Summary of the Related Art [0002] Cell-cell interactions play an important role in regulat- ing cell fate decisions and pattern formation during the develop- ment of multicellular organisms. One of the evolutionarily con- served pathways that plays a central role in local cell interac- tions is mediated by the transmembrane receptors encoded by the Notch (N) gene of Drosophila, the lin-12 and glp-1 genes of C. elegans, and their vertebrate homologs (reviewed in Artavanis- Tsakonas, S. , et al. (1995) Notch Signaling. Science 268,225- 232), collectively hereinafter referred to as NOTCH receptors.

Several lines of evidence suggest that the proteolytic processing of NOTCH receptors is important for their function. For example, in addition to the full length proteins, antibodies against the intracellular domains of NOTCH receptors have detected C-terminal fragments of 100-120 kd; see, e. g., Fehon, R. G. , et al. (1990).

Cell 61,523-534 ; Crittenden, S. L. , et al. (1994). Development 120,2901-2911 ; Aster, J. , et al. (1994) Cold Spring Harbor Symp.

Quant. Biol. 59,125-136 ; Zagouras, P. , et al. (1995). Proc. Natl.

Acad. Sci. U. S. A. 92,6414-6418 ; and Kopan, R. , et al. (1996).

Proc. Natl. Acad. Sci. U. S. A. 93,1683-1688. However, the mecha- nism (s) of NOTCH activation have been hitherto largely unknown.

[0003] During neurogenesis, a single neural precursor is singled out from a group of equivalent cells through a lateral inhibition process in which the emerging neural precursor cell prevents its neighbors from taking on the same fate (reviewed in Simpson, P.

(1990). Development 109,509-519). Genetic studies in Drosophila have implicated a group of"neurogenic genes"including N in lat- eral inhibition. Loss-of-function mutations in any of the neuro- genic genes result in hypertrophy of neural cells at the expense of epidermis (reviewed in Campos-Ortega, J. A. (1993) In: The De- velopment of Drosophila melanogaster M. Bate and A. Martinez- Arias, eds. pp. 1091-1129. Cold Spring Harbor Press.).

[0004] Rooke, J., Pan, D. J. , Xu, T. and Rubin, G. M. (1996).

Science 273,1227-1231, discloses neurogenic gene family, kuzba- nian (kuz). Members of the KUZ family of proteins are shown to belong to the recently defined ADAM family of transmembrane pro- teins, members of which contain both a disintegrin and metallopro- tease domain (reviewed in Wolfsberg, T. G. et al. , (1995). J. Cell Biol. 131,275-278, see also Blobel, C. P. , et al. (1992). Nature 356, 248-252, 1992; Yagami-Hiromasa, T. , et al. (1995). Nature 377,652-656 ; Black, R. A. , et al. (1997). Nature 385,729-733, 1997; and Moss, M. L. , et al. (1997). Nature 385,733-736 ; see also U. S. 5,922, 546 and U. S. 5,935, 792).

[0005] Genes of the ADAM family encode transmembrane proteins containing both metalloprotease and disintegrin domains (reviewed in Black and White, 1998 Curr. Opin. Cell Biol. 10,654-659 ; Wolfsberg and White, 1996 Dev. Biol. 180,389-401), and are in- volved in diverse biological processes in mammals such as fertili- zation (Cho et al. , 1998 Science 281, 1857-1859), myoblast fusion (Yagami-Hiromasa et al. , 1995 Nature 377,652-656) and ectodomain shedding (Moss et al. , 1997 Nature 385,733-736 ; Black et al., 1997 Nature 385,729-733 ; Peschon et al. , 1998 Science 282,1281- 1284). The Drosophila kuzbanian (kuz) gene represents the first ADAM family member identified in invertebrates (Rooke et al. , 1996 Science 273,1227-1231). Previous genetic studies showed that kuz is required for lateral inhibition and axonal outgrowth during Drosophila neural development (Rooke et al. , 1996; Fambrough et al. , 1996 PNAS. USA 93, 13233-13238; Pan and Rubin, 1997 Cell 90, 271-280; Sotillos et al. , 1997 Development 124,4769-4779). Spe- cifically, during the lateral inhibition process, kuz acts up- stream of Notch (Pan and Rubin, 1997; Sotillos et al. , 1997), which encodes the transmembrane receptor for the lateral inhibi- tion signal encoded by the Delta gene. More recently, a homolog of kuz was identified in C. elegans (SUP-17) that modulates the activity of a C. elegans homolog of Notch in a similar manner (Wen et al. , 1997 Development 124,4759-4767).

[0006l Vertebrate homologs of kuz have been isolated in Xenopus, bovine, mouse, rat and human. The bovine homolog of KUZ (also called MADM or ADAM 10) was initially isolated serendipitously based on its in vitro proteolytic activity on myelin basic pro- tein, a cytoplasmic protein that is unlikely the physiological substrate for the bovine KUZ protease (Howard et al. , 1996 Bio- chem. J. 317,45-50). Expression of a dominant negative form of the murine kuz homolog (mkuz) in Xenopus leads to the generation of extra neurons, suggesting an evolutionarily conserved role for mkuz in regulating Notch signaling in vertebrate neurogenesis (Pan and Rubin, 1997). U. S. patent application. No. 09/697,854, to Pan et al., filed October 27,2000, discloses that mkuz mutant mice die around embryonic day (E) 9.5, with severe defects in the nerv- ous system, the paraxial mesoderm and the yolk sac vasculature.

In the nervous system, mkuz mutant embryos show ectopic neuronal differentiation. In the paraxial mesoderm, mkuz mutant embryos show delayed and uncoordinated segmentation of the somites. These phenotypes are similar to those of mice lacking Notch-1 or compo- nents of the Notch pathway such as RBP-Jk (Conlon et al, 1995, De- velopment 121, 1533-1545; Oka et al. , 1995), indicating a con- served role for mkuz in modulating Notch signaling in mouse devel- opment. Furthermore, no visible defect was detected in Notch processing in the kuz knockout animals. In addition to the neuro- genesis and somitogenesis defect, mkuz mutant mice also show se- vere defects in the yolk sac vasculature, with an enlarged and disordered capillary plexus and the absence of large vitelline vessels. Since such phenotype has not been observed in mice lack- ing Notch-1 or RBP-Jk (Swiatek et al. , 1994 Genes Dev 15,707-719 ; Conlon et al. , 1995; Oka et al. , 1995 Development 121,3291-3301), Pan et al. determined that this phenotype reveals a novel function of mkuz that is distinct from its role in modulating Notch signal- ing, specifically, that kuz plays an essential role for an ADAM family disintegrin metalloprotease in mammalian angiogenesis.

[0007] In view of the important role of KUZ (ADAM-10) in biologi- cal processes and disease states, inhibitors of this protein are desirable.

[0008] All patents, applications, and publications recited herein are hereby incorporated by reference in their entirety.

SUMMARY OF THE INVENTION [0009] The present invention provides compounds useful for inhib- iting or otherwise modulating the activity of the ADAM-10 protein.

Such compounds are useful in the in vitro study of the role of ADAM-10 (and its inhibition) in biological processes. The present invention also comprises pharmaceutical compositions comprising one or more ADAM-10 inhibitors according to the invention in com- bination with a pharmaceutically acceptable carrier. Such compo- sitions are useful for the treatment of cancer, arthritis, and diseases related to angiogenesis. Correspondingly, the invention also comprises methods of treating forms of cancer, arthritis, and diseases related to angiogenesis in which ADAM-10 plays a critical role.

DETAILED DESCRIPTION OF THE INVENTION [0010] The present invention comprises inhibitors of ADAM-10. In one embodiment, the invention comprises a compound of structural formula I : or a pharmaceutically acceptable salt thereof, wherein R1 is selected from hydrogen, alkyl, alkanoyl, arylalkyl, and arylalkanoyl, wherein the arylalkyl and arylalkanoyl groups are unsubstituted or substituted with 1,2, 3,4, or 5 R6 groups; R6 at each occurrence is independently selected from halogen, hydroxy,-NO2,-CO2RloS-CN, alkyl, alkoxy, haloalkyl, and haloalkoxy; R2 is selected from hydrogen, alkyl, alkoxy, alkanoyl, ary-' lalkyl and arylalkanoyl, wherein the arylalkyl and arylalkanoyl groups are unsubstituted or substituted with 1,2, 3,4, or 5 R6 groups; R3 is-Z-Q-J, wherein Z is selected from alkyl, alkoxyalkyl, alkylthioalkyl, and alkenyl, each of which is unsubstituted or substituted with 1 or 2 groups that are independ- ently selected from alkoxy, hydroxy, and halogen; Q is selected from a direct bond between Z and J,- C (=O)-, aryl, heteroaryl, and heterocycloalkyl, wherein the aryl, heteroaryl, or heterocycloalkyl group is unsubstituted or substituted with 1 or 2 groups that are independently selected from alkyl, halogen,-NR8R9, and alkoxy; J is selected from-NR8Rg,-NR7C (=O) NR8Rg,- NR7C (=O) alkylNR8R9,-NR7C (=0) OR9,-C (=NR7) NR8R9, and -NH-C (=NR7) NR8R, wherein R7 is selected from H, CN, NO2, alkyl, alkanoyl, arylal- kanoyl and-C (=O) NR1oR11, wherein Rio and Rll are independently selected from H, and alkyl, and R8 and Rg are independently selected from H, alkyl, hy- droxy, alkoxy, alkoxyalkyl, heterocycloalkylal- kyl, arylalkyl, and heteroarylalkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or R8 and Rg and the nitrogen to which they are attached form a 5,6 or 7 membered heterocycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from alkyl, alkoxy, hydroxy, and halogen; or R. 7, Rg, and the nitrogens to which they are attached form a 5,6 or 7 membered heterocycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently selected from al- kyl, alkoxy, hydroxy, and halogen; and R9 is selected from H, alkyl, hydroxy, alkoxy, alkoxyalkyl, heterocycloalkylalkyl, arylalkyl, and heteroarylalkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; R4 is selected from H, alkyl, and arylalkyl, wherein the ary- lalkyl group is unsubstituted or substituted with 1,2, 3,4, or 5 R6 groups; and Rs is-M-G-A, wherein M is selected from aryl and heteroaryl, wherein M is unsub- stituted or substituted with 1,2, 3, or 4 groups that are independently selected from halogen, alkyl, hy- droxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hy- droxyalkyl ; G is selected from a direct bond between M and A, CH2,- alkyl-0-,-0-alkyl-, 0, S, SO, and SO2 ; A is selected from aryl and heteroaryl, wherein A is unsub- stituted or substituted with 1,2, 3,4, or 5 groups that are independently selected from halogen, alkyl, alkoxy, haloalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy, haloalkoxy, -CN, and N02 ; with the proviso that when M is phenyl, G is a direct bond between M and A, and A is phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independ- ently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl ; [0011] In one example, the invention comprises a compound of for- mula I as described in paragraph [0010], wherein RI. is selected from the group consisting of hydrogen, C1-C6 alkyl, phenyl C1-C6 alkyl, and phenyl C1-C6 alkanoyl, wherein the phenylalkyl and phenylalkanoyl groups are unsubstituted or substituted with 1,2, 3,4, or 5 R6 groups, and R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkanoyl, phenyl Cl-C6 alkyl and phenyl C1- C6 alkanoyl, wherein the phenylalkyl and phenylalkanoyl groups are unsubstituted or substituted with 1,2, 3, 4, or 5 R6 groups, wherein R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, -NO2, -CN, C1-C6 alkyl, C1-C6 alkoxy, CF3, and OCF3.

[0012] In another example, the invention comprises a compound of formula I as described in paragraph [0010], wherein R3 is-Z-Q-J, wherein Z is a C1-C6 alkyl, Cl-C6 alkoxy C1-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 groups independ- ently selected from Ci-C4 alkyl, halogen, and C1-C4 alkoxy ; Q is a direct bond between Z and J,-C (=O)-, piperid- inyl, pyrrolyl, piperazinyl, imidazolidinyl, mor- pholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each is unsubstituted or substituted with 1 or 2 groups that are independently selected from C1-C4 alkyl, halogen, and C1-C4 alkoxy; J is-C (=NR7) NR8Rg or-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H,-CN,- NO2, C1-C6 alkyl, Ci-Ce alkanoyl, phenyl C1-C6 alka- noyl and-C (=O) NR10R11, wherein Rio and Rll are independently selected from H and Ci-Cg alkyl, R8 and Rg are each independently selected from the group consisting of H, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 al- kyl, thiomorpholinyl, thiomorpholinyl S, S- dioxide, thiomorpholinyl S-oxide, piperidinyl C1- C6 alkyl, pyrrolidinyl C1-C6 alkyl, imidazolidinyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1- C6 alkyl, phenyl C1-C6 alkyl, and pyridyl C1-C6 al- kyl, pyridazyl C1-C6 alkyl, pyrimidyl C1-C6 alkyl, pyrazinyl C1-C6 alkyl, thienyl Cl-C6 alkyl, and furyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or R8 and Rg and the nitrogen to which they are attached form a 5,6 or 7 membered heterocycloalkyl ring, which is un- substituted or substituted with 1,2, or 3 groups that are independently selected from C1-C6 alkyl, C1-C6 alkoxy, hydroxy, and halogen; or R7, R8, and the nitrogens to which they are attached form a 5,6 or 7 membered heterocycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently selected from C1- C6 alkyl, Ci-Cg alkoxy, hydroxy, and halogen; and Rg is selected from the group consisting of H, C1-C6 al- kyl, C1-C6 alkoxy, Cl-C6 alkoxy Cl-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkyl substituted with at least one of morpholinyl, piperidinyl, thiomor- pholinyl, thiomorpholinyl S-oxide, phenyl, naphthyl, thiomorpholinyl S, S-dioxide, pyrrolid- inyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl, wherein each of the above is unsubstituted or substi- tuted with 1,2, 3, or 4 R6 groups, wherein R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO2, C1- C6 alkyl, C1-C6 alkoxy, CF3, and OCF3.

[0013] In another example, the invention comprises a compound of formula I as described in paragraph [0010], wherein Rs is-M-G-A, wherein M is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyr- rolyl, wherein M is unsubstituted or substituted with 1,2, 3, or 4 groups that are independently selected from the group consisting of halogen, C1-C6 alkyl, hy- droxy, C1-C6 alkoxy, halo C1-C6 alkyl, halo Cl-C6 alkoxy, and hydroxy C1-C6 alkyl, G is selected from a direct bond between M and A, CH2, 0, S, SO, and SO2 ; A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrrolyl, benzo [1, 3] dioxyl, quinolinyl, isoquinolinyl, tetrahy- droisoquinolinyl, tetrahydronaphthyl, and dihy- dronaphthyl, wherein each of the above is unsubstituted or substituted with 1,2, 3,4, or 5 groups that are independently selected from halogen, Cl-C6 alkyl, C1-C6 alkoxy, halo C1-C6 alkyl, halo Cl-C6 alkoxy, CN, and NO2; with the proviso that when M is phenyl, G is a direct bond between M and A, and A is phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independ- ently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl.

[0014] In another example, the invention comprises a compound of formula I as described in paragraph [0010], wherein R1 is hydrogen, C1-C6 alkyl or benzyl; R2 is hydrogen, C1-C6 alkyl or benzyl; and R3 is-Z-Q-J, wherein Z is Cl-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or Cl-C4 alkoxy ; Q is a direct bond between Z and J,-C (=O)-, piperid- inyl, pyrrolyl, piperazinyl, imidazolidinyl, mor- pholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each of the above is unsubstituted or substituted with 1 or 2 groups that are independ- ently C1-C4 alkyl, halogen, or C1-C4 alkoxy; J is-C (=NR7) NR8Rg or-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H,-CN,- NO2, Cl-C6 alkyl, Cl-C6 alkanoyl, phenyl C1-C6 alka- noyl and-C (=O) NR10R11, wherein Rio and Rll are independently H, or C1-C6 alkyl, and R8 and Rg are independently selected from the group con- sisting of H, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 alkyl, thio- morpholinyl, thiomorpholinyl S, S-dioxide, thio- morpholinyl S-oxide, piperidinyl C1-C6 alkyl, pyr- rolidinyl C1-C6 alkyl, imidazolidinyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, phenyl C1-C6 alkyl, and pyridyl C1-C6 alkyl, pyri- dazyl C1-C6 alkyl, pyrimidyl C1-C6 alkyl, pyrazinyl C1-C6 alkyl, thienyl C1-C6 alkyl, and furyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or R8 and Rg and the nitrogen to which they are attached form a 5,6 or 7 membered heterocycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from Ci-Cg alkyl, C1-C6 alkoxy, hydroxy, and halogen; or R7, R8, and the nitrogens to which they are attached form a 5,6, or 7 membered heterocycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently selected from C1- C6 alkyl, C1-C6 alkoxy, hydroxy, and halogen, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups, wherein R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO2, C1-C6 alkyl, C1-C6 alkoxy, CF3, and OCF3 ; and Rg is selected from the group consisting of H, C1-C6 al- kyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkyl substituted with at least one of morpholinyl, piperidinyl, thiomor- pholinyl, thiomorpholinyl S-oxide, phenyl, naphthyl, thiomorpholinyl S, S-dioxide, pyrrolid- inyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl, wherein each of the above is un- substituted or substituted with 1,2, 3, or 4 R6 groups; R4 is selected from the group consisting of H, C1-C4 alkyl, benzyl and phenethyl, wherein the benzyl and phenethyl groups are unsubstituted or substituted with 1,2, 3, or 4 R6 groups; Rs is-M-G-A, wherein M is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thio- phenyl, and pyrrolyl, wherein M is unsubstituted or substituted with 1,2, 3, or 4 groups that are independently selected from the group consisting of halogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halo C1-C6 alkyl, halo C1-C6 alkoxy, and hydroxy C1-C6 alkyl, G is selected from a direct bond between M and A, CH2, O, S, SO, and S02 ; A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyridazyl, pyraz- inyl, pyrrolyl, benzo [1, 3] dioxyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahy- dronaphthyl, and dihydronaphthyl, wherein each of the above is unsubstituted or substituted with 1, 2,3, 4, or 5 groups that are independently halo- gen, Cl-C6 alkyl, Cl-C6 alkoxy, halo C1-C6 alkyl, halo Cl-C6 alkoxy, CN, or NO2, with the proviso that when M is phenyl, G is a direct bond between M and A, and A is-phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl.

[0015] In another example, the invention comprises a compound as in paragraph [0014], wherein Rs is-M-G-A, wherein M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyrrolyl, each of which is unsubsti- tuted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, C1-C4 alkyl, hydroxy, methoxy, ethoxy, isopro- poxy, CF3, OCF3, halo C1-C4 alkyl, halo Cl-C4 alkoxy, and hydroxy C1-C4 alkyl ; G is selected from a direct bond between M and A, CH2, 0, S, SO, and SO2 ; A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, benzo [1, 3] dioxyl, quino- linyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahy- dronaphthyl, and dihydronaphthyl, wherein each is un- substituted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, Cl-C4 alkyl, Cl-C4 alkoxy, halo C1-C4 alkyl, CF3, OCF3, -CN, and-NO2 ; with the proviso that when M is phenyl, G is a direct bond between M and A, and A is phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independ- ently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl.

