1 in dioxane (3 mL) and methanol (300 uL). After 1 hr at ambient temperature, the reaction mixture was poured into rapidly stirring diethyl ether (50 mL).

A white solid was collected and dried over P205 under vacuum. The title compound was obtained as a faint pink solid. ESMS m/z = 493 [M+H] +. HRMS calculated for C23H28N208S : 493.1645 [M+H] +, found: 493.1636.

[831] Additional compounds (such as those having a structure corresponding to generic Formula EX-E) can be prepared by one skilled in the art using similar methods with either the t-butyl ester or free acid of 4- [ [4- (3-aminopropoxy)-phenyl] sulfonyl]- tetrahydro-2H-pyran-4-carboxylic acid 1, 1-dimethylethyl ester, monohydrochloride or similarly prepared starting materials. Also, one may use carboxylic acids as coupling agents in place of acid chlorides using standard peptide coupling conditions for formation of the amide bond.

EX-E [832] Example 18. Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-[3[(4- methoxybenzoyl) amino] propoxy] phenyl] sulfonyl]-4-piperidinecarboxamide, monohydrochloride.

[833] Part A. to a solution of ethyl isonipecotate (15.7 g, 0.1 mol) in tetrahydrofuran (100 mL) was added a solution of di-tert-butyl dicarbonate (21.8 g, 0.1 mol) in tetrahydrofuran (5 mL) dropwise over 20 min. The solution was stirred overnight at ambient temperature and concentrated in vacuo to yield a light oil. The oil was filtered through silica gel using ethyl acetate/hexanes then concentrated in vacuo to afford 26.2 g (100%) of the desired BOC-piperidine as a clear, colorless oil.

[834] Part B. A solution of 4-fluorothiophenol (50.29 g, 390 mmol) in dimethyl sulfoxide (500 mL) was heated to 65°C for 6 hr. The reaction was quenched by pouring into wet ice. The resulting solid was collected by vacuum filtration to afford 34.4 g (68. 9%) of the desired disulfide as a white solid.

[835] Part C. To a solution of the product from Part A (16 g, 62 mmol) in tetrahydrofuran (300 mL) cooled to-50°C was added lithium diisopropylamide (41.33 mL, 74 mmol). After being at 0°C for 1.5 hr, the product from Part B (15.77 g, 62 mmol) was added. The reaction mixture was stirred at ambient temperature for 20 hr, and then quenched by the addition of water. The solution was concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate and water. The organic layer was washed with 0.5 N KOH, water, and brine. Purification by column chromatography using ethyl acetate/hexanes provided 18.0 g (75%) of the desired sulfide as an oil.

[836] Part D. To a solution of the product from Part C (16.5 g, 43 mmol) in methylene chloride (500 mL) cooled to 0°C was added 3-chloroperbenzoic acid (18. 0 g, 86 mmoL). After stirring for 20 hr, the reaction mixture was diluted with water and extracted with methylene chloride. The organic layer was washed with 10% aqueous sodium sulfite, water, and brine, dried over magnesium sulfate, filtered, and concentrated

in vacuo. The crude product was purified by column chromatography using ethyl acetate/hexanes to afford 10.7 g (60%) of the desired sulfone as a solid.

[837] Part E. Into a solution of the product from Part D (10 g, 24.0 mmol) in ethyl acetate (250 mL) was bubbled HC1 gas for 10 min, followed by stirring at ambient temperature for 4 hr. Concentration in vacuo provided 7.27 g (86%) of the amine hydrochloride salt as a white solid.

[838] Part F. To a solution of the product from Part E (10.0 g, 28.4 mmol) in methanol (100 mL) was added acetic acid (16.2 mL, 284 mmol), powdered 4A molecular sieves (9.1 g), and [(l-ethoxycyclopropyl) oxyl trimethyl silane (17.1 mL, 85. 2 mmol).

Sodium cyanoborohydride (4,82 g, 76.7 mmol) was then added slowly. The reaction was heated at reflux with vigorous stirring for 4.5 hr. The reaction mixture was cooled to room temperature, filtered through celite, and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate solution (3X) and brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material crystallized upon standing providing 10.9 g (100%) of the alkylated amine compound as a pale yellow oily crystal. ESMS m/z = 356 (M+H) . This material was used without purification.

[839] Part G. The product from Part F (28.4 mmol) was hydrolized in tetrahydrofuran (65 mL) with LiOH (3.58 g, 85.2 mmol) in 35 mL of water at 60°C over 3 days. The solution was concentrated in vacuo, diluted with water, and washed with diethyl ether. The aqueous layer was acidified with IN HC1 to a pH of-4. 5, causing a white precipitate to form. The solid was collected by filtration, washed with water, and washed with ethyl acetate. After drying over silica on a high vacuum, 8.06 g (78.2 %) of the acid was obtained as a crude white solid. ESMS m/z = 328 (M+H) +. HRMS calculated for Cl5HI8NO4SE : 328.1019 (M+H) +, found: 328.1014. This material was used without purification.

[840] Part H. To a solution of the crude acid of Part G (7.92 g, 21.8 mmol) in N, N-dimethylformamide (48 mL) was added N-methylmorpholine (12. 0 mL, 109 mmol) and PyBOP (12.5 g, 24.0 mmol). After stirring 15 min, tetrahydropyranhydroxylamine (3.07 g, 26.2 mmol) was added. The solution was stirred for 22 hr at ambient temperature.

The solution was diluted with water (240 mL) and extracted with ethyl acetate (3X). The combined organics were washed with saturated aqueous sodium bicarbonate solution (2X)

and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to a foamy oil.

The crude material was filtered through a silica plug using 1 % Et3N in ethyl acetate/hexanes to afford 7.12 g (76.60) of the protected hydroxamate as a foamy oil.

ESMS m/z = 427 (M+H) +. HRMS calculated for C2oH27N205SF : 427. 1703 (M+H) +.

Found: 427.1693.

[841] Part I. To a solution of 3- (dibenzylamino)-1-propanol (4.3 g, 16.88 mmol) in anhydrous N, N-dimethylformamide (35 mL) was added sodium hydride (1.3 g, 32.35 mmol; 60% dispersion in mineral oil). The reaction mixture was stirred for 15 min, then cooled to 0°C in an ice bath and treated with a solution of the product from Part H (6.0 g, 14.07 mmol) in anhydrous N, N-dimethylformamide (15 mL). After the addition was completed, the ice bath was removed and the reaction was allowed to stir at ambient temperature for 18 hr. The reaction was quenched with water and concentrated in vacuo.

The oily residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (3X). The organic extracts were combined and washed with brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude yellow solid was re-crystallized from hot acetonitrile. 6.5 g (70%) of the pure desired product was collected as a white powder. ESMS m/z = 662 [M+H] +.

[842] Part J. The product from Part I (1.0 g, 1.51 mmol) and glacial acetic acid (0.2 g, 3.02 mmol) were slurried in methanol (15 mL) in a small Fisher/Porter bottle.

After purging with a stream of nitrogen for 5 min, the reaction was charged with 20% palladium on carbon catalyst (0.5 g, Degussa E169X/W, 50% water) and pressurized to 50 psi with hydrogen. After 5 hr, hydrogen uptake had ceased, and HPLC analysis indicated the reaction was complete. The reaction was filtered through a bed of celite, and the filtrate was concentrated to yield 0.8 g (1000) of the desired mono-acetate salt as a dry, white foam. ESMS m/z = 481 [M+H] +.

[843] Part K. To a solution of the product from Part J (0.7 g, 1.06 mmol) in anhydrous methylene chloride (11 mL) at ambient temperature was added triethylamine (0.73 mL, 6.35 mmol), followed by p-anisoyl chloride (0.3 g, 1.59 mmol). After 10 min, HPLC analysis showed the reaction to be complete. The reaction mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated, and the aqueous layer extracted

with ethyl acetate (3X). The organic extracts were combined and washed with brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo to yield a tan foam. The crude product was purified by flash chromatography using 60-100% [5% (2M ammonia in methanol) ethyl acetate]/hexanes to yield 0.2 g (34%) of the desired product as a dry white foam. ESMS m/z = 616 [M+H] +.

[844] Part L. The product from Part K (0.2 g, 0.34 mmol) was slurried in 4N HC1 in dioxane (2 mL). After 5 min, methanol (0.2 mL) was added. After stirring for 10 min at ambient temperature, the reaction mixture was poured into rapidly stirring diethyl ether (50 mL). A white solid was collected and dried under vacuum. The title compound (as the HC1 salt) was obtained as an off-white solid. ESMS m/z = 532 [M+H] +. HRMS calculated for C26H33N307S : 532.2117 [M+H] +, found: 532.2098.

[845] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-F.

EX-F [846] Example 19. Preparation of 4-[[4-[3-[[4-(dimethylamino) benzoyl] methylamino] propoxy] phenyl] sulfonyl tetrahydro-N-hydroxy-2H-pyran-4- carboxamide.

[847] Part A. To a solution of 4-[[4-[3-[[4(dimethylamino)- benzoyl] amino] propoxy] phenyl] sulfonyl] tetrahydro-2H-pyran-4carboxylic acid, 1,1-

dimethylethyl ester (prepared as in Example 17) in anhydrous N, N-dimethylformamide (3 mL) was added iodomethane (61 uL, 0.98 mmol), followed by sodium hydride (24 mg, 0.59 mmol; 60% dispersion in mineral oil). After 1 hr the reaction mixture was quenched with water, washed with brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo to yield the desired N-methylated product as a sticky solid. ESMS m/z = 561 [M+H] +. HRMS calculated for C29H4oN307S : 561.2634 [M+H] +, found: 561.2628.

[848l Part B. The product from Part A (400 mg, 0.71 mmol) was taken up in neat trifluoroacetic acid (1 mL). After 1 hr, the trifluoroacetic acid was removed in vacuo at 60°C to give the free acid as a sticky solid. ESMS m/z = 505 [M+H] +. To a solution of this material in anhydrous N, N-dimethylformamide (5 mL) was added 1- hydroxybenzotriazole (113 mg, 0.83 mmol), tetrahydropyranhydroxylamine (246 mg, 2.10 mmol), and triethylamine (390 uL, 2.8 mmol), followed by 1- (3dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride (188 mg, 0.98 mmol). The reaction mixture was heated to 40°C for 4 hr, and then cooled to ambient temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution (2X) and brine (4X), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was de-protected and simultaneously purified by reverse phase HPLC to give 59 mg of the title compound as an off-white solid. ESMS m/z = 520 [M+H] +. HRMS calculated for C25H33N307S : 520.2117 [M+H] +, found: 520.2120.

[849] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-G.

EX-G 18501 Example 20. Preparation of 4-[[4-[[5-[[4-(dimethylamino)- phenyl] amino]-5-oxopentyl] oxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4- carboxamide, monohydrochloride.

[851] Part A. To a solution of 4- [ [4- (4-carboxybutoxy) phenyl- ] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid, 1, 1-dimethylethyl ester (446 mg, 0.91 mmol, prepared as in Example 7) in anhydrous N, N-dimethylformamide (6 mL) was added 1-hydroxybenzotriazole (150 mg, 1.11 mmol), triethylamine (400 uL, 2.87 mmol), N, N-dimethyl-1, 4-phenylenediamine (188 mg, 1.38 mmol), and finally 1- (3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (300 mg, 1.56 mmol). The reaction mixture was stirred at ambient temperature for 18 hr, and then concentrated in vacuo at 60°C. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine (2X), dried over sodium sulfate, filtered, and concentrated in vacuo to give the desired amide. ESMS m/z = 561 [M+H] +. This material was taken up in neat trifluoroacetic acid (5 mL). After 3 hr the trifluoroacetic acid was removed in vacuo at 60°C to give the free acid. ESMS m/z = 505 [M+H] +. To a solution of this material in anhydrous N, N-dimethylformamide (5 mL) was added 1-hydroxybenzotriazole (148 mg, 1.10 mmol), triethylamine (400 uL, 2.87 mmol), and tetrahydropyranhydroxylamine (320 mg, 2.73 mmol), followed by 1- (3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (262 mg, 1.37 mmol). The reaction mixture was stirred at ambient temperature overnight, and then partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo.

The crude material was purified by flash chromatography using 80% ethyl acetate/hexanes as eluant to afford the desired THP hydroxamate. ESMS m/z = 604 [M+H] +. HRMS calculated for C30H41N30sS : 604. 2693 [M+H] +, found: 604.2709.

[852l Part B. The product from Part A was dissolved in 4N HC1 in dioxane (5 mL) and methanol (500 uL). After 3 hr at ambient temperature the reaction mixture was poured into rapidly stirring diethyl ether (50 mL). A purplish-pink solid was collected and

subsequently purified by reverse phase HPLC. The title compound was obtained as a faint pink solid 131 mg (28% from the starting acid in part A). ESMS m/z = 520 [M+H] +.

HRMS calculated for C25H33N307SHC1 : 520.2117 [M+H] +, found : 520.2127.

[853] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-H.

EX-H [854] Example 21. Preparation of 4-[[4-[3-(1,3-dihydro-I, 3-dioxo2H- isoindol-2-ylpropoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4- carboxamide [8551 Part A. To a solution of 4- [ (4-fluorophenyl) sulfonyl] tetrahydro-2H-pyran- 4-carboxylic acid, 1, 1-di-methylethyl ester (6.7 g, 19 mmol, as prepared in Example 1, Part C) in anhydrous N, N-dimethylformamide (40 ml) at ambient temperature was added N- (3-hydroxypropyl) phthalimide (4 g, 19 mmol), followed immediately by NaH (700 mg, 20 mmol, 60% dispersion in mineral oil). After 1.5 hr, HPLC showed less than 1% of the starting electrophile. The reaction mixture was quenched with water (60 ml). The cloudy mixture was extracted with ethyl acetate (2x100 ml). The organic layers were combined, washed with brine (1x200 ml), dried over sodium sulfate, filtered, and concentrated ill vacuo to give a tan, viscous oil that crystallized from methanol (3.2 g, 52%). ESMS m/z = 489 [M+H] +. This material was used without further purification.

[856] Part B. The product from Part A (3 g, 6 mmol) was dissolved in methylene chloride (304 ml) and trifluoroacetic acid (6 ml). After 12 hr, the mixture was concentrated in vacuo, and the residue was triturated with diethyl ether to form a solid which was collected and dried to afford the carboxylic acid as a beige solid (3 g, 90%).

ESMS m/z = 474 [M+H] +. This material was used without further purification.

[857] Part C. To a solution of the product from Part B (3 g, 6.2 mmol) in anhydrous N, N-dimethylformamide (25 ml) was added triethylamine (2 ml, 18 mmol), followed by tetrahydropyranhydroxylamine (1 g, 8 mmol), 1-hydroxybenzotriazole (0.5 g, 3 mmol), and 1- (3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (2 g, 8 mmol). The reaction mixture was heated at 40°C for 0.5 hr. The reaction was monitored by RPHPLC. After 2 hr, the mixture was concentrated in vacuo, the residue was flooded with water, and the product separated as a solid. The solid was filtered, and was of sufficient purity to carry on to the next step. Mass spectral data and NMR were consistent with the desired product.

[858] Part D. The solid from Part C (3 g) was slurried in methanol (1 mL) and diethyl ether (30 ml). To this was added 4N HC1 in dioxane (10 ml) and stirred for 2 hr.

RPHPLC showed complete reaction. The reaction mixture was concentrated by half, diethyl ether (lOOmL) was added, and the white solid (1.5 g, 70% yield) filtered and dried under vacuum. 1H NMR was consistent with the desired product ESMS m/z C23H24N20sS = 49 [M+H] +. HRMS calculated for C23H24N208S : 489.1332 [M+H] +, found: 489. 1298.

[859] Example 22. Preparation of 4-[[4-[3-(1,3-dihydro-1-oxo-2H-isoindol-2- yl) propoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide [860] Part A. To a solution of 4- [ (4-fluorophenyl)-sulfonyl] tetrahydro-2H-pyran- 4-carboxylic acid, 1, 1-dimethylethyl ester (5.2 g, 15 mmol, as prepared in Example 1, Part C) in dimethyl sulfoxide (40 ml) at ambient temperature was added N- (3- hydroxypropyl) phthalide (3 g, 15 mmol, prepared according to J. Med. Chem., 146-157

(1996)), followed by cessium carbonate (12 g, 45 mmol). After 15 hr at 80°C, HPLC indicated complete reaction. The reaction mixture was quenched with water (60 ml). The cloudy mixture was extracted with ethyl acetate (2x100 ml). The organic layers were combined, washed with brine (1x200 ml), dried over sodium sulfate, filtered, and concentrated in vacuo to give a tan, viscous oil that crystallized from methanol (7 g, 720).

ESMS m/z = 516 [M+H] +, NMR was consistent with desired product. This material was used without further purification.

[861] Part B. The product from Part A (3 g, 6 mmol) was dissolved in methylene chloride (300 ml) and trifluoroacetic acid (6 ml). After 12 hr of stirring, the mixture was concentrated in vacuo and the residue was triturated with diethyl ether to form a solid which was collected and dried to afford the carboxylic acid as a beige solid (3 g, 91 %). ESMS m/z = 474 [M+H] +. This material was used without further purification.

[862] Part C. To a solution of the product from Part B (3 g, 6.2 mmol) in N, N- dimethylformamide (25 ml) was added triethylamine (2 ml, 18 mmol), followed by tetrahydropyranhydroxylamine (1.2 g, 8 mmol), 1-hydroxybenzotriazole (0.5 g, 3 mmol), and 1- (3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 g, 8 mmol). The reaction mixture was heated at 40°C for 0.5 hr. The reaction was monitored by RPHPLC.

After completion the mixture was concentrated and the residue was flooded with water.

The resulting solid was filtered, and was of sufficient purity to carry on to the next step.

Mass spectral data and NMR were consistent with the desired product.

[863] Part D. The solid from Part C (3 g) was slurried in methanol (1 mL) and diethyl ether (30 ml). To this was added 4N HC1 in dioxane (10 ml) and stirred for 2 hr.

RPHPLC showed complete reaction. The reaction mixture was concentrated by half, diethyl ether (100 mL) was added, and the white solid (2.5 g, 90% yield) filtered and dried under vacuum. 1H NMR was consistent with the desired product. HRMS calculated for C23H26N207S : 475.1525 [M+H] +, found: 475.1510.

[864] Example 23. Preparation of 4-[[4-[[4E)-5- [-4-(dimethylamino) phenyl]-4-pentenyl] oxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4- carboxamide and 4-[[4-[[4Z)-5-[-4-(dimethyl-amino) phenyl]-4- pentenyl] oxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide, monohydrochloride [865] Part A. To a solution of 4- [ (4-fluorophenyl) sulfonyl] tetrahydro-2H-pyran- 4-carboxylic acid, 1, 1-di-methylethyl ester (10.0 g, 29.0 mmol, as prepared in Example 1, Part C) in N, N-dimethylformamide (60 ml) at ambient temperature was added 4-penten- l-ol (3.1 ml, 30.0 mmol), followed immediately by NaH (1.4 g, 34.8 mmol, 60% dispersion in mineral oil). After 1.5 hr, HPLC showed less than 1% of the starting material. The reaction mixture was quenched with water (60 ml). The cloudy mixture was extracted with ethyl acetate (3x-300 ml). The organic layers were combined; washed with 5% potassium hydrogensulfate (1x200 ml), saturated sodium bicarbonate solution (lx-200 ml), water (lx-200 ml), and brine (lx-200 ml); dried over sodium sulfate; filtered; and concentrated in vacuo to give a tan oil. The crude product was partially purified by flash chromatography using 15% ethylacetate/hexanes to provide 11.7 g (98%) of the desired ether product as a clear, colorless oil. ESMS m/z = 433 [M+Na] +. This material was used without further purification.

[866] Part B. To a solution of the product from Part A (2.0 g, 4.9 mmol) in N, N-dimethylformamide (3 ml) was added 4-bromo-N, N-dimethylaniline (1.2g, 5.8 mmol), followed by triethylamine (1.4 ml, 9.8 mmol), tri-ortho-tolylphosphine (34 mg, 0.10 mmol), and palladium (II) acetate (12 mg, 0.05 mmol). The reaction was heated at 100°C for 12 hr. The reaction was cooled and diluted with water (5 ml). The aqueous was extracted with ethyl acetate (3x15 ml). The organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a black oil (3.2 g). The black crude product was partially purified by flash chromatography using 5% ethyl acetate/hexanes to

provide 1.2 g of the olefinic product as a tan oil (45% yield, trans: cis, 3: 1). ESMS m/z = 552 [M+Na] +. This material was used without further purification.

[867] Part C. The product from Part B (1.2 g, 2.3 mmol) was dissolved in methylene chloride (4 ml) and trifluoroacetic acid (4 ml). After 1 hr of stirring, the mixture was concentrated and the residue was triturated with diethyl ether to form a solid which was collected and dried to afford the carboxylic acid-TFA salt as a beige solid (0.73 g, 510). ESMS m/z = 474 [M+H] +. This material was used without further purification.

[868] Part D. To a solution of the product from Part C (0.73 g, 1.2 mmol) in N, N-dimethylformamide (4 ml) was added triethylamine (0.9 ml, 6.2 mmol), followed by tetrahydropyranhydroxylamine (0.28 g, 2.4 mmol), 1-hydroxybenzotriazole (0.19 g, 1.4 mmol), and 1- (3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (0.32 g, 1.8 mmol). The reaction mixture was heated at 40°C for 24 hr. The mixture was concentrated and the residue was purified via reverse phase chromatography (Cig, acetonitrile/water/TFA). Fractions (10 ml) were collected to separate the isomers. While analyzing, the aqueous TFA mixtures de-protected the product affording the hydroxamic acid final products. 4- [ [4- [ [4E)-5- [-4- (dimethylamino) phenyl]-4-pentenyl] oxy] phenyl] sulfonyl]-tetrahydro-N-hydroxy-2H-pyran-4-carboxamide, (98% trans isomer by HPLC, 0.12 g, 17% yield). HRMS calculated for C23H28N208S : 489.2059 [M+H] +, found: 489.2067. lu NMR confirmed trans isomerization (Job = 15. 9 Hz). 4- [ [4- [ [4Z)-5- [-4- (dimethyl-amino) phenyl]-4-pentenyl] oxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H- pyran-4-carboxamide, monohydrochloride, (79% cis/17% trans by HPLC, 15 mg tan solid, 2% yield). HRMS calculated for C2sH32N206S : 489.2059 [M+H] +, found: 489.2067.

[869l Example 24. Preparation of tetrahydro-N-hydroxy-4- [ [4- [ [5 (4- methoxyphenyl)-5-oxopentyl] oxy] phenyl] sulfonyl]-2H-pyran-4-carboxamide [870] Part A. To a mixture of magnesium turnings (344 mg, 14.18 mmol) etched with iodine in anhydrous tetrahydrofuran (4 mL) at reflux was added 4-bromoanisole (1.2 mL, 9.45 mmol) dropwise over 10 min. The reaction mixture was heated at reflux for 45

min, and then cooled to ambient temperature. The prepared grignard reagent was added to a mixture of tetrahydro-4-[[4-[[5-(methoxymethylamino)-5- oxopentyl] oxy] phenyl] sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl) oxy]-2H-pyran-4- carboxamide (1.0 g, 1.9 mmol, as prepared in Example 7) in anhydrous tetrahydrofuran (10 mL) at 0°C. The reaction mixture was warmed to ambient temperature and left stirring overnight. The reaction was quenched with saturated ammonium chloride, and then partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using 50-100% ethyl acetate/hexanes to afford 320 mg (29%) of the desired ketone as a white powder. ESMS m/z = 593 [M+NH4] +. HRMS calculated for C29H37NOoS : 593.2533 [M+NH4] +, found: 593.2555.

[871] Part B. The product from Part A (300 mg, 0.52 mmol) was dissolved in 4N HC1 in dioxane (3 mL) and methanol (300 uL). After 10 min at ambient temperature, the reaction mixture was poured into hexanes (75 mL), and the product precipitated out as an oil. The solvent was decanted and additional hexanes was added. The resulting solid was triturated with diethyl ether, and the title compound was obtained as an off-white solid. ESMS m/z = 492 [M+H] +. HRMS calculated for C24H2gNOgS : 492.1692 [M+H] +, found: 492.1713.

[872] Additional compounds can be prepared by one skilled in the art using similar methods with either the t-butyl ester, THP protected hydroxamate, or resin bound hydroxamate of the weinreb amide. Examples of such compounds include those having a structure corresponding to generic formula EX-I.

[873] Example 25. Preparation of tetrahydro-N-hydroxy-4- [ [4- [ [5-<BR> <BR> (hydroxyimino)-5- (4-methoxyphenyl) pentyl] oxy] phenyl]-sulfonyl]-2H-pyran-4- carboxamide.

[874] Part A. To a mixture of magnesium turnings (1.2 g, 49.4 mmol) etched with iodine in anhydrous tetrahydrofuran (4 mL) at reflux was added 1-bromo-2, 4- dimethyoxybenzene (6.0 mL, 41.7 mmol) dropwise over 10 min. The reaction mixture was heated at reflux for 30 min, and then cooled to ambient temperature. The prepared grignard reagent was added to a mixture of tetrahydro-4- [ [4- [3- (methoxymethyl-amino)-3- oxopropoxy] phenyl] sulfonyl]-2H-pyran-4-carboxylic acid, 1, 1-dimethylethyl ester (1.0 g, 1.9 mmol, prepared as in Example 7) in anhydrous THF (10 mL) at 0°C. The reaction mixture was warmed to ambient temperature, and, after 2 hr, was quenched with saturated ammonium chloride, and then partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was covered with diethylether.

The resulting green solid was triturated with diethyl ether. The final solid was collected to afford 2.2 g (94%) of the desired ketone as a pale green powder. ESMS m/z = 585 [M+Na] +. HRMS calculated for C2gH3sNOgS : 563.2315 [M+H] +, found: 563.2319.

[875] Part B. The product from Part A (2.2 g, 3.91 mmol) was taken up in neat trifluoroacetic acid (6 mL). After 2 hr, the trifluoroacetic acid was removed in vacuo at 50°C to give the free acid as a purple oil. ESMS m/z = 507 [M+H] +. To a solution of this material in anhydrous N, N-dimethylformamide (20 mL) was added 1- hydroxybenzotriazole (670 mg, 4.96 mmol), triethylamine (1.8 mL, 12.91 mmol), tetrahydropyranhydroxylamine (1.48 g, 12.63 mmol), and 1- (3-dimethyaminopropyl)-3- ethylcarbodiimide hydrochloride (1.13 g, 5.89 mmol). After 16 hr, the reaction mixture was concentrated in vacuo at 60°C. The crude material was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic layer was washed with

brine (2X), dried over sodium sulfate, filtered, and concentrated in vacuo to yield a yellow oil. Purification by flash chromatography using 80% ethyl acetate/hexanes afforded a mixture of THP hydroxamate/THP oxime (78%) and THP hydroxamate ketone (12%).

ESMS m/z = 621 [M+H] + and ESMS m/z = 628 [M+H] + respectively. These products were not separated, and instead were carried forward as a mixture.

[876] Part C. The product from Part B (540 mg, 0.77 mmol) was dissolved in 4N HC1 in dioxane (5 mL) and methanol (500 uL). After 2 hr at ambient temperature the reaction mixture was poured into rapidly stirring diethyl ether. A pale pinkish/purple solid was collected and purified by reverse phase HPLC. The title compound was obtained as a white solid. ESMS m/z = 537 [M+H] +. HRMS calculated for C25H32N209S : 537.1907 [M+H] +, found: 537.1921.

[877] Example 26. Preparation of tetrahydro-N-hydroxy-4-[[4-[[5-(4- methyloxyphenyl)-4-methyl-5-oxopentyl] oxy] phenyl] sulfonyl]-2H-pyran-4-carboxamide [878] Part A. To a solution of tetrahydro-4- [ [4- [ [5- (4methoxyphenyl)-5- oxopentyl] oxy] phenyl] sulfonyl]-2H-pyran-4-carboxylic acid, 1,1-dimethylethyl ester (532 mg, 1.0 mmol, prepared as in Example 24) and iodomethane (623 mg, 4.4 mmol) in 5 ml N, N-dimethylformamide was added sodium hydride (125 mg, 3.1 mmol, 60% dispersion in mineral oil). The reaction was stirred 40 min then quenched with 1N HClaq. The reaction mixture was partitioned between ethyl acetate and 5% aqueous potassium hydrogensulfate. The organic phase was dried over sodium sulfate, filtered, and concentrated in vacuum to give a crude oil. Purification by flash chromatography using 40% ethyl acetate/hexanes afforded 370 mg (68% yield) of the desired monomethyl ketoester. ESMS m/z = 547 [M+H] +.

