AU2013204088A1 - Pyridyl inhibitors of hedgehog signalling - Google Patents

Abstract

The invention provides novel inhibitors of hedgehog signaling that are useful as a therapeutic agent for treating malignancies where the compounds have the general formula (I): where A, X, Y R1, R 2, R 3, R4, m and n are as described herein.

Description

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING The present application is a divisional application of Australian Application No. 2009234196, which is incorporated in its entirety herein by reference. 5 PRIORITY CLAIM This application claims priority to provisional United States application 61/044451 filed on 11 April 2008. FIELD OF THE INVENTION The present invention relates to organic compounds useful for therapy and/or 10 prophylaxis in a mammal, in particular to pyridyl compounds that inhibit the hedgehog signaling pathway and are useful in the treatment of hyperproliferative diseases and angiogenesis mediated diseases. BACKGROUND OF THE INVENTION Hedgehog (Hh) protein was first identified in Drosophila melanogaster as a segment 15 polarity gene involved in embryo patterning (Nusslein-Volhard et al., Roux. Arch. Dev. Biol. 193: 267-282 (1984)). Three orthologs of Drosophila hedgehog (Sonic, Desert and Indian) were later identified to occur in all vertebrates including 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 20 involved in bone development during embryogenesis 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 ectopic expression of SHh in transgenic animals have shown that SHh plays a key role in neuronal tube patterning (Echelard et al., supra.; Ericson et al., Cell 81 : 747-56 (1995); Marti et al., 25 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: 1431 44 (1993); Laufer et al., Cell 79, 993-1003 (1994)), somites (Fan and Tessier-Lavigne, Cell 79, 1175-86 (1994); Johnson et al., Cell 79: 1165 1 73 (1994)), lungs (Bellusci et al., Develop. 124: 53-63 (1997) and skin (Oro et al., Science 276: 817-21 (1997)). Likewise, IlHh and DHh are involved in bone, gut and germinal cell development (Apelqvist et al.. Curr. Biol. 7: 801-4 (1997); Bellusci et al.. Dev. Suppl. 124: 53-63 (1997); Bitgood ct al., Curr. Biol. 6: 298-304 (996); Roberts ct al., Development 121: 3163-74 (1995)). 5 Human SHh is synthesized as a 45 kDa precursor protein that upon autocatalytic cleavage yields a 20 kDa N-tenninal fiagnient that is responsible for normal hedgehog 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; 10 Bumerot, D.A., et al. (1995), Mol. Cell Biol. 15, 2294-2303: Porter, LA., 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) Science 274, 255- 258; Porter, JA., et al. (1995) Cell 86, 21-34). Cholesterol conjugation is responsible for the tissue localization of the hedgehog signal, 15 At the cell surface, the Hh signal is thought to be relayed by the 12 transneibrane domain protein Patched (Ptc) (Hooper 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: 221-232 (1996); van den Heuvel and Ingham, Nature 382: 547-551 (1996)). Both genetic and 20 biochemical evidence support a receptor model where Pte and Smn are part of a multicomponent receptor complex (Chen and Struhl, Cell 87: 553-63 (1996); Marigo et al., Nature 384: 176-9 (1996); Stone ct al., Nature 384: 129-34 (1996)). Upon binding of Hh to Ptc, the normal inhibitory effect of Pic on Smo is relieved, allowing Smo to transduce the Hh signal across the plasma membrane. However, the exact mechanism by which Pic controls Smo activity still has 25 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 HipI in a negative feedback 30 loop indicating that tight control the Hh pathway activity is required for proper cellular differentiation and organ formation. Uncontrolled activation of Hh signaling pathway are associated with malignancies in particular those of the brain, skin and muscle as well as angiogenesis. An explanation for this is that Hh pathway has been shown to regulate cell 2 proliferation in adults by activation of genes involved in cell cycle progression such as cyclin D which is involved in G-S transition. Also, SHh blocks cell-cycle arrest mediated by p 2 1, an inhibitor of cyclin dependent kinases. HI signaling is further implicated in cancer by inducing components in the EGFR pathway (EGF, Her2) involved in proliferation as well as components in 5 the PDGF (PDGFa) and VEGF pathways involved in angiogenesis. Loss of function mutations in the Pic gene have been identified in patients with the basal cell nevus syndrome (.BCNS), a hereditary disease characterized by multiple basal cell carcinomas (BCCs). 