NZ612477B2 - Hedgehog antagonists having zinc binding moieties - Google Patents

Abstract

Provided are benzimidazole and pyridine derivative compounds of the general formula (I) or (II), wherein the variables are as defined in the specification. Examples of the compounds include (E)-2-chloro-N-(4-chloro-3-(5-(3-(hydroxyamino)-3-oxoprop-1-enyl)pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide and 2-((3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide. The compounds contain zinc binding moieties and can inhibit histone deacetylase (HDAC) and the hedgehog pathway. The compounds may be useful in the treatment of cancer, psoriasis or macular degeneration. mide and 2-((3-(4-Chloro-3-(5-(dimethylamino)-1H-benzo[d]imidazol-2-yl)phenylcarbamoyl)-5-methoxybenzyl)(methyl)amino)-N-hydroxypyrimidine-5-carboxamide. The compounds contain zinc binding moieties and can inhibit histone deacetylase (HDAC) and the hedgehog pathway. The compounds may be useful in the treatment of cancer, psoriasis or macular degeneration.

Description

HEDGEHOG ANTAGONISTS HAVING ZINC BINDING MOIETIES RELATED APPLICATIONS This application claims the benefit ofUS. Provisional ation No. 61/429,350, filed on January 3, 2011 and US. Provisional Application No. 61/564,549, filed on November 29, 2011. The entire teachings of the above applications are incorporated herein by nce.

BACKGROUND OF THE INVENTION Hedgehog (Hh) protein was first identified in Drosophila melanogaster as a segment-polarity gene involved in embryo patterning (Nusslein-Voihard et al., Roux.

Arch. Dev. Biol., 193: 267-282 (1984)). Three orthologs of hila hedgehog (Sonic, Desert and Indian) were later found to occur in all vertebrates, ing fish, birds and mammals. Desert hedgehog (DHh) is expressed principally in the testes, both in mouse embryonic development and in the adult rodent and human; Indian hedgehog (IHh) is involved in bone development during genesis and in bone formation in the adult; and, Sonic hedgehog (SHh) is expressed at high levels in the notochord and floor plate of developing vertebrate embryos. In vitro explant assays as well as c expression of SHh in transgenic animals have shown that SHh plays a key role in neuronal tube patterning (Echelard et al., Cell, 75:1417-1430 ; Ericson et al., Cell, 81: 747-56 (1995); Marti et al., Nature, 375: 322—5 (1995); Krauss et al., Cell, 75: 1432-44 (1993); Riddle et al., Cell, 75: 1401-16 (1993); Roelink et al., Cell, 81: 445-55 (1995); Hynes et al., Neuron, 19: 15-26 (1997)). Hh also plays a role in the development of limbs (Krauss et al., Cell, 75: 143—144 (1993); Laufer et al., Cell, 79: 993-1003 (1994)), s (Fan and Tessier—Lavigne, Cell, 79: 1175—86 (1994); n et al., Cell, 79: 3 (1994)), lungs (Bellusci et al., Develop., 124: 53-63 (1997) and skin (Oro et al., Science, 276: 817-21 (1997)).

Likewise, IHh and DHh are involved in bone, gut and germinal cell development (Apelqvist et al., Curr. Biol., 7: 80 1—4 (1997); Bellusci et al., pment, 124: 53-63 (1997); Bitgood et al., Curr. Biol., 6: 298-304 (1996); Roberts et al., Development, 121: 3163-74 (1995)).

Human SHh is synthesized as a 45 kDa precursor protein which is autocatalytically cleaved to yield a 20 kDa N—terminal fragment that is responsible for normal hedgehog WO 94328 signaling activity; and a 25 kDa C— terminal fragment that is responsible for autoprocessing activity in which the N-terminal fragment is conjugated to a cholesterol moiety (Lee, J.J., et al. (1994) Science, 266: 1528- 1536; Bumcrot, D.A., et al. (1995), Mol. Cell Biol, 15 : 2294-2303; Porter, J.A., et al. (1995) Nature, 374: 363-366). The N- terminal fragment consists of amino acid residues 24-197 of the full-length precursor sequence which remains membrane- associated through the cholesterol at its C-terminus (Porter, J.A., et al. (1996) e, 274: 255—258; Porter, J.A., et al. (1995) Cell, 86(2): 1— 34). Cholesterol ation is responsible for the tissue zation of the hedgehog signal.

At the cell e, the Hh signal is thought to be d by the 12 transmembrane domain protein Patched (Ptc) r and Scott, Cell, 59: 751-65 (1989); Nakano et al., Nature, 341: 508-13 (1989)) and the G- protein-coupled-like receptor Smoothened (Smo) (Alcedo et al., Cell, 86(22): 1-232 (1996); van den Heuvel and Ingham, Nature, 382: 547- 551 (1996)). Both genetic and biochemical evidence support a or model where Ptc and Smo are part of a multicomponent receptor complex (Chen and Struhl, Cell, 87: 553- 63 (1996); Marigo et al., Nature, 384: 176-9 (1996); Stone et al., Nature, 384: 129-34 (1996)). Upon binding ofHh to Ptc, the normal inhibitory effect of Ptc on Smo is ed, allowing Smo to transduce the Hh signal across the plasma membrane. However, the exact mechanism by which Ptc controls Smo activity has yet to be clarified.

The signaling cascade initiated by Smo results in activation of Gli transcription factors that translocate into the nucleus where they control transcription of target genes.

Gli has been shown to influence transcription of Hh pathway inhibitors such as Ptc and Hip 1 in a negative feedback loop indicating that tight control of Hh pathway activity is required for proper cellular differentiation and organ formation.

Hedgehog pathway signaling has been ated in tumorigenesis when vated in adult tissues through sporadic mutations or other mechanisms. Three mechanisms have been proposed for the Hedgehog pathway’s involvement in cancer: Type 1 cancers are caused by loss-of—function mutations in Patched 1 (PTCHl) or gain-of- function ons in ened (SMOH) lead to constitutive Hedgehog (Hh) pathway activation. Type 2 cancers rely on an autocrine model in which tumor cells themselves produce and respond to Hh ligand. Type 3 is a paracrine model in which tumor cells produce Hh ligand and surrounding stromal cells respond by producing onal growth factors to support tumor growth or survival, for example, IGF (Insulin-Like Growth Factor) and VEGF (Vascular Endothelial Growth Factor) (Rubin, LL. and de Sauvage, PCT/U52012/020092 F.J. Nature Rev. Drug Discovery, 5: 1026-1033 (2006)).

Dysfunctional Ptc gene mutations have also been associated with a large percentage of sporadic basal cell carcinoma tumors (Chidambaram et al., Cancer Research, 56: 4599-601 (1996); Gailani et al., Nature Genet, 14: 78- 81 (1996); Haim et al., Cell, 85: 841-51 (1996); Jolmson et al., Science, 272: 1668-71 (1996); Unden et al., Cancer Res., 56: 4562-5; Wickingetal., Am. J. Hum. Genet, 60: 21-6 (1997)). Loss of Ptc function is thought to cause an uncontrolled Smo ing in basal cell carcinoma.

Similarly, activating Smo mutations have been identified in sporadic BCC tumors (Xie et al., , 391: 90—2 (1998)), emphasizing the role of Smo as the signaling subunit in the receptor complex for SHh.

The development ofresistance to Shh pathway inhibitors has been ed in animal tumor models (Buonamici, S. et al., Science Trans. Med., 2010, 2: 51ra70; Osherovich, L. SciBX 2010, 3(40)) and in humans (Yauch, R. et al, Science, 2009).

Several mechanisms for resistance were identified, including SMO ons, Gli2 amplification and lation of the lGF—lR—PISK signaling pathway.

Various inhibitors of hedgehog signaling have been investigated. The first Hedgehog signaling inhibitor to be discovered was cyclopamine, a natural alkaloid that has been shown to arrest cell cycle at GO-Gl and to induce apoptosis in SCLC. A number of synthetic small molecule Hedgehog pathway inhibitors are currently under pment (Trembley, M.R. et al., Expert Opin. Ther. Patents, 19(8):1039—56 (2009)). Despite advances with these and other compounds, there remains a need for potent inhibitors of the hedgehog signaling pathway.

Histone acetylation is a reversible modification, with deacetylation being catalyzed by a family of enzymes termed e deacetylases (HDACs). HDAC’s are represented by 18 genes in humans and are divided into four distinct classes (J. Mol Biol, 2004, 338(1): . In mammalians class I HDAC’s -3, and HDAC8) are related to yeast RPD3 HDAC, class 2 HDAC’s (HDAC4—7, HDAC9 and HDAC10) are related to yeast HDACl, class 4 (HDAC11), and class 3 HDAC’s (a distinct class assing the sirtuins) are related to yeast Sir2.

Csordas (Biochem. J., 1990, 286: 23-3 8) s that histones are subject to post- translational acetylation of the s—amino groups of inal lysine residues, a reaction that is catalyzed by histone acetyl transferase (HATl). Acetylation neutralizes the positive charge of the lysine side chain, and is thought to impact chromatin ure. Indeed, access of transcription factors to chromatin templates is enhanced by histone hyperacetylation, and enrichment in cetylated histone H4 has been found in transcriptionally silent regions of the genome (Taunton et al., Science, 1996, 2722408- 411). In the case of tumor suppressor genes, transcriptional silencing due to histone modification can lead to oncogenic transformation and cancer.

Several classes ofHDAC inhibitors currently are marketed or under evaluation in clinical trials. Examples include the hydroxamic acid derivatives suberoylanilide hydroxamic acid (SAHA) and Romidepsin, which are marketed, and PXDlOl, LH—5 89 and LAQ824, which are tly in clinical development. In the benzamide class of HDAC inhibitors, MS-275, 03 and CI-994 are currently being investigated in clinical trials. Mourne et a1. (Abstract #4725, AACR 2005), trate that thiophenyl modification of ides significantly es HDAC inhibitory activity against HDAC 1.

In addition, recent studies have shown that the acetylation of Gli proteins functions as a key transcriptional oint of Hedgehog signaling. It was found that an autoregulatory loop exists whereby Shh increases HDACl levels and HDACl in turn enhances Hh-induced signal activation by deacetylation of Glil and Gli2. Moreover, inhibitors of class 1 HDACs suppress Glil and Gli2 activation, thus suppressing Hh— dependent growth of neural progenitors and tumor cells. (Canettieri, G. et al., Nature Cell Biology, 2010, 12: 132 -142). n s have been effectively treated with agents targeting multiple ing pathways. A recent study trated that the combined targeting of HDACs and Hh signaling ed cytotoxicity in pancreatic adenocarcinoma. (Chun, S. et al., Cancer Biol. & Therapy, 2009, 8(14): 1328-1339). However, treatment regimes using a il of cytotoxic drugs often are limited by dose limiting toxicities and rug interactions. More recent advances with molecularly targeted drugs have provided some new approaches to combination treatment for cancer, allowing multiple targeted agents to be used simultaneously, or combining these new therapies with standard chemotherapeutics or radiation to improve outcome without reaching dose limiting toxicities. However, in many cases, dose-limiting toxicities are reached before pharmacologically meaningful levels of exposure are achieved, and the ability to use such combinations currently is limited to drugs that show compatible pharmacokinetic and pharmacodynamic properties. In addition, the regulatory ements to demonstrate safety and efficacy of combination therapies can be more costly and lengthy than PCT/U82012/020092 corresponding single agent trials. Once approved, combination strategies may also be associated with increased costs to patients, as well as decreased patient compliance.

SUMMARY OF THE INVENTION The present invention relates to hedgehog antagonist compounds having zinc- binding moieties and their use in the treatment of hedgehog and HDAC related es and disorders such as cancer and other diseases and ers characterized by uncontrolled cell proliferation. The nds of the present invention act as HDAC inhibitors by virtue of their ability to bind zinc ions and as inhibitors of the Hedgehog signaling pathway. Combining hedgehog antagonism and HDAC inhibition into a single molecule may provide a synergistic effect in therapeutic applications, and in particular, to the treatment of cancer.

Accordingly, one aspect of the present invention provides a compound of Formula (I) or Formula (H): K O L X E D B x Q n or a geometric isomer, enantiomer, diastereomer, te, pharmaceutically acceptable salt or prodrug thereof; wherein: Ring A is an aromatic, saturated or partially unsaturated carbocycle; preferably a monocyclic, ic or clic C3-C12-carbocycle; 2012/020092 E is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; L is substituted or unsubstituted aryl or substituted or unsubstituted aryl or substituted or unsubstituted saturated or lly unsaturated cyclyl; Q is substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; G is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; K is halogen, preferably C1; X is absent, -O-, -N(R2)-, -S-, -S(O)-, -S(O)2-, -C(O)-,-C(O)O-, -OC(O)—, -C(O)N(R2)-, - N(R2)C(O)-, -S(O)2N(R2)-, or -N(R2)S(O)2-; R2 is hydrogen or aliphatic, preferably hydrogen or C1-C6-alkyl, and more preferably hydrogen or methyl; n is 0 or 1 ; B is a bond or a ; and D is selected from: Rat’LEEi—SHO (a) J ; where W is O or S; J is O, NH or NCH3; and R31 is hydrogen or lower alkyl; RsaZJLYZ/‘a, l I (b) R33 R32 ; where W is O or S; Y2 is absent, N, or CH; Z is N or CH; R32 and R34 are independently hydrogen, OR’, aliphatic group, provided that if R32 and R34 are both present, one of R32 or R34 must be OR’ and if Y2 is , R34 must be OR’; R33 is hydrogen or aliphatic group; and R’ is hydrogen, tic or acyl, preferably hydrogen; preferably Y2 and R32 are absent, Z is N, R34 is hydroxy and R33 is en; (c) “v” ; Where W is O or S; Y1 and 21 are independently N, C or CH; PCT/U52012/020092 R21 NH2 Rafi AWL 2 Rig % T? (d) R12 R11 ; where Z, Y2, and W are as previously defined; R11 and R12 are independently selected from hydrogen or aliphatic; R21, R22 and R23 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF3, CN, N02, yl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and tuted heterocyclic.

Another aspect of the invention provides methods of inhibiting hedgehog signaling activity in a cell, by contacting the cell with an effective hedgehog inhibitory amount of a compound of Formula I or Formula II, or a stereoisomer, geometric isomer, tautomer, e, metabolite, or ceutically acceptable salt or prodrug thereof.

Another aspect of the invention provides methods of inhibiting HDAC activity in a cell, by contacting the cell with an effective HDAC inhibitory amount of a nd of a I or Formula II, or a stereoisomer, geometric isomer, tautomer, solvate, metabolite, or pharmaceutically acceptable salt or prodrug thereof.

DETAILED DESCRIPTION OF THE INVENTION In one embodiment, the t invention provides compounds which are ented by Formula 111 or Formula IV: L X B D (111) PCT/U52012/020092 D—B—X—Q (1V), Where Ring A, K, G, Q, X, B, D, L and B have the meanings given above.

In another embodiment, the compounds of the invention are represented by Formula V or VI: D—B—X—Q (V1) and stereoisomers, geometric isomers, ers, pharmaceutically acceptable salts and prodrugs thereof, wherein E, K, L, X, B, G, Q and D have the meanings given above.

In an ment, the compounds ofthe invention are represented by Formula VII or VIII: PCT/U52012/020092 E o (v11) D—B—X—Q (VIII) and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof, wherein E, K, L, X, B, G, Q and D have the meanings given above. ably, G and L are each independently substituted or unsubstituted aryl or tuted or unsubstituted heteroaryl, and more preferably G and L are each independently substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl. Preferably, E and Q are each independently substituted or unsubstituted heteroaryl.

In an embodiment, the compounds of the ion are represented by Formula IX or X: E/\\_\/\ L—X—B—D (1X) PCT/U52012/020092 D—B—X—Q/\\ &/ and stereoisomers, geometric isomers, tautomers, ceutically acceptable salts and prodrugs thereof, wherein E, K, L, X, B, G, Q and D have the meanings given above.

Preferably, G and L are each independently heterocyclyl, preferably heterocycloalkyl.

In one ment, the present ion provides compounds which are represented by Formula XI: \7v2 (X1) and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts and prodrugs f; wherein one ofW1-W5 is C(X—B-D) and the others are each independently N or CR3, provided that no more than three of Wl-Ws are N; each R3 is independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF3, CN, N02, sulfonyl, acyl, aliphatic, substituted tic, aryl, tuted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, and X, B and D have the meanings given for these variables above.

In preferred embodiments of the compounds of Formula XI, E is substituted or unsubstituted pyridyl, such as substituted or unsubstituted pyridyl, pyridyl or pyrid- 4-yl, or substituted or unsubstituted benzimidazolyl, such as substituted or unsubstituted PCT/U52012/020092 benzimidazol-Z-yl. In particularly red embodiments, E is selected from the groups set forth below: /“ ©:/: E U} E In another preferred embodiment of the compounds of Formula XI, the group w5/ W\1\w2 \W =W/ is selected from the groups shown below: X\B\D X\B\D_ In another embodiment, the present invention provides nds which are represented by Formula XII: PCT/U52012/020092 D—B—X—Q X5/ \\X2 \ / X4—X3 (XII) and stereoisomers, geometric isomers, tautomers, pharmaceutically acceptable salts and prodrugs thereof; wherein Xl-Xs are each independently selected from N and CR3, provided that at least two of X1- X5 are CR3; and Q, D, B, X and R3 have the meanings given for these variables above.

In red embodiments of the compounds of Formula XII, Q is tuted or unsubstituted pyridyl, substituted or unsubstituted pyrimidyl or substituted or unsubstituted idazolyl. In particularly preferred embodiments, Q is ed from the groups below, I{N\H I / \ é / n N wherein the bond to the benzene ring is denoted by g, and the bond to X is denoted by In other preferred embodiments of the compounds of Formula XII, the group 2012/020092 x5/ \\x2 \ / X4—X3 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, such as substituted or unsubstituted pyridyl, pyrid—3—yl or pyridyl, or tuted or unsubstituted pyrimidyl, such as pyrimid—Z—yl, pyrimidyl or d—S—yl. In particularly preferred embodiments, this group is selected from those set forth below. o .7773 F30 N 02 / In a preferred embodiment, the bivalent B is a direct bond or straight- or branched— substituted or unsubstituted , alkyl, substituted or unsubstituted alkenyl, substituted or tituted alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, cycloalkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, eteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, lheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, eterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, laryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or alkynylheteroaryl, in which groups one or more methylenes can be interrupted or terminated by O, S, 8(0), 802, N(R2), C(O), substituted or unsubstituted aryl, tuted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic; such divalent B linkers include but are not limited to alkyl, l, alkynyl, alkylaryl, alkenylaryl, PCT/U52012/020092 alkynylaryl, alkylheterocyclylaryl, eterocyclylarylalkyl, alkylheterocyclylheteroaryl, alkylheterocyclylheteroarylalkyl, alkoxyaryl, alkylaminoaryl, alkoxyalkyl, alkylaminoalkyl, alkylheterocycloalkyl, alkylheteroarylalkyl, alkylamino, aryl, heteroaryl, heterocyclyl, N(R2)alkeny1, lkynyl, lkoxyalkyl, 1kylaminoalky1, N(R2)a1ky1aminocarbonyl, N(R2)alky1ary1, N(R2)alkenylaryl, N(R2)alkynylary1, lkoxyary1, N(R2)alkylaminoaryl, ycloalkyl, N(R2)ary1, N(R2)heteroaryl, N(R2)heterocycloalkyl, N(R2)alkylheterocycloalkyl, alkoxy, O-alkenyl, O—alkynyl, O- alkoxyalkyl, laminoalkyl, O-alkylaminocarbonyl, O-alkylaryl, O-alkenylaryl, O- alkynylaryl, O-alkoxyaryl, O-alkylaminoaryl, O-cycloalkyl, O—aryl, O-heteroaryl, O- heterocycloalkyl, O-alkylheterocycloalkyl, C(O)alkyl, C(O)—a1kenyl, C(O)alkynyl, C(O)alky1aryl, C(O)alkeny1ary1, C(O)alkynylary1, C(O)alk0xyalky1, C(O)alky1aminoalkyl, C(O)alky1aminocarbony1, C(O)cycloalkyl, C(O)aryl, C(O)heteroaryl, C(O)heter0cycloalkyl, CON(R2), CON(R2)alky1, CON(R2)alkeny1, CON(R2)alkyny1, CON(R2)alky1aryl, )alkenylary1, CON(R2)a1kynylaryl, CON(R2)alkoxyalky1, CON(R2)alky1aminoalkyl, CON(R2)alky1aminocarbonyl, CON(R2)alkoxyary1, CON(R2)alky1aminoaryl, CON(R2)cycloalkyl, CON(R2)aryl, )heter0ary1, CON(R2)heterocycloalkyl, CON(R2)alkylheterocycloalkyl, N(R2)C(O)alkyl, N(R2)C(O)alkenyl, N(R2)C(O)— alkynyl, N(R2)C(O)alky1aryl, N(R2)C(O)a1kenylary1, N(R2)C(O)alkyny1aryl, N(R2)C(O)alk0xyalky1, N(R2)C(O)alky1arninoalkyl, N(R2)C(O)a]kylaminocarbonyl, N(R2)C(O)alkoxyary1, N(R2)C(O)alkylaminoaryl, N(R2)C(O)cyc10alky1, N(R2)C(O)aryl, (O)heteroaryl, N(R2)C(O)heterocycloalkyl, N(R2)C(O)alky1heterocycloalky1, NHC(O)NH, NHC(O)NH—alkyl, NH-alkenyl, NHC(O)NH-alkynyl, NHC(O)NH-alkylaryl, NHC(O)NH-alkenylaryl, NHC(O)NH- alkynylaryl, NHC(O)NH-alkoxyaryl, NHC(O)NH-alkylaminoaryl, NHC(O)NH- cycloalkyl, NHC(O)NH—aryl, NHC(O)NH—heteroaryl, NHC(O)NH—heterocycloalkyl, NHC(O)NH—alkylheter0cycloalkyl, l, S-alkenyl, S-alkynyl, S-alkoxyalkyl, S- alkylaminoalkyl, S-alkylaryl, S-alkylaminocarbonyl, S-alkylaryl, S-alkynylaryl, S- aryl, S-alkylaminoaryl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, S— alkylheterocycloalkyl, S(O)a1kyl, keny1, S(O)alkyny1, S(O)a1k0xya1kyl, S(O)alkylaminoalky1, S(O)alkylaminocarbony1, S(O)alky1aryl, S(O)alkeny1ary1, S(O)alkyny1ary1, S(O)alkoxyary1, S(O)alkylaminoary1, S(O)cycloalky1, S(O)ary1, S(O)heter0ary1, S(O)heterocycloalky1, S(O)alky1heterocycloalky1, S(O)2alky1, S(O)2alkeny1, S(O)2alkyny1, S(O)2alkoxyalkyl, S(O)2alkylaminoalkyl, S(O)2alky1aminocarbonyl, S(O)2alkylaryl, S(O)2alkenylaryl, S(O)2alkynylaryl, PCT/U52012/020092 S(O)2alkoxyaryl, S(O)2alkylaminoaryl, S(O)zcycloalkyl, S(O)2aryl, S(O)2heteroaryl, S(O)2heterocycloalkyl, S(0)2alkylheterocycloalkyl, S(O)2heterocyclylalkyl, S(0)2heterocyclylalkenyl, S(O)2heterocyclylalkynyl, SOZNH, SOzNH-alkyl, SOZNH- alkenyl, SOZNH-alkynyl, SOZNH-alkylaryl, SOZNH-alkenylaryl, SOZNH-alkynylaryl, cycloalkyl, SOzNH-aryl, SOZNH-heteroaryl, SOzNH-heterocycloalkyl, SOzNH- alkylheterocycloalkyl, alkylaryloxyalkoxy, alkylaryloxyalkylamino, alkylarylaminoalkoxy, rylaminoalkylamino, rylalkylaminoalkoxy, alkylarylalkylaminoalkoxy, alkenylaryloxyalkoxy, alkenylaryloxyalkylamino, alkenylarylaminoalkoxy, alkenylarylaminoalkylamino, alkenylarylalkylaminoalkoxy, larylalkylaminoalkylamino.