[0016] In another example, the invention comprises a compound as in paragraph [0015], wherein R3 is-Z-Q-J, wherein Z is a Cl-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 alkyl- thio C1-C6 alkyl, each of which is unsubstituted or sub- stituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J,-C (=O)-, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each is unsubstituted or sub- stituted with 1 or 2 groups that are independently C1-C4 alkyl, halogen, or C1-C4 alkoxy; J is -C(=NR7)NR8R9 or-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, Cl-C6 alkyl, C1-C6 alkanoyl, and -C(=O)NR10R11, wherein Rlo and Rll are independently H, or C1-C6 alkyl, and R8 and Rg are independently selected from the group con- sisting of H, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy Cl-C6 alkyl, morpholinyl C1-C6 alkyl, thio- morpholinyl, C3-CB cycloalkyl, and C3-C8 cycloalkyl C1-C6 alkyl, wherein each of the above is unsub- stituted or substituted with 1,2, 3, or 4 R6 groups; wherein R6 at each occurrence is independently selected from the group consisting of halogen, hy- droxy, NO2, C1-C6 alkyl, Cl-C6 alkoxy, CF3, and OCF3, or R8 and Rg and the nitrogen to which they are attached form a 5 or 6 membered heterocycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hydroxy, or halogen.

[0017] In another example, the invention comprises a compound as in paragraph [0016], wherein R3 is-Z-Q-J, wherein Z is a C1-C6 alkyl, Cl-C6 alkoxy Cl-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is piperidinyl, pyrrolyl, piperazinyl, imidazolid- inyl, morpholinyl, or thiomorpholinyl, wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C1-C4 alkyl, halo- gen, or Ci-C, alkoxy ; and J is-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, N02, C1-C6 alkyl, C1-C6 alkanoyl, and- C (=O) NR10R11, wherein Rio and Rll are independently H, or C1-C6 al- kyl, and R8 and Rg are independently selected from the group consisting of H, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 alkyl, thiomorpholinyl, C3-CB cycloal- kyl, and Cs-Cg cycloalkyl Cl-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups, wherein R6 at each occurrence is independently se- lected from the group consisting of halogen, hydroxy, NO2, C1-C6 alkyl, C1- C6 alkoxy, CF3, and OCF3 ; or R8 and Rg and the nitrogen to which they are at- tached form a 5 or 6 membered heterocycloal- kyl ring, which is unsubstituted or substi- tuted with 1,2, or 3 groups that are inde- pendently C1-C6 alkyl, C1-C6 alkoxy, hydroxy, or halogen.

[0018] In another example, the invention comprises a compound as in paragraph [0016], wherein R8 and Rg and the nitrogen to which they are attached form a morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl or pyrrolidinyl ring, each of which is unsubstituted or substituted with 1,2, or 3 groups that are independ- ently C1-C6 alkyl, C1-C6 alkoxy, hydroxy, or halogen.

[0019] In another example, the invention comprises a compound as in paragraph [0015], wherein R3 is-Z-Q-J wherein Z is a C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 alkyl- thio C1-C6 alkyl, each of which is unsubstituted or sub- stituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J,-C (=O)-, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each is unsubstituted or sub- stituted with 1 or 2 groups that are independently C1-C4 alkyl, halogen, or C1-C4 alkoxy; J is-C (=NR7) NR8R9 or-NH-C (=NR7) NR8Rg, wherein R7, R8, and the nitrogens to which they are attached form a 5,6, or 7 membered heterocycloalkyl group that is unsubstituted or substituted with 1, or 2 groups that are independently Cl-C6 alkyl, Cl-C6 alkoxy, hydroxy, or halogen; and Rg is selected from the group consisting of H, C1-C6 al- kyl, C1-C6 alkoxy, Cl-C6 alkoxy Ci-Cs alkyl, C3-C8 cycloalkyl, and C1-C6 alkyl substituted with at least one of morpholinyl, piperidinyl, thiomor- pholinyl, phenyl, naphthyl, pyrrolidinyl, pyridyl, pyridazyl, and imidazolyl, wherein each of the above is unsubstituted or substituted with 1, or 2 R6 groups; wherein R6 at each occurrence is independently selected from the group consisting of halogen, hy- droxy, NO2, C1-C6 alkyl, Ci-Ce alkoxy, CF3, and OCF3.

[0020] In another example, the invention comprises a compound as in paragraph [0015], wherein R3 is-Z-Q-J wherein Z is a Cl-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 alkyl- thio Ci-Ce alkyl, each of which is unsubstituted or sub- stituted with 1 or 2 Cl-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each is unsub- stituted or substituted with 1 or 2 groups that are in- dependently C1-C4 alkyl, halogen, or C1-C4 alkoxy; and J is-C (=NR7) NRBR9 or-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, C1-C6 alkyl, Cl-C6 alkanoyl, and-C (=O) NR10R11, wherein Rlo and Ril are independently H, or C1-C6 alkyl, and R8 and Rg are independently selected from the group con- sisting of H, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy Cl-C6 alkyl, morpholinyl C1-C6 alkyl, thio- morpholinyl, C3-CB cycloalkyl, and C3-C8 cycloalkyl C1-C6 alkyl, wherein each of the above is unsub- stituted or substituted with 1,2, 3, or 4 R6 groups; wherein R6 at each occurrence is independently selected from the group consisting of halogen, hy- droxy,. NO2, Cl-C6 alkyl, Cl-C6 alkoxy, CF3, and OCF3.

[0021] In another example, the invention comprises a compound as in paragraph [0010] of structural formula II wherein R3, R4, and Rs are as defined in paragraph [0010].

[0022] In another example, the invention comprises a compound as in paragraph [0021], wherein R4 is selected from the group consisting of H, C1-C4 alkyl, and benzyl wherein the benzyl group is unsubstituted or substituted with 1,2, 3, or 4 R6 groups, wherein R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy,-N02, C1-C6 alkyl, Cl-C6 alkoxy, CF3, and OCF3.

[00231 In another example, the invention comprises a compound as in paragraph [0022], wherein Rs is-M-G-A, wherein M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyraz- inyl, thiophenyl, and pyrrolyl, each of which is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, C1-C4 alkyl, hy- droxy, methoxy, ethoxy, isopropoxy, CF3, OCF3, halo C1-C4 alkyl, halo C1-C4 alkoxy, and hydroxy Cl-C4 alkyl ; G is selected from a direct bond between M and A, CH2, O, S, SO, and SO2 ; A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, benzo [1, 3] dioxyl, quinolinyl, isoquinolinyl, tet- rahydroisoquinolinyl, tetrahydronaphthyl, and di- hydronaphthyl, wherein each is unsubstituted or substituted with 1,2, or 3 groups that are inde- pendently selected from the group consisting of F, Cl, Br, Cl-C4 alkyl, C1-C4 alkoxy, halo C1-C4 al- kyl, CF3, OCF3, CN, and NO2 ; with the proviso that when M is phenyl, G is a direct bond between M and A, and A is phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl.

[0024] In another example, the invention comprises a compound as in paragraph [0022], wherein R3 is-Z-Q-J, wherein Z is a C1-C6 alkyl, C1-C6 alkoxy Cl-C6 alkyl, or Cl-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or Ci-C4 alkoxy groups; Q is a direct bond between Z and J,-C (=O)-, piperid- inyl, pyrrolyl, piperazinyl, imidazolidinyl, mor- pholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C1-C4 alkyl, halogen, or Cl-C4 alkoxy; J is-C (=NR7) NRBR9 or-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, C1-C6 alkyl, C1-C6 alkanoyl, phenyl C1-C6 alkanoyl and-C (=O)NR10R11, wherein Rlo and R11 are independently H, or Cl-C6 alkyl, R8 and Rg are independently selected from the group con- sisting of H, Cl-C6 alkyl, hydroxy, Cl-C6 alkoxy, alkoxy Cl-C6 alkyl, morpholinyl Cl-C6 alkyl, thio- morpholinyl, thiomorpholinyl S, S-dioxide, thio- morpholinyl S-oxide, piperidinyl C1-C6 alkyl, pyr- rolidinyl C1-C6 alkyl, imidazolidinyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, phenyl Cl-C6 alkyl, and pyridyl C1-C6 alkyl, pyri- dazyl C1-C6 alkyl, pyrimidyl C1-C6 alkyl, pyrazinyl C1-C6 alkyl, thienyl Cl-C6 alkyl, and furyl Cl-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or R8 and Rg and the nitrogen to which they are attached form a 5,6 or 7 membered heterocycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently C1-C6 alkyl, Cl-C6alkoxy, hydroxy, or halogen; or R7, R8, and the nitrogens to which they are attached form a 5,6, or 7 membered heterocycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hydroxy, or halogen, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; wherein R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO2, C1- C6 alkyl, C1-C6 alkoxy, CF3, and OCF3.

[0025] In another example, the invention comprises a compound as in paragraph [0021] of structural formula III wherein R3 is-Z-Q-J, wherein Z is a C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J,-C (=O)-, piperid- inyl, pyrrolyl, piperazinyl, imidazolidinyl, mor- pholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each is unsubstituted or substituted with 1 or 2 groups that are independently Cl-C4 alkyl, halogen, or C1-C4 alkoxy ; J is-C (=NR7) NR8R9 or-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, C1-C6 alkyl, Cl-C6 alkanoyl, phenyl C1-C6 alkanoyl and-C (=O) NR1R11, wherein Rio and RI, are independently H, or Cl-C6 al- kyl, R8 and Rg are independently selected from the group consisting of H, Cl-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy Cl-C6 alkyl, morpholinyl C1-C6 alkyl, thiomorpholinyl, thiomorpholinyl S, S-dioxide, thiomorpholinyl S-oxide, piperidinyl C1-C6 alkyl, pyrrolidinyl C1-C6 alkyl, imidazolidinyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl Ci-Ce alkyl, phenyl C1-C6 alkyl, and pyridyl Cl-C6 alkyl, pyridazyl C1-C6 alkyl, pyrimidyl Cl-C6 alkyl, pyrazinyl C1-C6 alkyl, thienyl C1-C6 alkyl, and furyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or Rs and Rg and the nitrogen to which they are at- tached form a 5,6 or 7 membered hetero- cycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently Cl-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen ; or R7, R8, and the nitrogens to which they are at- tached form a 5,6, or 7 membered hetero- cycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; wherein R6 at each occurrence is independently se- lected from the group consisting of halogen, hydroxy, NO2, C1-C6 alkyl, C1- C6 alkoxy, CF3, and OCF3; and Rs is-M-G-A, wherein M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyraz- inyl, thiophenyl, and pyrrolyl, each of which is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, C1-C4 alkyl, hy- droxy, methoxy, ethoxy, isopropoxy, CF3, OCF3, halo C1-C4 alkyl, halo C1-C4 alkoxy, and hydroxy Ci-C4 alkyl ; G is selected from a direct bond between M and A, CH2, O, S, SO, and SO2 ; and A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, benzo [1, 3] dioxyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, and dihydronaphthyl, wherein each is unsubstituted or substituted with 1,2, or 3 groups that are inde- pendently selected from the group consisting of F, Cl, Br, Cl-C4 alkyl, C1-C4 alkoxy, halo Cl-C4 al- kyl, CF3, OCF3, CN, and NO2 ; with the proviso that when M is phenyl, G is a direct bond between M and A, and A is phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl.

[0026] In another example, the invention comprises a compound as in paragraph [0025], wherein R3 is-Z-Q-J, wherein Z is a C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 Ci-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J, -C (=O)-, piperid- inyl, pyrrolyl, piperazinyl, imidazolidinyl, mor- pholinyl, or thiomorpholinyl, wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C1-C4 alkyl, halo- gen, or C1-C4 alkoxy; J is-C (=NR7) NR8Rg or-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, Cl-C6 alkyl, C1-C6 alkanoyl, and- C (=O) NR10R11, wherein Rlo and RI, are independently H, or Ci-Cg al- kyl, R8 and Rg are independently selected from the group consisting of H, Cl-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 alkyl, piperidinyl C1-C6 alkyl, pyr- rolidinyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, benzyl, phenethyl, and pyridyl C1-C6 alkyl, pyridazyl C1-C6 al- kyl, and furyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or R8 and Rg and the nitrogen to which they are at- tached form a 5,6 or 7 membered hetero- cycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently Cl-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; or R7, R8, and the nitrogens to which they are at- tached form a 5,6, or 7 membered hetero- cycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; wherein R6 at each occurrence is independently se- lected from the group consisting of halogen, hydroxy, NO2, C1-C6 alkyl, C1- C6 alkoxy, CF3, and OCF3 ; and Rs is-M-G-A, wherein M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyraz- inyl, thiophenyl, and pyrrolyl, each of which is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, C1-C4 alkyl, hy- droxy, methoxy, ethoxy, isopropoxy, CF3, OCF3, halo C1-C4 alkyl, halo C1-C4 alkoxy, and hydroxy C1-C4 alkyl ; G is selected from a direct bond between M and A, CH2, and O ; and A is selected from the group consisting of phenyl, naphthyl, pyridyl, tetrahydronaphthyl, benzo [1, 3] dioxyl, and dihydronaphthyl, wherein each is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, C1, Br, C1-C4 alkyl, C1-C4 alkoxy, halo Cl-C4 alkyl, CF3, OCF3, CN, and NO2, with the proviso that when M is phenyl, G is a direct bond between M and A, and A is phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl.

[0027] In another example, the invention comprises a compound as in paragraph [0026] of structural formula IV wherein R3 is defined in paragraph [0026], and X is CH, CRlz, or N; R12 and R13 are at each occurrence are independently selected from the group consisting of H, halogen, CF3, Cl-C4 al- kyl, and C1-C4 alkoxy; A is selected from the group consisting of phenyl, naphthyl, pyridyl, benzo [1, 3] dioxyl, and tetrahydronaphthyl, wherein each is unsubstituted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy, halo Ci-C alkyl, CF3, OCF3, CN, and NO2 ; and G is selected from a direct bond between M and A, CH2, and O ; with the proviso that when M is phenyl (in this case when X is equivalent to CH), G is a direct bond between M and A, and A is phenyl, then at least one of R12 and R13 cannot be H. [0028] In another example, the invention comprises a compound as in paragraph [0027] of structural formula V wherein R3, is as defined in paragraph [0026], A is phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-cyanophenyl, benzo [1, 3] dioxyl, 3,5-dimethylphenyl, 2- naphthyl, or 2-tetrahydronaphthyl; G is a direct bond between M and A, or G is oxygen; and R12 and R13 are independently H, fluoro, chloro, CF3, methyl or methoxy; with the proviso that when G is a direct bond to A, and A is phenyl, then at least one of R12 and R13 cannot be H.

[0029] In another example, the invention comprises a compound as in paragraph [0028], wherein R3 is-Z-Q-J, wherein Z is a Cl-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 al- kylthio Ci-Ce alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J or-C (=O)-, J is-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, Cl-C6 alkyl, C1-C6 alkanoyl, and- C (=O) NR10R11, wherein Rio and Rll are independently H, or C1-C6 al- kyl, and Rs and Rg are independently selected from the group consisting of H, Cl-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl Cl-C6 alkyl, Cg-Cg cycloalkyl, and C3-C8 cycloalkyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups, wherein R6 at each occurrence is independently selected from the group consist- ing of halogen, hydroxy, NO2, C1- C6 alkyl, C1-C6 alkoxy, CF3, and OCF3, or R8 and Rg and the nitrogen to which they are at- tached form a 5,6 or 7 membered hetero- cycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen.

[0030] In another example, the invention comprises a compound as in paragraph [0028], wherein R3 is-Z-Q-J, wherein Z is a C1-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J or-C (O)-, J is-NH-C (=NR7) NR8R9, wherein R7, R8, and the nitrogens to which they are at- tached form a 5,6, or 7 membered hetero- cycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently C1-C6 alkyl, Ci-Ce alkoxy, hy- droxy, or halogen; and Rg is selected from the group consisting of H, C1- C6 alkyl, Cl-C6 alkoxy, C1-C6 alkoxy C1-C6 al- kyl, C3-C8 cycloalkyl, and C1-C6 alkyl sub- stituted with at least one of morpholinyl, piperidinyl, thiomorpholinyl, phenyl, naphthyl, pyrrolidinyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups, wherein R6 at each occurrence is independently se- lected from the group consisting of halogen, hydroxy, NO2, C1-C6 alkyl, C1- C6 alkoxy, CF3, and OCF3.

[0031] In another example, the invention comprises a compound as in paragraph [0028], wherein R3 is-Z-Q-J, wherein Z is a Cl-C6 alkyl, Cl-C6 alkoxy Cl-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J, piperidinyl, pyrro- lyl, piperazinyl, imidazolidinyl, morpholinyl, or thio- morpholinyl, wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C1-C4 alkyl, halogen, or C1-C4 alkoxy ; J is-C (=NR7) NR8R9 wherein R7 is selected from the group consisting of H, CN, NO2, Cl-C6 alkyl, C1-C6 alkanoyl, and- C (=O) NRloRlg, wherein Rlo and Ril are independently H, or C1-C6 al- kyl, R8 and Rg are independently selected from the group consisting of H, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or R8 and Rg and the nitrogen to which they are at- tached form a 5,6 or 7 membered hetero- cycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; wherein R6 at each occurrence is independently se- lected from the group consisting of halogen, hydroxy, NO2, C1-C6 alkyl, C1- C6 alkoxy, CF3, and OCF3.

[0032] In another example, the invention comprises a compound as in paragraph [0027] of structural formula VI wherein R3, is as defined in paragraph [0027], A is phenyl, 3-fluorophenyl, 4-fluorophenyl, benzo [1, 3] dioxyl, 4-chlorophenyl, 4-cyanophenyl, 3,5- dimethylphenyl, 2-naphthyl, or 2-tetrahydronaphthyl G is a direct bond between M and A, or G is oxygen; R12 is selected from the group consisting of H, halogen, C1-C4 alkyl,-CF3, and Cl-C4 alkoxy.

[0033] In another example, the invention comprises a compound as in paragraph [0032], wherein R3 is-Z-Q-J, wherein Z is a Cl-C6 alkyl, C1-C6 alkoxy Ci-Cg alkyl, or C1-C6 al- kylthio Cl-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J or-C (O)-, J is -NH-C=(NR7)NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, C1-C6 alkyl, Cl-C6 alkanoyl, and- C (=O) NR10R11, wherein Rio and Rll are independently H, or C1-C6 al- kyl, and R8 and Rg are independently selected from the group consisting of H, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; wherein R6 at each occurrence is independently se- lected from the group consisting of halogen, hydroxy, NO2, C1-C6 alkyl, C1- C6 alkoxy, CF3, and OCF3, or R8 and Rg and the nitrogen to which they are at- tached form a 5,6 or 7 membered hetero- cycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently C1-C6 alkyl, Cl-C6 alkoxy, hy- droxy, or halogen.

[0034] In another example, the invention comprises a compound as in paragraph [0032], wherein R3 is-Z-Q-J, wherein Z is a C1-C6 alkyl, Cl-C6 alkoxy Cl-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J or-C (=O)-, J is-NH-C (=NR7) NR8R9, wherein R7, R8, and the nitrogens to which they are at- tached form a 5,6, or 7 membered hetero- cycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; and Rg is selected from the group consisting of H, C1- C6 alkyl, C1-C6 alkoxy, C1-C6 alkoxy C1-C6 al- kyl, C3-C8 cycloalkyl, and C1-C6 alkyl sub- stituted with at least one of morpholinyl, piperidinyl, thiomorpholinyl, phenyl, naphthyl, pyrrolidinyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups, wherein R6 at each occurrence is independently se- lected from the group consisting of halogen, hydroxy, NO2, Cl-C6 alkyl, Cl- C6 alkoxy, CF3, and OCF3.

[0035] In another example, the invention comprises a compound as in paragraph [0032], wherein R3 is-Z-Q-J, wherein Z is a Cl-C6 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 al- kylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J, piperidinyl, pyrro- lyl, piperazinyl, imidazolidinyl, morpholinyl, or thio- morpholinyl, wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C1-C4 alkyl, halogen, or C1-C4 alkoxy; J is-C (=NR7) NR. 8R9 wherein R7 is selected from the group consisting of H, CN, NO2, Cl-C6 alkyl, Cl-C6 alkanoyl, and- C (=O) NR10R11, wherein Rio and Rll are independently H, or Cl-C6 al- kyl, R8 and Rg are independently selected from the group consisting of H, Ci-Ce alkyl, hydroxy, C1-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 alkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; or Ra and Rg and the nitrogen to which they are at- tached form a 5,6 or 7 membered hetero- cycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; wherein R6 at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO2, C1-C6 al- kyl, C1-C6 alkoxy, CF3, and OCF3.