[879] Part B. The product from Part A (370 mg, 0.68 mmol) was taken up in neat trifluoroacectic acid. After 45 min, HPLC analysis indicated that the reaction was complete. The trifluoroacetic acid was removed in vacuo, and the residue chased with

acetonitrile (2x10 ml), and then vacuum dried to yield 335 mg of the free acid. ESMS m/z = 491 [M+H] +. To a solution of this material in anhydrous N, N-dimethylformamide (4 mL) was added 1-hydroxybenzotriazole (138 mg, 0.68 mmol) and 1- (3- dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (150 mg, 0.78 mmol), followed by triethylamine (190 uL, 1.36 mmol) and tetrahydropyranhydroxylamine (160 mg, 1.37 mmol). After 16 hr, the reaction mixture was partitioned between ethyl acetate and 5% aqueous potassium hydrogensulfate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to a crude oil.

Purification by flash chromatography using 60% ethyl acetate/hexanes as eluant afforded 270 mg (67%) of the desired THP protected hydroxamate. ESMS m/z = 590 [M+H] +.

[880] Part C. The product from Part B (270 mg, 0.46 mmol) was dissolved in 4N HC1 in dioxane (2 mL) and methanol (500 uL). After 15 min at ambient temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 200 mg (86%) of the title compound. ESMS m/z = 406 [M+H] +. HRMS calculated for C25H3lNO8S 506.1849 [M+H] +, found: 506.1828.

[881] Example 27. Preparation of 4- [ [4- [ [ (4Z)-5-cyano-5- (4- methoxyphenyl)-4-pentenyl] oxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4- carboxamide Part A. To a solution of tetrahydro-4-[[4-[[5-(4-methoxyphenyl)-5- oxopentyl] oxy] phenyl] sulfonyl]-2H-pyran-4-carboxylic acid, 1,1-dimethylethyl ester (1.0 g, 1.9 mmol, prepared as in Example 24) in 15 ml methylene chloride was added trimethylsilyl cyanide (300 uL, 2.2 mmol) and zinc iodide (660 mg, 2.1 mmol). The reaction was stirred at ambient temperature for 3 hr, and then concentrated in vacuo. The residue was partitioned between ethyl acetate and 1 N HClaq. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography using 25% ethyl acetate/hexanes to afford 950 mg (81%) of the

silylated cyanohydrin. This material was taken up in trifluoroacetic acid (15 mL). The dark red solution showed various peaks by HPLC analysis over the first 40 min. After 1 hr, HPLC analysis indicated 1 new peak at 93%. The reaction mixture was concentrated in vacuo and chased with acetonitrile (2x10 ml). The crude solid was dissolved in methanol and added to 40 ml diethyl ether. The resulting white solid was filtered and dried to yield 630 mg of the free acid/cyano olefin. ESMS m/z = 486 [M+H] +.

[882] Part B. To a solution of the product from Part A (630 mg, 1.3 mmol) in anhydrous N, N-dimethylformamide (15 mL) was added 1-hydroxybenzotriazole (285 mg, 2.1 mmol) and 1- (3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (285 mg, 1.5 mmol), followed by N-methylmorpholine (545 uL, 5.0 mmol) and tetrahydropyranhydroxylamine (456 mg, 3.9 mmol). After 20 hr, the reaction mixture was concentrated in vacuo, and then partitioned between ethyl acetate and 5% aqueous potassium hydrogensulfate. The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography using 80% ethyl acetate/hexanes to afford 530 mg (70%) of the desired THP protected hydroxamate. ESMS m/z = 585 [M+H] +.

[883] Part C. The product from Part B (530 mg, 0.91 mmol) was dissolved in 4N HC1 in dioxane (5 mL) and methanol (1 mL). After 15 min at ambient temperature, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 360 mg of the desired hydroxamate. Purification by reverse phase HPLC afforded 270 mg (59%) of the title compound. ESMS m/z = 504 [M+H] +. HRMS calculated for C25H28N207S : 501.

1695 [M+H] +, found: 501.1689.

[884] Example 28. Preparation of tetrahydro-N-hydroxy-4- [ [4 [ [ (4E)-5- (4- methoxyphenyl)-4-hexenyl] oxy] phenyl] sulfonyl]-2H-pyran-4-carboxamide [885] Part A. To a cooled (0°C) solution of 4-[(4-{[5-(4-methoxyphenyl)-5- oxopentyl] oxy} phenylSulfonyl]-N-(tetrahydro-2H-pyran-2-yloxy) tetrahydro-2H-pyran-4-

carboxamide (0.2 g, 0.4 mmol, as prepared in Example 24) in tetrahydrofuran (2 ml) was added a 3.0 M solution of methyhnagnesium bromide (1.2 ml, 3.6 mmol). The ice bath was removed, and the reaction stirred for 2 hr at room temperature. HPLC showed less than 1% of the ketone starting material. The reaction mixture was diluted with ethyl acetate and washed with saturated ammonium chloride solution, water, and brine. After drying over sodium sulfate and filtering, the organic layer was concentrated in vacuo to afford 0.25 g (100%) of a tan oil. ESMS m/z = 614 [M+Na] +. This material was used without further purification.

[886] Part B. To the product from Part A (0.24 g, 0.4 mmol) was added methanol (0.5 ml) and 4 N HC1 in dioxane (4.0 ml). After stirring 2 hr, HPLC showed no remaining starting material. Diethyl ether was added to form a solid but a gummy residue developed. The mixture was concentrated and the oily residue was purified via reverse phase HPLC (Cig, acetonitrile/water/TFA) to afford 0.11 g (55%) of the desired product as a tan oil. 1H NMR (N. O. E) confirmed the isomerized mixture as 70% trans: 30% cis.

HRMS calculated for C25H3iNO7S : 490.1899 [M+H], found: 490.1898.

[887] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-J.

EX-J l888] Example 29 Preparation of 3,4-dihydro-N- [3- [4- [[tetrahydro-4-[(hydroxyamino) carbonyl]-2H-pyran-4-yl] sulfonyl]-phenoxy]<BR> propyl]-2- (lH)-isoquinolinecarboxamide

[8891 Part A. To a solution of 4- [ [4- (3-aminopropoxy)- phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid 1, 1-dimethylethyl ester, monohydrochloride (467 mg, 1.07 mmol, prepared in Example 1) in anhydrous chloroform (3 mL) at ambient temperature was added triethylamine (170 uL, 1.22 mmol) and 1, l'-carbonyldiimidazole (180 mg, 1.11 mmol). After 1 hr at 50°C, 1,2,3,4- tetrahydroisoquinoline (162 mg, 1.22 mmol) was added neat. After an additional 2 hr at 50°C, HPLC indicated complete reaction. The reaction mixture was partitioned between ethyl acetate and 5% aqueous potassium hydrogen sulfate. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give a yellow oil. ESMS m/z = 559 [M+H] +. This material was used without further purification.

[890] Part B. The product from Part A was taken up in neat trifluoroacetic acid (3 mL). After 13 hr, the trifluoroacetic acid was removed in vacuo at 50°C to give the free acid. ESMS m/z = 503 [M+H] +. To a solution of this material in anhydrous N, N- dimethylformamide (5 mL) was added 1-hyrdoxybenzotriazole (176 mg, 1.30 mmol), triethylamine (500 uL, 3.59 mmol), and tetrahydropyranhydroxylamine (254 mg, 2.17 mmol), followed by 1- (3-dimethyaminopropyl)-3-ethylcarbodiimide hydrochloride (310 mg, 1.62 mmol). The reaction mixture was heated at 40°C for 4 hr, and then stirred at ambient temperature overnight. The reaction mixture was concentrated in vacuo at 60°C.

The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated, and the organic layer was washed with brine (3X), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography to give 260 mg (40% from the starting amine) of the desired THP protected hydroxamate as a white solid. ESMS m/z == 624 [M+Na] +. HRMS calculated for C30H3gN3oss : 602.2536 [M+H] +, found: 602.2546.

[891] Part C. The product from Part B (252 mg, 0.42 mmol) was dissolved in 4N HC1 in dioxane (5 mL) and methanol (500 uL). After 1 hr at ambient temperature, the reaction mixture was poured into rapidly stirring diethyl ether. A white solid was collected and dried over P205 under vacuum. The title compound was obtained as a white solid. ESMS m/z = 518 [M+H] +. HRMS calculated for C25H31N307S : 518.1961 [M+H] +, found: 518.1961.

[8921 Additional compounds can be prepared by one skilled in the art using similar methods (urea formation also can be achieved by coupling the starting amine with and an isocyanate). Examples of such compounds include those having a structure corresponding to generic formula EX-K.

[893] Example 30. Preparation of tetrahydro-N-hydroxy-4- [ [4- [3- [4- (4- methoxyphenyl)-2-oxazolyl] propoxy] phenyl] sulfonyl]-2Hpyran-4-carboxamide [894] Part A. To a solution of 4- [ [4- (3- carboxypropoxy) phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid, 1, 1- dimethylethyl ester (3.2 g, 7.5 mmol, prepared as in Example 7) in acetone (15 mL) was added 2-bromo-4-methoxyacetophenone (1.72 g, 7.5 mmol) and potassium carbonate (1.04 g, 7.5 mmol). The reaction mixture was stirred at ambient temperature for 3 hr. The reaction mixture was filtered, and the cake washed with acetone. The acetone solution was concentrated iii vacuo. Purification by flash column chromatography using ethyl acetate/hexanes provided 3.68 g (85%) of the substituted ester as a white solid. ESMS m/z = 599 [M+Na] +.

[895] Part B. The product from Part A (3.6 g, 6.25 mmol) was refluxed in acetic acid (12 mL) with ammonium acetate (2.41 g, 31.25 mmol) for 24 hr. The reaction was diluted with ethyl acetate (50 mL) and washed 2 times with water (25 mL) and filtered. The ethyl acetate filtrate was extracted with a 10% aqueous NaOH (50 mL). The basic solution was then acidified to a pH of 1, and then extracted with ethyl acetate (25 mL). The organic solution was then washed with water (25 mL), dried over sodium

sulfate, filtered, and concentrated in vacuo to give 1.5 g (48%) of the carboxylic acid of the oxazole as a brown solid. ESMS m/z = 502 [M+H] +.

[896] Part C. In dry equipment under nitrogen, the carboxylic acid from Part B (1.3 g, 2.59 mmol) was dissolved in dry N, N-dimethylformamide (5 mL), and the remaining reagents were added to the solution in the following order: 1- hydroxybenzotriazole (490 mg, 3.63 mmol), triethylamine (0.43 mL, 3.11 mmol), tetrahydropyranhydroxylamine (364 mg, 3.11 mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (746 mg, 3.89 mmol). After 12 hr at 40°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography using ethyl acetate/hexanes provided 0.70 g (450) of the THP hydroxamate as a white foam. ESMS m/z = 601 [M+H] +.

[897] Part D. To a solution of the product from Part C (0.6 g, 1.0 mmol) in 1,4- dioxane (1.0 mL) was added 4N HC1 in dioxane (1.25 mL, 5 mmol) and methanol (0.13 mL). After 1 hr at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo.

Methylene chloride (20 mL) was added, and the solution was stripped to afford 0.29 g (56%) of the title compound as a light pink solid. HRMS calculated for C25H28N208S : 517.1645 [M+H] +, found: 517.1651.

[898] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-L.

[899] Example 31. Preparation of tetrahydro-N-hydroxy-4- [ [4- [3- [3 [4- (trifluoromethoxy) phenyl-1, 2,4-oxadiazol-5-yl] propoxy] phenyl] sulfonyl]- 2H-pyran-4-carb oxamide

[900] Part A. In dry equipment under nitrogen, 4- [ [4- (3-carboxypropoxy) phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid, 1, 1-dimethylethyl ester (2.57 g, 6.0 mmol, prepared as in Example 7) was dissolved in dry N, N-dimethylformamide (12 mL), and the remaining reagents were added to the solution in the following order: 1-hydroxybenzotriazole hydrate (1.13 g, 8.4 mmol), triethylamine (1.0 mL, 7.2 mmol), 4- (trifluoromethoxy) benzamidoxime (1.58 g, 7.2 mmol), and 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.73 g, 9.0 mmol). After 2 hr at 35°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography using ethyl acetate/hexanes afforded 3.05 g (81%) of the desired product as a clear glass. ESMS m/z = 631 [M+Na] +.

[901] Part B. The product from Part A (2.9 g, 4.60 mmol) was heated at 90°C in toluene (15 mL) for 30 hr. The reaction was concentrated in vacuo. Purification by column chromatography using ethyl acetate/hexanes afforded 2.06 g (73%) of the oxadiazole as a white solid. ESMS m/z = 635 [M+Na] +.

[902] Part C. The product from Part B (2.0 g, 3.27 mmol) was dissolved in trifluoroacetic acid (8 mL) and stirred at ambient temperature for 2 hr. The reaction was diluted with methylene chloride (10 mL) and concentrated in vacuo. Methylene chloride (10 mL) was added to the residue and concentrated in vacuo again to provide 1.8 g (99%) of the free acid as an off-white solid. ESMS m/z = 557 [M+H] +.

[903] Part D. In dry equipment under nitrogen, the product from Part C (1.7 g, 3.06 mmol) was dissolved in dry N, N-dimethylformamide (6 mL), and the remaining reagents were added to the solution in the following order: 1-hydroxybenzotriazole

hydrate (578 mg, 4.28 mmol), triethylamine (0.51 mL, 3.67 mmol), tetrahydropyranhydroxylamine (429 mg, 3.67 mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (879 mg, 4.59 mmol). After 90 min at 40°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated sodium bicarbonate solution, and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography using ethyl acetate/hexanes provided 1.9 g (95%) of the THP hydroxamate as a white foam. ESMS m/z = 678 [M+Na] +.

[904] Part E. To a solution of the product from Part D (1.8 g, 2.75 mmol) in 1,4-dioxane (1.0 mL) was added 4N HC1 in dioxane (3.5 mL, 13.7 mmol) and methanol (0.35 mL). After 2 hr at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over sodium sulfate, filtered, and concentrated iii vacuo.

Reverse phase chromatography provided 1.12 g (71 %) of the title compound as a white solid. HRMS calculated for C24H24N308SIF3 : 572.1314 [M+H] +, found: 572.1290.

[905] Example 32. Preparation of tetrahydro-N-hydroxy-4- [ [4- [3- [5- (2- methylphenyl)-1, 3,4-oxadiazol-2-yl] propoxy] phenyl] sulfonyl]-2H-pyran-4- carboxamide Part A. In dry equipment under nitrogen, 4- [ [4- (3- carboxypropoxy) phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid, 1, 1- dimethylethyl ester (2.14 g, 5.0 mmol, prepared as in Example 7) was dissolved in dry N, N-dimethylformamide (10 mL), and the remaining reagents were added to the solution in the following order: 1-hydroxybenzotriazole hydrate (945 mg, 7.0 mmol), triethylamine (0.84 mL, 6.0 mmol), o-toluic hydrazide (901 mg, 6.0 mmol), and 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.44 g, 7. 5 mmol). After 2 hr at 35°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl

acetate; washed with water, saturated sodium bicarbonate solution, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo. Purification by flash column chromatography using ethyl acetate/hexanes provided 2.32 g (83%) of the desired product as a white foam. ESMS m/z = 583 [M+Na] +.

[907l Part B. The product from Part A (2.1 g, 3.75 mmol) was heated to reflux in toluene (25 mL) with p-toluenesulfonic acid (100 mg) for 4 hr. The reaction was concentrated in vacuo. Recrystalization from hot methanol provided 1.6 g (88%) of the free acid of the oxadiazole as a white solid. ESMS m/z = 487 [M+Na] +.

[908] Part C. In dry equipment under nitrogen, the product from Part B (1.5 g, 3.09 mmol) was dissolved in dry N, N-dimethylformamide (6 mL), and the remaining reagents were added to the solution in the following order: 1-hydroxybenzotriazole hydrate (578 mg, 4.28 mmol), triethylamine (0.51 mL, 3.67 mmol), tetrahydropyranhydroxylamine (429 mg, 3.67 mmol), and 1- (3 dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (879 mg, 4.59 mmol). After 6 hr at 40°C, the reaction was concentrated in vacuum. The residue was taken up in ethyl acetate; washed with water, saturated sodium bicarbonate solution, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo. Purification by flash column chromatography using ethyl acetate/hexanes provided 1.53 g (85%) of the THP hydroxamate as a white foam. ESMS m/z = 608 [M+Na] +.

[sos] Part D. To a solution of the product from Part C (1.4 g, 2.39 mmol) in 1,4-dioxane (1.0 mL) was added 4N HC1 in dioxane (6 mL, 23.9 mmol) and methanol (0.6 mL). After 2 hr at ambient temperature, the reaction was diluted with ethyl acetate and washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo.

Reverse phase chromatography provided 1.02 g (85%) of the title compound as a white solid. HRMS calculated for C24H27N307Sl : 502.1648 [M+H] +, found: 502.1652. lglo] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-M..

[911] Example 33. Preparation of 4-1 [4- [3- (2- benzoxazolylthio) propoxy] phenyl] sulfonyl] tetrahydro-N-N-hydroxy-2H-pyran-4- carboxamide.

[912] Part A. To a solution of 2-mercaptobenzoxazole (290 mg, 1.92 mmol) in N, N-dimethylformamide (5 mL) at 0°C was added NaH (128 mg, 1.92 mmol, 60% dispersion in mineral oil). After 30 min, tetrahydro-4-[[4-[3-[(methylsulfonyl- ) oxy] propoxy] phenyl] sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl) oxy]-2H-pyran-4- carboxamide (1.0 g, 1.92 mmol, prepared as in Example 29) was added, and the solution was stirred for 2 hr at 65°C. The solution was partitioned between ethyl acetate and water.

The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 510 mg (46%) of the thiobenzoxazole as a crude dark oil. ESMS m/z = 577 [M+H] +.

[913] Part B. To a solution of the crude thiobenzoxazole of Part A (505 mg, 0.88 mmol) in 1,4-dioxane (5 mL) was added 4 N HC1 in dioxane (5 mL), and was stirred for 2 hr. Purification by reverse phase HPLC (C18, acetonitrile/water) provided 257 mg (60%) of the title compound as a white solid. ESMS m/z = 493 [M+H] +. HRMS calculated for C22H24N207S2 : 493.1103, found 493.1122. Analytical calculation for C22H24N207S2'0. 3H20 : C, 53.06; H, 4.98; N, 5.63; S, 12.88. Found: C, 53.08; H, 5.03; N, 5.62; S 12.69.

[914] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-N.

[915] Example 34. Preparation of 4- [ [4- [ [tetrehydro-4- [ (hydroxyamino) carbonyl]-2H-pyran-4-yl] sulfonyl] cyclohexyl] oxy] butyl ester 3,4- dihydro-2 (1H)-isoquinolinecarboxylic acid , [9161 Part A. To a solution of tetrahydro-4-[[4-[4-[(methyl- sulfonyl) oxy] butoxy] phenyl] sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl) oxy]-2H-pyran-4- carboxamide (200 mg, 0.37 mmol, synthesized in a fashion similar to Example 29) in anhydrous N, N-dimethylformamide (2 mL) was added to 1,2,3,4-tetrahydroisoquinoline (0.24 mL, 1.9 mmol) and cesium carbonate (0.62 g, 1.9 mmol). The reaction mixture was stirred at ambient temperature overnight. The crude reaction mix was poured onto a 20 mL ChemElut tube (celite) prewetted with 15 mL of water, and eluted with 1: 1 ethyl acetate: methylene chloride. Purification by reverse phase HPLC (C18, acetonitrile/water), followed by treatment with 2 mL of 4N HC1 in dioxane, provided 12.2 mg (6.2 %) of the desired product as an amorphous solid after lyophilization. ESMS m/z = 531 [M+H]'.

HRMS calculated for C26H33N208S : 533.1958 [M+H] +, found: 533.1943.

[917] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-O.

[918] Example 35. Preparation of 4-[[4-[4-(1,3-dihydro-1, 3-dioxo-2H- isoindol-2-yl) butyl] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4-carboxamide [919] Part A. A solution of 4-bromobenzenethiol (28.5 g, 151 mmol) in N, N- dimethylformamide (250 mL) was purged with nitrogen for 10 min and then potassium carbonate (22.9 g, 166 mmol) was added. After purging for another 10 min with nitrogen, t-butyl bromoacetate (24.5 g, 166 mmol) was added, and the reaction was stirred at ambient temperature for 1 hr. The reaction was chilled to 0°C and diluted with water (250 mL). The slurry was extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo to provide 49.8g (100%) of the sulfide as a light yellow oil. ESMS m/z = 3 2 0 [M+NH4] +.

[920] Part B. To a solution of the product from Part A (45.67 g, 151 mmol) in tetrahydrofuran (300 mL) was added water (75 mL) and Oxone (278.5 g, 453 mmol) at 20°C. An exotherm to 43°C was observed. After 3 hr, the reaction was filtered, and the cake was washed well with tetrahydrofuran. The filtrate was concentrated in vacuo to 1 third the volume. The residue was taken up in ethyl acetate, washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 51. 0 g (100%) of the sulfone as a crystalline solid. ESMS m/z = 335 [M+H] +.

[9211 Part C. To a solution of the product from Part B (23.45 g, 16 mmol) in N, N-dimethylformamide (140 mL) was added potassium carbonate (19.3 g, 140 mmol),

bis- (2-bromoethyl) ether (9.1 mL, 70 mmol), and 18-Crown-6 (1 g). The slurry was stirred at 60°C. After 16 hr, the reaction was filtered, and the filtrate was concentrated in vacuo.

The residue was taken up in ethyl acetate, washed with water (3X) and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The product was recrystallized from methanol to provide 19.79 g (70%) of the desired compound as a white solid. (ESMS m/z = 405 [M+H] +.

[922] Part D. To a solution of N- (3-buten-1-yl) phthalimide (1.2 g, 5.97 mmol) in anhydrous tetrahydrofuran (3 mL) at 0°C was added 0.5 M 9-borobicyclononane in tetrahydrofuran (11.9 mL, 5.97 mmol) dropwise. The resultant solution was stirred with cooling for 10 min, and then the ice bath was removed. After 18 hr, the product from Part C (1 g, 2.98 mmol), tetrakis (triphenyl-phosphine) palladium (0) (172 mg, 0.15 mmol) and 2 M sodium carbonate (3 mL, 6 mmol) were added, and the reaction mixture was heated to 65°C for 2 hr. After cooling to ambient temperature, the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated, and the organic layer was washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Purification by flash column chromatography using 25-50% ethyl acetate/hexanes yielded 1.21 g of the desired compound as an off-white solid. HRMS calculated for C28H37N207S : 545.2321 [M+H] +, found: 545.2311.

[923] Part E. To a solution of the product from Part D (1. 16 g, 2.2 mmol) in anhydrous methylene chloride (20 mL) at ambient temperature was added trifluoroacetic acid (20 mL). The solution was stirred for 2 hr, and then concentrated in vacuo. The resulting residue was dissolved in methanol (50 mL) and concentrated in vacuo, and subsequently dissolved in methylene chloride (50 mL) and concentrated in vacuo.

Trituration with hexanes yielded 0.98 g of the carboxylic acid as an off-white solid.

HRMS calculated for C28H37N207S : 489.1695 [M+NH4], found: 489.1702.

[924] Part F. To a solution of the product from Part E (0.95 g, 2.01 mmol) in a mixture of methylene chloride (4 mL) and N, N-dimethylformamide (4 mL) was added triethylamine (0.28 mL, 2.01 mmol), 1-hydroxybenzotriazole (0.407 g, 3.015 mmol), and 1- [3- (dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (0.538 g, 2.814 mmol).

After 10 min, additional triethylamine (0.56 mL, 4.02 mmol) and tetrahydropyranhydroxylamine (0.706 g, 6.03 mmol) were added. The solution was

warmed to 38°C and stirred for 20 hr. The mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The organic layer was washed with 1 M HC1 (50 mL), water, brine. After drying over magnesium sulfate, the organic layer was concentrated to give 1.31 g of an off white solid. Purification by flash column chromatography using 25-50% ethyl acetate/hexanes yielded 1.05 g of the pure product as a white solid. HRMS calculated for C29H34N208SNa : 593.1934 [M+Na], found: 593.1967.

[925] Part G. To a solution of the product from Part F above (0.255 g, 0.446 mmol) in a mixture of methanol (3 mL) and dioxane (3 mL) was added 4 N HC1 in dioxane (3 mL). The mixture was stirred at ambient temperature for 10 min, and then concentrated in vacuo. Trituration with diethyl ether/hexanes yielded 224 mg of the title compound as a white solid. HRMS calculated for C24H27N207S : 487.1539 [M+H], found: 487.1559.

[926] Example 36. Preparation of 2H-pyran-4-carboxamide, tetrahydro-N- hydroxy-4 [ [4- [3- (2-naphthalenyl) propoxy]-phenyl] sulfonyl] [927] To a solution of (tetrahydro-4- [ [4- (2propenyloxy) phenyl] sulfonyl]-N- [ (tetrahydro-2H-pyran-2-yl) oxy]-2H-pyran-4-carboxamide (200 mg, 0.47 mmol, prepared as in Example 35) in tetrahydrofuran (1 mL) was added 0.5 M 9-borobicyclononane (0.94 mL, 0.47 mmol). The solution was stirred at ambient temperature for 16 hr. To this solution was added 2 M sodium carbonate (0.5 mL, 1 mmol), 2-bromonaphthalenylene (108 mg, 0.52 mmol), and tetrakis (triphenylphosphine) palladium (0) (54 mg, 0.047 mmol).

The mixture was heated to 65°C for 4 hr, and then cooled to ambient temperature.

Saturated ammonium chloride solution (3 mL) was added to the reaction mixture. The resulting mixture was filtered through a small column of celite. The column was washed with ethyl acetate (35 mL). The eluant was concentrated in vacuo, and the residue was dissolved in methanol (3 mL), dioxane (3 mL), and 4 N HC1 in dioxane. After 10 min, the solution was concentrated in vacuo, and the residue purified by preparative reverse

phase HPLC (10-90% acetonitrile/0. 05% TFA in water) yielding 20 mg of the title compound as a white solid. HRMS calculated for C2sH28NO6S : 470.1670 [M+H], found: 470.1614.

[928] Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-P.

EX-P.

[929] Example 37. Preparation of 4- [ [4- [3- (2- benzoxazolyl) propoxy] phenyl] sulfonyl] tetrahydro-N-hydroxy-2H-pyran-4- carboxamide [930] Part A. To a solution of 4-[[4-(3- carboxypropoxy) phenyl] sulfonyl] tetrahydro-2H-pyran-4-carboxylic acid, 1,1- dimethylethyl ester (3.0 g, 7.0 mmol) in N, N-dimethylformamide (14 mL) was added 1- (3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (1.88 g, 9.8 mmol) and 1- hydroxybenzotriazole (1.32 g, 9.8 mmol). The resulting suspension became a clear amber solution after stirring at 50°C for 1.5 hr. The reaction was then treated with 2- aminophenol (0.76 g, 7.0 mmol), followed by N-methylmorpholine (2.3 mL, 21.0 mmol).

The reaction was stirred at 50°C overnight. After 21 hr, the reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated sodium

bicarbonate solution, water, 1: 1 solution of water : brine, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate/hexanes to afford 2.98 g (82%) of the amide as an amber oil. ESMS m/z = 542 [M+Na] +.

[931] Part B. To a suspension of the product from Part A the (1.59 g, 3.1 mmol) toluene (50.0 mL) was added p-toluenesulfonic acid (0.12 g, 0.6 mmol), and the resulting mixture heated at reflux under Dean-Stark conditions. After 39 hr, the reaction was concentrated in vacuo, and the resulting residue was partitioned between ethyl acetate and 1 M aqueous hydrochloric acid. The organic layer was washed with 1 M aqueous hydrochloric acid, water, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo to afford 1.25 g (92%) of the crude carboxylic acid benzoxazole as a tan, white solid. ESMS m/z = 446 [M+H] +.

[932] Part C. To a solution of the product from Part B (0.98 g, 2.2 mmol) in N, N-dimethylformamide (10.0 mL) was added 1- (3-dimethylamino-propyl)-3- ethylcarbodiimide hydrochloride (0.59 g, 3.1 mmol) and 1-hydroxybenzotriazole (0.42 g, 3.1 mmol). The resulting suspension became a clear amber solution after stirring at 50°C for 0.5 hr. The reaction was then treated with tetrahydropyranhydroxylamine (0.36 g, 3.1 mmol), followed by N-methylmorpholine (0.73 mL, 6.6 mmol). The reaction was stirred at 50°C overnight. After 12 hr, the reaction was partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The organic layers were combined and washed with saturated sodium bicarbonate solution, water, 1: 1 solution of water: brine, and brine; dried over sodium sulfate; filtered; and concentrated in vacuo. The resulting oil was purified on silica gel using ethyl acetate/hexanes as eluant to afford 1. 2 g (98%) of the THP hydroxamate benzoxazole as an amber oil. ESMS m/z = 545 [M+H] +.