In a more preferred embodiment, B is a straight chain alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, cyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, lkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, larylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, lheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, lheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or alkynylhereroaryl. In these linkers, one or more methylenes can be upted or terminated by —O-, -N(R2)—, , -C(O)N(R2)—, or -C(O)O-.

In one embodiment, the linker B is between 1-24 carbon atoms, preferably 4—24 carbon atoms, preferably 4-18 carbon atoms, more preferably 4-12 carbon atoms, and most preferably about 4-10 carbon atoms.

In a preferred embodiment, B is selected from straight chain C1-C10 alkyl, C1-C10 alkenyl, C1-C10 alkynyl, C1—C10 alkoxy, alkoxyCl-Cloalkoxy, C1-C10 alkylamino, alkoxyCl-Cloalkylamino, C1-C10 alkylcarbonylamino, C1-C10 alkylaminocarbonyl, aryloxyCl—Cloalkoxy, aryloxyCl-Cloalkylamino, aryloxyCl-Cloalkylamino carbonyl, C1- C10-alkylaminoalkylaminocarbonyl, C1-C10 alkyl(N-alkyl)aminoalkyl-aminocarbonyl, alkylaminoalkylamino, alkylcarbonylaminoalkylamino, alkyl(N—alkyl)aminoalkylamino, m-alkyl)alkylcarbonylaminoalkylamino, alkylaminoalkyl, alkylaminoalkylaminoalkyl, PCT/U52012/020092 alkylpiperazinoalkyl, piperazinoalkyl, alkylpiperazino, alkenylaryloxyCl—Cloalkoxy, alkenylarylaminoCl-Cloalkoxy, laryllalkylaminoC1-Cloalkoxy, laryloxyCl- Cloalkylamino, alkenylaryloxyCl-Cloalkylaminocarbonyl, piperazinoalkylaryl, heteroarlel-Cloalkyl, heteroarleZ-Cloalkenyl, heteroarleZ-Cloalkynyl, heteroarlel- Cloalkylamino, arlel-Cloalkoxy, heteroaryloxyCl-Cloalkyl, heteroaryloxyCz- Cloalkenyl, heteroaryloxyCz-Cloalkynyl, heteroaryloxyC1—C10alkylamino, aryloxyCl—Cloalkoxy. In the most preferred embodiments, the D group is attached to B Via an aliphatic moiety carbon chain, an aryl group or a aryl group Within B.

In another preferred embodiment, B is a direct bond, aryl, heteroaryl, C2-C10-alky1, C2-C10-alkenyl, aryl-Cz-Clo-alkyl, aryl-Cz—Clo-alkenyl, aryloxy-Cl-Clo-alkyl, heterocyclylheteroaryl, C1-C10-alkylheterocyclylheteroaryl, or C1-C10- alkylaminoheteroaryl.

It is understood that alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocyclyl and the like can be further substituted.

In certain embodiments, the compounds of Formulas I and II are represented by Formulas XIII and XIV, respectively: HN4< i L-M1-M2-M3-M4—M5—T2 $4134 R32 R33 (XIII) R33 R32 RIM—Z Y2_M5'M4'M3'M2‘M1—Q HN—< (XIV) PCT/U52012/020092 wherein M1 is , 0, S, NR2, C1-C6 alkyl, C2-C6 alkenyl, C2—C6 alkynyl, aryl, aryl, heterocyclic, SO, 802 or C=O; M2 is absent, C1-C6 alkyl, 0, NR2,, heterocyclic, aryl, heteroaryl, or C=O; M3 is absent, 0, NR2, S, SO, S02, CO, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl, heteroaryl, or heterocyclic; M4 is absent, 0, NR2, heteroaryl, heterocyclic or aryl; and M5 is absent, C1-C8 alkyl, C2-C8 alkenyl, C2- Cgalkynyl, heteroaryl, heterocyclic or aryl; and E, L, Q, G, Z, Y2, R32, R33 and R34 have the definitions given for these variables above. Preferably, Y2 and R32 are absent, Z is N, R33 is H and R34 is hydroxy.

Specific nds of the invention are set forth in the Table below.

WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 PCT/U52012/020092 ;38:n=2;39:n=3;40:n=4;412n=5g422n=6 43:n=1;44:n=2;45:n=3;46:n=4;47:n=5;48:n=6 Ho/Waw / \ 49:n=1;50:n=2;51:n=3;52:n=4;53:n=5;54:n=6 55:n=1;56:n=2;57:n=3;58:n=4;59:n=5;60:n=6 2012/020092 61:n=1;62:n=2;63:n=3;64:n=4;652n=5g662n=6 79:n=1;80:n=2;81:n=3;82:n=4;83:n=5;84:n=6 / \ O// \ WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 107: n=1; 108: n=2; 109: 11:3; 110: n=4; 111: n=5; 112: n=6 2012/020092 131:n=1;132:n=2;133:n=3;134:n=4;135:n=5;136:n=6 137:n=1;l38:n=2;139:n=3;140:n=4;141:n=5;142zn=6 149:n=1;150:n=2;151:n=3;152:n=4;153:n=5;154:n=6 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 183: n=1; 184: n=2; 185: 11:3; 186: n=4; 187: n=5; 188: n=6 2012/020092 201:n=1;202:n=2;203:n=3;204:n=4;205:n=5;206:n=6 / \ 207:n=1;208:n=2;209:n=3;2102n=4;211:n=5;212:n=6 / \ WO 94328 PCT/U52012/020092 219: n=1; 220: n=2; 221: 11:3; 222: n=4; 223: n=5; 224: n=6 WO 94328 PCT/U52012/020092 237: n=1; 238: n=2; 239: 11:3; 240: n=4; 241: n=5; 242: n=6 WO 94328 PCT/U52012/020092 WO 94328 PCT/U52012/020092 256: R=H; 257: R=Me WO 94328 PCT/U52012/020092 258: R=H; 259: R=Me 262: R=H; 263: R=Me / \ PCT/U52012/020092 The ion further provides methods for the prevention or treatment of hedgehog-related diseases or disorders, and in particular, diseases or disorders ing aberrant proliferation, differentiation or survival of cells. In one embodiment, the PCT/U52012/020092 invention further provides for the use of one or more compounds of the invention in the manufacture of a medicament for halting or decreasing diseases involving aberrant proliferation, entiation, or al of cells. In preferred ments, the disease is cancer. In one embodiment, the invention relates to a method of treating cancer in a subject in need of treatment comprising administering to said subject a therapeutically effective amount of a compound of the invention. In r embodiment, the invention further provides s for the prevention or treatment of non—cancer hedgehog-related diseases or disorders, such as psoriasis. The compounds of the invention can also be used to treat diseases or disorders associated with aberrant or uncontrolled angiogenesis, including macular degeneration, diabetic retinopathy, retinopathy of prematurity, rheumatoid arthritis and obesity. In addition, nds of the invention may be used to down-regulate hair growth.

By virtue of the dual HDAC and Hedgehog inhibitory activities of the compounds of the present ion, the invention further provides a method for ng certain cancers which are resistant to the action of Hedgehog y ing inhibitors alone.

Such resistance may be characterized by one or more mutations in proteins involved in the og signaling cascade above the level of Gli transcription activation. The t nds having HDAC inhibiting activity may nonetheless be usefiil for treating cancers having increased hedgehog levels by inhibiting the deacetylation of the Glil and Gli2 transcription activators.

The term "cancer" refers to any cancer caused by the proliferation of ant neoplastic cells, such as tumors, neoplasms, carcinomas, sarcomas, leukemias, lymphomas and the like. For example, cancers include, but are not limited to, mesothelioma, leukemias and lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneous peripheral T-cell lymphomas, lymphomas associated with human T-cell lymphotrophic Virus (HTLV) such as adult T-cell leukemia/lymphoma (ATLL), B-cell lymphoma, acute nonlymphocytic leukemias, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, lymphomas, and multiple myeloma, dgkin lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), Hodgkin’s lymphoma, Burkitt ma, adult T-cell leukemia lymphoma, acute-myeloid leukemia (AML), chronic myeloid leukemia (CML), or hepatocellular carcinoma. Further examples include myelodisplastic syndrome, childhood solid tumors such as brain tumors, neuroblastoma, retinoblastoma, Wilms' tumor, bone , and soft—tissue sarcomas, common solid tumors of adults such as head and neck cancers (e.g., oral, laryngeal, nasopharyngeal and esophageal), genitourinary cancers (e.g., prostate, bladder, renal, uterine, ovarian, ular), lung cancer (e.g., small—cell and non small cell), breast , pancreatic cancer, melanoma and other skin cancers, stomach cancer, brain tumors, tumors related to Gorlin’s me (e.g., medulloblastoma, meningioma, etc.), and liver . onal ary forms of cancer which may be treated by the subject compounds e, but are not limited to, cancer of skeletal or smooth , h cancer, cancer of the small intestine, rectum carcinoma, cancer of the salivary gland, endometrial cancer, adrenal cancer, anal cancer, rectal cancer, parathyroid cancer, and pituitary cancer.

In preferred embodiments, the cancer is associated with nt hedgehog signaling, for example, when Patched fails to, or inadequately, represses Smoothened (Ptc loss of function phenotype) and/or when ened is active regardless of Patched repression (Smo gain-of function phenotype) and/or when the og ligand is upregulated regardless of patched or smoothened mutational status. Examples of such cancer types include basal cell carcinoma, neuroectodermal tumors, such as medulloblastoma, meningioma, hemangioma, glioblastoma, pancreatic adenocarcinoma, us lung carcinoma, small cell lung cancer, all cell lung cancer, ovarian cancer, prostate cancer, liver cancer, chondrosarcoma, breast carcinoma, rhabdomyosarcoma, esophageal cancer, stomach , biliary tract cancer, renal carcinoma and thyroid carcinoma. Furthermore, compounds ofthe invention may be useful in the treatment of hematologic tumors such as ias, lymphomas and myelomas as listed above.

Additional cancers that the compounds described herein may be useful in treating are, for example, colon carcinoma, familiary adenomatous sis carcinoma and hereditary non-polyposis colorectal cancer, or melanoma. Further, cancers include, but are not limited to, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, thyroid cancer (medullary and papillary thyroid carcinoma), renal carcinoma, kidney parenchyma carcinoma, cervix carcinoma, uterine corpus oma, endometrium carcinoma, chorion carcinoma, testis carcinoma, urinary carcinoma, melanoma, brain tumors such as astoma, astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermal tumors, gall bladder carcinoma, bronchial carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyosarcoma, craniopharyngeoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma.

PCT/U52012/020092 In one aspect of the invention, the present invention provides for the use of one or more compounds of the invention in the manufacture of a medicament for the treatment of cancer.

In one embodiment, the present ion includes the use of one or more compounds of the invention in the manufacture of a medicament that prevents further aberrant proliferation, differentiation, or survival of cells. For example, compounds of the invention may be useful in preventing tumors from increasing in size or from reaching a metastatic state. The subject compounds may be administered to halt the progression or advancement of cancer or to induce tumor sis or to inhibit tumor angiogenesis. In on, the instant invention es use of the t compounds to prevent a recurrence of cancer.

This invention flirther es the ent or prevention of cell proliferative disorders such as lasias, dysplasias and pre-cancerous lesions. Dysplasia is the earliest form of ncerous lesion recognizable in a biopsy by a pathologist. The subject compounds may be administered for the purpose of preventing said hyperplasias, dysplasias or pre-cancerous lesions from continuing to expand or from becoming cancerous. Examples of pro—cancerous lesions may occur in skin, esophageal tissue, breast and cervical intra-epithelial tissue.

"Combination therapy" includes the administration of the subject compounds in further combination with other biologically active ingredients (such as, but not limited to, a second and different antineoplastic agent) and non-drug therapies (such as, but not limited to, surgery or radiation ent). For instance, the compounds of the invention can be used in combination with other pharmaceutically active compounds, preferably compounds that are able to enhance the effect of the compounds of the ion. The compounds of the ion can be administered aneously (as a single preparation or separate preparation) or sequentially to the other drug therapy. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

In one aspect of the invention, the subject compounds may be administered in combination with one or more separate agents that modulate protein kinases involved in various disease states or targets ream thereof. Examples of such kinases may include, but are not limited to: serine/threonine specific kinases, receptor ne specific kinases and non-receptor tyrosine specific kinases. Serine/threonine kinases include mitogen activated protein kinases , meiosis specific kinase (MEK), RAF and PCT/U52012/020092 aurora kinase. Examples of receptor kinase families include epidermal growth factor receptor (EGFR) (e. g., HERZ/neu, HER3, HER4, ErbB, ErbB2, ErbB3, ErbB4, erk, DER, ; fibroblast growth factor (FGF) receptor (e.g., FGF-Rl,GFF-R2/BEK/CEK3, FGF-R3/CEK2, FGF-R4/TKF, KGF-R); hepatocyte growth/scatter factor receptor (HGFR) (e. g., MET, RON, SEA, SEX); n receptor (e.g., IGFI-R, PI3K, AKT, mTor); Eph (e.g., CEKS, CEK8, EBK, ECK, EEK, EHK-l, EHK-2, ELK, EPH, ERK, HEK, MDK2, MDKS, SEK), Axl (e.g., Mer/Nyk, Rse); RET, and platelet—derived growth factor receptor (PDGFR) (e.g., PDGFoc-R, PDGB-R, CSFl-IUFMS, SCF-R/C-KIT, VEGF- PJFLT, NEK/FLKI , FLT3/FLK2/STK—1). Non-receptor tyrosine kinase families include, but are not limited to, BCR-ABL (e.g., p433“, ARG); BTK (e.g., ITK/EMT, TEC); CSK, FAK, FPS, JAK, SRC, BMX, FER, CDK and SYK.

In another aspect of the invention, the subject compounds may be administered in combination with one or more separate agents that modulate non-kinase biological targets or processes. Such targets include histone deacetylases (HDAC), DNA methyltransferase (DNMT), heat shock proteins (e.g., HSP90), and proteosomes.

In a preferred embodiment, t compounds may be combined with oplastic agents (e. g., small molecules, monoclonal antibodies, antisense RNA, and fusion proteins) that inhibit one or more biological targets such as Zolinza, Tarceva, Iressa, Tykerb, c, Sutent, l, r, CNF2024, RG108, BMS3 87032, Affinitak, Avastin, Herceptin, Erbitux, AG24322, PD325901, ZD6474, PDl84322, Obatodax, ABT737 and AEE788. Such ations may enhance therapeutic efficacy over efficacy achieved by any of the agents alone and may prevent or delay the appearance ofresistant mutational variants. For example, the subject compounds may advantageously be used in ation with a BCL-ABL inhibitor such as l for the treatment of hematologic tumors such as leukemias, mas and myelomas.

In certain preferred embodiments, the compounds of the ion are stered in combination with a chemotherapeutic agent. Chemotherapeutic agents encompass a wide range of therapeutic treatments in the field of oncology. These agents are administered at various stages of the disease for the purposes of shrinking tumors, destroying remaining cancer cells left over after surgery, inducing remission, maintaining remission and/or alleviating symptoms ng to the cancer or its treatment. Examples of such agents include, but are not limited to, alkylating agents such as mustard gas derivatives (Mechlorethamine, cylophosphamide, chlorambucil, lan, ifosfamide), ethylenimines (thiotepa, hexamethylmelanine), Alkylsulfonates (Busulfan), Hydrazines PCT/U52012/020092 and Triazines (Altretamine, Procarbazine, Dacarbazine and Temozolomide), Nitrosoureas (Carmustine, Lomustine and Streptozocin), Ifosfamide and metal salts (Carboplatin, tin, and Oxaliplatin); plant alkaloids such as yllotoxins (Etoposide and Tenisopide), Taxanes (Paclitaxel and Docetaxel), Vinca alkaloids (Vincristine, Vinblastine, Vindesine and lbine), and Camptothecan analogs (Irinotecan and can); anti-tumor antibiotics such as Chromomycins (Dactinomycin and Plicamycin), Anthracyclines ubicin, Daunorubicin, Epirubicin, Mitoxantrone, Valrubicin and Idarubicin), and miscellaneous antibiotics such as Mitomycin, mycin and Bleomycin; anti-metabolites such as folic acid antagonists (Methotrexate, Pemetrexed, Raltitrexed, Aminopterin), pyrimidine nists (5- Fluorouracil, Floxuridine, Cytarabine, Capecitabine, and Gemcitabine), purine antagonists (6-Mercaptopurine and 6-Thioguanine) and adenosine deaminase inhibitors (Cladribine, Fludarabine, Mercaptopurine, Clofarabine, Thioguanine, Nelarabine and Pentostatin); topoisomerase tors such as topoisomerase 1 inhibitors (Ironotecan, topotecan) and topoisomerase II inhibitors (Amsacrine, etoposide, ide phosphate, teniposide); monoclonal antibodies (Alemtuzumab, Gemtuzumab ozogamicin, Rituximab, Trastuzumab, Ibritumomab an, Cetuximab, Panitumumab, Tositumomab, zumab); and miscellaneous anti-neoplastics such as ribonucleotide ase inhibitors (Hydroxyurea); adrenocortical steroid inhibitor (Mitotane); enzymes (Asparaginase and Pegaspargase); anti-microtubule agents (Estramustine); and ids (Bexarotene, Isotretinoin, Tretinoin (ATRA). For example, the subject compounds may advantageously be used in combination with a pyrimidine antagonist such as Gemcitabine for the treatment of solid tumors such as pancreatic cancers such as pancreatic arcinoma.

In certain red embodiments, the compounds of the invention are administered in combination with a chemoprotective agent. Chemoprotective agents act to protect the body or minimize the side effects of chemotherapy. Examples of such agents include, but are not limited to, amfostine, mesna, and dexrazoxane.

In one aspect of the invention, the subject compounds are administered in combination with radiation therapy. Radiation is commonly delivered internally (implantation of radioactive material near cancer site) or externally from a machine that employs photon (x-ray or gamma-ray) or particle radiation. Where the combination therapy further comprises ion treatment, the radiation treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and radiation treatment is achieved. For e, in appropriate cases, the ial effect is still achieved when the radiation treatment is temporally removed from the administration of the therapeutic agents, s by days or even weeks.

It will be appreciated that compounds of the invention can be used in combination with an immunotherapeutic agent. One form of immunotherapy is the generation of an active systemic tumor-specific immune response of host origin by stering a vaccine composition at a site distant from the tumor. Various types of vaccines have been proposed, including isolated tumor-antigen vaccines and anti-idiotype vaccines. Another approach is to use tumor cells from the subject to be treated, or a derivative of such cells (reviewed by Schirrmacher et al. (1995) J. Cancer Res. Clin. Oncol., 121 :487). In US.

Pat. No. 5,484,596, Hanna Jr. et a1. claim a method for treating a resectable oma to t recurrence or ases, comprising surgically removing the tumor, dispersing the cells with collagenase, irradiating the cells, and vaccinating the patient with at least three consecutive doses of about 107 cells.

It will be iated that the compounds of the invention may advantageously be used in conjunction with one or more adjunctive therapeutic agents. Examples of suitable agents for adjunctive y include a 5HT1 t, such as a triptan (e.g. sumatriptan or naratriptan); an inhibitor of the phosphoinositolkinase (PI3K) family; an inhibitor of the mammalian target ofrapamycin (mTOR); an inhibitor of Bcr-Abl; an adenosine Al t; an EP ; an NMDA modulator, such as a glycine antagonist; a sodium channel blocker (e.g. lamotrigine); a substance P antagonist (e.g. an NK1 antagonist); a cannabinoid; acetaminophen or phenacetin; a 5—lipoxygenase inhibitor; a leukotriene receptor antagonist; a DMARD (e.g. methotrexate); gabapentin and related compounds; a tricyclic antidepressant (e.g. amitryptilline); a neuron stabilising antiepileptic drug; a mono-aminergic uptake inhibitor (e.g. venlafaxine); a matrix metalloproteinase inhibitor; a nitric oxide synthase (NOS) inhibitor, such as an iNOS or an nNOS inhibitor; an inhibitor ofthe release, or action, of tumour necrosis factor alpha; an antibody therapy, such as a monoclonal dy y; an antiviral agent, such as a nucleoside inhibitor (e.g. lamivudine) or an immune system tor (e.g. interferon); an opioid analgesic; a local anaesthetic; a stimulant, including caffeine; an Hz-antagonist (e.g. ranitidine); a proton pump inhibitor (e.g. omeprazole); an antacid (e.g. aluminium or magnesium hydroxide; an antiflatulent (e.g. simethicone); a decongestant (e.g. phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, hrine, naphazoline, xylometazoline, hexedrine, or levo-desoxyephedrine); an antitussive (e. g. codeine, hydrocodone, carmiphen, carbetapentane, or dextramethorphan); a diuretic; or a sedating or non-sedating stamine.

The compounds may also be used in the treatment of a disorder involving, ng to or, associated with dysregulation of histone deacetylase (HDAC). There are a number of disorders that have been implicated by or known to be mediated at least in part by HDAC activity, where HDAC activity is known to play a role in triggering disease onset, or whose symptoms are known or have been shown to be alleviated by HDAC inhibitors.

Disorders of this type that would be expected to be amenable to ent with the compounds of the invention include the following but not limited to: Anti-proliferative disorders (e.g. cancers); Neurodegenerative diseases including Huntington's Disease, utamine disease, son's Disease, Alzheimer's Disease, Seizures, Striatonigral degeneration, Progressive supranuclear palsy, Torsion dystonia, Spasmodic torticollis and dyskinesis, Familial tremor, Gilles de la Tourette syndrome, Diffuse Lewy body disease, Progressive supranuclear palsy, Pick's disease, intracerebral hemorrhage, Primary lateral sclerosis, Spinal ar atrophy, Amyotrophic lateral sclerosis, Hypertrophic interstitial polyneuropathy, Retinitis pigmentosa, Hereditary optic atrophy, Hereditary spastic egia, ssive ataxia and ager syndrome; lic es including Type 2 diabetes; Degenerative Diseases of the Eye including Glaucoma, Age-related macular degeneration, Rubeotic glaucoma; Inflammatory diseases and/or Immune system disorders including Rheumatoid Arthritis (RA), Osteoarthritis, Juvenile chronic arthritis, Graft versus Host disease, Psoriasis, Asthma, Spondyloarthropathy, Crohn's Disease, inflammatory bowel disease Colitis Ulcerosa, Alcoholic hepatitis, Diabetes, Sjoegrens's syndrome, Multiple Sclerosis, Ankylosing spondylitis, Membranous glomerulopathy, Discogenic pain, Systemic Lupus Erythematosus; Disease ing angiogenesis including cancer, sis, rheumatoid arthritis; Psychological disorders including bipolar disease, schizophrenia, mania, depression and dementia; Cardiovascular es including the prevention and treatment of ischemia-related or usion-related vascular and myocardial tissue damage, heart failure, osis and arteriosclerosis; Fibrotic diseases including liver fibrosis, cystic fibrosis and angiofibroma; Infectious diseases including Fungal infections, such as candidiasis or Candida ns, Bacterial infections, Viral ions, such as Herpes Simplex, poliovirus, rhinovirus and coxsackievirus, Protozoal infections, such as Malaria, ania infection, Trypanosoma brucei infection, Toxoplasmosis and coccidlosis and Haematopoietic disorders including thalassemia, anemia and sickle cell anemia.

PCT/U52012/020092 nds of the invention inhibit angiongenesis and are therefore useful in the treatment of diseases or conditions mediated by angiogenesis such as tumors, in particular solid tumors such as colon, lung, pancreatic, n, breast and glioma. Furthermore, compounds of the invention are useful for treating macular degeneration, e.g., wet age- d macular degeneration. Compounds of the ion are also useful for treating atory/immune diseases such as Crohn’s disease, inflammatory bowel e, Sjogren’s syndrome, , organ transplant ion, systemic lupus erythmatoses, psoriatic arthritis, psoriasis and multiple sclerosis. The compounds can also be used for the down-regulation of hair growth or as a depilatory for cosmetic purposes or in the treatment of hirsutism.

The invention encompasses pharmaceutical compositions comprising pharmaceutically able salts of the compounds of the invention as described above.

