Abstract:
The present invention provides compounds useful for inhibiting 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 combination with a pharmaceutically acceptable carrier. Such compositions 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. The invention also provides methods for making bis-aryl ether sulfonyl chlorides and ADAM-10 modulators therefrom.

Description:
CROSS REFERENCE TO RELATED APPLICATIONS 
     This application is a divisional of U.S. Ser. No. 10/498,338 filed on May 11, 2005, now U.S. Pat. No. 7,498,358, which is a U.S. national phase of international application PCT/US02/39816 filed on Dec. 13, 2002, which claims priority to U.S. Provisional Patent Application Ser. No. 60/340,179 filed on Dec. 14, 2001, the disclosures of which are incorporated herein by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     Field of the Invention 
     The present invention is in the field of agents that inhibit human ADAM-10 (also known as human Kuzbanian) and their use in the treatment of cancer, arthritis, and diseases related to angiogenesis, such as renal diseases, heart diseases such as heart failure, atherosclerosis, and stroke, inflammation, ulcer, infertility, scleroderma, endometriosis, mesothelioma, and diabetes. 
     SUMMARY OF THE RELATED ART 
     Cell-cell interactions play an important role in regulating cell fate decisions and pattern formation during the development of multicellular organisms. One of the evolutionarily conserved pathways that plays a central role in local cell interactions 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 mechanism(s) of NOTCH activation have been hitherto largely unknown. 
     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 lateral inhibition. Loss-of-function mutations in any of the neurogenic genes result in hypertrophy of neural cells at the expense of epidermis (reviewed in Campos-Ortega, J. A. (1993) In: The Development of  Drosophila melanogaster  M. Bate and A. Martinez-Arias, eds. pp. 1091-1129. Cold Spring Harbor Press.). 
     Rooke, J., Pan, D. J., Xu, T. and Rubin, G. M. (1996). Science 273, 1227-1231, discloses neurogenic gene family, kuzbanian (kuz). Members of the KUZ family of proteins are shown to belong to the recently defined ADAM family of transmembrane proteins, members of which contain both a disintegrin and metalloprotease 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. Pat. No. 5,922,546 and U.S. Pat. No. 5,935,792). 
     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 involved in diverse biological processes in mammals such as fertilization (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). Specifically, during the lateral inhibition process, kuz acts upstream of Notch (Pan and Rubin, 1997; Sotillos et al., 1997), which encodes the transmembrane receptor for the lateral inhibition 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). 
     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 protein, a cytoplasmic protein that is unlikely the physiological substrate for the bovine KUZ protease (Howard et al., 1996 Biochem. 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 Oct. 27, 2000, discloses that mkuz mutant mice die around embryonic day (E) 9.5, with severe defects in the nervous 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 components of the Notch pathway such as RBP-Jk (Conlon et al, 1995, Development 121, 1533-1545; Oka et al., 1995), indicating a conserved role for mkuz in modulating Notch signaling in mouse development. Furthermore, no visible defect was detected in Notch processing in the kuz knockout animals. In addition to the neurogenesis and somitogenesis defect, mkuz mutant mice also show severe 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 lacking 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 signaling, specifically, that kuz plays an essential role for an ADAM family disintegrin metalloprotease in mammalian angiogenesis. 
     In view of the important role of KUZ (ADAM-10) in biological processes and disease states, inhibitors of this protein are desirable. 
     All patents, applications, and publications recited herein are hereby incorporated by reference in their entirety. 
     SUMMARY OF THE INVENTION 
     The present invention provides compounds useful for inhibiting 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 combination with a pharmaceutically acceptable carrier. Such compositions 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 
     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 
             R 1  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 R 6  groups;   
         
             R 6  at each occurrence is independently selected from halogen, hydroxy, —NO 2 , —CO 2 R 10 , —CN, alkyl, alkoxy, haloalkyl, and haloalkoxy; 
             R 2  is selected from hydrogen, alkyl, alkoxy, alkanoyl, arylalkyl and arylalkanoyl, wherein
           the arylalkyl and arylalkanoyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 R 6  groups;   
         
             R 3  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 independently 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, —NR 6 R 9  and alkoxy;   
               J is selected from —NR 8 R 9 , —NR 7 C(═O)NR 8 R 9 , —NR 7 C(═O) alkylNR 8 R 9 , —NR 7 C(═O)OR 9 , —C(═NR 7 )NR 8 R 9 , and —NH—C(═NR 7 )NR 8 R, wherein   R 7  is selected from H, CN, NO 2 , alkyl, alkanoyl, arylalkanoyl and —C(═O)NR 10 R 11 , wherein
               R 10  and R 11 , are independently selected from H, and alkyl, and   
               R 8  and R 9  are independently 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 R 6  groups; or   R 8  and R 9  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 , R 8 , 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 alkyl, alkoxy, hydroxy, and halogen; and   R 9  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 R 6  groups;   
         
             R 4  is selected from H, alkyl, and arylalkyl, wherein the arylalkyl group is unsubstituted or substituted with 1, 2, 3, 4, or 5 R 6  groups; and 
             R 5  is -M—G—A, wherein 
             M is selected from aryl and heteroaryl, wherein M is unsubstituted or substituted with 1, 2, 3, or 4 groups that are independently selected from halogen, alkyl, hydroxy, alkoxy, haloalkyl, —CN, haloalkoxy, and hydroxyalkyl; 
             G is selected from a direct bond between M and A, CH 2 , -alkyl-O—, —O-alkyl-, O, S, SO, and SO 2 ; 
             A is selected from aryl and heteroaryl, wherein A is unsubstituted 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 NO 2 ; 
             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; 
           
         
       
    
     In one example, the invention comprises a compound of formula I as described in paragraph [0010], wherein
         R 1  is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, phenyl C 1 -C 6  alkyl, and phenyl C 1 -C 6  alkanoyl, wherein the phenylalkyl and phenylalkanoyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 R 6  groups, and   R 2  is selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, phenyl C 1 -C 6  alkyl and phenyl C 1 -C 6  alkanoyl, wherein the phenylalkyl and phenylalkanoyl groups are unsubstituted or substituted with 1, 2, 3, 4, or 5 R 6  groups,   wherein R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, —NO 2 , —CN, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .       

     In another example, the invention comprises a compound of formula I as described in paragraph [0010], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 groups independently selected from C 1 -C 4  alkyl, halogen, and C 1 -C 4  alkoxy;   Q is a direct bond between Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein
               each is unsubstituted or substituted with 1 or 2 groups that are independently selected from C 1 -C 4  alkyl, halogen, and C 1 -C 4  alkoxy;   
               J is —C(═NR 7 )NR 8 R 9 , or —NH—C(═NR 7 )NR 8 R 9 , wherein   R 7  is selected from the group consisting of H, —CN, —NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, phenyl C 1 -C 6  alkanoyl and —C(═O)NR 10 R 11 , wherein
               R 10  and R 11  are independently selected from H and C 1 -C 6  alkyl,   
               R 8  and R 9  are each independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C 1 -C 6  alkyl, pyrrolidinyl C 1 -C 6  alkyl, imidazolidinyl C 1 -C 6  alkyl, C 1 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, phenyl C 1 -C 6  alkyl, and pyridyl C 1 -C 6  alkyl, pyridazyl C 1 -C 6  alkyl, pyrimidyl C 1 -C 6  alkyl, pyrazinyl C 1 -C 6  alkyl, thienyl C 1 -C 6  alkyl, and furyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; or   
           R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, and halogen;   or
           R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, and halogen; and   R 9  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 1 -C 6  alkyl substituted with at least one of morpholinyl, piperidinyl, thiomorpholinyl, thiomorpholinyl S-oxide, phenyl, naphthyl, thiomorpholinyl S,S-dioxide, pyrrolidinyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl,   wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups, wherein   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .   
               

     In another example, the invention comprises a compound of formula I as described in paragraph [0010], wherein
         R 5  is -M—G—A, wherein   M is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, 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, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, halo C 1 -C 6  alkyl, halo C 1 -C 6  alkoxy, and hydroxy C 1 -C 6  alkyl,   G is selected from a direct bond between M and A, CH 2 , O, S, SO, and SO 2 ;   A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, and dihydronaphthyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently selected from halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo C 1 -C 6  alkyl, halo C 1 -C 6  alkoxy, CN, and NO 2 ;   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.       

     In another example, the invention comprises a compound of formula I as described in paragraph [0010], wherein
         R 1  is hydrogen, C 1 -C 6  alkyl or benzyl;   R 2  is hydrogen, C 1 -C 6  alkyl or benzyl; and   R 3  is —Z—Q-J, wherein
           Z is C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   Q is a direct bond between Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each of the above is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   J is —C(═NR 7 )NR 8 R 9  or —NH—C(═NR 7 )NR 8 R 9 , wherein   R 7  is selected from the group consisting of H, —CN, —NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, phenyl C 1 -C 6  alkanoyl and —C(═O)NR 10 R 11 , wherein
               R 10 , and R 11  are independently H, or C 1 -C 6  alkyl, and   
               R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C 1 -C 6  alkyl, pyrrolidinyl C 1 -C 6  alkyl, imidazolidinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, phenyl C 1 -C 6  alkyl, and pyridyl C 1 -C 6  alkyl, pyridazyl C 1 -C 6  alkyl, pyrimidyl C 1 -C 6  alkyl, pyrazinyl C 1 -C 6  alkyl, thienyl C 1 -C 6  alkyl, and furyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; or   
               

     R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, and halogen;
         or
           R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, and halogen, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups, wherein R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 ; and   R 9  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 1 -C 6  alkyl substituted with at least one of morpholinyl, piperidinyl, thiomorpholinyl, thiomorpholinyl S-oxide, phenyl, naphthyl, thiomorpholinyl S,S-dioxide, pyrrolidinyl, pyridyl, pyridazyl, pyrimidyl, pyrazinyl, and imidazolyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups;   
           R 4  is selected from the group consisting of H, C 1 -C 4  alkyl, benzyl and phenethyl, wherein the benzyl and phenethyl groups are unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups;   R 5  is -M—G—A, wherein
           M is selected from the group consisting of phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, thiophenyl, 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, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, halo C 1 -C 6  alkyl, halo C 1 -C 6  alkoxy, and hydroxy C 1 -C 6  alkyl,   G is selected from a direct bond between M and A, CH 2 , O, S, SO, and SO 2 ;   A is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrimidyl, pyridazyl, pyrazinyl, pyrrolyl, benzo[1,3]dioxyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, tetrahydronaphthyl, and dihydronaphthyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, 4, or 5 groups that are independently halogen, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo C 1 -C 6  alkyl, halo C 1 -C 6  alkoxy, CN, or NO 2 ;   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.   
               

     In another example, the invention comprises a compound as in paragraph [0014], wherein
         R 5  is -M—G—A, wherein   M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 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, C 1 -C 4  alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF 3 , OCF 3 , halo C 1 -C 4  alkyl, halo C 1 -C 4  alkoxy, and hydroxy C 1 -C 4  alkyl;
           G is selected from a direct bond between M and A, CH 2 , O, S, SO, and SO 2 ;   
           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 independently selected from the group consisting of F, Cl, Br, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo C 1 -C 4  alkyl, CF 3 , OCF 3 , —CN, and —NO 2 ;   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.       

     In another example, the invention comprises a compound as in paragraph [0015], wherein
         R 3  is —Z—Q-J, wherein   Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  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 substituted with 1 or 2 groups that are independently C 1 -C 4 alkyl, halogen, or C 1 -C 4  alkoxy;   J is —C(═NR 7 )NR 8 R 9  or —NH—C(═NR 7 )NR 8 R 9 , wherein
           R 1  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 R 11 , wherein
               R 10  and R 11  are independently H, or C 1 -C 6  alkyl, and   
               R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, C 3 -C 8  cycloalkyl, and C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; wherein
               R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 ,   
               or   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen.   
               

     In another example, the invention comprises a compound as in paragraph [0016], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy; and   J is —C(═NR 7 )NR 8 R 9 , wherein
               R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 R 11 , wherein
                   R 10  and R 11  are independently H, or C 1 -C 6  alkyl, and   
                   R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, C 3 -C 8  cycloalkyl, and C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups, wherein
                   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 ,   
                   or   R 8 , and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen.   
               
               

     In another example, the invention comprises a compound as in paragraph [0016], wherein
         R 8 , and R 9  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 independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen.       

     In another example, the invention comprises a compound as in paragraph [0015], wherein
         R 3  is —Z—Q-J wherein   Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  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 substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   J is —C(═NR 7 )NR 8 R 9  or —NH—C(═NR 7 )NR 8 NR 9 , wherein
           R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen; and   R 9  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 1 -C 6  alkyl substituted with at least one of morpholinyl, piperidinyl, thiomorpholinyl, phenyl, naphthyl, pyrrolidinyl, pyridyl, pyridazyl, and imidazolyl, wherein each of the above is unsubstituted or substituted with 1, or 2 R 6  groups; wherein
               R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .   
               
               

     In another example, the invention comprises a compound as in paragraph [0015], wherein
         R 3  is —Z—Q-J wherein   Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy; and   J is —C(═NR 7 )NR 8 R 9  or —NH—C(═NR 7 )NR 8 R 9 , wherein
           R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 R 11 , wherein
               R 10  and R 11  are independently H, or C 1 -C 6  alkyl, and   
               R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, C 3 -C 8  cycloalkyl, and C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; wherein
               R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .   
               
               

     In another example, the invention comprises a compound as in paragraph [0010] of structural formula II 
     
       
                 
         
             
             
         
      
     
     wherein R 3 , R 4 , and R 5  are as defined in paragraph [0010]. 
     In another example, the invention comprises a compound as in paragraph [0021], wherein
         R 4  is selected from the group consisting of H, C 1 -C 4  alkyl, and benzyl wherein the benzyl group is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups, wherein   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, —NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .       

     In another example, the invention comprises a compound as in paragraph [0022], wherein
         R 5  is -M—G—A, wherein
           M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 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, C 1 -C 4  alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF 3 , OCF 3 , halo C 1 -C 4  alkyl, halo C 1 -C 4  alkoxy, and hydroxy C 1 -C 4  alkyl;   G is selected from a direct bond between M and A, CH 2 , O, S, SO, and SO 2 ;   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 independently selected from the group consisting of F, Cl, Br, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo C 1 -C 4  alkyl, CF 3 , OCF 3 , CN, and NO 2 ;   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.   
               