[0036] In another example, the invention comprises a compound of structural formula VII : wherein R3 is-Z-Q-J, wherein Z is a Cl-Cl0 alkyl, C1-C6 alkoxy C1-C6 alkyl, or C1-C6 alkylthio C1-C6 alkyl, each of which is unsubsti- tuted or substituted with 1 or 2 C1-C4 alkyl, halogen, or C1-C4 alkoxy groups; Q is a direct bond between Z and J,-C (=O)-, piperid- inyl, pyrrolyl, piperazinyl, imidazolidinyl, mor- pholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C1-C4 alkyl, halogen, or C1-C4 alkoxy; J is-NH-C (=NR7) NR8R9, wherein R7 is selected from the group consisting of H, CN, NO2, Cl-C6 alkyl, C1-C6 alkanoyl, phenyl Cl-C6 alkanoyl and-C (=O) NR10R11, wherein Rio and RI, are independently H, or C1-C6 al- kyl, R8 and Rg are independently selected from the group consisting of H, C1-C6 alkyl, hydroxy, Cl-C6 alkoxy, alkoxy C1-C6 alkyl, morpholinyl C1-C6 alkyl, thiomorpholinyl, thiomorpholinyl S, S-dioxide, thiomorpholinyl S-oxide, piperidinyl C1-C6 alkyl, pyrrolidinyl C1-C6 alkyl, imidazolidinyl C1-C6 alkyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl C1-C6 alkyl, phenyl C1-C6 alkyl, and pyridyl Cl-C6 alkyl, pyridazyl C1-C6 alkyl, pyrimidyl C1-C6 alkyl, pyrazinyl C1-C6 alkyl, thienyl C1-C6 alkyl, and furyl C1-C6 alkyl, wherein each of the above is unsubstituted or substituted with 1, 2,3, or 4 R6 groups ; or R8 and R9 and the nitrogen to which they are at- tached form a 5,6 or 7 membered hetero- cycloalkyl ring, which is unsubstituted or substituted with 1,2, or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; or R7, R8, and the nitrogens to which they are at- tached form a 5,6, or 7 membered hetero- cycloalkyl group that is unsubstituted or substituted with 1,2 or 3 groups that are independently C1-C6 alkyl, C1-C6 alkoxy, hy- droxy, or halogen; wherein each of the above is unsubstituted or substituted with 1,2, 3, or 4 R6 groups; wherein R6 at each occurrence is independently selected from the group consisting of halogen, hy- droxy, NO2, C1-C6 alkyl, Cl-C6 alkoxy, CF3, and OCF3 ; and Rs is-M-G-A, wherein M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, and pyrrolyl, each of which is substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, C1-C4 alkyl, hy- droxy, methoxy, ethoxy, isopropoxy, CF3, OCF3, halo C1- C4 alkyl, halo C1-C4 alkoxy, and hydroxy C1-C4 alkyl ; G is selected from a direct bond between M and A, and 0 ; and A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyrrolyl, benzo [1, 3] dioxyl, quino- linyl, isoquinolinyl, tetrahydroisoquinolinyl, tetra- hydronaphthyl, and dihydronaphthyl, wherein each is un- substituted or substituted with 1,2, or 3 groups that are independently selected from the group consisting of F, Cl, Br, Cl-C4 alkyl, C1-C4 alkoxy, halo C1-C4 alkyl, CF3, OCF3, CN, and Nos ; with the proviso that when M is phenyl, G is a direct bond between M and A, and A is phenyl, then at least one of the four remaining hydrogens on the phenyl ring of M, of M-G-A, must be substituted with a group independ- ently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl,-CN, haloalkoxy, and hydroxyalkyl.

[0037] In another example, the invention comprises a compound or pharmaceutically acceptable salt thereof of structural formula VIII : wherein R3 is selected from: H H H OMe N'N02 CN '''NH N0,'CN -K, 1 0 Y, CN CN NCN LU LU H H CN v CN po 4 N, x N N J '3 J '4 J -/4 N ce O :'. . % Y, 4 N, CN H CN H H H'IoNyN-_oMe N CN"-CN Y p N NH2 p \/S O <N NH N>CN 4CN O neo /- (J 2 --CN CON % s. ^N'"^N H % '' [v H XH XCN NO4 N ZIZI H'"CN CN N NH2 N NH2 NH2 i 4, ut Lazzi zon 2 NH2 . X N NH2 N NH2 N N _ J4 IVH 4 XH'y :'. ^N H H H Me N C L t H O N NO.. yy J "IcN O H NH. Y 0 0 and Rs is selected from F 1 JS'°) O, ) ! "F zon F F O -\&OF cl F. F 0 O i O i o . i OF F F F Br 0 N-N F O N-N N/II\ S/1 0 sac , F F 3 F F 0 S ni F . F /O OMe 0 , o I \ F F F O-J p p_/ F F F F N NN ° w o o < ON 0 0 F p zu H F F F con F cl F//I O /I O N I/ N I/ . u F and [0038] In another example, the invention comprises a compound or pharmaceutically acceptable salt thereof listed in Table 1: Table 1 # Compound Name N²-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N1-hydroxy-D- 1 argininamide 2 N1-hydroxy-N2-[(4-phenoxyphenyl)sulfonyl]-D-argininamide N2- {[4-(4-fluorophenoxy)phenyl]sulfonyl}-N1-hydroxy-D- 3 argininamide N2_ [ (3-fluoro-4-phenoxyphenyl) sulfonyl]-N-hydroxy-D- 4 argininamide N2- [ (3, 5-difluoro-4-phenoxyphenyl) sulfonyl]-Nl-hydroxy-D- 5 argininamide N2_ {[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N1- 6 hydroxy-D-argininamide N2-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N1- 7 hydroxy-D-argininamide N2-{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N1- 8 hydroxy-D-argininamide N2- { [3-fluoro-4- (4-fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy- 9 D-argininamide N2-{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N1-hydroxy - 10 D-argininamide N2-{[4-(4-cyanophenoxy)-3-fluorophenyl]sulfonyl}-N1-hydroxy- 11 D-argininamide N2-{[4-)3,5-dimethylphenoxy)-3-fluorophenyl]sulfonyl}-N1- 12 hydroxy-D-argininamide 13 N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulfonyl}-D-lysinamide N1-hydroxy-N2-{[6-(5,6, 7,8-tetrahydronaphthalen-2- 14 yloxy) pyridin-3-yl] sulfonyl}-D-argininamide N5-[(Z)-amino (nitroimino) methyl]-N2-{[6-(3- 15 fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-D- ornithinamide Compound Name N-5- [ (Z)-amino (nitroimino) methyl]-N1-hydroxy-N2-[(4- 16 phenoxyphenyl) sulfonyl]-D-ornithinamide N6- [ (E)-amino (cyanoimino) methyl]-N2-{[6-(3- 17 fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-D-lysinamide N6- [ (E)-amino (cyanoimino) methyl]-N1-hydroxy-N2-[(4- 18 phenoxyphenyl) sulfonyl]-D-lysinamide 19 {(E)-(cyanoimino)[(2-methoxyethyl) amino] methyl}-N2-{[6-(3- 19 fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-D-lysinamide N6- { (Z)- (cyanoimino) [ (2-methoxyethyl) amino] methyl}-Nl- 20 hydroxy-N2- [ (4-phenoxyphenyl) sulfonyl] -D-lysinamide N6-{(Z)-(cyanoimino)[(2-methoxyethyl0maino]methyl}-N2-{[4-(4 - 21 fluroophenoxy)phenyl]sulfonyl}-N1-hydroxy-D-loysinamide N6- [ (E)- (cyanoimino) (propylamino) methyl]-N2-{[6-(3- 22 fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-D-lysinamide N6- [ (E)- (cyanoimino) (propylamino) methyl]-N1-hydroxy-N2-[(4- 23 phenoxyphenyl) sulfonyl]-D-lysinamide N6- [ (E)- (cyanoimino) (propylamino) emthyl[-N2-{[4-(4- 24 fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy-D-lysinamide N6- { (Z)- (cyanoimino) [ (2-morpholin-4-ylethyl) amino] methyl}-N2- 25 {[6-(3-fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-D- lysinamide N6-{(Z)-(cyanoimino) [(2-morpholin-4-ylethyl)amino]methyl}-N1- 26 hydroxy-N2-[(4-phenoxyphenyl) sulfonyl]-D-lysinamide N6- [ (Z)- (cyanoimino) (cyclopropylamino) methyl]-Nl-hydroxy-N2- 28 [(4-phenoxyphenyl) sulfonyl]-D-lysinamide N6-[(E)-[(aminocarbonyl)imino] (hydroxyamino)methyl]-N2-{[4- 29 (4-fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy-D-lysinamide N1-hydroxy-5-morpholin-4-yl-N2-[(4-phenoxyphenyl)sulfonyl]-D - 30 norvalinamide N2-{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N1-hydroxy-5- 31 morpholin-4-yl-D-norvalinamide Compound Name N2_f {[6-(3-fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-6- 32 morpholin-4-yl-D-norleucinamide N1-hydroyx-6-morpholin-4-yl-N2-[(4-phenoxyphenyl)sulfonyl]-D - 33 norleucinamide 34 {[4-(4-fluorophenoxy)phenyl]sulfonyl}-N1-hydroxy-6- 34 morpholin-4-yl-D-norleucinamide N2-[(3-fluroo-4-phenoxyphenyl)sulfonyl]-N-1hydroxy-6- 35 morpholin-4-yl-D-norleucinamide N2-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N1- 36 hydroxy-6-morpholin-4-yl-D-norleucinamide N2_ {[3,5-difluoro-4-(4-fluoropenoxy)phenyl]sulfonyl}-N1- 37 hydroxy-6-morpholin-4-yl-D-norleucinamide N6- [ (E)- (cyanoimino) (morpholin-4-yl) methyl]-N2-{[4-(4- 38 fluorophenoxy) phenyl] sulfonyl}-N1-hydroxy-D-lysinamide N6- [ (Z)- (cyanoimino) (morpholin-4-yl) methyl]-N- { [3-fluoro-4- 39 (4-fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy-D-lysinamide 3- {1- [amino (imino) methyl] piperidin-4-yl}-N1-hydroxy-N2-[(4- 40 phenoxyphenyl) sulfonyl] alaninamide 3- {1- [ (Z)- (cyanoimino) (propylamino) methyl] piperidin-4-yl}- 41 N-hydroxy-N- [ (4-phenoxyphenyl) sulfonyl] alaninamide 3-(1-{(Z)-(cyanoimino)[(2- 42 methoxyethyl) amino] methyl} piperidin-4-yl)-N-hydroxy-N- [ (4- phenoxyphenyl) sulfonyl] alaninamide 3-(1-{(E)-(cyanoimino)[(2- 43 methoxyethyl) amino]methyl}piperidin-4-yl)-N2-{[3, 5-difluoro- 4-(4-fluorophenoxy)phenyl]sulfonyl}-N1-hydroxyalaninamide 3- (1- { (Z)- [ (aminocarbonyl) imino] [ (2- 44 methoxyethyl) amino] methyl} piperidin-4-yl)-N-hydroxy-N- [ (4- phenoxyphenyl) sulfonyl] alaninamide N2-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N1- 45 hydroxy-3-[(2-morpholin-4-ylethyl) thio]-D-valinamide # Compound Name N2-{[3-fluroo-4-(4-fluorophenoxy)phenyl]sulfonyl}-N1-hydroxy - 46 3-[(2-morpholin-4-ylethyl) thio]-D-valinamide 47 { [3-fluoro-4- (4-fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy- 47 3- [ (2-morpholin-4-yl-2-oxoethyl) thio] -D-valinamide N- { [4- (4-chlorophenoxy)-3-fluorophenyl] sulfonyl}-N-hydroxy- 48 3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide N-4, 5-dihydro-lH-imidazol-2-yl-N- { [4- (4- 49 fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy-D-lysinamide N6- [ (Z)- (cyanoimino) (cyclopropylamino) methyl]-N2-{[6-(3- so fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-D-lysinamide N1-hydroxy-N2- { [4- (phenyloxy) phenyl] sulfonyl}-3-piperidin-3- 51 ylalaninamide N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulfonyl}-3-pyrrolidin-3 - 52 ylalaninamide N2-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N1-hydroxy-D- 53 lysinamide N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulonyl}-D- 54 tryptophanamide N1-hydroxy-N2-({5-[2-(methylthio)pyriidin-4-yl]-2- 55 thienyl}sulfonyl)lysinamide 56 N1-hydroxy-N2-{[4-(phenylxoy)phenyl]sulfonyl}-D-histidinamid e N1-hydroxy-N2-methyl-N2-{[4-(phenylxoy)phenyl]sulfonyl}-3- 57 piperidin-3-ylalaninamide N1-hydroxy-N2-{[4-(phenylxoy)phenyl]sulfonyl}-3-piperidin-4- 58 ylalaninamide N1-hydroyx-N2-{[4-(phenyloxy)phenyl]sulfonyl}-3-pyridin-3-yl - 59 D-alaninamide N6-glycyl-N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulfonyl}-D- 60 lysinamide # Compound Name N1-hydroxy-N2,N6,N6-trimethyl-N2-{[4- 61 (phenyloxy) phenyl] sulfonyl}-D-lysinamide 3- [4- (aminomethyl) cyclohexyl]-N-hydroxy-N- { [4- 62 (phenyloxy) phenyl] sulfonyl} alaninamide N1-hydroxy-N2-{[6-(naphthalen-1-yloxy)pyridin-3-yl]sulfonyl} - 63 D-argininamide N1-hydroxy-N2-{[6-(5,6, 7,8-tetrahydronaphthalen-2- 64 yloxy) pyridin-3-yl] sulfonyl}-D-lysinamide N6- [ (E)- (cyanoimino) (hydroxyamino) methyl]-N2-({4-[(4- 65 fluorophenyl) oxy]phenyl}sulfonyl)-N1-hydroxy-D-lysinamie N2-({4-[(4-fluorohenyl)oxy]phenyl}sulfonyl)-N1-hydroxy-D- 66 lysinamide N6-{(Z)-(cyanoimino) [(2-morpholin-4-ylethyl)amino]methyl}-N2- 67 {[6-(3-fluorophenyl) pyridin-3-yl] sulfonyl}-Nl-hydroxy-D- lysinamide N2-({6-[(4-fluorophenyl)oxy]pyridin-3-yl}sulfonyl)-N1- 68 hydroxy-D-argininamide N- ( {6- [ (4-chlorophenyl) oxy] pyridin-3-yl} sulfonyl)-N- 69 hydroxy-D-argininamide N2-({3,5-difluoro-4-[(4-fluoophenyl)oxy]phenyl}sulfonyl)-N1- 70 hydroxy-N6- (morpholin-4-ylcarbonyl)-D-lysinamide 4-cyano-N1-hydroxy-N2-{[4-(phenylxoy)phenyl]sulfonyl}-D- 71 phenylalaninamide 4-cyano-N2-({3,5-difluoro-4-[(4- 72 fluorophenyl) oxy] phenyl} sulfonyl)-Nl-hydroxy-D- phenylalaninamide 3-cyano-N2-({3, 5-difluoro-4-[(4- 73 fluorophenyl) oxy] phenyl} sulfonyl)-Nl-hydroxy-D- phenylalaninamide 3-cyano-N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulfonyl}-D- 74 phenylalaninamide # Compound Name 75 ( {3, 5-difluoro-4- [ (4-hydroxyphenyl) oxy] phenyl} sulfonyl)- 75 N-hydroxyargininamide 76 {[3,5-difluoro-4-(pyridin-3-yloxy)phenyl]sulfonyl}-N1- 76 # hydroxyargininamide N2-({3,5-difluroo-4-[(4-fluroophenyl)oxy]phenyl}sulfonyl)-N1 - 77 hydroxy-N6-({{2-(methyloxy)ethyl] amino} carbonyl)-D- lysinamide N2-({3, 5-difluoro-4-[(4-fluorophenyl) oxy] phenyl} sulfonyl)-N6- 78 [1- (4, 4-dimethyl-2,6-dioxocyclohexylidene) ethyl]-Nl-hydroxy- D-lysinamide N2-{[3,5-difluoro-4-({4- 79 [(phenylmethyl) oxy] phenyl} oxy) phenyl] sulfonyl}-Nl- hydroxyargininamide N2-{[3,5-difluoro-4-(pyridin-3-yloxy)phenyl]sulfonyl}-N1- 80 hydroxy-6-morpholin-4-yl-D-norleucinamide N2-{[3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl}-N1- 81 hydroxy-3-morpholin-4-yl-D-alaninamide N2-({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N1 - 82 hydroyx-4-[[(hydroxyamino) (imino) methyl]-D-phenylalaninamide N- ( {3, 5-difluoro-4- [ (4-fluorophenyl) oxy] phenyl} sulfonyl)-N- 83 hydroxy-3- [ (hydroxyamino) (imino) methyl]-D-phenylalaninamide N2-({4-[(4-chlorophenyl)oxy]-3, 5-difluorophenyl} sulfonyl)-Nl- 84 hydroxy-3- [1- (morpholin-4-ylcarbonyl) piperidin-4- yl] alaninamide N2-({3,5-difluoro-4-[(4-fluroophenyl)oxy]phenyl}sulfonyl)-N1 - 85 hydroxy-3- [1- (morpholin-4-ylcarbonyl) piperidin-4- yl] alaninamide 3- [amino (imino) methyl]-N2-({3,5-difluroo-4-[(4- 86 fluorophenyl) oxy] phenyl} sulfonyl)-Nl-hydroxy-D- phenylalaninamide # Compound Name 4- [amino (imino) methyl]-N2-({3,5-difluoro-4-[(4- 87 fluorophenyl) oxy] phenyl} sulfonyl)-Nl-hydroxy-D- phenylalaninamide 88 (aminocarbonyl)-N2-({-fluoro-4-[(4- 88 fluorophenyl)oxy]phenyl}sulfonyl)-N1-hydroxy-D-ornithinamide (2R)-N2-[({4-[(4-chlorophenyl)oxy]-3, 5- 89 difluorophenyl} sulfonyl) amino]-4-(dimethylamino)-Nl- hydroxybutanamide (2R)-N2-[({4-[(4-chlorophenyl)oxy]-3, 5- difluorophenyl} sulfonyl) amino]-4-{[1-(4, 4-dimethyl-2,6- 90 dioxocyclohexylidene)-2-methylbutyl]amino}-N1- hydroxybutanamide 91 ( {4- [ (4-chlorophenyl) oxy]-3, 5-difluorophenyl} sulfonyl)-Nl- 91 hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl) thio]-D-valinamide (2R)-4-maino-N2-[({4-[(4-chlorophenyl) oxy] -3,5- 92 difluorophenyl} sulfonyl) amino]-Nl-hydroxybutanamide (2R)-4- { [amino (imino) methyl] maino}-N2-[({4-[(4- 93 chlorophenyl) oxy]-3, 5-difluorophenyl} sulfonyl) amino]-Nl- hydroxybutanamide N2-[({4-[(4-chlorophenyl)oxy]-3, 5- 94 difluorophenyl} sulfonyl) amino]-Nl-hydroxy-2-piperidin-4- ylacetamide N2-[({4-[(4-chlorophenyl) oxy] -3- 95 fluorophenyl} sulfonyl) amino]-N1-hydroxy-2-piperidin-4- ylacetamide N2-[({3-fluoro-4-[(4- 96 fluorophenyl) oxy] phenyl} sulfonyl) amino]-Nl-hydroxy-2- piperidin-4-ylacetamide N2-[({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)amino]-N1- 97 hydroxy-2-piperidin-4-ylacetamide N- ( { [6- (3-fluorophenyl) pyridin-3-yl] sulfonyl} amino)-N- 98 hydroxy-2-piperidin-4-ylacetamide # Compound Name N2-[({4-[(3, 5-dimethylphenyl) oxy]-3, 5- 99 difluorophenyl} sulfonyl) amino]-Nl-hydroxy-2-piperidin-4- ylacetamide 3- [4- (aminomethyl) cyclohexyl]-N- ( {4- [ (4-chlorophenyl) oxy] - 100 3, 5-difluorophenyl} sulfonyl)-Nl-hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]-N- ( {3, 5-difluoro-4- [ (4- 101 fluorophenyl) oxy] phenyl} sulfonyl)-Nl-hydroxyalaninamide 3-[4-(aminomethyl)cyclohexyl]-N2-({4-[(4-chlorophenyl)oxy]- 102 3-fluorophenyl} sulfonyl)-Nl-hydroxyalaninamide 3-[4-(aminomethyl)cyclohexyl]-N2-({3-fluoro-4-[(4- 103 fluorophenyl) oxy] phenyl} sulfonyl)-Nl-hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]-N- ( {4- [ (4- 104 fluorophenyl) oxy] phenyl} sulfonyl)-Nl-hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]-N- { [6- (3- 105 fluorophenyl) pyridin-3-yl] sulfonyl}-N-hydroxyalaninamide 3-[4-(aminomethyl)cyclohexyl]-N2-({4-[(3, 5- 106 dimethylphenyl) oxy]-3, 5-difluorophenyl} sulfonyl)-Nl- hydroxyalaninamide [0039] In another example, the invention comprises a pharmaceuti- cal composition comprising a compound as described in any of para- graphs [0010]- [0038] and a pharmaceutically acceptable carrier.