The invention also encompasses solvates of the compounds of the invention and pharmaceutical itions comprising such es, such as hydrates, methanolates or ethanolates. The term “solvate” refers to a solid, preferably crystalline, form of a compound which includes the presence of solvent molecules within the crystal lattice. A solvate of a compound comprising a given solvent is typically prepared by crystallization ofthe compound from that solvent. Solvates can include a variety of solvents, including water, methanol and ethanol. The term "hydrate" refers to a solvate in which the solvent is water, and includes, but is not limited to, hemihydrate, drate, ate, trihydrate and the like. The invention further encompasses pharmaceutical compositions comprising any solid or liquid physical form of the compound of the ion, including crystalline and crystalline solvate forms. For example, the compounds can be in a lline form, in amorphous form, and have any particle size. The particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other -solid or liquid physical form.

The nds of the invention, and derivatives, fragments, analogs, homologs, pharmaceutically acceptable salts or solvates thereof can be incorporated into pharmaceutical itions suitable for administration, together with a pharmaceutically acceptable carrier or excipient. Such compositions typically comprise a therapeutically effective amount of any of the compounds above, and a pharmaceutically acceptable carrier. Preferably, the effective amount when treating cancer is an amount effective to selectively induce terminal differentiation of suitable neoplastic cells and less than an amount which causes toxicity in a patient.

PCT/U52012/020092 Compounds of the invention may be administered by any suitable means, including, without limitation, eral, intravenous, intramuscular, subcutaneous, implantation, oral, sublingual, buccal, nasal, pulmonary, transdermal, topical, vaginal, , and transmucosal administrations or the like. Topical administration can also involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Pharmaceutical preparations e a solid, semisolid or liquid ation (tablet, pellet, troche, capsule, suppository, cream, ointment, aerosol, powder, , emulsion, suspension, syrup, injection etc.) containing a compound of the invention as an active ingredient, which is suitable for selected mode of administration. In one embodiment, the pharmaceutical compositions are administered orally, and are thus formulated in a form suitable for oral administration, i.e., as a solid or a liquid preparation.

Suitable solid oral formulations include tablets, capsules, pills, granules, pellets, sachets and effervescent, powders, and the like. Suitable liquid oral formulations include solutions, suspensions, dispersions, emulsions, oils and the like. In one embodiment of the present invention, the composition is formulated in a capsule. In accordance with this embodiment, the itions of the present ion comprise in on to the active compound and the inert carrier or diluent, a hard gelatin capsule.

Any inert excipient that is commonly used as a carrier or diluent may be used in the formulations of the present invention, such as for example, a gum, a starch, a sugar, a cellulosic al, an acrylate, or mixtures thereof. A preferred diluent is microcrystalline cellulose. The compositions may further comprise a disintegrating agent (e.g., croscarmellose sodium) and a lubricant (e. g., magnesium stearate), and may additionally comprise one or more additives selected from a binder, a buffer, a protease tor, a surfactant, a solubilizing agent, a plasticizer, an emulsifier, a izing agent, a viscosity increasing agent, a sweetener, a film forming agent, or any combination thereof. Furthermore, the compositions of the present invention may be in the form of controlled release or immediate release formulations.

For liquid formulations, pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, emulsions or oils. es of non-aqueous solvents are propylene glycol, polyethylene , and injectable c esters such as ethyl oleate. s carriers include water, alcoholic/aqueous solutions, ons or suspensions, including saline and buffered media. Examples of oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, mineral oil, olive oil, sunflower oil, and fish-liver oil. Solutions or suspensions can also PCT/U52012/020092 include the following ents: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide.

In addition, the compositions may further comprise binders (e.g., , cornstarch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, povidone), disintegrating agents (e.g., cornstarch, potato starch, alginic acid, silicon dioxide, croscarmellose sodium, crospovidone, guar gum, sodium starch glycolate, Primogel), buffers (e. g., tris-HCI., acetate, ate) of various pH and ionic strength, additives such as albumin or gelatin to prevent tion to surfaces, detergents (e.g., Tween 20, Tween 80, Pluronic F68, bile acid salts), protease inhibitors, surfactants (e.g., sodium lauryl sulfate), permeation enhancers, solubilizing agents (e. g., glycerol, hylene glycerol), a glidant (e.g., colloidal silicon dioxide), anti-oxidants (e. g., ascorbic acid, sodium metabisulfite, butylated hydroxyanisole), stabilizers (e.g., hydroxypropyl cellulose, hydroxypropylmethyl cellulose), viscosity sing agents (e. g., carbomer, colloidal silicon e, ethyl cellulose, guar gum), sweeteners (e. g., e, aspartame, citric acid), flavoring agents (e.g., peppermint, methyl salicylate, or orange flavoring), preservatives (e. g., Thimerosal, benzyl l, parabens), lubricants (e.g., stearic acid, magnesium stearate, polyethylene glycol, sodium lauryl sulfate), ds (e.g., dal silicon dioxide), plasticizers (e.g., diethyl phthalate, yl citrate), emulsifiers (e.g., carbomer, hydroxypropyl cellulose, sodium lauryl sulfate), polymer coatings (e. g., poloxamers or poloxamines), coating and film forming agents (e.g., ethyl cellulose, acrylates, polymethacrylates) and/or nts.

In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and ncapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ne vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. s for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained cially from Alza ation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to PCT/U52012/020092 viral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in US. PatentNo. 4,522,811.

It is especially advantageous to formulate oral itions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be d; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active nd and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with ctions for administration.

Daily administration may be repeated continuously for a period of several days to several years. Oral treatment may continue for between one week and the life of the patient. Preferably the administration may take place for five consecutive days after which time the t can be evaluated to determine if further administration is required.

The administration can be continuous or intermittent, e.g., treatment for a number of consecutive days followed by a rest period. The compounds of the present invention may be administered intravenously on the first day of treatment, with oral administration on the second day and all consecutive days thereafter.

The preparation of pharmaceutical compositions that n an active ent is well understood in the art, for example, by mixing, granulating, or tablet—forming processes. The active therapeutic ient is often mixed with excipients that are pharmaceutically acceptable and compatible with the active ingredient. For oral administration, the active agents are mixed with additives ary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin es, aqueous, alcoholic or oily solutions and the like as ed above.

The amount of the compound administered to the patient is less than an amount that would cause toxicity in the patient. In certain embodiments, the amount of the compound that is stered to the patient is less than the amount that causes a concentration of the compound in the patient's plasma to equal or exceed the toxic level of PCT/U52012/020092 the compound. Preferably, the concentration of the compound in the patient's plasma is maintained at about 10 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 25 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 50 nM. In one embodiment, the concentration of the compound in the patient's plasma is maintained at about 100 nM.

In one embodiment, the concentration of the compound in the t's plasma is maintained at about 500 nM. In one embodiment, the tration of the nd in the patient's plasma is maintained at about 1000 nM. In one embodiment, the concentration of the nd in the patient's plasma is maintained at about 2500 nM. In one embodiment, the concentration of the compound in the patient's plasma is ined at about 5000 nM. The l amount ofthe compound that should be administered to the t in the practice of the present invention will depend on the particular compound used and the type of cancer being treated.

DEFINITIONS Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

An “aliphatic group” or atic” is non-aromatic moiety that may be saturated (e.g. single bond) or contain one or more units of unsaturation, e.g., double and/or triple bonds. An aliphatic group may be straight chained, branched or cyclic, contain carbon, hydrogen or, optionally, one or more heteroatoms and may be substituted or unsubstituted.

An aliphatic group, when used as a linker, preferably contains between about I and about 24 atoms, more preferably between about 4 to about 24 atoms, more preferably between about 4-12 atoms, more typically between about 4 and about 8 atoms. An aliphatic group, when used as a substituent, preferably contains between about 1 and about 24 atoms, more preferably n about I to about 10 atoms, more preferably n about 1—8 atoms, more typically between about I and about 6 atoms. In addition to aliphatic hydrocarbon groups, aliphatic groups include, for example, polyalkoxyalkyls, such as kylene glycols, polyamines, and polyimines, for example. Such aliphatic groups may be further substituted. It is understood that aliphatic groups may include alkyl, tuted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl groups described herein.

PCT/U52012/020092 The term "substituted carbonyl" includes compounds and moieties which n a carbon connected with a double bond to an oxygen atom, and tautomeric forms f.

Examples ofmoieties that contain a substituted carbonyl e des, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "carbonyl moiety" refers to groups such as carbonyl" groups wherein an alkyl group is covalently bound to a carbonyl group, "alkenylcarbonyl" groups wherein an alkenyl group is covalently bound to a carbonyl group, "alkynylcarbonyl" groups wherein an l group is covalently bound to a carbonyl group, "arylcarbonyl" groups wherein an aryl group is covalently attached to the carbonyl group. Furthermore, the term also refers to groups wherein one or more heteroatoms are covalently bonded to the carbonyl moiety. For example, the term includes moieties such as, for example, aminocarbonyl moieties, (wherein a nitrogen atom is bound to the carbon of the carbonyl group, e.g., an amide).

The term "acyl" refers to hydrogen, alkyl, partially saturated or fully ted cycloalkyl, partially saturated or fully saturated heterocycle, aryl, and heteroaryl substituted carbonyl groups. For example, acyl includes groups such as (C1-C6)alkanoyl (e.g., formyl, acetyl, propionyl, butyryl, valeryl, caproyl, t-butylacetyl, etc.), (C3- C6)cycloalkylcarbonyl (e.g., ropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc.), heterocyclic carbonyl (e.g., pyrrolidinylcarbonyl, pyrrolid—2—onecarbonyl, piperidinylcarbonyl, piperazinylcarbonyl, tetrahydrofuranylcarbonyl, etc.), aroyl (e.g., benzoyl) and heteroaroyl (e.g., thiophenyl-2— yl, thiophenyl—3-carbonyl, furanyl-Z-carbonyl, furanylcarbonyl, lH—pyrroyl carbonyl, lH—pyrroyl—3—carbonyl, benzo[b]thiophenyl—2—carbonyl, etc.). In addition, the alkyl, cycloalkyl, heterocycle, aryl and heteroaryl n of the acyl group may be any one ofthe groups described in the tive definitions. When indicated as being "optionally substituted", the acyl group may be unsubstituted or optionally substituted with one or more substituents (typically, one to three substituents) independently selected from the group of substituents listed below in the definition for "substituted" or the alkyl, cycloalkyl, heterocycle, aryl and aryl portion of the acyl group may be tuted as described above in the preferred and more preferred list of substituents, respectively.

The term "alkyl" embraces linear or branched ls having one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkyl ls are "lower alkyl" radicals having one to about ten carbon atoms. Most preferred are lower alkyl radicals having one to about eight carbon atoms. Examples of such radicals PCT/U52012/020092 include methyl, ethyl, yl, isopropyl, n-butyl, isobutyl, tyl, tert-butyl, pentyl, iso-amyl, hexyl and the like.

The term "alkenyl" embraces linear or branched ls having at least one carbon-carbon double bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkenyl radicals are "lower alkenyl" radicals having two to about ten carbon atoms and more preferably about two to about eight carbon atoms. Examples of alkenyl radicals include ethenyl, allyl, propenyl, butenyl and 4- methylbutenyl. The terms "alkenyl", and "lower alkenyl", embrace radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations.

The term ”alkynyl" embraces linear or branched radicals having at least one carbon-carbon triple bond of two to about twenty carbon atoms or, preferably, two to about twelve carbon atoms. More preferred alkynyl radicals are "lower alkynyl" radicals having two to about ten carbon atoms and more preferably about two to about eight carbon atoms. Examples of alkynyl radicals e propargyl, ynyl, 2-propynyl, l-butyne, 2-butynyl and l-pentynyl.

The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. The term "cycloalkyl" embraces saturated carbocyclic radicals having three to about twelve carbon atoms. More preferred lkyl radicals are "lower cycloalkyl" radicals having three to about eight carbon atoms. Examples of such radicals include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term alkenyl" embraces partially unsaturated carbocyclic radicals having three to twelve carbon atoms. lkenyl radicals that are partially unsaturated carbocyclic radicals that n two double bonds (that may or may not be conjugated) can be called "cycloalkyldienyl". More preferred cycloalkenyl radicals are "lower cycloalkenyl" radicals having four to about eight carbon atoms. Examples of such radicals include cyclobutenyl, cyclopentenyl and cyclohexenyl.

The term "alkoxy" embraces linear or branched oxy-containing radicals each having alkyl portions of one to about twenty carbon atoms or, ably, one to about twelve carbon atoms. More preferred alkoxy radicals are "lower " radicals having one to about ten carbon atoms and more preferably having one to about eight carbon atoms. Examples of such radicals include methoxy, ethoxy, y, butoxy and tert— butoxy.

WO 94328 PCT/U52012/020092 The term "alkoxyalkyl" embraces alkyl radicals having one or more alkoxy radicals attached to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals.

The term , alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces ic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane and biphenyl.

The terms “heterocyclyl”, “heterocycle” “heterocyclic” or “heterocyclo” embrace saturated, partially unsaturated and unsaturated heteroatom—containing ring—shaped radicals, which can also be called "heterocyclyl", "heterocycloalkenyl" and "heteroaryl" correspondingly, where the atoms may be selected from nitrogen, sulfur and oxygen. es of saturated heterocyclyl radicals include saturated 3 to 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms (e. g. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.) ; saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and l to 3 nitrogen atoms (e. g. morpholinyl, etc.); saturated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms (e. g., thiazolidinyl, etc.). Examples of partially unsaturated heterocyclyl radicals include dihydrothiophene, dihydropyran, dihydrofuran and dihydrothiazole.

Heterocyclyl radicals may include a pentavalent nitrogen, such as in olium and nium radicals. The term "heterocycle" also embraces radicals where heterocyclyl radicals are fused with aryl or cycloalkyl radicals. Examples of such fused bicyclic radicals include benzofuran, hiophene, and the like.

The term "heteroaryl" embraces unsaturated heterocyclyl radicals. Examples of heteroaryl radicals include unsaturated 3 to 6 membered heteromonocyclic group containing 1 to 4 nitrogen atoms, for example, pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dyl, pyrazinyl, pyridazinyl, lyl (e. g., 4H-1,2,4-triazolyl, 1H-1,2,3- triazolyl, 2H-l,2,3-triazolyl, etc.) tetrazolyl (e.g. lH—tetrazolyl, 2H-tetrazolyl, etc.), etc.; unsaturated condensed heterocyclyl group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (e.g., olo[l ,5-b]pyridazinyl, etc.), etc.; rated 3 to 6-membered heteromonocyclic group containing an oxygen atom, for example, l, furyl, etc.; unsaturated 3 to 6-membered heteromonocyclic group containing a sulfur atom, for e, l, etc.; unsaturated 3- to 6—membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for PCT/U52012/020092 example, oxazolyl, isoxazolyl, oxadiazolyl (e.g., 1,2,4-oxadiazolyl, 1,3,4—oxadiazolyl, 1,2,5-oxadiazolyl, etc.) etc. ; unsaturated condensed heterocyclyl group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms (e.g. benzoxazolyl, benzoxadiazolyl, etc.); rated 3 to 6-membered heteromonocyclic group containing 1 to 2 sulfur atoms and l to 3 en atoms, for example, thiazolyl, thiadiazolyl (e. g., 1,2,4- thiadiazolyl, 1,3,4- thiadiazolyl, 1,2,5-thiadiazolyl, etc.) etc.; unsaturated condensed heterocyclyl group ning 1 to 2 sulfur atoms and l to 3 nitrogen atoms (e. g., benzothiazolyl, benzothiadiazolyl, etc.) and the like.

The term "heterocycloalkyl" embraces heterocyclo-substituted alkyl radicals. More preferred heterocycloalkyl radicals are "lower heterocycloalkyl" radicals having one to six carbon atoms in the cyclo radicals.

The term "alkylthio" embraces radicals containing a linear or branched alkyl l, of one to about ten carbon atoms ed to a divalent sulfur atom. red alkylthio radicals have alkyl radicals of one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylthio radicals have alkyl radicals are "lower alkylthio" radicals having one to about ten carbon atoms. Most preferred are alkylthio radicals having lower alkyl radicals of one to about eight carbon atoms.

Examples of such lower alkylthio radicals are methylthio, ethylthio, propylthio, butylthio and hexylthio.

The terms "aralkyl" or “arylalkyl” embrace ubstituted alkyl radicals such as benzyl, diphenylmethyl, nylmethyl, phenylethyl, and diphenylethyl.

The term "aryloxy" embraces aryl ls attached h an oxygen atom to other radicals.

The terms "aralkoxy" or “arylalkoxy” embrace aralkyl radicals attached through an oxygen atom to other radicals.

The term "aminoalkyl" embraces alkyl radicals substituted with amino radicals.

Preferred aminoalkyl radicals have alkyl radicals having about one to about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred aminoalkyl radicals are "lower aminoalkyl" that have alkyl radicals having one to about ten carbon atoms. Most preferred are lkyl radicals having lower alkyl radicals having one to eight carbon atoms. Examples of such radicals include aminomethyl, aminoethyl, and the like.

The term "alkylamino" denotes amino groups which are substituted with one or two alkyl radicals. red alkylamino radicals have alkyl radicals having about one to PCT/U52012/020092 about twenty carbon atoms or, preferably, one to about twelve carbon atoms. More preferred alkylamino radicals are "lower alkylamino" that have alkyl radicals having one to about ten carbon atoms. Most preferred are alkylamino radicals having lower alkyl ls having one to about eight carbon atoms. Suitable lower alkylamino may be monosubstituted N-alkylamino or disubstituted N,N—alky1amino, such as N-methylamino, N—ethylamino, N,N—dimethylamino, N,N-diethylamino or the like.

The term "linker" means an organic moiety that connects two parts of a compound.

Linkers typically comprise a direct bond or an atom such as oxygen or sulfur, a unit such as NR2, C(O), C(O)NH, SO, 80;, SOZNH or a chain of atoms, such as substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, arylalkyl, kenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, cyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, lkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkyl, alkenylarylalkenyl, larylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, alkylheteroarylalkyl, alkylheteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylhererocyclylalkynyl, lheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, eteroaryl, lheteroaryl, lhereroaryl, which one or more methylenes can be interrupted or terminated by O, S, S(O), S02, N(R2), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic; where R2 is hydrogen, acyl, aliphatic or tuted aliphatic. In one embodiment, the linker B is between 1-24 atoms in length, preferably 4-24 atoms in length, preferably 4-18 atoms in length, more preferably 4-12 atoms in length, and most preferably about 4—10 atoms in length. In some embodiments, the linker is a C(O)NH(alkyl) chain or an alkoxy chain. It is to be understood that an asymmetric linker, such as alkylaryl, can connect two urally distinct moieties in either of its two possible orientations.

The term "substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified tuent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, PCT/U52012/020092 arylthioalkyl, alkylsulfonyl, ulfonylalkyl, lfonylalkyl, alkoxy, aryloxy, aralkoxy, arbonyl, alkylaminocarbonyl, arylaminocarbonyl, carbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphonic acid, aryl, heteroaryl, heterocyclic, and aliphatic. It is understood that the substituent may be further substituted.

For city, chemical moieties are defined and referred to throughout can be univalent chemical es (e. g., alkyl, aryl, etc.) or multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For e, an "alkyl" moiety can be referred to a monovalent radical (e.g. CH3-CH2-), or in other instances, a bivalent linking moiety can be "alkyl," in which case those skilled in the art will understand the alkyl to be a divalent l (e.g., -CH2-CH2-), which is equivalent to the term "alkylene." Similarly, in circumstances in which divalent moieties are required and are stated as being “alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, "aryl", “heteroaryl”, “heterocyclic”, “alkyl” “alkenyl”, “alkynyl”, “aliphatic”, or “cycloalkyl”, those skilled in the art will tand that the terms alkoxy”, “alkylamino”, “aryloxy”, “alkylthio”, "aryl", “heteroaryl”, “heterocyclic”, “alkyl”, “alkenyl”, “alkynyl”, “aliphatic”, or “cycloalkyl” refer to the ponding divalent moiety.

The terms "halogen" or “halo” as used herein, refers to an atom selected from fluorine, chlorine, e and iodine.

As used herein, the term “aberrant proliferation” refers to abnormal cell growth.

The phrase "adjunctive therapy" encompasses treatment of a subject with agents that reduce or avoid side effects associated with the combination therapy of the present invention, including, but not limited to, those agents, for e, that reduce the toxic effect of anticancer drugs, e.g., bone resorption inhibitors, cardioprotective agents; prevent or reduce the incidence ofnausea and vomiting associated with chemotherapy, herapy or operation; or reduce the incidence of infection associated with the administration of myelosuppressive anticancer drugs.

The term “angiogenesis,” as used herein, refers to the formation of blood vessels.

Specifically, angiogenesis is a multi-step s in which endothelial cells focally degrade and invade through their own basement membrane, migrate through interstitial stroma toward an angiogenic stimulus, proliferate al to the migrating tip, organize into blood vessels, and reattach to newly synthesized basement membrane (see Folkman et al., Adv. Cancer Res., Vol. 43, pp. 175—203 (1985)). Anti—angiogenic agents interfere with this process. Examples of agents that interfere with several of these steps include thrombospondin-l , angiostatin, endostatin, interferon alpha and compounds such as matrix oproteinase (MMP) inhibitors that block the actions of enzymes that clear and create paths for newly forming blood vessels to follow; nds, such as .alpha.v.beta.3 tors, that interfere with molecules that blood vessel cells use to bridge between a parent blood vessel and a tumor; agents, such as specific COX-2 inhibitors, that prevent the growth of cells that form new blood vessels; and protein-based compounds that simultaneously interfere with several of these targets.

The term “apoptosis” as used herein refers to programmed cell death as signaled by the nuclei in normally oning human and animal cells when age or state of cell health and condition dictates. An osis inducing agen ” triggers the process of programmed cell death.

The term r” as used herein denotes a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these cells to invade other tissues, either by direct grth into adjacent tissue through on or by implantation into distant sites by metastasis.

The term “compound” is defined herein to include pharmaceutically acceptable salts, solvates, hydrates, polymorphs, enantiomers, reoisomers, racemates and the like of the compounds having a a as set forth herein.

The term "device" refers to any appliance, usually mechanical or electrical, designed to perform a particular function.

As used herein, the term “dysplasia” refers to abnormal cell , and typically refers to the earliest form of pre-cancerous lesion recognizable in a biopsy by a pathologist.

As used herein, the term “effective amount of the subject compounds,” with respect to the subject method of treatment, refers to an amount of the subject compound which, when delivered as part of d dose n, brings about, e.g. a change in the rate of cell eration and/or state of differentiation and/or rate of survival of a cell to ally acceptable standards. This amount may further relieve to some extent one or more of the symptoms of a neoplasia disorder, including, but is not limited to: 1) reduction in the number of cancer cells; 2) reduction in tumor size; 3) inhibition (i.e., slowing to some extent, preferably stopping) of cancer cell infiltration into peripheral organs; 4) inhibition (i.e., slowing to some extent, preferably stopping) of tumor metastasis; 5) PCT/U52012/020092 inhibition, to some extent, of tumor growth; 6) relieving or reducing to some extent one or more of the symptoms associated with the disorder; and/or 7) relieving or reducing the side s associated with the administration of anticancer agents.

The term “hyperplasia,” as used herein, refers to excessive cell division or growth.

The phrase an "immunotherapeutic agen " refers to agents used to er the immunity of an immune donor, e.g., another person or an animal, to a host by inoculation.

The term embraces the use of serum or gamma globulin containing performed antibodies produced by another individual or an animal; nonspecific systemic ation; adjuvants; active specific immunotherapy; and adoptive immunotherapy. Adoptive immunotherapy refers to the ent of a disease by therapy or agents that include host inoculation of sensitized lymphocytes, transfer factor, immune RNA, or antibodies in serum or gamma globulin.

The term "inhibition," in the context of neoplasia, tumor growth or tumor cell growth, may be assessed by delayed appearance ofprimary or secondary tumors, slowed pment of primary or secondary tumors, decreased occurrence of primary or secondary tumors, slowed or decreased ty of ary effects of disease, arrested tumor growth and regression of tumors, among others. In the extreme, complete inhibition, is referred to herein as tion or revention.