     In another example, the invention comprises a compound as in paragraph [0022], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   J is —C(═NR 7 )NR 8 R 9  or —NH—C(═NR 7 )NR 8 R 9 , wherein   
           R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, phenyl C 1 -C 6  alkanoyl and —C(═O)NR 10 R 11 , wherein
           R 10  and R 11  are independently H, or C 1 -C 6  alkyl,   
           R 8  and R 93  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C 1 -C 6  alkyl, pyrrolidinyl C 1 -C 6  alkyl, imidazolidinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, phenyl C 1 -C 6  alkyl, and pyridyl C 1 -C 6  alkyl, pyridazyl C 1 -C 6  alkyl, pyrimidyl C 1 -C 6  alkyl, pyrazinyl C 1 -C 6  alkyl, thienyl C 1 -C 6  alkyl, and furyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; or   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen; or   R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; wherein   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .       

     In another example, the invention comprises a compound as in paragraph [0021] of structural formula III 
     
       
                 
         
             
             
         
      
     
     wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein each is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   J is —C(═NR 7 )NR 9  or —NH—C(═NR 7 )NR 8 R 9 , wherein
               R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, phenyl C 1 -C 6  alkanoyl and —C(═O)NR 10 R 11 , wherein
                   R 10 , and R 11  are independently H, or C 1 -C 6  alkyl,   
                   R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C 1 -C 6  alkyl, pyrrolidinyl C 1 -C 6  alkyl, imidazolidinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, phenyl C 1 -C 6  alkyl, and pyridyl C 1 -C 6  alkyl, pyridazyl C 1 -C 6  alkyl, pyrimidyl C 1 -C 6  alkyl, pyrazinyl C 1 -C 6  alkyl, thienyl C 1 -C 6  alkyl, and furyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; or   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen; or   R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen; wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; wherein
                   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 ;   
                   
               
           and   R 5  is -M—G—A, wherein
           M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 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, C 1 -C 4  alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF 3 , OCF 3 , halo C 1 -C 4  alkyl, halo C 1 -C 4  alkoxy, and hydroxy C 1 -C 4  alkyl;   G is selected from a direct bond between M and A, CH 2 , O, S, SO, and SO 2 ; 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 independently selected from the group consisting of F, Cl, Br, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo C 1 -C 4  alkyl, CF 3 , OCF 3 , CN, and NO 2 ;   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.   
               

     In another example, the invention comprises a compound as in paragraph [0025], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  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 substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   
               J is —C(═NR 7 )NR 8 R 9  or —NH—C(═N 7 )NR 8 R 9 , wherein
               R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 R 11 , wherein
                   R 10  and R 11  are independently H, or C 1 -C 6  alkyl,   
                   R 8  and R 9 , are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, piperidinyl C 1 -C 6  alkyl, pyrrolidinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, benzyl, phenethyl, and pyridyl C 1 -C 6  alkyl, pyridazyl C 1 -C 6  alkyl, and furyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; or   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen; or   R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen;   
               wherein
               R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 ; and   
               
           R 5  is -M—G—A, wherein
           M is phenyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, 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, C 1 -C 4  alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF 3 , OCF 3 , halo C 1 -C 4  alkyl, halo C 1 -C 4  alkoxy, and hydroxy C 1 -C 4  alkyl;   G is selected from a direct bond between M and A, CH 2 , 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, Cl, Br, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo C 1 -C 4  alkyl, CF 3 , OCF 3 , CN, and No 2 ;   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.   
               

     In another example, the invention comprises a compound as in paragraph [0026] of structural formula IV 
                                
wherein
         R 3  is defined in paragraph [0026], and   X is CH, CR 12 , or N;   R 12  and R 13  are at each occurrence are independently selected from the group consisting of H, halogen, CF 3 , C 1 -C 4  alkyl, and C 1 -C 4  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, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo C 1 -C 4  alkyl, CF 3 , OCF 3 , CN, and NO 2 ; and   G is selected from a direct bond between M and A, CH 2 , 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 R 12  and R 13  cannot be H.       

     In another example, the invention comprises a compound as in paragraph [0027] of structural formula V 
                                
wherein
         R 3 , 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   R 12  and R 13  are independently H, fluoro, chloro, CF 3 , methyl or methoxy;   with the proviso that when G is a direct bond to A, and A is phenyl, then at least one of R 12  and R 13  cannot be H.       

     In another example, the invention comprises a compound as in paragraph [0028], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J or —C(═O)—,   
           J is —NH—C(═NR 7 )NR 8 R 9 , wherein
           R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 , R 11 , wherein
               R 10  and R 11  are independently H, or C 1 -C 6  alkyl, and   
               R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 4  alkyl, morpholinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups, wherein
               R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 ,   
               or   R 8  and R 9 , 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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen.   
               

     In another example, the invention comprises a compound as in paragraph [0028], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J or —C(O)—,   J is —NH—C(═NR 7 )NR 8 R 9 , wherein
               R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen; and   R 9  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 1 -C 6  alkyl substituted 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 R 6  groups, wherein
                   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .   
                   
               
               

     In another example, the invention comprises a compound as in paragraph [0028], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein
               each is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   
               J is —C(═NR 7 )NR 8 R 9 , wherein
               R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 R 11 , wherein
                   R 10  and R 11  are independently H, or C 1 -C 6  alkyl,   
                   R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups;   or   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen; wherein
                   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .   
                   
               
               

     In another example, the invention comprises a compound as in paragraph [0027] of structural formula VI 
     
       
                 
         
             
             
         
      
     
     wherein
         R 3 , 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;   R 12  is selected from the group consisting of H, halogen, C 1 -C 4  alkyl, —CF 3 , and C 1 -C 4  alkoxy.       

     In another example, the invention comprises a compound as in paragraph [0032], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J or —C(O)—,   J is —NH—C(═NR 7 )NR 8 R 9 , wherein
               R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 R 11 , wherein
                   R 10  and R 11  are independently H, or C 1 -C 6  alkyl, and   
                   R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; wherein
                   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 , or   
                   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen.   
               
               

     In another example, the invention comprises a compound as in paragraph [0032], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J or —C(═O)—,   J is —NH—C(═NR 7 )NR 8 R 9 , wherein
               R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen; and   R 9  is selected from the group consisting of H, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, C 1 -C 6  alkoxy C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and C 1 -C 6  alkyl substituted 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 R 6  groups, wherein
                   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .   
                   
               
               

     In another example, the invention comprises a compound as in paragraph [0032], wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 6  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, or thiomorpholinyl, wherein
               each is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   
               J is —C(═NR 7 )NR 8 R 9  wherein
               R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, and —C(═O)NR 10 R 11 , wherein
                   R 10  and R 11  are independently H, or C 1 -C 6  alkyl,   
                   R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, and C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups;   or   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6 alkoxy, hydroxy, or halogen; wherein
                   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 .   
                   
               
               

     In another example, the invention comprises a compound of structural formula VII: 
     
       
                 
         
             
             
         
      
     
     wherein
         R 3  is —Z—Q-J, wherein
           Z is a C 1 -C 10  alkyl, C 1 -C 6  alkoxy C 1 -C 6  alkyl, or C 1 -C 6  alkylthio C 1 -C 6  alkyl, each of which is unsubstituted or substituted with 1 or 2 C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy groups;   Q is a direct bond between Z and J, —C(═O)—, piperidinyl, pyrrolyl, piperazinyl, imidazolidinyl, morpholinyl, thiomorpholinyl, azepanyl, or azocanyl wherein   each is unsubstituted or substituted with 1 or 2 groups that are independently C 1 -C 4  alkyl, halogen, or C 1 -C 4  alkoxy;   J is —NH—C(═NR 7 ) NR 3 R 9 , wherein
               R 7  is selected from the group consisting of H, CN, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkanoyl, phenyl C 1 -C 6  alkanoyl and —C(═O)NR 10 R 11 , wherein
                   R 10  and R 11  are independently H, or C 1 -C 6  alkyl,   
                   R 8  and R 9  are independently selected from the group consisting of H, C 1 -C 6  alkyl, hydroxy, C 1 -C 6  alkoxy, alkoxy C 1 -C 6  alkyl, morpholinyl C 1 -C 6  alkyl, thiomorpholinyl, thiomorpholinyl S,S-dioxide, thiomorpholinyl S-oxide, piperidinyl C 1 -C 6  alkyl, pyrrolidinyl C 1 -C 6  alkyl, imidazolidinyl C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, C 1 -C 8  cycloalkyl C 1 -C 6  alkyl, phenyl C 1 -C 6  alkyl, and pyridyl C 1 -C 6  alkyl, pyridazyl C 1 -C 6  alkyl, pyrimidyl C 1 -C 6  alkyl, pyrazinyl C 1 -C 6  alkyl, thienyl C 1 -C 6  alkyl, and furyl C 1 -C 6  alkyl, wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; or   R 8  and R 9  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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen; or   R 7 , R 8 , 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 C 1 -C 6  alkyl, C 1 -C 6  alkoxy, hydroxy, or halogen; wherein each of the above is unsubstituted or substituted with 1, 2, 3, or 4 R 6  groups; wherein   R 6  at each occurrence is independently selected from the group consisting of halogen, hydroxy, NO 2 , C 1 -C 6  alkyl, C 1 -C 6  alkoxy, CF 3 , and OCF 3 ; and   
               
           R 5  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, C 1 -C 4  alkyl, hydroxy, methoxy, ethoxy, isopropoxy, CF 3 , OCF 3 , halo C 1 -C 4  alkyl, halo C 1 -C 4  alkoxy, and hydroxy C 1 -C 4  alkyl;   G is selected from a direct bond between M and A, and O; 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 independently selected from the group consisting of F, Cl, Br, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo C 1 -C 4  alkyl, CF 3 , OCF 3 , CN, and NO 2 ;   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.       

     In another example, the invention comprises a compound or pharmaceutically acceptable salt thereof of structural formula VIII: 
     
       
                 
         
             
             
         
      
     
     wherein R 3  is selected from: 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     and R 3  is selected from 
     
       
                 
         
             
             
         
      
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
     In another example, the invention comprises a compound or pharmaceutically acceptable salt thereof listed in Table 1: 
     
       
         
               
               
             
               
               
             
           
               
                 TABLE 1 
               
               
                   
               
               
                 # 
                 Compound Name 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 N 2 -{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 argininamide 
               
               
                 2 
                 N 1 -hydroxy-N 2 -[(4-phenoxyphenyl)sulfonyl]-D-argininamide 
               
               
                 3 
                 N 2 -{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 argininamide 
               
               
                 4 
                 N 2 -[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N 1 -hydroxy-D- 
               
               
                   
                 argininamide 
               
               
                 5 
                 N 2 -[(3,5-difluoro-4-phenoxyphenyl)sulfonyl]-N 1 -hydroxy-D- 
               
               
                   
                 argininamide 
               
               
                 6 
                 N 2 -{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 7 
                 N 2 -{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 8 
                 N 2 -{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 9 
                 N 2 -{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy- 
               
               
                   
                 D-argininamide 
               
               
                 10 
                 N 2 -{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N 1 -hydroxy- 
               
               
                   
                 D-argininamide 
               
               
                 11 
                 N 2 -{[4-(4-cyanophenoxy)-3-fluorophenyl]sulfonyl}-N 1 -hydroxy- 
               
               
                   
                 D-argininamide 
               
               
                 12 
                 N 2 -{[4-(3,5-dimethylphenoxy)-3-fluorophenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 13 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-D-lysinamide 
               
               
                 14 
                 N 1 -hydroxy-N 2 -{[6-(5,6,7,8-tetrahydronaphthalen-2- 
               
               
                   
                 yloxy)pyridin-3-yl]sulfonyl}-D-argininamide 
               
               
                 15 
                 N 5 -[(Z)-amino(nitroimino)methyl]-N 2 -{[6-(3- 
               
               
                   
                 fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 ornithinamide 
               
               
                 16 
                 N 5 -[(Z)-amino(nitroimino)methyl]-N 1 -hydroxy-N 2 -[(4- 
               
               
                   
                 phenoxyphenyl)sulfonyl]-D-ornithinamide 
               
               
                 17 
                 N 6 -[(E)-amino(cyanoimino)methyl]-N 2 -{[6-(3- 
               
               
                   
                 fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 18 
                 N 6 -[(E)-amino(cyanoimino)methyl]-N 1 -hydroxy-N 2 -[(4- 
               
               
                   
                 phenoxyphenyl)sulfonyl]-D-lysinamide 
               
               
                 19 
                 N 6 -{(E)-(cyanoimino)[(2-methoxyethyl)amino]methyl}-N 2 -{[6-(3- 
               
               
                   
                 fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 20 
                 N 6 -{(Z)-(cyanoimino)[(2-methoxyethyl)amino]methyl}-N 1 - 
               
               
                   
                 hydroxy-N 2 -[(4-phenoxyphenyl) sulfonyl]-D-lysinamide 
               
               
                 21 
                 N 6 -{(Z)-(cyanoimino)[(2-methoxyethyl)amino]methyl}-N 2 -{[4-(4- 
               
               
                   
                 fluorophenoxy)phenyl] sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 22 
                 N 6 -[(E)-(cyanoimino)(propylamino)methyl]-N 2 -{[6-(3- 
               
               
                   
                 fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 23 
                 N 6 -[(E)-(cyanoimino)(propylamino)methyl]-N 1 -hydroxy-N 2 -[(4- 
               
               
                   
                 phenoxyphenyl)sulfonyl]-D-lysinamide 
               
               
                 24 
                 N 6 -[(E)-(cyanoimino)(propylamino)methyl]-N 2 -{[4-(4- 
               
               
                   
                 fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 25 
                 N 6 -{(Z)-(cyanoimino)[(2-morpholin-4-ylethyl)amino]methyl}-N 2 - 
               
               
                   
                 {[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 26 
                 N 6 -{(Z)-(cyanoimino)[(2-morpholin-4-ylethyl)amino]methyl}-N 1 - 
               
               
                   
                 hydroxy-N 2 -[(4-phenoxyphenyl) sulfonyl]-D-lysinamide 
               
               
                 28 
                 N 6 -[(Z)-(cyanoimino)(cyclopropylamino)methyl]-N 1 -hydroxy-N 2 - 
               
               
                   
                 [(4-phenoxyphenyl) sulfonyl]-D-lysinamide 
               
               
                 29 
                 N 6 -[(E)-[(aminocarbonyl)imino](hydroxyamino)methyl]-N 2 -{[4- 
               
               
                   
                 (4-fluorophenoxy)phenyl] sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 30 
                 N 1 -hydroxy-5-morpholin-4-yl-N 2 -[(4-phenoxyphenyl)sulfonyl]-D- 
               