[0040] In another example, the invention comprises a method of making a compound as described in any of paragraphs [0010]- [0038].

In particular are described, methods of making bis-aryl ether sul- fonyl halide intermediates, which are used to make compounds of the invention, methods of making compounds of the invention both in solution-phase as well as on solid-phase.

[0041] The following paragraphs provide definitions of the vari- ous chemical moieties that make up the compounds of the invention and are intended to apply uniformly throughout the specification and claims unless expressly stated otherwise.

[0042] The term alkyl refers inclusively to a univalent C1 to C20 (unless explicitly stated otherwise) saturated straight, branched, cyclic, and combinations thereof alkane moiety and specifically includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t- butyl, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3- dimethylbutyl. In certain instances, specific cycloalkyls are de- fined (e. g. C3-C8 cycloalkyl) to differentiate them from generi- cally described alkyls (that, again, are intended to construe in- clusion of cycloalkyls). Thus"alkyl"includes, e. g., C3-C8 cycloalkyl. The term"alkyl"also includes, e. g., C3-C8 cycloal- kyl C1-C6 alkyl, which is a C1-C6 alkyl having a C3-C8 cycloalkyl terminus. Alkyl's can be optionally substituted with any appro- priate group, including but not limited to one or more moieties selected from halo, hydroxyl, amino, arylalkyl, heteroarylalkyl, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art or as taught, for example, in Greene, et al.,"Protec- tive Groups in Organic Synthesis, "John Wiley and Sons, Second Edition, 1991.

[0043] The term alkoxy refers to an alkyl (as defined above) moi- ety having a terminal-0-with a free valence, e. g., CH3CH2-0- ; [0044] The term alkenyl refers to a univalent C2-C6 straight, branched, or in the case of Cs8, cyclic hydrocarbon with at least one double bond.

[0045] The term aryl refers to a univalent phenyl, biphenyl, napthyl, and the like. The aryl group can be optionally substi- tuted with any suitable group, including but not limited to one or more moieties selected from halo, hydroxyl, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al. ,"Protective Groups in Or- ganic Synthesis, "John Wiley and Sons, Second Edition, 1991). As well, substitution on an aryl can include fused rings such as in tetrahydronaphthalene, chromen-2-one, dibenzofuran, and the like.

In such cases, e. g. tetrahydronaphthalene, the aryl portion of the tetrahydronaphthalene is attached to the portion of a molecule de- scribed as having an aryl group.

[0046] The term heteroatom means O, S, or N.

[0047] The term heterocycle refers to a cyclic alkyl, alkenyl, or aryl moiety as defined above wherein one or more ring carbon atoms is replaced with a heteroatom.

10048] The term heteroaryl specifically refers to an aryl that includes at least one of sulfur, oxygen, and nitrogen in the aro- matic ring. Non-limiting examples are pyrryl, furyl, pyridyl, 1,2, 4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, ben- zothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl.

[0049] The term halo refers to chloro, fluoro, iodo, or bromo. l0050] As used herein, the term pharmaceutically acceptable salts or complexes refers to salts or complexes that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. The compounds can also be administered as pharmaceutically acceptable quaternary salts known by those skilled in the art, which specifically include the quaternary am- monium salt of the formula-NR + Z-, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, io- dide,-O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzo- ate, cinnamoate, mandeloate, benzyloate, and diphenylacetate).

[0051] The term pharmaceutically active derivative refers to any compound that upon administration to the recipient, is capable of providing directly or indirectly, the compounds disclosed herein.

[0052] In some examples, as will be appreciated by those skilled in the art, two adjacent carbon containing groups on an aromatic system may be fused together to form a ring structure. The fused ring structure may contain heteroatoms and may be substituted with one or more substitution groups"R". It should additionally be noted that for cycloalkyl (i. e. saturated ring structures), each positional carbon may contain two substitution groups, e. g. R and R'.

[0053] Some of the compounds of the invention may have imino, amino, oxo or hydroxy substituents off aromatic heterocyclic ring systems. For purposes of this disclosure, it is understood that such imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i. e. , amino, imino, hydroxy or oxo, respectively.

[0054] Compounds of the invention are generally named using ACD/Name (available from Advanced Chemistry Development, Inc. of Toronto, Canada). This software derives names from chemical struc- tures according to systematic application of the nomenclature rules agreed upon by the International Union of Pure and Applied Chemistry (IUPAC), International Union of Biochemistry and Molecu- lar Biology (IUBMB), and the Chemical Abstracts Service (CAS).

[0055] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sul- fur atoms or quaternized nitrogen atoms in their structure.

[0056] The compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention.

[0057] Methods for the preparation and/or separation and isola- tion of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art. For example, optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When desired, the R-and S-isomers may be resolved by methods known to one skilled in the art, for example by: forma- tion of diastereoisomeric salts or complexes which may be sepa- rated, for example, by crystallization; via formation of di- astereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separa- tion of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where a desired enantiomer is converted into another chemical en- tity by one of the separation procedures described above, a fur- ther step may be required to liberate the desired enantiomeric form. Alternatively, specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting on enantiomer to the other by asymmetric transformation. For a mixture of enantiomers, en- riched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by re- crystallization.

[00581"Prodrug"refers to compounds that are transformed (typi- cally rapidly) in vivo to yield the parent compound of the above formulae, for example, by hydrolysis in blood. Common examples include, but are not limited to, ester and amide forms of a com- pound having an active form bearing a carboxylic acid moiety. Ex- amples of pharmaceutically acceptable esters of the compounds of this invention include, but are not limited to, alkyl esters (for example with between about 1 and about 6 carbons) wherein the al- kyl group is a straight or branched chain. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of this invention include, but are not limited to, primary amides, and secondary and tertiary alkyl amides (for example with between about 1 and about 6 carbons). Amides and es- ters of the compounds of the present invention may be prepared ac- cording to conventional methods. A thorough discussion of prod- rugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems, "Vol 14 of the A. C. S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, Ameri- can Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. l0059l"Metabolite/'refers to the break-down or end product of a compound or its salt produced by metabolism or biotransformation in the animal or human body; e. g. , biotransformation to a more po- lar molecule such as by oxidation, reduction, or hydrolysis, or to a conjugate (see Goodman and Gilman, "The Pharmacological Basis of Therapeutics"8. sup. th Ed. , Pergamon Press, Gilman et al. (eds), 1990 for a discussion of biotransformation). As used herein, the metabolite of a compound of the invention or its salt may be the biologically active form of the compound in the body. In one ex- ample, a prodrug may be synthesized such that the biologically ac- tive form, a metabolite, is released in vivo. In another example, a biologically active metabolite is discovered serendipitously, that is, no prodrug design per se was undertaken. An assay for activity of a metabolite of a compound of the present invention is known to one of skill in the art in light of the present disclo- sure.

[00601 In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceuti- cally acceptable solvents such as water, ethanol, and the like.

In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[00611 In addition, it is intended that the present invention cover compounds made either using standard organic synthetic tech- niques, including combinatorial chemistry or by biological meth- ods, such as bacterial digestion, metabolism, enzymatic conver- sion, and the like.

General Administration [00621 Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropri- ate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, na- sally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, in- tracistemally, or rectally, in the form of solid, semi-solid, ly- ophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin cap- sules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

[0063] The compositions will include a conventional pharmaceuti- cal carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc. Composi- tions of the invention may be used in combination with anticancer or other agents that are generally administered to a patient being treated for cancer. Adjuvants include preserving, wetting, sus- pending, sweetening, flavoring, perfuming, emulsifying, and dis- pensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for exam- ple, parabens, chlorobutanol, phenol, sorbic acid, and the like.

It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0064] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolau- rate, triethanolamine oleate, butylalted hydroxytoluene, etc.

100651 Compositions suitable for parenteral injection may com- prise physiologically acceptable sterile aqueous or nonaqueous so- lutions, dispersions, suspensions or emulsions, and sterile pow- ders for reconstitution into sterile injectable solutions or dis- persions. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol, polyethyleneglycol, glycerol, and the like), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

[0066] One preferable route of administration is oral, using a convenient daily dosage regimen that can be adjusted according to the degree of severity of the disease-state to be treated, propha- lactically or otherwise.

[0067] Solid dosage forms for oral administration include cap- sules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert cus- tomary excipient (or carrier) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, as for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) bind- ers, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humec- tants, as for example, glycerol, (d) disintegrating agents, as for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, croscarmellose sodium, complex silicates, and sodium carbonate, (e) solution retarders, as for example paraffin, (f) absorption accelerators, as for example, quaternary ammonium com- pounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorb- ents, as for example, kaolin and bentonite, and (i) lubricants, as for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.

In the case of capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[00681 Solid dosage forms as described above can be prepared with coatings and shells, such as enteric coatings and others well known in the art. They may contain pacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances and waxes. The active compounds can also be in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.

100691 Liquid dosage forms for oral administration include phar- maceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dis- solving, dispersing, etc. , a compound (s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceu- tical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like; solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1, 3-butyleneglycol, dimethylformamide; oils, in particular, cottonseed oil, groundnut oil, corn germ oil, olive oil, castor oil and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan; or mixtures of these substances, and the like, to thereby form a so- lution or suspension.

[0070] Suspensions, in addition to the active compounds, may con- tain suspending agents, as for example, ethoxylated isostearyl al- cohols, polyoxyethylene sorbitol and sorbitan esters, microcrys- talline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.

10071l Compositions for rectal administrations are, for example, suppositories that can be prepared by mixing the compounds of the present invention with for example suitable non-irritating excipi- ents or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liq- uid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein.

[0072] Dosage forms for topical administration of a compound of this invention include ointments, powders, sprays, and inhalants.

The active component is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also contemplated as being within the scope of this invention.

10073l Generally, depending on the intended mode of administra- tion, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound (s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. In one example, the composition will be between about 5% and about 75% by weight of a compound (s) of the invention, or a pharmaceutically accept- able salt thereof, with the rest being suitable pharmaceutical ex- cipients.

[0074] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed. , (Mack Publish- ing Company, Easton, Pa. , 1990). The composition to be adminis- tered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically ac- ceptable salt thereof, for treatment of a disease-state in accor- dance with the teachings of this invention.

[0075] The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors includ- ing the activity of the specific compound employed, the metabolic stability and length of action of the compound, the age, body weight, general health, sex, diet, mode and time of administra- tion, rate of excretion, drug combination, the severity of the particular disease-states, and the host undergoing therapy. The compounds of the present invention can be administered to a pa- tient at dosage levels in the range of about 0.1 to about 1,000 mg per day. For a normal human adult having a body weight of about 70 kilograms, a dosage in the range of about 0.01 to about 100 mg per kilogram of body weight per day is an example. The specific dosage used, however, can vary. For example, the dosage can de- pend on a number of factors including the requirements of the pa- tient, the severity of the condition being treated, and the phar- macological activity of the compound being used. The determina- tion of optimum dosages for a particular patient is well known to one skilled in the art.

10076l The compounds of the invention can be made following the teachings provided in the Examples, below, and method routine to those of ordinary skill in the art. The Examples describe how to make sulfonyl chloride intermediates used to make compounds of the invention, as well as solution and solid-phase methods of making compounds of the invention. The Examples are illustrative and are not intended to be limiting.

EXAMPLES Example 1 Synthesis of Intermediates 4- (4-fluorophenoxy)-3, 5-difluorophenylsulfonyl chloride [0077] Step 1: A mixture of 3,4, 5-trifluoronitrobenzene (20. 0g, 113mmol, commercially available from AsymChem of Durham, North Carolina), dry DMF (100ml), 4-fluorophenol (13.9g, 124mmol), and Cs2CO3 (56g, 172mmol) was stirred under N2 at 60-70°C for 1-2hrs.

After cooling to room temperature, the reaction mixture was parti- tioned between H20 and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2x). The EtOAc extractions were washed with sat'd NaCl (lx), dried over Na2SO4, and concentrated in vacuo to give 4- (4-fluorophenoxy)-3, 5- difluoronitrobenzene (32. 0g, 105%) which was used in the next step without further purification. NMR (DMSO-d6) : 8 7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J = 7.6 Hz).

[0078] Step 2: A mixture of 4- (4-fluorophenoxy)-3, 5- difluoronitrobenzene (30.4g, 113mmol), EtOAc (300ml), 10% Pd/C (2.6g) was stirred under an atmosphere of H2 at room temperature and pressure for approximately 6 hrs. The reaction mixture was filtered through Celite and concentrated in vacuo to give 4- (4- fluorophenoxy)-3, 5-difluoroaniline (26.5g, 98%) which was used in the next step without further purification. lH NMR (CDC13) : 8 3.82 (s, 2H), 6. 26 (d, 2H, J = 8.4 Hz), 6. 88 (m, 2H), 6. 93 (m, 2H).

[0079] Step 3: A solution of NaNO2 (8.4g, 122mmol) in H20 (20ml) was added dropwise to a mixture of 4- (4-fluorophenoxy)-3, 5- difluoroaniline (26.5g, lllmmol), AcOH (160ml), and conc. HC1 (160ml) cooled in an ice/NaCl/H2O bath. After addition was com- plete, the mixture was stirred an additional 20-30 minutes before a mixture of SO2 (74g, 1. 15mol) in AcOH (140ml) and CuCl2-2H20 (ll. lg, 65mmol) in H20 (16ml) was added. The reaction mixture was removed from the ice bath and stirred at room temperature for 1-2 hrs. The reaction mixture was poured into ice water and extracted with CH2C12 (3x). The combined CH2C12 extractions were washed with sat'd NaCl (lx), dried over Na2SO4, and concentrated in vacuo.

The resulting crude oil was purified by flash chromatography (9: 1 hexanes: EtOAC) to give 4- (4-fluorophenoxy)-3, 5- difluorophenylsulfonyl chloride (29.8g, 83%). 1H NMR (CDC13) : 8 6.94 (m, 2H), 7.10 (m, 2H), 7.71 (d, 2H, J = 6.4 Hz).

4- (4-Chlorophenoxy)-3, 5-difluorophenylsulfonyl chloride [0080] Step 1: A mixture of 3,4, 5-trifluoronitrobenzene (6.6g, 37mmol), dry DMF (30ml), 4-chlorophenol (5.26g, 41mmol), and Cs2CO3 (18.8g, 58mmol) was stirred under N2 at 60-70 C for 1-2hrs.

After cooling to room temperature, the reaction mixture was parti- tioned between H20 and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2x). The EtOAc extractions were washed with sat'd NaCl (lx), dried over Na2SO4, and concentrated in vacuo to give 4- (4-chlorophenoxy)-3, 5- difluoronitrobenzene (11.3g, 106%) which was used in the next step without further purification. H NMR (CDC13) : # 6. 90 (d, 2H, J = 7.6 Hz), 7. 28 (d, 2H, J = 7. 6 Hz), 7. 94 (d, 2H, J = 6.4 Hz).

Note: K2CO3/acetonitrile can be used in lieu of Cs2CO3/DMF.

[0081] Step 2: A mixture of 4- (4-chlorophenoxy)-3, 5- difluoronitrobenzene (10.6g, 37mmol), toluene (150ml), HzO (150ml), iron powder (6.9g, 124mmol), and ammonium acetate (9.3g, 120mmol) was heated to reflux with stirring for 2-3 hrs. After cooling to room temperature, the reaction mixture was filtered through Celite with thorough washing with H20 and EtOAc. The fil- trate was transferred to a separatory funnel and the phases sepa- rated. The aqueous phase was further extracted with EtOAc (2x).

The combined organic phases were washed with H2O (Ix), sat'd NaCl (lx), dried over Na2SO4, and concentrated in vacuo to give 4- (4- chlorophenoxy) -3,5-difluoroaniline (10.8g, 113%) which was used in the next step without further purification. lH NMR (CDC13) : 8 3.81 (s, 2H), 6.27 (d, 2H, J = 9.2 Hz), 6.85 (d, 2H, J = 9.2 Hz), 7.21 (d, 2H, J = 9.2 Hz).

[0082] Step 3: A solution of NaN02 (2.8g, 41mmol) in H20 (7. Oml) was added dropwise to a mixture of 4- (4-chlorophenoxy)-3, 5- difluoroaniline (9.5g, 37mmol), AcOH (50ml), and conc. HC1 (50ml) cooled in an ice/NaCl/H20 bath. After addition was complete, the mixture was stirred an additional 20-30 minutes before a mixture of SO2 (25g, 290mmol) in AcOH (50ml) and CuCl2-2H2O (3.8g, 22mmol) in H20 (6. Oml) was added. The reaction mixture was removed from the ice bath and stirred at room temperature for 1-2 hrs. The re- action mixture was poured into ice water and extracted with CH2C12 (3x). The combined CH2Cl2 extractions were washed with sat'd NaCl (lx), dried over Na2S04, and concentrated in vacuo. The resulting crude oil was purified by flash chromatography (9: 1 hexanes : EtOAC) to give 4- (4-chlorophenoxy)-3, 5-difluorophenylsulfonyl chloride (11. Og, 87%). 1H NMR (CDC13) : 8 6.92 (d, 2H, J = 7.2 Hz), 7.30 (d, 2H, J = 7. 2 Hz), 7.72 (d, 2H, J= 4.8 Hz).

3,4, 5-trifluorobenzenesulfonyl chloride [0083] To a 2000 mL round-bottomed flask was added 800 mL dis- tilled H20 and a stir bar. Upon stirring, the flask was cooled to - 10 °C in an ice-acetone bath. The flask was fitted with a 500 mL addition funnel and SOC12 (300 mL, 4.1 mol, 10 eq. ) was added dropwise over a period of 1 h. After complete addition, the solu- tion was stirred for 4 h while warming to room temperature.

10084l Meanwhile, in a separate 500 mL recovery flask was added 3,4, 5-trifluoroaniline (61 g, 0.41 mol, 1.0 eq. ), conc. HCl (150 mL), and a stir bar. The resulting suspension was stirred vigor- ously and cooled to-10 °C. The flask was fitted with a 250 mL addition funnel and a solution of NaNO2 (34.3 g, 0.50 mol, 1.2 eq. ) in H20 (125 mL) was added to the suspension dropwise over a period of 10 min. The reaction mixture, now nearly homogeneous, is yellow-orange in color. The reaction mixture was stirred for an additional 30 min while carefully maintaining the temperature at-10 °C.