[933] Part D. To a solution of the product from Part C (0.104 g, 0.19 mmol) in a mixture of methanol (0.3 mL) and dioxane (2 mL) was added 4 N HC1 in dioxane (0.5 mL). The mixture was stirred at ambient temperature for 30 min, concentrated in half in vacuo, and diluted with diethyl ether. Filtration afforded 17 mg (20%) of the title compound as a tan solid. HRMS calculated for C22H24N207S : 461.1382 [M+H], found: 461.1374.

[s34l Additional compounds can be prepared by one skilled in the art using similar methods. Examples of such compounds include those having a structure corresponding to generic formula EX-Q.

EX-Q.

[935] Example 38. Preparation of: [936] Part A. Preparation of :

To a solution of ethyl 4- [ (4-fluorophenyl) sulfonyl] piperidine-4-carboxylate hydrochloride (60.0 g, 170 mmol) in methanol (600 mL), were added acetic acid (97 mL, 1.7 mole), [ (1- ethoxycyclopropyl) oxy] trimethylsilane (102 mL, 510 mmol) and 4A molecular sieves (55 g) followed by sodium cyanoborohydride (28.8 g, 459 mmol). The solution was stirred at ambient temperature overnight, then refluxed for 6 hr. The reaction mixture was filtered through celite and concentrated to solid/oil mix. Ethyl acetate and saturated sodium bicarbonate were added very carefully. When aqueous layer stayed basic, the layers were

separated and the organic layer was washed 3 times with saturated sodium bicarbonate, then with brine and then dried over sodium sulfate. Concentration in vacuo and crystallization from ethyl acetate/hexane provided the n-cyclopropyl compound as an off white solid (53.8 g, 88. 8%). ESMS m/z= 356 (M+H).

[937] Part B. Preparation of :

To a solution of 3- (3-bromophenyl) propionic acid (10.0 g, 43.7 mmol) in anhydrous THF (150 mL) was added 1.0 M BH3-THF (150 mL, 150 mmol) via addition funnel. After BH3-THF was added, the reaction was refluxed for 18 hrs. The reaction was quenched with water (100 mL) and 1N HC1 (300 mL). The solution was saturated with sodium chloride and extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The organic material was purified by chromatography on silica gel eluting with ethyl acetate in hexane to produce 9.39 g (100 %) of the desired alcohol as a colorless oil. NMR (CDC13) 8 1.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11 7.15 (m, 1H), 7.29-7.31 (m, 1H), 7.34 (s, 1H).

[938] Part C. Preparation of :

In a flask were combined the alcohol from Part B (3.43 g, 16.0 mmol), phenyl boronic acid (2.93 g, 24.0 mmol), palladium tetrakistriphenylphosphine (0.92 g, 0.8 mmol), 2M cesium carbonate (24 mL, 48 mmol) and dimethoxyethylether (48 mL). The mixture was stirred vigorously under nitrogen at reflux. After 1.5 hr the reaction was cooled to ambient temperature, diluted with water and extracted with ether 3 times. The combined organic extracts were washed with brine and dried over magnesium sulfate. 2.74 g (81 % yield) purified product was obtained as a crystalline solid by chromatography (on silica, ethyl acetate/hexane). NMR (CDC13) 5 1.91-1.98 (m, 2H), 2.77 (t, 2H), 3.71 (t, 2H), 7.19 (d, 1H), 7.31-7.38 (m, 2H), 7.41-7.45 (m, 4H), 7.58 (d, 2H).

[939] Part D. Preparation of :

To a solution of the alcohol from Part C (2.7 g, 12.7 mmol) in anhydrous dimethylformamide (12 mL) at 0°C was added 60 % sodium hydride (0.58 g, 14.5 mmol) in portions. After that the reaction was stirred at 0°C for 15 min and then at ambient temperature for 15 min. The reaction mixture was cooled to 0°C and the cyclopropyl compound from Part A (4.3 g, 12.4 mmol) in anhydrous dimethylfoi-rmamide (10 mL) was added slowly. Upon completion of addition, ice bath was removed and the reaction stirred at ambient temperature for 1 hr the reaction, then diluted with water and extracted with ethyl acetate 3 times. The combined organic extracts were washed with saturated NaHC03 and brine and dried over sodium sulfate. After concentration 4.63 g of material was obtained. This material was used without purification.

[940] Part E. Preparation of : The ester of Part D (4.61 g, 8.4 mmol) was hydrolyzed in 1: 1: 0.56 mixture of ethanol : 1, 4- dioxane: 6N NaOH (25.6 mL) at 60°C. The solution was concentrated iii vacuo, diluted with water and extracted with ether to remove color. Acidification with IN HC1 caused precipitation of the acid which was collected by filtration, washed with water and hexane and dried under high vacuum yielding the acid as an off white solid (3.45 g, 79 % yield).

ESMS m/z = 520 (M+H) +. This material was used without purification.

[941] Part F. Preparation of :

To a suspension of the crude acid of Part E (3.44 g, 6.62 mmol) in DMF (27 mL) were added HOBt (1.52 g, 9.93 mmol), N-methylmorpholine (2.2 mL, 19.9 mmol) and EDC (1.77 g, 9.27 mmol). After heating at 40°C, acid slowly went into solution. When reaction was clear, it was cooled to ambient temperature and THP-hydroxylamine (1.16 g, 9.93 mmol) was added. The solution was stirred for 18 hr at ambient temperature. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexanes) provided the protected hydroxamate as a crystalline solid (3.20 g, 74 %).

NMR 5 0.36 (d, 4H), 1.50-1.92 (m, 8H), 2.05-2.21 (m, 3H), 2.32 (s, 2H), 2.86 (t, 2H), 2.98 (s, 2H), 3.69 (d, 1H), 3.96-4.07 (m, 3H), 5.00 (s, 1H), 6.95 (d, 2H), 7.17 (d, 1H), 7.30-7-43 (m, 6H), 7.54 (d, 2H), 7.73 (d, 2H), 9.41 (s, 1H).

19421 Part G. Preparation of : To the semi pure product from Part F (3.03 g, 4.89 mmol) in methanol (10 mL) and 1,4- dioxane (10 mL) was added 4M hydrochloric acid in 1,4-dioxane (10 mL) and after stirring 20-30 min the product began to crystallize out. Reverse phase chromatography (on Cis, acetonitrile/water) to remove color followed by conversion to HC1 salt with methanol and 4N HCl/dioxane then recrystallization from methanol/iso propanol provided 1.95 g (70 %) of the title compound as a hydrochloric acid salt that was colorless. ESMS

= 535 (M+H) +. HRMS calcd. for C3oH35N2005S H: 535.2261 (M+H) +. Found: 535.2270.

[943] Example 39. Preparation of : [944] Part A. Preparation of :

A solution of the alcohol from Part B, Example 38 (4.4 g, 20.4 mmol), tert-butyl 4- [ (4- fluorophenyl) sulfonyl] tetrahydro-2H-pyran-4-carboxylate (5.0 g, 14.6 mmol) and Cs2C03 (9.5 g, 29.2 mmol) in anhydrous dimethylformamide (30 mL) was stirred at 80°C for 30 hr. The reaction was diluted with water (300 mL) and extracted with ethyl acetate (3 times). The combined organic extracts were washed with brine and dried over magnesium sulfate. Crystallization from methylene chloride/hexane gave 6.95 g (88%) of the product as a colorless solid. ESMS m/z = 556 (M+NH4)+. HRMS calcd. for C25H35BrNO6S H: 556.1368 (M+NH4) +. Found: 556.1318.

[945] Part B. Preparation of :

The ester of Part A (6.81 g, 12.6 mmol) was hydrolyzed in 1: 1 TFA: methylene chloride (50 mL) at ambient temperature for 1.5 hr. The solution was concentrated in vacuo, taken up in toluene, concentrated to a colorless solid and dried under high vacuum yielding the acid as an impure white solid (6.28 g, 100 % yield). ESMS m/z = 500 (M+NH4) +. HRMS calcd. for C2lH23BrO6SNH4 : 500.0742 (M+NH4) +. Found: 500.0761.

Part C. Preparation of :

To a suspension of the impure acid of Part B (theoretically 12.5 mmol) in anhydrous DMF (25 mL) were added HOBt (2.0 g, 15 mmol), triethylamine (5.2 mL, 37.5 mmol) and EDC (3.4 g, 17.5 mmol). After heating at 40°C for 1 hr, THP hydroxylamine (4.4 g, 37.5 mmol) was added. The solution was stirred for 18 hr at ambient temperature, then at 40°C for 3 hr. The reaction was diluted with water (150 mL) and extracted with ethyl acetate (3 times). The combined organic extracts were washed with brine and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexanes) provided the protected hydroxamate as a viscous oil (4.32 g, 60 %). ESMS Ir, iz = 601 (M+NH4) +. HRMS calcd. for C26H32BrNO7SNH4 : 601.1410 (M+NH4) +. Found: 601.1448.

[947] Part D. Preparation of :

In a vial were combined the aryl bromide from Part C (0.20 g, 0.34 mmol) in 1 mL of dimethoxyethyl ether, 4-fluorobenzeneboronic acid (74 mg, 0.53 mmol), palladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) in 0.5 mL of dimethoxyethyl ether and 2M cesium carbonate (0.51 mL, 1.02 mmol). The mixture stirred vigorously at 65°C for 18 hr. The eaction mixture was poured onto 5 mL Chem-Elut tube pre-wetted with 3 mL of water and eluted with 10% ethyl acetate/methylene chloride. Concentration under nitrogen gave 254 mg of crude product that was carried on as is.

[948] Part E. Preparation of :

The crude product from Part D (254 mg) was taken up in 4M hydrochloric acid in 1,4- dioxane (2 mL) and methanol (1-2 mL) and stirred for 2 hr then concentrated. Material purified by reverse phase chromatography (on Cl8, acetonitrile/water). Product crystallized upon concentration yielding 108.5 mg (62%) of the title compound as colorless solid. ESMS m/z = 514 (M+H) +. HRMS calcd. for C27H29FNOS : 514.1700 (M+H) +. Found: 514.1694.

[949] Example 40. Preparation of :

[950] Part A. Preparation of : 3-bromophenethyl alcohol (5.0 g, 24.9 mmol) and 2-(kibutylstannyl) pyridine (13.6 g, 37.4 mmol) were combined in a round bottom flask with PdCl2 (PPh3) 2 (0.84 g, 1.2 mmol), Cul

(0.23 g, 1.2 mmol) and anhydrous THF (100 mL) and heated to reflux. After refluxing overnight, additional PdCl2 (PPh3) 2 (0.84 g, 1.2 mmol) and Cul (0.23 g, 1.2 mmol) were added and the reaction refluxed overnight. The reaction was cooled to ambient temperature, Norit A charcoal added, the mixture stirred and then filtered through a bed of celite. Chromatography (on silica, ethyl acetate/hexanes) provided the alcohol as an orange oil (2.76 g, 55.8%). ESMS m/z = 200 (M+H) +.

[951] Part B. Preparation of : To a solution of the alcohol from Part A (2.75 g, 13.8 mmol) in anhydrous dimethylformamide (13 mL) at 0°C was added 60 % sodium hydride (0.58 g, 14.4 mmol) in portions. After completion of the addition, the reaction was stirred at 0°C for 30 min. tert-butyl 4- [ (4-fluorophenyl) sulfonyl] tetrahydro-2H-pyran-4-carboxylate (4.51 g, 13.1 mmol) in anhydrous dimethylformamide (10 mL) was added over 15 min. Upon completion of addition, the ice bath was removed and the reaction stirred at ambient temperature. After 1.5 hr the reaction was diluted with water and extracted with ethyl acetate 3 times. The combined organics were washed with saturated NaCl and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexanes) provided the product as an off white solid (5.44 g, 79 %). ESMS,,,/, = 524 (M+H) +.

[952] Part C. Preparation of : The ester of Part B (5.45 g, 10.4 mmol) was hydrolyzed in 1: 1 mixture of TFA : methylene chloride (30 mL) at ambient temperature for 8 hr. The solution was concentrated in vacuo, taken up in methanol and 4N HC1 in dioxane and concentrated. This was repeated to give a viscous oil (6.25 g, > 100 % yield). This material was used without further purification.

[953] Part D. Preparation of

To a suspension of the crude acid of Part C (assume 10.4 mmol) in NMP (40 mL) were added HOBt (2.39 g, 15.6 mmol), N-methylmorpholine (3.4 mL, 31.2 mmol) and EDC (2.79 g, 14.6 mmol). After heating at 40°C overnight, HPLC still showed acid to be present so additional added HOBt (2.39 g, 15.6 mmol), N-methylmorpholine (3.4 mL, 31.2 mmol) and EDC (2.7 9 g, 14.6 mmol) were added. After 1 hr at 40°C, THP hydroxylamine (3.66 g, 31.2 mmol) was added. After 1 hr, the solution was diluted with water and extracted with ethyl acetate 3 times. The combined organic layers were washed with brine and dried over magnesium sulfate. Chromatography (on silica, ethyl acetate/hexanes) provided the protected hydroxamate as a colorless foam (5.05 g, 85.7).

ESMS m/z= 567 (M+H) +.

[954] Part E. Preparation of : To the product from Part D (5.0 5 g, 8.91 mmol) in methanol (15 mL) and 1,4-dioxane (15 mL) was added 4M hydrochloric acid in 1,4-dioxane (15 mL) and after stirring 1 hr reaction was complete. Concentration followed by crystallization from methanol/iso- propanol provided 3.88 g (84 %) of the title compound as a hydrochloric acid salt that was colorless. ESMSm/z=483 (M+H) +. HRMS calcd. for C25H27N206S H: 483.1584 (M+H) +. Found: 483. 1585.

[955] Example 41. Preparation of 1-ethyl-N-hydroxy 4- { [4- (3- {3- [4- (trifluoromethoxy) phenyl-1, 2,4-oxadiazol-5-yl} propoxy) phenyl] sulfonyl} piperidine- 4-carboxamide hydrochloride.

[956] Part A. To a slurry of ethyl 4- [ (4-fluorophenyl) sulfonyl]-4- piperidinecarboxylate, monohydrochloride (14.06 g, 40 mmol) in dimethylacetamide (80 mL) were added potassium carbonate (13.82 g, 100 mmol) and iodoethane (3.36 mL, 42 mmol). The slurry was stirred at ambient temperature. After 3 hr the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water three times, saturated sodium chloride solution, dried over Na2S04, filtered, and concentrated in vacuo. Chromatography (on silica, methylene chloride/hexanes) provided the N-ethyl piperidine as a white solid (13.05 g, 95%).

[957] Part B. In dry equipment under nitrogen, potassium trimethylsilanolate (10.52 g, 73.8 mmol) was dissolved in dimethylsulfoxide (40 mL) and gamma- butyrolactone (4.26 mL, 55.4 mmol) was added over 5 min while the reaction temperature rose to 49 C. After stirring at ambient temperature for 90 min, sodium hydride (2.2 g of a 60% oil dispersion, 55.4 mmol) was added portion wise over 20 min and the reaction temperature rose to 38°C. Gas evolution was also observed. After stirring at ambient temperature for 40 min, a solution of the N-ethyl piperidine from Part A (12.66 g, 36.9 mmol) in dimethylsulfoxide (10 mL) was added over 10 min as the reaction rose to 8°C.

The reaction was stirred at ambient temperature for t30 min. The slurry was slowly poured into ice water (400 mL) and then extracted with hexanes (100 mL) two times followed by a diethyl ether extraction (100 mL). The aqueous layer was chilled to 5°C and the pH adjusted to 7 with concentrated hydrochloric acid. The aqueous solution was extracted with methylene chloride (150 mL) until there was no UV activity in the extract.

The combined methylene chloride extracts were washed with saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The solid was

recrystallized from isopropanol (65 mL) to give the butyric acid as a white solid (8.2 g, 52%). LCMS m/z = 428 [M+H] +.

[958] Part C. In dry equipment under nitrogen, the butyric acid from Part B (5.12 g, 12.0 mmol) was dissolved in dry dimethylacetamide (20 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (2.43 g, 18. 0 mmol), triethylamine (3.34 mL, 24.0 mmol), 4- (trifluoromethoxy) benzamidoxime (3.96 g, 18. 0 mmol), and 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (4.6 g, 24.0 mmol). After 24 hr at 70°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated NaHC03, saturated sodium chloride solution, dried over Na2S04, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/methanol/hexanes) provided the oxadiazole as a light yellow solid (5.05 g, 69%). LCMS = 612 [M+H] +.

[959l Part D. A slurry of the oxadiazole from Part C (4.9 g, 8. 02 mmol), 2.5N sodium hydroxide (9.6 mL, 24.06 mmol) and sodium hydroxide (1.28 g, 32.08 mmol) in isopropanol (40 ml) were stirred at 70°C for 7 hr. The heat was removed and the reaction diluted with water (100 ml) and chilled to 5°C. The pH was adjusted to 7 with concentrated hydrochloric acid. The solids were filtered, washed with hexanes, and dried in vacuo to give the carboxylic acid as a white solid (4.54 g, 97%). LCMS n, xz = 584 [M+H] +.

[960] Part E. In dry equipment under nitrogen, the carboxylic acid from Part D (4.5 g, 7.72 mmol) was dissolved in dry dimethylacetamide (15 ml) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (1.56 g, 11.6 mmol), triethylamine (3.22 mL, 23.2 mmol), 0- (tetrahydro-2H- pyran-2-yl) hydroxylamine (1.35 g, 11.6 mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2.96 g, 15. 4 mmol). After 29 hr at 50°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated NaHC03, saturated sodium chloride solution, dried over Na2S04, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/methanol/hexanes) provided the THP hydroxamate as a light yellow solid (2.4 g, 46%). LCMS 683 [M+H] +.

[961] Part F. To the THP hydroxamate from Part E (2.3 g, 3.37 mmol) was added 4N HC1 dioxane solution (8. 4 mL, 33.7 mmol) and methanol (0.84 mL). The slurry

became very thick. Diethyl ether (50 ml) was added to and after 1 hr at ambient temperature the reaction was filtered under nitrogen. The solids were washed with diethyl ether (150 ml) under nitrogen and dried in vacuo over phoshorus pentoxide to give the title compound as a white solid (1.92 g, 91%). HRMS (ES+) M+H calculated for C26H29N407SlF3 : 599.1787, found 599.1766.

[962] Example 42. Preparation of : [963] Part A. In dry equipment under nitrogen, potassium trimethylsilanolate (42.76 g, 0.3 mol) was dissolved in dimethylsulfoxide (170 mL) and gamma-butyrolactone (17.31 mL, 0.225 mol) was added over 5 min while the reaction temperature rose to 49 C.

After stirring at ambient temperature for 90 min, sodium hydride (9.0 g of a 60% oil dispersion, 0.225 mol) was added portion wise over 20 min and the reaction temperature rose to 38°C. Gas evolution was also observed. After stirring at ambient temperature for 40 min, a solution of ethyl 4- [ (4-fluorophenyl) sulfonyl]-l- (2-methoxyethyl) piperidine-4- carboxylate (56 g, 0.15 mol) in dimethylsulfoxide (20 mL) was added over 10 mins as the reaction rose to 38°C. The reaction was stirred at ambient temperature for 30 min. The slurry was slowly poured into ice water (1.1 L) and then extracted with hexanes (300 mL) two times followed by a diethyl ether extraction (200 mL). The aqueous layer was chilled to 5°C and the pH adjusted to 7 with concentrated hydrochloric acid. The aqueous solution was extracted with methylene chloride (150 mL) until there was no W activity in the extract. The combined methylene chloride extracts were washed with saturated sodium chloride solution, dried over Na2S04, filtered, and concentrated in vacuo. The solid was recrystallized from methanol (200 mL) to give the butyric acid as a white solid (34.8 g, 51%). LCMS m/z = 458 [M+H]'*'.

[964] Part B. In dry equipment under nitrogen, the butyric acid from Part A (19.19 g, 42.0 mmol) was dissolved in dry dimethylformamide (100 mL) and the

remaining reagents were added to the solution in the following order: N- hydroxybenzotriazole hydrate (8.5 g, 63.0 mmol), triethylamine (11.7 mL, 84. 0 mmol), 4- (trifluoromethoxy) benzamidoxime (13.9 g, 63.0 mmol), and 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.1 g, 84.0 mmol). After 24 hr at 70°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated NaHC03, saturated sodium chloride solution, dried over Na2S04, filtered, and concentrated in vacuo. The solid was recrystallized from methanol (35 mL) to give the oxadiazole as an off white solid (17.86 g, 66%). LCMS m/z = 642 [M+H] +.

[965] Part C. A slurry of the oxaziazole from Part B (16.9 g, 26.4 mmol), 2. 5N sodium hydroxide (31.6 mL, 79.1 mmol) and sodium hydroxide (4.22 g, 105.5 mmol) in isopropanol (30 mL) were stirred at 70°C for 7 hr. The heat was removed and the reaction diluted with water (150 mL) and chilled to 5°C. The pH was adjusted to 7 with concentrated hydrochloric acid. The solids were filtered, washed with hexanes, and dried in vacuo to give the carboxylic acid as a white solid (15.78 g, 98%). LCMS m/z = 614 [M+H]+.

[966] Part D. In dry equipment under nitrogen, the carboxylic acid from Part C (15.7 g, 25.6 mmol) was dissolved in dry dimethylformamide (70 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (5.19 g, 38. 4 mmol), triethylamine (10.7 mL, 76.8 mmol), 0- (tetrahydro-2H- pyran2-yl) hydroxylamine (5.99,51.2 mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (10.8 g, 56.3 mmol). After 12 hr at 40°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated NaHCO3, saturated sodium chloride solution, dried over Na2S04, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/hexanes) provided the THP hydroxamate as a white foam (14.94 g, 82%). LCMS,/, = 713 [M+H] +.

[967] Part E. To the THP hydroxamate from Part D (14.88 g, 20.9mmol) was added 4N HC1 dioxane solution (52 mL, 209.0 mmol) and methanol (5.2 mL). The slurry became very thick. Dioxanes (50 mL) and diethyl ether (100 mL) were added to facilitate stirring. After 1 hr at ambient temperature the reaction was filtered under nitrogen. The solids were washed with acetonitrile (100 mL) under nitrogen and dried in vacuo over

phoshorus pentoxide to give the title compound as a white solid (13.25 g, 95%). HRMS (ES+) M+ Hp calculated for C27H3lN408SIF3 : 629.1893, found 629.1913.

[968] Example 43. Preparation of 4- (14- [3- (1, 3-benzoxazol-2- ylthio) propoxy] phenyl] sulfonyl)-N-hydroxy-1-(2-methoxyethyl) piperidine-4- carboxamide hydrochloride.

[969l Part A. A solution of 1-benzyl 4-tert-butyl 4- [ (4- fluorophenyl) sulfonyl] piperidine-1, 4-dicarboxylate (16.0 g, 33.5 mmol) in methanol/tetrahydropyran was hydrogenated for 1 hr at 5 psi in the presence of 5% Pd/C.

The solution was filtred to remove the catalyst and concentrated in vacuo. 11.0 g (95% yield) of the amine was obtained as a white solid.

[970] Part B. The solution of the amine of Part A (11.0 g, 32.1 mmol) in N, N- dimethylformamide (100 mL) was cooled to 0°C on an ice bath. Potassium carbonate (13.3 g, 96.4 mmol) and 2-bromoethylmethyl ether (7.54 mL, 80.2 mmol) were added to the chilled solution. The solution was stirred for 72 hr at ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. 14.5 g of the desired alkylated amine was obtained as an orange oil by concentration in vacuo. ls71l Part C. To a solution of propanediol (10.44 mL, 144 mmol) in 1-methyl- 2-pyrrolidinone (40 mL) cooled to 0°C was added sodium hydride (60% suspension in mineral oil, 3.85 g, 96.3 mmol). The alkylated amine from Part B (14.5 g, 32.1 mmol) was dissolved into 1-methyl-2-pyrrolidinone (50 mL) and added dropwise to the cooled solution. The solution was stirred at ambient temperature for 1 hr. The reaction was quenched by adding water and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate.

The desired alcohol was obtained as an orange oil by concentration in vacuo. MS (CI) MH+ calculated for C22H3sNO7S : 457, found 457.

[972] Part D. To a solution of the alcohol of Part C (32.1 mmol) in methylene chloride (100 mL) was added triethylamine (4.92 mL, 35.3 mmol). The solution was cooled to 0°C and methanesulfonyl choride (2.56 mL, 33.0 mmol) was added dropwise.

After 1 hr the reaction was concentrated in macho. The residue was dissolved into ethyl actate and washed with water, saturated sodium bicarbonate and saturated sodium chloride and dried over sodium sulfate. The solution was concentrated in vacuo to provide 17.5 g of the desired mesylate. MS (CI) MH+ calculated for C23H37NO9S2 : 536, found 536.

[973] Part E. To a solution of 2-mercaptobenzoxazole (4.86 g, 32.1 mmol) in N, N-dimethylformamide (30 mL) cooled to 0°C was added sodium hydride (60% suspension in mineral oil, 1.54 g, 38.5 mmol). After 30 min the mesylate of Part D (17.5 g, 32.1 mmol) in N, N-dimethylformamide (30 mL) was added dropwise. The solution was heated at 60°C for 4 hr and at 45°C for 18 hr. The solution was returned to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate.

Chromotography (ethyl acetate, on silica) provided the mercaptobenzoxazole as a colorless oil (7.3 g, 39% yield over four steps). MS (CI) MH+ calculated for C29H38N207S2 : 591, found 591.

[974] Part F. To a solution of the mercaptobenzoxazole of Part E (7.3 g, 12.4 mmol) was added trifluoroacetic acid (20 mL) and the solution stirred for 3 hr. The solution was concentrated in vacuo and azotroped with toluene to provide the acid as an oil. The material was carried on without additional purification. MS (CI) MH+ calculated for C25H3oN207S2 : 535, found 535.

[975] Part G. To a solution of the acid of Part F (12.4 mmol) in N, N- dimethylformamide (50 mL) were added 1-hydroxybenztriazole (2.01 g, 14.9 mmol), 4- methylmorpholine (6.82 mL, 62 mmol) and tetrahydropyranylamine (2.18 g, 18.6 mmol).

After30 min 1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.33 g, 17.4 mmol) was added. The solution was heated to 65°C for 2 hr. The solution was partitioned between ethyl acetate and water. The organic layer was washed with water and saturated sodium chloride and dried over sodium sulfate. Chromotography (ethyl acetate/methanol,

on silica) provided the protected hydroxamate as a colorless oil (3.9 g, 50 % yield).

MS (CI) MH+ calculated for C30H39N308S2 : 634, found 634.

[976j Part H. To a solution of the protected hydroxamate of Part G (3.9 g, 6.2 mmol) in 1,4-dioxane (10 mL) was added 4M hydrochloric acid in 1,4-dioxane (10 mL).

The reaction was complete after 1 hr. The solution was concentrated in vacuo. The residue was purified via reverse phase chromatography (acetonitrile/water, on silica) to provide the title compound as a white solid (1.49 g, 41% yield). MS (CI) MH+ calculated for C2sH3N307S2 : 550, found 550. HRMS calculated for C25H3lN307S2 : 550.1682, found 550.1668. Analytical calculation for C25H3lN307S2. HCl. H20 : C, 49.70; H, 5.67; N, 6.96; S, 10.62; Cl, 5.87. Found: C, 49.91; H, 6.03; N, 6.74; S, 10.75; Cl, 6.35.

[977] Example 44. Preparation of : [978] Part A. Preparation of : To a solution of 3- (3-bromophenyl) propionic acid (15.0 g, 65.5 mmol) in anhydrous THF (200 mL) at 5°C was added, via addition funnel, 1.0 M BH3-THF (200 mL, 200 mmol).

The reaction temperature was kept below 14°C during the addition of the BH3-THF. After all the BH3#THF was added, the reaction was refluxed for 22 hr and then quenched with water (100 mL) and IN HC1 (300 mL). The solution was saturated with sodium chloride and extracted with ethyl acetate (3x300 mL). The organic extract was washed with brine, dried over magnesium sulfate, and concentrated providing 14.4 g (100%) of crude alcohol as a colorless oil. NMR (CDC13) 6 1.82-1.89 (m, 2H), 2.67 (t, 2H), 3.64 (t, 2H), 7.11-7.15 (m, 1H), 7.29-7.31 (m, 1H), 7.34 (s, 1H).

[979] Part B. Preparation of :

In a flask were combined the alcohol from Part A (65.5 mmol), phenyl boronic acid (12.0 g, 98.2 mmol), palladium tetrakistriphenylphosphine (3.8 g, 3.3 mmol), 2M cesium carbonate (98 mL, 196 mmol) and dimethoxyethylether (100 mL). The mixture was stirred vigorously under nitrogen at reflux overnight. The reaction was cooled to ambient temperature, poured into water (300 mL) and extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulfate.

Chromatography (on silica, ethyl acetate/hexane) provided the coupled product as a golden oil (11.95 g, 86. 0 %). NMR (CDCl3) 6 1.91-1.98. (m, 2H), 2.77 (t, 2H), 3.71 (t, 2H), 7.19 (d, 1H), 7.31-7.38 (m, 2H), 7.41-7.45 (m, 4H), 7.58 (d, 2H).