               
                   
                 norvalinamide 
               
               
                 31 
                 N 2 -{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-5- 
               
               
                   
                 morpholin-4-yl-D-norvalinamide 
               
               
                 32 
                 N 2 -{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-6- 
               
               
                   
                 morpholin-4-yl-D-norleucinamide 
               
               
                 33 
                 N 1 -hydroxy-6-morpholin-4-yl-N 2 -[(4-phenoxyphenyl)sulfonyl]-D- 
               
               
                   
                 norleucinamide 
               
               
                 34 
                 N 2 -{[4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-6- 
               
               
                   
                 morpholin-4-yl-D-norleucinamide 
               
               
                 35 
                 N 2 -[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N 1 -hydroxy-6- 
               
               
                   
                 morpholin-4-yl-D-norleucinamide 
               
               
                 36 
                 N 2 -{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-6-morpholin-4-yl-D-norleucinamide 
               
               
                 37 
                 N 2 -{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-6-morpholin-4-yl-D-norleucinamide 
               
               
                 38 
                 N 6 -[(E)-(cyanoimino)(morpholin-4-yl)methyl]-N 2 -{[4-(4- 
               
               
                   
                 fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 39 
                 N 6 -[(Z)-(cyanoimino)(morpholin-4-yl)methyl]-N 2 -{[3-fluoro-4- 
               
               
                   
                 (4-fluorophenoxy)pheny]sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 40 
                 3-{1-[amino(imino)methyl]piperidin-4-yl}-N 1 -hydroxy-N 2 -[(4- 
               
               
                   
                 phenoxyphenyl)sulfonyl]alaninamide 
               
               
                 41 
                 3-{1-[(Z)-(cyanoimino)(propylamino)methyl]piperidin-4-yl}-N 1 - 
               
               
                   
                 hydroxy-N 2 -[(4-phenoxyphenyl)sulfonyl]alaninamide 
               
               
                 42 
                 3-(1-{(Z)-(cyanoimino)[(2- 
               
               
                   
                 methoxyethyl)amino]methyl}piperidin-4-yl)-N 1 -hydroxy-N 2 -[(4- 
               
               
                   
                 phenoxyphenyl)sulfonyl]alaninamide 
               
               
                 43 
                 3-(1-{(E)-(cyanoimino)[(2- 
               
               
                   
                 methoxyethyl)amino]methyl}piperidin-4-yl)-N 2 -{[3,5-difluoro- 
               
               
                   
                 4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxyalaninamide 
               
               
                 44 
                 3-(1-{(Z)-[(aminocarbonyl)imino][(2- 
               
               
                   
                 methoxyethyl)amino]methyl}piperidin-4-yl)-N 1 -hydroxy-N 2 -[(4- 
               
               
                   
                 phenoxyphenyl)sulfonyl]alaninamide 
               
               
                 45 
                 N 2 -{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-3-[(2-morpholin-4-ylethyl)thio]-D-valinamide 
               
               
                 46 
                 N 2 -{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy- 
               
               
                   
                 3-[(2-morpholin-4-ylethyl)thio]-D-valinamide 
               
               
                 47 
                 N 2 -{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy- 
               
               
                   
                 3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 
               
               
                 48 
                 N 2 -{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N 1 -hydroxy- 
               
               
                   
                 3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 
               
               
                 49 
                 N 6 -4,5-dihydro-1H-imidazol-2-yl-N 2 -{[4-(4- 
               
               
                   
                 fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 50 
                 N 6 -[(Z)-(cyanoimino)(cyclopropylamino)methyl]-N 2 -{[6-(3- 
               
               
                   
                 fluorophenyl)pyridin-3-yl] sulfonyl}-N 1 -hydroxy-D-lysinamide 
               
               
                 51 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-3- 
               
               
                   
                 ylalaninamide 
               
               
                 52 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-3-pyrrolidin-3- 
               
               
                   
                 ylalaninamide 
               
               
                 53 
                 N 2 -{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 54 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 tryptophanamide 
               
               
                 55 
                 N 1 -hydroxy-N 2 -({5-[2-(methylthio)pyrimidin-4-yl]-2- 
               
               
                   
                 thienyl}sulfonyl)lysinamide 
               
               
                 56 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-D-histidinamide 
               
               
                 57 
                 N 1 -hydroxy-N 2 -methyl-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-3- 
               
               
                   
                 piperidin-3-ylalaninamide 
               
               
                 58 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-3-piperidin-4- 
               
               
                   
                 ylalaninamide 
               
               
                 59 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-3-pyridin-3-yl- 
               
               
                   
                 D-alaninamide 
               
               
                 60 
                 N 6 -glycyl-N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 61 
                 N 1 -hydroxy-N 2 ,N 6 ,N 6 -trimethyl-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D-lysinamide 
               
               
                 62 
                 3-[4-(aminomethyl)cyclohexyl]-N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}alaninamide 
               
               
                 63 
                 N 1 -hydroxy-N 2 -{[6-(naphthalen-1-yloxy)pyridin-3-yl]sulfonyl}- 
               
               
                   
                 D-argininamide 
               
               
                 64 
                 N 1 -hydroxy-N 2 -{[6-(5,6,7,8-tetrahydronaphthalen-2- 
               
               
                   
                 yloxy)pyridin-3-yl]sulfonyl}-D-lysinamide 
               
               
                 65 
                 N 6 -[(E)-(cyanoimino)(hydroxyamino)methyl]-N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-D-lysinamide 
               
               
                 66 
                 N 2 -({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 67 
                 N 6 -{(Z)-(cyanoimino)[(2-morpholin-4-ylethyl)amino]methyl}-N 2 - 
               
               
                   
                 {[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 68 
                 N 2 -({6-[(4-fluorophenyl)oxy]pyridin-3-yl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 69 
                 N 2 -({6-[(4-chlorophenyl)oxy]pyridin-3-yl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 70 
                 N 2 -({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-N 6 -(morpholin-4-ylcarbonyl)-D-lysinamide 
               
               
                 71 
                 4-cyano-N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 72 
                 4-cyano-N 2 -({3,5-difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 73 
                 3-cyano-N 2 -({3,5-difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 74 
                 3-cyano-N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 75 
                 N 2 -({3,5-difluoro-4-[(4-hydroxyphenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxyargininamide 
               
               
                 76 
                 N 2 -{[3,5-difluoro-4-(pyridin-3-yloxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxyargininamide 
               
               
                 77 
                 N 2 -({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-N 6 -({[2-(methyloxy)ethyl]amino}carbonyl)-D-lysinamide 
               
               
                 78 
                 N 2 -({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 6 - 
               
               
                   
                 [1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl]-N 1 -hydroxy- 
               
               
                   
                 D-lysinamide 
               
               
                 79 
                 N 2 -{[3,5-difluoro-4-({4- 
               
               
                   
                 [(phenylmethyl)oxy]phenyl}oxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxyargininamide 
               
               
                 80 
                 N 2 -{[3,5-difluoro-4-(pyridin-3-yloxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-6-morpholin-4-yl-D-norleucinamide 
               
               
                 81 
                 N 2 -({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-3-morpholin-4-yl-D-alaninamide 
               
               
                 82 
                 N 2 -({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-4-[(hydroxyamino)(imino)methyl]-D-phenylalaninamide 
               
               
                 83 
                 N 2 -({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-3-[(hydroxyamino)(imino)methyl]-D-phenylalaninamide 
               
               
                 84 
                 N 2 -({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-3-[1-(morpholin-4-ylcarbonyl)piperidin-4- 
               
               
                   
                 yl]alaninamide 
               
               
                 85 
                 N 2 -({3,5-difluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-3-[1-(morpholin-4-ylcarbonyl)piperidin-4- 
               
               
                   
                 yl]alaninamide 
               
               
                 86 
                 3-[amino(imino)methyl]-N 2 -({3,5-difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 87 
                 4-[amino(imino)methyl]-N 2 -({3,5-difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 88 
                 N 5 -(aminocarbonyl)-N 2 -({3-fluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-D-ornithinamide 
               
               
                 89 
                 (2R)-N 2 -[({4-[(4-chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-4-(dimethylamino)-N 1 - 
               
               
                   
                 hydroxybutanamide 
               
               
                 90 
                 (2R)-N 2 -[({4-[(4-chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-4-{[1-(4,4-dimethyl-2,6- 
               
               
                   
                 dioxocyclohexylidene)-2-methylbutyl]amino}-N 1 - 
               
               
                   
                 hydroxybutanamide 
               
               
                 91 
                 N 2 -({4-[(4-chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-3-[(2-morpholin-4-yl-2-oxoethyl)thio]-D-valinamide 
               
               
                 92 
                 (2R)-4-amino-N 2 -[({4-[(4-chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-N 1 -hydroxybutanamide 
               
               
                 93 
                 (2R)-4-{[amino(imino)methyl]amino}-N 2 -[({4-[(4- 
               
               
                   
                 chlorophenyl)oxy]-3,5-difluorophenyl}sulfonyl)amino]-N 1 - 
               
               
                   
                 hydroxybutanamide 
               
               
                 94 
                 N 2 -[({4-[(4-chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-N 1 -hydroxy-2-piperidin-4- 
               
               
                   
                 ylacetamide 
               
               
                 95 
                 N 2 -[({4-[(4-chlorophenyl)oxy]-3-fluorophenyl}sulfonyl)amino]- 
               
               
                   
                 N 1 -hydroxy-2-piperidin-4-ylacetamide 
               
               
                 96 
                 N 2 -[({3-fluoro-4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)amino]- 
               
               
                   
                 N 1 -hydroxy-2-piperidin-4-ylacetamide 
               
               
                 97 
                 N 2 -[({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)amino]-N 1 - 
               
               
                   
                 hydroxy-2-piperidin-4-ylacetamide 
               
               
                 98 
                 N 2 -({[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}amino)-N 1 - 
               
               
                   
                 hydroxy-2-piperidin-4-ylacetamide 
               
               
                 99 
                 N 2 -[({4-[(3,5-dimethylphenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-N 1 -hydroxy-2-piperidin-4- 
               
               
                   
                 ylacetamide 
               
               
                 100 
                 3-[4-(aminomethyl)cyclohexyl]-N 2 -({4-[(4-chlorophenyl)oxy]- 
               
               
                   
                 3,5-difluorophenyl}sulfonyl)-N 1 -hydroxyalaninamide 
               
               
                 101 
                 3-[4-(aminomethyl)cyclohexyl]-N 2 -({3,5-difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxyalaninamide 
               
               
                 102 
                 3-[4-(aminomethyl)cyclohexyl]-N 2 -({4-[(4-chlorophenyl)oxy]-3- 
               
               
                   
                 fluorophenyl}sulfonyl)-N 1 -hydroxyalaninamide 
               
               
                 103 
                 3-[4-(aminomethyl)cyclohexyl]-N 2 -({3-fluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxyalaninamide 
               
               
                 104 
                 3-[4-(aminomethyl)cyclohexyl]-N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxyalaninamide 
               
               
                 105 
                 3-[4-(aminomethyl)cyclohexyl]-N 2 -{[6-(3-fluorophenyl)pyridin- 
               
               
                   
                 3-yl]sulfonyl}-N 1 -hydroxyalaninamide 
               
               
                 106 
                 3-[4-(aminomethyl)cyclohexyl]-N 2 -({4-[(3,5- 
               
               
                   
                 dimethylphenyl)oxy]-3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxyalaninamide 
               
               
                   
               
             
          
         
       
     
     In another example, the invention comprises a pharmaceutical composition comprising a compound as described in any of paragraphs [0010]-[0038] and a pharmaceutically acceptable carrier. 
     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 sulfonyl 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. 
     The following paragraphs provide definitions of the various 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. 
     The term alkyl refers inclusively to a univalent C 1  to C 20  (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 defined (e.g. C 3 -C 8  cycloalkyl) to differentiate them from generically described alkyls (that, again, are intended to construe inclusion of cycloalkyls). Thus “alkyl” includes, e.g., C 3 -C 8  cycloalkyl. The term “alkyl” also includes, e.g., C 3 -C 8  cycloalkyl C 1 -C 6  alkyl, which is a C 1 -C 6  alkyl having a C 3 -C 8  cycloalkyl terminus. Alkyl&#39;s can be optionally substituted with any appropriate 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., “Protective Groups in Organic Synthesis,” John Wiley and Sons, Second Edition, 1991. 
     The term alkoxy refers to an alkyl (as defined above) moiety having a terminal —O— with a free valence, e.g., CH 3 CH 2 —O—; 
     The term alkenyl refers to a univalent C 2 -C 6  straight, branched, or in the case of C 5-8 , cyclic hydrocarbon with at least one double bond. 
     The term aryl refers to a univalent phenyl, biphenyl, napthyl, and the like. The aryl group can be optionally substituted 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 Organic 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 described as having an aryl group. 
     The term heteroatom means O, S, or N. 
     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. 
     The term heteroaryl specifically refers to an aryl that includes at least one of sulfur, oxygen, and nitrogen in the aromatic ring. Non-limiting examples are pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, and isoxazolyl. 
     The term halo refers to chloro, fluoro, iodo, or bromo. 
     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 ammonium salt of the formula —NR+Z—, wherein R is hydrogen, alkyl, or benzyl, and Z is a counterion, including chloride, bromide, iodide, —O-alkyl, toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate (such as benzoate, succinate, acetate, glycolate, maleate, malate, citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate, benzyloate, and diphenylacetate). 
     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. 
     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′. 
     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. 
     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 structures 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 Molecular Biology (IUBMB), and the Chemical Abstracts Service (CAS). 
     The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure. 
     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. 
     Methods for the preparation and/or separation and isolation 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: formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric 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 separation 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 entity by one of the separation procedures described above, a further 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, enriched in a particular enantiomer, the major component enantiomer may be further enriched (with concomitant loss in yield) by recrystallization. 
     “Prodrug” refers to compounds that are transformed (typically 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 compound having an active form bearing a carboxylic acid moiety. Examples 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 alkyl 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 esters of the compounds of the present invention may be prepared according to conventional methods. A thorough discussion of prodrugs 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, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. 
     “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 polar 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 example, a prodrug may be synthesized such that the biologically active 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 disclosure. 
     In addition, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically 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. 
     In addition, it is intended that the present invention cover compounds made either using standard organic synthetic techniques, including combinatorial chemistry or by biological methods, such as bacterial digestion, metabolism, enzymatic conversion, and the like. 
     General Administration 
     Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate 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, nasally, parenterally (intravenous, intramuscular, or subcutaneous), topically, transdermally, intravaginally, intravesically, intracistemally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. 
     The compositions will include a conventional pharmaceutical 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. Compositions 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, suspending, sweetening, flavoring, perfuming, emulsifying, and dispensing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, 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. 
     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 monolaurate, triethanolamine oleate, butylalted hydroxytoluene, etc. 
     Compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. 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. 
     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, prophalactically or otherwise. 
     Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert customary 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) binders, as for example, cellulose derivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose, and gum acacia, (c) humectants, 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 compounds, (g) wetting agents, as for example, cetyl alcohol, and glycerol monostearate, magnesium stearate and the like (h) adsorbents, 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. 
     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. 
     Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Such dosage forms are prepared, for example, by dissolving, dispersing, etc., a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and optional pharmaceutical 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 solution or suspension. 
     Suspensions, in addition to the active compounds, may contain suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like. 
     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 excipients or carriers such as cocoa butter, polyethyleneglycol or a suppository wax, which are solid at ordinary temperatures but liquid at body temperature and therefore, melt while in a suitable body cavity and release the active component therein. 
     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. 
     Generally, depending on the intended mode of administration, 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 acceptable salt thereof, with the rest being suitable pharmaceutical excipients. 
     Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington&#39;s Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state in accordance with the teachings of this invention. 
     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 including 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 administration, 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 patient 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 depend on a number of factors including the requirements of the patient, the severity of the condition being treated, and the pharmacological activity of the compound being used. The determination of optimum dosages for a particular patient is well known to one skilled in the art. 
     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 
     