[0085] The flask containing the SOC12/H20 solution is cooled again to-10 °C and a catalytic amount of Cu (I) Cl (-50 mg) was added. The solution turns dark green in color. The flask was fitted with a 500 mL addition funnel (previously chilled to 0 °C) and the 3,4, 5-trifluorodiazobenzene solution was quickly trans- ferred to the funnel. The solution was immediately added dropwise over a period of 3 min. After addition, the reaction mixture slowly turns darker green in color, but after stirring for 5 min becomes bright, lime green. The reaction was stirred for an addi- tional hour while warming to room temperature. The reaction mix- ture was transferred to a separatory funnel and extracted with CH2Cl2 (3 X 200 mL). The organic phases are combined and dried over anhydrous Na2SO4, filtered, and concentrated to give a dark- bronze oil (79.5 g, 83%).

Example 2 Synthesis of N2-{[3, 5-dífluoro-4-(4- fluorophenoxyJphenyl] sulfonyl}-N1-hydroxy-D-argininamide Arginine-derived trifluoroarylsulfonamide intermediate [00861 To a 1000 mL round-bottomed flask was added H-D-Arg (Pmc)- OH (15.7 g, 35.7 mmol, 1.0 eq. ), CHzCl2 (250 mL), and a stir bar.

The resulting suspension was stirred vigorously and trimethylsilyl chloride (TMS-C1) (7.76 g, 71.4 mmol, 2.0 eq. ) was added via sy- ringe over a period of 30 sec. After stirring for approximately 20 min, the solution becomes homogeneous. Et3N (20 mL, 143 mmol, 4.0 eq. ) was added via syringe over a period of 1 min. After stirring for an additional 20 min, the reaction flask was fitted with a 250 mL addition funnel and a solution of 3,4, 5- trifluorobenzenesulfonyl chloride (9.06 g, 39.3 mmol, 1.1 eq. ) in CH2C12 (50 mL) was added dropwise over a period of 3 min. The re- action mixture was stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo and dissolved in saturated NaHCO3 (500 mL) with stirring. The homogeneous solution was transferred to a separatory funnel and extracted with Et20 (2 X 100 mL). The aqueous phase was drained into a 2000 mL beaker and acidified to pH 2 with 1 N HC1. Upon acidification, the de- sired sulfonamide precipitated as a white solid (sulfonamide).

The aqueous suspension was extracted with EtOAc (2 X 300 mL). The organic phase was washed with brine (1 X 100 mL) and the organic phases were combined and dried over anhydrous NaHCO3, filtered, and concentrated to give an off-white solid. The solid was puri- fied via flash chromatography (10% MeOH in CH2C12 w/0. 05% AcOH, Rf =0.33), yielding the pure sulfonamide as an off-white solid as a foam (14.5 g, 64%). LC/MSD (HP Series 1100 MSD): Expected MW : 634.17, Observed M+H: 635.1, Retention time: 1.5 min.

Arginine-derived bis-aryl ether intermediate [0087] To a 1000 mL recovery flask was added trifluorobenzene sulfonamide (7.0 g, 11.0 mmol, 1.0 eq. ), 4-fluorophenol (12.4 g, 110 mmol, 10 eq. ), DMSO (230 mL), and a stir bar. With stirring the flask was fitted with a 100 mL addition funnel and potassium tert-butoxide (1 M in t-BuOH, 99 ml, 99 mmol, 9.0 eq. ) was added dropwise over a period of 5 min. Upon complete addition the reac- tion, flask was heated overnight in an oil bath at 65 °C. The re- action color becomes an opaque brown as the reaction progressed.

The reaction mixture was removed from the oil bath, allowed to cool to room temperature, and diluted with EtOAc (300 mL). The mixture was then acidified to pH 2-3 with 1N HC1. The aqueous layer was extracted with EtOAc (3 X 50 mL). The organic phases were combined and washed with brine (1 X 100 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a dark, viscous oil that was carried onto the next step without purification. LC/MSD (HP Series 1100 MSD): Expected MM : 726.20, Observed M+H: 727.1, Retention time: 1.62 min.

Arginine-derived bis-aryl ether intermediate : ester formation [00881 To a 200 mL recovery flask was added crude biphenyl ether (-6. 6 g, 9.04 mmol, 1.0 eq. ) and anhydrous MeOH (125 mL). HC1 gas was bubbled into the reaction until the solution was saturated.

The reaction was fitted with a septum and stirred overnight at room temperature. The reaction mixture was concentrated to a vis- cous oil and purified via flash chromatography (gradient of 100% Hex to 100% EtOAc) to yield a off-white bubbly solid (3.3 g, 49% over two steps from the trifluorobenzene sulfonamide free acid).

LC/MSD (HP Series 1100 MSD): Expected MW : 740.22, Observed M+H: 741.1, Retention time: 1.95 min. Arginine-derived bis-aryl ether intermediate: removal of guanidine protecting group [0089] To a 500 mL recovery flask was added biphenyl ether methyl ester (3.3 g, 4.45 mmol, 1.0 eq. ) and a stir bar. In a separate Erlenmeyer flask, 60% TFA/CH2Cl2 solution (250 mL) was prepared.

The solution was added to the reaction flask and the resulting so- lution was stirred for 1.5 h. The reaction mixture was concen- trated in vacuo and azeotroped with toluene (3 X 20 mL). The oil was further concentrated under high vacuum to remove residual toluene and TFA. The resulting oil was carried onto the next step with further purification. LC/MSD (HP Series 1100 MSD): Expected MW: 474.12, Observed M+H: 475.1, Retention time: 1.45 min.

N2_ ( [3, 5-difluoro-4-(4-fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy- D-argininamide [0090] Trifluoroacetate salt of N-2- { [3, 5-difluoro-4- (4- fluorophenoxy) phenyl] sulfonyl}-N-l-hydroxy-D-argininamide Solu- tions of HONHz-HCl (6.18 g, 89.0 mmol, 20 eq. ) in hot anhydrous MeOH (31 mL) and KOH (7.48 g, 133 mmol, 30.0 eq. ) in hot anhydrous MeOH (19 mL) were prepared. Upon dissolving, both solutions were removed from the hotplate and the KOH solution was added directly to the HONH2-HCl solution. Upon addition, a white solid (KCl) im- mediately precipitated. The resulting solution was allowed to stand for 20 min. The solution was filtered into a 200 mL recov- ery flask containing the methyl ester (2.1 g, 4.45 mmol, 1.0 eq. ) and a stir bar. Considerable bubbling occurred upon addition.

The reaction was stirred at room temperature for 1.5 h. The reac- tion mixture was acidified to pH 5 with 1N HC1. A viscous solid formed in the flask. The solution was concentrated and then re- dissolved in MeOH. An off-white solid (HONH2) remains out of so- lution. The solution was filtered and concentrated. Filtration was repeated as necessary until no more HONH2 was evident. The resulting dark solid was redissolved in MeOH and purified via re- verse phase HPLC (0. 5% TFA/AcCN, 0. 5% TFA/H2O) to give an off- white solid (1.0 g, 48% over two steps from Pmc-protected methyl ester). LC/MSD (HP Series 1100 MSD): Expected MW: 475.11, Ob- served M+H: 476.1, Retention time: 1.33 min.

Example 3 Synthesis of A [4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N1-hydroxy - D-argininamide and <BR> <BR> <BR> <BR> <BR> <BR> N2-{[4-(4-bromophenoxy)-3, 5-difluorophenyl] sulfonyl}-Nl-hydroxy-D- argininamide [0091] The above compounds (X = Cl, Br) were prepared via solu- tion phase chemistry in a manner similar to description above: N2- { [4- (4-chlorophenoxy)-3, 5-difluorophenyl] sulfonyl}-Nl- hydroxy-D-argininamide LC/MSD (HP Series 1100 MSD): Ex- pected MW: 491.08, Observed M+H: 492.0, Retention time: 1.37 min N2-{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N1- hydroxy-D-argininamide LC/MSD (HP Series 1100 MSD): Ex- pected MW : 535.03, Observed M+H: 536.0, Retention time: 1.39 min Example 4 N-2- [ (3, 5-difluoro-4-phenoxyphenyl) sulfonyl]-N-1-hydroxy-D- argininamide 10092l The above compound was prepared according to solid phase methods described below. LC/MSD (HP Series 1100 MSD) Expected MW: 457.12, Observed M+H: 458.1 Retention time: 1.38 min.

Example 5 Alternative synthesis of N-2-{[4-(4-chlorophenoxy)-3, 5- difluorophenyl] sulfonyl}-N-1-hydroxy-D-argininamide [0093] The following synthetic scheme illustrates how bis-aryl ether sulfonyl halide intermediates, as described above, can be used to make compounds of the invention. That is, rather than forming a bis-aryl ether sulfonamide from an existing haloaryl sulfonamide, as described above, in this case a bis-aryl ether sulfonyl halide is used to acylate, for example, an arginine- derived intermediate on its alpha-nitrogen to make the correspond- ing sulfonamide. Further steps to convert such bis-aryl ether sulfonamide intermediates to corresponding compounds of the inven- tion is also illustrated, specifically regarding alternative pro- tection de-protection strategies on route to hydroximate-derived compounds of the invention. F 0 1 0 0. 0 ci-I H 'NH CS I F I CI -N \ I I/ HO'v 2 HO'v S FCI O O O 00 TMSCI TMSCI NHo CH3 TEA NH MeOH H3C CH2CI2 PMC reflux N NU H CH3 P, Mc !'-"'3 b CH3 Chu b p H3Co_k__N_S HO, NIN, HsC AJA, tU HOAN A, , F <oN H F ci zK, NH20H-KOH nu NH MeOH NH HN4tH HN4rH NH PMC PMC C 50% TFA-CH2CI2 50% TFA-CH2C12 , F F O/ \ O/ 3c, _ N, o p O NH20H-KOH NH MeOH NH NH2 HN° (NH NHs NHg d Sulfonamide b [00941 D-Arg (pmc) -OH (3.21g) is suspended in dichloromethane (40ml) and 4-chlorophenoxy-3,5-difluorophenylsulfonyl chloride (2.5g), triethylamine (4. lml) and catalytic amount of DMAP are added. The mixture is stirred at room temperature for 5 hrs. Af- ter concentrated the reaction mixture, sat. NaHC03 (60ml), water (20ml) and diethyl ether (80ml) are added and extracted with ether.

[00951 The aqueous phase, after acidifying with 6N HC1, is ex- tracted with ethyl acetate. The combined organic phases are washed with brine, dried (MgS04) and concentrated under reduced pressure to give compound b as a white solid (5.3 g, 98%). MK830- 68: M+1=743. 1 Methyl ester c [0096] Compound b is dissolved in dry MeOH (150ml) and TMSC1 (1. 82ml) is added. The reaction mixture is stirred under the re- flux condition for 2 hrs. The reaction mixture is concentrated un- der reduced pressure to give compound 3 as a white solid. Purifi- cation by column chromatography with EtOAc-Hexane (3: 1) gives 2.8g (54%). MK830-70: M+1=757. 1 Guanidine d [0097] Compound c (2.8g) is treated with 50%-trifluoroacetic acid in DCM (50ml) included triethylsilane (0. 5ml) for 3 hrs. After con- centrated the reaction mixture, it was co-evaporated with toluene.

The residue is extracted with ether to remove the impurity and gives compound 4 as dark-gray solid (2. 1g, 116%). MK830-73 : M+1= 491.0 N2-{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N1-hyd roxy- D-argininamide [0098] Compound d (2.1g) is treated with 1.76M hydroxylamine in KOH methanol solution (preparation: 6.96g of NH20H). HC1 is dis- solved in MeOH (36ml) and 8.4g of potassium hydroxide is dissolved in MeOH (21ml), then mix together and filtered) for 2 hrs. After neutralizing the reaction mixture with 6N HC1, the reaction mix- ture is filtered to move the salt. The reaction mixture is concen- trated and purified by prep-HPLC. Prep-HPLC conditions: 20% to 70% in 60min (A: water with 0. 1% TFA, B: acetonitrile with 0. 1% TFA), ca 25 min RT is desired product.

[00991 After lyophilization, the product was triturated with 1N- HC1 three times, and then with water. White solid 0.87g (38%). MK 830-80 : M+1=492. 0. H-NMR (CD30D, 400 MHz Varian): 8 7.58 (d, J=7.2Hz, 2H), 7.30 (d, J=9.2Hz, 2H), 6.99 (d, J=9.2Hz, 2H), 3.68 (t, 1H), 3.18 (m, 2H), 1.70 (m, 3H), 1.59 (m, 1H) Example 6 Alternative synthesis of N2-{[3,5-Difluoro-4-(4- Fluorophenoxy) Phenyl] Sulfonyl}-Nl-Hydroxy-D-Argininamide [00100] This compound was synthesized via a similar route to N1- hydroxy-N2-[(4-phenoxyphenyl) sulfonyl]-D-argininamide and N2-{[4- (4-chlorophenoxy) -3,5-difluorophenyl] sulfonyl}-Nl-hydroxy-D- argininamide: H-D-Arginine (Pmc) -OMe b' [001011 To a round bottom flask equipped with a magnetic stir bar was added H-D-Arginine (Pmc) -OH (13.1 g, 29.7 mmol, 1.0 eq. ), dry MeOH (300 mL), and trimethyl silyl chloride (TMSC1) (16.2 g, 18.9 ml, 148.8 mmol, 5.0 eq. ). The reaction was then allowed to stir at rt for a total of 36 h before concentrating via rotary evapora- tion. The viscous oil residue was then dissolved in 400 mL of saturated NaHCO3 and allowed to stir for 10 min. The aqueous layer was then extracted three times with ethyl acetate (300 mL).

The combined EtOAc layers were then dried with Na2SO4, concen- trated and dried on high vacuum overnight to give H-D- Arginine (Pmc)-OMe b'as a white foam (12.4 g, 92 % yield): LC/MS Calcd for [M+H] +454. 0, found 455.1.

Sulfonamide d' [00102] To a round bottom flask equipped with a magnetic stir bar was added H-D-Arginine (Pmc)-OMe b' (13.0 g, 27.3 mmol, 1.0 eq. ), dry CH2C12 (200 mL), Triethyl amine (TEA) (7.23g, 9.2 mL, 71.5 mmol, 2.5 eq. ), and sulfonyl chloride cl (9.6 g, 30 mmol, 1.05 eq). The reaction was then allowed to stir at rt for a total of 3 h. An additional 100 ml of CH2Cl2and the organic layer was washed 2X with water (200 mL), 2X with 0.5M HC1, and 2X with brine. The organic layer was dried with Na2SO4, concentrated, and the solid was columned using the biotage system with the eluant being 2: 1 hexane/ethyl acetate. Sulfonamide d'was obtained as a pale yellow foam (20.5 g, 96 % yield) : LC/MS Calcd for [M+H] +740. 0, found 741.1. 2.

Guanidine e' [001031 To a round bottom flask was added Sulfonamide d (20.5 g, 27.7 mmol), 1: 1 TFA: CH2Cl2 (500 mL), and triethyl silane (5.0 mL).

The reaction was allowed to sit at rt for 90 min before concen- trating via rotary evaporation. The residual TFA was then removed via azeotroping with toluene. The oil was then triturated 3X with ether (125 mL) to give crude guanidine el as a white solid. Gua- nidine e'was then dissolved in 50 mL of EtOAc, concentrated via rotary evaporation, and triturated again 2X with ether (50 mL).

Drying of crude guanidine e'on high vacuum overnight afforded a yellow brown foam, which was then rinsed 2X with ether (100 mL), and dried on high vacuum, yielding guanidine ew as a yellow foam which was taken on crude to the next step. LC/MS Calcd for [M+H] +474. 46, found 475.1.

Hydrochloride salt of N- { [3, 5-difluoro-4- (4- fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy-D-argininamide [00104] To a round bottom flask was added the above crude Gua- nidine e' (12. 1g, 26.7 mmol, 1.0 eq. ), and freshly made 1.76 M HONH2 in MeOH (300 mL, 528 mmol, 20 eq. ). The reaction was al- lowed to sit at rt overnight before filtering off the precipitate, and concentrating the supernatant to one fourth the original vol- ume. The supernatant was then neutralized to pH 7. Odropwise with neat TFA, concentrated via rotary evaporation, and triturated with ether (100 mL). The crude material was then dissolved in 60 mL of 20: 80 acetonitrile: water and purified via three 20 mL injections on a Varian Prep HPLC system: gradient = 15% B to 70% B in 40 min where A = 100 % water, 0.1 % TFA, and B = 100% acetonitrile, 0. 1% TFA; flow rate = 160 mL/min, fraction size = 100 mL. Each frac- tion was analyzed on analytical HPLC, and LC/MS. Pure fractions were combined, lyophilized, HCl exchanged with 1N HC1 3X, and wa- ter exchanged 1X to give pure N2_ [3, 5-difluoro-4- (4- fluorophenoxy) phenyl] sulfonyl}-Nl-hydroxy-D-argininamide as a white solid (6.5 g, 45% yield). LC/MS Calcd for [M+H] +475. 44, found 476.1 ; 1HNMR (400 MHz, MeOD) : # 7. 68 (dt, J = 8.8, 3.2Hz, 2 H), 7.14 (M, J = 8.4Hz, 6 H), 3.65 (t, J = 7.6Hz, 1 H), 3.15 (t, J = 6.4 Hz, 2 H), 1.51-1. 69 (m, 4 H).

Example 7 <BR> <BR> <BR> _y-N-2- [ (4-Phenoxyphenyl) Sulfon. Yll- D-Argininamide This compound was made via two different pathways as shown below.

Sulfonamide c'' [00105] To a round bottom flask equipped with a magnetic stir bar was added H-D-Arginine (Pmc) -OH (60.0 g, 136. 4 mmol, 1.0 eq. ), dry CH2C12 (1000 mL), 4-phenoxy benzene sulfonyl chloride (b'') (36.4 g, 136 mmol, 1.0 eq.), and triethyl amine (75.0 mL, 542.4 mmol, 4.0 eq. ). Trimethyl silyl chloride (34.2 mL, 271 mmol, 2.0 eq. ) was then dropwise to the stirring reaction. The reaction was then allowed to stir at rt for an additional 3 h before concentrating via rotary evaporation. The solid residue was then dissolved in 300 mL of saturated NaHCO3 and 300 mL H20. The aqueous layer was then washed twice with ether (200 mL), acidified with 2N HC1 (200 mL), and extracted 3X with EtOAc. The combined EtOAc layers were then dried with Na2SO4, concentrated and dried on high vacuum overnight to give Sulfonamide c''as a white foam (90.0 g, 98% yield) : LC/MS Calcd for [M+H] +673. 0, found 673.2.

Methyl Ester d'' [00106] To a round bottom flask equipped with a magnetic stir bar was added crude Sulfonamide c'' (45.0 g, 67.0 mmol, 1.0 eq. ), dry MeOH (500 mL), and Trimethyl silyl chloride (13.2 mL, 100 mmol, 1.5 eq. ). The reaction was then refluxed under nitrogen for 4 h, cooled to rt, and concentrated via rotary evaporation. Water (200 mL) and saturated NaHCO3 (20 mL) were added to the solid residue, and the aqueous layer was extracted 3X with EtOAc (200 mL), dried with Na2S04, concentrated and further dried on high vacuum over- night to give Methyl Ester d''as a pale yellow foam (43.0 g, 93.5 % yield): LC/MS Calcd for [M+H] +687. 0, found 687.2.