[980] Part C. Preparation of : To a solution of the alcohol from Part B (11.9 g, 56.1 mmol) in anhydrous dimethylformamide (56 mL) at 0°C was added 60% sodium hydride (2.55 g, 63.8 mmol) in portions. After completion of the addition, the reaction was stirred at 0°C for 15 min then ambient temperature for 15 min. The reaction was cooled to 0°C and ethyl 4- [ (4- fluorophenyl) sulfonyl]-1-(2-methoxyethyl) piperidine-4-carboxylate (19.0 g, 51 mmol) in anhydrous dimethylformamide (60 mL) was added slowly. Upon completion of addition, the ice bath was removed and the reaction stirred at ambient temperature overnight.

Reaction was poured into water (1 L) and extracted with ethyl acetate (800 mL). The combined organics were washed with water (2x500 mL) and brine and dried over magnesium sulfate. Concentration gave 34.4 g of crude material. This material was used without purification.

[981] Part D. Preparation of.

The impure ester of Part C (34.4 g, 51 mmol theoretical) was hydrolyzed in 41 mL of ethanol, 41 mL of 1,4-dioxane and 26.5 mL of 6 N NaOH at 60°C. The solution was poured into water and extracted with ether to remove color. Acidification with 1N HC1 caused precipitation of the acid which was collected by filtration and washed with water, ethyl acetate and hexane then dried under high vacuum yielding the acid as an off white solid (18.8 g, 68.6% yield). NMR (CD30D w/K2CO3) 6 1.98 (t, 2H), 2.07-2.19 (m, 4H), 2.32 (d, 2H), 2.48 (t, 2H), 2.85-2.95 (m, 4H), 3.25 (s, 3H), 4.06 (t, 2H), 7.04 (d, 2H), 7.20 (d, 1H), 7.27-7.48 (m, 5H), 7.54 (d, 2H), 7.78 (d, 2H). ESMS m/z = 538 (M+H) +.

[982] Part E. Preparation of : To the acid of Part D (12.7 g, 23.6 mmol), HOBt (5.42 g, 35.4 mmol), EDC (6.30 g, 3.30 mmol) in a flask under N2 was added 70 mL anhydrous DMF. The mixture was heated to 60°C and triethylamine (9.85 mL, 70.8 mmol) was added. After heating at 60°C for 1 hr, THP-hydroxylamine (4.14 g, 35.4 mmol) was added. The solution was stirred for 16.5 hr at 60°C. The solution was partitioned between ethyl acetate (300 mL) and water (500 mL).

The organic layer was washed with brine and dried over magnesium sulfate.

Concentration provided the protected hydroxamate as an oil (14.86 g, 98.7 %).

NMR (CDCl3) 6 1.55-1.90 (m, 6H), 2.09-2.27 (m, 8H), 2.50 (t, 2H), 2.87 (t, 2H), 2.90-2.98 (m, 2H), 3.32 (s, 3H), 3.42 (t, 2H), 3.7.1 (d, 1H), 3.98 (d, 1H), 4.03 (t, 2H), 4.99 (s, 1H), 6.97 (d, 2H), 7.19 (d, 1H), 7.30-7.46 (m, 6H), 7.57 (d, 2H), 7.77 (d, 2H), 9.42 (s, 1H).

ESMS m/z = 637 (M+H)+.

[983] Part F. Preparation of :

To the product from Part E (14.7 g, 23.1 mmol) in methanol (23 mL) and 1,4-dioxane (23 mL) was added 4M hydrochloric acid in 1,4-dioxane (23 mL) and after stirring 1 hr, material dripped in to stirring IPA, let stand overnight. Collection of solid under N2 followed by washing with IPA and hexane then drying on high vacuum over P205 provided 12.5 g (91.8 %) of the title compound as a hydrochloric acid salt that was colorless. NMR (DMSO) 6 2.05-2.25 (m, 4H), 2.74, (t, 2H), 2.81 (t, 2H), 3.18-3.26 (m, 4H), 3.39 (s, 3H), 3. 51-3.61 (m, 4H), 4.09 (t, 2H), 7.15 (d, 2H), 7.22 (d, 1H), 7.29-7.49 (m, 6H), 7.58 (d, 2H), 7.45 (d, 2H).. ESMS m/z= 553 (M+H) +. HRMS calcd. for C3oH3sN20sS H: 553.2369 (M+H) +. Found: 553.2372.

[9841 Example 45. Preparation of: [98sl Part A. Preparation of :

In a flask were combined the 3-bromophenethyl alcohol (17.5 g, 87. 1 mmol), phenyl boronic acid (12.7 g, 104.5 mmol), palladium tetrakistriphenylphosphine (2.0 g, 1.74 mmol), 2M cesium carbonate (105 mL, 210 mmol) and dimethoxyethylether (105 mL).

Mixture stirred vigorously under nitrogen at reflux overnight. After cooling to ambient temperature, poured mixture into water (400 mL) and extracted with ethyl acetate (2x400 mL). Combined organics were washed with brine and dried over magnesium sulfate.

Silica gel chromotography (ethyl acetate/hexane) provided the coupled product as a crystalline solid (15.04 g, 87.3 %). NMR (CDC13) 6 2.95 (t, 2H), 3.93 (q, 2H), 7.19-18 (m, 2H), 7.31-7.51 (m, 5H), 7.58 (d, 2H). GCMS EI+ 198 (M+).

[986] Part B. Preparation of- To a solution of the alcohol from Part A (14.9 g, 75.2 mmol) in anhydrous dimethylformamide (70 mL) at 0°C was added 60 % sodium hydride (3.0 g, 75.2 mmol) in portions. After completion of the addition, the reaction was stirred at 0°C for 30 min. ethyl 4- [ (4-fluorophenyl) sulfonyl]-l- (2-methoxyethyl) piperidine-4-carboxylate (33.6 g, 90.2 mmol) in anhydrous dimethylformamide (50 mL) at 5°C was added slowly. Upon completion of addition let reaction slowly warm up overnight. Reaction was poured into water (700 mL) and extracted with ethyl acetate (3x500 mL). The combined organics were washed with brine and dried over sodium sulfate. Concentration gave 50.6 g of crude material. This material was used without purification. ESMS n/z = 552 (M+H) +.

[987] Part C. Preparation of :

The impure ester of Part B (75.2 mmol theoretical) was hydrolyzed in 75 mL of ethanol, 75 mL of 1,4-dioxane and 50 mL of 6 N NaOH at 60 C for 2.5 hr. The solution was poured into water and extracted with ether to remove color. Acidification with 1N HC1 caused precipitation of the acid which was collected by filtration and washed with water, ethyl acetate and diethyl ether then dried under high vacuum yielding the acid as a white solid (31.7 g, 80.6% yield). ESMS == 524 (M+H) +. HRMS calcd. for C29H34NO6S : 524.2101 (M+H) +. Found: 524.2075.

[988l Part D. Preparation of :

The acid of Part C (31.6 g, 60.4 mmol), HOBt (13.9 g, 90.6 mmol), EDC (16.2 g, 84.6 mmol), triethylamine (25.2 mL, 181 mmol) and THP-hydroxylamine (10.6 g, 90.6 mmol) were stirred in anhydrous dimethylfonnamide (200 mL) under N2 at 60°C overnight.

After cooling to room temperature solution was poured into 1.6 L of ice water and extracted with ethyl acetate (2xl L). The organic layer was washed with brine and dried over sodium sulfate. Silica gel chromatography (2.0M NH3 in MeOH/ethyl acetate/hexane) gave the desired product as a colorless foam (30.89 g, 82%). ESMS m/z = 623 (M+H) +. HRMS calcd. for C34H43N207S : 623.2786 (M+H) +. Found: 623. 2793.

[989] Part E. Preparation of :

To the product from Part D (30.7 g, 49.3 mmol) in methanol (49 mL) and 1,4-dioxane (49 mL) was added 4N HC1 in dioxane (50 mL). Material concentrated after 1 hr and crystallized from methanol providing the desired product as a colorless crystalline solid (25.6 g, 90.2%). ESMS t/Z = 539 (M+H) +. HRMS calcd. for C29H35N206S : 539.2210 (M+H) +. Found: 539.2187.

[990] Example 46. Preparation of: [991] Part A. Preparation of : To a solution of the alcohol from Example 38, Part B (12.0 g, 56.1 mmol) in anhydrous dimethylformamide (50 mL) at 0°C was added 60 % sodium hydride (2.58 g, 64.5 mmol) in portions. After completion of the addition, the reaction was stirred at 0°C for 15 min then ambient temperature for 15 min. The reaction was cooled to 0°C and ethyl 1-ethyl- 4- [ (4-fluorophenyl) sulfonyl] piperidine-4-carboxylate (17.7 g, 51.6 mmol) in anhydrous dimethylformamide (60 mL) was added slowly. Upon completion of addition, ice bath

was removed and reaction stirred at ambient temperature overnight. Reaction was poured into water and extracted with ethyl acetate 2 times. The combined organics were washed with water 2 times and brine and dried over sodium sulfate. Concentration gave 34.4 g of crude material. This material was used without purification. ESMS m/z = 536 (M+H) +.

19921 Part B. Preparation of :

The impure ester of Part A (51.6 mmol theoretical) was hydrolyzed in 50 mL of ethanol, 50 mL of 1,4-dioxane and 34.4 mL of 6 N NaOH at 60°C. After cooling to room temperature, the solution was poured into water (500 mL) and extracted with ether (2x250 mL) to remove color. Acidification with IN HCl caused precipitation of the acid which was collected by filtration and washed with water, ethyl acetate and hexane then dried under high vacuum yielding the acid as an off white solid (18. 4 g, 70% yield). ESMS m/z = 508 (M+H) +. HRMS calcd. for C29H34NO5S H: 508. 2152 (M+H) +. Found: 508.2176.

[993] Part C. Preparation of-

The acid of Part B (18. 0g, 35.4 mmol), HOBt (8.12 g, 53.1 mmol), EDC (9.47 g, 49.6 mmol), triethylamine (14.8 mL, 106.2 mmol) and THP-hydroxylamine (6.21g, 53.1 mmol) were stirred in anhydrous dimethylformamide (110 mL) under N2 at 60°C overnight.

After cooling to room temperature, the solution was poured into water (600 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine and dried over sodium sulfate. Silica gel chromatography (2.0M NH3 in MeOH/ethyl. acetate/hexane) gave the desired product as a colorless foam (11.0 g, 51%). ESMS 7n/z = 607 (M+H) +. HRMS calcd. for C34H43N206S : 607. 2836 (M+H) +. Found: 607.2829 [994] Part D. Preparation of :

To the product from Part C (10.8 g, 17.8 mmol) in methanol (18 mL) and 1,4-dioxane (18 mL) was added 4M hydrochloric acid in 1,4-dioxane (18 mL) and after stirring 1 hr, material concentrated. Co-crystallized with another batch from MeOH/4N HCl/dioxane.

Collection of solid followed by washing with methanol then drying on high vac provided 11.51 g (88 %) of the title compound as a hydrochloric acid salt that was colorless. ESMS m/z = 523 (M+H) +. HRMS calcd. for C29H35N2O5S H: 523.2261 (M+H) +. Found: 523.2224.

[995] Example 47. Preparation of 4- [ (4- {3- [4- (2, 4-difluorophenyl) thien-2- l] propoxy} phenyl) sulfonyl]-N-hydroxy-1- (2-methoxyethyl) piperidine-4-carboxamide hydrochloride.

[996] Part A. A round bottom flask was charged with 4-bromo-2-thiophene carboxaldehyde (Aldrich, 55.8 g, 292 mmol), 2,4-difluorophenyl boronic acid (Aldrich, 60.0 g, 380 mmol), tetrakis-triphenylphosphine palladium (Aldrich, 16.9 g, 14.6 mmol), 2 M Na2CO3 aq (190 ml, 380 mmol), and ethylene glycol-dimethyl ether (Aldrich, 500 ml).

The reaction was heated to 80°C and stirred for 5 hr. The reaction suspension was then poured into a mixture of methylene chloride (500 ml) and ice water (500ml). The organic layer was separated and washed with water (2x-200 ml) and brine (lx-300 ml) then dried

over Na2S04 and concentrated to afford the thiophene phenyl adduct as a brown oil. Silica gel purification (hexanes/ethyl acetate) yielded a white solid (34.2 g, 52 % yield). 1H NMR showed the desired compound.

[997] Part B. A solution of triethyl phosphonoacetate (Aldrich, 24.2 g, 108 mmol) in tetrahydrofuran (100 ml) was cooled to-78°C. A 1.6 M n-butyllithium solution in hexanes (68 ml, 108 mmol) was slowly dripped in then the reaction stirred for 30 min at -78°C. A solution of the thiophene phenyl carboxaldehyde product from Part A in tetrahydrofuran (100 ml) was slowly dripped in. The dry ice bath was removed and the reaction stirred as it came to ambient temperature overnight. The mixture was diluted with water (200 ml) to quench. The organic layer was separated and washed with water (2x- 200 ml) and brine (lx-300 ml) then dried over Na2S04 and concentrated to afford a tan solid. This solid was recrystallized from warm methanol to yield a light yellow solid (16.1 g, 56 % yield). 1H NMR showed the desired compound.

[9981 Part C. A solution of the ethyl ester olefin of Part B (16 g, 54.4 mmol) in methylene chloride was cooled to 0°C. A 1.0 M solution of lithium aluminum hydride was dripped in slowly, then the reaction continued stirring for 45 min at 0°C. A saturated solution of NH4Cl'aq was dripped in to quench, followed by a solution of sodium, potassium tartrate aq (10 ml). After stirring for 30 min, Na2S04 (40 g) was added. The mixture was filtered and concentrated to afford a yellow oil (16.8 g, 100+ % yield). 1H NMR showed the desired compound along with impurities.

[999] Part D. A hydrogenation flask was charged with the crude hydroxy olefin residue from Part C (-54. 4 mmol) was dissolved in tetrahydrofuran (125 ml) and methanol (20 ml). Nitrogen gas was bubbled through for 15 min then 10% Pd/C catalyst (Aldrich, 50% water, 2.7 g) was added. A hydrogenation head was attached and the vessel was purged with nitrogen (3x), followed by hydrogen (3x). The vessel was left at 50 psi of hydrogen. After 1 hr of stirring, the reaction was complete by LCMS. The mixture was filtered through a Celite pad and concentrated to afford a black oil that was purified on silica gel (hexanes/ethyl acetate). Collected fractions gave the product as a clear oil (8.6 g, 62% yield).). 1H NMR showed the desired compound.

[1000] Part E. The saturated alcohol from Part D (7.6 g, 30.0 mmol) was dissolved in dimethylsulfoxide (60 ml). Sodium hydride (Aldrich, 60 % in oil dispersion, 1.3 g, 32.6 mmol) was added portion wise over 30 min. After stirring for 1 hr, the aryl-

fluoride, SC 84087, was added and the reaction was stirred overnight at ambient temperature. The reaction was quenched with saturated NH4Cl aq (100 ml) then extracted with ethyl acetate (3x-125 ml). The combined organics were washed with water (2x-200 ml) and brine (lx-200 ml) then dried over Na2S04 filtered and concentrated to a brown oil.

The residue was purified on silica gel (hexanes/ethyl acetate) to afford the product as a tan solid (14.0 g, 81% yield).). H NMR showed the desired compound at 90% purity.

[1001] Part F. The t-butyl ester from Part E (9.5 g, 15.0 mmol) was dissolved in methylene chloride (30 ml) after which, trilfluoroacetic acid (Aldrich, 30 ml) was added.

The reaction stirred for 4 hr then was concentrated to one-third volume via a nitrogen stream. The slightly viscous residue was then dripped into stirring diethyl ether to form a solid that was filtered and dried to give the product as a tan solid (6.9 g, 66 % yield).).

'H NMR showed the desired compound. l1002] Part G. To a solution of the carboxylic acid of Part F (6.9 g, 9.9 mmol) in N, N-dimethylfonnamide (20 ml) was added triethylamine (Aldrich, 4.2 ml, 30.0 mmol) followed by N-hydroxybenzotriazole hydrate (Aldrich, 2.7 g, 20.0 mmol), O- (tetrahydro- 2H-pyran-2-yl) hydroxylamine (2.34 g, 20.0 mmol), and, lastly, 1- (3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (Sigma, 4.18 g, 21. 8 mmol).

The reaction stirred at room temperature for 18 hr. The mixture was diluted with water (30ml) then extracted with ethyl acetate (3x-100 ml). The organics were combined and washed with saturated NaHC03 aq (3x-100 ml), water (2x-100ml), and brine (lx-150 ml).

After drying over Na2S04, the mixture was filtered and concentrated for a tan oil. The oil was tritiated with ethanol (3x) and methanol (3x) to afford a tan oil (8.1 g, 100+ % yield).

'H NMR showed the desired compound with trace impurities.

110031 Part H. The crude protected hydroxamic acid of Part G (-9. 9 mmol) was slurried in methanol (4 ml) and stirred with 4 N HC1 in dioxane (20 ml) for 1 hr. The solvent volume was reduced in half then diethylether was added, providing a gummy solid that was purified by Reverse Phase LC (C18, acetonitrile/water). The resulting partial TFA salt was dissolved in 4 N HC1 in dioxane (20 ml) and stirred for 1 hr. The solvent volume was again reduced in half then diethyl ether was added, providing a white solid. The solid was collected and dried to afford the desired hydrochloride salt as a white powder (3.35g, 54% yield). 1H NMR showed the desired compound.

[1004] Example 48: Preparation of: 11005] Part A. Preparation of :

A mixture of lithium chloride (1.71 g, 40.3 mmol), trifluoromethoxy-benzonitrile (5.00 g, 26.7 mmol), and sodium azide (1.75 g, 26.7 mmol) in 2-methoxyethanol (26 mL) under an N2 atmosphere was refluxed for 4 lir. The ambient mixture was poured into a mixture of ice (84 g) and concentrated HC1 (8. 4 mL) and stirred until the ice melted. The white solid was collected by filtration, washed with water, and dried for 2 hr in a 40°C vacuum oven to produce the tetrazole in the form of an off white solid (4.86 g, 79% yield). MS MH+ calcd. for C8H6N40F3 231, found 231.

[1006] Part B. Preparation of A solution of the tetrazole of Part A (2.00 g, 8.69 mmol) in NMP (12 mL) was added dropwise to an ambient mixture of 95% sodium hydride (0.438 g, 18.2 mmol) in NMP (12 mL) under an N2 atmosphere. After an 1 hr of stirring, 2- (3-chloropropoxy) tetrahydro- 2H-pyran (1.58 mL, 9.56 mmol) was added dropwise. The mixture was stirred at ambient temperature for 18 hr and then at 70°C for 2 hr. The mixture was diluted with a solution of water (200 mL) and saturated NaHC03 (100 mL), and extracted with ethyl acetate (3x100 mL). Tlle organic layer was washed with water (2x100 mL) and brine (100 mL), dried over MgS04, and concentrated in vacuo to produce a yellow liquid. Flash chromatography purification (ethyl acetate-hexane/silica gel) provided the pyran in the form of a white solid (1.46 g, 45% yield). Anal. Calcd. for Cl6HlgN403F3 : C, 56.34; H, 5.98; N, 7.73; S, 4.42. Found C, 56.13; H, 6.08; N, 7.65; S, 4.75.

[1007] Part C. Preparation of : To an ambient solution of the pyran of Part B (1.40 g, 3.76 mmol) in MeOH (13.5 mL) was added a solution of acetyl chloride (0.896 mL, 13.1 mmol) in MeOH (13.5 mL).

After 15 min, the solution was concentrated in vacuo to provide the alcohol in the form of a solid (1.02 g, 94% yield). MS MH+ calcd. for CllHl2N402F3 289, found 289.

[10081 Part D. Preparation of : To an ambient mixture of 95% sodium hydride (0.110g, 3.58 mmol) in NMP (2.5 mL) under an N2 atmosphere was added dropwise a solution of the alcohol of Part C (1.00 g, 3.47 mmol) in NMP (3.2 mL), and then the mixture was heated at 55°C for 30 min. A solution of ethyl 4- [ (4-fluorophenyl) sulfonyl]-1- (2-methoxyethyl) piperidine-4-carboxylate (1.22 g, 3.27 mmol) in NMP (3.2 mL) was added dropwise to the 55°C reaction mixture.

After 1 hr at 55°C, the ambient mixture was diluted with a solution of water (600 mL) and NaHC03 (100 mL), and extracted with ethyl acetate (3x200 mL). The organic layer was washed with water (2x150 mL) and brine (150 mL), dried over MgS04, and concentrated in vacuo to form a yellow oil (1.96 g). Flash chromatography purification (MeOH- EA/silica gel) provided the sulfone in the form of a yellow oil (1.48 g, 70% yield). MS MH+ calcd. for C2sH35N507SF3 642, found 642. t1009] Part E. Preparation of :

A mixture of the sulfone of Part D (1.44 g, 2.24 mmol) and 50% aqueous NaOH (1.08 g, 22.4 mmol) in a solution of THF (23 mL) and EtOH (11 mL) was stirred at ambient temperature for 3 hr and then 60°C for 15 min. The mixture was concentrated in vacuo, diluted with a solution of acetonitrile and water, acidified to a pH of approximately 2 with concentrated HCI, and concentrated in vacuo to provide the acid (containing NaCI) as a crude tan foam (2.77 g). MS MH+ calcd. for C26H31N507SF3 614, found 614.

[1010] Part F. Preparation of : A mixture of the crude acid of Part E (2.24 mmol), 1-hydroybenzotriazole hydrate (0,534 g, 3.95 mmol), triethylamine (3.62mL, 25.9 mmol), 0- (tetrahydro-2H-pyran-2- yl) hydroxylamine (0.542 g, 4.63 mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (0.888 g, 4.63 mmol) in DMF (23 mL) under an N2 atmosphere was stirred at ambient temperature for 40 hr. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (3x100 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), dried over MgS04, and concentrated in vacuo to form a white foam (1.37 g). Chromatography purification (MeOH-EA/silica gel) produced the 0-protected hydroxamate in the form of a white foam (1.04 g, 65% based on the ester of Part 1D). MS MH+ calcd. for C3lH4oN6OgF3S 713, found 713. Anal.

Calcd. for C3lH39N608F3S : C, 52.24; H, 5.52; N, 11. 79. Found C, 52.47; H, 5. 73; N, 11.64.

[1011] Part G. Preparation of : A solution of the 0-protected hydroxamate of Part F (0.960 g, 1.35 mmol) and acetyl chloride (0.493 g, 6.53 mmol) in methanol (15 mL) was stirred at ambient temperature for

1 hr. The solution was concentrated in vacuo to a white solid. The solid was triturated with ether and concentrated in vacuo to provide the title compound in the form of a white solid (0.66 g, 74% yield). Anal. Calcd. for C26H3lN607F3S, HCI : C, 46.95; H, 4.85; N, 12.64; Cl, 5.33; S, 4.82. Found C, 46.59; H, 5.07; N, 12.64; Cl, 5.36; S, 5.20. MS NEEI+ calcd. for C26H32N607F3S 629, found 629.

[1012] Example 49. Preparation of : [1013] Part A. Preparation of : To an ambient mixture of 95% sodium hydride (0.397g, 16.5 mmol) in NMP (7 mL) under an N2 atmosphere was added dropwise a solution of the alcohol of Part C of Example 48 (3.44 g, 11.9 mmol) in NMP (7 mL). The mixture was then stirred at ambient temperature for 45 min. The ethyl 1-cyclopropyl-4- [ (4-fluorophenyl) sulfonyl] piperidine-4-carboxylate (4.00 g, 11.3 mmol) was added in one portion, and the mixture was heated to 60°C. After heating for 24 hr at 60°C and adding 2 more portions of 95% sodium hydride (0.10 g, 4.0 mmol and 0.08 g, 3.0 mmol), the mixture was diluted with water (300 mL) and extracted with ethyl acetate (3x100 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), dried over MgS04, and concentrated in vacuo to form a yellow oil (5.81 g). Flash chromatography purification (Hexane-EA/silica gel) produced the sulfone in the form of a yellow oil (3.10 g, 44% yield). The proton NMR (CDC13) spectrum was consistent with the desired sulfone product.

[1014] Part B. Preparation of :

A mixture of the sulfone of Part A (3.00 g, 4.81 mmol) and 50% aqueous NaOH (3.85 g, 48.1 mmol) in a solution of THF (50 mL) and EtOH (24 mL) was stirred for 2.5 hr at 60°C. The mixture was concentrated in vacuo, diluted with a solution of acetonitrile and water, acidified to a pH of approximately 2 with concentrated HC1, and concentrated in vacuo. The crude acid was purified by reverse phase HPLC (H2O-CH3CN) to produce the acid in the form of a white solid (1.86 g, 55% yield). MS MH+ calcd. for C26H29N506F3s 596, found 596. t1015] Part C. Preparation of : A mixture of the acid of Part B (1.80 g, 2.85 mmol), 1-hydroybenzotriazole hydrate (0.679 g, 5.02 mmol), triethylamine (4.61mL, 33.1 mmol), 0- (tetrahydro-2H-pyran-2- yl) hydroxylamine (0.692 g, 5.91 mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.13 g, 5.91 mmol) in DMF (29 mL) under an N2 atmosphere was stirred at ambient temperature for 24 hr and 57°C for 6.5 hr. The mixture was concentrated in vacuo, diluted with water (300 mL), and extracted with ethyl acetate (3x100 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), dried over MgS04, and concentrated in vacuo to form a yellow oil (1.80 g). Flash chromatography purification (MeOH-CH2Cl2/silica gel) produced the 0-protected hydroxamate in the form of a white foam (0.89 g, 45% yield). MS MH+ calcd. for C3lH38N607F3S 695, found 695. Anal. Calcd. for C31H37N607F3S : C, 53.59; H, 5.37; N, 12.10; S, 4.62. Found C, 53.30; H, 5.43; N, 12.05; S, 4.73.

110161 Part D. Preparation of :

A solution of the 0-protected hydroxamate of Part C (0.870 g, 1.25 mmol) and acetyl chloride (0.456 g, 6.04 mmol) in methanol (14 mL) was stirred at ambient temperature for 30 min. The mixture was poured into diethyl ether (250 mL). The white solid was isolate by filtration and dried in a 40°C vacuum oven to produce the title compound in the form of a white solid (0.56 g, 69% yield). MS MH+ calcd. for C26H3oN606F3S 611, found 611.

[1017] Example 50. Preparation of:

[1018] Part A. Preparation of :

To a solution of the alcohol from Part B of Example 38 (3.65 g, 17.0 mmol) in anhydrous dimethylformamide (17 mL) at 5°C was added 60% sodium hydride (0.77 g, 19.3 mmol) in portions. After completion of the addition, the reaction was stirred at 5°C for 15 min and then at ambient temperature for 15 min. The reaction was cooled to 5°C and ethyl 4- [ (4-fluorophenyl) sulfonyl]-1- (2-methoxyethyl) piperidine-4-carboxylate (6.0 g, 16.1 mmol) in anhydrous dimethylformamide (15 mL) was added slowly. Reaction stirred at room

temperature for 2 hr, then was diluted with water (250 mL) and extracted with ethyl acetate (3x150 mL). The combined organics were washed with brine and dried over magnesium sulfate. Silica Gel chromatography (ethyl acetate/hexane) gave the product as a colorless oil (8.06 g, 88%). NMR (CDC13) 6 1.20-1.26 (m, 3H), 1.88-2.02 (m, 2H), 2.06- 2.27 (m, 4H), 2.43 (d, 2H), 2,53 (bs, 2H), 2.78 (t, 2H), 2.97-3.08 (m, 2H), 3.32 (s, 3H), 3.47 (bs, 2H), 4.00 (t, 2H), 4.18 (q, 2H), 6.95 (d, 2H), 709-7.18 (m, 2H), 7.34 (d, 2H), 7.68 (d, 2H).

[1019] Part B. Preparation of : The impure ester of Part A (8. 06 g, 14.2 mmol theoretical) was hydrolyzed in 15 mL of ethanol, 15 mL of 1,4-dioxane and 9. 5 mL of 6 N NaOH at 60°C. The solution was poured into water and extracted with ether to remove color. Acidification with 1N HC1 caused precipitation of the acid which was collected by filtration and washed with water and hexane then dried under high vacuum yielding the acid as an off white solid (5.90 g, 76.8 % yield). NMR (CD30D w/K2C03) 6 2.00 (q, 2H), 2.07-2.19 (m, 4H), 2.32 (d, 2H), 2.48 (t, 2H), 2.79 (d, 2H), 2.91 (d, 2H), 3.45 (t, 2H), 4.06 (t, 2H), 7.04 (d, 2H), 7.20 (d, 2H), 7.29-7.35 (m, 1H), 7.40 (s, 1H), 7.78 (d, 2H).