       
                 
         
             
             
         
      
     
     Step 1: A mixture of 3,4,5-trifluoronitrobenzene (20.0 g, 113 mmol, commercially available from AsymChem of Durham, N.C.), dry DMF (100 ml), 4-fluorophenol (13.9 g, 124 mmol), and Cs 2 CO 3  (56 g, 172 mmol) was stirred under N 2  at 60-70° C. for 1-2 hrs. After cooling to room temperature, the reaction mixture was partitioned between H 2 O and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2×). The EtOAc extractions were washed with sat&#39;d NaCl (1×), dried over Na 2 SO 4 , and concentrated in vacuo to give 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (32.0 g, 105%) which was used in the next step without further purification.  1 H NMR (DMSO-d 6 ): δ 7.15 (m, 2H), 7.22 (m, 2H), 8.31 (d, 2H, J=7.6 Hz). 
     Step 2: A mixture of 4-(4-fluorophenoxy)-3,5-difluoronitrobenzene (30.4 g, 113 mmol), EtOAc (300 ml), 10% Pd/C (2.6 g) was stirred under an atmosphere of H 2  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 (26.5 g, 98%) which was used in the next step without further purification.  1 H NMR (CDCl 3 ): δ 3.82 (s, 2H), 6.26 (d, 2H, J=8.4 Hz), 6.88 (m, 2H), 6.93 (m, 2H). 
     Step 3: A solution of NaNO 2  (8.4 g, 122 mmol) in H 2 O (20 ml) was added dropwise to a mixture of 4-(4-fluorophenoxy)-3,5-difluoroaniline (26.5 g, 111 mmol), AcOH (160 ml), and conc. HCl (160 ml) cooled in an ice/NaCl/H 2 O bath. After addition was complete, the mixture was stirred an additional 20-30 minutes before a mixture of SO 2  (74 g, 1.15 mol) in AcOH (140 ml) and CUCl 2 -2H 2 O (11.1 g, 65 mmol) in H 2 O (16 ml) 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 CH 2 Cl 2  (3×). The combined CH 2 Cl 2  extractions were washed with sat&#39;d NaCl (1×), dried over Na 2 SO 4 , 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 (29.8 g, 83%).  1 H NMR (CDCl 3 ): δ 6.94 (m, 2H), 7.10 (m, 2H), 7.71 (d, 2H, J=6.4 Hz). 
     4-(4-Chlorophenoxy)-3,5-difluorophenylsulfonyl chloride 
     
       
                 
         
             
             
         
      
     
     Step 1: A mixture of 3,4,5-trifluoronitrobenzene (6.6 g, 37 mmol), dry DMF (30 ml), 4-chlorophenol (5.26 g, 41 mmol), and Cs 2 CO 3  (18.8 g, 58 mmol) was stirred under N 2  at 60-70 C for 1-2 hrs. After cooling to room temperature, the reaction mixture was partitioned between H 2 O and EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc (2×). The EtOAc extractions were washed with sat&#39;d NaCl (1×), dried over Na 2 SO 4 , and concentrated in vacuo to give 4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (11.3 g, 106%) which was used in the next step without further purification.  1 H NMR (CDCl 3 ): δ 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: K 2 CO 3 /acetonitrile can be used in lieu of Cs 2 CO 3 /DMF. 
     Step 2: A mixture of 4-(4-chlorophenoxy)-3,5-difluoronitrobenzene (10.6 g, 37 mmol), toluene (150 ml), H 2 O (150 ml), iron powder (6.9 g, 124 mmol), and ammonium acetate (9.3 g, 120 mmol) 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 H 2 O and EtOAc. The filtrate was transferred to a separatory funnel and the phases separated. The aqueous phase was further extracted with EtOAc (2×). The combined organic phases were washed with H 2 O (1×), sat&#39;d NaCl (1×), dried over Na 2 SO 4 , and concentrated in vacuo to give 4-(4-chlorophenoxy)-3,5-difluoroaniline (10.8 g, 113%) which was used in the next step without further purification.  1 H NMR (CDCl 3 ): δ 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). 
     Step 3: A solution of NaNO 2  (2.8 g, 41 mmol) in H 2 O (7.0 ml) was added dropwise to a mixture of 4-(4-chlorophenoxy)-3,5-difluoroaniline (9.5 g, 37 mmol), AcOH (50 ml), and conc. HCl (50 ml) cooled in an ice/NaCl/H 2 O bath. After addition was complete, the mixture was stirred an additional 20-30 minutes before a mixture of SO 2  (25 g, 290 mmol) in AcOH (50 ml) and CuCl 2 -2H 2 O (3.8 g, 22 mmol) in H 2 O (6.0 ml) 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 CH 2 Cl 2  (3×). The combined CH 2 Cl 2  extractions were washed with sat&#39;d NaCl (1×), dried over Na 2 SO 4 , 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 (11.0 g, 87%).  1 H NMR (CDCl 3 ): δ 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 
     
       
                 
         
             
             
         
      
     
     To a 2000 mL round-bottomed flask was added 800 mL distilled H 2 O 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 SOCl 2  (300 mL, 4.1 mol, 10 eq.) was added dropwise over a period of 1 h. After complete addition, the solution was stirred for 4 h while warming to room temperature. 
     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 vigorously and cooled to −10° C. The flask was fitted with a 250 mL addition funnel and a solution of NaNO 2  (34.3 g, 0.50 mol, 1.2 eq.) in H 2 O (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. 
     The flask containing the SOCl 2 /H 2 O 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 transferred 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 additional hour while warming to room temperature. The reaction mixture was transferred to a separatory funnel and extracted with CH 2 Cl 2  (3×200 mL). The organic phases are combined and dried over anhydrous Na 2 SO 4 , filtered, and concentrated to give a dark-bronze oil (79.5 g, 83%). 
     Example 2 
     Synthesis of N 2 -{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D-argininamide 
     Arginine-derived trifluoroarylsulfonamide Intermediate 
     (EXEL-01260235)→Same Compound as in Example 6 
     
       
                 
         
             
             
         
      
     
     To a 1000 mL round-bottomed flask was added H-D-Arg(Pmc)-OH (15.7 g, 35.7 mmol, 1.0 eq.), CH 2 Cl 2  (250 mL), and a stir bar. The resulting suspension was stirred vigorously and trimethylsilyl chloride (TMS-Cl) (7.76 g, 71.4 mmol, 2.0 eq.) was added via syringe over a period of 30 sec. After stirring for approximately 20 min, the solution becomes homogeneous. Et 3 N (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 CH 2 Cl 2  (50 mL) was added dropwise over a period of 3 min. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then concentrated in vacuo and dissolved in saturated NaHCO 3  (500 mL) with stirring. The homogeneous solution was transferred to a separatory funnel and extracted with Et 2 O (2×100 mL). The aqueous phase was drained into a 2000 mL beaker and acidified to pH 2 with 1 N HCl. Upon acidification, the desired sulfonamide precipitated as a white solid (sulfonamide). The aqueous suspension was extracted with EtOAc (2×300 mL). The organic phase was washed with brine (1×100 mL) and the organic phases were combined and dried over anhydrous NaHCO 3 , filtered, and concentrated to give an off-white solid. The solid was purified via flash chromatography (10% MeOH in CH 2 Cl 2  w/0.05% AcOH, R f =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 
     
       
                 
         
             
             
         
      
     
     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 reaction flask was heated overnight in an oil bath at 65° C. The reaction 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 HCl. The aqueous layer was extracted with EtOAc (3×50 mL). The organic phases were combined and washed with brine (1×100 mL). The organic phase was dried over anhydrous Na 2 SO 4 , 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 MW: 726.20, Observed M+H, 727.1, Retention time: 1.62 min. 
     Arginine-derived-bis-aryl ether Intermediate: ester Formation 
     
       
                 
         
             
             
         
      
     
     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). HCl 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 viscous 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 
     
       
                 
         
             
             
         
      
     
     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/CH 2 Cl 2  solution (250 mL) was prepared. The solution was added to the reaction flask and the resulting solution was stirred for 1.5 h. The reaction mixture was concentrated in vacuo and azeotroped with toluene (3×20 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. 
     N 2 -{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D-argininamide 
     
       
                 
         
             
             
         
      
     
     Trifluoroacetate salt of N-2-{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N-1-hydroxy-D-argininamide (EXEL-01260235): Solutions of HONH 2 .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 HONH 2 .HCl solution. Upon addition, a white solid (KCl) immediately precipitated. The resulting solution was allowed to stand for 20 min. The solution was filtered into a 200 mL recovery 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 reaction mixture was acidified to pH 5 with 1N HCl. A viscous solid formed in the flask. The solution was concentrated and then redissolved in MeOH. An off-white solid (HONH 2 ) remains out of solution. The solution was filtered and concentrated. Filtration was repeated as necessary until no more HONH 2  was evident. The resulting dark solid was redissolved in MeOH and purified via reverse phase HPLC (0.5% TFA/AcCN, 0.5% TFA/H 2 O) 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, Observed M+H, 476.1, Retention time: 1.33 min. 
     Example 3 
     Synthesis of N 2 -{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 -hydroxy-D-argininamide (EXEL-01260250)→Same Compound as in Example 5 and 
     N 2 -{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 -hydroxy-D-argininamide (EXEL-01348386) 
     
       
                 
         
             
             
         
      
     
     The above compounds (X=Cl, Br) were prepared via solution phase chemistry in a manner similar to description above:
         N 2 -{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 -hydroxy-D-argininamide (EXEL-01260250)LC/MSD (HP Series 1100 MSD): Expected MW: 491.08, Observed M+H, 492.0, Retention time: 1.37 min   N 2 -{[4-(4-bromophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 -hydroxy-D-argininamide (EXEL-01348386) LC/MSD (HP Series 1100 MSD): Expected 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 (EXEL-01260232) 
     
       
                 
         
             
             
         
      
     
     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 
     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 corresponding sulfonamide. Further steps to convert such bis-aryl ether sulfonamide intermediates to corresponding compounds of the invention is also illustrated, specifically regarding alternative protection de-protection strategies on route to hydroximate-derived compounds of the invention. 
                                
Sulfonamide b
 
     D-Arg (pmc)-OH (3.21 g) is suspended in dichloromethane (40 ml) and 4-chlorophenoxy-3,5-difluorophenylsulfonyl chloride (2.5 g), triethylamine (4.1 ml) and catalytic amount of DMAP are added. The mixture is stirred at room temperature for 5 hrs. After concentrated the reaction mixture, sat. NaHCO3 (60 ml), water (20 ml) and diethyl ether (80 ml) are added and extracted with ether. 
     The aqueous phase, after acidifying with 6N HCl, is extracted with ethyl acetate. The combined organic phases are washed with brine, dried (MgSO4) 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 
     Compound b is dissolved in dry MeOH (150 ml) and TMSCl (1.82 ml) is added. The reaction mixture is stirred under the reflux condition for 2 hrs. The reaction mixture is concentrated under reduced pressure to give compound 3 as a white solid. Purification by column chromatography with EtOAc-Hexane (3:1) gives 2.8 g (54%). MK830-70: M+1=757.1 
     Guanidine d 
     Compound c (2.8 g) is treated with 50%-trifluoroacetic acid in DCM (50 ml) included triethylsilane (0.5 ml) for 3 hrs. After concentrated 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 (2.1 g, 116%). MK830-73: M+1=491.0 
     N 2 -{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 -hydroxy-D-argininamide (EXEL-01260250) 
     Compound d (2.1 g) is treated with 1.76M hydroxylamine in KOH methanol solution (preparation: 6.96 g of NH 2 OH). HCl is dissolved in MeOH (36 ml) and 8.4 g of potassium hydroxide is dissolved in MeOH (21 ml), then mix together and filtered) for 2 hrs. After neutralizing the reaction mixture with 6N HCl, the reaction mixture is filtered to move the salt. The reaction mixture is concentrated and purified by prep-HPLC. Prep-HPLC conditions: 20% to 70% in 60 min (A: water with 0.1% TFA, B: acetonitrile with 0.1% TFA), ca 25 min RT is desired product. 
     After lyophilization, the product was triturated with 1N—HCl three times, and then with water. White solid 0.87 g (38%). MK 830-80: M+1=492.0. H-NMR (CD3OD, 400 MHz Varian): δ 7.58 (d, J=7.2 Hz, 2H), 7.30 (d, J=9.2 Hz, 2H), 6.99 (d, J=9.2 Hz, 2H), 3.68 (t, 1H), 3.18 (m, 2H), 1.70 (m, 3H), 1.59 (m, 1H) 
     Example 6 
     Alternative synthesis of N 2 -{[3,5-Difluoro-4-(4-Fluorophenoxy)Phenyl]Sulfonyl}-N 1 -Hydroxy-D-Argininamide (EXEL-01260235) 
     This compound was synthesized via a similar route to N 1 -hydroxy-N 2 -[(4-phenoxyphenyl)sulfonyl]-D-argininamide (EXEL-00987124) (Example 7) and N 2 -{[4-(4-chlorophenoxy)-3,5-difluorophenyl]sulfonyl}-N 1 -hydroxy-D-argininamide (EXEL-01260250): 
                                