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. 10 14: 78-81 (1996): Hahn et al., Cell 85: 841-51 (1996); Johnson ct al., Science 272: 1668-71 (1996); Unden et al., Cancer Res. 56: 4562-5; Wicking et al., Am. J. Hum. Genet. 60: 21-6 (1997)). Loss of Ptc function is thought to cause an uncontrolled Smo signaling in basal cell carcinoma. Similarly, activating Smo mutations have been identified in sporadic BCC tumors (Xie et al., Nature 391: 90-2 (1998)), emphasizing the role of Smo as the signaling subunit in the receptor 15 complex for SHh. Various inhibitors of hedgehog signaling have been investigated such as Cyclopamine, a natural alkaloid that has been shown to arrest cell cycle at GO-G1 and to induce apoptosis in SCLC. Cyclopamine is believed to inhibit Smo by binding to its heptalbelical bundle. Forskolin has been 20 shown to inhibit the Hh pathway downstream from Smo by activating protein kinase A (PKA) which maintains Gli transcription factors inactive. Despite advances with these and other compounds, there remains a need for potent inhibitors of the hedgehog signaling pathway. 25 SUMMARY OF THE INVENTION In one aspect of the present invention there is provided novel hedgehog inhibitors having the general formula (1) (Ra) x 3R 3 wherein A is a carbocycle or heterocycle; X is alkylene, N1hC(O), NR 4 C(S), N(C(O)R 1 )C(O), NR 4 SO. NRASO2, NR 4 C(O)NH, NIRC(S)NH, C(O)Nlt, C(S)Nit, NR 4 PO or NR 4 PO(OH); 5 Y is absent, CHll, 0, S, SO, SO, or NRi; R, is selected from the group consisting of alkyl, a carbocycle or a heterocycle each of which is optionally substituted with hydroxyl, halogen, amino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfainoyl, alkylsulfonamide, a carbocycle or a heterocycle; wherein said amino, 10 alkyl, acyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbanoyl, alkanoylamine, alkylsulfamoyl, alkylsulfonamide, carbocycle and heterocycle substituent is optionally substituted with amino, halogen, hydroxyl, carbonyl, or a carbocycle or heterocycle that is optionally substituted with hydroxyl, amino, halogen, haloalkyl, alkyl, alkoxy or acyl; R, is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, 15 amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; R, is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, alkylsulfinyl, alkylsulfonyl, a carbocycle or a heterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide. alkylsulfinyl, alkylsulfonyl, carbocycle and heterocycle is optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, 20 alkylsulfonyl or alkoxy: 1t is H or alkyl; m is 0-3; n is 0-3; and salts and solvates thereof. 25 In another aspect of the invention, there are provided compositions comprising compounds of formula I and a carrier, diluent or excipient. In another aspect of the invention, there is provided a method for treating cancer comprising 30 administering an effective amount of a compound of formula I to a mammal in need thereof. In another aspect of the invention, there is provided a method for inhibiting hedgehog signaling in a cell comprising contacting said cell with a compound of formula . 4 In another aspect of the invention, there is provided a method for treating a disease or condition associated with the hedgehog signaling in a mammal, comprising administering to said mammal an effective amount of a compound of formula 1. 