[1020] Part C. Preparation of : To the acid of Part B (5.90,10.9 mmol), EDC (2.9 g, 15.3 mmol), and HOBt (2.5g, 16.4 mmol) in anhydrous NMP (33 mL) was added triethylamine (4.5 mL, 32.7 mmol). After heating at 60°C for 1 hr, THP-hydroxylamine (1.9 g, 16.4 mmol) was added. The solution was stirred for 18 hr at 60°C, additional EDC (2.9 g, 15.3 mmol), HOBt (2.5g, 16.4

mmol), triethylamine (4.5 mL, 32.7 mmol) and THP-hydroxylamine (1.9 g, 16.4 mmol) were added. After 2 hr, the reaction was diluted with water (300 mL) and extracted with ethyl acetate (3x150 mL). The combined organics were washed with brine and dried over magnesium sulfate. Silica gel Chromatography (ethyl acetate/hexanes) provided the protected hydroxamate as a viscous impure colorless oil (5.70 g). ESMS m/z = 641 (M+H) +.

[1021] Part D. Preparation of :

In a vial were combined the aryl bromide from Part C (0.50 g, 0.78 mmol) in 3 mL of dimethoxyethyl ether, 4-chlorobenzeneboronic acid (185 mg, 1.17 mmol), palladium tetrakistriphenylphosphine (-45 mg, 0.04 mmol) and 2M cesium carbonate (1.17 mL, 2.34 mmol). Mixture stirred vigorously at 80°C for 18 hr. Reaction poured onto 2 mL Chem- Elut tube prewetted with 3 mL of water and eluted with ethyl acetate and methylene chloride. Purification by reverse phase chromatography (acetonitrile/water/0.05% TFA) gave the TFA salt of the deprotected material (239.6 mg) which was carried on as is.

[1022] Part E. Preparation of :

The product from Part D (239.6 mg) was taken up in 4M hydrochloric acid in 1,4-dioxane (2 mL) and methanol (1-2 mL) and stirred for 0. 5 hr then concentrated. This was repeated.

Product crashed out of solution, was collected by filtration, washed with diethyl ether and

dried under high vacuum yielding the title compound as colorless solid (170.5 mg, 35% over two steps). ESMS m/z = 587 (M+H) +. HRMS calcd. for C3oH36ClN206S : 587. 1977 (M+H) +. Found: 587.1979.

[1023] Example 51. Preparation of 1-cyclopropyl-N-hydroxy-4-[[4-(3-{3-[4- (trifluoromethoxy) phenyl-1, 2,4-oxadiazol-5-yl} propoxy) phenyl] sulfonyl} piperidine- 4-carboxamide hydrochloride.

[1024] Part A. In dry equipment under nitrogen, potassium trimethylsilanolate (35.9 g, 0.28 mol) was dissolved in dimethylsulfoxide (250 mL) and gamma-butyrolactone (16.14 mL, 0.21 mol) was added over 10 min while the reaction temperature rose to 38°C.

After stirring at ambient temperature for 40 min, sodium hydride (8.4 g of a 60% oil dispersion, 0.21 mol) was added portion wise over 20 min and the reaction temperature rose to 43°C. Gas evolution was also observed. After stirring at ambient temperature for 50 min, a solution of ethyl 1-cyclopropyl-4- [ (4-fluorophenyl) sulfonyl]-4- piperidinecarboxylate (49.7g, 0.14 mol) in dimethylsulfoxide (50 mL) was added over 10 min as the reaction temperature rose to 38°C. The reaction was stirred at ambient temperature for 30 min. The slurry was slowly poured into ice water (1.5 L) and then extracted with hexanes (150 mL) 3 times followed by a diethyl ether extraction (300 mL).

The aqueous layer was chilled to 5°C and the pH adjusted to 6 with concentrated hydrochloric acid. The slurry was filtered and the cake washed with 500 mL water two times. The solid was dried in vacuo to give the butyric acid as a white solid (47.5 g, 77%). LCMS m/z = 440 [M+H] +.

[1025] Part B. In dry equipment under nitrogen, the butyric acid from Part A (3.07 g, 7.0 mmol) was dissolved in dry dimethylacetamide (15 mL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (1.42 g, 10.5 mmol), triethylamine (1.95 mL, 14.0 mmol), 4-

(trifluoromethoxy) benzamidoxime (2.31 g, 10.5 mmol), and 1- (3-dimethylaminopropyl)- 3-ethylcarbodiimide hydrochloride (2.68 g, 14.0 mmol). Additional dry dimethylacetamide (5 mL) was added. After 24 hr at 70°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated NaHC03, saturated sodium chloride solution, dried over Na2S04, filtered, and concentrated in vacuo. Chromatography (on silica, ethyl acetate/methanol/hexanes) provided the oxadiazole as a light white solid (3.38 g, 78%). LCMS m/z = 624 [M+H] +.

[1026] Part C. A slurry of the oxadiazole from Part B (3.36 g, 5.39 mmol), 2.5N sodium hydroxide (6.5 mL, 16.2 mmol) and sodium hydroxide (0.86 g, 21.6 mmol) in isopropanol (27 mL) was stirred at 75°C for 5 hr. The heat was removed and the reaction diluted with water (50 mL) and chilled to5°C. The pH was adjusted to 7 with concentrated hydrochloric acid. The solids were filtered, washed with hexanes, and dried in vacuo to give the carboxylic acid as a white solid (3.1 g, 97%). LCMS m/z = 596 [M+H] +.

[1027] Part D. In dry equipment under nitrogen, the carboxylic acid from Part C (2.9 g, 4.87 mmol) was dissolved in dry dimethylacetamide (10 niL) and the remaining reagents were added to the solution in the following order: N-hydroxybenzotriazole hydrate (0.99 g, 7.3 mmol), triethylamine (2.03 mL, 14.6 mmol), 0- (tetrahydro-2H-pyran- 2-yl) hydroxylamine (0.86 g, 7.31 mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.87 g, 9.75 mmol). Additional dry dimethylacetamide (5 mL) was added. After 29 hr at 40°C, the reaction was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with water, saturated NaHC03, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo.

Chromatography (on silica, ethyl acetate/methanol/hexanes) provided the THP hydroxamate as a white foam (1.48 g, 44%). LCMS milz == 695 [M+H] +.

[1028] Part E. To the THP hydroxamate from Part D (1.4 g, 2.02 mmol) was added 4N HC1 dioxane solution (5 mL, 20.2 mmol) and methanol (0.5 mL). The slurry became very thick. Diethyl ether (50 mL) was added to and after 1 hr at ambient temperature the reaction was filtered under nitrogen. The solids were washed with diethyl ether (150 mL) under nitrogen and dried in vacuo over phosphorus pentoxide to give the title compound as a white solid (1.4 g, 100%). HRMS (ES+) M+ H + calculated for C27H29N407S1F3 611.1787, found 611.1773.

[1029J Example 52. Preparation of :

11030] Part A. In a vial were combined the aryl bromide from Part C of Example 50 (0.50 g, 0.78 mmol) in 3 mL of dimethoxyethyl ether, 3,4- difluorobenzeneboronic acid (185 mg, 1.17 mmol), palladium tetrakistriphenylphosphine (-45 mg, 0.04 mmol) and 2M cesium carbonate (1.17 mL, 2.34 mmol). Mixture stirred vigorously at 80°C for 18 hr. Reaction poured onto 2 mL Chem-Elut tube prewetted with 3 mL of water and eluted with ethyl acetate and methylene chloride. Purification by reverse phase chromatography (acetonitrile/water/0. 05% TFA) gave the TFA salt of the deprotected material (354.8 mg) which was carried on as is.

[1031] Part B. The product from Part D (354.8 mg) was taken up in 4M hydrochloric acid in 1,4-dioxane (2 mL) and methanol (1-2 mL) and stirred for 30 min and then concentrated. This was repeated. Product crashed out of solution, was collected by filtration, washed with diethyl ether and dried under high vacuum yielding the title compound as a colorless solid (298.0 mg, 61% over two steps). ESMS m/z = 589 (M+H) +.

HRMS calcd. for C3oH3sF2N206S : 589. 2178 (M+H) +. Found: 589. 2192.

11032] Example 53. Preparation of : [1033] Part A. Preparation of :

A mixture of lithium chloride (1.71 g, 40.3 mmol), trifluoromethoxy-benzonitrile (5.00 g, 26.7 mmol), and sodium azide (1. 75 g, 26.7 mmol) in 2-methoxyethanol (26 mL) under an N2 atmosphere was refluxed for 4 hr. The ambient mixture was poured into a mixture of ice (84 g) and concentrated hydrochloric acid (8.4 mL), and then stirred until the ice melted. The resulting white solid was collected by filtration, washed with water, and dried for 2 hr in a 40°C vacuum oven to provide the tetrazole in the form of an off white solid (4.86 g, 79% yield). MS MH+ calcd. for C8H6N40F3 231, found 231.

[1034] Part B. Preparation of : A solution of the tetrazole of Part A (2.00 g, 8.69 mmol) in NMP (12 mL) was added dropwise to an ambient mixture of 95% sodium hydride (0.438 g, 18.2 mmol) in NMP (12 mL) under an N2 atmosphere. After an 1 hr of stirring, 2- (3-chloropropoxy) tetrahydro- 2H-pyran (1. 58 mL, 9.56 mmol) was added dropwise. The mixture was stirred at ambient temperature for 18 hr and then at 70°C for 2 hr. The mixture was diluted with a solution of water (200 mL) and saturated NaHC03 (100 mL), and extracted with ethyl acetate (3x100 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), dried over MgS04, and concentrated in vacuo to give a yellow liquid. Flash chromatography purification (ethyl acetate-hexane/silica gel) provided the pyran in the form of a white solid (1.46 g, 45% yield). Anal. Calcd. for C16Hl9N403F3 : C, 56. 34; H, 5.98; N, 7.73; S, 4.42. Found C, 56.13; H, 6.08; N, 7.65; S, 4.75.

[1035] Part C. Preparation of- To an ambient solution of the pyran of Part B (1.40 g, 3.76 mmol) in MeOH (13.5 mL) was added a solution of acetyl chloride (0.896 mL, 13.1 mmol) in MeOH (13.5 mL).

After 15 min, the solution was concentrated in vacuo to provide the alcohol in the form of a solid (1.02 g, 94% yield). MS MH+ calcd. for CllHl2N402F3 289, found 289.

[1036] Part D. Preparation of :

To an ambient mixture of 95% sodium hydride (0.923g, 38.5 mmol) in NMP (16 mL) under an N2 atmosphere was added dropwise a solution of the alcohol of Part C (8.00 g, 27.7 mmol) in NMP (16 mL), and the mixture was stirred at ambient temperture for 35 minutes. A solution of 1-benzyl 4-tert-butyl 4- [ (4-fluorophenyl) sulfonyl] piperidine-1, 4- dicarboxylate (12.5 g, 26.3 mmol) in NMP (16 mL) was added dropwise to the reaction mixture. After 3 hr at 55°C, the ambient mixture was diluted with water (700 mL) and extracted with ethyl acetate (3x150 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), dried over MgS04, and concentrated in vacuo to produce a yellow oil (18.6 g). Chromatography purification (hexane-EA/silica gel) provided the sulfone as a yellow oil (10.1 g, 52% yield). MS MHA calcd. for C35H39N5O8SF3 746, found 746. Anal. Calcd. for C35H38N5OgSF3 C, 56.37; H, 5.14 ; N, 9.39; S, 4.30. Found C, 56.22; H, 4.96; N, 9.22; S, 4.37.

[1037] Part E. Preparation of : A mixture of the sulfone of Part D (10.0 g, 13.4 mmol) and 10% palladium on carbon (1.43g, 1.34 mmol) in methanol (50 mL) was placed under an H2 atmosphere with a balloon at ambient temperature for 20 hr. The mixture was filtered through a bed of celite and concentrated in vacuo to provide the piperidine in the form of a pale yellow oil (7.57 g, 92%). The proton NMR spectrum was consistent for the desired compound.

[10381 Part F. Preparation of :

A mixture of the piperidine of Part E (3.50 g, 5.72 mmol), (bromomethyl) cyclopropane (0.67 mL, 6.87 mmol), and potassium carbonate (2.38 g, 17.2 mmol) in DMF (15 mL) was stirred at ambient temperature for 20 hr under an N2 atmosphere. The mixture was diluted with water (700 mL) and extracted with ethyl acetate (3x100 mL). The organic layer was washed with water (2x75 mL) and brine (75 mL), dried over MgS04, and concentrated in vacuo to produce a yellow oil. Flash chromatography purification (hexane-EA/silica gel) provided the alkylpiperidine in the form of a colorless oil (2.08 g, 55% yield): MS MH+ calcd. for C3lH39N506SF3 666, found 666. Anal. Calcd. for C31H38N506SF3 : C, 55.93; H, 5.75; N, 10.52; S, 4.82. Found C, 55.85; H, 5.91; N, 10.25; S, 4.99.

[1039] Part G. Preparation of.

A solution of the alkylpiperidine of Part F (2.00 g, 3.00 mmol) in trifluoroacetic acid (10 mL, 130 mmol) was stirred at ambient temperature for 1.7 hr. The mixture was concentrated in vacuo, triturated twice with ether, and dried in a 40°C vacuum to provide the acid as a white solid (2.21 g, 102%). MS MH+ calcd. for C27H3lN506SF3 610, found 610.

11040] Part H. Preparation of :

A mixture of the crude acid of Part G (2.10 g, 3.44 mmol), 1-hydroybenzotriazole hydrate (0. 820 g, 6.07 mmol), triethylamine (5.57mL, 39.9 mmol), 0- (tetrahydro-2H- pyran-2-yl) hydroxylamine (0. 835 g, 7.13mmol), and 1- (3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (1.37 g, 7.13 mmol) in DMF (35 mL) under an N2 atmosphere was stirred at ambient temperature for 20 hr. The mixture was diluted with water (700 mL) and extracted with ethyl acetate (3x200 mL). The organic layer was washed with water (2x100 mL) and brine (100 mL), dried over MgS04, and concentrated in vacuo to produce a yellow foam. Chromatography purification (MeOH-CH2Cl2/silica gel) produced the 0-protected hydroxamate in the form of a white foam (1.60 g, 66%).

MS MH calcd. for C32H4oN607F3S 709, found 709.

[1041] Part I. Preparation of : A solution of the 0-protected hydroxamate of Part H (1.50 g, 2.12 mmol) and acetyl chloride (0. 677 mL, 10.2 mmol) in methanol (23 mL) was stirred at ambient temperature for 1 hr. The solution was diluted with ether and a solid formed. The solid was isolated by filtration, washed with ether, and dried in a 40°C vacuum oven to produce the title compound as a white solid (1.55 g, 82% yield). Anal. Calcd. for C27H31N606F3S HC1 : C, 49.05; H, 4.88; N, 12.71; Cl, 5.36; S, 4.85. Found C, 48.94; H, 4.72; N, 12.71; Cl, 5.29; S, 4.94 [1042] Example 54. Preparation of: [1043] Part A. Preparation of :

To a solution of tert-butyl 4- [ (4-fluorophenyl) sulfonyl] tetrahydro-2H-pyran-4-carboxylate (5.0 g, 14.6 mmol) and cesium carbonate (14.3 g, 43.8 mmol) in anhydrous DMSO (30 mL) was added ethylene glycol (8.1 mL, 146 mmol). The resulting reaction mixture was stirred at 80°C for 3 hr. After cooling to room temperature, the mixture was poured into water (350 mL) and extracted with ethyl acetate (3x). The organics were washed with brine and dried over magnesium sulfate. Silica gel chromatography (ethyl acetate/methylene chloride) provided the alcohol as a colorless solid (2.33 g, 41%).

NMR (CDCl3) 6 1.45 (s, 9H), 2.13-2.20 (m, 4H), 3.22-3.33 (m, 2H), 3.94-4.03 (m, 4H), 4.16 (q, 2H), 7.02 (d, 2H), 7.73 (d, 2H). ESMS m/z = 404 (M+NH4) +. HRMS calcd. for C18H2607S NH4 : 404.1743 (M+NH4) +. Found: 404.1734.

[1044] Part B. Preparation of :

To a solution of the alcohol from Part A (0.50 g, 1.3 mmol) in CH2C12 (2.5 mL) was added triethylamine (0.24 mL g, 1.7 mmol), followed by mesyl chloride. The resulting mixture was stirred at room temperature for 1.5 hr. The mixture was diluted with methylene chloride and washed with 10% citric acid, washed with 5% sodium bicarbonate, washed with brine, and dried over MgSO4. Concentration produced the desired compound in the form of a tan solid (0.62 g, 100%). NMR (CDCl3) 1.45 (s, 9H), 2.13-2.22 (m, 4H), 3.07 (s, 3H), 3.22-3.37 (m, 2H), 4.00 (dt, 2H), 4.32-4.37 (m, 2H), 4.58- 4.62 (m, 2H), 7.02 (d, 2H), 7.75 (d, 2H). ESMS m/z = 482 (M+NH4) +.

[1045] Part C. Preparation of :

To a solution of 60% sodium hydride (39 mg, 0.98 mmol) in anhydrous dimethylformamide (2.5 mL) was added 3-cyanophenol (108 mg, 0.91 mmol). After stirring for 15 min, solution was clear. The mesylate from Part B (0.30 g, 0.65 mmol) in

anhydrous dimethylformamide (1 mL) was added. After completion of the addition, the mixture as stirred at ambient temperature overnight. The next morning, the mixture was poured onto a 10 mL Chem-Elut tube, prewetted with 5 mL of water, and eluted with ethyl acetate and CH2Cl2. Chromatography (silica gel with ethyl acetate/hexane) produced the desired ester (0.27 g, 85%). NMR (CDC13) 81. 46 (s, 9H), 2.17-2.21 (m, 4H), 3.22-3.36 (m, 2H), 3.98 (dt, 2H), 4.35-4.43 (m, 4H), 7.04 (d, 2H), 7.15-7.20 (m, 2H), 7.28 (dt, 1H), 7.39 (t, 1H), 7.74 (d, 2H). ESMS m/z = 505 (M+NH4) +. HRMS calcd. for C25H33N207S : 505.2008 (; X+NH4) +. Found: 505.2019.

[1046] Part D. Preparation of : The ester of Part C (0.24 g, 0.49 mmol) was hydrolyzed in 5 mL of methylene chloride and 5 mL of trifluoroacetic acid. Concentration and drying under high vacuum produced the desired acid (0.21 g, 100%). NMR (CD3OD w/ K2CO2) # 2. 01-2.11 (m, 2H), 2.20 (d, 2H), 3.32-3.42 (m, 2H), 3.95 (dt, 2H), 4.38-4.45 (m, 4H), 7.13 (d, 2H), 7.26-7.34 (m, 3H), 7.45 (t, 1H), 7.76 (d, 2H). ESMS m/z = 449 (M+NH4) +. HRMS calcd. for C21H21NO7S NH4: 449.1382 (M+NH4) +. Found: 449.1407.

[1047] Part E. Preparation of : To a slurry of the acid of Part D (0.20 g, 0.46 mmol), HOBt (76 mg, 0.55 mmol), and EDC (130 mg, 0.68 mmol) was added triethylamine (1.4 mmol) and THP-hydroxylamine (167 mg, 1.4 mmol) in a flask under N2 in 2 mL anhydrous DMF. The resulting mixture was stirred at 40°C overnight. The next morning, the mixture was poured onto 10 mL Chem-Elut tube prewetted with 6 mL of water and eluted with ethyl acetate and CH2Cl2. Chromatography (silica gel, ethyl acetate/hexane) produced the product as a colorless oil (0.18 g, 74%).

11048] Part F. Preparation of :

To the product from Part E (0.18 g, 0.34 mmol) in methanol (1-2 mL) was added 4M HC1 in 1,4-dioxane (2.5 mL). The resulting mixture was stirred overnight. Reverse phase chromatography (water/acetonitrile/0.05% TFA) produced the desired compound as a colorless crystalline solid (25.0 mg 16 %). NMR (DMSO) 1.82-1.98 (m, 2H). 2.15-2.30 (m, 2H), 3.15, (t, 2H), 3.86 (d, 2H), 4.44 (d, 4H), 7.10-7.25 (m, 3H), 7.38 (t, 1H), 7.44- 7.52 (m, 2H), 7.68 (d, 2H). ESMS m/z = 465 (M+H) +. HRMS calcd. for C2IH2sN20sS : 465.1332 (M+H) +. Found: 465.1354.

[1049] Examples 55-89. I7z Vitro MMP Inhibition Analysis 11050] Several hydroxamates and salts thereof were analyzed in ill vitro assays to determine their ability to inhibit the MMP cleavage of peptide substrates. Inhibition (Ki) and ICso constants were calculated from the assayed hydroxamate-MMP interactions.

[1051] Human recombinant MMP-1, MMP-2, MMP-9, MMP-13, and MMP-14 were used in this assay. All enzymes were prepared in Assignee's laboratories following usual laboratory procedures. Protocols for the preparation and use of these enzymes are available in the scientific literature. See, e. g., Enzyme Nomenclature (Academic Press, San Diego, CA, 1992) (and the citations therein). See also, Frije et al., JBiol. Chem., 26 (24), 16766-73 (1994).

[1052] The MMP-1 proenzyme was purified from the spent media of MMP-1- transfected HT-1080 cells provided by Dr. Harold Welgus of Washington University (St.

Louis, MO). The protein was purified on a zinc chelating column.

[1053] The MMP-2 proenzyme was purified by gelatin Sepharose chromatography from MMP-2-transfected p2AHT2 cells provided by Dr. Gregory Goldberg of Washington University (St. Louis, MO).

ll054] The MMP-9 proenzyme was purified by gelatin Sepharose chromatography from spent media of MMP-9-transfected HT1080 cells provided by Dr. Howard Welgus of Washington University (St. Louis, MO).

[1055] The MMP-13 was obtained as a proenzyme from a full-length cDNA clone using baculovirus, as described by V. A. Luckow,"Insect Cell Expression Technology," Protein Engineering : Principles and Practice, pp. 183-218 (edited by J. L. Cleland et al., Wiley-Liss, Inc., 1996). The expressed proenzyme was first purified over a heparin agarose column, and then over a chelating zinc chloride column. The proenzyme was then activated by APMA for use in the assay. Further details on baculovirus expression systems may be found in, for example, Luckow et al., R Virol., 67,4566-79 (1993). See also, O'Reilly et al, Baculovirus Expression Vectors : A Laboratory Manual (W. H.

Freeman and Co., New York, NY, 1992). See also, King et al., The Baculovirus Expression System : A Laboratory Guide (Chapman & Hall, London, England, 1992).

[10561 The MMP-14 full length cDNA was provided by Dr. Gregory Goldberg of Washington University (St. Louis, MO). The catalytic domain enzyme was expressed in E. coli inclusion bodies, solubilized in urea, purified on a preparative C-14 reverse phase HPLC column, and then refolded in the presence of zinc acetate and purified for use.

[10571 All MMPs were activated using 4-aminophenyhnercuric acetate ("APMA", Sigma Chemical, St. Louis, MO) or trypsin. MMP-9 also was activated using human recombinant MMP-3 (purified in Assignee's laboratory following standard cloning and purification techniques).

[1058] Two fluorogenic, methoxycoumarin-containing polypeptide substrates were used in the MMP inhibition assays: MCA-ProLeuGlyLeuDpaAlaArgNH2 <BR> <BR> <BR> <BR> (I)<BR> <BR> <BR> <BR> <BR> <BR> MCA-ArgProLeuGlyLeuDpaAlaArgGluArgNH2<BR> <BR> <BR> <BR> <BR> <BR> <BR> (II) Here,"Dpa"is 3- (2, 4-dinitrophenyl)-L-2,3-diaminopropionyl group, and"MCA"is 7- methoxycoumarin-4-yl acetyl. Substrate (I) was purchased from Baychem (Redwood City, CA), and substrate II was prepared Assignee's laboratory. Substrate I was used in the ICso determination assays, while substrate II was used in the K ; determination assays.

In the absence of MMP inhibitory activity, either substrate is cleaved at the Gly-Leu

peptide bond. This cleavage separates the highly fluorogenic peptide from the 2,4- dinitrophenyl quencher, thus resulting in increase of fluorescent intensity.

[10591 The stock solutions of the assayed hydroxamates (or salts thereof) were prepared in 1% dimethyl sulfoxide (DMSO). These stock solutions were diluted in Buffer A (100 mM Tris-HCl, 100 mM NaCl, 10 mM CaCl2, 0.05% polyoxyethylene 23 lauryl ether, pH 7.5) to obtain solutions with different hydroxamate concentrations, i. e., assay solutions with different concentrations of the assayed MMP inhibitory compound. The experiment controls contained the same amount of Buffer A/DMSO as the assayed sample, but contained no hydroxamate (or salt thereof).

[1060] The assays from which the ICso determinations were made were performed as follows. The MMPs were activated with either trypsin or APMA (4- aminophenylmercuric acetate, Sigma Chemical, St. Louis, MO). The assayed hydroxamate samples were incubated in Microfluor White Plates (Dynatech, Chantilly, VA) and analyzed on a Perkin Elmer L550 plate reader (Norwalk, CT). The excitation wavelength was 328 mn, and the emission wavelength-415 nm. All samples (assayed hydroxamates and controls) were incubated in separate plates at room temperature in the presence of 4 uM of MMP substrate (I). As stated in the previous paragraph, samples containing varying concentrations of the same assayed hydroxamate were prepared.

Inhibition was measured as a reduction in fluorescent intensity as a function of MMP inhibitor concentration.

[1061] The assays from which the Ki determinations were made were performed as follows. The assayed hydroxamate samples were incubated in separate wells of untreated white polystyrene plates (Nunc Nalgene International, Rochester, NY), and analyzed on a Tecan SpectraFlour Plus plate reader. The excitation wavelength was 330 nm, and the emission wavelength-420 nm. All samples (assayed hydroxamates and controls) were incubated in separate plate wells at room temperature for 1 hr in the presence of 4/. tM of MMP substrate (II). In the absence of MMP inhibitory activity, substrate II was cleaved at the Gly-Leu bond resulting in an increase of relative fluorescence. Inhibition was observed as a reduced rate of this increase in relative fluorescence. The various hydroxamates were analyzed using a single low enzyme concentration with a single substrate concentration fixed at or below the Km. This protocol is a modification of method by Knight et al., FEBSLett., 296 (3), 263-266 (1992). Apparent inhibitory

constants were determined by non-linear regression of reaction velocity as a function of inhibitor and enzyme concentration using Morrison's equation, as described by Kuzmic, Anal. Biochem. 286,45-50 (2000). Modifications were made in the non-linear regression method to allow a common control reaction rate and effective enzyme concentration to be shared between all dose-response relationships on a given assay plate. Since the substrate concentration was chosen to be at or below the Km, the apparent Ki's from this analysis were reported as Ki's without correction for the influence of substrate.

[1062] The above protocols were used to determine IC50 constants and K ; values values for several of the compounds in Examples 1-52 above. The results are shown in Table 5. All values in Table 5 are given in nM units. The K ; measurements are in parenthesis.