H-D-Arginine (Pmc)-OMe b′
 
     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 (TMSCl) (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 evaporation. The viscous oil residue was then dissolved in 400 mL of saturated NaHCO 3  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 Na 2 SO 4 , concentrated 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′ 
     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 CH 2 Cl 2  (200 mL), Triethyl amine (TEA) (7.23 g, 9.2 mL, 71.5 mmol, 2.5 eq.), and sulfonyl chloride c′ (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 CH 2 Cl 2  and the organic layer was washed 2× with water (200 mL), 2× with 0.5M HCl, and 2× with brine. The organic layer was dried with Na 2 SO 4 , 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′ 
     To a round bottom flask was added Sulfonamide d′ (20.5 g, 27.7 mmol), 1:1 TFA:CH 2 Cl 2  (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 3× with ether (125 mL) to give crude guanidine e′ as a white solid. Guanidine e′ was then dissolved in 50 mL of EtOAc, concentrated via rotary evaporation, and triturated again 2× with ether (50 mL). Drying of crude guanidine e′ on high vacuum overnight afforded a yellow brown foam, which was then rinsed 2× 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] +  474.46, found 475.1. 
     Hyrochloride salt of N 2 -{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D-argininamide (EXEL-01260235) 
     To a round bottom flask was added the above crude Guanidine e′ (12.1 g, 26.7 mmol, 1.0 eq.), and freshly made 1.76 M HONH 2  in MeOH (300 mL, 528 mmol, 20 eq.). The reaction was allowed to sit at rt overnight before filtering off the precipitate, and concentrating the supernatant to one fourth the original volume. The supernatant was then neutralized to pH 7.0 dropwise with neat TFA, concentrated via rotary evaporation, and triturated with ether (100 mL). The crude material EXEL-01260235 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 fraction was analyzed on analytical HPLC, and LC/MS. Pure fractions were combined, lyophilized, HCl exchanged with 1N HCl 3×, and water exchanged 1× to give pure N 2 -{[3,5-difluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N 1 -hydroxy-D-argininamide EXEL-01260235 as a white solid (6.5 g, 45% yield). LC/MS Calcd for [M+H] +  475.44, found 476.1;  1 HNMR (400 MHz, MeOD): δ 7.68 (dt, J=8.8, 3.2 Hz, 2 H), 7.14 (M, J=8.4 Hz, 6 H), 3.65 (t, J=7.6 Hz, 1H), 3.15 (t, J=6.4 Hz, 2 H), 1.51-1.69 (m, 4 H). 
     Example 7 
     Hydrochloride salt of N-1-Hydroxy-N-2-[(4-Phenoxyphenyl)Sulfonyl]-D-Argininamide (Exel-00987124) 
     This compound was made via two different pathways as shown below. 
                                
Sulfonamide c″
 
     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 CH 2 Cl 2  (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 NaHCO 3  and 300 mL H 2 O. The aqueous layer was then washed twice with ether (200 mL), acidified with 2N HCl (200 mL), and extracted 3× with EtOAc. The combined EtOAc layers were then dried with Na 2 SO 4 , 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″ 
     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 NaHCO 3  (20 mL) were added to the solid residue, and the aqueous layer was extracted 3× with EtOAc (200 mL), dried with Na 2 SO 4 , concentrated and further dried on high vacuum overnight 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″ 
     To a round bottom flask was added crude Methyl Ester d″ (32.0 g, 46.6 mmol), 1:1 TFA:CH 2 Cl 2  (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 3× with ether (125 mL) to give crude guanidine e″ as a white solid. Guanidine e″ was then dissolved in 50 mL of EtOAc, concentrated via rotary evaporation, and triturated again 2× with ether (50 mL). Drying of crude guanidine e″ on high vacuum overnight afforded a yellow brown foam, which was then rinsed 2× 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 N 1 -hydroxy-N 2 -[(4-phenoxyphenyl)sulfonyl]-D-argininamide (EXEL-00987124) 
     To a round bottom flask was added to the above crude Guanidine e″ (19.0 g, 45.2 mmol, 1.0 eq.), and freshly made 1.76 M HONH 2  in MeOH (380 mL, 668.8 mmol, 14.8 eq.). The reaction was allowed to sit at rt overnight before filtering off the precipitate, and concentrating the supernatant to one fourth the original volume. The supernatant was then neutralized to pH 7.0 dropwise 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 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, lyophilized, HCl exchanged with 1N HCl 3×, and water exchanged 1× to give pure N-hydroxy-N 2 -[(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;  1 HNMR (400 MHz, MeOD): δ 7.81 (dt, J=8.8, 3.2 Hz, 2 H), 7.42 (t, J=7.4 Hz, 2 H), 7.22 (t, J=7.4 Hz, 1 H), 7.1 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.8 Hz, 2 H), 3.65 (t, J=7.6 Hz, 1 H), 3.15 (t, J=6.4 Hz, 2 H), 1.51-1.69 (m, 4 H). 
     Hydroxamic acid f″ 
     To a round bottom flask was added methyl ester d″ (46.0 g, 61.0 mmol, 1.0 eq.) and freshly prepared 1.76 M HONH 2  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 HONH 2 . The reaction was continued for another 4 h before quenching with 1N HCl (250 mL) to a pH of 5.0. The methanol was evaporated and the water 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 Biotage FLASH 75L pre-packed cartridge, and eluted with 100% 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 N 2 -hydroxy-N 2 -[(4-phenoxyphenyl)sulfonyl]-D-argininamide (EXEL-00987124) 
     To a round bottom flask was added hydroxamic acid f″ (19.7 g, 46.9 mmol), 1:1 TFA:CH 2 Cl 2  (400 mL), and triethyl silane (4.0 mL). The reaction was stirred at rt for 90 min, and concentrated via rotary evaporation. The residual TFA was then removed via azeotroping with toluene. The oil was then triturated 3× with ether (125 mL) to give crude 2 EXEL-00987124 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, HCl exchanged with 1N HCl 3×, and water exchanged 1× to give pure N 1 -hydroxy-N 2 -[(4-phenoxyphenyl)sulfonyl]-D-argininamide as a white solid (5.2 g, 26.3% yield). Mixed fractions contaminated with a small impurity 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;  1 HNMR (400 MHz, MeOD): δ 7.81 (dt, J=8.8, 3.2 Hz, 2 H), 7.42 (t, J=7.4 Hz, 2 H), 7.22 (t, J=7.4 Hz, 1 H), 7.1 (d, J=8.4 Hz, 2H), 7.05 (d, J=8.8 Hz, 2 H), 3.65 (t, J=7.6 Hz, 1 H), 3.15 (t, J=6.4 Hz, 2 (m, 4 H). 
     Example 8 
     General Experimental Procedures for the Synthesis of Cyanoguanidines 
                                
Sulfonamide c′″
 
     To a round bottom flask equipped with a magnetic stirrer was added Methylester a′″ (17.0 mmol, 1.0 eq.), dry CH 2 Cl 2  (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 before quenching with H 2 O (100 mL) and saturated NH 4 Cl (20 mL). The aqueous layer was extracted 3× with EtOAc (100 mL), and the combined organic layers were dried with Na 2 SO 4  before concentrating to give crude sulfonamide c′″ as a clear oil. Trituration with 20:80 EtOAc:Hexanes, followed by drying on high vacuum then affords relatively pure sulfonamide c′″ as a white solid that can be taken on directly to the next step. 
     Amine d′″ 
     To a round bottom flask equipped with a magnetic stir bar was added Sulfonamide c′″ (1.14 mmol), dry MeOH (20.0 mL), dry CH 2 Cl 2  (3.0 mL) and 10% Pd/C (120 mg). The reaction was stirred at rt over an atmosphere of hydrogen for 5 h before filtering over a pad of celite and rinsing 3× with EtOAc. The washes were combined and concentrated to give crude amine d′″ as a clear oil which can be taken directly onto the next step. 
     Cyanoguanidine f′″ 
     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 AgNO 3  (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 cyanoguanidine f′″ was then purified via silica gel chromatography. 
     Hydroxamic Acid g′″ 
     To a round bottom flask was added cyanoguanidine f′″ (0.47 mmol, 1.0 eq.) and freshly prepared 1.76 M HONH 2  (1.9 mmol, 4.0 eq.). The reaction was stirred at rt for 1 h before adding another 1.0 mL of 1.76 M HONH 2 . After stirring for an additional 3 h, the reaction was neutralized to a pH of 7.0 with 1N HCl. (Care was taken during the neutralization such that the pH was never below 7.0 to prevent cyanoguanidine conversion to the urea.) Silica gel chromatography then afforded pure hydroxamic acid g′″. Alternatively, 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 NaHCO 3  prior to concentration to prevent hydrolysis of the cyanoguanidine to the corresponding urea). 
     In the case where R 2 =H: 
                                
Cyanoimine i′″
 
     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 carbonimidate (0.56 mmol, 1.1 eq.). The reaction was stirred at rt overnight, concentrated via rotary evaporation, and purified via silica gel chromatography. 
     Cyanoguanidine j′″ 
     To a round bottom flask was added cyanoimine i′″ (0.11 mmol), isopropanol (2.0 mL), and concentrated NH 4 OH (1.0 mL). The reaction was stirred at rt overnight, and concentrated via rotary evaporation to afford crude cyanoguanidine j′″ which can be carried 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: 
                                
Fmoc Deprotection of Resin Bound N-(Fmoc)hydroxylanine:
 
     2-Chlorotrityl polystyrene resin functionalized with N-(Fmoc)hydroxylamine (0.2 g, 0.154 mmole) was welling in dichloromethane (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 O-(resin)hydroxylamine: 
     O-(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-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate, 2 eq.) and diisopropylethylamine (DIEA, 4 eq.). The resulting slurry was agitated for 13 hrs. The resin was filtered and washed with DMF, MeOH, and DC 
     α-N-Fmoc Deprotection of Resin Bound Amino Acid hydroxylamine: 
     O-(resin)hydroxylamine-amino acid (α-N-Fmoc) (0.154 mmole) was treated with 20% piperidine in DCM. The resin was agitated for 1 hr then filtered, washed with DCM, MeOH and DCM. 
     Formation of sulfonamide: 
     O-(resin)hydroxylamino-amino acid (0.154 mmole) was treated with appropriate sulfonyl chloride (2 eq.) containing 2,6-lutidine (2 eq.) in DCM for 13 hrs. The resin was filtered and washed with DCM, MeOH and DCM. 
     Compound Release from the Resin: 
     The α-N-substituted resin bound amino acid sulfonamide hydroxamate was treated with 20% Trifluoroacetic acid (TFA) containing 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-2-{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N-1-hydroxy-D-argininamide, N-1-hydroxy-N-2-[(4-phenoxyphenyl)sulfonyl]-D-argininamide, N-2-([4-(4-fluorophenoxy)phenyl]sulfonyl)-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-1-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 Support 
     Formation of pyridylarylether-sulfonamide: 
     O-(resin)hydroxylamino-amino acid (0.154 mmole) was treated with 2-chloropyridyl sulfonyl chloride (2 eq.) containing 2,6-lutidine (2 eq.) in DCM for 13 hrs. The resin was filtered and washed with DCM, MeOH and DCM. 
     Formation of pyridyl-aryl ether: 
     The α-N-substituted resin bound amino acid sulfonamide hydroxamate was treated with arylalcohol (10 eq.), cesium carbonate (5 eq.) in N-methylpyrrolidinone (NMP) at 80° C. for 13 hrs. The resin filtered and washed with DMF, MeOH, water, MeOH and DCM. 
     Compound Release from the Resin: 
     The α-N-substituted resin bound amino acid sulfonamide hydroxamate was treated with 20% Trifluoroacetic acid (TFA) containing 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 (EXEL-01284764) 
             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 Support 
     
       
                 
         
             
             
         
      
     
     Following compounds are prepared using method described above:
     N-2-[(3-fluoro-4-phenoxyphenyl)sulfonyl]-N-1-hydroxy-D-argininamide (4) (EXEL-01154260)   N-2-{[3-fluoro-4-(4-fluorophenoxy)phenyl]sulfonyl}-N-1-hydroxy-D-argininamide (9) (EXEL-01295474)   N-2-{[4-(4-chlorophenoxy)-3-fluorophenyl]sulfonyl}-N-1-hydroxy-D-argininamide (10) (EXEL-01260233)   N-2-{[4-(4-cyanophenoxy)-3-fluorophenyl]sulfonyl}-N-1-hydroxy-D-argininamide (11) (EXEL-01295489)   N-2-{[4-(3,5-dimethylphenoxy)-3-fluorophenyl]sulfonyl}-N-1-hydroxy-D-argininamide (12) (EXEL-01284765)   

     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 # 
                 MWt 
                 Observed 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 
               
               
                 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 
               
               
                 40 
                 559.6 
                 M + H = 
                 1.44 
                 HP 
               
               
                   
                   
                 598.0 (M + K, 100%) 
                   
                   
               
               
                 41 
                 576.05 
                 M + H = 
                 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 
               
               
                 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 
               
               
                   
               
             
          
         
       
     
     Table 3 shows proton NMR data for selected compounds: 
     
       
         
               
               
               
             
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                 Entry 
                 Name 
                   1 H-NMR 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}- 
                 H-NMR; δ (CD3OD): 7.79 (d, 2H), 
               
               
                   
                 D-lysinamide 
                 7.42 (t, 2H), 7.22 (t, 1H), 7.09 (d, 2H), 
               
               
                   
                   
                 7.05 (d, 2H), 3.63 (t, 1H), 2.87 (t, 2H), 
               
               
                   
                   
                 1.57-1.68 (m, 4H), 1.44 (m, 1H), 
               
               
                   
                   
                 1.37 (m, 1H) 
               
               
                 2 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}- 
                 H-NMR; δ (CD3OD): 7.79 (q, 2H), 
               
               
                   
                 3-piperidin-3-ylalaninamide 
                 7.42 (t, 2H), 7.22 (t, 1H), 7.10 (d, 2H), 
               
               
                   
                   
                 7.05 (d, 2H), 3.72 (m, 1H), 
               
               
                   
                   
                 3.23-3.47 (m, 2H), 2.87 (m, 1H), 2.64 (t, 
               
               
                   
                   
                 1H), 1.83-2.01 (m, 3H), 1.17-1.74 (m, 
               
               
                   