Guanidine e'' [00107] To a round bottom flask was added crude Methyl Ester dz (32.0 g, 46.6 mmol), 1: 1 TFA : CH2Cl2 (500 mL), and triethyl silane (5.0 mL). The reaction was allowed to sit at rt for 90 min before concentrating via rotary evaporation. The residual TFA was then removed via azeotroping with toluene. The oil was then triturated 3X with ether (125 mL) to give crude guanidine e''as a white solid. Guanidine e''was then dissolved in 50 mL of EtOAc, con- centrated via rotary evaporation, and triturated again 2X with ether (50 mL). Drying of crude guanidine e''on high vacuum over- night afforded a yellow brown foam, which was then rinsed 2X with ether (100 mL), and dried on high vacuum, yielding guanidine e'' as a yellow foam which was taken on crude to the next step. LC/MS Calcd for [M+H] +421. 0, found 421.1.

Hydrochloride salt of Nl-hydroxy-N2-l (4-phenoxyphenyl) sulfonyl]-D- argininamide 100108] To a round bottom flask was added to the above crude Gua- nidine e'' (19.0 g, 45.2 mmol, 1.0 eq. ), and freshly made 1.76 M HONH2 in MeOH (380 mL, 668.8 mmol, 14.8 eq. ). The reaction was allowed to sit at rt overnight before filtering off the precipi- tate, and concentrating the supernatant to one fourth the original volume. The supernatant was then neutralized to pH 7. Odropwise with neat TFA, concentrated via rotary evaporation, and triturated with ether (100 mL). Crude EXEL-00987124 was then dissolved in 60 mL of 20: 80 acetonitrile: water and purified via three 20 mL injec- tions on a Varian Prep HPLC system: gradient = 15% B to 70% B in 40 min where A = 100 % water, 0.1 % TFA, and B = 100% acetoni- trile, 0. 1% TFA; flow rate = 160 mL/min, fraction size = 100 mL.

Each fraction was analyzed on analytical HPLC, and LC/MS. Pure fractions were combined, lyophilized, HC1 exchanged with IN HC1 3X, and water exchanged 1X to give pure Nl-hydroxy-N2- [ (4- phenoxyphenyl) sulfonyl]-D-argininamide as a white solid (6.8 g, 35.9 % yield). Mixed fractions contaminated with a small impurity were also collected in a separate flask and repurified (2.0 g, 10.5 % yield). LC/MS Calcd for [M+H] +422. 0, found 422.1 ; 1HNMR (400 MHz, MeOD) : 8 7.81 (dt, J = 8.8, 3.2Hz, 2 H), 7.42 (t, J = 7.4Hz, 2 H), 7. 22 (t, J = 7.4Hz, 1 H), 7.1 (d, J = 8.4Hz, 2 H), 7. 05 (d, J = 8.8Hz, 2 H), 3.65 (t, J = 7.6Hz, 1 H), 3.15 (t, J = 6.4 Hz, 2 H), 1.51-1. 69 (m, 4 H).

Hydroxamic acid fil [00109] To a round bottom flask was added methyl ester d'' (46.0 g, 67.0 mmol, 1.0 eq. ) and freshly prepared 1.76 M HONH2 in MeOH (152.0 mL, 268 mmol, 4.0 eq. ). The reaction was allowed to sit at rt for 3 h before adding another 152 mL of 1.76M HONH2. The reac- tion was continued for another 4 h before quenching with IN HC1 (250 mL) to a pH of 5.0. The methanol was evaporated and the wa- ter was decanted from the residual solid crude product. The crude hydroxamic acid f'was purified in two batches (approximately 25 g each batch) by dissolving in EtOAc, and dry loading onto a Bio- tage FLASH 75L pre-packed cartridge, and eluted withlO0% EtOAc to afford pure hydroxamic acid f''as an orange solid (34.7 g, 75% yield). LC/MS Calcd for [M+H] +688. 0, found 688.2 Hydrochloride salt of Nl-hydroxy-N2-l (4-phenoxyphenyl) sulfonyl]-D- argininamide [00110] To a round bottom flask was added hydroxamic acid f (19.7 g, 46.9mmol), 1 : 1 TFA: CH2Cl2 (400 mL), and triethyl silane (4.0 mL). The reaction was stirred at rt for 90 min, and concen- trated via rotary evaporation. The residual TFA was then removed via azeotroping with toluene. The oil was then triturated 3X with ether (125 mL) to give crude 2 as a brown solid. The solid was then dissolved in 40 mL of 20: 80 acetonitrile: water and purified via two 20 mL injections on a Varian Prep HPLC system: gradient = 15% B to 70% B in 40 min where A = 100 % water, 0.1 % TFA, and B = 100% acetonitrile, 0. 1% TFA; flow rate = 160 mL/min, fraction size = 100 mL. Each fraction was analyzed on analytical HPLC, and LC/MS. Pure fractions were combined, lyophilyzed, HC1 exchanged with IN HC1 3X, and water exchanged 1X to give pure N1-hydroxy-N2- [ (4-phenoxyphenyl) sulfonyl]-D-argininamide as a white solid (5.2 g, 26.3 % yield). Mixed fractions contaminated with a small impu- rity were also collected in a separate flask and repurified (1.4 g, 7.2 % yield). LC/MS Calcd for [M+H] +422. 0, found 422.1 ; 1HNMR (400 MHz, MeOD) : 6 7.81 (dt, J = 8.8, 3.2Hz, 2 H), 7.42 (t, J = 7. 4Hz, 2 H), 7.22 (t, J = 7.4Hz, 1 H), 7.1 (d, J = 8.4Hz, 2 H), 7.05 (d, J = 8.8Hz, 2 H), 3.65 (t, J = 7.6Hz, 1 H), 3.15 (t, J = 6.4 Hz, 2 H), 1.51-1. 69 (m, 4 H).

Example 8 General Experimental Procedures for the Synthesis of Cyanoguanidi- nes Sulfonamide cl'' [00111] To a round bottom flask equipped with a magnetic stirrer was added Methylester a''' (17.0 mmol, 1.0 eq. ), dry CH2C12 (170 mL), Sulfonyl Chloride b''' (18.5 mmol, 1.1 eq. ), and 2,6-lutidine (42.5 mmol, 2.5 eq. ). The reaction was stirred at rt for 5 h be- fore quenching with H20 (100 mL) and saturated NH4C1 (20 mL). The aqueous layer was extracted 3X with EtOAc (100 mL), and the com- bined organic layers were dried with Na2SO4 before concentrating to give crude sulfonamide c"'as a clear oil. Trituration with 20: 80 EtOAc: Hexanes, followed by drying on high vacuum then af- fords relatively pure sulfonamide cl''as a white solid that can be taken on directly to the next step.

Amine d''' [00112] To a round bottom flask equipped with a magnetic stir bar was added Sulfonamide c''' (1.14 mmol), dry MeOH (20.0 mL), dry CH2C12 (3.0 mL) and 10% Pd/C (120 mg). The reaction was stirred at rt over an atmosphere of hydrogen for 5h before filtering over a pad of celite and rinsing 3X with EtOAc. The washes were com- bined and concentrated to give crude amine d'''as a clear oil which can be taken directly onto the next step.

Cyanoguanidine fol'' [00113] To a round bottom flask equipped with a magnetic stir bar was added amine d''' (1.14 mmol, 1.0 eq. ), dry DMF (6.0 mL), dry triethylamine (6.0 mL), thiomethylcyanoguanidine e''' (1.14 mmol, 1.0 eq. ), and AgN03 (1.23 mmol, 1.1 eq. ). The brown slurry was stirred at rt overnight in the absence of light before filtering out the brown precipitate. The filtrate was concentrated and placed on high vacuum to remove any residual DMF. Crude cyanogua- nidine f'''was then purified via silica gel chromatography.

Hydroxamic acid g''' [00114] To a round bottom flask was added cyanoguanidine f'' (0.47 mmol, 1.0 eq. ) and, freshly prepared 1.76 M HONHz (1. 9 mmol, 4.0 eq. ). The reaction was stirred at rt for 1 h before adding an- other 1.0 mL of 1.76 M HONH2. After stirring for an additional 3 h, the reaction was neutralized to a pH of 7.0 with 1N HC1. (Care was taken during the neutralization such that the pH was never be- low 7.0 to prevent cyanoguanidine conversion to the urea. ) Silica gel chromatography then afforded pure hydroxamic acid g'''. Al- ternatively, hydroxamic acid g'''can be purified via prep HPLC (solvent system = water/acetonitrile with 0. 1% TFA), although fractions containing hydroxamic acid g'''must be neutralized with saturated NaHC03 prior to concentration to prevent hydrolysis of the cyanoguanidine to the corresponding urea).

[00115] In the case where R2 = H: Cyanoimine ill' [00116] To a round bottom flask equipped with a magnetic stir bar was added amine d''' (0.51 mmol, 1.0 eq. ), isopropanol (3.0 mL), triethyl amine (0.51 mmol, 1.0 eq. ), and diphenyl cyano carbonimi- date (0.56 mmol, 1.1 eq. ). The reaction was stirred at rt over- night, concentrated via rotary evaporation, and purified via sil- ica gel chromatography.

Cyanoguanidine j"' [00117] To a round bottom flask was added cyanoimine ill, (0.11 mmol), isopropanol (2.0 mL), and concentrated NH40H (1.0 mL). The reaction was stirred at rt overnight, and concentrated via rotary evaporation to afford crude cyanoguanidine j'''which can be car- ried onto the next step without further purification.

Example 9 Preparation of sulfonamide hydroxamates on solid support General procedure for the sulfonamide hydroxamate synthesis on solid support: General procedure in solid phase syntheses: i i i) 20% Piperidine-CH2CI2, NH-Fmoc Nu-For //H R 0. 71 mmole/g ii) HATU, Amino Acid, DIEA NovaBiochem CH2CI2-DMF 0 SWELLING NH-Fmoc 2hr in DCM Hp 1) 20% Pip. DCM R on 2) RS02CI, 2, 6-lutidine c N DCM, RT x cil Y/=\ TC ! o r 0 H r"-) LILX HO O H// /, NN. S\ W X _ p. 0 H R O. 0 I R 50% TFA-DCM-TES 30min Fmoc deprotection of resin bound N- (Fmoc) hydroxylamine: [00118] 2-Chlorotrityl polystyrene resin functionalized with N- (Fmoc) hydroxylamine (0.2g, 0.154 mmole) was welling in dichloro- methane (DCM). The resin was treated with 20% piperidine in DCM for 1 hr. After filtration the resin was washed with DCM then with methanol (MeOH) and DCM.

Amino acid coupling to 0- (resin) hydroxylamine : [00119] 0- (resin) hydroxylamine (0.154 mmole) was treated with a solution of the appropriate N- (Fmoc) protected amino acid (2 eq.) in dimethylformamide (DMF) -DCM containing HATU (O- (7- azabenzotriazol-l-yl)-N, N, N', N', -tetramethyluronium hexafluoro- phosphate, 2eq. ) and diisopropylethylamine (DIEA, 4eq. ). The re- sulting slurry was agitated for 13 hrs. The resin was filtered and washed with DMF, MeOH, and DC a-N-Fmoc deprotection of resin bound amino acid hydroxylamine : [00120] 0- (resin) hydroxylamine-amino acid (a-N-Fmoc) (0.154 mmole) was treated with 20% piperidine in DCM. The resin was agi- tated for 1 hr then filtered, washed with DCM, MeOH and DCM.

Formation of sulfonamide: [00121] 0- (resin) hydroxyl amino-amino acid (0.154mmole) was treated with appropriate sulfonyl chloride (2 eq. ) containing 2,6- lutidine (2eq. ) in DCM for 13hrs. The resin was filtered and washed with DCM, MeOH and DCM.

Compound release from the resin: [00122] The (X-N-substituted resin bound amino acid sulfonamide hydroxamate was treated with 20% Trifluoroacetic acid (TFA) con- taining 2% triethylsilane in DCM for 30 min. The resin filtered and evaporated to dryness then purified by semi-prep HPLC.

[00123] Following compounds are prepared using method described above: N-2- { [6- (3-fluorophenyl) pyridin-3-yl] sulfonyl}-N-l-hydroxy- D-argininamide, N-l-hydroxy-N-2- [ (4-phenoxyphenyl) sulfonyl]-D- argininamide, N-2- { [4- (4-fluorophenoxy) phenyllsulfonyl}-N-1- hydroxy-D-argininamide, N-2- [ (3-fluoro-4-phenoxyphenyl) sulfonyl] - N-1-hydroxy-D-argininamide, N-2- { [4- (4-chlorophenoxy)-3, 5- difluorophenyl] sulfonyl}-N-l-hydroxy-D-argininamide, N-2- { [3, 5- difluoro-4- (4-fluorophenoxy) phenyl] sulfonyl}-N-1-hydroxy-D- argininamide, and N-2- (1, 1'-biphenyl-4-ylsulfonyl)-N-1-hydroxy-D- argininamide Example 9 Preparation of pyridylether sulfonamide hydroxamate on solid sup- port Formation of pyridylarylether-sulfonamide : [00124] 0- (resin) hydroxyl amino-amino acid (0. 154mmole) was treated with 2-chloropyridyl sulfonyl chloride (2 eq. ) containing 2,6- lutidine (2eq. ) in DCM for 13hrs. The resin was filtered and washed with DCM, MeOH and DCM.

Formation of pyridyl-aryl ether: [00125] The a-N-substituted resin bound amino acid sulfonamide hydroxamate was treated with arylalcohol (10eq.), cesium carbon- ate (5eq. ) in N-methylpyrrolidinone (NMP) at 80°C for 13hrs. The resin filtered and washed with DMF, MeOH, water, MeOH and DCM.

Compound release from the resin : [00126] The a-N-substituted resin bound amino acid sulfonamide hydroxamate was treated with 20% Trifluoroacetic acid (TFA) con- taining 2% triethylsilane in DCM for 30 min. The resin filtered and evaporated to dryness then purified by semi-prep HPLC.

Following compounds are prepared using method described above: - N-1-hydroxy-N-2- { [6- (5, 6,7, 8-tetrahydronaphthalen-2- yloxy) pyridin-3-yl] sulfonyl}-D-argininamide - Series of Mono-fluoro aryl ether: 3,4-difluorosulfonyl chloride is used instead of 2-chloropyridyl sulfonyl chloride.

Example 10 Preparation of pyridylether sulfonamide hydroxamate on solid sup- port \ \ CI i 20% Pi eridine-CH CI, I/CI p NH-Fmoc NH-Fmoc N H 0. 71 mmole/g ii) HATU, Amino Acid, DIEA NovaBiochem CH2CI2-DMF o O SWELLING NH-Fmoc 1-2hr in DCM Hp 1) 20% pip.-DCM 2) 2, 6-lutidine CI-S DCM, RT F F F F CIO PF /H R -S\/H 01 Ho w Ix 50% TFA-DCM-TES Cs2C03, NMP 20-30min 60-70oC, l3hrs F ozon HO, N, S, H 6-0 [00127] Following compounds are prepared using method described above: - N-2-[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N-1-hydroxy-D- argininamide (4) - N-2- { [3-fluoro-4- (4-fluorophenoxy) phenyllsulfonyl)-N-1- hydroxy-D-argininamide (9) - N-2-{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N-1- hydroxy-D-argininamide (10) - N-2-{[4-(4-cyanophenoxy)-3-fluorophenyl]sulfonyl}-N-1- hydroxy-D-argininamide (11) - N-2- { [4- (3, 5-dimethylphenoxy)-3-fluorophenyllsulfonyll- N-1-hydroxy-D-argininamide (12) [00128] The following, Table 2, provides some physical data for some of the compounds synthesized. The compound numbers in Table 2 correlate to compound numbers in Table 1.