Table 5 Ex. # Compound MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 ICso (Ki) IC50 (Ki) ICso (Ki) IC50 (Ki) ICso (Ki) 55 Example 17 550 1. 6 56 Example 18 >10000 537 6000 1.8 >10000 57 Example 19 >10000 9000 5190 15 >10000 58 Example 20 >10000 1.8 498 1.8 >10000 59 Example 21 >10000 450 >10000 3.5 >10000 60 Example 22 >10000 1000 >10000 4.9 >10000 61 Example 25 >10000 247.2 8498 1. 8 >10000 62 Example 26 >10000 52.0 4429 3.4 >10000 63 Example 27 >10000 83.9 9366 0.2 >10000 64 Example 28 >10000 76.4 3710 7.0 >10000 65 Example 30 >10000 22.6 809 1.3 >10000 66 Example 31 >10000 346. 3 5651 2.1 >10000 (>10000) (412.93) (1596.8) (1.503) (>10000) 67 Example 32 >10000 217.7 4076 0.8 >10000 68 Example 33 >10000 16 7.9, 1 4936 69 Example 34 429 36.6 >10000 3.0 >10000 70 Example 35 >10000 600 >10000 3 >10000 71 Example 36 95 2. 4 72 Example 37 8708 30.3 449 1.4 >10000 73 Example 38 >10000 157.5 1026.3 0. 9 >10000 (>10000) (369.98) (6.55) (4451.2) 74 Example 39 (>10000) 1299 (2360) 0. 9 (>10000) (1640) (3.04) 75 Example 40 >10000 112.4 413 0.5 >10000 (>10000) (215.98) (585. 44) 0.58) (>10000) Ex. Compound MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 ICso (Ki) ICso (Ki) ICso (Ki) Iso (Ki) ICso (Ki) 76 Example 41 >10000 357.5 1597 2.0 >10000 (>10000) (414. 99) (1465.7) (1.056) (>10000) 77 Example 42 >10000 100.3 382.5 0.3 >10000 (>10000) (186.28) (661.7) (0. 486) (>10000) 78 Example 43 >10000 4.8 1.0 1.0 2084 79 Example 44 >10000 133.2 154.5 1.4 4976 80 Example 45 (>10000) (224.78) (499.18) (0.62) (>10000) 81 Example 46 >10000 320.9 1966 3.1 >10000 (>10000) (786.36) (417.51) (2.29) (>10000) 82 Example 47 (>10000) 18. 2 (118.75) 0.2 (3317.66) (19.15) (308.77) (0.304) (5293) (46.49) (0.423) 83 Example 48 >10000 104.6 4450.3 0.2 >10000 (>10000) (227.54) (159.2) (0. 127) (>10000) 84 Example 49 >10000 273.9 4056 0.3 >10000 (>10000) (439.76) (1947.90) (0.439) (>10000) 85 Example 50 (>10000) (1127.89) (304.41) (0.60) (>10000) 86 Example 51 >10000 251.. 6 7983 0.2 >10000 (5160.20) (93.68) (98. 72) (1. 697) (687. 93) 87 Example 52 (>10000) (542.89) (617. 14) (0.81) (>10000) 88 Example 53 >10000 383.5 75.5 1.0 >10000 (>10000) (697) (2900) (0.662) (>10000) 89 Example 54 (>10000) 35.5 (388) 10.5 (4120) (64. 8)

[1063] Example 90. In Vivo Angiogenesis Assay [1064] The study of angiogenesis depends on a reliable and reproducible model for the stimulation and inhibition of a neovascular response. The corneal micropocket assay provides such a model of angiogenesis in the cornea of a mouse. See, A Model of Angiogenesis in the Mouse Corraea ; Kenyon, BM, et al., Investigative Ophthalmology & Visual Science, July 1996, Vol. 37, No. 8. ll065] In this assay, uniformLy sized Hydros pellets containing bFGF and sucralfate are prepared and surgically implanted into the stroma mouse cornea adjacent to the temporal limbus. The pellets are formed by making a suspension of 20 je, L sterile saline containing 10 ytg recombinant bFGF, 10 mg of sucralfate and 10 pL of 12 percent Hydron in ethanol. The slurry is then deposited on a 10 x 10 min piece of sterile nylon mesh. After drying, the nylon fibers of the mesh are separated to release the pellets.

[1066] The corneal pocket is made by anesthetizing a 7 week old C57B1/6 female mouse, then proptosing the eye with a j eweler's forceps. Using a dissecting microscope, a central, intrastromal linear keratotomy of approximately 0.6 mm in length is performed with a &num 15 surgical blade, parallel to the insertion of the lateral rectus muscle. Using a modified cataract knife, a lamellar micropocket is dissected toward the temporal limbus.

The pocket is extended to within 1.0 mm of the temporal limbus. A single pellet is placed on the corneal surface at the base of the pocket with a jeweler's forceps. The pellet is then advanced to the temporal end of the pocket. Antibiotic ointment is then applied to the eye.

[1067] Mice are dosed on a daily basis for the duration of the assay. Dosing of the animals is based on bioavailability and overall potency of the compound. An exemplary dose is 10 or 50 mg/kg (mpk) bid, po. Neovascularization of the corneal stroma is permitted to continue under the influence of the assayed compound for 2 days. At that point, the degree of angiogenic inhibition is scored by viewing the neovascular progression with a slit lamp microscope.

[1068] The mice are anesthetized and the studied eye is once again proptosed. The maximum vessel length of neovascularization, extending from the limbal vascular plexus toward the pellet is measured. In addition, the contiguous circumferential zone of neovascularization is measured as clock hours, where 30 degrees of arc equals one clock hour. The area of angiogenesis is calculated as follows. area = (0. 4xclock hours x 3.14 x vessel length (in mm)) 2 [1069] Five to six mice should be utilized for each compound in each study. The studied mice are thereafter compared to control mice and the difference in the area of neovascularization is recorded as an averaged value. Each group of mice so studied constitutes an"n"value of one, so that"n"values greater than one represent multiple studies whose averaged result is provided in the table. A contemplated compound typically exhibits about 25 to about 75 percent inhibition, whereas the vehicle control exhibits zero percent inhibition.

[1070] Example 91. Tumor Necrosis Factor Assays [1071] Cell Culture.

[1072] The cells used in the assay are the human moncytic line U-937 (ATCC CRL-1593). The cells are grown in RPMI w/10% FCS and PSG supplement (R-10) and are not permitted to overgrow. The assay is carried out as follows: [1073] 1. Count, then harvest cells by centrifugation. Resuspend the pellet in R- 10 supplement to a concentration of 1.540 x 106 cells/mL.

[1074] 2. Add test compound in 65 uL R-10 to the appropriate wells of a 96-well flat bottom tissue culture plate. The initial dilution from a DMSO stock (100 mM compound) provides a 400 uM solution, from which five additional three-fold serial dilutions are made. Each dilution of 65 ul (in triplicate) yields final compound test concentrations of 100 piM, 33.3 juM, 11.1 HM, 3.7 MM, 1.2 µM and 0.4 M.

[1075] 3. The counted, washed and resuspended cells (200,000 cells/well) in 130 µL are added to the wells.

[1076] 4. Incubation is for 45 min to 1 hr at 37°C in 5% C02 in a water saturated container.

[1077] 5. R-10 (65 uL) containing 160 ng/mL PMA (Sigma) is added to each well.

[1078] 6. The test system is incubated at 37°C in 5% C02 overnight (18-20 hr) under 100% humidity.

[1079} 7. Supernatant, 150 jj. L, is carefully removed from each well for use in the ELISA assay.

[1080] 8. For toxicity, a 50 gL aliquot of working solution containg 5 mL R-10,5 mL MTS solution [CellTiter 96 AQueous One Solution Cell Proliferation Assay Cat. #G358/0, 1 (Promega Biotech)] and 250 ul PMS solution are added to each well containing the remaining supernatant and cells and the cells incubated at 37°C in 5% CO2 until the color develops. The system is excited at 570 nm and read at 630 nm.

[1081] TNF Receptor II ELISA Assay [1082] 1. Plate 100 µL/well 2 ug/mL mouse anti-human TNFrII antibody (R&D Systems #MAB226) in 1 x PBS (pH 7.1, Gibco) on NtJNC-Irmnuno Macisorb plate.

Incubate the plate at 4°C overnight (about 18-20 hr).

[1083] 2. Wash the plate with PBS-Tween (1 x PBS w/0.05% Tween).

[1084] 3. Add 200 pL 5% BSA in PBS and block at 37°C in a water saturated atmosphere for 2 hr.

[1085] 4. Wash the plate with PBS-Tween.

[1086] 5. Add sample and controls (100 ul of each) to each well. The standards are 0,50,100,200,300 and 500 pg recombinant human TNFrII (R&D Systems &num 226-B2) in 100 zip 0.5% BSA in PBS. The assay is linear to between 400-500 pg of standard.

[1087] 6. Incubate at 37°C in a saturated atmosphere for 1.5 hr.

[10881 7. Wash the plate with PBS-Tween.

[1089] 8. Add 100 L goat anti-human TNFrII polyclonal (1. 5 µg/mL R&D Systems #AB226-PB in 0.5% BSA in PBS).

[1090] 9. Incubate at 37°C in a saturated atmosphere for 1 hr.

[1091] 10. Wash the plate with PBS-Tween.

[1092] 11. Add 100 LL anti-goat IgG-peroxidase (1: 50, 000 in 0.5% BSA in PBS, Sigma #A5420).

[1093] 12. Incubate at 37°C in a saturated atmosphere for 1 hr.

[1094] 13. Wash the plate with PBS-Tween.

[1095] 14. Add 10 I1L KPL TMB developer, develop at room temperature (usually about 10 min), then terminate with phosphoric acid and excite at 450 nm and read at 570 nm.

[1096] TNFa ELISA Assay.

[1097] Coat Immulon# 2 plates with 0.1 mL/well of lug/mL Genzyme mAb in 0.1 M NaHC03 pH 8.0 buffer overnight (about 18-20 hr) at 4°C, wrapped tightly in Saran wrap.

[1098] Flick out coating solution and block plates with 0.3 mL/well blocking buffer overnight at 4°C, wrapped in Saran wrap.

[1099] Wash wells thoroughly 4X with wash buffer and completely remove all wash buffer. Add 0.1 mL/well of either samples or rhTNFα standards. Dilute samples if necessary in appropriate diluant (e. g. tissue culture medium). Dilute standard in same diluant. Standards and samples should be in triplicates.

[1100] Incubate at 37°C for 1 hr in humified container.

[1101] Wash plates as above. Add 0. 1 mL/well of 1: 200 dilution of Genzyme rabbit anti-hTNFa.

[1102] Repeat incubation.

[1103] Repeat wash. Add 0.1 mL/well of 1 µg/mL Jackson goat anti-rabbit IgG (H+L)-peroxidase.

[1104] Incubate at 37°C for 30 min.

[1105] Repeat wash. Add 0.1 mL/well of peroxide-ABTS solution.

[1106] Incubate at room temperature for 5-20 min.

[1107] Read OD at 405 nm.

[1108] 12 Reagents are: Genzyme mouse anti-human TNF monoclonal (Cat. # 80-3399-01) Genzyme rabbit anti-human TNF polyclonal (Cat. #IP-300) Genzyme recombinant human TNF (Cat. &num TNF-H).

Jackson Immunoresearch peroxide-conjugated goat anti-rabbit IgG (H+L) (Cat.#111-035-144).

Kirkegaard/Perry peroxide ABTS solution (Cat#50-66-01).

Immulon 2 96-well microtiter plates.

Blocking solution is 1 mg/mL gelatin in PBS with 1X thimerasol.

Wash buffer is 0.5 mL Tween 20 in 1 liter ofPBS.

[1109] Example 92. In Vitro Aggrecanase Inhibition Analysis [1110] Assays for measuring the potency (ICso) of a compound toward inhibiting aggrecanase are known in the art.

[1111] One such assay, for example, is reported in European Patent Application Publ. No. EP 1 081 137 Al. In that assay, primary porcine chondrocytes from articular joint cartilage are isolated by sequential trypsin and collagenase digestion followed by collagenase digestion overnight and are plated at 2x105 cells per well into 48 well plates with 5 tCi/M135S (1000 Ci/mmol) sulphur in type 1 collagen coated plates. Cells are allowed to incorporate label into their proteoglycan matrix (approximately 1 week) at 37°C under an atmosphere of 5% C02. The night before initiating the assay, chondrocyte monolayers are washed 2 times in DMEM/1% PSF/G and then allowed to incubate in fresh DMEM/1% FBS overnight. The next morning, chondrocytes are washed once in DMEM/1% PSF/G. The final wash is allowed to sit on the plates in the incubator while making dilutions. Media and dilutions are made as described in the following Table 6: Table 6

control media DMEM alone IL-1 media DMEM + IL-1 (5ng/ml) drug dilutions Make all compound stocks at 10 mM in DMSO. Make a 100, AM stock of each compound in DMEM in 96-well plate. Store in freezer overnight. The next day, perform serial dilutions in DMEM with IL-1 to 5 , uM, 500 nM, and 50 nM. Aspirate final wash from wells and add 50 uM of compound from above dilutions to 450 zL of IL-1 media in appropriate wells of the 48 well plates. Final compound concentrations equal 500 nM, 50 nM, and 5 nM. All samples completed in triplicate with control and IL-1 alone on each plate.

Plates are labeled and only the interior 24 wells of the plate are used. On one of the plates, several columns are designated as IL-1 (no drug) and control (no IL-1, no drug). These control columns are periodically counted to monitor 35S-proteoglycan release. Control and IL-1 media are added to wells (450, ltL) followed by compound (50, ut) so as to initiate the assay. Plates are incubated at 37°C with 5% C02 atmosphere. At 40-50% release (when CPM from IL-1 media is 4-5 times control media) as assessed by liquid scintillation counting (LSC) of media samples, the assay is terminated (about 9 to about 12 hours). Media is removed from all wells and placed into scintillation tubes. Scintillate is added and radioactive counts are acquired (LSC). To solubilize cell layers, 500 juL of papain digestion buffer (0.2 M Tris, pH 7.0,5 mM DTT, and 1 mg/ml papain) is added to each well. Plates with digestion solution are incubated at 60°C overnight. The cell layer is removed from the plates the next day and placed in scintillation tubes. Scintillate is then added, and samples counted (LSC). The percent of released counts from the total present in each well is determined. Averages of the triplicates are made with control background

subtracted from each well. The percent of compound inhibition is based on IL-1 samples as 0% inhibition (100% of total counts).

[1112] Another assay for measuring aggrecanase inhibition is reported in WIPO Int'l Publ. No. WO 00/59874. That assay reportedly uses active aggrecanase accumulated in media from stimulated bovine cartilage (BNC) or related cartilage sources and purified cartilage aggrecan monomer or a fragment thereof as a substrate. Aggrecanase is generated by stimulation of cartilage slices with interleukin-1 (IL-1), tumor necrosis factor alpha (TNF-a), or other stimuli. To accumulate BNC aggrecanase in culture media, cartilage reportedly is first depleted of endogenous aggrecan by stimulation with 500 ng/ml human recombinant IL-ß for 6 days with media changes every 2 days. Cartilage is then stimulated for an additional 8 days without media change to allow accumulation of soluble, active aggrecanase in the culture media. To decrease the amounts of matrix metalloproteinases released into the media during aggrecanase accumulation, agents which inhibit MMP-1,-2,-3, and-9 biosynthesis are included during stimulation. This BNC conditioned media containing aggrecanase activity is then used as the source of aggrecanase for the assay. Aggrecanase enzymatic activity is detected by monitoring production of aggrecan fragments produced exclusively by cleavage at the Glu373-Ala374 bond within the aggrecan core protein by Western analysis using the monoclonal antibody, BC-3 (Hughes, et al., Biochem J, 306: 799-804 (1995)). This antibody reportedly recognizes aggrecan fragments with the N-terminus, 374ARGSVIL, generated upon cleavage by aggrecanase. The BC-3 antibody reportedly recognizes this neoepitope only when it is at the N-terminus and not when it is present internally within aggrecan fragments or within the aggrecan protein core. Only products produced upon cleavage by aggrecanase reportedly are detected. Kinetic studies using this assay reportedly yield a Km of 1.5+/-0.35, uM for aggrecanase. To evaluate inhibition of aggrecanase, compounds are prepared as 10 mM stocks in DMSO, water, or other solvents and diluted to appropriate concentrations in water. Drug (50 AL) is added to 50 yL of aggrecanase-containing media and 50 jus of 2 mg/ml aggrecan substrate and brought to a final volume of 200 its in 0.2 M Tris, pH 7.6, containing 0.4 M NaCI and 40 mM CaCl2. The assay is run for 4 hr at 37°C, quenched with 20 mM EDTA, and analyzed for aggrecanase-generated products. A sample containing enzyme and substrate without drug is included as a positive control and enzyme incubated in the absence of substrate serves as a measure of background.

Removal of the glycosaminoglycan side chains from aggrecan reportedly is necessary for the BC-3 antibody to recognize the ARGSVIL epitope on the core protein. Therefore, for analysis of aggrecan fragments generated by cleavage at the Glu373-Ala374 site, proteoglycans and proteoglycan fragments are enzymatically deglycosylated with chondroitinase ABC (0.1 units/10, ug GAG) for 2 hr at 37°C and then with keratanase (0.1 units/I 0 Itg GAG) and keratanase II (0.002 units/10 0 itg GAG) for 2 hr at 37°C in buffer containing 50 mM sodium acetate, 0.1 M Tris/HCI, pH 6.5. After digestion, aggrecan in the samples is precipitated with 5 volumes of acetone and resuspended in 30, uL of Tris glycine SDS sample buffer (Novex) containing 2.5% beta mercaptoethanol. Samples are loaded and then separated by SDS-PAGE under reducing conditions with 4-12% gradient gels, transferred to nitrocellulose and immunolocated with 1: 500 dilution of antibody BC3.

Subsequently, membranes are incubated with a 1: 5000 dilution of goat anti-mouse IgG alkaline phosphatase second antibody and aggrecan catabolites visualized by incubation with appropriate substrate for 10-30 minutes to achieve optimal color development. Blots are quantitated by scanning densitometry and inhibition of aggrecanase determined by comparing the amount of product produced in the presence versus absence of compound.

[11131 Examples 93-645.

[1114] Additional hydroxamate compounds (and salts thereof) can be prepared by one skilled in the art using methods similar to those described in Examples 1-54 alone or in combination with techniques well known in the art. Such compounds include, for example, the compounds summarized in the following Table 7. Table 7 also summarizes in vitro MMP inhibition results obtained by Applicants with the listed hydroxamates. As with Table 5, all in vitro Ki and ICso results in Table 7 are given in nM units. The Ki measurements are in parenthesis.