The term “metastasis,” as used herein, refers to the migration of cancer cells from the original tumor site through the blood and lymph vessels to produce cancers in other tissues. Metastasis also is the term used for a ary cancer growing at a distant site.

The term “neoplasm,” as used herein, refers to an abnormal mass of tissue that s from ive cell division. Neoplasms may be benign (not cancerous), or malignant (cancerous) and may also be called a tumor. The term “neoplasia” is the pathological process that results in tumor formation.

As used , the term “pre-cancerous” refers to a condition that is not malignant, but is likely to become malignant if left untreated.

The term “proliferation” refers to cells undergoing mitosis.

The phrase "hedgehog related disease or disorder" refers to a disease or disorder characterized by inappropriate hedgehog signaling activity. Such inappropriate hedgehog signaling activity can occur when Patched fails to, or inadequately, represses Smoothened (Ptc loss of on phenotype) and/or when ened is active regardless of Patched repression (Smo gain—of function phenotype).

PCT/U52012/020092 The phrase a "radio therapeutic agen " refers to the use of electromagnetic or particulate radiation in the ent of neoplasia.

The term “recurrence” as used herein refers to the return of cancer after a period of remission. This may be due to incomplete l of cells from the initial cancer and may occur locally (the same site of initial ), regionally (in vicinity of initial cancer, possibly in the lymph nodes or tissue), and/or distally as a result of metastasis.

The term ment" refers to any process, action, application, therapy, or the like, wherein a mammal, including a human being, is subject to l aid with the object of ing the mammal's condition, directly or indirectly.

The term "vaccine” includes agents that induce the patient's immune system to mount an immune response against the tumor by attacking cells that express tumor associated antigens (Teas).

As used herein, the term aceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic se and the like, and are commensurate with a reasonable /risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically able salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid or inorganic acid. Examples of pharmaceutically acceptable nontoxic acid addition salts include, but are not limited to, salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, ic acid, citric acid, succinic acid lactobionic acid or malonic acid or by using other s used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not d to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, sulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, e, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, nate, stearate, succinate, sulfate, tartrate, thiocyanate, p- toluenesulfonate, undecanoate, te salts, and the like. Representative alkali or ne earth metal salts include , lithium, potassium, m, ium, and the like. Further pharmaceutically able salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.

As used herein, the term "pharmaceutically acceptable ester" refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for e, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, es, propionates, butyrates, acrylates and uccinates.

The term “pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, tion, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the present invention.

"Prodrug", as used herein, means a compound which is convertible in vivo by lic means (e.g. by hydrolysis) to a compound of the invention. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed), Design of Prodrugs, er (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard—Larsen, et al., (ed). "Design and Application of gs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991); Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-3 8(1992); Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. ; Higuchi and Stella (eds.) gs as Novel Drug Delivery Systems, American Chemical Society (1975); and Bernard Testa & m Mayer, “Hydrolysis In Drug And Prodrug Metabolism: Chemistry, Biochemistry And Enzymology,” John Wiley and Sons, Ltd. (2002).

As used herein, "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical WO 94328 PCT/U52012/020092 administration, such as sterile pyrogen—free water. Suitable rs are described in the most recent edition of ton's Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by nce. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, finger's solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.

Supplementary active compounds can also be incorporated into the compositions.

As used herein, the term “pre-cancerous” refers to a condition that is not malignant, but is likely to become malignant if left untreated.

The term “subject” as used herein refers to an animal. Preferably the animal is a mammal. More preferably the mammal is a human. A subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.

The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase ical penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

The sized compounds can be separated from a reaction mixture and further purified by a method such as column tography, high pressure liquid tography, or recrystallization. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the ae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds. Synthetic try transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as bed in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Sflthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and 's Reagents for Organic Synthesis, John Wiley and Sons ; and L. Paquette, ed., Encyclopedia of ts for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. 2012/020092 The compounds described herein can contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)— or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be ed from their respective lly active precursors by the procedures described above, or by resolving the racemic es. The resolution can be carried out in the presence of a resolving agent, by chromatography or by ed crystallization or by some combination of these techniques which are known to those skilled in the art. Further details regarding resolutions can be found in Jacques, et al., Enantiomers Racemates and Resolutions (John Wiley & Sons, 1981). When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless ed otherwise, it is intended that the compounds include both E and Z geometric isomers and/or cis- and trans- s. Likewise, all tautomeric forms are also intended to be included. The ration of any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a -carbon double bond or carbon—heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.

Pharmaceutical Compositions The pharmaceutical compositions of the present invention se a therapeutically effective amount of a compound of the present invention formulated together with one or more ceutically acceptable carriers or excipients.

As used herein, the term "pharmaceutically acceptable carrier or excipient" means a non-toxic, inert solid, semi-solid or liquid filler, diluent, ulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; cyclodextrins such as alpha- (0t), beta- ([3) and gamma- (y) extrins; starches such as corn starch and potato ; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic PCT/U52012/020092 saline; Ringer's solution; ethyl alcohol, and ate buffer solutions, as well as other non—toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, g agents, sweetening, flavoring and ing , preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or Via an implanted reservoir, preferably by oral administration or administration by injection. The pharmaceutical compositions of this invention may n any conventional non—toxic pharmaceutically-acceptable carriers, adjuvants or vehicles. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its ry form. The term parenteral as used herein es aneous, intracutaneous, enous, intramuscular, intraarticular, intraarterial, intrasynovial, intracistemal, intrathecal, intralesional and intracranial injection or infusion techniques.

Liquid dosage forms for oral administration include pharmaceutically able emulsions, microemulsions, solutions, suspensions, syrups and s. In on to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl ate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Inj ectable preparations, for example, sterile inj ectable aqueous or oleaginous suspensions, may be formulated ing to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile inj ectable on, suspension or emulsion in a nontoxic erally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable es and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or ding medium. For this purpose any bland fixed oil can be PCT/U52012/020092 employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of inj ectables.

The inj ectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating izing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile inj ectable medium prior to use.

In order to prolong the effect of a drug, it is often ble to slow the absorption ofthe drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous al with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide— polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be lled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot inj ectable formulations are also prepared by entrapping the drug in liposomes or mulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, hylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and e the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable ent or carrier such as sodium e or dicalcium phosphate and/or: a) fillers or ers such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) egrating agents such as agar-agar, calcium carbonate, potato or a starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) tion accelerators such as quaternary ammonium compounds, g) g agents such as, for example, cetyl alcohol and glycerol monostearate, h) PCT/U52012/020092 absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and es thereof. In the case of capsules, tablets and pills, the dosage form may also se buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard—filled gelatin capsules using such excipients as lactose or milk sugar as well as high lar weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, es, pills, and granules can be prepared with coatings and shells such as enteric coatings and other gs well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or entially, in a certain part of the intestinal tract, optionally, in a delayed manner.

Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include nts, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or s. The active component is admixed under e conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic ation, ear drops, eye ointments, powders and ons are also contemplated as being within the scope of this invention.

The ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, hylene glycols, silicones, ites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures ofthese substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. ermal patches have the added advantage ofproviding controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or sing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

For pulmonary delivery, a eutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., tion into the respiratory system. Solid or liquid particulate forms of the active nd prepared for cing the present invention include les of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. Delivery of aerosolized therapeutics, particularly aerosolized antibiotics, is known in the art (see, for example US.

Pat. No. 5,767,068 to VanDevanter et al., US. Pat. No. 5,508,269 to Smith et al., and WO 98/43650 by Montgomery, all of which are incorporated herein by reference). A discussion of pulmonary delivery of antibiotics is also found in US. Pat. No. 6,014,969, incorporated herein by reference.

By a "therapeutically effective amount" of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the d subject, at a reasonable benefit/risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., able by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect). An effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present ion Will be decided by the attending physician within the scope of sound medical judgment. The c eutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the c compound employed; the c composition employed; the age, body weight, l health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.

The total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In general, ent regimens according to the t invention comprise 2012/020092 administration to a patient in need of such treatment from about 10 mg to about 1000 mg ofthe compound(s) of this invention per day in single or multiple doses.

The compounds of the formulae described herein can, for e, be administered by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, y, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body , alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug. The methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated . Typically, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous on. Such administration can be used as a chronic or acute therapy. The amount of active ingredient that may be combined with pharmaceutically excipients or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active nd (w/w).

Alternatively, such preparations may contain from about 20% to about 80% active compound.

Lower or higher doses than those recited above may be required. Specific dosage and ent regimens for any particular patient will depend upon a variety of factors, including the activity of the specific nd employed, the age, body weight, general health status, sex, diet, time of administration, rate of ion, drug combination, the severity and course of the disease, condition or symptoms, the patient’s disposition to the disease, condition or symptoms, and the judgment of the treating physician.

Upon improvement of a patient’s condition, a maintenance dose of a nd, composition or combination of this invention may be administered, if necessary.

Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

Synthetic Methods The compounds and ses of the present invention will be better understood in tion with the following synthetic s and examples that illustrate the methods PCT/U52012/020092 by which the compounds of the invention may be prepared, which are intended as an ration only and not limiting of the scope of the invention.

General methods for the sis of key intermediates :5 -fiat CI 0 0 C\©_’ Fe/NH4CI PdCl2(dppf) O\ B N H2 I NH2 0 N02 trifluorometham.L sulfonic acid ClI; \ NaNOZ. KI H2N NO2 12 03,,(o \n/QE'K NH2 0 Cl Cl E: o RUNH2 N02 N02 SnCl2/EtOH R NH N02 0 2—1 2-3 Scheme 1 o W / 8\ ’OTWT‘N figfll / T f.“ 5 «*3 0 N o Y Br(orCl) OS’/\‘O 0 Cl 1002 NH OH/MeOH2 H HO’ TW / N fi\ l H 0 O \ 0 c1 WO 94328 PCT/U52012/020092 /\ JLHAE" N Br ' N\ B' O UN\ HBF4,NaNOZ n O U —> I —> / AOWO / HQN H0 2001 2002 2003 0 Cl o.Ban 7X5 NHKGX/ CI 0 Cl o" “o 179 N NHZOH O \ n —> AOWO I / / n O O 2004 0 CI O N I H Ho\ 16% / N S/ O I/ \\ H n O 0 Scheme 3 0 CI 0 CI 0 CI HZN o\/ Fe 1.NaN02 wfior RO _>R0 —> R0 2. 802, CuCI S,CI N02 NH2 O’/ \\O 3001 3002 3003 0 CI |N\ Cl NH2 0 CI RO / o H 1-8 N g’NWOV \ a N H o H n / II N O u x \/ O 0 E \W O O 3005 3004 0 CI NHZOH N —’ N | H / H n fit W ‘OH O O PCT/U52012/020092 Scheme 4 K o O Urea/HCI Na/EtOH EtOH V Vfir Vo 0 O/\ —> ' —> \/o o\/ O HCOOEt O iml 4001 4003 4002 /\ Boc Br2/H0Ac O POCI3 OO/\ ’ OAN I CJNL': H HN01; 4004 4005 4006 0 Cl HOXQ9850! C] 0 CI le NH2 0 O / 3003 18 HO ' —> 0 _Nl—W o \__/N—<\ NN:=>—_<o—/ 4007 / / \ _ O HN Cl HN Cl NHZOH 3”0\ x3]:/ N/fi N N Y ‘ 1‘2\ N n 4008 O\/ ‘OH O O PCT/U52012/020092 Scheme 5 CI ”0&0 0 CI 0* 0 R N NaOH/HZO \ N\ N O — N H 5001 0 Br’H‘n’lLON o \ n —> N\ N O R NH OH R /\ o o 5002 5003 NHZOH N NH OWNHn .OH Scheme6 CI CI Cl Br NBS Br Br MeNHBoc n-BuLi —> Ill —> CCI4 Br \Boc 0‘)_N/—\O H \_/ 6001 6002 6003 1.THF 0/ / | RuCI NalO O 3. 4 I N N\ N\ ° T Boc 2 - A N / o\/ 6004 cIJ‘N’ 6005 4005 0 CI HO 1.SOC|2 I N —> \ N N n | T ‘ N 2. c. / N\ N / 0v N T | ”“2 N / 0\/ 6006 o / 1’5 6007 0 0 CI NH20H N\ N H | / N TN\ H N / N 2012/020092 Scheme 7 0 Cl 0 Cl 0 CI |N\ NHZ B00 0 /’ NH3 2 R0 RO R0 18 —> —> —> S,Cl ,NH2 S’N‘Boc ’l\‘ O O O,’S\\O 01/ \\O 7002 3003 7001 W ‘\ o’~\ Cl Cl 0 Cl 0 Cl CIAN/ N\ 4005 N —> \ N | H o H H / / Cu) 'Sl/N\ NH / 2 7003 7004 CI CI 0 CI 0 Cl N NHZOH ‘\ Nghee“ N\ N N / 9 H N / / SIT\ S T \ / N\/ / C C 7005 WO 94328 PCT/U52012/020092 Scheme 8 W:S.CI OH o" “o Ho/V 3003 —> —> OZN CHO 02N 8001 8003 0 CI LiOH RO 1»8 048:0 O 8004 0 CI N\ N H I2 Z]: ‘0 /’ S/N \ o” “o 8006 $3 0 Cl /O-I? 0/ /O N NH20H 0 CI fl H 1” 4’“! l/S\\ o o 2012/020092 Scheme 9 *6 mam LiOH THF/HZO O¢s$0 S O¢ %O 3003 9001 0 CI HO s’N\/©HNBoc 1-8/Irij\/©\JBOC—A> o"o/\ O¢S<0 9002 9003 CI i/jlfl CI CI N” O/’\\ \/2 4005 N\\ N N \ZI I 12 H 4” 43; o o 9004 9005 0 CI NHZOH N A ———————————————;» \~ N N N I H // S/H60 ’/\\ (3 (D Scheme 10 WN’\\’O 0 Cl 0 O\’/ |N\ NH2 H0 0 O/\ HO 1 -8 H ————————————————a- 0? § 3003 666*6w 0 o/\ NHZOH ———————————————u- 008$0 1002 0 CI C N\ ,OH fl N H H / s/ \/\O C C WO 94328 PCT/U52012/020092 Scheme 11 O O H DMF Jones Br|\N _,H 2_3 |\N _>HO |\N / n-BuLi / / Br Br Br 1101 1102 1103 CI CI \ NBoc \ N O —> N O H H H“ HN / \ N / \N Br HN 1104 1105 CI bNBoc N o 1) CF3COOH NH20H / \ 2) o N \ O/\ HN JL / (:1 N 4005 1106 R(IN N o / \ 2012/020092 Scheme 12 0 O \ O \ O 0 o \o MBAbH Pan NaNs PPh3 I ——————i> —————a> ---*> —> o OH Br I ——o -—o -O 1202 1203 1204 1201 \3 o O m’kN/W/fTJkO/ HO HO 1)NaOH 4005 —————;- mHCI NHZ NH2 —0 —o —O 1207 1205 1206 Cl C| R(:0N R N N NH 0 2 H 2-3 HN N_. o 1208 -—o N 0— R\[:::[:N\N O HN__<N__ "O \::>——(o/ N HN-OH 2012/020092 Scheme 13 CH3NH2/MeOH (Boc)20 DMAP NaOH,H20 TEADCM 1°C MBOH 1203 1301 1302 0/ Cl 0/ R N\ 3°61 TFA N\ —> DIPEAHATUDMA H 1304 1303 Cl 0/ n TEA DCM 1305 1306 CI 0/ NHZOH R N \ _. N\ N \6 NHOH H N / SYNTHESIS OF INTERMEDIATES 1) Preparation of 1-chloroiodonitrobenzene (compound 1-3) 2-Chloro—5-nitroaniline (40 g, 232.0 mmol) was added to a solution of concentrated sulfuric acid (32 mL) in water (320 mL) with mechanical stir. The solution was cooled to - °C and a on of sodium nitrite (18.2 g, 0.26 mol) in water (69 mL) was added slowly. The mixture was stirred for 0.5 h in ice bath and then a solution of potassium iodide (69.3 g, 0.41 mol) in water (277 mL) was added dropwise while keeping the internal temperature below 5°C. The solution was stirred for 3 h at 0°C followed by extraction with ethyl acetate. The combined orangnic layers were washed with saturated NaZSZOg, dried over Na2SO4 and trated. The residue was recrystallized from iPrOH/hexanes (300 mL/100 mL) to afford nd 1-3 as a light tan crystalline solid (38 g, 58% yield). 1H NMR (400 MHz,CDC13): 5 7.61 (d, J=8.8 Hz, 1H), 8.16 (dd, J=8.8 Hz, 2.4 Hz, 1H), 8.70 (d, J=2.8 Hz, 1H).

PCT/U52012/020092 2) Preparation of 4-chloroiodoaniline (compound 1-4) A mixture of compound 1-3 (37 g, 0.13 mol), iron powder (29.3 g, 0.52 mol), and NH4C1 (7g, 0.13 mol) in EtOH/HZO (200 mL/ 100 mL) was stirred at 75°C for 3 h. The reaction mixture was filtered and concentrated to remove most of EtOH. The remaining mixture was extracted with ethyl acetate, washed with water and brine, dried over Na2S04.

The titled compound 1-4 was obtained as a yellow solid (32 g, 97% yield) after cocentration. LCMS: m/z 254.0 . 1H NMR (400 MHz, CDC13)I 8 3.65 (br, 2H), 6.58 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.15-7.17 (m, 2H). 3) Preparation of 4-chloro(4,4,5,5,-tetramethyl-1,3,2-dioxaborolanyl)aniline (compound 1-5) A mixture of compound 1-4 (10 g, 39.5 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi (1,3,2-dioxaborolane) (20.0 g, 79.0 mmol), KOAc (11.6 g, 118.5 mmol), and PdC12(dppf) (960 mg, 1 mmol) in oxane (60 mL) was stirred at 105°C for 8 h under N2. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography (hexanes/dichloromethane: 3/1 to 1/ 1) to afford compound 1-5 as a light yellow solid (6.0 g, 60% yield). LCMS: m/z 295.1 +. 1H NMR (400 MHz, CDCl3)I 1.36 (s, 12H), 3.61 (br, 2H), 6.65 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.00 (d, J=2.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H). 4) Preparation of 4-chloro(pyridineyl)aniline (compound 1-8) A e of compound 1-5 (1.50 g, 5.9 mmol), 2—bromopyridine (1.87 g, 11.8 mmol), sodium bicarbonate (1.49 g, 17.8 mmol), PdC12(Ph3P)2 (100 mg, 0.09 mmol) in 1,4- e /water (20 mL/ 10 mL) was heated at 110°C overnight. After cooling to room temperature, the mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography es/ethyl acetate: 3/ 1) to afford compound 1-8 as a yellow solid (1.38 g, ~100%). LCMS: m/z 205.1 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 5.32 (s, 2H), 6.61 (dd, J=8.4 Hz, 2.8 Hz, 1H), 6.77 (d, J=2.8 Hz, 1H), 7.14 (d, J=8.4 Hz, 1H), 7.35— 7.39 (m, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.83-7.87 (m, 1H), 8.63-8.65 (m, 1H).

PCT/U52012/020092 ) Preparation of 2-chloro-N-(4-chloro(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)phenyl)(methylsufonyl)benzamide (compound 1-9) A mixture of compound 1-5 (1 g, 3.9 mmol), 2-chloro-4—(methylsulfonyl)benzoic acid (1.1 g, 4.7 mmol) and N,N-Diisopropylethylamine (1 g, 7.8 mmol) and O-(Benzotriazol— 1-yl)-N,N,N',N'-tetramethyluroniumtetrafluoroborate (2.6 g, 7.8 mmol) in dichloromethane (20 mL) was stirred at room temperature overnight. The reaction e was quenched with water, filtered. The solid was collected and dried in vacuo to afford compound 1-9 as a white solid (1.2 g, 65% yield). LCMS: m/z 470.1 [M+1]+ .OlH NMR: (400 MHz, DMSO'd6): 8 1.32 (s, 12H), 3.35 (s, 3H), 7.43 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8 Hz, 2.8 Hz,lH), 7.89 (d, J=8.0 Hz, 1H), 7.98-8.01 (m, 2H), 8.12 (d, J=1.6 Hz, 1H), 10.82 (s, 1H). 6) Preparation of 2-chloronitro—N-(2-nitrophenyl)benzamide (compound 2-2) To a solution of 2-nitroaniline (5.0 g, 0.036 mol) in CH3CN (50 mL) was added a solution of 2-chloronitrobenzoyl chloride (8.0 g, 0.037 mol) in CH3CN (10 mL) dropwise while keeping the internal temperature below 25°C under N2. When addition was complete the reaction mixture was heated at 75°C for 1 h. The mixture was cooled to 0°C and filtered. The solid was rinsed with cold CH3CN to afford 2-2 as a light yellow solid (5.3 g, 50%). 7) Preparation of 3-(1H-benzo[d]imidazol-Z-yl)chloroaniline (compound 2-3) Compound 2-2 (5.3 g, 0.017 mol) was taken into EtOH (100 mL) and heated to 40°C.When the internal temperature d 40°C, 1St t SnClz/HCl (3 vol tively, divided into 3 ns) was added. The reaction mixture was heated to 60°C and the 2Ild aliquot of SnClz/HCI was added. The on mixture was heated to 80°C and the 3rd aliquot SnClz/HCl was added and continued to reflux 2 h. The reaction mixture was cooled to 0°C and NaOH (1N s solution) was added below 10°C to adjust pH to 12- 13. The mixture was diluted with EA and water. The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography eluted with dichloromethane/ methanol (60:1) to afford compound 2-3 as a yellow solid (2.7 g, 68% yield). LCMS: m/z M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 5.48 (s, 2H), 6.71 (d, J=8.8Hz, 1H), 7.13 (s, 1H), 7.21-7.24 (m, 3H), 7.57 (br, 1H), 7.64 (br, 1H), 12.52 (s , 1H).

PCT/U52012/020092 EXAMPLE 1: Preparation of (E)chloro—N-(4-chlor0(5-(3-(hydroxyamino)—3- oxopropenyl)pyridinyl)phenyl)(methylsulfonyl)benzamide (compound 1) Step la. (E)-Methyl 3-(6-br0mopyridin-3 -yl)acrylate (compound 1001-l) A mixture of 6-bromonicotinaldehyde (500 mg, 2.7 mmol) and methyl (triphenylphosphoranylidene) (1 g, 3.2 mmol) in romethane (10 mL) was stirred at room temperature for 1 h. The e was concentrated in vacuo and filtered. The solid was washed with hexanes to afford crude compound 1001-1 as a white solid (1.5 g).

Step 1b. (E)-Methyl(6-(2-ch10ro(2-chloro(methylsulfonyl)benzamido)phenyl) pyridin-3 -yl)acrylate (1002- 1) A mixture of 1001 (121 mg, 0.5 mmol), 1-9 (200 mg, 0.4 mmol), Pd(PPh3)2C12 (30 mg) in 1,4-di0xane (6 mL) and aq NaHC03 (2 mL) was stirred at 110 °C for 3 h under N2.

After cooling to room temperature, the reaciton mixture was quenched with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium e, evaporated in vacuo. The crude product was purified by column chromatography (methanol /dichloromethane: 1/20) to afford compound 1002 as a pale yellow solid (160 mg, 74% yield). 1H NMR (400 MHz, : 8 3.09 (s, 3H), 3.85 (s, 3H), 6.57 (d, J=16.0 Hz, 1H), 7.44—7.48 (m, 1H), 7.52—7.55 (m, 1H), 7.62-7.67 (m, 1H), 7.73 (d, J=16.0 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.81-7.86 (m, 2H), 7.89 (s, 1H), 7.89-7.95 (m, 2H), 8.03 (d, J=l.2 Hz, 1H), 8.14 (s, 1H), 8.80 (d, J=2.0 Hz, 1H).