                   
                 4H) 
               
               
                 3 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}- 
                 H-NMR; δ (CD3OD): 7.80 (d, 2H), 
               
               
                   
                 3-pyrrolidin-3-ylalaninamide 
                 7.42 (t, 2H), 7.22 (t, 1H), 7.10 (d, 2H), 
               
               
                   
                   
                 7.06 (d, 2H), 3.72 (q, 2H), 2.22-2.3 (m, 
               
               
                   
                   
                 1H), 1.96-2.18 (m, 4H), 1.83 (m, 1H), 
               
               
                   
                   
                 1.65 (m, 1H) 
               
               
                 4 
                 N 2 -{[6-(3-fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 - 
                 (CD 3 OD) 9.21 (br. s, 1H), 9.01 (d, 
               
               
                   
                 hydroxy-D-lysinamide 
                 1H), 8.24 (dd, 1H), 8.04 (d, 1H), 
               
               
                   
                   
                 7.92 (dd, 1H), 7.88 (dt, 1H), 7.54 (m, 1H), 
               
               
                   
                   
                 7.22 (td, 1H), 3.72 (t, 1H), 3.20 (br. q, 
               
               
                   
                   
                 2H), 1.65 (m, 2H), 1.53 (m, 2H), 
               
               
                   
                   
                 1.45 (m, 2H) ppm 
               
               
                 5 
                 N-hydroxy-N-{[4-(phenyloxy)phenyl]sulfonyl}-D- 
                 H-NMR; δ (CD3OD): 7.50 (d, 2H), 
               
               
                   
                 tryptophanamide 
                 7.42 (m, 3H), 7.32 (d, 1H), 7.24 (m, 
               
               
                   
                   
                 2H), 7.06 (m, 2H), 6.99 (s, 1H), 
               
               
                   
                   
                 6.94 (t, 1H), 6.76 (d, 1H), 6.64 (d, 1H), 
               
               
                   
                   
                 3.84 (t, 1H), 3.13 (q, 1H), 2.87 (q, 1H) 
               
               
                 6 
                 N 1 -hydroxy-N 2 -({5-[2-(methylthio)pyrimidin-4- 
                 H-NMR; δ (CD3OD): 8.6 (d, 1H), 
               
               
                   
                 yl]-2-thienyl}sulfonyl)lysinamide 
                 7.9 (d, 1H), 7.6 (d, 1H), 7.58 (d, 1H), 
               
               
                   
                   
                 3.8 (t, 1H), 2.9 (t, 2H), 2.6 (s, 3H), 
               
               
                   
                   
                 1.6-1.75 (m, 4H), 1.5 (m, 1H), 1.4 (m, 1H) 
               
               
                 7 
                 N-hydroxy-N-{[4-(phenyloxy)phenyl]sulfonyl}-D- 
                 H-NMR; δ (CD3OD): 8.78 (s, 1H), 
               
               
                   
                 histidinamide 
                 7.74 (d, 2H), 7.43 (t, 2H), 7.31 (s, 1H), 
               
               
                   
                   
                 7.23 (t, 1H), 7.10 (d, 2H), 7.02 (d, 2H), 
               
               
                   
                   
                 3.94 (q, 1H), 2.96-3.12 (q, 2H) 
               
               
                 8 
                 N 1 -hydroxy-N 2 -methyl-N 2 -{[4- 
                 H-NMR; δ (CD3OD): 7.75 (m, 2H), 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-3-piperidin-3- 
                 7.42 (m, 2H), 7.23 (m, 1H), 
               
               
                   
                 ylalaninamide 
                 7.01-7.12 (m, 4H), 3.34 (m 1H), 3.30 (s, 
               
               
                   
                   
                 3H), 2.82-3.00 (m, 3H), 2.63-2.71 (m, 
               
               
                   
                   
                 1H), 1.85-2.06 (m, 9H) 
               
               
                 9 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}- 
                 H-NMR; δ (CD3OD): 7.80 (d, 2H), 
               
               
                   
                 3-piperidin-4-ylalaninamide 
                 7.43 (t, 2H), 7.22 (t, 1H), 7.10 (d, 2H), 
               
               
                   
                   
                 7.05 (d, 2H), 3.71 (q, 1H), 3.35 (d, 1H), 
               
               
                   
                   
                 2.91 (dt, 2H), 1.89 (d, 2H), 
               
               
                   
                   
                 1.24-1.76 (m, 6H) 
               
               
                 10 
                 N 1 -hydroxy-N 2 -{[4-(phenyloxy)phenyl]sulfonyl}- 
                 H-NMR; δ (CD3OD): 8.71 (d, 1H), 
               
               
                   
                 3-pyridin-3-yl-D-alaninamide 
                 8.64 (s, 1H), 8.34 (d, 1H), 7.91 (q, 1H), 
               
               
                   
                   
                 7.79 (d, 1H), 7.69 (d, 2H), 7.43 (t, 2H), 
               
               
                   
                   
                 7.23 (t, 1H), 7.10 (d, 2H), 7.00 (d, 2H), 
               
               
                   
                   
                 3.94 (q, 1H), 3.18 (q, 1H), 3.05 (q, 1H) 
               
               
                 11 
                 N 6 -glycyl-N 1 -hydroxy-N 2 -{[4- 
                 H-NMR; δ (CD3OD): 7.79 (d, 2H), 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D-lysinamide 
                 7.42 (t, 2H), 7.22 (t, 1H), 7.10 (d, 2H), 
               
               
                   
                   
                 7.05 (d, 2H), 3.64 (s, 2H), 3.60 (t, 1H), 
               
               
                   
                   
                 3.19 (m, 2H), 1.60 (m, 2H), 1.48 (m, 
               
               
                   
                   
                 2H), 1.34 (m, 2H) 
               
               
                 12 
                 N 1 -hydroxy-N 2 ,N 6 ,N 6 -trimethyl-N 2 -{[4- 
                 H-NMR; δ (CD3OD): 7.80 (d, 2H), 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D-lysinamide 
                 7.42 (m, 2H), 7.22 (t, 1H), 
               
               
                   
                   
                 6.96-7.10 (m, 4H), 3.66 (t, 1H), 3.30 (m, 
               
               
                   
                   
                 2H), 3.11 (s, 9H), 1.75-1.85 (m, 2H), 
               
               
                   
                   
                 1.69 (q, 2H), 1.36-1.50 (m, 2H) 
               
               
                 13 
                 3-[4-(aminomethyl)cyclohexyl]-N 1 -hydroxy-N 2 - 
                 H-NMR; δ (CD3OD): 7.80 (d, 2H), 
               
               
                   
                 {[4-(phenyloxy)phenyl]sulfonyl}alaninamide 
                 7.42 (t, 2H), 7.22 (t, 1H), 7.10 (d, 2H), 
               
               
                   
                   
                 7.05 (d, 2H), 3.67 (q, 1H), 2.99 (m, 
               
               
                   
                   
                 1H), 1.99 (m, 2H), 1.79 (m, 2H), 
               
               
                   
                   
                 1.54 (t, 1H), 1.35-1.42 (m, 3H), 
               
               
                   
                   
                 1.26 (m, 1H), 1.06 (q, 1H), 0.96 (q, 1H) 
               
               
                 14 
                 N 1 -hydroxy-N 2 -{[6-(naphthalen-1-yloxy)pyridin- 
                 H-NMR; δ (CD 3 OD): 8.46 (br. d, 1H), 
               
               
                   
                 3-yl]sulfonyl}-D-argininamide 
                 8.18 (d, 1H), 7.95 (d, 1H), 7.84 (m, 
               
               
                   
                   
                 2H), 7.50 (m, 3H), 7.30 (d, 1H), 
               
               
                   
                   
                 7.18 (d, 1H), 3.54 (br. t, 1H), 3.04 (br. t, 
               
               
                   
                   
                 2H), 2.50 (m, 1H), 1.8 (m, 3H) ppm. 
               
               
                 17 
                 N 6 -[(E)-(cyanoimino)(hydroxyamino)methyl]-N 2 - 
                 H-NMR; δ (CD3OD): 7.78 (d, 2H), 
               
               
                   
                 ({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
                 7.14 (m, 4H), 7.01 (d, 2H), 3.56 (t, 
               
               
                   
                 hydroxy-D-lysinamide 
                 1H), 1.47 (m, 4H), 1.37 (m, 2H), 
               
               
                   
                   
                 1.19 (m, 2H) 
               
               
                 18 
                 N 2 -({4-[(4-fluorophenyl)oxy]phenyl}sulfonyl)-N 1 - 
                 H-NMR; δ (CD3OD): 7.67 (d, 2H), 
               
               
                   
                 hydroxy-D-lysinamide 
                 7.04 (m, 4H), 6.92 (d, 2H), 3.52 (t, 
               
               
                   
                   
                 1H), 1.53 (m, 4H), 1.38 (m, 2H), 
               
               
                   
                   
                 1.25 (m, 2H) 
               
               
                 19 
                 N 6 -{(Z)-(cyanoimino)[(2-morpholin-4- 
                 H-NMR; δ (CD 3 OD) 9.01 (br. s, 1H), 
               
               
                   
                 ylethyl)amino]methyl}-N 2 -{[6-(3- 
                 8.26 (d, 1H), 8.06 (d, 1H), 7.89 (dd, 
               
               
                   
                 fluorophenyl)pyridin-3-yl]sulfonyl}-N 1 -hydroxy- 
                 2H), 7.52 (br. q, 1H), 7.24 (br. t, 1H), 
               
               
                   
                 D-lysinamide 
                 3.72 (m, 4H), 3.32 (m, 4H), 3.15 (br. 
               
               
                   
                   
                 t, 2H), 2.52 (m, 6H), 1.3-1.8 (m, 5H) 
               
               
                   
                   
                 ppm. 
               
               
                 20 
                 N 2 -({6-[(4-fluorophenyl)oxy]pyridin-3- 
                 H-NMR; δ (CD 3 OD) 8.45 (br. s, 1H), 
               
               
                   
                 yl}sulfonyl)-N 1 -hydroxy-D-argininamide 
                 8.19 (br s, 1H), 7.20 (m, 5H), 
               
               
                   
                   
                 3.65 (br. s, 1H), 3.25 (m, 4H), 1.65 (m, 
               
               
                   
                   
                 3H) ppm. 
               
               
                 21 
                 N 2 -({6-[(4-chlorophenyl)oxy]pyridin-3- 
                 H-NMR; δ (CD 3 OD) 8.45 (d, 1H), 
               
               
                   
                 yl}sulfonyl)-N 1 -hydroxy-D-argininamide 
                 8.19 (dd, 1H), 7.42 (d, 2H), 7.19 (dd, 
               
               
                   
                   
                 3H), 3.85 (br. t, 1H), 3.20 (m, 2H), 
               
               
                   
                   
                 1.80 (m, 4H) ppm 
               
               
                 22 
                 N 2 -({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CD3OD): 7.52 (d, 2H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy- 
                 6.95 (d, 2H), 6.91 (m, 2H), 3.26 m, 
               
               
                   
                 N 6 -(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) 
               
               
                 23 
                 4-cyano-N-hydroxy-N-{[4- 
                 H-NMR; δ (CD3OD): 7.4 (m, 4H), 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
                 7.28 (m, 1H), 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) 
               
               
                 25 
                 3-cyano-N-({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CDCl3): 7.1-7.4 (m, 6H), 
               
               
                   
                 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) 
               
               
                 26 
                 3-cyano-N-hydroxy-N-{[4- 
                 H-NMR; δ (CDCl3): 7.42 (m, 2H), 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
                 7.39 (t, 2H), 7.34 (d, 1H), 7.26 (m, 1H), 
               
               
                   
                 phenylalaninamide 
                 7.21 (t, 2H), 7.15 (m, 1H), 7.04 (d, 2H), 
               
               
                   
                   
                 6.74 (d, 2H), 4.1 (m, 1H), 3.2 (m, 1H), 
               
               
                   
                   
                 2.9 (m, 1H) 
               
               
                 27 
                 N 2 -({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CD3OD): 7.6 (d, 2H), 
               
               
                   
                 hydroxyphenyl)oxy]phenyl}sulfonyl)-N 1 - 
                 6.8 (d, 2H), 6.7 (d, 2H), 3.7 (t, 1H), 
               
               
                   
                 hydroxyargininamide 
                 3.2 (t, 2H), 1.6-1.8 (m, 4H) 
               
               
                 28 
                 N 2 -{[3,5-difluoro-4-(pyridin-3- 
                 H-NMR; δ (CD3OD): 8.5 (s, 1H), 
               
               
                   
                 yloxy)phenyl]sulfonyl}-N 1 -hydroxyargininamide 
                 8.4 (s, 1H), 7.62 (d, 2H), 7.5 (m, 2H), 
               
               
                   
                   
                 3.7 (t, 1H), 3.2 (t, 2H), 1.7 (m, 4H) 
               
               
                 30 
                 N 2 -({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CD 3 OD) 7.60 (d, 2H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 6 -[1-(4,4- 
                 7.05 (m, 4H), 3.65 (t, 1H), 3.45 (t, 
               
               
                   
                 dimethyl-2,6-dioxocyclohexylidene)ethyl]-N 1 - 
                 1H), 2.60 (s, 3H), 2.40 (s, 3H), 
               
               
                   
                 hydroxy-D-lysinamide 
                 1.65 (m, 4H), 1.45 (m, 3H), 1.0 (s, 4H) 
               
               
                   
                   
                 ppm 
               
               
                 31 
                 N 2 -{[3,5-difluoro-4-({4- 
                 H-NMR; δ (CD3OD): 7.6 (d, 2H), 
               
               
                   
                 [(phenylmethyl)oxy]phenyl}oxy)phenyl]sulfonyl}- 
                 7.4 (d, 2H), 7.35 (m, 2H), 6.9 (s, 5H), 
               
               
                   
                 N 1 -hydroxyargininamide 
                 5.02 (s, 2H), 3.65 (t, 1H), 3.1 (t, 2H), 
               
               
                   
                   
                 1.7 (m, 4H) 
               
               
                 32 
                 N 2 -{[3,5-difluoro-4-(pyridin-3- 
                 H-NMR; δ (CD3OD): 1.3-1.5 (m, 2H), 
               
               
                   
                 yloxy)phenyl]sulfonyl}-N 1 -hydroxy-6-morpholin- 
                 1.5-1.7 (m, 4H), 1.99 (s, 3H), 
               
               
                   
                 4-yl-D-norleucinamide 
                 2.57 (t, 2H), 2.70 (br s, 4H), 3.68 (t, 
               
               
                   