Table 7 ; x structure tzalc. Ubserved MMP-1 lVIM ?-Z MlVll : w-Y l\iL\I ?-IJ lVr-14 Mass Mass Mass ICso ICSO ICso ICSa Ki ICSO Ki 93 0 oo (>10000) 746. 6 (1120) 15.5 (>10000) HO s (676) (9.29) zon O, HCI 94 o oo 17.8 3.7 Ho 0 o I H3 CH3 95 0 0", 0 >10000 91.4 1204.6 2.7 >10000 HOHNXY o (>10000) (149) (788) (5410) /$3C 1 96 0 qp 39.1 15.3 O,. Horn H3C CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso Ki ICSO ICSO Ki ICSO Ki ICSO Ki 97 o °S"o 486.1586 486.1602 (7360) 185.0 (473) 3.3 (>10000) HO s (295)(5.57) ° td o i o 98 0 oo 510. 1950 510.1947 >10000 316.2 2418 1. 8 >10000 Ao S I w (>10000) (625) (1450) (9.15) (>10000) zozo o I i Iw 99 0 0 0 482. 1637 482.1661 >10000 245.8 3435 0. 4 >10000 o" HOHN S W w w o I 100 0 oo 1691. 4 152. 6 H3 H3 hoir ) chug HCI 0 OCHg 101 o oo 503.1480 503.1465 18.2 0. 2 o" HOHN S I O o °N v i v N-'-O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso Ki ICso Ki ICso Ki ICso 102 0 oo 483.1260 483.1264 12.4 1.2 < ONm oJ o-rr H 103 0 o\/o 613 613 >10000 85.8 1134 0.4 >10000 HO I F3. N U oy HCI OCH 3 1040 oo 44. 2 0. 8 \\E4 I,"z, 02CH HOHN 3 iN \/ tN)NON OCHs 105 o o o >10000 1368.8 7694 9.7 >10000 HOHN s 0 H3 CH3 ON zon ""Y l06 0 0 0 >10000 1046.6 >10000 3. 5 >10000 HOHNvH3 H3 O O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 107 0 oxo 34.0 5.5 gors I N O 108 0 oo 433.7 20.0 o" HOHN S \ O N Nez Oc3 OCH3/ OCH3 J 109 0 qo 524. 2107 524.2136 (>10000) 5410.3 (>10000) 152.1 (>10000) HO (8100) (93.1) zozo o I /Hs H3 110 0 0 0 518. 1449 SI8. 1505 (>10000) 1198.5 (4340) 7. 6 (>10000) w I w (1120) (11. 4) / F O I./ 111 0 0 0 500. 1543 500. 1561 (>10000) 559.4 (2680) 2. 0 (>10000) HO \"S-ao (769) (6. 39) oJ i o i I w o td Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass ICSO Ki ICso Ki ICso ICso ICso 112 o 0 566.1460 566.1500 (>10000) 66.4 (8850) 37.9 (>10000) HO s (3970) (51.2) o oM) CF3 TT3'o qp483. 1590 483. 1597 >1000020319805027725 notSX (>10000) (42.30) (161.22) (0. 312) (3481.8) i HCI HCI Ha 114 0 o o 516.1248 516.1259 (>10000) 1010.6 (4870) 5.2 (>10000) HOHN s (1500) (4. 2) Ho o o I 115 0 0 0 500. 1543 500.1550 >10000 311.9 >10000 0. 9 >10000 \/i w (>10000) (807) (1980) (2.24) (>10000) HN o I o I 116 0 0 0 496. 1794 496.1811 (>10000) 1053.2 (5550) 11. 2 (>10000) HOHN CH3 (1250) (5. 1) o td o J 117 0 oo 510. 1950 510.1965 (>10000) 1744.7 (9910) 16. 0 (>10000) HN"n3 (3640) (21) f 3 H H3 3 3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 118 o oo 530.1404 530.1418 (>10000) 1862.0 (>10000) 29.8 (>10000) ROFIN s (2650) (18. 8) 91 0 i i CHs 119 0 qp 526.1899 526.1920 (>10000) 1187.6 (3950) 18.3 (>10000) As' s (1680)(31.4) 4\OCH3 HO cl3 H3 20o p514. 1700 514. 1724 >10000 1171.6 >10000 5. 8 >10000 HO] EIN w _ CH3 r H3 121 0 os 550. 0858 550.0846 (>10000) 2469.3 (>10000) 21. 6 (>10000) HOHN C, (4620) (26.9) ° yoC I I 1 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass IC50 (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 122 o oo 518.1449 518.1470 >10000 759.7 7668 1.9 >10000 j'c w I w HORN " j) M i HO han 123 0 F 123 o QS 500.1543 500.1545 >10000 383.0 >10000 1. 4 >10000 HO s (>10000) (793) (2130) (7. 35) (>10000) han F F 124 0 oo 550. 0858 550.0896 (>10000) 2151.5 (>10000) 21. 9 (>10000) Ho s (5730) (20. 1) HO (5730) (20.1) 0 1250 0 0 2937 27. 3 962. 9 0. 2 5825 HO HCI (3584. 24) (51. 34) (146. 43) (0. 17) (1666. 65) HO I 0 126 0 o o 550. 0858 550. 0881 (>10000) 3260.4 (>10000) 349. 0 (>10000) \/Y w (6360) (81. 3) 0) j J o I i i Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICSO Ki ICso Ki ICSO ICso ICSO Ki 127 0 oo 496.1794 496.1800 >10000 1380.0 >10000 5.5 >10000 ss' HO s (>I 0000) (2160) (4230) (16.2) (>10000) Hor o o A H3 128 o oo 615.2902 615.2852 (>10000) 658.7 (3550) 23.7 (>10000) HOHN"R3 (1130)(13.8) LJ1013 aCfl3 HCl CH 3 129 ° O""O H2N O (>10000) 41.4 (110) 1.9 (>10000) HOHN (50)(0.27) N NO N 0 O-N FOC OH 130 4611 4. 7 50. 2 0. 3 499. 8 HORN HOHN 0 HCI NON OCHg CHg 131 0 oo 107.9 4.5 HOHN /dz Il l CF3CO2H O-N Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICp (Ki) ICso (Ki) ICso (Ki) 132 0 oo 61.7 3.7 HORN OU Or"\ N OCF CF3 133 8 °t, 84. 4 4. 3 i) U ; Hui HCl/ zu \) CF3 i CFg 134 0 o,"O O >10000 2382 >10000 7.7 >10000 HOHN-Y 0 H3 for H3 °tX 135 0 o/o 637. 1332 637.1315 (>10000) 24. 3 (457) 2. 9 (9510) (58. 5) (0. 761) NJ o^-' Cl3 OCHg Ex Structure Cale. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso Ki ICSO Ki ICSa ICSO ICso 136 0 oxo 229.4 4. 4 HOHN 0 tN HOHN Y-A3 O O J \ r CF3 137 0 °t//° (>10000) 20. 4 (604) 7. 0 (>10000) \\ li Ho S \ (36. 6) (0. 976) N HCI A 138 0 oo >10000 247.3 1896 2.1 >10000 As' HORN o CH,3 nci / 139 qu553. 2172 553.2176 >10000 207.7 4514 0. 4 >10000 \\ li HO s (>10000) (1410) (1390) (2.89) (>10000) Anal Y X I Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 140 0 oo >10000 48.0 1692 0.5 >10000 t no (>10000) (708) (754) (0.895) (>10000) J NU OCH3 OCH3 i 141 0 oo 577 577 32. 5 3. 6 HO H3C N IaF N \F HCl N N I OCH3 142 0 oxo 0 (>10000) 58.6 (310) 7.5 (>10000) ROHN NH (96. 4) (1. 34) N HCI O-N HCI O-N ..... 143 ß O O 4.9 1.4 s Ns HOHN NJ I HCI N=N NU Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 144 0 oo >10000 238.6 5989 2.5 >10000 o O Nt HO 0 TY O OCF3 9 « <OCF3 _ _ 145 0 ou >10000 816.9 9438 2.0 >10000 HOHN 0 Hor ° o I 0 0<Y 146 o O O 11. 1 0. 4 o" SU OCHg 0 N N N-N 1 o 0 0 580. 1617 580. 1620 (>10000) 4746. 8 (7970) 28. 3 (>10000) HO (>10000) (23.9) oJ o i I CF3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 148 0 00 (8790) 272.0 (427) 3.1 (5150) HO s (213) (1. 72) oJ o Aci HCI 149 0 oxo (>10000) 77. 1 (94.5) 1. 3 (2530) HOHN (84. 1) (1.18) laci ACE N" N 150 o Ro >10000 135.5 529.9 0.6 6630 horn (>10000) (159) (125) (0.587) (5510) o HCI WN 151 0 00 559 559 38. 4 2. 6 Horn Ion ) ! J M HOHN hui HCI % OCHg CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso ICso ICso ICso (Ki) ICso (Ki) ICso (Ki) 152 0 0 0 629.1893 629.1885 >10000 58.8 72.3 11.8 >10000 HOEIN s (>10000) (149) (44.5) (2.66) (>10000) I 0 N X HCI CF3 N 0 153 a o 0 192.5 7.6 su Hoir ! hui HCI HCI N 15a. o 0 0 498. 0586 498. 0591 >10000 10. 9 111 0. 8 9123 ROHN (>10000) (33. 9) (151) (0.95) (3910) 0 r r 155 0 oo 573. 2383 573.2413 >10000 13. 8 1173. 7 9.7 >10000 (>10000) (37.9) (172) (1. 58) (9370) HUIHCI O-N CH3 NI CH3 CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass Mass ICso ICso ICSO Ki ICso Ki ICso 156 0 os 32.1 1.0 HOHNY OH, N HCI N--N OCHg 3 157 0 qp >10000 182.1 2473 3.5 >10000 Ho (>10000) (419) (1390) (4.01) (>10000) tOJ +0~f A C 58 ° OV/O 530. 1404 530.1446 >10000 2184 5630 3. 6 >10000 HOHNt<) Yq (>10000) (2730) (3950) (5.1) (>10000) aï i 0 159 0 0 0 532. 1605 532.1632 1368. 6 24. 4 HORN w o 0 F F F F Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 160 0 oo 538.2263 538.2275 >10000 >10000 (>10000) 505.1 (>10000) no (>10000) (>10000) 0 IN HgC CH3 161 0 0 0 514.1700 514.1708 >10000 1001. 1 2625 2.6 >10000 HOHN (>10000) (1760) (1730) (20.3) oJ o I w I F 162 HO oo 530.1404 530.1428 (>10000) 1596.6 (3150) 15.6 (>10000) \/i (2370) (12) i w 0 cri cl i Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 163 0 514.1700 514.1680 >10000 1370.7 2880 2.5 >10000 HOHN (>10000) (1010) (2500) (11.6) (>10000) J F 164 o Qso 510. 1950 510.1940 (>10000) 1073.2 (2720) 20.0 (>10000) HO s (978) (6. 85) HN C113 i \ CH3 165 qu524. 2107 524.2112 (>10000) 3396.2 (9750) 146.9 (>10000) HOHN (>10000) (144) oJ i o I w 0 CHg H3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICsn (Ki) ICso (Ki) ICso (Ki) ICgp (Ki) 166 0 o\\//o 544.1561 644.1606 (>10000) 3081.7 (8690) 135.9 (>10000) HO (8090) (63. 4) koJ o0m xi 0 HCI IN HgC 1 167 qp540. 2056 540.2029 (>10000) 3739.4 (68.1) 147.0 (>10000) HO (128) (78. 9) 0 0 HCI OCH3 H3C/ CH3 168 0 oo 528. 1856 528.1863 (>10000) 3428.2 (6500) 34. 3 (>10000) o" ou oJ -o I w Iw H3C Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 169 0 o o 564.1014 564.1026 (>10000) 4363.5 (6500) 70.7 (>10000) HO (5360) (20.4) 0 o i ci Jazz 170 0 oo 532. 1605 532.1618 (>10000) 1608.7 (1500) 3. 3 (>10000) HO (1410) (6.79) 0 o i F 171 0 oo 564. 1014 564.1028 (>10000) 2288.8 (6600) 62. 8 (>10000) Ho S (3190) (12. 5) kOJ VoX 0 1 tir 1 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass M ? ss ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 172 0 oo 564.1014 564.1032 (>10000) 5163.1 (9440) 377.0 (>10000) HOHN S0 (>10000) (71.1) oJ o I w c c 73-o o>"o 509. 1950 509.1954 (>10000) 2120.4 (3480) 12. 2 (>10000) HOHN \ (4090) (11.5) WOJ VoX CHUG CHg 174 0 ou >10000 708.6 4017 5.2 >10000 As' Ao o i 0 \C) O 175 o o o H3C CH3 601.2696 601.2657 >10000 438.0 7296.6 1.4 >10000 (>10000) (872) (1390) (2.01) (>10000) W BCI O-N ROI OCH CH 3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ° °p \ cN \ ocH3108.9 7. 8 $OARS i o i 0 0 177 0 oxo 333.2 17.0 °s Ao, o HO -0 o 178 o oo >10000 28.4 1166.4 7.8 >10000 asz IROM*4 s (>10000) (39.3) (306) (1.71) (>10000) l NN F N \N--iV F3 CF3C02H OCH3 179 H3C CH3 246. 9 1.1 0 Q. U a--"J 'N-N O 180 0 0 0 443.0 17.0 Horn HOHN s I W HCI 6CH3 HCl N N C3 OCH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 181 o q >10000 13. 9 26.4 0.3 8059 HOHN H CF3 (1850) (15.8) (40.5) (0.27) (4830) /Nw w CF3 0" 182 0 oo >10000 33.1 62.1 0.5 >10000 ion// HOHN 3 (6540) (34.3) (85.4) (0.212) (5850) j3 O O /Hs ° g'° >10000)708.0 (2510) 21. 0 (>10000) lK°ENtDZl. o (>loooo w (643) (15.1) C$3 OO-N-. 184 o oo 1528.7 30.4 103. 5 3.9 2715.4 °s o gor Ho o 0 185 0 °"s/'° (>10000) 84.7 (220) 12.4 (>10000) HOHNX rYY (116) (3.73) Horn ICI OH3 186 o g o H3609.9 13. 5 HOHW H3 o ovrr Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 187 o q 3868 3.6 11.2 1.8 1425 HOHN 0 Zozo ! HCl A) Ha H3CCH3 188 o °"S'° >10000 4.7 48.2 0. 3 3537.7 o,, HOHN yHci Cl cri 189 0 1070 19.3 24.1 1.9 4316 CH3 H HOHN", t OH o O O 0 190 ° o"o >10000 165.9 1742.6 0. 5 >10000 Horn (>10000) (283) (669) (0.6) (>10000) Y own N \ F CF3C02H OCH3 6956 341. 2 383. 4 9. 5 >10000 IIN ON O U Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso (Kj) ICso (Ki) ICso (Ki) ICso (Ki) 1920 RO 1256. 4 15.4 R 0 M, Cor 193 o q"o 5931. 6 312. 3 272. 5 6. 8 >10000 HOw o aCF3 Ho 194 o a, o >10000 221.6 515.7 6. 2 >10000 HOHN S I p I s HOHN 0 CF3 Q <y-- 0 19s o o, 0 4381.7 20.6 45.8 7.5 2741.5 1 \40 HOHNII "-O^-NN' O U 196 0 oo 32.2 11.4 HO HO S I O u. Co 197 0 oo >10000 13. 2 432.2 0.5 >10000 HOHN (>10000) (30.7) (334) (0.37) (>10000) XIao o 11 1 Pq HCI I Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 198 o qp 4527. 4 834.9 s Oxo CH3 0 I CHg O CHs 199 0 o/o CH3 (>10000) 133.2 (59.5) 7.4 (>10000) (228) (3. 09) KOHN HCI O N HUI 200 0 qjo 7498 84. 0 1207. 2 0.6 >10000 HO' hoher ON\N CF3 /CF3 201 0 o o 538. 2376 538.2362 >10000 127.7 4509.5 0. 7 >10000 s HOHN CH3 HORN CH3 N O A CF3CO2H cH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 202 HOHN 1604.4 41. 9 no HOHN N HCI/\ \ FOC CH3"OCHg 203 0 o o >10000 4.2 6.0 1.0 >10000 o,, HOHN s I I \ pSJO NIHCI A 204 o oo >10000 145.7 1824. 8 0.6 >10000 NO1i N HO han 0 0 H3C CH3 205 0 oo 4780. 2 17. 6 HOHN 0 O'- IN-k 3 LH3 CH3LOCH3 206 O os >10000 92.6 59.4 15.8 3112 holz N '', HCl % CH t H3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 207 HORINX >10000 114. 3 126.7 3.7 >10000 HOmv w /ozon 0 g3 208 0 ON"O >10000 230.2 6587.6 0.6 >10000 li s ROHN 0 HCl H ! CF a >10000 172.5 905.6 1.4 >10000 HORN Non ion H3 210 0 oso rto2 >10000 6.9 284.6 1.3 >10000 HOHN O-N 211 0 oo 9653 26.2 863.5 0.4 >10000 HOHN s O-N O N F 212 0 0 0 1408 4.1 212.2 0.3 >10000 asz HOHL "O-N O-N Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 213 0 oo >10000 54.8 2204 2.2 >10000 aov S w 0 O-N C; 1 214 0 6\ o >10000 15. 8 4239 3. 3 >10000 Houx c Horn O N 1 2150 oo >10000 20. 3 767. 9 0. 3 >10000 Horn O-N O 216 0 °t"° SF3 1952.2 51.2 o" Roan HOHN lIl l \ O "\//F3 O-N 217 o qp ocH3 >10000 48.9 5179 4.6 >10000 horn Hoher Q 0---- O-N 218 0 oo >10000 40.4 2973 1.4 >10000 HOIHMN H3 horn N Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 219 0 qp >10000 60.8 77.7 0.4 >10000 HOHN-0 (5600) (105) (59. 5) (0. 355) (7940) 220 0 0 0 220 o QS >10000 409.7 1466.8 5. 7 >10000 HOHN 'N, N \/ A3C. o'/ TF8796. 4243. 8 HOHN I g Hs O N CH3 HCI HCI Ha A 222 o o o 138. 1 13.3 HOSyo HOHN S /F ON \ w Zona ICI CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 223 0 0 0 69. 7 11. 9 no/ FIN HCI CH3 OCHs 224 0 oo >10000 193. 5 1466.8 4. 7 >10000 s or j o Ive zu ICI "vS W 225 0 o o 2332. 3 17. 8 HOHNc CH3 0 /O N l H CH3 226 0 oxo >10000 222.0 2144.0 4.3 >10000 HOHN 0 Aor o LIN/CH3 L d-w c 2. 7 0.2 Homv S w I O N w N CH3 CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 228 o oo 6871 11.4 180.4 0.2 >10000 H0B XSn H (3940) (22. 4) (247) (0. 324) (6290) 0N-aOCF3 \ O OCF3 zip 5033 12.2 293.7 1.7 >10000 Hou H 3 (955) (10.4) (281) (0.27) (7870) N O u 230 0 o/o >10000 555.2 1017.7 1. 1 >10000 HOH 0 HOHN S OII tT N O OCH3H3C\H3 231 0 qp >10000 1.6 10.2 0.2 641.7 jet O HOHN 0 CH3 232 o Qso >10000 74.2 877.7 5.6 >10000 HOHN 0 zoo bd ZON O CF3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICSO ICSO Ki ICso ICso ICso 233 0 0 N >10000 25.5-831.8 0.1 >10000 HOHN c (>10000) (60.18) (509.42) (0.137) (>10000) zoo N HCIHCI n OCH3 234 oH 596. 2430 596.2441 213. 4 10. 3 B [OIIN X Honv o s I 0 HCl, OCH3 2350 p 421. 7 26. 0 Ho hui Ho S w HCl fCH3 HCI HUI 236 o qp 7.6 3. 4 /OCH3 HOHL nu CN N 237 0 qo >10000 42.5 1111 0.7 >10000 HOHN OCH3 < O N "0-N Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 238 0 oo >10000 78.7 1186. 1 1.2 >10000 os' HOHL or O H3C 239 o qp 236. 9 2.5 HN o. 0 0 t \/ CF3 240 0 0 0 >10000 84.0 1428.4 0.7 >10000 Horn HOHN L,zu A 241qp>l0000602944. 2L3'>10000 \/Y HORN Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 242 o So ° 2720. 2 203.0 H3C CH 0 O N CH3 0H 243 0 oxo 9313.6 49.4 2101. 9 0.5 >10000 Houv S w Horn zu \/ N 244 o c, o 3250. 6 18. 8 108. 2 0. 7 >10000 HOHN Xm /\ NS 245 0 0 0 >10000 8.6 61.1 0.2 >10000 s HORN 0 N N I HOTCH3 OCH3 246 0 oo 1166. 7 7.5 104.7 3.0 >10000 HOH g OII I/,., N. N "O H CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso ICSO ICso Ki ICso 247 JU"m 3610. 8 445. 1 341. 1 1. 1 >10000 HOHN H3 H3 N-N CH3 248 o p >10000 15.7 105.6 0.2 1704.1 HOHN 0 N N-CH3 CH2 r CH OCH3 3 249 0 °% A° >10000 226 3628.6 5.09 >10000 ROHN s 3 (>10000) (333) (1490) (1.49) (>10000) OCF3 0 kkoCF3 250 0 oo 4406. 1 2. 5 22. 5 0. 3 7630. 2 (1440) (3.12) (12. 5) (0.127) (1700) N zozo O ocF3 251 0 oxo 182.4 5.4 Aomv Ou(V F N- /cl3 Hic H3C" Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICSO (Ki) ICso (Ki) ICso (M) ICso (Ki) ICso (Ki) 5602. 7 47.9 1052.4 0.2 >10000 °s' o O N-N\4J O v N=N 253 0 oxo 1448.2 32.4 HORN F3 F3C/ N N F N OCEt3 254 0 o/o >10000 138.3 968.2 1.7 >10000 o" HOHN IEH3 N t ! j. HCI L ° HsC CH3 2ss o oS 51.3 1.9 HOHN N hui hui 256 0 0 0 >10000 0.1 37.9 <0.1 >10000 H," omr S w l C H3 X Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass ICso ICso ICso rCso ZCso 257 Cl >10000 173.8 6227 0.5 >10000 HOHEN 0 HOHN N N<3 258 o a o >10000 173.5 1956 1. 7 >10000 HOHNt CH3 HOHN o N 259 0 p 7256 201. 1 1876 0. 7 >10000 HOHN JA n N O 260 o qp H59 132 391.0 1.8 >10000 HOHN o/\ N'-N 261 0 ouzo >10000 178.3 1185. 0 1. 9 >10000 vs Homv 0 ci 262 0 qp >10000 118.3 1702.3 3.0 >10000 Hoary N-N N N Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 263 o g o->10000 87.7 3267.5 3.8 >10000 or S I o HOHN/> < O 0 zon O/ '264'op>10000 162.8 287.1 5. 3 >10000 Horn 0 o-/\ CH3 zozo CH3 26540. 0 0. 2 0 N 1 SC'nrTT HCI 266 0 0 0 >10000 391.2 202.6 9. 1 >10000 o,, HOHN s \ N CF3 67o qp>1000015106. 7>10000 .," HN-_-'I If-, HCl N NHCI-CH3 7H3 CHg Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) IC50 (Ki) ICso (Ki) 268 0 0"0 >10000 125.9 674.0 2.5 >10000 HOHN zon HCI O-N 3 A 269 0 zoo >10000 897.9 2755 1.8 >10000 no s oJ i i 20 0 0 0 521.8 8.1 omr w HO o I EN 271 0 oo H3 >10000 8. 7 531. 8 2. 9 >10000 s ego o-----'-s H3 Oxo 272 0 oSO 399 4. 2 152. 1 2. 8 >10000 | X tSa H aor N, H ace CI Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 273 o o\\//o 405.1332 405.1335 1010.7 304.0 HO H O HN 274 0 o o 402. 1223 402.1225 9864 15. 4 33. 6 4. 1 >10000 gor s' I CH3 O O 275 0 os115.2 1. 7 HOHN H3 O _ O- 276 0 0 0 6670.4 17.4 196. 3 2.8 7019.9 HOHN s \ H3 w II 0 277 o ( >10000 3.5 41.5 0.2 >10000 .," Homr s o o HOBS0 N, Hci CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 28 0 0 0 544, 2117 544.2104 >10000 207.9 494 3.7 >10000 Ho s ego I i o. H3C0 X H3CtCH3 H3 15. 9 9. 4 HOH N HOH s) I--a-- OUZO "0 0 280 0 oo 518.1597 518.1578 >10000 170.1 2034 1.5 >10000 HO Ho P 0 CH3 281 0 oo 529.0329 529.0353 >10000 70.4 276. 1 1.3 >10000 HO HO S w N S _ Cl Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 282 0 0 0 525.0824 525.0827 >10000 43.3 704. 3 2.6 >10000 \\/i HO HOzon O S \/-OCH3 283 0 oo 468. 1263 468.1257 186. 2 29. 3 HN U o-'Y y--c Fun g3 284 o 543. 0485 543.0500 >10000 10. 1 18.5 1. 1 >10000 0 oo zizi 'os s o 285 0 CH3 539. 0980 539.0978 >10000 16. 7 23. 6 1. 8 >10000 \\ p a, o HOHN S I l \ p'S. JS O 286 0 0 o H3 482.1420 482.1421 >10000 74.9 1134.5 4.0 >10000 AomV I o--w, srr 1 HORNN 287 0 o/o 553. 1137 553.1137 >10000 3. 6 16. 4 0. 8 >10000 HO - Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 288 o oo 509.0875 509.0880 >10000 2. 3 10.6 0.8 >10000 HOHN XSn 9 I oss 0 289 0 oo 527. 1852 527.1838 >10000 2720.2 >10000 10. 1 >10000 HOHN 0 HOHN S, O oJ o Erz 290 o q"o >10000 590.2 >10000 >10000 HOHN/, H ÇH3 (>10000) (1009.04) (>10000) (0.547) (>10000) O/ 0 W17H3 , p 100 8. 0 291 9k, °"S'° 100 8. 0 HN 0 0 cl3 cH CH3 292 0 R, p 970 14. 4 163.5 2.4 >10000 HN -s-N O O O / 293 0 0 6147 2. 3 447. 9 2. 6 >10000 HA HOs o A Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass ICgo (Ki) ICsc (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 294 O oo 4623 100.0 447.9 4.3 >10000 Ha HOt CH3 0 HgCCHs 295 0 oo >10000 15.6 172.1 2.6 >10000 .,,. tOJ o° H3 0 0 0 296 0 0 0 1335.9 564.8 HO s I 0,--,_,, SNH2 O O 297o p454. 0944 454.0986 6812 8. 1 64. 6 0. 5 6562 onr S \ oJ o HOHN/Xu 298 0 0%"0 I H3 561.2634 561.2641 11. 9 18.1 HOHN 'N O H C Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 299 0 0 o i I 498.1586 498.1588 3.2 0.1 X C e°<S X Horn 0 300 0 oo 524. 1743 524.1729 12. 5 6.7 HN o Hoo0 0 0 301 0 qo 492. 1692 492.1687 3655. 3 0. 2 9. 1 <0. 1 3 19. 9 HOHN ) ao 0 CH3 0 /C3 302 0 o\\//o 496.1197 496.1192 2728.9 0.2 2.9 0.1 94.9 Horn o 0 t°Jci 303 0 RO 303 o gso 576. 2016 576.2198 50. 0 9.9 HORN HN kOJ W°Ho ? \N 0,-,-CH3 0 "CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 304 0 qp 538.1648 538.1629 138.6 0.2 HO S'- J I 305 0 oo 569. 1474 569.1444 175. 9 3. 9 Ao HO s OCH 0 oc3 SCH3 306 0 oo >10000 92.9 185. 2 I. 7 >10000 OCH Hot ,., 0 O 307 0 oxo 8135 135 139. 5 4. 5 >10000 s HOHNI/.'y/ N O-N Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso Ki ICso ICso rCso 308 0 0 0 519.1801 519.1780 >10000 175.8 1601.1 3.7 >10000 HORN toJ O N O H3C 309 0 os 519. 1801 519.1772 >10000 135.3 1557. 8 1. 8 >10000 HOHN t t0 NXO O H3c' : I. W 310 o oo CH3 >10000 32.0 1980.5 3.0 >10000 3 r HO CH3 LÓ Õ o A "00 311 O q"O CH 543.2165 543.2165 25.6 2.6 HOHN CH3 s I HN CH3 O H 3 312 0 0 0 529. 1645 529.1635 9. 1 0. 2 0 J o I Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICgo (Ki) ICso (Ki) ICso (Ki) ICsp (Ki) 313 0 0 0 511.1539 511.1535 18.1<0.1 C HOHN S W zoo O N/ 314. o o"p 7.8 2.5 HO H 0 OCH3 / NN \ N-N O H 0 315 0 oo 12. 812.7 OHN Honv X O óStó O O 60HoHN J 558. 2274 558.2274 2678 2842 692. 0 13. 6 >10000 HOBI'A , N n a 3 317 0 oo 501.1695 501.1693 >10000 120.4 244. 3 3.1 >10000 ROHN I , N I v CH3 A3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 318 o oxo 615 97.3 gor S w Ho o 0111 CH3 3190 oo >10000 5. 8 258 1. 0 4225 HO N NJ i o r CF3C02H 3200 oo 5864 6110 HO Huilet O HCI N S C 321 0 oo >10000 1701 625. 6 3. 7 >10000 OHN HOFIN S I I \ 0H HCI O g HCI 322 0 0 601.2220 601.2226 354 233 HOCH3 0 u W O CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso Ki ICso Ki ICso ICso ICso 323 o oo 358. 8 108 In/1, ho s Ho- I ou CHUG 324 o o o 468.1151 468.1148 2990 4.2 500 0. 5 8002 no0 S S/ o o v 1 325 0 oo 538.1899 538. 1918 >10000 11. 0 4042 0. 5 >10000 ,. Aofnr s I w o I w HOHNI o f 326 0 o o 462. 1586 462.1582 >10000 7. 4 263 0. 3 8316 asz HOH I O 0 I 327 0 oo 518. 2212 518.2203 >10000 50. 7 5284 0. 9 >10000 HORN 0 /y O /vs H3 H3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso ICso Ki ICso 328 o OXyO 542.1849 542.1866 61.3 <0.1 HORN 0 w w O 3 329 a o 0 103.1 8.6 o" HOHN S O \. i I/O //NH3 ICH3 OCH3 330 0 oo 539. 0980 539.0985 >10000 261.7 216 16. 0 592 Ao °s' ° H ts HO HN--h' "su og3 331 o qo 506.1961 506.1954 386 261.4 HO S g N H 0 332 ° 0o o 2459 3.6 132. 4 2.6 >10000 LX g O 0 0 I ° oo Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (wi) ICso (Ki) IC<Ki) ICso (Ki) ICso (Ki) 333 0 oo 557.0552 557.0562 >10000 656. 3 3240 1.8 >10000 Ho s 0 o o 0 o i i 33a. o 0 0 489. 2059 489.2073 >10000 16. 4 866 5. 1 2876 gonv °s' wu I O HCl 335 P q. p 607. 2325 607.233 >10000 2.3 172.3 6.5 >10000 HOHNS / 0 H3 0 H3 336 669.2482 669.2463 300.6 19.8 00, 0 HOHN qs/ N, CH J I O \ I C$ N 0 C] 13 337 0 oxo 563. 2427 563. 2414 41.9 12.2 H3C CH3 Ho HCl 338 0 oxo 549.2271 549.2242 20.6 137. 7 HOHL o ° HCI OCH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 339 Ho a oso \/cH3 478. 1648 478.1631 1205.8 932.9 H I NN I H HCI p 340 0 oo 534.2162 534.2161 >10000 253.0 5590 1.9 >10000 HOHN/X, tq ° CH3 p W H3 'o H3 O H3 341 0 oxo 495.0718 495.0689 >10000 16.8 1122 0.5 6400 HO HOHN S I \ 3 342 Uo o\"o 512.1743 512. 1769 >10000 41. 2 2165 2. 0 >10000 HOHN/ or 7702. 4 2. 4 HOHN ozon O O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 344 0 qu 575.2791 575.2819 12.7 4.6 HO s 0 H3 CH3 ri J. i /cH3 /Hs, CH3 H3 O H3 CH3 34. 5 o g"o 520.2005 520.1988 271.1 14.3 HORN CH3 CH3 \3CHg CL3 CH3 346 1° A/P 532. 1754 532.171 >10000 2. 6 2010 0. 9 >10000 X <0w0o p\O O 347 0 oso 103 1.8 HO HO CH3 p o j OCH3 348 qp>100006L8>10000 4.4 >10000 HO HOHNO QJ W0 SO 0 34. 9 H3 505. 3 39. 0 o asp HOHN 0 ! ! O \OCH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 350 0 479.1488 479.1484 3283 2.6 271 0.5 2670 HOHN H OH N 0 0 351 Ho g) 0 522.1798 522.1791 >10000 34.1 2225 1.0 >10000 ir HO s 0 CH3 O CH3 352 0 RO 498.1586 498.1576 >10000 33.6 3601 2.0 6238 Ho s I I SH) CSu v LJ"oYT! 0 k 353524.1743 524. 1703 >10000 25. 1 1152 1. 8 >10000 0 oxo os Homr I zozo 0 0 354 o os H3 528.1692 528.1658 HOHNCSa <CH3 O O 0 0 355 0 o H3C H3 504.2056 504.2017 >10000 17.4 1072 1.1 3622 HOHN CH3 O lui °0 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICS Ki) ICso(Ki) ICso ICso IC50o 356 0, w 524.1743 524.1731 >10000 33.1 1650 0.8 >10000 HO o w I 0 0 357 0 oo 506.1961 506.1964 >10000 10.2 952 1.7 >10000 HOHN \ H O N w O /NH3 CH3 358 0 oo 492. 1804 492.1813 768. 4 14. 6 no s 0 H R H n HCl Cg3 359 0 o >1 0000 2. 3 1183 1.0 7956 Aor S w -UT zoo hic HCl 360 0 °% s° 503.2216 503.2226 >10000 9.7 547 6.4 962 HOHN s HCI gci 0 ()) Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 361 0 oo 506.1961 516.1965 6000 500 >10000 0.5 >10000 HO HCI 0 HAN H N, CH3 CH3. 362 0 oo 523. 1750 523.1763 347 3.7 ,, oJ O\N OCH3 J o OCH3 363 o a, o 493. 1645 493.1660 430 7 HOHN/XS o, OCH3 0 O 364 0 oo 535.2114 535.2105 >10000 250 >10000 1.8 >10000 Aor S I o X n0N S H 365 0 qo 539.1852 539.1846 21 0.6 HO 0 oJ H 0 0 366 0 366 ° o, \"o 513. 1695 513.1699 347 0.3 s Ho 0 g // Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso Ki ICso (Ki) ICso ICso (Ki) 367 o qjo 488.1491 488.1496 235 4.5 HO s 0 N 0 tut S'k 368 0 °tA° 521.1594 521.1594 >10000 150 9000 0.8 >10000 HO HO s I O Ozon 0 H/3 O 369 0 oo 508.1390 508.1390 155 1.5 HO 0 HOHN S I O 0 H LJ. _ 0 O 2 370 0 oo 505. 2008 505.1990 900 37 % tXoNX < X HO 0 H3 HN-fao" HIC CHUS 371 0 o o 491.1852 491.1894 >10000 1100 9600 2.4 >10000 " Ao S I o no 0 O 0 H31 I Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso TCSO ICSO Ki ICso ICso 372 o OX"O 479.1488 479.1491 210 6 Ao S I w o oH HO 0 S'ka 373 0 oo 491. 