Step 1c. (E)Chlor0-N-(4-chlor0-3 -(5-(3-(hydroxyamino)—3-0x0pr0p- l -enyl)pyridin nyl)(methylsulfonyl)benzamide (compound 1) A mixture ofNH20H.HC1 (80g, 1.15 mol) in MeOH (400 mL) was heated at 60-65°C while stirring to form a clear solution. After additional 1 h at reflux, it was cooled to 0 — 10°C. To the reaction mixture a pre-formed solution of KOH (96 g, purity >85%) in MeOH (237 mL) (prepared by adding KOH in portion to methanol at 0 — 10°C) was added dropwise while maintaining internal temperature <10°C. The resulting e was ued to stir at 0 - 10°C for 30 min. The suspension was poured into pressure equalizing addition funnel (1L) pre-packed with anhydrous Na2S04 (700g) and let it sit for 0.5h. The clear filtrate was collected as NHzOH methanolic solution.

A mixture of 1002 (150 mg, 0.3 mmol) in NHZOH methanolic solution (5 mL, 1.79M) was stirred at room ature for 3~4 h. The reaction mixture was adjusted pH to 6-7 with 1.2 M HCl and concentrated. The residue was triturated with water and filtered, dried in vacuo to afford compound 1 as an off white solid (90 mg, 60% yield). M.p:185~187°C.

WO 94328 PCT/U52012/020092 LCMS: m/z 506.1[M+1]+. 1H NMR (400 MHz, DMSO-dg): 5 3.35 (s, 3H), 6.65 (d, J=16.0 Hz, 1H), 7.55-7.61 (m, 2H), 7.74-7.78 (m, 2H), 7.91 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 8.11-8.13 (m, 2H), 8.90 (s, 1H), 10.90 (br, 1H), 10.96 (s, 1H).

EXAMPLE 2: ation of 6-(2-Chloro(2-chloro(methylsulfonyl) benzamido)phenyl)-N-hydroxynicotinamide (compound 5) Step 22. Methyl 6-bromonicotinate (compound 1001-5) To a solution of onicotinic acid (500 mg, 2.5 mmol) in dichloromethane (10 mL) and THF (5 mL) was added oxalyl chloride (1.4 mL, 0.016 mol) followed by addition of one drop ofDMF. The mixture was stirred at room temperature for 1 h. After removal of solvent, the residue was dissolved in anhydrous methanol (5 mL) and continued to stir for 10 min. The on e was quenched with ice water and filtered to afford 1001-5 as a pale yellow solid (212 mg, 40%). LCMS: m/z 213.1 [M+l]+. 1H NMR (400 MHz, CDC13)C 5 3.96 (s, 3H), 7.42 (d, J=8.4 Hz, 1H), 8.25 (dd, J=8.0 Hz, 2.0 Hz, 1H), 9.00 (d, J=2.0 Hz, 1H).

Step 2b. Methyl 6-(2-chloro(2-chloro(methylsulfonyl)benzamido)phenyl) nicotinate (compound 1002-5) A mixture of compound 1001-5 (200 mg, 0.9 mmol), l-9 (367 mg, 0.8 mmol) and Pd(PPh3)4 (21 mg, 0.018 mmol) in saturated NaHC03 (2 mL) and 1,4-dioxane (6 mL) was stirred at 100°C for 3 h. To the reaction mixture was added NaOH (37mg, 0.9 mmol) and stirred for 0.5 h. The reaction mixture was adjusted pH to 6 with l.2M HCl and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over ous sodium sulfate. The methyl ester was hydrolyzed during this reaction condition, and the obtained crude acid product (365 mg) (LCMS: m/z 465.1 ) was used for the next step without further purification. The mixture of the crude acid product (365 mg, 0.8 mmol) in MeOH (15 mL) and H2SO4 (0.25 mL) was stirred at 85°C for 1 h. The reaction mixture was concentrated. The residue was partitioned between water and ethyl acetate. The organic layers were washed with water and brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography (dichloromethane/methanol: 20/1) to afford 1002—5 as a white solid (176 mg, 39% yield via two steps). LCMS: m/z 479.1 [M+1]+. 1H NMR(400 MHz, CDClg): 5 3.07 (s, 3H), 3.99 (s, 3H), 7.52 (d, J=8.8Hz,lH), .86 (m, 4H), 7.88 (dd, J=8.8 Hz, 2.8Hz ,lH), 7.97 (d, J=l.2 Hz, 1H) ,8.37 (dd, J=8.4 Hz, 2.4 Hz ,lH), 8.62 (s, 1H), 9.17 (d, J=l.2Hz, 1H).

PCT/U52012/020092 Step 20. 6-(2-Chloro(2-chloro(methylsulfonyl)benzamido)phenyl)—N— hydroxynicotinamide und 5) A mixture of 1002-5 (176 mg, 0.4mmol) in NHZOH methanolic on (5 mL, 1.79 M) was stirred at room temperature for 1 h. The reaction mixture was adjusted pH to 6~7 with 1.2 M HCl. The reaction mixture was filtered, washed with water, dried in vacuo to afford compound 5 as an off-white solid (120mg 70% yield). M.p.: 3°C. LCMS: m/z 480.2 [M+1]+. HNMR: (400 MHz, 6): 5 3.35 (s, 3H), 5 7.61 (d, J=8.4 Hz, 1H), 7.76 (dd, J=8.8 Hz, 2.4 Hz ,1H), 7.82 (d, J=8.0 Hz ,1H), 7.91 (d, J=8.0 Hz ,1H), 8.01 (dd, J=8.0Hz, 1.6Hz, 1H), 8.05 (d, J=2.4 Hz ,1H), 8.13 (d, J=1.6 Hz ,1H), 8.22 (dd, J=8.0 Hz, 2.0 Hz ,1H) 9.02 (d, J=1.6 Hz, 1H), 9.28 (s, 1H), 10.96 (s, 1H), 11.48 (s, 1H).

EXAMPLE 3: Preparation of 2-[2-Chlor0(2-ch10r0methanesulf0nyl— benzoylamino)—phenyl]-pyrimidine—5-carboxylic acid hydroxyamide (compound 7) Step 3a. 2-Chloro-pyrimidinecarboxy1ic acid methyl ester (compound 1001-7) A mixture ofNaH (27 g, 60% in mineral oil, 0.675mol) in anhydrous 1,2- dimethoxyethane (3 00 mL) was heated to 40—50°C. Methyl 3,3-dimethoxy nate (100 g, 0.675 mol) was added dropwise. The resulting mixture was stirred for 0.5 h and anhydrous methyl formate (81 g, 1.35mol) was added dropwise at 40-5 0°C. The resulting mixture was stirred at 40-50°C (inner temperature) for 2 h before it was cooled to 0°C. The reaction mixture was allowed to warm to 25°C slowly and stirred overnight. EtzO (150 mL) was added and stirred for 30 min. The resulting suspension was filtered. The solid was washed with EtZO (100mL), collected and dried to afford sodium (Z) (dimethoxymethyl)—3—methoxyoxopropenolate as an off-white solid (82 g, 61%).

LCMS: m/z 130.8 [M+1]+. 1HNMR (400 MHz, CD3OD)I 8 3.36 (s, 6H), 3.60 (s, 3H), 5.34 (s, 1H), 8.92 (s, 1H).

To a mixture of guanidine hydrochloride (42.2 g, 0.44 mol) in DMF (300 mL) was added above off—white solid (80 g, 0.40 mol). The resulting mixture was heated at 100°C for 1 h. The reaction mixture was filtered before . The filter cake was washed with 50 mL ofDMF and the ed filtrate was concentrated to leave a residue which was suspended in cold EtOH and washed with cold EtOH (50 mL) to afford the intermediate 2- amino-pyrimidine-S-carboxylic acid methyl ester as a yellow solid (38 g, 61.5%). LCMS: PCT/U52012/020092 m/z 154.2 [M+l]+, 195.1[M+42]+. 1HNMR (400 MHz, CD30D): 6 3.88 (s, 3H), 8.77 (s, 2H).

The obove intermediate (7 g, 0.046 mol) was added to a mixture of concentrated hydrochloric acid (15.2 mL) and CHzClz (60 mL). After cooling, ZnClz (18.6 g, 0.138 mol) was added at 15-20°C. The mixture was stirred at 15-20°C for 0.5 h and cooled to 5- °C. NaNOz (9.5 g, 0.138 mol) was added portion wise while keeping the internal temperature 5-10°C. The reaction was continued for ~ 2 h. The reaction mixture was poured into ice—water (50 mL). The organic layer was separated and the aqueous phase was ted with CHgClz (30 mL x 2). The combined c extracts were concentrated to afford crude product (4.2 g). The crude compound was suspended in hexane (20 mL), heated at 60°C for 30 minutes and filtered. The filtrate was trated to afford the titled compound 1001-7 (3.5 g, 44.4 %) as an off-white solid. LCMS: m/z 214.1[M+42]+.

IHNMR (400 MHz, CDClg): 5 4.00 (s, 3H), 9.15 (s, 2H).

Step 3b. 2-[2-Chloro—5-(2-chloromethanesulfonyl-benzoylamino)—phenyl]—pyrimidi necarboxylic acid methyl ester (compound 1002-7) A mixture of 1001-7 (200 mg, 1.1 mmol), 1-9 (756 mg, 1.6 mmol) and Pd(PPh3)4 (60 mg, 0.05 mmol) in ted NaHC03 (2 mL) and DMSO (6 mL) was stirred at 100°C for 3 h. After cooling to room temperature, NaOH (43 mg, 1.1 mmol) was added to reaction solution and stirred for 0.5 h. The reaction mixture was extracted with ethyl acetate. The aqueous layer was adjusted pH to 6 with 1.2 M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2S04, concentrated to afford crude acid (300 mg) without r purification.

The e of the crude acid (300 mg) in MeOH (15 mL) and H2SO4 (0.25 mL) was d at 85°C for l h. After removal of solvent, the residue was partitioned between water and ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2S04. The crude product was purified by column chromatography (hexanes/ethyl acetate: 1/1) to afford compound 1002—7 as a white solid (160 mg, 78% yield Via two . LCMS: m/z 480.2[M+l]+. 1H NMR: (400 MHz, I 8 3.36 (s, 3H), 3.96 (s, 3H), 7.65 (d, J=8.8 Hz, 1H), 7.81 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.02 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.14 (d, J=l.2Hz, 1H), 8.30 (d, J=2.4 Hz, 1H), 9.40 (s, 2H), 11.02 (s, 1H).

Step 3c. 2-[2-Chloro(2-chloromethanesulfonyl-benzoylamino)—phenyl]—pyrimidi necarboxylic acid hydroxyamide (compound 7) PCT/U52012/020092 A mixture of compound 1002-7 (160 mg, 0.3 mmol) in NH20H olic solution (5 mL, 1.79 M) was stirred at room temperature for 1 h. The reaction mixture was adjusted pH to 6N7 with 1.2 M HCl and concentrated. The residue was triturated with water and filtered. The crude product was purified by prep-HPLC to afford compound 7 as an off- white solid (28 mg, 18% yiled). M.p.: 170~172°C. LCMS: m/z 481.1 [M+1]+. 1H NMR: (400 MHz, DMSO-dg): 5 3.35 (s, 3H), 7.63 (d, J=8.8 Hz, 1H), 7.79 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.01 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.14 (d, J=1.6Hz, 1H), 8.26 (d, J=2.4 Hz, 1H), 9.23 (s, 2H), 11.01 (s, 1H).

EXAMPLE 4: 2-Chlor0-N-{4-chlor0[5-(6-hydr0xycarbamoyl-hexyloxy)-pyridin yl]-phenyl}methanesulfonyl—benzamide und 23) Step 4a. 6-Bromo-pyridinol und 2002) 3-Aminobromopyridine (1 g, 5.8 mmol) was dissolved in HBF4 (3.6 mL, 40% aq) and water (3 mL). To the cooled brownish solution under an ice-bath was added dropwise NaNOz (441 mg, 6.4 mmol) solution in water (3 mL). The resulting e was stirried for 1 h at this tempreture. After addition of water (3 mL), the mixture was stirred at 100°C for 3.5 h. The reaction mixture was neutralized by aqueous NaHC03 (5%) and extracted with ethyl acetate. The combined c layers were washed with water and brine, dried over anhydrous Na2SO4 and evaporated in vacuo, The residue was purified by column chromatography (hexanes/ethyl acetate: 9/ 1) to afford compound 2002 as a white solid (270 mg, 27% yield). LCMS: m/z 174.0 [M+1]+. 1H NMR (400 MHz, CDClg): 5 6.65 (br, 1H), 7.13 (dd, J=8.4 Hz, 3.2 Hz, 1H), 7.36 (d, J=8.4 Hz, 1H), 8.03 (d, J=3.2 Hz, 1H).

Step 4b. 7-(Pyridin—3—yloxy)-heptanoic acid ethyl ester (compound 2003—23) A mixture of 2002 (270 mg, 1.5 mmol), ethyl 7-bromoheptanoate (736 mg, 3.1 mmol) and K2C03 (430 mg, 3.1 mmol) in DMF (10 mL) was stirred at 75°C for 1 h. The solution was partitioned between water and ethyl acetate. The ed organic layers were washed with water and brine, dried over anhydrous Na2S04 and evaporated in vacuo.

The residue was purified by column chromatography (hexanes/ethyl acetate: 20/ 1) to afford compound 2003-23 as a white solid (440 mg, 86% . LCMS: m/z 330.1 [M+1]+. 1H NMR: (400 MHz, CDC13)I 8 1.25 (t, J=7.2 Hz, 3H), 1.36-1.52 (m, 4H), 1.62- 1.68 (m, 2H), 1.76-1.83 (m, 2H), 2.31 (t, J=7.2 Hz, 2H), 3.97 (t, J=6.4 Hz, 2H), 4.13 (q, PCT/U52012/020092 J=7.2 Hz, 2H), 7.08 (dd, J=8.8 Hz, 3.2 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 8.04 (d, J=2.8 Hz, 1H).

Step 4c. 7-{6-[2-Chloro(2-chloro-4—methanesulfonyl-benzoylamino)-phenyl]-pyridi n-3 -yloxy} -heptanoic acid ethyl ester (compound 2004-23) A mixture of 2003-23 (168 mg, 0.51 mmol), 1-9 (200 mg, 0.43 mmol) and Pd(PPh3)4 (24.6 mg, 0.03 mmol) in ted NaHC03 (2 mL) and 1,4-dioxane (6 mL) was stirred at 100°C for 3 h. The solution was partitioned n water and ethyl e. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4 and evaporated in vacuo. The residue was purified by column chromatography (dichloromethane/ methanol: 100/1) to afford 3 as a white solid (130 mg, 43% yield). LCMS: m/z 593.2 [M+1]+. 1H NMR (400 MHz, CDC13)I 8 1.26 (t, J=7.2 Hz, 3H), 1.37-1.54 (m, 4H), 1.63-1.71 (m, 2H), 1.78-1.85 (m, 2H), 2.32 (t, J=7.2 Hz, 2H), 3.00 (s, 3H), 3.98 (t, J=6.4 Hz, 2H), 4.12 (q, J=7.2 Hz, 2H), 7.19 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.58 (d, J=1.2 Hz, 1H), 7.61 (d, J=1.2Hz, 1H), 7.63 (d, J=1.6Hz, 1H), 7.69 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.73 (d, J=2.4 Hz, 1H), 7.86 (d, J=1.6 Hz, 1H), 8.02 (dd, J=8.8 Hz, 2.8 Hz, 1H), 8.05 (d, J=2.8 Hz, 1H), 9.88 (s, 1H).

Step 4d. 2-Chloro-N— {4—chloro[5—(6-hydroxycarbamoyl-hexyloxy)-pyridinyl]—ph enyl} methanesulfonyl-benzamide (compound 23) A mixture of 2004-23 (130 mg, 0.22 mmol) in NHgOH methanolic solution (5 mL, 1.79 M) was stirred at room temperature for 1 h. The reaction mixture was adjusted pH to 6-7 with 1.2 M HCl. The resulting mixture was filtered. The collected solid was purified by prep-HPLC to afford compound 23 as a white solid (27 mg, 21% yiled). M.p.: 140— 145°C. LCMS: m/z 580.2 [M+l]+. 1H NMR (400 MHz, DMSO-d6): 5 .35 (m, 2H), 1.40-1.47 (m, 2H), 1.49-1.56 (m, 2H), 1.72-1.78 (m, 2H), 1.96 (t, J=7.2 Hz, 2H), 3.35 (s, 3H), 4.10 (t, J=6.4 Hz, 2H), 7.50 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.55 (d, J=8.8Hz, 1H), 7.64 (d, J=8.8Hz, 1H), 7.70 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.99-8.02 (m, 2H), 8.13 (d, J=1.6Hz, 1H), 8.40 (d, J=2.8 Hz, 1H), 8.66 (s, 1H), s, 1 H), 10.90 (s, 1H).

EXAMPLE 5: 2—Chloro-N-(4-chloro—3-(pyridiny])phenyl)—4—(N-(7— (hydroxyamin0)0x0heptyl)sulfamoyl)benzamide (compound 59) Step 5a. 4-Aminochlorobenzoic acid (compound 3002) A mixture of 2-chloronitrobenzoic acid (5.0 g, 24.8 mmol), iron powder (8.0 g, 142.9 mmol) and NH4C1 (7.6 g, 142.9 mmol) in EtOH/water (50/50 mL) was heated at PCT/U52012/020092 reflux for 2 h. The hot mixture was filtered through Celite and washed with ethyl acetate.

The mixture was separated and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (hexanes/ethyl acetate: 5/1 , 3/ 1 , 1/ 1) to afford compound 3002 as a white solid (1.0 g, 24% yield). 1H NMR (400 MHz, DMSO- d6): 8 6.04 (s, 2H), 6.49 (dd, J=8.4 Hz, 2.0 Hz, 1H), 6.61 (d, J=2.0 Hz, 1H), 6.63 (d, J=8.8 Hz, 1H), 12.21 (br, 1H).

Step 5b. 2-Chloro(chlorosulfonyl)benzoic acid (compound 3003) To a solution of 3002 (1 .00g, 5.4 mmol) in HOAc (20 mL) was added conc. HCl (5 mL) at 0°C. After 15 min, NaNOz aqueous on (1 . 10g, 16.2 mmol in water 4.5 mL) was added dropwise at -5~-10°C and continued to stir at this temperature for 45 min.

The above reaction mixture was added dropwise to s de (0.14 g, 1.4 mmol) and saturated sulfur dioxide in acetic acid (40 mL) at 0°C. After addition was te the resulting mixture was warmed to 10°C and stirred for 30 min. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The ed organic layers were washed with water and brine, dried over ous sodium sulfate. The crude product was purified by column chromatography (dichloromethane/methano1: 100/2, 100/5, 100/ 10) to afford compound 3003 as an off-white solid (500 mg, 34% yield).

Step 5c. 2-Chloro(N—(7-ethoxy—7—oxoheptyl)sulfamoyl)benzoic acid und 3004- 59) To a mixture of ethyl 7-aminoheptanoate hydrochloride (777 mg, 3.7 mmol) and N, N- diisopropylethylamine (4.0 g, 31.2 mmol) in dichloromethane (80 mL) was added compound 3003 (1.0 g, 3.9 mmol). The resulting mixture was stirred at room temperature overnight. The reaction e was adjusted pH to 6~7 with 2M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (dichloromethane/methanol: 100/2, 100/5, 100/ 10) to afford compound 3004—59 as a white solid (520 mg, 44% yield). LCMS: m/z 392.1 [M+1]+. 1H NMR (400 MHz, CDC13)I 8 1.25-1.33 (m, 7H), 1.44-1.62 (m, 4H), 2.28 (t, J=7.2 Hz, 2H), 2.98-3.02 (m, 2H), 4.13 (q, J=7.2Hz, 2H), 5.07 (t, J=5.6 Hz, 1H), 7.82 (d, J=8.0Hz, 1H), 7.97 (s, 1H), 8.08 (d, z, 1H).

Step 5d. Ethyl 7-(3-chloro(4-chloro(pyridinyl)phenylcarbamoy1)phenyl sulfonamido)heptanoate (3005-59) A mixture of 3004-59 (520 mg, 1.3 mmol), oxalyl chloride (1.59 g, 12.5 mmol) and DMF (0.05 mL) in dichloromethane was stirred at room temperature for 2 h. After evaporation, the residue was dissolved in dichloromethane, compound 1-8 (244 mg, 1.2 mmol) and N, N-diisopropylethylamine (325 mg, 2.5 mmol) were added. The reaction mixture was stirred at room temperature overnight. The on mixture was quenched with water and extracted with dichloromethane. The ed organic layers were washed with water and brine, dried over anhydrous sodium sulfate. The crude product was purified by column tography (hexanes/ethyl acetate: 5/1 , 3/1, 1/ 1) to afford compound 3005-59 as a white solid (250 mg, 33% yield). LCMS: m/z 578.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.13-1.22 (m, 7H), 1.38-1.49 (m, 4H), .27 (m, 2H), 2.76 (t, J=6.8Hz, 2H), 4.03 (q, J=6.8 Hz, 2H), 7.44-7.47 (m, 1H), 7.59 (dd, J=8.4 Hz, 3.2 Hz, 1H), 7.69 (d, J=7.6Hz, 1H), 7.74-7.79 (m, 1H), 7.85 (s, 2H), 7.91-7.95 (m, 3H), 8.02 (d, J=2.0 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 10.93 (s, 1H).

Step 5e. 2-Chloro-N-(4—chloro(pyridinyl)phenyl)(N-(7-(hydroxyamino)—7- oxoheptyl)sulfamoyl)benzamide (compound 59) A mixture of 3005-59 (150 mg, 0.2 mmol) in NHZOH methanolic solution (10mL, 1.79 M) was stirred at room temperature for 2.5 h. TLC showed on complete. The on mixture was adjusted pH to 5~6 with 2 M HCl, concentrated. The residue was triturated with water and filtered, purified by prep-HPLC to afford nd 59 as a white solid (46 mg, 32%). M.p.: 158.7~159.3°C. LCMS: m/z 565.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 6 .23 (m, 2H), 1.36—1.46 (m, 4H), 1.91 (t, J=7.2 Hz, 2H), 2.77 (q, J=6.4Hz, 2H), 3.40—3.47 (m, 2H), 7.44—7.47 (m, 1H), 7.58 (d, J=8.8H, 1H), 7.69 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.4Hz, 2.4Hz, 1H), 7.83-7.85 (m, 3H), 7.91-7.95 (m, 2H), 8.02 (d, J=2.4 Hz,lH), 8.71 (d, J=4.8 Hz, 1H), 10.32 (s, 1H), 10.89 (s, 1H).

EXAMPLE 6: 2—{4-[2-Chlor0(4-ch10r0pyridinyl-phenylcarbamoyl)- benzenesulfonyl]-piperazinyl}-pyrimidine—5—carboxylic acid hydroxyamide (compound 86) Step 63. (Z)-ethyl(ethoxymethyl)methoxyacrylate (Compound 4002) Sodium (27.6 g, 1.2 mol) was added to hexane (400 mL) and ethanol (27 g, 1.17 mol) was added se at room temperature. The e was stirred at room temperature for 1 h. Then ethyl 3-ethoxypropanoate (88.0 g, 602 mmol) was added dropwise at 0°C followed by ethyl formate (90 g, 1.22 mol). The reaction mixture was stirred at 0°C for 2 h. and dimethyl sulfate (160 g, 1.27 mol) was added dropwise at the PCT/U52012/020092 same temperature. The resulting mixture was heated at 50°C overnight, filtered, and washed with hexane (300-500 mL). To the ed filtrate was added triethylammonium chloride (80 g, 0.58 mol) and sodium hydroxide (14.00 g, 0.35 mol). The mixture was stirred at room temperature for 4 h and filtered. The filtrate was washed with water, dried over NaZSO4 and concentrated. The residue was purified by distillation to give the desired compound 4002 (63.5 g, 56%) as a colorless oil. LCMS: m/z 211 [M+23]+. 1H NMR (400 MHz, CDC13)I 5 1.20 (t, J= 7.2 Hz, 3H), 1.28 (t, J= 7.2 Hz, 3H), 3.50 (q, J= 7.2 Hz, 2H), 3.88 (s, 3H), 4.20 (m, 4H), 7.45 (s, 1H).