Table 2 Calculated Retention Time Cmpd # Observed MWt MWt (min.) 1 424.4 M+H = 425.1 1. 1 HP 2 518.6 M+H =519.1 1.39 HP 3 536.577 M+H = 537. 1 1.31 Shimadzu 4 502.2 M+H = 503.1 1.45 HP 5 463.5 M+H = 464.1 1.25 HP 6 520. 578 M+H = 521.1 1.71 Shimadzu 7 460.5 M+H = 461.1 1.35 HP 8 521.6 M+H = 522.1 1.35 HP 9 469.4 M+H = 470.0 1.25 HP 10 576.6 M+H = 577.1 1.25 HP 11 466.5 M+H = 467.0 1.32 HP 12 573.2 M+H = 574.2 1.32 HP 14 512.513 M+H = 513.1 1.32 Shimadzu 15 421.47 M+H = 422.1 (100%) 1.15 HP 16 457 M+H = 458 1.28 HP 17 439.46 M+H = 440.1 (100%) 1.2 HP 18 473.9 M+H = 474.0 (100%) 1.3 HP 19 439.46 M+H = 440.1 (100%) 1.25 HP 20 505.6 M+H = 506.2 1.4 HP Calculated Retention Time Cmpd # Observed MWt MWt (min.) 21 548.588 M+H = 549. 1 1.51 Shimadzu 22 457.12 M+H = 458. 1 1.38 HP 23 464 M+H = 465 1.25 HP 24 566.57 M+H = 567.1 (100%) 1.4 HP 25 491.89 M+H = 492.1 (100%) 1.32 HP 26 467.51 M+H = 468.1 (100%) 1.31 HP 28 405.47 M+H = 406.1 (100%) 1.46 HP 29 575.56 M+H = 576 1.22 HP 30 449.52 M+H = 450.1 (100%) 1.21 HP 31 476.55 M+H = 477.1 (100%) 1.32 HP 32 535.03 M+H = 536. 0 1.39 HP 33 467.5 M+H = 468. 14 1.793 Shimazu 34 528.6 M+H = 529 1.45 HP 35 466 M+H = 467. 1 1.15 HP 36 544.62 M+H = 545 1.59 HP 37 598.6 M+H =599 1.48 HP 38 563.61 M+H = 564.1 (100%) 1.5 HP 39 463.54 M+H = 464.2 (100%) 1.32 HP M+H = 40 559.6 1 : 44 HP 598.0 (M+K, 100%) M+H = 41 576.05 1.6 HP 614. 0 (M+K, 100%) 42 479.526 M+H = 480.1 1.34 Shimadzu 43 562.64 M+H = 563 1.25 HP 44 503. 5 M+H = 504. 1 1. 37 HP Calculated Retention Time Cmpd # Observed MWt MWt (min.) 45 481.538 M+H = 482.1 1.27 HP 46 481.53 M+H = 482.1 (100%) 1.23 HP 47 517.519 M+H = 518. 1 1.42 Shimadzu 48 533.973 M+H = 534.1 1.39 HP 49 545.62 M+H = 546.1 (100%) 1.45 HP 50 475.11 M+H = 476.1 1.33 HP [00129] Table 3 shows proton NMR data for selected compounds: Table 3 Entry Name'H-NMR H-NMR; 8 (CD30D): 7.79 (d, 2H), 7.42(t,2H), 7.22(t, 1H), 7.09(d, 2H), N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulfonyl}- 1 7.05(d, 2H), 3.63(t,1H), 2.87(t, 2H), D-lysinamide 1.57-1. 68 (m, 4H), 1.44 (m, 1 H), 1.37 (m, 1 H) H-NMR; 5 (CD30D): 7.79 (q, 2H), 7. 42 (t, 2H), 7.22 (t, 1H), 7. 10 (d, 2H), 2 N1-hydroxy-N2-{[4-(phenyloxy) phenyl] sulfonyl}-7. 05 (d, 2H), 3.72 (m, 1H), 3.23- 3-piperidin-3-ylalaninamide 3.47 (m, 2H), 2.87 (m, 1 H), 2.64 (t, 1H), 1.83-2. 01 (m, 3H), 1.17-1. 74 (m, 4H) H-NMR; 8 (CD30D): 7.80 (d, 2H), 7.42(t, 2H),7.22(t, 1H), 7.10(d, 2H), N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulfonyl}- 3 7.06(3, 2H), 3.72(q, 2H), 2.22-2.3(m, 3-pyrrolidin-3-ylalaninamide 1 H), 1. 96-2.18 (m, 4H), 1.83 (m, 1 H), 1.65 (m, 1H) (CD30D) 9.21 (br. s, 1H), 9.01 (d, 1H), 8.24 (dd, 1H), 8.04 (d, 1H), 7.92 4 N2-{[6-(3-fluorophenyl) pyridin-3-yl] sulfonyl}-N1- (dd, 1 H), 7.88 (dt, 1 H), 7.54 (m, 1 H), hydroxy-D-lysinamide 7.22 (td, 1 H), 3.72 (t, 1 H), 3.20 (br. q, 2H), 1.65 (m, 2H), 1.53 (m, 2H), 1.45 (m, 2H) ppm H-NMR; # (CD3OD): 7.50(d, 2H), 7.42(m, 3H), 7.32(d,1H), 7.24(m, N-hydroxy-N-{[4-(phenyloxy)phenyl]sulfonyl}-D- 5 2H), 7.06(m, 2H), 6.99(s,1H), typtophanamide tryptophanamide 2H), 7.06(m, 2H), 6.99(s,1H), 6.94 (t, 1 H), 6.76 (d, 1 H), 6.64 (d, 1 H), 3. 84(t,1H), 3. 13(q,1H), 2. 87(q, 1H H-NMR ; 8 (CD30D): 8.6 (d, 1 H), N'-hydroxy-N2-({5-[2-(methylthio) pyrimidin-4-7. 9 (d, 1 H), 7.6 (d, 1 H), 7.58 (d, 1 H), yl]-2-thienyl} sulfonyl) lysinamide 3.8 (t, 1 H), 2.9 (t, 2H), 2.6 (s, 3H), 1.6- 1. 75 (m, 4H), 1. 5 (m, 1 H), 1. 4 (m, 1 H) Entry Name 1H-NMR H-NMR; S (CD30D): 8.78 (s, 1 H), 7 N-hydroxy-N-{[4-(phenyloxy) phenyl] sulfonyl}-D-7. 74 (d, 2H), 7.43 (t, 2H), 7.31 (s, 1 H), histidinamide 7.23 (t, 1 H), 7. 10 (d, 2H), 7.02 (d, 2H), 3. 94(q, 1H), 2.96-3. 12 (q, 2H) H-NMR ; S (CD30D): 7.75 (m, 2H), N'-hydroxy-N2-methyl-N2-{[4-7. 42 (m, 2H), 7.23 (m, 1 H), 7.01- 8 (phenyloxy)phenyl]sulfonyl}-3-piperidin-3- #7. 12 (m, 4H), 3.34 (m 1 H), 3.30 (s, ylalaninamide 3H), 2.82-3. 00 (m, 3H), 2.63-2. 71 (m, 1 H), 1.85-2. 06 (m, 9H) H-NMR; 8 (CD30D): 7.80 (d, 2H), 7.43(t, 2H), 7.22(t, 1H), 7.10(d, 2H), N1-hydroxy-N2-{[4-(phenyloxy)phenyl]sulfonyl}- 9 7.05(d,2H), 3.71(q, 1H), 3.35(d, 1H), 3-piperidin-4-ylalaninamide 2. 91 (dt, 2H), 1. 89 (d, 2H), 1. 24- 1.76 (m, 6H) H-NMR; 8 (CD30D): 8.71 (d, 1H), N¹-hydroxy-N²-{[4-(phenyloxyl)phenyl]sulfonyl}- 8.64(s, 1H), 8.34(d, 1H), 7.91(q, 1H), 10 7. 79 (d, 1 H), 7.69 (d, 2H), 7.43 (t, 2H), 3-pyridin-3-yl-D-alaninamide 7.23(t, 1H), 7.10(d, 2H),7.00(d, 2H), 3. 94 (q, 1H), 3. 18(q, 1H), 3. 05(q, 1H H-NMR; # (CD30D): 7.79 (d, 2H), 7.42(t, 2H), 7.22(t, 1H), 7.10(d, 2H), N6-glycyl-N¹-hydroxy-N²-{[4- 7.05(d, 2H), 3.64(s, 2H), 3.60(t, 1H). (phenyloxy)phenyl]sulfonyl}-D-lysinamide 3.19(m, 2H), 1.60(m, 2H), 1.48(m, 2H), 1. 34 (m, 2H) 2H), 1. 34(m, 2H) H-NMR ; 8 (CD30D): 7.80 (d, 2H), 7.42 (m, 2H), 7.22 (t, 1 H), 6.96- 12 N¹-hydroxy-N²-N6,N6-trimethyl-N²-{[4- 7.10(m, 4H), 3.66(t, 1H), 3.30(m, (phenyloxy)phenyl]sulfonyl}-D-lysinamide 2H), 3.11(s, 9H), 1.75-1.85(m, 2H), 1. 69(q, 2H), 1.36-1. 50 (m, 2H) H-NMR; 8 (CD3OD): 7. 80 (d, 2H), 7. 42 (t, 2H), 7.22 (t, 1H), 7. 10 (d, 2H), 13 3- [4- (aminomethyl) cyclohexyl]-Nl-hydroxy-N'- 7. 05 (d, 2H), 3.67 (q, 1 H), 2.99 (m, {[4-(phenyloxy)phenyl]sulfonyl}alaninamide 1 H), 1.99 (m, 2H), 1.79 (m, 2H), 1.54 (t, 1 H), 1.35-1. 42 (m, 3H), 1. 26 (m, 1 H), 1. 06 (q, 1 H), 0. 96 (q, 1 H) H-NMR; 8 (CD30D) : 8.46 (br. d, 1 H), 8.18 (d, 1H), 7.95 (d, 1H), 7.84 (m, N1-hydroxy-N2-{[6-(naphthalen-1-yloxy)pyridin- 14 2H), 7.50 (m, 3H), 7.30 (d, 1H), 7.18 3-yl]sulfonyl}-D-argininamide (d, 1 H), 3.54 (br. t, 1H), 3.04 (br. t, 2H), 2.50 (m, 1H), 1.8 (m, 3H) ppm. H-NMR; # (CD3OD): 7.78 (d, 2H), N6-[(E)-(cyanoimino)(hydroxyamino)methyl]-N2- 7.14 (m, 4H), 7.01 (d, 2H), 3.56 (t, 17 ({4-[(4-fluoropehnyl)oxy]phenyl}sulfonyl)-N- 1H), 1.47 (m, 4H), 1.37 (m, 2H), 1.19 hydroxy-D-lysinamide (m, 2H) H-NMR; # (CD3OD): 7.67 (d, 2H), 18 N2-({4-[(4-fluorophenyl) oxy] phenyl} sulfonyl)-N'-7. 04 (m, 4H), 6.92 (d, 2H), 3.52 (t, hydroxy-D-lysinamide 1H), 1.53 (m, 4H), 1.38 (m, 2H), 1.25 (m, 2H) H-NMR; 8 (CD30D) 9.01 (br. s, 1 H), N6-{(Z)-(cyanoimino) [(2-morpholin-4-8. 26 (d, 1 H), 8.06 (d, 1 H), 7.89 (dd, 19 ylethyl) amino] methyl}-N2-{[6-(3-2H), 7.52 (br. q, 1 H), 7.24 (br. t, 1 H), fluorophenyl) pyridin-3-yl] sulfonyl}-N-hydroxy-3. 72 (m, 4H), 3. 32 (m, 4H), 3.15 (br. D-lysinamide t, 2H), 2.52 (m, 6H), 1.3-1. 8 (m, 5H) m. Entry Name'H-NMR H-NMR ; 8 (CD30D) 8.45 (br. s, 1 H), 20 N²-({6-[(4-fluorophenyl)oxy]pyridin-3- 8.19 (br s, 1 H), 7.20 (m, 5H), 3.65 yl}sulfonyl)-N1-hydroxy-D-argininamide (br. s, 1 H), 3.25 (m, 4H), 1.65 (m, 3H) m. H-NMR ; 8 (CD30D) 8.45 (d, 1 H), 21 N2-({6-[(4-chlorophenyl) oxy] pyridin-3- 8. 19 (dd, 1 H), 7.42 (d, 2H), 7.19 (dd, yl} sulfonyl)-N-hydroxy-D-argininamide 3H), 3.85 (br. t, 1 H), 3.20 (m, 2H), 1.80 (m, 4H) ppm H-NMR; # (CD3OD): 7.52 (d, 2H), N²-({3,5-difluoro-4-[(4- 6.95 (d, 2H), 6.91 (m, 2H), 3.26 m, 22 fluorophenyl)oxy]phenyl}sulfonyl)-N1-hydroxy- 5H), 3.22 (4H, m), 3.04 (m, 2H), 1.54 N6-(morpholin-4-ylcarbonyl)-D-lysinamide 5H), 3.22 (4H, m), 3.04 (m, 2H), 1. 54 m, 2H, 1. 40 m, 2H, 1. 25 m, 2H 4-cyano-N-hydroxy-N-{[4- H-NMR; # (CD3OD): 7.4(m, 4H), 23 (phenyloxy) phenyl] sulfonyl}-D- 7. 28 (m, 1 H), 7. 25 (s, 2H), 7. 05 (m, phenylalaninamide 4H), 6.78(M, 2H), 4.03(m, 1H), 3. 10 (m, 1H, 2. 85 (m, 1H) 3-cyano-N- (13, 5-difluoro-4- [ (4- H-NMR ; 8 (CDCl3) : 7.1-7. 4 (m, 6H), 25 fluorophenyl) oxy] phenyl} sulfonyl)-N-hydroxy-D- 6. 94 (m, 2H), 6.84 (m, 2H), 4.2 (m, phenylalaninamide 1H), 3.0-3. 3 (m, 2H) H-NMR; 8 (CDCl3) : 7.42 (m, 2H), 3-cyano-N-hydroxy-N-{[4- 7. 39 (t, 2H), 7.34 (d, 1 H), 7.26 (m, 1 H), 26 (phenyloxy)phenyl]sulfonyl}-D- 7. 21 (t, 2H), 7.15 (m, 1H), 7.04 (d, 2H), phenylalaninamide 6.74 (d, 2H), 4.1 (m, 1H), 3.2 (m, 1H), 2.9 m, 1H) N 2_ ( {3, 5-difluoro-4- [ (4- H-NMR ; 8 (CD30D): 7.6 (d, 2H), 27 hydroxyphenyl) oxy] phenyl} sulfonyl)-N1- 6. 8 (d, 2H), 6.7 (d, 2H), 3.7 (t, 1 H), hydroxyargininamide 3.2 (t, 2H), 1. 6-1.8 (m, 4H) H-NMR ; # (CD30D): 8.5 (s, 1H), 28 N²-{[3,5-difluoro-4-(pyridin-3- 8.4(s, 1H)m, 7.62(d, 2H), 7.5(m, 2H), yloxy)phenyl]sulfonyl}-N¹-hydroxyargininamide 3.7(t, 1H), 3.2(t, 2h), 1.7 (m, 4H) H-NMR; # (CD3OD) 7.60 (d, 2H), N²-({3,5-difluoro-4-[(4- 7.05 (m, 4H), 3.65 (t, 1H), 3.45 (t, fluorophenyl)oxy]phenyl}sulfonyl)-N6-[1-(4,4- 30 1H), 2.60 (s, 3H), 2.40 (s, 3H), 1.65 dimethyl-2,6-dioxocyclohexylidene)ethyl]-N1- hydroxy-D-lysinamide ppm pom N2- { [3,5-difluoro-4- ( {4- H-NMR; 8 (CD3OD) : 7.6 (d, 2H), 31 [ (phenylmethyl)oxy]phenyl}oxy)phenyl]sulfonyl}- 7.4(d, 2H), 7.35(m, 2H), 6.9(s, 5H), N¹-hydroxyargininamide 5.02(s, 2H), 3.65(t, 1H), 3.1(t, 2H), 1.7 m, 4H H-NMR; 8 (CD30D): 1.3-1. 5 (m, 2 N2- { [3, 5-difluoro-4- (pyridin-3- H), 1.5-1. 7 (m, 4 H), 1.99 (s, 3 H), 32 yloxy) phenyl] sulfonyl}-Nl-hydroxy-6-morpholin-2. 57 (t, 2 H), 2.70 (br s, 4 H), 3.68 (t, 4-yl-D-norleucinamide 1 H), 3.76 (t, 4 H), 7.43 (d, 1 H), 7.63 (d, 2 H), 8.33 (dd, 1 H), 8.42 (d, 1 H N 2_ ( {3-fluoro-4- [ (4- H-NMR ; # (CD30D) : 7.70 (m, 2H), 33 fluorophenyl) oxy] phenyl} sulfonyl)-N'-hydroxy-3-7. 10 (m, 5H), 3.80 (br. t, 2H), 3.20 morpholin-4-yl-D-alaninamide (m, 6H) ppm N- ( {3,5-difluoro-4-[ (4- H-NMR; # (CD3OD): 7.61 (d, 2H), 34 fluorophenyl)oxy] phenyl} sulfonyl)-N-hydroxy-4- 7.49 (m, 4H), 7.01 (m, 4H), 3.90 (dd, [(hydroxyamino) (imino) methyl]-D-1H) 3. 00 (m 2H) ppm phenylalaninamide N-({3,5-difluoro-4-[(4- H-NMR; # (CD3OD): 7.54 (m, 6H), 36 fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-3- 7.02 (m, 4H), 3.94 (t, 1H), 3.01 (m, [ (hydroxyamino) (imino) methyl]-D- 2H) ppm henylalaninamide Entry Name H-NMR; # (CDCl3): 7.54(d, 2H), N2-({4-[(4-chlorophenyl)oxy]-3,5- 7.23(d, 2H), 6.85(d, 2H), 3.98(m, difluorophenyl}sulfonyl)-N1-hydroxy-3-[1- 37 1H), 3.63(br, 4h), 3.21(br, 2H), (morpholin-4-ylcarbonyl)piperidin-4- yl] alaninamide 2.81(m, 1H), 2.66(m, 1 H), 1. 60 (br, 2H), 1. 10m, 1H H-NMR ; # (DMSO-d6): 10.65 (s, 1H), N2-({3, 5-difluoro-4-[(4-8. 45 (d, 1 H), 7.62 (d, 2H), 7. 18 (d, 2H), 38 fluorophenyl) oxy] phenyl} sulfonyl)-N'-hydroxy-3- 7. 10 (d, 2H), 3.64 (m, 1H), 3.54 (m, [1- (morpholin-4-ylcarbonyl) piperidin-4- 4H), 3.08 (m, 2H), 2.63 (m, 1 H), yl] alaninamide 2,49 (m, 1 H), 1.53 (m, 1 H), 1.38 (m, 1H), 1.0(m, 1H 3- [amino (imino) methyl]-N- (13, 5-difluoro-4- [ (4- H-NMR ; 8 (CD30D) : 7.58 (m, 6H), 39 fluorophenyl) oxy] phenyl} sulfonyl)-N-hydroxy-D-6. 99 (m, 4H), 3.88 (t, 1H), 3.01 (m, phenylalaninamide 2H) ppm 4- [amino (imino) methyl]-N- ( {3, 5-difluoro-4- [ (4- H-NMR ; # (CD30D) : 7.75 (d, 2H), 40 fluorophenyl) oxy] phenyl}sulfonyl)-N-hydroxy-D- 7. 50 (d, 4H), 7.01 (m, 4H), 3.90 (dd, phenylalaninamide 1 H), 3.05 (m, 2H) ppm. N5-(aminocarbonyl)-N#2#({3-fluoro-4-[(4- H-NMR ; 8 (CD30D) : 7.65 (d, 1 H), 41 fluorophenyl) oxy] phenylsulfonyl)-N-hydroxy-7. 60 (d, 1 H), 7.10 (m, 5H), 3.82 (t, D-ornithinamide 1H), 3.05 (m, 2H), 1.60 (m, 4H) ppm H-NMR; # (CD3OD): 1.97 (q, 2 H), (2R)-2-[({4-[(4-chlorophenyl)oxy]-3,5- 42 difluorophenyl}sulfonyl)amino]-4- 2.11 (q, 2H), 2.78 (s, 6 H), 3.71 (t, 1 (dimethylamino)-N-hydroxybutanamide (dd 2 H) dd, 2 H (2R)-2-[({4-[(4-chlorophenyl) oxy] -3, 5-H-NMR ; 8 (CD30D): 7.61 (d, 2H), 43 difluorophenyl} sulfonyl) amino]-4- { [i- (4, 4- 7. 31 (d, 2H), 7.00 (d, 2H), 3.77 (t, 1H), dimethyl-2, 6-dioxocyclohexylidene)-2- 3. 64 (t, 2H), 3.04 (d, 2H), 2.38 (s, 4H), methylbutyl] amino}-N-hydroxybutanamide 1.97 (m, 3H), 0.99-1. 02 (m, 12H) N2-({4-[(4-chlorophenyl)oxy]-3,5- H-NMR ; 8 (CD30D) : 7.60 (d, 2H), 44 difluorophenyl} sulfonyl)-N'-hydroxy-3-[(2-7. 30 (m, 2H), 7.00 (d, 2H), 3.80 (m, morpholin-4-yl-2-oxoethyl) thio]-D-valinamide 10H), 1.40 (d, 6H) ppm (2R)-4-amino-2- [ ( {4- [ (4-chlorophenyl) oxy] -3, 5- H-NMR ; 8 (CD30D): 7.62 (d, 2H), 45 difluorophenyl}sulfonyl)amino]-N- 7. 32 (d, 2H), 7.01 (d, 2H), 3.79 (t, 1 H), hydroxybutanamide 3.08 (m, 1 H), 2.98 (m, 1H), 1.99 (q, 2H) (2R)-4-{[amino (imino) methyl] amino}-2-[({4-[(4-H-NMR ; 8 (CD30D): 7.61 (d, 2H), 46 chlorophenyl) oxy] -3, 5- 7. 32 (d, 2H), 7.00 (d, 2H), 3.80 (t, 1 H), difluorophenyl} sulfonyl) amino]-N-3. 10 (m, 1H), 2.98 (m, 1H), 2.00 (q, hydroxybutanamide 2H) Example 11 Enzyme Assays [00130] mADAM-10 or hADAM-10 activity was measured as the ability to cleave a 10-residue peptide (DABCYL-Leu-Leu-Ala-Gln-Lys-*-Leu- Arg-Ser-Ser-Arg-EDANS). This peptide is based on the TNF-a cleav- age site (Leu62-Arg71), however, we found that replacement of Als76- Val77 with Lys-Leu resulted in a peptide with a 5-fold greater af- finity for ADAM-10 than the native TNF-α peptide. Enzyme was di- luted to a final active concentration of 5nM in Buffer A (50mM HEPES 8.0, 100mM NaCl, 1mM CaCl2 and 0. 01% NP-40). Serial dilu- tions for compounds were performed ranging from 100uM to 0.5nM us- ing a Beckman Biomek 2000 in polypropylene plates (Greiner). 20 pl of enzyme solution was added to 10p1 of compound in buffer A, and allowed to incubate for 15min in 384 well black, Greiner, micro- titer plates (#781076). 20ul of substrate (12.5uM in Buffer A) was then added, resulting in final reaction conditions of 2nM ADAM-10, 5 uM substrate, and compound concentrations ranging from 20uM to 0. lnM. The reaction was incubated for 2hr at RT, and fluorescence was measured at Ex355, Em460 on a Wallac Victor 2 fluorescence reader. For final analysis of potent inhibitors, a similar reac- tion was set up with a final active ADAM-10 concentration of 0. lnM. This reaction was incubated for 16hr at RT and fluores- cence was read using identical conditions.

[00131] Table 4 below shows structure activity relationship data for selected compounds of the invention when tested in vitro with various metalloproteases. Inhibition is indicated as IC50 with the following key: A = ICso less than 50 nM, B = ICso greater than 50 nM, but less than 1000 nM, C = ICso greater than 50 nM, but less than 20,000 nM, and D = ICso greater than 20,000 nM.