1852 491.1843 >10000 940 3945 7 >10000 HO 0 H3 0-in '-'tuf /B 3 374 ° oo 519.2165 519.2148 800 8 HO 0 on o I X H3 H H3 LCHg H3 3s o c"o 513.1695 513.1695 425 17 L X HX : X 0) ao--N "'tir \ 376 0 oo 529.1645 529. 1625 >10000 360 >10000 0. 8 >10000 gomr S o ERIOo po H no Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 377 o °sSS/P 559.1750 559.1761 1271 5.9 HOEO OCH3 /ON I OCH3 H HO 378 0 oo 545.1594 545.1596 655 2.7 Ho S I o HO N 0 Ho HO 379 o oo 545.1594 545.1585 258 10 HO 0----'N i i H H 380 0 qp 380 q, p 543. 1801 543.1835 450 0. 2 Hofnv S I o HO s 0 o g I //cl3 381 0 o o 498.1102 498.1090 193 1.4 HO 0 ON I N / 1 382 0 0 0 464.1491 464.1475 59 1.7 HOHNY 0 ' O-N H Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 383 0 qp 464.1491 464.1487 351 7.5 HOHN 0 LJ"ON-\ B kan ion 384 o og, 532. 0712 532.0709 >10000 176 2628 0.8 >10000 or S I o HOHN 0 -ha ' TJ C1 ci 385 0 o"p 464. 1491 464.1490 4341 253 >10000 3.3 >10000 HOHN X < ° v O'N N G N-N p 468. 1441 468.1459 >10000 131 35. 3 1. 2 9725 HO S, 0 ao N I \ CH, 0 387 HO o o 488. 1491 488.1508 83 2.2 gor s I o HO 0 N 0 H 388 qu529. 1645 529.1640 185 2 OH Ho s I w o ox o i i Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 389 0 0,, 0 514.1648 514.1623 47 0.5 HOHN << o hornho N N_ // 390 0 oxo 514. 1648 514.1641 >10000 907 >10000 2.7 >10000 Nl\/1, Ho s i o J i Ho-a N 391 0 qp 466.1648 466.1647 900 7 HN ON N H L 392 0 521.1958 521.1947 >10000 >10000 >10000 40 >10000 HOHN 0 0 J H3CCH3 CH3 393 0 oo 479. 1488 479.1497 50 45 HOHN Horn o O 394/, ° CH3 506.1961 506.1961 3200 1900 BOHN N H HOHN S I H- I NCH3 0 hui o = ici CH3 O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 395 0 0 R3 506. 1961 506.1947 6000 305 Q, o HOI st Hv CH3 HAN HCI ut 396 0 qo 507.1801 507. 1807 4 4 HOHN9<, < SOCH3 HOHN zon "t O 397 0 oo SH3 520.2117 520.2093 3 14 HN N ici "cl3 398 0 398 o a, o 433 433 730 22 FIN H CH3 H H3 O H H 3 3 399 0 oo 469.2008 469.1988 650 8 HORN0 0----,--N H LJ H 400 0 oo 455.1852 455.1843 326 9 Hoarr S I o v'ON Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICSO Ki ICso Ki ICSO ICso 401 0 °tA/° 551.1287 551.1264 700 25 HOHN 0 CF CF3 B H H H3 402 osp 402 0 471. 2165 471.2144 454 30 HOHN C O 1 t nooNX 3 H3C CH3 "H3C C% 3 403 0 oo 457. 2008 457.1997 >10000 454 >10000 5.2 >10000 xom S o HH3 O g3 404 o, p 505.2008 505.1992 254 15 HOHN S \ O oN HH3C 3 405 0 oo 521.5321 521.2323 >10000 2352 >10000 1.9 >10000 HOHN) \Cq O kob0 N 406 0 ou 545.2434 545. 2441 >10000 2200 >10000 >10000 IIIOHN- 0 H N'CH3 On N N, CH3 CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 407 cri 561. 0324 561.0366 285 25 horn o, p omr'w oso 0 408 0 0 0 527.0713 527.0694 >10000 90 49 2. 5 6813 omV S i /' oJ os o 409'o qp547. 0167 547.0196 >10000 23 160 1 5644 HOHN s 0 O O/ 1 410"S/'° 479.0947 479. 0978 4700 12 202 1. 1 515- Aomr s w toJ <St b zu 463. 1175 463. 1204 >10000 1517 >10000 587 >10000 ROHN S", 0-- 00 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICsp (Ki) ICso (Ki) ICso (Ki) 412 CF3C02H 475.1903 475.0916 313 41 1 vu OSO OHNt X 0 O a. 13 0 0 0 489. 2059 489.2068 61 8 pCF3CO2H horn 414 o psp CFgCO2H 503.2216 503.2215 37 14 HOHN \ i o u 415 1° oo 517.2372 517.2377 >10000 51 1784 15 >10000 o HOHN oJ CHU I g3 416 0 oo 533.2321 533.2314 17 8.6 HOEIN s HUI 0 ci I OCH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 417 o qp 463.1539 463.1546 315 2.6 HO 0 N L. H i '418'oco>100001500 >1000064>10000 HOHN--'n H H HOHN H H ON N O OCH3 419oqp1204 S HO C J p p ao"'N"S O H CH3 ocp>1000067>100004>10000 HOHN/X \n IERIO /^ OCHg O 0 0 421 0 oo 649 256 "" Cl31 O O /I/CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 422 0 oxo 7200 1484 0 HOEIN S, c N- 423o O O 9000 1585 HORN CL3 - X) CF3 o CF3 a. 24 0 0 0 485 192 Aor °s' HO NtA N9F3 otiJ 42o qp>100003308 fX OHNt< X ' ; c 26'oqp>100005151 l aCH3 " CH3 CHg 427 0 oo 251 114 HOHN HOHNt A CND O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 428 0 o\ o 20 1.4 Ho HOHN O O s oui \o \OCH3 6. 5 >10000 0.5 >10000 HOHL L J (T'Y) oXo Sm HAN 430 0\\//0 2700 195 HO nô HIC CHUG 431 o qp 115 4 HO s CH3 O S' 0 zozo c3 HOFIN I \/, oJ os CHUG 433O p\ p 220 7 HO s CH3 zozo 0 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso Ki ICSO Ki ICso ICSO Ki 434 0 oo LI 0.6 C-H3 JOHN oJ os cl3 CHg 435 o op >10000 >10000 500 CF H I 3 Ho HgC CHs H3C CH3 436 ° 0\"0 >10000 1500 100 zozo HORN S O HgCCH3 437 o oo >10000 >10000 >10000 90 >10000 I ROHN S", HIC CHUS H3C CH3 4380 0 0 >10000 SOS 3800 11 >10000 HOH1V \ J toJ0-4"0 3 439'o o, p>10000 2000600025>10000 Horn tOJ o°-SX 0 I Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 440 ° °%//° >10000 4 140 1 2500 HOHN HO CL3 441 ° A"° 9000 13 110 2 2290 HOHN CF3 \O 442 ° o"o >10000 6. 2 5. 4 1. 8 997 HO S Cg3 ? N HCI 443 0 oxo >10000 25 375 3.5 2429 HO 7 HCI OU"CF N 3 HCI A 444. 0 oxo 8. 9 7.6 X Horn Cog O F3 445 O Q\ 0 3325 2.2 44 0.5 546 HO O . O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso ICSO ICso Ki ICso Ki 766.6 HOHI tSX X0 Hoher CHg H3 HO O O >10000 8.9 12. 2 2 1360 zozo HOHN s I W I CH3 o 448 0 oo 3080 9 116 2. 7 832 A v 1 J oJ o^ 449 0 O O 1929 3. 7 41 7 5 8 HOHN \S HO HAN 4. so o c"o >10000 6. 6 44 0. 9 4937 oar I w o I CHg t°S 451 o p 4.7 9 Horn 452 0 o 4o 2. 2 14. 8 Ho 0 452 a o 0 2.2 14.8 onr S I w oJ o Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICSO ICso Ki ICso Ki ICso 453 o c"o >10000 13 800 3 5000 HoHrr S I \ HOHN s OCH3 T CH3 4s4 o Qsp >10000 165 27 HOHN) iX < EIN Y F3 455 0 oxo 900 690 HOHN s Homo H3C CH3 O H3C Cg 456qu425350 HO S" HOHN XoJ OvO\CH3 H3C CH3 457 0 oo >10000 >10000 >10000 HOHN 0 tO t O 458 o qp >10000 3500 1400 o . HOHN J o o 3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass IC5n (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 459 o o o >10000 700 670 CH3 | X Horn N H3 '460o q>l0000 145 70025>10000 ozr S w I HOHN H a61 0 0 0 >10000 2200 590 JOHN Oh O 462 o oo >10000 11 18 7 6500 HOHN N rt H 463 0 oxo 484.1794 484.1776 17 7 HO xo o 464'oqp498. 195 498.1925 46 1. 4 S\ ^ HOEIN n \ \ Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICSO ICso ICSO Ki ICSO Ki 465 XS'O 450.1586 450.1577 >10000 4 180 0.3 1800 Su HOHN O CH3 466 0 0 0 480. 1692 480. 1732 >10000 110 45 15 >10000 HOHN) t 0 o" ! O \OCH3 467 0 os >10000 940 450 120 >10000 HOHN t 0 468 0 oxo >10000 2500 1500 i HOHN t H OJ/O W 4690 0 0 >10000 145 60 HAN X ao3cHCH3 0 CHg 470 ° 0%"0 >10000 7 3 HOHMN--Ih--\, \/ O '1 ; H3 O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 471 0 o o aCH3 >10000 270 120 )) / HOHN lOHNtt ACH3 CH3CH3 dH 472 o oo >10000 3 40 6 400 Ho 0, CH3 X J Wo CH3 \/"O v C : Hg O 473qp>100005455600 \\ li HOHN J 0'' 0CH3 3 474 0 oxo >10000 12 3 HOHNEIN s H3 J J o 0 475 o qp >10000 30 120 2 3600 HOHN S I S''3 C3 0 H3 476 o o/o >10000 2500 >10000 230 >10000 HOHN \s toJ o° CH3 O 3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICSO ICSO Ki ICSO ICSO Ki ICso 477 0 ou 1300 1.5 2 Roan LJ o-Y-j 0 R3 478p>l000013451450 HOHN HOHN aJ O a. 79 0 0 0 2700 4 14 3 2000 lROHNtv X X If H3 480 11 4200 18 60 11 1400 HOHN HOHN S I O QU 481 0 oo 1.3 2 HOHN toJ W0, pCH2 0 482 CH3 3300 40 O 0oo 00 0 HOHN s- 0 O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 483 H3C, 2000 29 o qp qp 9=o HOHN S I r-, ls I \ NJ o 640 12 HORN oc 0 CH3 485qppcHg400064 ci HO o Ao o 486 o g"o >10000 106 255 4. 6 >10000 HOHN oJ o w 0 k° I ì, CH3 CHg p >10000 3.1 169 0.5 1570 HOHN, >S39 °I H HORNOH O CL3 CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso ICSO Ki ICso ICso Ki ICso 488 JRuS"505. 2008 505.1991 HOHN 0 0 /NaH H3 489 o oo 512.1743 512.1766 >10000 58.2 >10000 0.4 >10000 HORN s 0 HOHN S I O W W 490 0 O O VH3 491.1852 491.1856 >10000 18.2 928 0.2 5630 o" HO I /I NC$3 0 O O 491 0 OCH3 478. 1536 478.1540 7310 6.8 94.2 0.8 981 HO CH3 Horn O O O 492 0 °t A/° 448.1430 448.1428 3550 3.5 67.3 0.7 574 o, i HOHN 0 O O 493 o 0 471.1695 471.1695 4770 15.9 752 0.9 3230 horn 0 Po NH CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass ICso (Ki) ICso (Ki) IC50 (Ki) ICso (Ki) IC50 (Ki) 494 o OS 464.1392 464.1379 1520 <0. 1 13.6 <0. 1 197 HOHN 0 /\ O CH3 495 0 °% A° 434.1273 434.1277 815 1.9 25.8 1.7 505 1 X < 0 W 496 0 oxo 578. 2172 578.2164 242 8. 4 HOHNZ X < O t°J vlIaCEI33 H H 497 o OK"O 472.1754 472.1769 1450 23.5 ROHN s) ae 0 N-'-N-) H o 498 0 oxo 522.191 522.1915 160 14.8 LOCH HOIE, 4 OC"3 O /OiV. N / H H 499 9 os 508.1754 508.1753 56.2 7.0 BOv, x, yq R fl ° A) 0'J 1ICH3 OCH Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 500 0 oo 494. 1597 494.1596 2390 1,9 63.2 8.5 2960 ONN HH so1 0 0 0 518. 1597 518.158 >10000 184 7710 1. 4 >10000 HOHr*4 CH3 0 N N 502 o p 513.0557 513.0574 >10000 22.7 160 1.0 5640 S HOHN 0 0 503 o 475. 1903 475.1907 F3C-I-OH HOHN tOJ Vo+~C3 04o oo514. 1700 514.1735 (>10000) (434) (2310) (4.65) (>10000) y H 0 0 F Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso Ki) ICso ICso ICso (Ki) ICso (Ki) 505 0 0 0 414. 1581 414.1586 (850) (2.56) (10.2) (0.81) (962) N Jt zon H f 1 1 rn H X J CH3 ZU 0 506 Hou,) S 428.1738 428.1751 (1465) (1.92) (11.4) (0.23) (681) HO, HCI N H 0 507 ° °%"° 400.1767 400.1788 (3590) (0.84) (0.44) (0.19) (444) HO, \\ N J o 0 508 0 0 0 554.2319 554.2347 (4850) (22.8) (160) (0.141) (2790) HO, N N,'I N N, HCI 0-cl3 OCg3 \ 509 o o os, o 554. 2319 554.2308 (>10000) (89.26) (50.85) (0.297) (4158.92) N zozo N, gCl I/ CH, Fit ol CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 510 ? o (>10000) (7. 85) (39. 82) (0. 25) (2183.66) 0 HO-N po E HCI W Ha tj ft < CHs 511 qo571. 2273 571. 2255 (>10000) (525.78) (38. 53) (1. 36) (>10000) HA, N PO N gCl I, O-CH, F 512 o ° °%"° 571.2273 571.2281 (>10000) (757.99) (25.71) (1.07) (>10000) N PO N, gCl I, 1/F O-CH3 kJ 13'o o o589. 2178 589.2193 (>10000) (879.71) (254. 58) (0.98) (9274. 4) Xi po N R OuX F CH3 W F F Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 #Mass Mass ICso (Ki) ICgp (Ki) ICgp (Ki) ICgp (Ki) ICso (Ki) 514 0 0 0 578. 2319 578.2305 (>10000) (292.63) (223.53) (0.28) (4082.05) Ho. °s' HA, N Po N I 0ICI F3C OH CH3 X CN 515 0 0 0 >10000 89.76 154.32 24.23 >10000 HO,°s' R 05 N HCL 516 Ho o os, o gl >10000 41.94 119.72 9.55 9434.24 Tjrt Ji e ttD Y N "Q oJJ hui 517 O O o HCI >10000 34.66 137.63 6.19 >10000 HO, N H W OO O 518 0 0 0 >10000 26.35 115.39 169.48 967.13 Ho s C X Co~° HC. nui Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 519 0 0 0 >10000 170. 25 421. 64 2.18 >10000 hou hui N-a HCI HL JL 0 520 o oo->10000 54.24 36.38 0.62 4296.13 HO, \\ N Hui H 0 521 Ho o os, o 62. 0 5. 8 N Hou N °LNJ 0 N 522 0 0 0 (>10000) 12. 9 (135) 0.3 (6290) HO, N s (32. 1) H I '-N HCI J Br 523 0 0 0 515.1647 515.1690 8069 161.6 1647.2 0.3 >10000 NJX n1 (3213) (196.7) (1253) (0.234) (>10000) NHCI F F F Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 524 Ho\ o os, o 497.1741 497.1763 >10000 38.3 1841.5 0.2 >10000 RolN S' (51. 8) (739.5) (0.244) (>10000) Ho cl 0ilz, 525 o p o 520. 1576 520.1581 7. 5 1. 5 HO, N s SrT f , j N-- NI HCI CH3 s26 ° 0S0 557. 1871 557.1863 (>10000) (1680) (2070) (3.96) (>10000) HO tS'557. 1843 Iw N HCt k I HCICl 3 ci 527 H 0 Ctseo (5100) (21. 3) (30.4) (. 044) (1360) H H i N I vH3 3 vCH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) IC50 (Ki) IC50 (M) 528 Ho O S (>10000) (83. 5) (238) (2. 57) (5700) H S'0 H I O w CHs CL3 529 OQ o 529. 2003 529.1982 (>10000) (3550) (1870) (20.2) (>10000) H HO S,- OH ou 530 ? <\. o 512. 1738 512.1774 (>10000) (699) (220) (7.33) (>10000) HO, Sa oJ o w LJ i N 531 HO\ O 0. s o , o 498. 1581 498. 1614 (>10000) (337) (774) (2.72) (>10000) HO,N 9,/ zozo O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 532 HO p OO 498.1581 498.1610 (>10000) (739) (1320) (1.02) (>10000) Nt vOH X i 533 0 0 0 (>10000) (29.3) (141) (0.226) (6680) N HO, N s HUI /CH3 534 xo S\3/XCt (>10000) (25.4) (324) (0.493) (6810) N HOCH /\p \N $CI OU roi 535 0 0 0 (>10000) (23.2) (128) (0.261) (3870) Ho s' i HCI O ICH3 536 0 0 0 (>10000) (744) (3400) (3. 4) (>10000) HO-1 s N H 0 /SN A NHCI 0 CHUG Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICSO ICSO ICso ICso ICso 537 o 0 0 535. 1138 535. 1160 (>10000) (985) (900) (0. 657) (>10000) CH3 N S N HO 0 ZON HCI I CH3 538 1°l ot//o 540.2163 540.2142 (>10000) (24.6) (117) (0.184) (1700) Ho, s N XCI XN ICI ! na o CH3 539 0 0 0 540. 2163 540.2160 (9130) (38.6) (85.5) (0.21) (1180) ego< HO, Ns H au HCI HCl CH3 540 00 0 557.2116 557.2132 (>10000) (270) (689) (0. 58) (>10000) Ho s Ho, N H HCI HCI u'CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso ICso Ki ICso Ki 541 0 0 0 561. 1295 561.1266 (>10000) (302.15) (269. 03) (0. 24) (>10000) HA, 1 \ I N 'N N HCI O A 542 Ho 0 oso 544.1571 544. 1566 (>10000) (234. 13) (921. 73) (0.86) (>10000) Ho, N (J UsJ N HO HCI O HCl 543 0 0 0 N 564.2163 564.2192 (>10000) (124.15) (207. 41) (0. 23) (3094. 73) HO, N \H I I N N O CHg CH3 544 o oo 557. 2116 557.2087 (>10000) (302.23) (787. 01) (0.898) (>10000) Rol N O \ N Hci i F CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 545 0 0 0 557.2116 557.2101 (>10000) (309.81) (922.55) (1. 11) (>10000) HO,, N s H HCI F CH3 546 P .. o 575.2022 557.5023 (>10000) (426.17) (1269.5) (1.06) (>10000) HA, N Ha N O HCI F FF 547 0 0 0 573.1821 573.1848 (>10000) (727.08) (1863. 44) (2.28) (>10000) HA, N wN/I/I Hui cri 0\ CH3 1 0 cr3 548 0 0 0 540.2163 540.2193 (>10000) (1.58) (278. 57) (0. 38) (7415. 08) xi TT r O N 7 u HCI hui O OC1I3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICsp (Ki) ICsp (Ki) ICsp (Ki) ICso (Ki) 549 0 0 0 575.2022 575.2042 (>10000) (503.95) (1770. 79) (1.87) (>10000) Ho, N NJ o HCI N ""CH3 550 0 0 0 (>10000) (5. 49) (7.51) (0.52) (2180) HO, s N I \ N hui 0 N HCI Cl3- A3 551 0 (>10000) (5.07) (48.2) (0.62) (2055) 0\//0 w i HO, N O I/CH3 0 N HCI CH3 552 0 0 0 (>10000) (4. 94) (2. 22) (1. 78) (2440) HO,N w ici CL3 0 f 'CHs Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso ICso 553 0 0 0 546.1905 546.1896 (>10000) (7.797) (71.205) (0.259) (2257.112) HO, NY B P-- ( XHCI L H 0 HCI Cul 0 Ssa. o 0 0 (>10000) (61.27) (442.07) (14.50) (>10000) \\, ; i HO,, N s H 0'-"0 N N) N HCI 555 0 0 0 (>10000) (3.383) (50.012) (0.261) (688.63) no,, N s n N zoo HC ! HCI 5560 0 0 (8972. 84) (68. 058) (211. 92) (53. 22) (3496. 68) zu Ho, N s 0hic1 o hui Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 557 0 0 0 (>10000) (6.46) (33.57) (3.68) (52.23) go s Hui HCI 558 HXnS~Ns 562.1676 562. 1714 (>10000) (352. 06) (1357. 7) (2. 163) (>10000) NsHCI O HCI 0 0 CH3 559 0 0 0 (>10000) (11.65) (57.56) (1.51) (845.5) HO, N , H I 0 560 0 0 o Hci (>10000) (10.26) (7.17) (0.616) (549.16) HOLZ N H o, 561 0 0 0 579. 1400 579.1389 (>10000) (336.04) (467.44) (0.31) (>10000) HO k s (, HOS N N II N Hui O CL3 O-CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 562 go 0 o HCI 488.1486 488.1476 (2738.33) (241.03) (785.83) (2.97) (9265.67) NU A N / HO, N H o, 563 496.1425 496.1453 (>10000) 73. 5 (132. 06) 1. 1 (4400. 5) (70. 11) (0. 70) 0 0 0 s ho, N i 0 0 v 564 HO JRKSS/° 455.1343 455.1345 144.9 19.4 N Ho,, N H N HCI 0 N-NH 565 0 0 0 565 ° °%"° 545.1813 545.1825 14.0 1.6 N C, 0 4,-N 0 ROI N-N \ Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso (1) ICso (Ki) ICso (Ki) s66 ° °\,, 0 467. 1595 467.1643 65.7 18.8 H H N 9\ H 0/ ° N==/Ha 567 HCI 549. 0931 549. 0955 660.5 21. 9 N ION HO, N s 00 \ ON II O O O 568 HO 0 0 489. 1438 489.1435 21.0 1.5 Ho s' N Hou-N HCl N-N 569 Ha 506.1050 506. 1028 1405 171. 8 0 N Rol N s 0 H H \ I ON \ 0 O s70 j ? o (3061. 49) 4. 8 (6. 15) 0.2 (1357.46) N H (10. 09) (0.142) \ N\I O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 11. 9 1.6 HO, N s H O O r _ 37. 3 4. 7 HOC, \ H g g3C CHg \ O lOl N I \ CH3 . H 573 0 0 556. 1223 556.1214 1707. 7 75. 1 lao, N s i HJ X o I CF3 Cl CFg CF3 74o o o (>10000) 29. 4 (83. 02) 0. 7 (5386. 06) / (112. 25 (5386. 06) H 0,-HCI N 0 N Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 575 0 0 0 8.4 2.0 HO, N s hui pu J o 1;, o i 576 0 0 0 506. 1050 506.1069 >10000 232. 7 397. 0 0. 3 >10000 HoN s N H son 0 0 577 0 0 48. 2 1. 2 Ho, N N I b O 578 0 0 0 489. 1438 489.1428 (>10000) 20. 5 (578) 2. 9 (>10000) N (72.1) (1.72) H ao 0-1N OHCI -. X / Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 579 0 0 0 595.1743 595.1767 >10000 37.8 136.0 0.4 >10000 HO, N H 0 ICI F F F 580 0 0 0 555. 1430 555.1454 >10000 136.0 417.2 0.6 >10000 HO, N s H s H ILS F F F 581 0 0 0 HCI 536.1156 536.1173 2534.3 29.8 HO, N s N N O H H "'cl3 "o o nol OCH °N"> S-\ ou 0H N OJ g Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 583 go 0 0 ° ° 15. 7 1. 6 A OCH X0 CH3 °o L 584 0 0 0 (2760) 72.9 (12.6) 3.6 (6630) HON S I HO, (20. 8) (0. 944) N Zon HCl N 585 0 o a 85. 4 4. 0 \\ el HO, J CH3 H O-CH3 C O/3 H3C0 586 0 0 10. 1 0. 6 HA, \ H o- HsCO H3C 0 i H3C O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ss7 0 /o 538. 1164 538. 1191 >10000 81. 7 1372. 9 0. 1 >10000 HOu Soe (> 10000) (124.9) (8180) (1.424) (4154) N / 0 F 588 o 492. 1804 492.1773 94.9 15. 0 O FgC''OH HO oS wH \/I \ NH /O-N o OiCgg 5s9 0 0 0 506.1050 506.1054 9. 9 0. 4 Ho s S /ON II N 0A O 590 0 0 857. 7 48.0 go s nazi J ° 0 0 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICsp (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 591 0 0 0 536.1348 536.1372 >10000 3.5 12.0 0.3 >10000 HO, NI'd v (>10000) (4.4) (4.22) (0. 19) (8742. 7) H S,/Ts N HUI N HO "CH3 592 go\ o oso gci 502. 1648 502.1639 336. 4 38. 7 HC /1V no, N s N osa O/O _ 593 0 an. 0 504.1263 504.1254 6.5 15. 6 Ao N han o o _ 594 0 0 0 140. 1 3. 8 A 0 po Ho, N nci 595 0 0 0 502.1353 502.1359 >10000 482.5 1733 1.0 >10000 00 HOu s (>10000) (586.2) (2056.6) (7.245) (>10000) H o I w 0 /dz Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 596 0 0 0 519.1260 519.1265 >10000 10.3 194.5 2.7 2491 9ot G\ (>1 0000) (11.2) (307. 7) (0.398) (1160) A /\O-N I 0 0 S S 597 0 0 0 521.0875 521.0910 471.1 12.1 HO, s , N I \ H I SN o6 oJ o 598 0 0 0 522. 0827 522.0932 (>10000) (599.35) (705. 33) (0. 27) (>10000) Ho H I N I O O 599 HO 0 0 488. 1491 488.1491 >10000 <0.1 11.6 0.1 57.01 . (>10000) (0.38) (11.34) (0.24) oxoN N 0 0 FOC OH 600 0 0 0 448. 1542 448.1542 205. 7 214.4 \\, i'l HO, N s H NH hui HO Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICSO Ki ICSO Ki ICSO Ki ICso ICSo 601 0 0 0 469.1103 469.1093 4916 1.9 42.6 1.3 2062 goEX N I \ "ICso N oJ o o S 602 HX H 493. 1639 493.1608 13.7 3.6 N C I \ ON \ OwCH3 N 0, cl3 603 ° a o 515. 1158 515.1145 34. 0 2. 4 HON \ /\/ OCH H I/NS. dizzy 6040 0 o r 36. 6 3. 3 \\ 'i Tj r i" HO, N s HOHN oc 605 0 Q. zoo 44.0 3.8 \\ 4 1 /DN \ O O Hyo 606 0 0 0 489.1332 489.1326 >10000 5.0 234.0 0.4 2566 r HO, N s H (>10000) (11.574) (105. 89) (0. 432) (2053. 20) "pN O 0 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (X) ICso (Ki) ICso (Ki) ICso (Ki) 607 HOu"S 520.1264 520.1297 >10000 45.2 2298 0.1 >10000 HO, N o Lez F F 608 0 0 586. 1181 586.1160 >10000 342.1 1794 6.6 >10000 Ho s° >10000 > HO, N (>10000) (723.95) (1368.3) (9.34) (>10000) g OCF o / O-CF3 CF3 609 0 0 0 >10000 579.9 6887 7. 7 >10000 Ho s' N H N HCI N hui HUI U Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICSO Ki ICso Ki ICso ICso 610 0 0 0 488. 3 4. 1 aoN s ( O CF3 0 ° o, o i 733. 2 13. 6 HoN s Ho, J oYj 512 0 0 504. 2414 504.2413 1232. 2 16. 1 HO, N s RIZ J o Iw CH3 CH3 CHg 613 0 0 34. 3 6. 6 no, N A H J o I w HCI rr HCi H3 C \CHg Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 614 X o X 562.1504 562.1516 >10000 1.8 8. 5 0.7 9440 HO, Ha 1> Hui 615 0 0 0 566.1443 566.1453 >10000 1.1 3. 6 0.4 6696 HO, N s N O HCi OCH OCH t <, CH3 493. 1645 493.1617 1584 5.3 54. 8 2. 0 1969 HO, N s o cH3 0, N 617 0 0 0 469. 1103 469.1086 2074 0. 8 413 0. 6 4133 HO, N 1112 s 0 0 HO, N ci 822.1 27.5 rT I \ g/CI H -0 0 O Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 619 Ho\ o o s o 66.2 1. 5 HO, N s S O 620 0 0 0 16. 2 4. 1 xo s' ZON 00 Ber (o 621 0 0 0 488. 1491 488. 1489 367. 6 17. 8 HO, N s , H I \ H I - oJ H o 622 0 0 0 505.1103 505.1120 >10000 273.1 1756 1.5 >10000 HO,, N s (>10000) (450.85) (2077. 1) (2.68) (>10000) "pN O O 0 623 0 0 0 546.1733 546.1728 >10000 5.2 3. 1 1.2 5520 Ho s'- I N hui HCl Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass ICso ICso Ki ICso Ki ICso Ki ICso 624 O o 0 521.1746 521.1753 >10000 214.4 1029 0.3 >10000 HX 13s (>1 0000) (623) (443) (0. 9) (7580) kOJ ° 'lu 0 con CN o 625 0 0 564. 1668 564.1643 (>10000) 3499.5 (4600) 33.6 (>10000) (6860)(43.6) (, o°H xi CF3 626 0 0 0 558.191 558.1925 >10000 142.8 885 0.4 >10000 HO, N (>10000) (645) (1100) (7.5) (>10000) \ 0 o i NOZ Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso Ki ICso Ki ICso ICso ICso 627 0 0 0 554.1849 554.1884 (>10000) 2072.7 (3150) 14. 9 (>10000) HO, (3950) (40. 9) N H 0) 0 0 Xi 0 o 628 0 °\ s° 540. 1692 540.1712 >10000 1701.3 1754 3.3 >10000 Ho s >10000 2750 > () () (1930) (19. 8) (10000) zozo 0 zu Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 629 0 0 0 546.1950 546.1965 (>10000) 536.8 (1300) 78.6 (>10000) HO, N (1020)(89.1) ° (d 0 " J I I 630 0 0 0 532. 1605 532.1598 >10000 1166. 6 5990 0. 4 >10000 Ho s >10000 2070 > HO, N s (>10000) (2070) (2280) (6.02) (>10000) H zozo F F 631 0 0 552. 1515 552.1520 (>10000) 2143.2 (5810) 117.7 (>10000) HO,, (4960) (57.6) J o I w H o- i S ° td Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass Mass (Ki) ICso (Ki) ICsp (Ki) ICsp (Ki) ICso (Ki) 632 0 0 0 502.1358 502.1387 >10000 91.0 411 1.6 >10000 HO, (>10000) (279) (716) (6.54) (>10000) Ici 0 O W N (0) 633 8 Ax 552. 1515 552.1510 (>10000) 2828.1 (6780) 117.0 (>10000) HORN s (4580)(92.4) 0 zu 634 ? 0 0 536.1743 536.1730 (>10000) 486.4 (1300) 16.3 (>10000) HO", N (983) (19.4) A J o w 0 0 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 635 0 0 o 522.1950 522.1973 (>10000) 2309.5 (4830). 20.0 (>10000) e (4680) (26. 2) x J o w 0 I II H 636 ? O 0 512.1743 512.1755 (>10000) 195.0 (763) 3.2 (>10000) HO, N'- (527) (3.21) oJ o I w 0 0 HOI:) HO HO 637 A8w/y 486. 1586 486.1576 >10000 137.6 830 1. 8 >10000 no, (>10000) (498) (881) (4.63) (>10000) Kob H 0 -0 0 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 638 A/, ° 546.1950 546.1950 (>10000) 4400.9 (8770) 400.4 (>10000) HO, N- (8120) (68.1) H o I w o, i 639 0 0 0 516. 1515 516.1501 (>10000) 247.1 (688) 4. 3 (>10000) HO, N s (505) (12.5) H s c CHg 640 0 0 0 476. 2101 476.2114 324. 5 10. 4 H r! J. HO, J \C0/% o I w 07 hic H3C CH3 Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 # Mass Mass ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) ICso (Ki) 641 I Aw//134. 7 5.0 HO o S \H o I w N HUI H C N H 642 2 0 0 528.1799 528.1771 2889. 0 36. 9 Ho., s N H H o A tJ 643 0 0 0 560. 2794 560. 2793 1134. 1 11. 4 HO, N s H i N HCI 4- [ (4- {3- [ (l-adamantylcarbonyl) amino] propoxy} phenyl) sulfonyl]- 1-cyclopropyl-N-hydroxypiperidine-4-carboxamidehydrochloride Ex Structure Calc. Observed MMP-1 MMP-2 MMP-9 MMP-13 MMP-14 Mass Mass ICso ICso'ICso ICSO Ki ICSO Ki 644 ? ° 574.2951 574.2943 2633.4 20.9 HO O S N HUIH3 I 11 1 1°l N HCI Cl l 4- [ (4- {3- [ (1- adamantylcarbonyl) (methyl) amino] propoxy} phenyl) sulfonyl]-l- cyclopropyl-N-hydroxypiperidine-4-carboxamide hydrochloride 645 0 0 557 557 9283 22.9 1726 4.3 >10000 no, N S" H'o H 0 H O lOl H 4-[(4-{3-[(2-adamantylaniino) sulfonyl] propoxy} phenyl) sulfonyl]- N-hydroxytetrahydro-2H-pyran-4-carboxamide 646 o o os, o (>10000) (288. 84) (76.21) (0. 16) (4296. 95) H t j o<, A w zoo O t W 0il F3C H 0 CH CH

[1115] The above detailed description of preferred embodiments is intended only to acquaint others skilled in the art with the invention, its principles, and its practical application so that others skilled in the art may adapt and apply the invention in its numerous forms, as they may be best suited to the requirements of a particular use. This invention, therefore, is not limited to the above embodiments, and may be variously modified.