Step 6b. Ethyl 2-oxo-1,2,3,4-tetrahydropyrimidinecarboxylate (Compound 4003) A mixture of nd 4002 (63.5 g, 337 mmol), urea (18.7 g, 312 mmol) and concentrated hydrochloric acid (16 mL) in ethanol (300 mL) was heated at reflux overnight. After evaporating the most of l (~250 mL), the resulting suspension was filtered, washed with small amount of ethanol, and dried to give compound 4003 (23.5 g, 44%) as a white solid. LCMS: m/z 171 [M+1]+. 1H NMR (400 MHz, I 5 1.27 (t, J = 7.2 Hz 4.19 (m, 4H), 5.28 (s, 1H), 7.21 (d, J= 5.6 Hz, 1H), 7.40 (s, 1H). , 3H), Step 6c. Ethyl 2-oxo-1,2-dihydropyrimidinecarboxylate (Compound 4004) To a solution of compound 4003 (23.5 g, 138 mmol) in acetic acid (300 mL) was added bromine (22.7 g, 142 mmol). The mixture was heated at reflux for 3 h and concentrated in vacuum to afford the romide salt of crude compound 4004 as a yellow solid. The product was used directly in next step without further purification.

LCMS: m/z 169 [M+1]+. 1H NMR (400 MHz, CDClg): 5 1.27 (t, J: 7.2 Hz 4.28 (q, , 3H), J: 7.2 Hz 8.85 (s, 2H), 12.19 (br, s, 2H). , 2H), Step 6d. Ethyl 2-chloropyrimidinecarboxylate (Compound 4005) A mixture of crude compound 4004 and phosphoryl trichloride (300 mL) was heated at reflux for 3 h, cooled to room temperature and trated. The residue was cooled to room temperature and dissolved in ethyl acetate (500 mL). The EtOAc solution was treated with ice water (300 mL) carefully, washed with ice-water and brine, dried over Na2S04, ated, and d by column chromatography (eluted with EtOAc/Hexane: 10%) to afford compound 4005 (14 g, 54%, two steps) as a white solid. LCMS: m/z 187 [M+1]+. 1H NMR (300 MHz, CDC13)§ 5 1.42 (t, J: 7.5 Hz 4.48 (q, J: 7.5 Hz, , 3H), 2H), 9.15 (s, 2H).

Step 6e. Ethyl 2-(piperazinyl)pyrimidinecarboxylate (compound 4006) PCT/U52012/020092 A mixture of tert—butyl piperazine—l—carboxylate (1.1 g, 5.9 mmol) and 4005 (1 g, 5.4 mmol), Et3N (1.1 g, 10.8 mmol) in CH2C12 (10 mL) was stirred at room temperature for 2 h. The on mixture was washed with H20. The organic layer was concentrated. The residue was purified by chromatography eluting with Hexane/EtOAc = 250: 10, then 250:20 to afford the compound ethyl tert-butoxycarbonyl)piperazinyl)pyrimidine— -carboxylate (900 mg, 45.4%) as a white solid. 1H NMR (400 MHz, CDCl3)2 8 1.37 (t, 3H, J=6.8Hz), 1.49 (s, 9H), 3.51 (t, 4H, J=4.8Hz), 3.92 (t, 4H, J=5.2Hz), 4.35 (q, 2H, J=7.2 Hz), 8.85 (s, 2H).

A mixture of above product (500 mg, 1.49 mmol) and oxane (10 mL) was d at room temperature for 2 h. The reaction mixture was concentrated. The residue was partitioned between EtOAc and saturated aq. NaHCOg. The organic layer was washed with brine, dried over Na2SO4 and concentrated to afford the titled compound 4006 (370 mg, 88.2%) as a white solid. 1H NMR (400 MHZ, CDC13)C 5 1.39 (t, 3H, J=6.8Hz), 2.96 (t, 4H, J=4.8Hz), 3.95 (t, 4H, J=5.2Hz), 4.36 (q, 2H, J=7.2 Hz), 8.86 (s, 2H).

Step 6f. 4-Carboxychloro-benzenesulfonyl)—piperaziny1]-pyrimidine-5— carboxylic acid methyl ester (compound 4007) To a mixture of 4006 (1 .04g, 4.7mmol) and DIPEA (4.0g, 31.2mmol) in dicholoromethane (80mL) was added compound 3003 (1.0g, l). The e solution was stirred at room temperature overnight. The reaction mixture was adjusted pH to 6~7 with 2M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate, evaportated in vacuo.

The crude product was purified by column chromatography (methane/dichloromethane: 1/20) to afford compound 4007 as a white solid (520 mg, 30% yield). LCMS: m/z 455.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.27 (t, J=7.2 Hz, 3H), 3.08 (br, 4H), 3.96 (br, 4H), 4.25 (q, J=7.2 Hz, 2H), 7.72 (dd, J=8.0Hz, 1.6Hz, 1H), 7.78 (d, J=1.2Hz, 1H), 7.87 (d, J=8.0Hz, 1H), 8.76 (s, 2H).

Step 6g. 2- {4-[2-Chloro(4-chloropyridiny1-phenylcarbamoyl)—benzenesulfonyl]- piperazin-l-y1}-pyrimidinecarboxy1ic acid methyl ester (compound 4008) A mixture of 4007 (500 mg, 1.1 mmol), oxalyl chloride (1.59 g, 12.5 mmol) and DMF (0.05mL) in dichloromethane (10mL) was d at room temperature for 2 h. The reaction mixture was concentrated and the residue was dissolved in dichloromethane (15mL). Compound 1-8 (278 mg, 1.2 mmol) and DIPEA (325 mg, 2.5 mmol) were added.

The resulting mixture was d at room temperature overnight. The reaction mixture was quenched with water and extracted with dichloromethane. The combined organic layers PCT/U52012/020092 were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was d by column tography (methanol/dichloromethane: 1/20) to afford compound 4008 as a white solid (180 mg, % yield). LCMS: m/z 641.2[M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.28 (t, J=7.2Hz, 3H), 3.11 (br, 4H), 3.99 (br, 4H), 4.26 (q, J=7.2Hz, 2H), 7.43-7.46 (m, 1H), 7.58 (d, J=8.8Hz, 1H), 7.69 (d, J=8.0Hz, 1H), 7.72 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.83 (dd, J=8.0Hz, 1.2Hz, 1H), 7.88-7.91 (m, 2H), 7.93 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.99 (d, J=2.8 Hz, 1H), 8.71 (d, J=4.4 Hz, 1H), 8.78 (s, 2H), 10.84 (s, 1H).

Step 6h. 2-{4-[2-Chloro(4-chloro—3—pyridin—2-yl—phenylcarbamoyl)—benzenesulfonyl]- piperazinyl}-pyrimidinecarboxylic acid hydroxyamide und 86) A mixture of 4008 (180mg, 0.3mmol) and NHZOH (15mL, 1.79M) methanolic solution was stirred at room temperature for 2.5 h. The reaction mixture was adjusted pH to 5~6 with 2M HCl and evaporated. The resulting mixture was filtered. The crude product was purified by prep-HPLC to afford compound 86 as a white solid (50 mg, 26% yield).

M.p.:158.7-159.3°C LCMS: m/z 628.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 3.09 (br, 4H), 3.93 (br, 4H), 7.43-7.46 (m, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.69-7.73 (m, 2H), 7.83 (dd, J=8.0Hz, 1.2Hz, 1H), 7.87-7.90 (m, 2H), 7.93 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.99 (d, J=2.4Hz, 1H), 8.66 (s, 2H), 8.70 (d, J=4.0Hz, 1H), 9.02 (s, 1H), 10.84 (s, 1H), 11.09 (s, 1H).

EXAMPLE 7: N-(4-Chlor0(5-(dimethylamino)—1H—benzo[d]imidazol—Z-yl)phenyl)— 3-(7-(hydroxyamino)oxoheptyloxy)benzamide (compound 111) Step 72. 3-(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazol yl)phenylcarbamoyl)phenyl acetate (compound 5001-1 1 l) 3-Acetoxybenzoic acid (2.6 g, 0.015 mol) was added to a mixture of compound 2-3 (3.5 g, 0.012 mol), HATU (6.9 g, 0.018 mol) and Eth (2.5 mL, 0.018 mol) in dichloromethane (30 mL). The on mixture was stirred at room temperature overnight. The mixture was quenched with water and extracted with romethane. The combined organic layers were washed with water and brine, dried over iydrous .

The crude product was purified by column chromatography es/ethyl acetate: 1/ 1) to afford compound 5001-1 11 as a white solid (2.6 g, 49% yield). LCMS: m/z 449.2 [M+1]+.

Step 7b. N-(4-Chloro(5-(dimethylamino)—1H-benzo[d]imidazolyl)phenyl) hydroxybenzamide (compound 5002—1 1 1) PCT/U52012/020092 To a solution of compound 5001—111 (1.0 g, 0.002 mol) in MeOH (15 mL) was added a solution ofNaOH (0.89 g, 0.02 mol) in H20 (15 mL). The reaction mixture was heated at reflux overnight. After cooling at ice bath, the mixture was adjusted pH to 7~8 with 1M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2S04, ated in vacuo to afford crude compound 5002411 as a yellow solid (0.81 g, 100% yield). LCMS: m/z 407.2 [M+l]+.

Step 7c. 7—(3-(4-chloro(5-(dimethylamino)-lH-benzo[d]imidazol yl)phenylcarbamoyl)phenoxy)heptanoate (compound 5003-111) To a mixture of compound 11 (1.40 g, 0.0034 mol), ethyl 7- hydroxyheptanoate (0.89 g, 0.0052 mol) and PPh3 (1.8 g, 0.0069 mol) in anhydrous THF (20 mL) was added DIAD (1.39 g, 0.0069 mol) at 0°C under nitrogen atmosphere. The resulting solution was heated at 65°C overnight. After g to room temperature, the reaction mixture was concentrated in vacuo. The crude product was purified by column chromatography (dichloromethane/ ethyl acetate: 1:1) to afford compound 5003-111 as a white solid (0.9 g, 47% yield). LCMS: m/z 563.3 [M+1]+.

Step 7d. N-(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazolyl)phenyl)—3-(7- (hydroxyamino)oxoheptyloxy)benzamide (Compound 1 l 1) Compound 5003-111 (120 mg, 0.21 mmol) was taken into NHZOH olic solution (10 mL, 1.79 M). The mixture stirred at room temperature for 40 min. The reaction mixture was ed pH to 8-9 with acetic acid and concentrated in vacuo. The residue was purified by prep-HPLC to afford compound 111 as a white solid (30 mg, 26% yield). M.p: l40~142°C. LCMS: m/z 550.3 [M+l]+. 1H NMR (400 MHz, 6): 6 1.28-1.35 (m, 2H),1.40-1.56 (m, 4H), 1.72-1.76 (m, 2H), 1.96 (t, J=3.2 Hz, 2H), 2.93 (s, 6H), 4.05 (t, J=6.4 Hz, 2H), 6.84 (d, J=8.4 Hz, 2H), 7.16-7.18 (m, 1H), 7.43-7.61 (m, 5H), 7.97 (dd, z, 2.4Hz, 1H), 8.23 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 10.36 (s, 1H), 10.47 (s, 1H), 12.23 (br, 1H).

E 8: 2—((3-Chlor0(4-ch10r0(pyridinyl)phenylcarbamoyl)benzyl) (methyl)amin0)-N-hydroxypyrimidinecarb0xamide (compound 263) Step 8a. 1-Bromo(bromomethyl)—2-chlorobenzene (compound 6002) A mixture of 1-bromochloromethylbenzene (5 g, 24 mmol), NBS (5.19g, 29 mmol), AIBN (0.39g, 2.0 mmol) in CCl4 (50mL) was heated at reflux overnight. The hot reaction mixture was filtered and rinsed with CCl4. The combined organic layer was washed with water and brine, dried over NaSO4, evaporated in vacuo to afford compound PCT/U52012/020092 6002 as a white solid (5.6g, 82% yield). 1H NMR (400 MHz, CDCl3)I 8 4.39 (s, 2H), 7.14 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H).

Step 8b. tert—Butyl 4-bromochlorobenzyl(methyl)carbamate (compound 6003) To a stirring solution of MeNHBoc in DMF (10mL) cooled to 0°C was added sodium hydride (590 mg, ol). The ing mixture was stirred for 10 min followed by the addition of a solution of 6002 (4.67g, 16.0 mmol) in DMF (5 mL). The reaction mixture was warmed to room temperature and stirred for 8 h. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (ethyl acetate/hexanes: 1/10) to afford 6003 as a white solid (1.8 g, 34% yield). 1H NMR (400 MHz, CDC13): 8 1.47 (s, 9H), 2.83 (d,J=18.4 Hz, 3H), 4.35 (s, 2H), 6.99 (s, 1H), 7.32 (s, 1H), 7.56 (d, J=8.4 Hz, 1H).

Step 8c. tert-Butyl 3-chloro—4—formylbenzyl(methyl)carbamate (compound 6004) To a solution of 6003 (2.15g, 6.4 mmol) in anhydrous THF (20 mL) was added n- BuLi (3.8 mL, 2.5 M, 9.5 mmol) dropwise at -78°C. The ing mixture was continued to stir for 2 h followed by the on ofN—formyl morpholine (884 mg, 7.7 mmol) at - 78°C. The resulting mixture was warmed to room temperature and stirred overnight. The reaction e was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (ethyl e/hexanes: 1/10) to afford compound 6004 as a red oil (570 mg, 25% . LCMS: m/z 282.1 [M-1]‘. 1H NMR (400 MHz, CDClg): 5 1.45, 1.50 (two single peaks, 9H), 2.85, 2.90 (two single peaks, 3H), 4.46 (br, 2H), 7.23 (d, J=6.8 Hz, 1H), 7.31 (s, 1H), 7.90 (d, J=8.0Hz, 1H), 10.45 (s, 1H).

Step 8d. Ethyl 2-((3 -chloroformylbenzyl)(methyl)amino)pyrimidinecarboxylate (compound 6005) A mixture of 6004 (570 mg, 2.0 mmol) in TFA (10 mL) was stirred at room temperature for 2 h. The reaction mixture was concentrated. The residue was mixed with 4005 (560 mg, 3.0 mmol) and TEA (10 ml) and the resulting mixture was stirred at room temperature overnight. The reaction e was quenched with water and extracted with ethyl acetate. The combined c layers were washed with water and brine, dried over NaZSO4. The crude product was purified by column chromatography (ethyl acetate/hexanes: 1/5) to afford compound 6005 as a yellow solid (425 mg, 65% yield). 2012/020092 LCMS: m/z 334.1 [M+l]+. 1H NMR(400 MHz, DMSO-dg): 8 1.29 (t, J=7.2 Hz, 3H), 3.22 (s, 3H), 4.27 (q, J=7.2 Hz, 2H), 5.02 (s, 2H), 7.36 (d, J=8.0 Hz, 1H), 7.47 (s, 1H), 7.83 (d, J=8.0 Hz, 1H), 8.79, 8.86 (two single peaks, 2H), 10.29 (s, 1H).

Step 8e. 2-Chloro(((5-(ethoxycarbonyl)pyrimidinyl)(methyl)amino)methyl)benzc acid (compound 6006) A mixture of compound 6005 (425 mg, 1.27 mmol), NaIO4 (408 mg, 1.9 mmol), RuC13 (40 mg, 0.2 mmol) in CH3CN (15 mL) was d at room temperature for 16 h.

The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over Na2S04. The crude compound 6006 was obtained as a white solid (188 mg) which used directly for the next step. LCMS: m/z 350.1 [M+l]+. 1H NMR (400 MHz, DMSO-d6): 8 1.29 (t, J=7.2 Hz, 3H), 3.21 (s, 3H), 4.28 (q, J=7.2 Hz, 2H), 4.98 (s, 2H), 7.26 (d, J=8.0 Hz, 1H), 7.40 (s, 1H), 7.76 (d, J=7.6 Hz, 1H), 8.80, 8.86 (two single peaks, 2H).

Step 8f. Ethy12-((3—chloro(4-chloro—3—(pyridinyl)phenylcarbamoyl)benzyl) (methyl)amino)pyrimidinecarboxylate (compound 6007) A mixture of 6006 (118 mg, 0.3 mmol) in DMF (0.10 mL), thionyl chloride (2 mL, 27.5 mmol) was stirred at room temperature ght. The reaction mixture was trated and the residue was dissolved in anhydrous dichloromethane (5 mL) and cooled at ice bath. To the mixture was added DIPEA (1.0 mL, 6.0 mmol) and compound 1—8 (83 mg, 0.4 mmol) and the resultuing mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate.

The combined organic layers were washed with water and brine, dried over NaSO4. The crude t was purified by column chromatography (ethyl e/ dichloromethane: /1) to afford compound 6007 as a white solid (100 mg 50% yield). LCMS: m/z 536.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 1.29 (t, J=7.2 Hz, 3H), 3.22 (s, 3H), 4.28 (q, J=7.2 Hz, 2H), 4.99 (s, 2H), 7.31 (d, J=7.6Hz, 1H), 7.43-7.45 (m, 2H), .58 (m, 2H), 7.68 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.90-7.94 (m, 1H), 8.02 (d, J=2.8 Hz, 1H), 8.70 (d, J= 4.4 Hz, 1H), 8.82-8.86 (m, 2H), 10.71 (s, 1H).

Step 8g. 2-((3-Chloro(4-chloro(pyridinyl)phenylcarbamoyl)benzyl) (methyl)amino)-N-hydroxypyrimidine-5—carboxamide (compound 263) Compound 6007 (100 mg, 0.2 mmol) was taken into NHZOH methanolic solution (10 mL, 1.79 M). The resulting mixture was stirred at room ature for 2 h. The reaction mixture was adjusted pH to 7~8 with acetic acid and concentrated. The residue was triturated with water and filtered to afford compound 263 as a white solid (60 mg, 60% PCT/U52012/020092 yield). LCMS: m/z 523.2 . 1H NMR (400 MHz, DMSO-d6): 3.19 (s, 3H), 4.96 (s, 2H), 7.29 (d, J=8.0Hz, 1H), 7.42-7.46 (m, 2H), 7.54—7.57 (m, 2H), 7.67 (d, J=8.0Hz, 1H), 7.75 (d, J=8.8 Hz, 2.8 Hz, 1H), 7.90-7.94 (m, 1H), 8.01 (d, J=2.4 Hz, 1H), 8.70 (d, J=4.4 Hz, 1H), 8.74 (s, 2H), 9.03 (s, 1H), 10.75 (s, 1H), 11.21 (s, 1H).

EXAMPLE 9: 2—(3-Chloro(4-chloro(pyridinyl)phenylcarbamoyl) phenylsulfonamido)—N-hydroxypyrimidine-S-carboxamide (compound 265) Step 93. Methyl 2-chlorosulfamoylbenzoate (compound 7001) Compound 3003 (200 mg, 0.7 mmol) was dissolved in dichloromethane (5 mL) ed by the addition of saturated NH3 methanolic solution (0.5 mL) at 0°C. After addition, the reaction mixture was warmed to room temperature and stirred for 5 min.

After evaporation, the e was purified by column tography (hexanes/ethyl acetate: 3/ 1) to afford compound 7001 as a white solid (160 mg, 86% yield). LCMS: m/z 248.0[M—1]'. 1H NMR (400 MHz, DMSO-dé): 8 3.91 (s, 3H), 7.69 (s, 2H), 7.88 (dd, J=8.4 Hz, 1.6 Hz, 1H), 7.97 (d, J=1.2 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H).

Step 9b. 4-(N-(tert-Butoxycarbonyl)sulfamoyl)—2-chlorobenzoic acid (compound 7002) A mixture of 7001 (1.44 g, 5.8 mmol), BoczO (2.51g, 11.5 mmol) and DMAP (71 mg) in dichloromethane (30 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was ed with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2SO4.

The crude product was purified by column chromatography (hexanes/ethyl acetate: 2/ 1) to afford compound methyl 4-(N—(tert-butoxycarbonyl)sulfamoyl)chlorobenzoate as a white solid (1.20 g, 60% yield). LCMS: m/z 350.2 [M+1]+. 1H NMR (400 MHz, DMSO- d6): 8 1.32 (s, 9H), 3.91 (s, 3H), 7.94 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.97 (d, J=l.6 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 12.03 (br, 1H).

A mixture of above product (1.22g, 3.5 mmol), LiOH (1.46g, 34.9 mmol) in THF/HZO (10mL /10 mL) was stirred at room temperature ght. After evaporation, the mixture was adjusted to pH 1~2 with 1M HCl and extracted with ethyl acetate. The combined organic layers were washed with water and brine, evaporated in vacuo to afford compound 7002 as a white solid (1.00 g, 85% yield). LCMS: m/z 334.0 [M—1]'. 1H NMR (400 MHz, 6): 5 1.32 (s, 1H), 7.90 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.94 (d, J=1.6 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 11.99 (br, 1H).

Step 9c. tert-Butyl 3-chloro—4—(4-chloro-3 -(pyridinyl)phenylcarbamoyl)phenyl sulfonylcarbamate (compound 7003) PCT/U52012/020092 A mixture of compound 7002 (328 mg, 1.0 mmol), 1-8 (100 mg, 0.5 mmol), HATU (559 mg, 1.5 mmol), DIPEA (253 mg, 2.0 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was quenched with saturated sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2804. The crude product was purified by column chromatography (dichloromethane / ethyl acetate: 2/ 1) to afford compound 7003 as a white solid (270 mg, ~100% yield). LCMS: m/z 522.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.36 (s, 9H), 7.44-7.47 (m, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.76 (dd, J=8.8 Hz, J=2.4 Hz, 1H), 7.91—7.98 (m, 4H), 8.01 (d, J=2.4 Hz, 1H), 8.71 (d, J=4.4 Hz, 1H), 10.93 (s, 1H), 11.98 (br, 1H).

Step 9d. 2-Chloro-N-(4-chloro(pyridinyl)phenyl)sulfamoylbenzamide (compound 7004) A mixture of 7003 (270 mg, 0.5 mmol) in TFA (5 mL) was stirred at room temperature for 2 h. After evaporation, the mixture was quenched with saturated NaHC03 and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2804, evaporated in vacuo to afford compound 7004 as a white solid (180 mg, 84% . LCMS: m/z 422.1 [M+1]+. 1H NMR (400 MHz, DMSO— d6): 5 7.43-7.47 (m, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.64 (s, 2H), 7.69 (d, J=8.0 Hz, 1H), 7.75 (dd, J=8.8 Hz, 2.4 Hz, 1H), 7.82-7.88 (m, 2H), 7.91-7.96 (m, 2H), 8.01 (d, J=2.4 Hz, 1H), 8.71 (d, J=4.8 Hz, 1H), 10.88 (s, 1H).

Step 9e. Ethyl 2-(3-chloro(4-chloro(pyridinyl)pheny1carbamoyl)phenyl sulfonamido)pyrimidine-S-carboxylate (compound 7005) A mixture of compound 7004 (460 mg, 1.1 mmo), 4005 (203 mg, 1.1 mmol), cesium carbonate (533 mg, 1.6 mmol), Xantphos (20 mg, 0.03 mmol), a)3 (20 mg, 0.02 mmol) in oxane (15 mL) was heated at 85°C overnight. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl e. The combined organic layers were washed with water and brine, dried over anhydrous Na2S04. The crude product was d by column tography (dichloromethane / ethyl acetate: 2/ 1) to afford compound 7005 as a pale yellow solid (300 mg, 48% yield). LCMS: m/z 572.1 . 1H NMR (400 MHz, g): 5 1.29 (t, J=7.2 Hz, 3H), 4.29 (q, J=7.2 Hz, 2H), 7.43-7.46 (m ,1H), 7.57 (d, J=8.8 Hz, 1H), 7.67- 7.73 (m, 2H), 7.84 (d, J=8.0 Hz, 1H), 7.90-7.94 (m, 1H), 7.99 (d, J=2.8 Hz, 1H), 8.06 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 8.69—8.71 (m, 1H), 8.96 (s, 2H), 9.05 (s, 1H).