                   
                 1H), 3.76 (t, 4H), 7.43 (d, 1H), 
               
               
                   
                   
                 7.63 (d, 2H), 8.33 (dd, 1H), 8.42 (d, 1H 
               
               
                 33 
                 N 2 -({3-fluoro-4-[(4- 
                 H-NMR; δ (CD 3 OD): 7.70 (m, 2H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-3- 
                 7.10 (m, 5H), 3.80 (br. t, 2H), 
               
               
                   
                 morpholin-4-yl-D-alaninamide 
                 3.20 (m, 6H) ppm 
               
               
                 34 
                 N-({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CD 3 OD): 7.61 (d, 2H), 
               
               
                   
                 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 
                   
               
               
                 36 
                 N-({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CD 3 OD): 7.54 (m, 6H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-3- 
                 7.02 (m, 4H), 3.94 (t, 1H), 3.01 (m, 
               
               
                   
                 [(hydroxyamino)(imino)methyl]-D- 
                 2H) ppm 
               
               
                   
                 phenylalaninamide 
                   
               
               
                 37 
                 N 2 -({4-[(4-chlorophenyl)oxy]-3,5- 
                 H-NMR; δ (CDCl3): 7.54 (d, 2H), 
               
               
                   
                 difluorophenyl}sulfonyl)-N 1 -hydroxy-3-[1- 
                 7.23 (d, 2H), 6.85 (d, 2H), 3.98 (m, 
               
               
                   
                 (morpholin-4-ylcarbonyl)piperidin-4- 
                 1H), 3.63 (br, 4H), 3.21 (br, 2H), 
               
               
                   
                 yl]alaninamide 
                 2.81 (m, 1H), 2.66 (m, 1H), 1.60 (br, 
               
               
                   
                   
                 2H), 1.10 (m, 1H) 
               
               
                 38 
                 N 2 -({3,5-difluoro-4-[(4- 
                 H-NMR; δ (DMSO-d6): 10.65 (s, 1H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy-3- 
                 8.45 (d, 1H), 7.62 (d, 2H), 7.18 (d, 2H), 
               
               
                   
                 [1-(morpholin-4-ylcarbonyl)piperidin-4- 
                 7.10 (d, 2H), 3.64 (m, 1H), 3.54 (m, 
               
               
                   
                 yl]alaninamide 
                 4H), 3.08 (m, 2H), 2.63 (m, 1H), 
               
               
                   
                   
                 2.49 (m, 1H), 1.53 (m, 1H), 1.38 (m, 
               
               
                   
                   
                 1H), 1.0 (m, 1H) 
               
               
                 39 
                 3-[amino(imino)methyl]-N-({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CD 3 OD): 7.58 (m, 6H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-D- 
                 6.99 (m, 4H), 3.88 (t, 1H), 3.01 (m, 
               
               
                   
                 phenylalaninamide 
                 2H) ppm 
               
               
                 40 
                 4-[amino(imino)methyl]-N-({3,5-difluoro-4-[(4- 
                 H-NMR; δ (CD 3 OD): 7.75 (d, 2H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N-hydroxy-D- 
                 7.50 (d, 4H), 7.01 (m, 4H), 3.90 (dd, 
               
               
                   
                 phenylalaninamide 
                 1H), 3.05 (m, 2H) ppm. 
               
               
                 41 
                 N 5 -(aminocarbonyl)-N~2~-({3-fluoro-4-[(4- 
                 H-NMR; δ (CD 3 OD): 7.65 (d, 1H), 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)-N 1 -hydroxy- 
                 7.60 (d, 1H), 7.10 (m, 5H), 3.82 (t, 
               
               
                   
                 D-ornithinamide 
                 1H), 3.05 (m, 2H), 1.60 (m, 4H) ppm 
               
               
                 42 
                 (2R)-2-[({4-[(4-chlorophenyl)oxy]-3,5- 
                 H-NMR; δ (CD3OD): 1.97 (q, 2H), 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-4- 
                 2.11 (q, 2H), 2.78 (s, 6H), 3.71 (t, 1H), 
               
               
                   
                 (dimethylamino)-N-hydroxybutanamide 
                 6.90 (dd, 2H), 7.21 (d, 2H), 
               
               
                   
                   
                 7.51 (dd, 2H) 
               
               
                 43 
                 (2R)-2-[({4-[(4-chlorophenyl)oxy]-3,5- 
                 H-NMR; δ (CD3OD): 7.61 (d, 2H), 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-4-{[1-(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) 
               
               
                 44 
                 N 2 -({4-[(4-chlorophenyl)oxy]-3,5- 
                 H-NMR; δ (CD 3 OD): 7.60 (d, 2H), 
               
               
                   
                 difluorophenyl}sulfonyl)-N 1 -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 
               
               
                 45 
                 (2R)-4-amino-2-[({4-[(4-chlorophenyl)oxy]-3,5- 
                 H-NMR; δ (CD3OD): 7.62 (d, 2H), 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-N- 
                 7.32 (d, 2H), 7.01 (d, 2H), 3.79 (t, 1H), 
               
               
                   
                 hydroxybutanamide 
                 3.08 (m, 1H), 2.98 (m, 1H), 1.99 (q, 2H) 
               
               
                 46 
                 (2R)-4-{[(amino(imino)methyl]amino}-2-[({4-[(4- 
                 H-NMR; δ (CD3OD): 7.61 (d, 2H), 
               
               
                   
                 chlorophenyl)oxy]-3,5- 
                 7.32 (d, 2H), 7.00 (d, 2H), 3.80 (t, 1H), 
               
               
                   
                 difluorophenyl}sulfonyl)amino]-N- 
                 3.10 (m, 1H), 2.98 (m, 1H), 2.00 (q, 
               
               
                   
                 hydroxybutanamide 
                 2H) 
               
               
                   
               
             
          
         
       
     
     Example 11 
     Enzyme Assays 
     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-α cleavage site (Leu 62 -Arg 71 ), however, we found that replacement of Ala 76 -Val 77  with Lys-Leu resulted in a peptide with a 5-fold greater affinity for ADAM-10 than the native TNF-α peptide. Enzyme was diluted to a final active concentration of 5 nM in Buffer A (50 mM HEPES 8.0, 100 mM NaCl, 1 mM CaCl2 and 0.01% NP-40). Serial dilutions for compounds were performed ranging from 100 uM to 0.5 nM using a Beckman Biomek 2000 in polypropylene plates (Greiner). 20 •l of enzyme solution was added to 10 •l of compound in buffer A, and allowed to incubate for 15 min in 384 well black, Greiner, microtiter plates (#781076). 20 ul of substrate (12.5 uM in Buffer A) was then added, resulting in final reaction conditions of 2 nM ADAM-10, 5 •M substrate, and compound concentrations ranging from 20 uM to 0.1 nM. The reaction was incubated for 2 hr at RT, and fluorescence was measured at Ex355, Em460 on a Wallac Victor 2 fluorescence reader. For final analysis of potent inhibitors, a similar reaction was set up with a final active ADAM-10 concentration of 0.1 nM. This reaction was incubated for 16 hr at RT and fluorescence was read using identical conditions. 
     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 IC 50  with the following key: A=IC 50  less than 50 nM, B=IC 50  greater than 50 nM, but less than 1000 nM, C═IC 50  greater than 50 nM, but less than 20,000 mM, and D=IC 50  greater than 20,000 mM. 
     One aspect of the invention is the combination of, for example, guanidine-containing sidechains on an amino acid derived hydroximate; and substitution (particularly halo, more particularly fluoro) on the proximal ring (ring bonded directly to the sulfonamide moiety) of a two-ring-substituted sulfonamide derivative of the amino acid derived hydroximate. For example, by combining 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 
               
               
                   
               
               
                   
                   
                 ADAM-10 
                 MMP1 
                 MMP2 
                 MMP3 
                 MMP8 
                 MMP9 
                 MMP13 
                 TACE 
               
               
                 # 
                 Compound Name 
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
                 IC 50   
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 1 
                 N 1 -hydroxy-N 2 -{[4- 
                 A 
                 B 
                 C 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 2 
                 N 1 -hydroxy-N 2 -{[4- 
                 A 
                 C 
                 A 
                 B 
                 A 
                 A 
                 A 
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 argininamide 
               
               
                 3 
                 N 1 -hydroxy-N 2 -{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-3- 
               
               
                   
                 piperidin-3-ylalaninamide 
               
               
                 4 
                 N 1 -hydroxy-N 2 -{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 C 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-3- 
               
               
                   
                 pyrrolidin-3-ylalaninamide 
               
               
                 5 
                 N 2 -{[6-(3-fluorophenyl)pyridin- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
                 C 
               
               
                   
                 3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 6 
                 N-hydroxy-N-{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 tryptophanamide 
               
               
                 7 
                 N 1 -hydroxy-N 2 -({5-[2- 
                 B 
                 D 
                 A 
                 C 
                   
                   
                 A 
                 C 
               
               
                   
                 (methylthio)pyrimidin-4-yl]-2- 
               
               
                   
                 thienyl}sulfonyl)lysinamide 
               
               
                 8 
                 N-hydroxy-N-{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 histidinamide 
               
               
                 9 
                 N 1 -hydroxy-N 2 -methyl-N 2 -{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-3- 
               
               
                   
                 piperidin-3-ylalaninamide 
               
               
                 10 
                 N 1 -hydroxy-N 2 -{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-3- 
               
               
                   
                 piperidin-4-ylalaninamide 
               
               
                 11 
                 N 1 -hydroxy-N 2 -{[4- 
                 A 
                 D 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-3- 
               
               
                   
                 pyridin-3-yl-D-alaninamide 
               
               
                 12 
                 N 1 -hydroxy-6-morpholin-4-yl-N 2 - 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 C 
               
               
                   
                 {[4-(phenyloxy)phenyl]sulfonyl}- 
               
               
                   
                 D-norleucinamide 
               
               
                 13 
                 N 6 -glycyl-N 1 -hydroxy-N 2 -{[4- 
                 A 
                 A 
                 A 
                   
                   
                   
                   
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 14 
                 N 2 -{[6-(3-fluorophenyl)pyridin- 
                 A 
                 B 
                 A 
                 B 
                   
                   
                 A 
                 C 
               
               
                   
                 3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 argininamide 
               
               
                 15 
                 N 1 -hydroxy-N 2 ,N 6 ,N 6 -trimethyl-N 2 - 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 {[4-(phenyloxy)phenyl]sulfonyl}- 
               
               
                   
                 D-lysinamide 
               
               
                 16 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}alaninamide 
               
               
                 17 
                 N 2 -{[6-(3-fluorophenyl)pyridin- 
                 A 
                 D 
                 A 
                 B 
                   
                   
                 A 
                 C 
               
               
                   
                 3-yl]sulfonyl}-N 1 -hydroxy-6- 
               
               
                   
                 morpholin-4-yl-D-norleucinamide 
               
               
                 18 
                 N 6 -[(E)- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
                 C 
               
               
                   
                 (cyanoimino)(propylamino)methyl]- 
               
               
                   
                 N 2 -{[6-(3-fluorophenyl)pyridin- 
               
               
                   
                 3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 19 
                 N 1 -hydroxy-5-morpholin-4-yl-N 2 - 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 {[4-(phenyloxy)phenyl]sulfonyl}- 
               
               
                   
                 D-norvalinamide 
               
               
                 20 
                 N 6 -[(E)- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
                 B 
               
               
                   
                 amino(cyanoimino)methyl]-N 2 -{[6- 
               
               
                   
                 (3-fluorophenyl)pyridin-3- 
               
               
                   
                 yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 21 
                 N 1 -hydroxy-N 2 -{[6-(naphthalen-1- 
                 B 
                 C 
                 B 
                 C 
                   
                   
                 A 
               
               
                   
                 yloxy)pyridin-3-yl]sulfonyl}-D- 
               
               
                   
                 argininamide 
               
               
                 22 
                 N 2 -{[3-fluoro-4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 23 
                 N 6 -[(E)- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 (cyanoimino)(propylamino)methyl]- 
               
               
                   
                 N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 24 
                 N 6 -((Z)-(cyanoimino){[2- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 (methyloxy)ethyl]amino}methyl)- 
               
               
                   
                 N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 25 
                 N 6 -[(E)- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 amino(cyanoimino)methyl]-N 1 - 
               
               
                   
                 hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 26 
                 N 2 -({4-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-argininamide 
               
               
                 27 
                 N 5 -[(Z)- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 amino(nitroimino)methyl]-N 1 - 
               
               
                   
                 hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 ornithinamide 
               
               
                 28 
                 N 1 -hydroxy-N~2~-{[6-(5,6,7,8- 
                   
                 D 
                   
                 B 
                   
                   
                 A 
               
               
                   
                 tetrahydronaphthalen-2- 
               
               
                   
                 yloxy)pyridin-3-yl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 29 
                 N 6 -{(Z)-(cyanoimino)[(2- 
                 A 
                 B 
                 A 
                   
                   
                   
                 A 
                 A 
               
               
                   
                 morpholin-4- 
               
               
                   
                 ylethyl)amino]methyl}-N 1 - 
               
               
                   
                 hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 30 
                 N 6 -[(Z)- 
                 A 
                 A 
                 A 
                   
                   
                   
                 A 
                 A 
               
               
                   
                 (cyanoimino)(cyclopropylamino)methyl]- 
               
               
                   
                 N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 lysinamide 
               
               
                 31 
                 N 2 -{[3,5-difluoro-4- 
                 A 
                   
                   
                   
                   
                   
                   
                 B 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 32 
                 N 2 -({4-[(4-chlorophenyl)oxy]-3- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 fluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 33 
                 N 2 -({3,5-difluoro-4-[(4- 
                 A 
                 D 
                 C 
                 C 
                 B 
                 B 
                 A 
                 B 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-argininamide 
               
               
                 34 
                 3-[1-((Z)-(cyanoimino){[2- 
                   
                 B 
                   
                 A 
                   
                   
                 A 
               
               
                   
                 (methyloxy)ethyl]amino}methyl)piperidin- 
               
               
                   
                 4-yl]-N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}alaninamide 
               
               
                 35 
                 3-{1-[(Z)- 
                 A 
                 B 
                   
                   
                   
                   
                 A 
               
               
                   
                 (cyanoimino)(propylamino)methyl] 
               
               
                   
                 piperidin-4-yl}-N 1 -hydroxy-N 2 - 
               
               
                   