[00132] One aspect of the invention is the combination of, for ex- ample, guanidine-containing sidechains on an amino acid derived hydroximate; and substitution (particularly halo, more particu- larly flouro) on the proximal ring (ring bonded directly to the sulfonamide moiety) of a two-ring-substituted sulfonamide deriva- tive of the amino acid derived hydroximate. For example, by com- bining an arginine-derived hydroximate having a bis-aryl ether sulfonamide on the alpha-nitrogen, particularly when the proximal ring of the bis-aryl ether is substituted with, for example at least one fluorine, inhibitors that are selective for ADAM-10 are produced.

Table 4 0 Lu V o ci U H V n 0 Ln 0 U Name U U U e W H H H H H H Compound Name M co M pj H N1-hydroxy-NZ- { [4- (phenyloxy) phenyl] sulfonyl}-D- A B C A A B lysinamide Nl-hydroxy-NZ- ( [4- 2 (phenyloxy) phenyl] sulfonyl}-D-A C A B A A A B argininamide N1-hydroxy-NZ- { [4- (phenyloxy) phenyllsulfonyl)-3- piperidin-3-ylalaninamide N-hydroxy-N- { [4- (phenyloxy) phenyllsulfonyll-3- pyrrolidin-3-ylalaninamide N2-{[6-(3-fluorophenyl) pyridin- 5 3-yl] sulfonyl}-Nl-hydroxy-D-A C A B A C lysinamide N-hydroxy-N- { [4- 6 (phenyloxy) phenyl] sulfonyl}-D-A B A A A A tryptophanamide Nl-hydroxy-N2-({5-[2- 7 (methylthio) pyrimidin-4-yl]-2-B D A C A C thienyl} sulfonyl) lysinamide N-hydroxy-N- { [4- 8 (phenyloxy) phenyl3sulfonyl}-D-A B A A A B histidinamide Nl-hydroxy-N2-methyl-N2- { [4- 9 (phenyloxy) phenyl] sulfonyl}-3-A B A A A B piperidin-3-ylalaninamide Nl-hydroxy-N2- { [4- 10 (phenyloxy) phenyl] sulfonyl}-3- A B A A A B piperidin-4-ylalaninamide Nl-hydroxy-NZ- {L 4- 11 (phenyloxy) phenyl] sulfonyl}-3-A D A A A A pyridin-3-yl-D-alaninamide 0 lu 0 0 H °m m m°n m U u u (i u u H C) H H H H H H H Compound Name Name o H « e e N-hydroxy-6-morpholin-4-yl-N- H N1-hydroxy-6-morpholin-4-yl-N- 12 {[4-(phenyloxy) phenyl] sulfonyl}-A B A A A C D-norleucinamide N6-glycyl-Nl-hydroxy-N2- { [4- 13 (phenyloxy) phenyl] sulfonyl}-D-A A A B lysinamide N- { [6- (3-fluorophenyl) pyridin- - 3-yl] sulfonyl}-N-hydroxy-D- A B A B AC argininamide Nl-hydroxy-N2, N6, N6-trimethyl-N2-_ __ 15 {[4-(phenyloxy) phenyl] sulfonyl}- A B A A A B D-lysinamide 3- [4- (aminomethyl) cyclohexyl]- 16 N1-hydroxy-Nz- { [4-A B A A A B (pheny- loxy) phenyl] sulfonyl} alaninamide N2-{[6-(3-fluorophenyl) pyridin- 17 3-yl] sulfonyl}-Nl-hydroxy-6-A D A B A C morpholin-4-yl-D-norleucinamide -N6-[(E)-_ (cyano- 18 imino) (propylamino) methyl]-N- A C A B A C { [6- (3-fluorophenyl) pyridin-3- yl] sulfonyl}-Nl-hydroxy-D- lysinamide Nl-hydroxy-5-morpholin-4-yl-N2- 19 [4- (phenyloxy) phenyllsulfonyll- D-norvalinamide N6-[(E)- amino (cyanoimino) methyl]-NZ- { [6- (3-fluorophenyl) pyridin-3- yl] sulfonyl}-Nl-hydroxy-D- lysinamide Nl-hydroxy-N2-{[6-(naphthalen-l- 21 yloxy) pyridin-3-yl] sulfonyl}-D-B C B C A argininamide N2_ { [3-fluoro-4- 22 (phenyloxy) phenyl] sulfonyl}-Nl-A B A A A B hydroxy-D-argininamide 0 lu 0 0 H ooooo ° H H H H H H H H H H H'' Compound Name M co cr* M H g6_ [ (E)- (cyano- 23 imino) (propylamino) methyl]-Nl- A B A A A A hydroxy-N { [4- (phenyloxy) phenyl] sulfonyl}-D- lysinamide N6- ( (Z)- (cyanoimino) { [2- (methyloxy) ethyl] amino} methyl)- 24 N1-hydroxy-Na- { [4-A B A A A B (phenyloxy) phenyl] sulfonyl}-D- lysinamide M'- [ (E)- amino (cyanoimino) methyl-N 25 hydroxy-N2- { [4- A B A A A A (phenyloxy) phenyl] sulfonyl}-D- lysinamide g2_ ( {4- [ (4- 26 fluoro-A B A A A A phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-argininamide NS-f (Z) _ amino (nitroimino) methyl]-Nl- hydroxy-N- { [4- (phenyloxy) phenyl] sulfonyl}-D- ornithinamide gl-hydroxy-N~2--{[6-(5, 6, 7, 8- 28 tetrahydronaphthalen-2-D B A yloxy) pyridin-3-yl] sulfonyl}-D- lysinamide N6- { (Z)- (cyanoimino) [ (2- morpholin-4- 29 ylethyl) amino] methyl}-Nl-A B A A A hydroxy-NZ- { [4- (phenyloxy) phenyl] sulfonyl}-D- lysinamide Nl- [ (z)- (cyano- 30 imino) (cyclopropylamino) methyl]-A A A A A Nl-hydroxy-N 2_ { [4- (phenyloxy) phenyl] sulfonyl}-D- lysinamide N- { [3, 5-difluoro-4- 31 (phenyloxy) phenyl] sulfonyl}-Nl-A B hydroxy-D-argininamide 0 Lu 0 U U U U U'H H H H H H H H U Campound Name H « X e ffi N g2_ ( {4- [ (4-chlorophenyl) oxy]-3- 32 fluorophenyl} sulfonyl)-Nl-A B A A A A hydroxy-D-argininamide N2-({3, 5-difluoro-4-[(4- 33 fluoro-A D C C B B A B phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-argininamide 3- [1- ( (Z)- (cyanoimino) { [2- (methy- 34 loxy) ethyl] amino} methyl) piperidi B A A n-4-yl]-N-hydroxy-N- { [4- (pheny- loxy) phenyl] sulfonyl} alaninamide 3- {1- [ (Z)- (cyano- 35 imino) (propylamino) methyl] piperi A B A din-4-yl}-Nl-hydroxy-N2-{[4- (pheny- loxy) phenyl] sulfonyl} alaninamide N=- [ (Z)- amino (nitroimino) methyl]-NZ- { [6- (3-fluorophenyl) pyridin-3- yl] sulfonyl}-Nl-hydroxy-D- orni thinamide N- ( {4- [ (4-chlorophenyl) oay]- 3, 5-difluorophenyl} sulfonyl)-N- ACABBBAB hydroxy-D-argininamide W-hydroxy-N2_ { [6- (5, 6, 7, 8- 38 tetrahydronaphthalen-2-A C A A A B yloxy) pyridin-3-yl] sulfonyl}-D- argininamide N'- ( {4- [ (3, 5- 39 dimethylphenyl) oxyl-3- A C A B A A fluorophenyl} sulfonyl)-Nl- hydroxy-D-argininamide N2- (f 3-f luoro-4- [ (4- 40 fluoro-A B A A A B phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-argininamide N2-({4-[(4-cyanophenyl) oxy]-3- 41 fluorophenyl} sulfonyl)-N1- A C A A A hydroxy-D-argininamide 0 lu H O O O O O H o H N H H H H H U H H H H H Compound Name rq H (4 m 00 m m ru ci N5-[(E)-(cyanoimino) (morpholin- 4-yl) methyl]-N2-({4-[(4- fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-lysinamide 3- [1- ( (Z)- [(aminocarbonyl) imino] {[2- (methy- loxy) ethyl] amino} methyl) piperidi n-4-yl]-Nl-hydroxy-N 2_ { [4- (pheny- loxy) phenyl] sulfonyl} alaninamide N6-(4, 5-dihydro-lH-imidazol-2- 44 fluõro-A A A A A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-lysinamide M6-[(E)- (cyano- 45 imino) (propylamino) methyl]-- ( {4- [ (4- fluoro- phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-D-lysinamide N6- [ (E)- [ (aminocar- bonyl) imino] (hydroxyamino) methyl 46 -N 4-L-A A A A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-lysinamide N6-[(E)- (cyano- imino) (hydroxyamino) methyl]-N 2_ A B A A A ( {4- [ (4- fluoro- phenyl) oxy] phenyl} sulfonyl)-N1- hydroxy-D-lysinamide N6_ ( (E)- (cyanoimino) { [2- (methyloxy) ethyl] amino} methyl)- 48 N2-{[6-(3-fluorophenyl) pyridin-A B A A A 3-yl] sulfonyl}-Nl-hydroxy-D- lysinamide lu o H in in °m°m°n U'^ H H H H H H H H Compound Name o n X g | i i i | i E N Ns_LZ) _ (cyano- 49 imino) (cyclopropylamino) methyl]-A D A B A N2-{[6-(3-fluorophenyl) pyridin- 3-yl] sulfonyl}-Nl-hydroxy-D- lysinamide N2- (4- [ (4- 50 fluoro-A B A A A phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-lysinamide N6- ( (Z)- (cyanoimino) { [2- (methyloxy) ethyl] amino} methyl)- 51N- ( {4- [ (4- A B A A A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-lysinamide N6-{(Z)-(cyanoimino) [(2-_ morpholin-4- 52 ylethyl) amino] methyl}-N2-{[6-(3-A B A A A fluorophenyl) pyridin-3- yl] sulfonyl}-Nl-hydroxy-D- lysinamide 3- {1- [amino (imino) methyl] piperidin-4- bj i urii- r2 rr A. B A A A B yl}-N-hydroxy-N- { [4- (pheny- loxy) phenyl] sulfonyl} alaninamide N2_ ( {4- [ (4- fluoro- 54 phenyl) oxy] phenyl} sulfonyl)-Nl-A B A A A phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-5-morpholin-4- ylnorvalinamide N2-({4-[(4- fluoro- 55 phenyl) oxy] phenyl} sulfonyl)-Nl-A B A A A A hydroxy-6-morpholin-4-yl-D- norleucinamide N2-({3, 5-difluoro-4-[(4- fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl-B C B B B hydroxy-3-[(2-morpholin-4- ylethyl) thio]-D-valinamide 0 Lu ci lu H °m °m m m °m U'" H H H H H H H u H H H H H H Compound Name o | i i H P4 ci 57 fluorophenyl) oxy] pyridin-3- A B A A A yl} sulfonyl)-Nl-hydroxy-D- argininamide N2-({3, 5-difluoro-4-[(4- fluors- phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-6-morpholin-4-yl-D- norleucinamide N6-[ (Z)- (cyanoimino) (morpholin- 4-yl) methyl]-N2-({3-fluoro-4- 59 [ (4- A B A A A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-lysinamide 3- [1- ( (E)- (cyanoimino) { [2- (methy- loxy) ethyl] amino} methyl) piperidi 60 n-4-yl]-N2-({3, 5-difluoro-4-[(4-B C A B A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxyalaninamide N2-({6-[(4_ 61 chlorophenyl) oxy] pyridin-3- A B A A A yl) sulfonyl)-Nl-hydroxy-D- argininamide N2-({3, 5-difluoro-4-[(4- fluoro- 62 phenyl) oxy] phenyl} sulfonyl)-Nl-A C A B A hydroxy-N6- (morpholin-4- ylcarbonyl)-D-lysinamide 4-cyano-N-hydroay-N- ( [4- (phenyloxy) phenyl] sulfonyl}-D- A B A A A phenylalaninamide 4-cyano-N- ( {3, 5-difluoro-4- [ (4- 64 fluoro-B B phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-D-phenylalaninamide N2-({4-[(4-chlorophenyl) oxy]-0 _ 65 3, 5-difluorophenyl} sulfonyl)-Nl-A C A B A hydroxy-6-morpholin-4-yl-D- norleucinamide 0 lu 0 H m°e°m°nmm°U'" H H o o o o o o o H UH UH HU UH H H # Campound Name o « 0 H H H H H H Coinpound Naine rq H C, 4 cn co 4m m rri H 3-cyano-N- ( {3, 5-difluoro-4- [ (4- 66 fluoro-B C B C B phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-D-phenylalaninamide 3-cyano-N-hydroxy-N- { [4- (phenyloxy) phenyl] sulfonyl}-D- A B A A A phenylalaninamide N2_ { [3-fluoro-4- 68 (phenyloxy) phenyl] sulfonyl}-Nl-A C A B A hydroxy-6-morpholin-4-yl-D- norleucinamide N2- ( {3, 5-difluoro-4- [ (4- 69 hydroxy-A D A B A phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxyargininamide N2- { [3, 5-difluoro-4- (pyridin-3- 70 yloxy) phenyllsulfonyl}-Nl- hydroxyargininamide N- ( {3, 5-difluoro-4- [ (4- fluoro- 1 phenyl) ox. y] phenyl} sul f onyl)-Nl- hydroxy-N6-2- (methy- loxy) ethyl] amino} carbonyl)-D- lysinamide N2-({3, 5-difluoro-4-[(4- fluoro- 72 phenyl) oxy] phenyl} sulfonyl)-N5-B C A B A [1- (4, 4-dimethyl-2, 6- dioxocyclohexylidene) ethyl]-Nl- hydroxy-D-lysinamide N2_ { [3, 5-difluoro-4- ( {4- 73 [ (phenyl- A D A B A methyl) oxy] phenyl} oxy) phenyl] sul fonyl}-N-hydroxyargininamide W- ( {3-fluoro-4- [ (4- fluoro- phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-3-[(2-morpholin-4- ylethyl) thio]-D-valinamide 0 o 0 H tn Ln Ln Ln in H H U H UH U H UH H H H H H H # Compound Name o H « e e X _ i i i i i B M N2- (4- [ (4-bromophenyl) oxy]-3, 5- 75 difluorophenyl} sulfonyl)-Nl-A C A B A hydroxy-D-argininamide N2_ ( {3-fluoro-4- [ (4- fluor- 76 phenyl) oxy] phenyl} sulfonyl)-Nl-A B A A A hydroxy-3- [ (2-morpholin-4-yl-2- oxoethyl) thio]-D-valinamide N-({3-fluoro-4-[(4- fluor- 77 phenyl) oxy] phenyl} sulfonyl)-Nl-B C A B A hydroxy-3-morpholin-4-yl-D- alaninamide N- ( {3, 5-difluoro-4- [ (4- fluoro- 78 phenyl) oxy] phenyl} sulfonyl)-N-D B C B hydroxy-4- [ (hydroxyamino) (imino) methyl]-D- phenylalaninamide N- ( {3, 5-difluoro-4- [ (4- fluoro- 79 phenyl) oxy] phenyl} sulfonyl)-N- A C A C B hydroxy-3- [ (hydroxyamino) (imino) methyl]-D- phenylalaninamide N2-({4-[(4-chlorophenyl) oxy]- 80 3, 5-difluorophenyl} sulfonyl)-Nl- hydroxy-3- [1- (morpholin-4- ylcarbonyl) piperidin-4- yl] alaninamide 3- [amino (imino) methyl]-N- ( {3, 5- 81 difluoro-4- [ (4- A D A C B fluoro- phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-D-phenylalaninamide 4- [amino (imino) methyl]-N- ( {3, 5- 82 difluoro-4- [ (4- A D B c fluoro- phenyl) oxy] phenyl} sulfonyl)-N- hydroxy-D-phenylalaninamide a ton 0 V N o U o o o o o V o U U U U U H H H H H H H H H # Compound Name o « X | N | i i M i g H N5-(aminocarbonyl)-N2-({3- fluoro-4- [ (4- A B A A A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxy-D-ornithinamide (2R)-2- [ ( {4- [ (4- chlorophenyl) oxy]-3, 5-B A C B 84 difluorophenyl} sulfonyl) amino]- 4- (dimethylamino)-N- hydroxybutanamide (2R)-2- [ ( {4- [ (4- chlorophenyl) oxy]-3, 5- difluorophenyl} sulfonyl) amino]- 4- ( [I- (4, 4-dimethyl-2, 6- dioxocyclohexylidene)-2- methylbutyl] amino}-N- hydroxybutanamide N2-({4-[(4-chlorophenyl) oxy]- 86 3, 5-difluorophenyl} sulfonyl)-Nl-B C B C B hydroxy-3- [ (2-morpholin-4-yl-2- oxoethyl) thio]-D-valinamide (2R)-4-amino-2- [ ( {4- [ (4- 87 chlorophenyl) oxy]-3, 5-A C A C A difluorophenyl} sulfonyl) amino]- N-hydroxybutanamide (2R)-4- {[amino (imino) methyl] amino}-2-A C A [ ( {4- [ (4-chlorophenyl) oxy]-3, 5- difluorophenyl} sulfonyl) amino]- N-hydroxybutanamide 2- [ ( {4- [ (4-chlorophenyl) oxy]- 89 3, 5- A A C B difluorophenyl} sulfonyl) amino]- N-hydroxy-2-piperidin-4- ylacetamide 2- [ ( {4- [ (4-chlorophenyl) oxyl-3- 90 fluorophenyl} sulfonyl) amino]-N- A A B A hydroxy-2-piperidin-4- ylacetamide 0 C) 0 0 V N o _ U U O H O H O O H H H H H H H H H H'' Compound Name | i « | | | i W 1 r-i H 2- [ ( {3-fluoro-4- [ (4- 91 fluoro-B A B A phenyl) oxy] phenyl} sulfonyl) amino ]-N-hydroxy-2-piperidin-4- ylacetamide 2- [ ( {4- [ (4- 92 fluoro-A A B A phenyl) oxy] phenyl} sulfonyl) amino ]-N-hydroxy-2-piperidin-4- ylacetamide 2- ( { [6- (3-fluorophenyl) pyridin- 93 3-yl] sulfonyl} amino)-N-hydroxy- 2-piperidin-4-ylacetamide 2- [ ( {4- [ (3, 5- 94 dimethylphenyl) oxy]-3, 5-B C C C difluorophenyl} sulfonyl) amino]- N-hydroxy-2-piperidin-4- ylacetamide 3- [4- (aminomethyl) cyclohexyl]- 95 N2-({4-[(4-chlorophenyl) oxy]-B B C A 3, 5-difluorophenyl} sulfonyl)-Nl- hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]- 96 N2- ( {3, 5-difluoro-4- [ (4-A B c B fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]- 97 N2-({4-[(4-chlorophenyl) oxy]-3-A A A A fluorophenyl} sulfonyl)-Nl- hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]- 98 N2- ( {3-f luoro-4- [ (4-A C A A A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]- 99 N2- ( {4- [ (4-A A A A fluoro- phenyl) oxy] phenyl} sulfonyl)-Nl- hydroxyalaninamide 0 o 0 H Ln U U U in in H H Name H ci H'' Compouad Name, "'1 N 3- [4- (aminomethyl) cyclohexyl]- 100 N2-{[6-(3-fluorophenyl) pyridin-A A B A 3-yl] sulfonyl}-Nl- hydroxyalaninamide 3- [4- (aminomethyl) cyclohexyl]- 10 |N2-({4-[ (3, 5-C dimethylphenyl) oxy]-3, 5- difluorophenyl} sulfonyl)-Nl- hydroxyalaninamide