PCT/U52012/020092 Step 9f. 2-(3—Chloro(4—chloro(pyridinyl)phenylcarbamoyl)phenylsulfonamido) - N—hydroxypyrimidine-S-carboxamide (compound 265) nd 7005 (300 mg, 0.5 mmol) was taken into NHZOH methanolic solution (10 mL, 1.79 M). The ing mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted pH to 7~8 with acetic acid and concentrated. The residue was triturated with water and filtered. The solid was suspended in dichloromethane and stirred at room temperature overnight and filtered. The collected solid was dried in vacuo to afford compound 265 as a white solid (60 mg, 21% yield). M.p: 215~220°C.

LCMS: m/z 559.2 [M+l]+. 1H NMR (400 MHz, DMSO-d6): 8 7.42-7.46 (m, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.73 (dd, J=8.8 Hz, 2.8 Hz, 1H), 7.85 (d, J=8.0 Hz, 1H), 7.90-7.94 (m, 2H), 8.01 (d, J=2.4 Hz, 1H), 8.53 (s, 2H), 8.70 (d, J=4.4 Hz, 1H), 8.93 (s, 1H), 10.79 (s, 1H), 10.96 (br, lH).

EXAMPLE 10: Chlor0-N-(4—chloro(pyridinyl)phenyl)(N-(3-(3- (hydroxyamino)—3-oxopropeny])phenyl)sulfamoyDbenzamide (compound 254) Step 10:1. 2-(3-Nitrophenyl)—l,3-dioxolane (compound 8002) A mixture of 3-nitrobenzaldehyde (7.0 g, 46.3 mmol), ethylene glycol (14.4 g, 231.5 mmol), p-toluenesulfonic acid (0.79 g, 4.6 mmol) in toluene (80 mL) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was quenched with aqueous sodium onate and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous Na2S04 and evaporated in vacuo to afford compound 8002 as a yellow oil (8.6 g, 95%). 1H NMR (400 MHz, CDC13)Z 8 4.05-4.11 (m, 2H), 4.12-4.16 (m, 2H), 5.89 (s, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 8.21-8.24 (m, 1H), 8.35-8.36 (m, 1H).

Step 10b. -Dioxolanyl)aniline (compound 8003) A mixture of 8002 (215 mg, 1.1 mmol), Pd/C (100 mg, 50%) in ethanol (10 mL) was stirred under hydrogen at room temperature overnight. The e was d and the filtrate was evaporated in vacuo. The crude product was purified by column chromatography (hexanes/ethyl acetate: 8/ 1) to afford compound 8003 as a yellow solid (100 mg, 55%). LCMS: m/z 166.1 [M+l]+. 1H NMR (400 MHz, DMSO'd6): 8 3.86-4.03 (m, 4H), 5.10 (s, 1H), 5.55 (s, 1H), 6.54 (d, J=7.6 Hz, 2H), 6.63 (s, 1H), 6.99 (t, J=7.6 Hz, 1H).

Step 10c. Methyl 4—(N-(3—(1,3-dioxolanyl)phenyl)sulfamoyl)—2—chlorobenzoate (compound 8004) 2012/020092 A mixture of 8003 (1.12 g, 6.8 mmol), 3003 (2.21 g, 8.2 mmol), anhydrous pyridine (1.3 g, 16.4 mmol) in anhydrous CH2C12 (10 mL) was heated at reflux for 30 min. The mixture was quenched with water and adjusted pH to 2-3 with HCl (1.0M). The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude t was purified by column chromatography (hexanes/ethyl acetate: 10/1) to afford compound 8004 as a yellow oil (2.16 g, 80%). LCMS: m/z 398.1 [M+1]+. 1H NMR (400 MHZ, 6): 5 3.87 (s, 3H), 3.91-3.93 (m, 2H), 3.94-3.96 (m, 2H), 5.66 (s, 1H), 7.10- 7.17 (m, 3H), 7.29 (t, J=8 Hz, 1H). 7.77 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 10.58 (s, 1H).

Step 10d. 4-(N-(3-(1,3-Dioxolanyl)phenyl)sulfamoyl)—2-chlorobenzoic acid (compound 8005) LiOH (264 mg, 6.25 mmol) was added into a solution of 8004 (500 mg, 1.25 mmol) in THF/HzO (5 mL /5 mL). The e was stirred at room temperature overnight. The mixture was quenched with HCl (1 M) and adjusted pH to 1-2. The ing mixture was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo to afford compound 8005 as a red solid (450 mg, 94%). LCMS: m/z 384.1 . 1H NMR (400 MHz, DMSO-dg): 3.91-3.93 (m, 2H), 3.95-3.97 (m, 2H), 5.67 (s, 1H), 7.11-7.18 (m, 3H), 7.30 (t, J=8.0 Hz, 1H). 7.74 (dd, J=8.4 Hz, 2.0Hz, 1H), 7.83 (d, J=1.6 Hz, 1H), 7.92 (d, J=8.4 Hz, 1H), 10.57 (s, 1H).

Step 10c. 3-(1,3-Dioxolanyl)phenyl)sulfamoyl)chloro—N-(4-chloro—3—(pyridin yl)phenyl)benzamide und 8006) A mixture of 8005 (284 mg, 0.74 mmol), 1-8 (100 mg, 0.49 mmol), HATU (373 mg, 0.98 mmol), DIPEA (159 mg, 1.23 mmol) in anhydrous DMF (5 mL) was stirred overnight. The mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography (hexanes/ethyl acetate: 5/ 1) to afford compound 8006 as a yellow solid (248 g, 88%). LCMS: m/z 570.2 [M+1]+.

Step 10f. 2—chloro-N—(4-chloro-3—(pyridin-2—yl)phenyl)(N—(3-formylphenyl) sulfamoyl)benzamide (compound 8007) A mixture of 8006 (120 mg, 0.18 mmol) and HCl (5 mL) in THF/HZO (5 mL/5 mL) was refluxed for 1 h. The mixture was quenched with water and extracted with ethyl PCT/U52012/020092 acetate. The combined organic layers were washed with water and brine until pH 7. The organic layer was dried over anhydrous NaZSO4 and evaporated in vacuo. The crude product was purified by column chromatography (hexanes/ethyl acetate: 5/1) to afford nd 8007 as a yellow solid (90 mg, 82%). LCMS: m/z 526.2 [M+1]+. 1H NMR (400 MHz, 6): 7.42-7.50 (m, 2H), 7.53-7.57 (m, 2H), .72 (m, 5H), 7.81- 7.86 (m, 2H), 7.91 (dd, J=7.6Hz, 1.6Hz, 1H), 7.94 (br, 1H), 7.96 (d, J=2.4Hz, 1H), 8.70 (d, J=4.8 Hz, 2H), 9.94 (s, 1H), 10.84 (s, 1H), 10.91 (s, 1H).

Step 10g. (E)-methyl 3-(3-(3-chloro(4-chloro(pyridinyl)phenylcarbamoyl) phenylsulfonamido)phenyl)acrylate (compound 8008) A mixture of 8007 (110 mg, 0.21 mmol), -(dimethoxyphosphoryl) acetate (58 mg, 0.32 mmol) and sodium methoxide (34 mg, 0.63 mmol) in anhydrous DMF was stirred at room temperature overnight. The mixture was quenched with HCl (1 M) and extracted with ethyl e. The combined organic layers were washed with water and brine, dried over ous sodium sulfate and ated in vacuo. The crude product was purified by column chromatography (CHzClz/ethyl acetate: 6/1) to afford compound 8008 as a yellow solid (45 mg, 37%). LCMS: m/z 582.2[M+1]+. 1H NMR (400 MHz, DMSO-d6): 3.72 (s, 3H), 6.52 (d, J=16.4 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.34 (t, J=7.2 Hz, 1H), 7.41-7.49 (m, 3H), 7.55-7.61 (m, 2H), 7.66-7.72 (m, 2H), 7.80—7.86 (m, 2H), 7.90 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.93-7.96 (m, 2H), 8.70 (d, J=4.4 Hz, 1H), 10.7] (s, 1H), 10.83 (s, 1H).

Step 10h. (E)Chloro-N-(4-chloro(pyridin—2-yl)phenyl)(N-(3-(3- (hydroxyamino)oxopropenyl)phenyl)sulfamoyl)benzamide und 254) Compound 8008 (45 mg, 0.077 mmol) was taken into NH20H methanolic solution (10 mL, 1.79 M). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was adjusted pH to 7~8 with acetic acid and concentrated. The residue was triturated with water and filtered. The collected solid was purified with prep-HPLC to afford compound 254 as an off-white solid (13 mg, 31% yield). M.p.: 2l7~22l°C LCMS: m/z 583.2 [M+l]+. 1H NMR (400 MHz, DMSO-d6): 6.41 (d, J=15.6 Hz, 1H), 7.12 (d, J=7.6, 1H), 7.18 (s, 1H), 7.25-7.38 (m, 4H), 7.42-7.45 (m, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.66—7.72 (m, 2H), 7.80—7.90 (m, 1H), 7.90—7.97 (m, 3H), 8.70 (d, J=4.4 HZ, 1H), 10.71 (s, 1H), 10.80 (br, 1H), 10.84 (s, 1H).

PCT/U52012/020092 EXAMPLE 11: 2-(4-((3-Chloro(4-chloro(pyridin-2—yl)phenylcarbamoyl) sulfonamido)methyl)piperidinyl)-N-hydroxypyrimidine—5-carboxamide (compound 90) Step 11:1. tert-Butyl 4-((3-chloro(methoxycarbonyl)phenylsulfonamido)methyl) piperidine-l- carboxylate (compound 9001) To a mixture of tert—butyl 4-(aminomethyl)piperidinecarboxylate (570 mg, 2.6 mmol) and 3003 (600 mg, 2.2 mmol) in romethane (10 mL) was added triethylamine (0.6 mL, 4.4 mmol). The mixture was stirred at room temperature overnight.

The reaction mixture was diluted with ethyl acetate and washed with 1N HCl. The ethyl acetate layer was concentrated in vacuo and purified by column chromatography (hexanes: ethyl acetate = 5:1) to give compound 9001 as a white solid (610 mg, 62% yield). LCMS: m/z 445.1 [M-1]‘. 1H NMR (400 MHz, DMSO-d6): 8 0.87-0.98 (m, 2H), 1.37 (s, 9H), 1.49-1.60 (m, 3H), 2.62-2.70 (m, 4H), 3.86 (br, 2H), 3.90 (s, 3H), 7.84 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.94 (t, J=5.6 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H).

Step 11b. 4—(N—((1-(tert-Butoxycarbonyl)piperidinyl)methyl)sulfamoyl)—2- chlorobenzoic acid (compound 9002) To the solution of 9001 (610 mg, 1.4 mmol) in THF (16 mL) and H20 (8 mL) was added LiOH (286 mg, 12.0 mmol). The mixture was stirred at room temperature for 3 h.

The reaction mixture was acidified to pH=5 with 1N HCl and extracted with ethyl acetate.

The ethyl acetate layer was dried over Na2S04, filtered and concentrated in vacuo to give compound 9002 as a white solid (530 mg, 90% yield). 1H NMR (400 MHz, DMSO-d6): 5 0.89—0.98 (m, 2H), 1.37 (s, 9H), .61 (m, 3H), .69 (m, 4H), 3.89 (d, J=12.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 1H), 7.87 (s, 1H), 7.91 (t, J=6.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H).

Step 11c. tert-Butyl 4-((3-chloro(4-chloro(pyridinyl)pheny1carbamoy1)phenyl sulfonamido)methyl)piperidinecarboxylate (compound 9003) To a e of 9002 (530 mg, 1.2 mmol) and 1-8 (200 mg, 1.0 mmol) in DMF (2.0 mL) was added DIPEA (300 mg, 2.3 mmol) followed by HATU (733 mg, 1.9 mmol). The resulting solution was stirred at room temperature overnight. The reaction e was poured into water and extracted with ethyl acetate. The organic phase was washed with NH4Cl solution, water and brine, dried over Na2804 and concentration in vacuo. The crude solid was purified by column chromatography eluted with ethyl e:dichloromethane = 3:1 to give compound 9003 as a yellow solid (120 mg, 16%).

LCMS: m/z 619.2 [M+1]+. 1H NMR (400 MHz, 6): 8 0.90—1.09 (m, 2H), 1.38 (s, 9H), 1.52-1.63 (m, 3H), 2.66-2.69(m, 4H), 3.90 (d, J=10.8Hz, 2H), 7.40-7.47 (m, 1H), PCT/U52012/020092 7.58—7.60 (m, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.75 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.84 (s, 2H), 7.90-7.92 (m, 3H), 8.01 (d, J=2.0 Hz, 1H), 8.65, 8.70 (2 doublet peaks, J=5.2Hz, 1H), .87 (s, 1H).

Step 11d. 2-Chloro-N-(4-chloro(pyridinyl)phenyl)(N-(piperidin ylmethyl)sulfamoyl)benzamide (compound 9004) To the solution of 9003 (120 mg, 0.2 mmol) in dichloromethane (1 mL) was added TFA (1 mL). The mixture was stirred at room temperature for 1h. The reaction solution was trated. The residue was dissolved with ethyl acetate and washed with NaHC03 on. The ethyl acetate layer was dried over Na2S04, filtered and concentrated in vacuo to give nd 9004 as a yellow solid (100 mg, 99% yield).

LCMS: m/z 519.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.10—1.15 (m, 2H), 1.57 (br, 1H), 1.69 (d, J: 13.2Hz, 2H), 2.60-2.69 (m, 4H), 3.10 (d, J=12.0 Hz, 2H), 7.43 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.85 (s, 2H), 7.91-7.94 (m, 2H), 8.01 (s, 1H), 8.71 (d, J=4.4 Hz, 1H), 10.88 (s, 1H).

Step lle. Ethyl 2-(4-((3-chloro—4-(4-chloro(pyridinyl)phenylcarbamoyl)phenyl sulfonamido)methyl)piperidinyl)pyrimidinecarboxylate und 9005) To the on of 9004 (100 mg, 0.2 mmol) and Et3N (0.2 mL, 1.4 mmol) in DCM (2 mL) was added 4005 (39 mg, 0.2 mmol). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with 1N HC1. The ethyl acetate layer was dried over , filtered and concentrated to give compound 9005 as a yellow solid (135 mg, 96% yield). LCMS: m/z 669.3 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.10-1.18 (m, 2H), 1.29 (t, J=7.2Hz, 3H), 1.76 (d, J- 6.0Hz, 2H), 2.68-2.72 (m, 2H), 2.94-3.00 (m, 2H), 4.27 (q, J=6.8Hz, 2H), 4.72 (d, J=12.8 Hz, 2H), 7.45 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 1H), 7.86 (s, 2H), 7.92-8.01 (m, 3H), 8.71 (d, J=4.8 Hz, 1H), 8.77 (s, 2H), 9.28 (br, 1H), 10.89 (s, 1H).

Step 11f. 2-(4-((3-Chloro—4—(4-chloro(pyridinyl)phenylcarbamoyl) phenylsulfonamido)methyl)piperidinyl)—N-hydroxypyrimidine—5—carboxamide (compound 90) Compound 9005 (135 mg, 0.2 mmol) was taken into NHzOH methanolic solution (1.79M, 10mL). The resulting mixture was stirred in sealed tube at room temperature for 3 h. TLC showed reaction complete. Acetic acid was added to adjust pH to 6~7 ed by the addition of ice-water. The reaction mixture was d, washed with water. The crude product was purified by prepared HPLC to afford compound 90 as a white solid (30mg, PCT/U52012/020092 22% yield). M.p.: 172—17300 LCMS: m/z 656.2 [M+1]+. 1H NMR (400 MHz, DMSO- d6): 6 1.04—1.07 (m, 2H), 1.73-1.76 (m, 3H), 2.70—2.72 (m, 2H), 2.89—2.95 (m, 2H), 4.69 (d, J=12.8 Hz, 2H), 7.45 (t, J=6.0 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.86 (s, 2H), 7.91-7.95 (m, 2H), 8.02 (s, 1H), 8.65 (s, 2H), 8.71 (d, J=4.4 Hz, 1H), 8.99 (br, 1H), 10.88 (s, 1H), 10.99 (br, 1H).

EXAMPLE 12: 2-Chloro-N-(4-chloro(pyridinyl)phenyl)(N-(2-(4- (hydroxycarbamoyl)phenoxy)ethyl)sulfamoyl)benzamide (compound 266) Step 122. 2-Chloro—4—(N-(2—(4-(ethoxycarbonyl)phenoxy)ethyl)sulfamoyl)benzoic acid (compound 1001) To a e of ethyl 4-(2—amin0ethoxy)benzoate (330 mg, 1.6 mmol) and 3003 (400 mg, 1.6 mmol) in dichloromethane (10 mL) was added triethylamine (0.6 mL, 4.4 mmol).

The mixture was stirred at room temperature ght. The on mixture was diluted with ethyl acetate and washed with 1N HCl. The ethyl e layer was concentrated in vacuo and purified by column chromatography (dichloromethane: MeOH = 50:1) to give compound 1001 as a yellow solid (270 mg, 40% yield). LCMS: m/z 428.0 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 8 1.30 (t, J=7.2 Hz, 3H), 3.20—3.22 (m, 2H), 4.04 (t, J=4.8 Hz, 2H), 4.27 (q, J=7.2Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.77 (s, 1H), 7.87 (d, J=8.4 Hz, 2H), 8.12 (br, 1H).

Step 12b. Ethyl 4-(2—(3-chloro—4-(4-chlor0(pyridinyl)phenylcarbamoyl)phenyl sulfonamido)ethoxy)benzoate (compound 1002) To a mixture of compound 1001 (270 mg, 0.6 mmol) and l-8 (108 mg, 0.5 mmol) in DMF (2.0 mL) was added DIPEA (164 mg, 1.3 mmol) followed by HATU (289 mg, 0.8 mmol). The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The c phase was washed with 1N HCl solution, water, brine and dried over Na2S04. The crude solid was purified by column chromatography eluted with romethane/MeOH = 100/1 to give compound 1002 as a yellow solid (130 mg, 33%). LCMS: m/z 614.2 [M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 1.28 (t, z, 3H), 3.24-3.26 (m, 2H), 4.06- 4.09 (m, 2H), 4.25 (q, J=6.8Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 7.43—7.47 (m, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H), 7.80-7.95 (m, 7H), 8.01 (s, 1H), 8.24-8.27 (m, 1H), 8.70-8.72 (d, J=4.0 Hz, 1H), 10.86 (s, 1H).

Step 12c. 2-Chloro—N-(4-chloro—3—(pyridin—2—yl)phenyl)—4-(N—(2-(4- (hydroxycarbamoyl)phenoxy)ethyl)sulfamoyl)benzamide (compound 266) 2012/020092 Compound 1002 (130 mg, 0.2 mmol) was taken into NHzOH methanolic solution (1.79M, 10mL). The resulting mixture was stirred in sealed tube at room temperature for 3 h. TLC showed reaction complete. 1N HCl was added to adjust pH to 6N7 followed by the addition of ice-water. The reaction mixture was filtered, washed with water. The crude product was purified by prep-HPLC to afford compound 266 as a yellow solid (41mg, 32% yield). mp: 138-139°C. LCMS: m/z 601.2 [M+1]+. 1H NMR (400 MHz, DMSO—d6): 3.23 (t, J=4.0 Hz, 2H), 4.06 (t, J=4.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 7.45 (t, J=6.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.68-7.76 (m, 4H), 7.86-7.96 (m, 4H), 8.02 (s, 1H), 8.19 (d, J=4.0Hz, 1H), 8.71 (d, J=4.4 Hz, 1H), 8.89 (br, 1H), 10.88 (s, 1H), 11.05 (s, 1H).

EXAMPLE 13: 2-(4-((5-(3-(1H-Benz0[d]imidazol-Z-yl)—4-chlor0phenylcarbamoyl) pyridin-Z-ylamino)methyl)piperidinyl)-N-hydroxypyrimidine-S- carboxamide (compound 91) Step 13a. 6-Bromo—2—methylnicotinaldehyde und 1102) To a stirred solution of 3,6-dibromomethylpyridine (2.0 g, 8.0 mmol) in dry THF (20 mL) was added n-BuLi (1.6M, 6.0 mL) dropwise at -78°C. When the addition was complete the reaction was continued for 1 h. Dichloromethane (642.4 mg, 8.8 mmol) was added at -78°C and continued to stir for 1 h. The reaction was allowed to warm to room temperature followed by addition of HCl (1M, 10 mL) .The mixture was extracted with ethyl acetate. The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography eluted with dichloromethane/ ol (30:1) to afford compound 1102 as a white solid (1.4 g, 90%).

Step 13b. 6-Bromomethylnicotinic acid (compound 1103) To a stirred solution of compound 1102 (1.4 g, 6.7 mmol) in acetone (20 mL) was added Jones reagent (2.67M, 5.2ml) at 0°C. The reaction e was warmed to room temperature and d for 30 min. Saturated NaHC03 solution was added to adjust pH=5- 6. The mixture was ted with ethyl acetate. The organic layer was washed with brine and concentrated. The crude product was purified by column chromatography eluted with ethyl e/ hexanes (1 :8) to afford compound 1103 as a white solid (1.0 g, 66%). 1H NMR (400 MHz, CDCl3)I 8 2.87 (s, 3H), 7.46 (d, J=8.4Hz, 1H), 8.15 (d, J=8.4Hz, 1H).

Step 13c. N—(3-(1H-benzo[d]imidazolyl)—4-chlorophenyl)bromo methylnicotinamide (compound 1104) Compound 1103 (1.0 g, 4.6 mmol) was added to a mixture of compound 2-3 (1.2 g, 4.6mmol), HATU (3.5 g, 5.5 mmol) and Eth (19 mL, 13.8 mmol) in dichloromethane (30 PCT/U52012/020092 mL). The reaction mixture was stirred at room temperature overnight. The mixture was quenched with water, extracted with dichloromethane, trated. The crude t was purified by column chromatography eluted with s/ethyl acetate (1:1) to afford compound 1104 as a white solid (1.0 g, 50%). LCMS: In/Z 443.1[M+1]+.

Step 13d. tert-Butyl 4-((5-(3 -(1H-benzo[d]imidazolyl)chlorophenylcarbamoyl) methyl pyridinylamino)methyl)piperidinecarboxylate (compound 1105) To a stirred solution of compound 1104 (500 mg, 1.13 mmol) in i-PiOH (10 mL) was added tert-butyl 4-(aminomethyl)piperidinecarboxylate (930 mg, 4.4 mmol) and K2C03 (1.2 g, 8.7 mmol). The mixture was stirring under 100°C for 48 h. The mixture was quenched with water and extracted with dichloromethane. The crude product was purified by column chromatography eluted with hexane/ethyl acetate (1:1) to afford compound 1105 as a yellow solid (250 mg, 38% yield). LCMS: m/z 575.4[M+1]+ 1H NMR (400 MHz, DMSO-d6): 6 1.06-1.12 (m, 45 (s, 9H), 1.73-1.76 (m, 3H), 2.50 (s, 3H) ,2.73- 2.75 (m, 2H), 3.25 (s, 2H), 3.98-4.02 (m, 2H), 6.43 (d, J: 8.8Hz,1H),7.02—7.05 (m, 1H), 7.25-7.34 (m, 2H), 7.63-7.66 (m, 3H), 7.76 (d, J= 7.6Hz ,1H), 7.92 (d, J= 8.8Hz, 2H), 8.41 (s, 1H), 10.28 (s, 1H),12.72 (s, 1H).