                 {[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}alaninamide 
               
               
                 36 
                 N 5 -[(Z)- 
                 A 
                 B 
                 A 
                 B 
                   
                   
                 A 
                 B 
               
               
                   
                 amino(nitroimino)methyl]-N 2 -{[6- 
               
               
                   
                 (3-fluorophenyl)pyridin-3- 
               
               
                   
                 yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 ornithinamide 
               
               
                 37 
                 N 2 -({4-[(4-chlorophenyl)oxy]- 
                 A 
                 C 
                 A 
                 B 
                 B 
                 B 
                 A 
                 B 
               
               
                   
                 3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 38 
                 N 1 -hydroxy-N 2 -{[6-(5,6,7,8- 
                 A 
                 C 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 tetrahydronaphthalen-2- 
               
               
                   
                 yloxy)pyridin-3-yl]sulfonyl}-D- 
               
               
                   
                 argininamide 
               
               
                 39 
                 N 2 -({4-[(3,5- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
                 A 
               
               
                   
                 dimethylphenyl)oxy]-3- 
               
               
                   
                 fluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 40 
                 N 2 -({3-fluoro-4-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-argininamide 
               
               
                 41 
                 N 2 -({4-[(4-cyanophenyl)oxy]-3- 
                 A 
                 C 
                   
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 fluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 42 
                 N 6 -[(E)-(cyanoimino)(morpholin- 
                 A 
                 A 
                   
                 A 
                   
                   
                 A 
               
               
                   
                 4-yl)methyl]-N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 43 
                 3-[1-((Z)- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 [(aminocarbonyl)imino]{[2- 
               
               
                   
                 (methyloxy)ethyl]amino}methyl)piperidin- 
               
               
                   
                 4-yl]-N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}alaninamide 
               
               
                 44 
                 N 6 -(4,5-dihydro-1H-imidazol-2- 
                 A 
                 A 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 yl)-N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 45 
                 N 6 -[(E)- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 (cyanoimino)(propylamino)methyl]- 
               
               
                   
                 N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 46 
                 N 6 -[(E)- 
                 A 
                   
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 [(aminocarbonyl)imino](hydroxyamino) 
               
               
                   
                 methyl]-N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 47 
                 N 6 -[(E)- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 (cyanoimino)(hydroxyamino)methyl]- 
               
               
                   
                 N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 48 
                 N 6 -((E)-(cyanoimino){[2- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 (methyloxy)ethyl]amino}methyl)- 
               
               
                   
                 N 2 -{[6-(3-fluorophenyl)pyridin- 
               
               
                   
                 3-yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 49 
                 N 6 -[(Z)- 
                 A 
                 D 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 (cyanoimino)(cyclopropylamino)methyl]- 
               
               
                   
                 N 2 -{[6-(3- 
               
               
                   
                 fluorophenyl)pyridin-3- 
               
               
                   
                 yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 50 
                 N 2 -({4-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 51 
                 N 6 -((Z)-(cyanoimino){[2- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 (methyloxy)ethyl]amino}methyl)- 
               
               
                   
                 N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 52 
                 N 6 -{(Z)-(cyanoimino)[(2- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 morpholin-4- 
               
               
                   
                 ylethyl)amino]methyl}-N 2 -{[6-(3- 
               
               
                   
                 fluorophenyl)pyridin-3- 
               
               
                   
                 yl]sulfonyl}-N 1 -hydroxy-D- 
               
               
                   
                 lysinamide 
               
               
                 53 
                 3-{1- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 B 
               
               
                   
                 [amino(imino)methyl]piperidin-4- 
               
               
                   
                 yl}-N 1 -hydroxy-N 2 -{[4- 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}alaninamide 
               
               
                 54 
                 N 2 -({4-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-5-morpholin-4- 
               
               
                   
                 ylnorvalinamide 
               
               
                 55 
                 N 2 -({4-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-6-morpholin-4-yl-D- 
               
               
                   
                 norleucinamide 
               
               
                 56 
                 N 2 -({3,5-difluoro-4-[(4- 
                 B 
                 C 
                 B 
                 B 
                   
                   
                 B 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-3-[(2-morpholin-4- 
               
               
                   
                 ylethyl)thio]-D-valinamide 
               
               
                 57 
                 N 2 -({6-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]pyridin-3- 
               
               
                   
                 yl}sulfonyl)-N 1 -hydroxy-D- 
               
               
                   
                 argininamide 
               
               
                 58 
                 N 2 -({3,5-difluoro-4-[(4- 
                 A 
                 D 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-6-morpholin-4-yl-D- 
               
               
                   
                 norleucinamide 
               
               
                 59 
                 N 6 -[(Z)-(cyanoimino)(morpholin- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 4-yl)methyl]-N 2 -({3-fluoro-4- 
               
               
                   
                 [(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-lysinamide 
               
               
                 60 
                 3-[1-((E)-(cyanoimino){[2- 
                 B 
                 C 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 (methyloxy)ethyl]amino}methyl)piperidin- 
               
               
                   
                 4-yl]-N 2 -({3,5-difluoro- 
               
               
                   
                 4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxyalaninamide 
               
               
                 61 
                 N 2 -({6-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 chlorophenyl)oxy]pyridin-3- 
               
               
                   
                 yl}sulfonyl)-N 1 -hydroxy-D- 
               
               
                   
                 argininamide 
               
               
                 62 
                 N 2 -({3,5-difluoro-4-[(4- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-N 6 -(morpholin-4- 
               
               
                   
                 ylcarbonyl)-D-lysinamide 
               
               
                 63 
                 4-cyano-N-hydroxy-N-{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 64 
                 4-cyano-N-({3,5-difluoro-4-[(4- 
                 B 
                   
                 B 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N-hydroxy-D-phenylalaninamide 
               
               
                 65 
                 N 2 -({4-[(4-chlorophenyl)oxy]- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-6-morpholin-4-yl-D- 
               
               
                   
                 norleucinamide 
               
               
                 66 
                 3-cyano-N-({3,5-difluoro-4-[(4- 
                 B 
                 C 
                 B 
                 C 
                   
                   
                 B 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N-hydroxy-D-phenylalaninamide 
               
               
                 67 
                 3-cyano-N-hydroxy-N-{[4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 68 
                 N 2 -{[3-fluoro-4- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 (phenyloxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxy-6-morpholin-4-yl-D- 
               
               
                   
                 norleucinamide 
               
               
                 69 
                 N 2 -({3,5-difluoro-4-[(4- 
                 A 
                 D 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 hydroxyphenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxyargininamide 
               
               
                 70 
                 N 2 -{[3,5-difluoro-4-(pyridin-3- 
                 B 
                 D 
                 B 
                 D 
                   
                   
                 C 
               
               
                   
                 yloxy)phenyl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxyargininamide 
               
               
                 71 
                 N 2 -({3,5-difluoro-4-[(4- 
                 A 
                 C 
                 A 
                   
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-N 6 -({[2- 
               
               
                   
                 (methyloxy)ethyl]amino}carbonyl)- 
               
               
                   
                 D-lysinamide 
               
               
                 72 
                 N 2 -({3,5-difluoro-4-[(4- 
                 B 
                 C 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 6 -[1-(4,4-dimethyl-2,6- 
               
               
                   
                 dioxocyclohexylidene)ethyl]-N 1 - 
               
               
                   
                 hydroxy-D-lysinamide 
               
               
                 73 
                 N 2 -{[3,5-difluoro-4-({4- 
                 A 
                 D 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 [(phenylmethyl)oxy]phenyl}oxy)phenyl] 
               
               
                   
                 sulfonyl}-N 1 - 
               
               
                   
                 hydroxyargininamide 
               
               
                 74 
                 N 2 -({3-fluoro-4-[(4- 
                 B 
                 B 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-3-[(2-morpholin-4- 
               
               
                   
                 ylethyl)thio]-D-valinamide 
               
               
                 75 
                 N 2 -({4-[(4-bromophenyl)oxy]-3,5- 
                 A 
                 C 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-D-argininamide 
               
               
                 76 
                 N 2 -({3-fluoro-4-[(4- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-3-[(2-morpholin-4- 
               
               
                   
                 yl-2-oxoethyl)thio]-D-valinamide 
               
               
                 77 
                 N 2 -({3-fluoro-4-[(4- 
                 B 
                 C 
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-3-morpholin-4-yl-D- 
               
               
                   
                 alaninamide 
               
               
                 78 
                 N-({3,5-difluoro-4-[(4- 
                   
                 D 
                 B 
                 C 
                   
                   
                 B 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N-hydroxy-4- 
               
               
                   
                 [(hydroxyamino)(imino)methyl]-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 79 
                 N-({3,5-difluoro-4-[(4- 
                 A 
                 C 
                 A 
                 C 
                   
                   
                 B 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N-hydroxy-3- 
               
               
                   
                 [(hydroxyamino)(imino)methyl]-D- 
               
               
                   
                 phenylalaninamide 
               
               
                 80 
                 N 2 -({4-[(4-chlorophenyl)oxy]- 
                 A 
                 D 
                 A 
                 C 
                   
                   
                 B 
               
               
                   
                 3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-3-[1-(morpholin-4- 
               
               
                   
                 ylcarbonyl)piperidin-4- 
               
               
                   
                 yl]alaninamide 
               
               
                 81 
                 3-[amino(imino)methyl]-N-({3,5- 
                 A 
                 D 
                 A 
                 C 
                   
                   
                 B 
               
               
                   
                 difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N-hydroxy-D-phenylalaninamide 
               
               
                 82 
                 4-[amino(imino)methyl]-N-({3,5- 
                 A 
                 D 
                 B 
                 C 
                   
                   
                 B 
               
               
                   
                 difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N-hydroxy-D-phenylalaninamide 
               
               
                 83 
                 N 5 -(aminocarbonyl)-N 2 -({3-fluoro- 
                 A 
                 B 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxy-D-ornithinamide 
               
               
                 84 
                 (2R)-2-[({4-[(4- 
                 B 
                   
                 A 
                 C 
                   
                   
                 B 
               
               
                   
                 chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]- 
               
               
                   
                 4-(dimethylamino)-N- 
               
               
                   
                 hydroxybutanamide 
               
               
                 85 
                 (2R)-2-[({4-[(4- 
                 B 
                 D 
                 B 
                 C 
                   
                   
                 B 
               
               
                   
                 chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]- 
               
               
                   
                 4-{[1-(4,4-dimethyl-2,6- 
               
               
                   
                 dioxocyclohexylidene)-2- 
               
               
                   
                 methylbutyl]amino}-N- 
               
               
                   
                 hydroxybutanamide 
               
               
                 86 
                 N 2 -({4-[(4-chlorophenyl)oxy]- 
                 B 
                 C 
                 B 
                 C 
                   
                   
                 B 
               
               
                   
                 3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxy-3-[(2-morpholin-4-yl-2- 
               
               
                   
                 oxoethyl)thio]-D-valinamide 
               
               
                 87 
                 (2R)-4-amino-2-[({4-[(4- 
                 A 
                 C 
                 A 
                 C 
                   
                   
                 A 
               
               
                   
                 chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]- 
               
               
                   
                 N-hydroxybutanamide 
               
               
                 88 
                 (2R)-4- 
                 A 
                 C 
                 A 
                 C 
                   
                   
                 A 
               
               
                   
                 {[amino(imino)methyl]amino}-2- 
               
               
                   
                 [({4-[(4-chlorophenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]- 
               
               
                   
                 N-hydroxybutanamide 
               
               
                 89 
                 2-[({4-[(4-chlorophenyl)oxy]- 
                 A 
                   
                 A 
                 C 
                   
                   
                 B 
               
               
                   
                 3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]- 
               
               
                   
                 N-hydroxy-2-piperidin-4- 
               
               
                   
                 ylacetamide 
               
               
                 90 
                 2-[({4-[(4-chlorophenyl)oxy]-3- 
                 A 
                   
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl}sulfonyl)amino]-N- 
               
               
                   
                 hydroxy-2-piperidin-4- 
               
               
                   
                 ylacetamide 
               
               
                 91 
                 2-[({3-fluoro-4-[(4- 
                 B 
                   
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl) 
               
               
                   
                 amino]-N-hydroxy-2-piperidin-4- 
               
               
                   
                 ylacetamide 
               
               
                 92 
                 2-[({4-[(4- 
                 A 
                   
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl) 
               
               
                   
                 amino]-N-hydroxy-2-piperidin-4- 
               
               
                   
                 ylacetamide 
               
               
                 93 
                 2-({[6-(3-fluorophenyl)pyridin- 
                 B 
               
               
                   
                 3-yl]sulfonyl}amino)-N-hydroxy- 
               
               
                   
                 2-piperidin-4-ylacetamide 
               
               
                 94 
                 2-[({4-[(3,5- 
                 B 
                   
                 C 
                 C 
                   
                   
                 C 
               
               
                   
                 dimethylphenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)amino]- 
               
               
                   
                 N-hydroxy-2-piperidin-4- 
               
               
                   
                 ylacetamide 
               
               
                 95 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 B 
                   
                 B 
                 C 
                   
                   
                 A 
               
               
                   
                 N 2 -({4-[(4-chlorophenyl)oxy]- 
               
               
                   
                 3,5-difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxyalaninamide 
               
               
                 96 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 A 
                   
                 B 
                 C 
                   
                   
                 B 
               
               
                   
                 N 2 -({3,5-difluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxyalaninamide 
               
               
                 97 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 A 
                   
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 N 2 -({4-[(4-chlorophenyl)oxy]-3- 
               
               
                   
                 fluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxyalaninamide 
               
               
                 98 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 A 
                 C 
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 N 2 -({3-fluoro-4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxyalaninamide 
               
               
                 99 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 A 
                   
                 A 
                 A 
                   
                   
                 A 
               
               
                   
                 N 2 -({4-[(4- 
               
               
                   
                 fluorophenyl)oxy]phenyl}sulfonyl)- 
               
               
                   
                 N 1 -hydroxyalaninamide 
               
               
                 100 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 A 
                   
                 A 
                 B 
                   
                   
                 A 
               
               
                   
                 N 2 -{[(6-(3-fluorophenyl)pyridin- 
               
               
                   
                 3-yl]sulfonyl}-N 1 - 
               
               
                   
                 hydroxyalaninamide 
               
               
                 101 
                 3-[4-(aminomethyl)cyclohexyl]- 
                 C 
               
               
                   
                 N 2 -({4-[(3,5- 
               
               
                   
                 dimethylphenyl)oxy]-3,5- 
               
               
                   
                 difluorophenyl}sulfonyl)-N 1 - 
               
               
                   
                 hydroxyalaninamide