Step l3e. Methyl (5—(3-(1H-benzo[d]imidazolyl)—4—chlorophenylcarbamoyl)—6- methyl nylamino)methyl)piperidinyl)pyrimidinecarboxylate (compound 1106) To a stirred solution of compound 1105 (70 mg, 0.12 mmol) in dichloromethane was added TFA (3 mL). The mixture was stirred for 30 min. The reaction solution was concentrated and the residue was dissolved in dichloromethane (10 mL). To the solution was added 4005 (31 mg, 0.14 mmol) and Eth (lmL). The ing mixture was stirred at room temperature for 30 min and concentrated. The residue was purified by column chromatography eluted with hexanes/ethyl acetate (1:1) to afford compound 1106 as a yellow solid (70 mg, 94%). LCMS: m/z 611.3 [M+1]+ 1H NMR (400 MHz, DMSO-d6): 8 1.08—1.14 (m, 72-2.02 (m, 4H), 2.45 (s, 3H), 2.94—3.05 (m, 3H), 3.80 (s, 3H), 4.77 (d, J= 13.2Hz, 2H), 6.39 (d, J= 8.8Hz ,1H), 7.03 (d, J= 5.2Hz, 1H), 7.23-7.27 (m, 2H), 7.58-7.60 (m, 2H), 7.71 (d, J: 7.2Hz ,1H), 7.87 (d, J: 7.6Hz, 2H), 8.35 (s, 1H), 8.77 (s, 2H), 10.23 (s, 1H), 12.69 (s, 1H).

Step 13f. 2-(4—((5-(3-(1H-Benzo[d]imidazol-2—yl)—4-chlorophenylcarbamoyl) methylpyridinylamino)methyl)piperidinyl)-N—hydroxypyrimidinecarboxamide (compound 91) PCT/U52012/020092 Compound 1106 (70 mg, 0.11 mmol) was taken into NHzOH methanolic solution (10 mL, 1.79 M). The mixture was stirred at room temperature for 40 min. The reaction mixture was adjusted pH to 8-9 with acetic acid and trated. The residue was purified by HPLC to afford the titled compound 91 as a white solid (37 mg, 53%).

M.p.: 194-196°C. LCMS: m/z 612.3[M+1]+1H NMR (400 MHz, DMSO-d6): 5 1.13-1.18 (m, 2H), 1.78-2.00 (m, 3H), 2.45 (s, 3H), 2.91- 2.98 (m, 2H), 3.22 (s, 2H), 4.73 (d, J: 12.4Hz, 2H), 6.38 (d, J= 8.4Hz ,1H), 7.00—7.02 (m, 1H), 7.24—7.26 (m, 2H), 7.57-7.60 (m, 3H), 7.69-7.71 (d, J: 7.2Hz ,1H), 7.86 (d, J: 8.8Hz,1H), 8.35 (s, 1H), 8.65 (s, 2H), 8.97 (br, 1H),10.23 (s, 1H), 10.98 (br, 1H), 12.68 (s, 1H).

E 14: 4-Chloro(5-(dimethylamin0)—lH-benzo[d]imidazol yl)phenylcarbamoyl)methoxybenzylamino)—N-hydroxypyrimidine-S-carboxamide und 258) Step 14a. Methyl 3—(hydroxymethyl)methoxybenzoate (compound 1202) To a stirred solution of yl 5-methoxyisophthalate (1.0 g, 4.5 mmol) in THF (10 mL) was added DIBAL-H (6.6 mL, 6.6 mmol). The reaction mixture was stirred for overnight at room temperature. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over NaZSO4 and concentrated.

The crude t was purified by column chromatography eluted with hexanes/EA (2: 1) to afford compound 1202 as a yellow solid (600 mg, 68% yield).

LCMS: m/z 197.1[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 3.80 (s, 3H), 3.85 (s, 3H), 4.53 (d, J=6.0 Hz, 2H), 5.35 (t, J=5.8 Hz, 1H), 7.15 (s, 1H), 7.31 (s, 1H), 7.54 (s, 1H).

Step 14b. Methyl 3-(bromomethy1)methoxybenzoate und 1203) To a stirred solution of compound 1202 (800 mg, 4.0 mmol) in dichloromethane (10 mL) was added PBr3 (0.4 mL, 4.3 mmol). The reaction mixture was stirred for 1 h at room temperature. The reaction was diluted with ethyl acetate and washed with water and brine.

The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate (5:1) to obtain compound 1203 as a yellow oil. (640 mg, 61% yield). 1H NMR (400 MHz, CDClg): 5 3.85 (s, 3H), 3.92 (s, 3H), 7.12 (br, 1H), 7.49 (br, 1H), 7.65 (br, 1H).

Step 14c. Methyl 3-(azidomethyl)methoxybenzoate (compound 1204) To a stirred solution of nd 1203 (640 mg, 2.5 mmol) in DMF (5 mL) was added NaN3 (1.1 g 16.9 mmol). The reaction e was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate and washed with water and brine.

WO 94328 The organic phase was dried over Na2804 and concentrated. The crude product was purified by column chromatography eluted with hexanes/ethyl acetate (5: 1) to afford nd 1204 as a yellow oil (500 mg, 91% yield). LCMS: m/z 263.2[M+1+41]+.

Step 14d. Methyl 3-(aminomethyl)methoxybenzoate (compound 1205) To a d solution of compound 1204 (500 mg, 2.3 mmol) in THF (10 mL) was added PPh3 (650 mg, 2.5 mmol) and stirred for 30 min. Water (100 mg, 5.5 mmol) was added. The mixture was warmed to 60°C and stirred for 2 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over Na2SO4 and concentrated. The crude product was purified by column chromatography eluted with dichloromethane/MeOH (50:1) to afford compound 1205 as a yellow oil (300 mg, 68% yield). LCMS: m/z 196.1[M+l]+.

Step 14e. 3-(Aminomethy1)methoxybenzoic acid (compound 1206) Compound 1205 (300 mg, 1.5 mmol) was added to a e of LiOH (180 mg, 7.5 mmol) in EtOH (2 mL) and H20 (2 mL). The reaction mixture was stirred at room temperature for 3 h. The on mixture was adjusted pH to 6 with 2N HC1. The mixture was concentrated and directly used to next step without further purification.

Step 14f. 3—Methoxy((5-(methoxycarbony1)pyrimidiny1amino)methy1)benzoic acid (compound 1207) To a stirred solution of 1206 (200 mg, 1.0 mmol) and Et3N (300 mg, 3.0 mmol) in dichloromethane (5 mL) was added 4005 (176 mg, 1.0 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate and washed with water and brine. The c phase was dried over Na2804, then concentrated. The crude product was purified by column chromatography eluted with dichloromethane/MeOH (50: 1) to afford compound 1207 as a yellow solid (110 mg, 31% yield). LCMS: m/z 318.2[M+1]+. 1H NMR (400 MHZ, DMSO—d6): 8 3.78 (s, 3H), 3.79 (s, 3H), 4.60 (d, J=6.4 Hz, 2H), 7.13 (s, 1H), 7.31 (s, 1H), 7.49 (s, 1H), 8.67 (t, J=6.0 Hz, 1H), 8.75 (s, 2H).

Step 14g. Methyl 2-(3—(4-chloro(5-(dimethy1amino)-1H—benzo[d]imidazoly1)phenyl carbamoyl)methoxybenzylamino)pyrimidinecarboxylate und 1208) To a stirred solution of compound 1207 (110 mg, 0.3 mmol), 2—3 (90 mg, 0.3 mmol) and DIPEA (90 mg, 0.7 mmol) in DMF was added HATU (160 mg, 0.4 mmol). The reaction mixture was d at room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic phase was dried over Na2S04 and concentrated. The crude t was purified by column chromatography eluted with hexanes/ethyl acetate (1:1) to afford compound 1208 as a yellow solid (60 mg, 30% . LCMS: m/z 586.3[M+1]+.

Step 14h. 2-(3-(4-Chloro(5-(dimethy1amino)—1H-benzo[d]imidazol—2- yl)phenylcarbamoyl)methoxybenzylamino)-N-hydroxypyrimidinecarboxamide (compound 258) Compound 1208 (70 mg, 0.1 mmol) was taken into NHZOH methanolic solution (10 mL, 1.79 M). The mixture was stirred at room temperature for 40 min. The reaction mixture was adjusted pH to 8-9 with acetic acid and concentrated. The residue was purified by prep-HPLC to afford the titled compound 258 as a yellow solid (35 mg, 50%).

M.p.: 158—159°C. LCMS: m/z 587.3[M+1]+. 1H NMR (400 MHz, DMSO-d6): 5 2.93 (s, 6H), 3.82 (s, 3H), 4.60 (d, J=6.0 Hz, 2H), 6.78-6.97 (m, 2H), 7.10 (s, 1H), 7.41 (s, 1H), 7.49-7.52 (m, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.94 (dd, J=8.8, 2.8 Hz, 1H), 8.30 (t, J=6.2 Hz, 1H), 8.37 (br, 1H), 8.61 (s, 2H), 8.94 (br, 1H), 10.42 (s, 1H), 10.98 (br, 1H), 12.17, 12.30 (two single peaks, 1H).

EXAMPLE 15: 2-((3-(4-Ch10r0(5-(dimethylamino)-1H-benzo[d]imidazol—Z- yl)phenylcarbam0yl)meth0xybenzyl)(methyl)amin0)-N-hydroxypyrimidine-S- amide (compound 259) Step 153. Methyl 3-methoxy((methylamino)methyl)benzoate (compound 1301) To a solution of 1203 (150 mg, 0.6 mmol) in DMF (3 mL) was added methylamine methanol solution (2.5 mL). The reaction mixture was stirred at room temperature for 10 min. Water (10 mL) was added to the reaction mixture and the resulting reaction mixture was extracted with ethyl acetate (10 mL x 2). The combined c layers were washed with water. The organic phase was dried over Nast4, filterted and ated to give product 1301 as light yellow oil (100 mg, 83%). LCMS: m/z 210.1 [M+1]+. 1H NMR (400 MHZ, CDC13): 5 2.45 (s, 3H), 3.77 (s, 2H), 3.85 (s, 3H), 3.92 (s, 3H), 7.10 (s, 1H), 7.45 (s, 1H), 7.59(s, 1H).

Step 15b. Methyl 3-((tert-butoxycarbonyl(methyl)amino)methyl)-5—methoxybenzoate und 1302) (Boc)2O (154 mg, 0.7 mmol), NEt3 (101 mg, 1.0 mmol) and DMAP (6 mg, 0.05 mmol) were added to a on of compound 1301 (100 mg, 0.5 mmol) in anhydrous dichloromethane (10 mL). The reaction mixture was d at room temperature for 2 h until TLC indicated that compound 1301 had been consumed. The reaction mixture was concentrated and the residue was purified by column chromatography eluted with CHzClz: MeOH (10: 1) to afford the titled compound 1302 as light yellow oil (110 mg, 75%).

Step 15c. rt-Butoxycarbonyl(methyl)amino)methyl)—5—methoxybenzoic acid (compound 1303) NaOH aqueous solution (4.0M, 10 mL) was added to a solution of compound 1302 (160 mg, 0.5 mmol) in methanol (5 mL). The solution was stirred at room temperature for 2 h. The reaction e was acidified to pH 3~4 with conc. HCl solution and extracted with ethyl e (10 mL x 2) and dried over Na2S04. The title compound 1303 was obtained as a yellow solid after concentration (100 mg, 66%). 1H NMR (400 MHz, CDC13)I 8 1.42 (s, 9H), 2.78 (s, 3H), 3.78 (s, 3H), 4.37 (s, 2H), 6.96 (s, 1H), 7.44 (s, 1H), 7.50 (s, 1H).

Step 15d. tert-Butyl 3-(4-chloro(5-(dimethylamino)-1H-benzo[d]imidazolyl) phenylcarbamoyl)methoxybenzyl(methyl)carbamate (compound 1304) Compound 2-3 (97 mg, 0.3 mmol) was added to a solution of compound 1303 (100 mg, 0.3 mmol), HATU (137 mg, 0.4 mmol) and DIPEA (78 mg, 0.6 mmol) in DMF (4 mL). The reaction e was stirred at room temperature overnight. The mixture was d with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic layer was washed with water and dried over Na2804. The titled compound 1304 was obtained as yellow solid after concentration (150 mg, 89%). LCMS: m/z 564.3 [M+1]+.

Step 15e. N—(4-Chloro(5-(dimethylamino)-1H-benzo[d]imidazol—2—yl)phenyl)—3- methoxy((methylamino)methyl)benzamide (compound 1305) nd 1304 (150 mg) was dissolved in trifluoroacetic acid (10 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction was then concentrated to remove most trifluoroacetic acid. The residue was adjusted to pH 7~8 with saturated aqueous NaHC03 solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over Na2S04 and concentrated. The crude product was purified by column chromatography eluted with CH2C12: MeOH (20: 1) to afford the titled compound 1305 as a light yellow solid (50 mg, 40%). 1H NMR (400 MHz, CDCl3)I 8 2.69 (s, 3H), 3.00 (s, 6H), 3.76 (s, 3H), 3.91 (s, 2H), 6.85 (s, 2H), 6.90 (dd, J=9.2 Hz, 2.4 Hz, 1H), 7.33~7.38 (m, 2H), 7.52 (d, z, 1H), 7.58 (s, 1H), .11 (m, 2H), 9.03 (br, 1H).

Step 15f. Ethyl 2-((3 -(4-chloro-3 -(5-(dimethylamino)-1H—benzo[d]imidazolyl)phen ylcarbamoyl)-5—methoxybenzyl)(methyl)amino)pyrimidinecarboxylate (compound 1306) PCT/U52012/020092 To a solution of compound 1305 (50 mg, 0.1 mmol) in dichloromethane was added compound 4005 (19 mg, 0.1 mmol) and NEt3 (30 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction e was washed with water and concentrated to afford the title compound 1306 (90 mg). LCMS: 614.3 [M+1]+. 1H NMR (400 MHz, CD03) 5 1.36 (t, J=7.2Hz, 3H), 3.00 (s, 6H), 3.24 (s, 3H), 3.85 (s, 3H), 4.34 (q, J=7.2Hz, 2H), 4.99 (s, 2H), 6.87~6.92 (m, 2H), 6.98 (s, 1H), 7.32 (s, 2H), 7.47 (d, J=9.2 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 8.23~8.24 (m, 3H), 8.90 (s, 2H).

Step 15g. (4-Chloro(5-(dimethylamino)—1H-benzo[d]imidazol yl)phenylcarbamoyl)methoxybenzyl)(methyl)amino)—N-hydroxypyrimidine carboxamide (compound 259) Compound 1306 (90 mg, 0.1 mmol) was dissolved in NHZOH methanol solution (20 mL, 1.79M). The mixture was stirred at room temperature for 1h. The reaction mixture was adjusted pH to 8-9 with 2N HCl and evaporated in vacuo. The residue was triturated with water to afford the crude product. The crude product was r purified by prep- HPLC to afford compound 259 as a yellow solid (18 mg, 20%). M.p.: 207—208°C. LCMS: m/z 601.3 [M+l]+. 1H NMR (400MHz, DMSO-d6): 8 2.93 (s, 6H), 3.18 (s, 3H), 3.82 (s, 3H), 4.96 (s, 2H), .88 (m, 2H), 7.00 (s, 1H), 7.4l~7.51 (m, 3H), 7.57 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 8.37 (s, 1H), 8.71 (s, 2H), 8.98 (br, 1H), 10.42 (s, 1H), 11.03 (s, 1H), 12.15 (s, 1H).

EXAMPLE 16: An in vitro assay which determines the ability of a test compound to inhibit HDAC enzymatic activity HDAC inhibitory activity was ed using the Biomol Color de Lys system (AK-500, , Plymouth Meeting, PA). Briefly, HeLa cell nuclear extracts were used as a source of HDACs. Different trations of test compounds were serially diluted in dimethylsulfoxide (DMSO) and added to HeLa cell nuclear extracts in the presence of a colorimetric artificial ate. Final assay conditions ned 50 mM Tris/Cl, pH 8.0, 137 mM NaCl, 2.7 mM KCl and 1 mM MgC12. Reactions were carried out at room temperature (25°C) for 1 hour before addition of developer for termination. Relative enzyme activity was measured in the WALLAC Victor II 1420 microplate reader as fluorescence intensity (excitation: 350-3 80 nm; emission: 440-460 nm). Data were analyzed using GraphPad Prism ) with a sigmoidal dose response curve fitting for IC50 calculation. 2012/020092 EXAMPLE 17: An in vitro assay which determines the ability of a test compound to inhibit Hedgehog signalling nds to he tested were dissolved in DMSO to a concentration. of 'l 0 nth/l, and stored at £0951 Te activate the E: edgelieg pathway in the assay cells, an oetylated (lipidanodified) term ot‘the N—terminal fi'agh'ient of the Senie l-ledgehog pretein ((KIZ’Z‘» SHE) was used. This N~termiiial SHE fragment is produced bacterialljy'. See, for example, 'l‘ayler FR, et al, Biochemistry, 2901, 40: 1“ Compounds were tested in the”Giinl_.ue”assay helewg using the cell line iGTl/Z (le), n the cells contain a. l-Eedgehogvrespm‘asive reporter emistruet utilizing Luciferase as the er gene, in this way, Hedgehog pathway signaling activity is h‘ieasured Via. the . respense, lG'l‘l-‘Q {sl 2) cells were plated in a 96~well titer plate (Mil?) at 29,008 cells/"well in full medium {DMEM with ltl‘i/o PBS]. Then plates were placed in the incubator ‘l’or ineuhatien rivemight {til/N), at 37 “(I and 5‘34; (It); After 24 hi the medium was ed with Lueiterase~assay medium (DMEM with {3.5% PBS). Test compounds were thawed and diluted, in assay medium at 3: Will) (about 300~fold) resulting ill a starting concentration of aheut 3.0003 uh’l to 30 11M. Subsequently. lSO ul of each sample was added to the first wells (in. triplicate), The MT? samples were tl’teir diluted at 3~tbld dilutions to a tetal of seven wells, ultimately resulting in a regiment of seven ons in triplicate, for each compound. Next? the pretein ligand OCT~Sl-ll-l was diluted in Lrueiferase-assay medium and added in eaeh well at a final cencentratien of 3.3 gig/ml.

Plates were then returned to the incubator for further ineuhatien O/N, at 37°C and 5% {702. After aheut 24 h, plates were removed item the ineuhater and the medium was aspirated/disearded.

Wells were washed once with, assay hatter [PBS l mM Mg” and l mh’l Call}.

Then it} ill of assay huffer was added te each well. The Lueiferase assay t was prepared as described by the vendot ('l_,uel_.ite kt t li“t)l’t‘l d}, and 513 pl was added to each well. Plates were incubated at mom temperature (RT) fer aheut 30 minutes after which the signals were read, again at RT, on a Te'peo'uht (Packard).

Similar assays were performed using human eell lines (specifically himrah embryonic palatal mesenehyme cells, modified with the Gli—Lue construct as deserihed abuse} in a growth medium 'lii'l‘vl/Sodiuni lrlyruvate w/l 0‘34; PBS, and an assay medium efh'lEM/Sedium Pyravate nil/(3.594; PBS. OCTnSHH was added to reach a final (toneerrttation of l gig/ml, PCT/U52012/020092 Resuiis fifths EBAC h‘ihflpifign ami hcdgchag inhibition assays dcscribcd in es; 16 and 'E 7, respectiveiy, {iii set fm‘th in the table heiewfi which indicates the {€50 dafermh'ied 1'11 math assay 213 feiiows: 43> 1000 BM; 106mm;‘ if > WE} n‘d; 406 11‘»? 3‘: Hi > 10 11M; 14} 11M _>_ 'EV > 1 11M; 1 11M -_> V.

Eh Repm'ter assay SAHA ~49 m4 477 RM Ccmpound A_' LBH 589 ”.7 11M PCT/U52012/020092 \ Compound A EXAMPLE 18 An in vitro assa which determines the abilit of a test com ound to inhibit bindin of Hed eho t0 Smoothened Smo is transiently overexpressed in 293T cells, the membranes are harvested and a ion membrane-competition-binding assay is performed in a 96-well plate with [3H]— Hh-Ag 1.5 added at 2 nM. Membranes are prepared as s. Briefly, approximately 108 cells are transfected with pCMV6-XL5 constructs bearing human Smoothened (OriGene) using Fugene 6 (Roche). After 48 hours cells are ted by scraping in PBS, centrifuged at 1,000 X g for 10 s, and gently resuspended in around 10 ml of a 50 mM Tris pH 7.5, 250 mM sucrose buffer ning an EDTA-free protease inhibitor cocktail (Roche). This cell suspension is then placed in a nitrogen cavitation device (Parr Instrument Co, Moline, USA) and exposed to nitrogen gas (230 psi) for 10 minutes. Lysed cells are released from the device and mged at 20,000 rpm in an SS34 rotor for 20 minutes at 4°C. Supematants are discarded and the pellets are resuspended in 10% sucrose, 50 mM Tris pH 7.5, 5 mM MgC12, 1 mM EDTA solution using three lO-second pulses with a Polytron (Brinkman; Westbury, USA) at a power setting of 12. Using these membranes, ion binding assays are performed according to standard ols.

Briefly, a test nd is incubated for 1 hour at room temperature in the following binding buffer (50mm Tris 7.5, 5 mM MgC12, 1 mM EDTA, 0.1% BSA) containing cell membrane lysate, [3H]-Hh-Ag 1.5 and protease inhibitors. After incubation, the reaction is transferred to a 96—well filter plate, vacuum is applied to pull down the reaction buffer, the wells are washed twice and scintillation solution is added. The reactions are read on a Top Count microplate reader to determine the fraction of [3H]-Hh-Ag 1.5 bound to the smoothened containing membrane preparation.

WO 94328 PCT/U52012/020092 Hh-Ag 1.5 While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that s changes in form and details may be made therein Without departing from the scope of the invention encompassed by the appended claims.

Claims (2)

1. A compound of Formula (I): K O L X B D or a geometric isomer, omer, diastereomer, racemate, or pharmaceutically able salt thereof; wherein n is 0 or 1; Ring A is an ic, saturated or partially unsaturated carbocycle; E is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; L is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl or substituted or unsubstituted saturated or partially unsaturated heterocyclyl; K is halogen; X is absent, -O-, -N(R2)-, -S-, -S(O)-, -S(O)2-, -C(O)-,-C(O)O-, -OC(O)-, -C(O)N(R2)-, - N(R2)C(O)-, -S(O)2N(R2)-, or -N(R2)S(O)2-; R2 is hydrogen or aliphatic; B is a C2-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, aryl, heteroaryl, heterocyclyl, lkyl, lkenyl, alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, larylalkyl, alkenylarylalkenyl, alkenylarylalkynyl, alkynylarylalkyl, alkynylarylalkenyl, alkynylarylalkynyl, eteroarylalkyl, eteroarylalkenyl, alkylheteroarylalkynyl, alkenylheteroarylalkyl, alkenylheteroarylalkenyl, alkenylheteroarylalkynyl, alkynylheteroarylalkyl, alkynylheteroarylalkenyl, alkynylheteroarylalkynyl, alkylheterocyclylalkyl, alkylheterocyclylalkenyl, alkylheterocyclylalkynyl, alkenylheterocyclylalkyl, alkenylheterocyclylalkenyl, alkenylheterocyclylalkynyl, alkynylheterocyclylalkyl, alkynylheterocyclylalkenyl, alkynylheterocyclylalkynyl, alkylaryl, alkenylaryl, alkynylaryl, alkylheteroaryl, alkenylheteroaryl, or lheteroaryl, in which groups one or more methylenes can be upted or terminated by O, S, S(O), SO2, N(R2), C(O), substituted or unsubstituted aryl, tuted or unsubstituted heteroaryl, or substituted or unsubstituted heterocyclic; and D is selected from: (a) J ; where W is O or S; J is O, NH or NCH3; and R31 is hydrogen or lower alkyl; Z Y2 (b) R33 R32 ; where W is O; Y2 and R32 are absent; Z is N; R34 is y; and R33 is hydrogen or aliphatic group; Z1 Y1 (c) ; where W is O or S; Y1 and Z1 are independently N, C or CH; and R21 NH2 Z Y2 (d) R12 R11 ; where Z, Y2, and W are as previously defined; R11 and R12 are independently ed from hydrogen or aliphatic; R21, R22 and R23 are independently selected from hydrogen, hydroxy, amino, halogen, alkoxy, alkylamino, dialkylamino, CF3, CN, NO2, sulfonyl, acyl, aliphatic, substituted aliphatic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic.

2. The compound of claim 1 represented by Formula III: L X B D (III) {//