5 In another aspect of the invention, there are provided processes for preparing compounds of the invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 10 "Acyl" means a carbonyl containing substituent represented by the formula -C(O)-R in which R is H, alkyl, a carbocycle, a heterocycle, carbocycle-substituted alkyl or heterocycle-substituted alkyl wherein the alkyl, alkoxy, carbocycle and heterocycle are as defined herein. Acyl groups include alkanoyl (e.g. acetyl), aroyl (e.g. benzoyl), and heteroaroyl. 15 "Alkyl" means a branched or unbranched, saturated or unsaturated (i.e. alkenyl, alkynyl) aliphatic hydrocarbon group, having up to 12 carbon atoms unless otherwise specified. When used as part of another term, for example "alkylamino", the alkyl portion is preferably a saturated hydrocarbon chain, however also includes unsaturated hydrocarbon carbon chains such as "alkenylamino" and 20 "alkynylamino. "Alkylphosphinate" means a -P(O)R-alkyl group wherein R is Fi, alkyl, carbocycle-alkyl or heterocycle-alkyl. Examples of preferred alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl. iso-butyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2 dimethylpropyl, n-hexyl, 2-methylpentyl, 2,2-dimethylbutyl, n-heptyl, 3-heptyl, 2-methylhexyl, and the like. The terms "lower alkyl" "C[-C 4 alkyl" and "alkyl of I to 4 carbon atoms" are 25 synonymous and used interchangeably to mean methyl, ethyl, 1-propyl, isopropyl, cyclopropyl, I butyl, sec-butyl or t-butyl. Unless specified, substituted, alkyl groups may contain one (preferably), two, three or four substituents which may be the same or different. Examples of the above substituted alkyl groups include, but are not limited to; cyanomethyl, nitromethyl, hydroxymethyl, trityloxymethyl, propionyloxymethyl, aminomethyl, carboxymethyl, carboxyethyl, 30 carboxypropyl, alkyloxycarbonylmethyl, allyloxycarbonylaiinomethyl, carbamoyloxynethyl, methoxymethyl, ethoxymethyl, t-butoxymethyl, acetoxymethyl, chloromethyl, bromomethyl, iodomethyl, trifluoronethyl, 6-hydroxyhexyl, 2,4-dicbloro(n-butyl), 2-amino(iso-propyl), 2 carbamoyloxyethyl and the like. The alkyl group may also be substituted with a carbocycle group. Examples include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, and cyclohexylmethyl 35 groups, as well as the corresponding -ethyl, -propyl. -butyl, -pentyl, -hexyl groups, etc. Preferred substituted alkyls arc substituted methyls e.g. a methyl group substituted by the same substituents 5 as the "substituted C,-C. alkyl" group. Examples of the substituted methyl group include groups such as hydroxymethyl, protected hydroxymethyl (e.g. tetrahydropyranyloxymethyl), acetoxymethyl, carbamoyloxymethyl, trifluoromethyl, chloromethyl, carboxymetlyl, bromnonetby1 and iodomethyl. "Amidine" or "amidino" means the group -C(NH)-NRR wherein each R is independently .H, OH, alkyl, alkoxy, a carbocycle, a heterocycle, a carbocycle-substituted alkyl or a heterocycle substituted alkyl; or both R groups together form a heterocycle. A preferred amidine is the group -C(NH)-NH,. 10 "Amino" denotes primary (i.e. -NH2) , secondary (i.e. -NRH) and tertiary (i.e. -NRR) amines wherein R is independently alkyl, a carbocycle (e.g. aryl) , a heterocycle (e.g. heteroaryl), carbocycle-substituted alkyl (e.g. benzyl) or a heterocycle-substituted alkyl or alternatively two R groups together with the nitrogen atom from which they depend form a heterocycle. Particular 15 secondary and tertiary amines are alkylamine, dialkylamine, arylamine, diarylanine, aralkylamine and diaralkylarnine, Particular secondary and tertiary amines are methylamine, ethylamine, propylamine, isopropylamine, phenylamine, benzylamine dimethylamine, diethylamine, dipropylamine and diisopropylamine. 20 "Amino-protecting group" as used herein refers to a derivative of the groups commonly employed to block or protect an amino group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include carbamates, aides, alkyl and aryl groups, imincs, as well as many N-hetcroatom derivatives which can be removed to regenerate the desired amine group. Preferred amino protecting groups are Boc, Fmoc and Cbz. Further 25 examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2 " ed., John Wiley & Sons, Inc., New York, NY, 1991, chapter 7; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmic, Ed.. Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981. The term "protected amino" refers to an amino group 30 substituted with one of the above amino-protecting groups, "Aryl" when used alone or as pant of another term means a carbocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms. Aryl groups include phenyl, naphthyl. biphenyls, phenanthrenyl, naphthacenyl, and 35 the like (see e.g. Lang's Handbook of Chemistry (Dean, J. A., ed) l 3 cd. Table 7-2 [1985]). [n a particular embodiment aryl may be phenyl. Substituted phenyl or substituted arvi denotes a 6 phenyl group or aryl group substituted with one, two, three, four or five, such as 1-2, 1-3 or 1-4 substituents chosen, unless otherwise specified, from halogen (F, CI, Br, 1), hydroxy, protected hydroxy, cyano, nitro, alkyl (for example C 1

-C

6 alkyl), alkoxy (for example CI-C 6 alkoxy), bcnzyloxy, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, 5 protected hydroxymethyl, aminomethyl, protected aminomethyl, trifluoromethyl, alkvlsulfonylamino, arylsulfonylamino, heterocyclylsulfonylamino, heterocyclyl, aryl, or other groups specified. One or more methyne (CE) and/or methylene (CH2) gi-oups in these substituents may in turn be substituted with a similar group as those denoted above. Examples of the tern "substituted phenyl" includes but is not limited to a mono- or di(halo)phenyl group such as 2 10 chlorophenyl, 2-bromophenyl, 4-chlorophenyl, 2,6-dichloropbenyl, 2,5-dichlorophenyl, 3,4 dichloroplienyl, 3-chlorophenyl, 3-bromophenyl, 4-broiophenyl, 3,4-dibromophenyl, 3-chloro-4 fluorophenyl, 2-fluorophenyl and the like; a mono- or di(hydroxy)phenyl group such as 4 hydroxyphenyl, 3-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 3- or 4-nitrophenyl; a cyanophenyl group, for example, 15 4-cyanophenyl: a mono- or di(lower alkyl)phenyl group such as 4-methylplienyl, 2,4 dimethylphenyl, 2-nethylphenyl, 4-(iso-propyl)phenyl, 4-ethyliphenyl, 3-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example. 3,4-dimethoxyphenyl, 3-nethoxy-4 benzyloxyphenyl, 3-methoxy-4-(1 -chloromethyl)benzyloxy-phenyl, 3-ethoxyphenyl, 4 (isopopoxy)phenyl, 4-(t-butoxy)pbenyl. 3-eihoxy-4-methoxypbenyl and the like; 3- or 4 20 trifluoromiethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such 4 carboxyphenyl, ; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phcnyl such as 3-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phcnyl such as 2-(aminomethyl)phenyl or 2,4 (protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 3-(N 25 methylsulfonylamino))phcnyl. Also, the term "substituted phenyl" represents disubstituted phenyl groups where the substituents are different, for example, 3-methyl-4-hydroxyphenyl. 3 chloro-4-hydroxyphenyl, 2-nethoxy-4-bromophenyl, 4-cthyl-2-bydroxyphenyl, 3-hydroxy-4 nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like, as well as trisubstituted phenyl groups where the substituents are different, for example 3-methoxy-4-benzyloxy-6-methyl sulfonylamino, 3 30 methoxy-4-benzyloxy-6-plhenyl sulfonylamino, and tetrasubstituted phenyl groups where the substituents are different such as 3-methoxy4-bcnzyloxy-5-methyl-6-phenyl sulfonylamnino. Substituted phenyl groups include 2-chlorophenyl, 2-aminophenyl, 2-bromophenyl, 3 methoxyphenyl, 3-ethoxy-phenyl, 4-benzyloxyphenyl, 4-methoxyphenyl, 3-ethoxy-4 benzyloxyphenyl, 3,4-diethoxyphenyl, 3-methoxy-4-benzyloxyphenyl. 3-nethoxy-4-(1 35 chloromethyl)bcnzyloxy-phenyl, 3-methoxy-4-(I-chloromethyl)bcnzyloxy -6- methyl sulfonyl 7 aminophenyl groups. Fused aryl rings may also be substituted with any (for example 1, 2 or 3) of the substituents specified herein in the same manner as substituted alkyl groups. "Carbamoyl" means an ammocarbonyl containing substituent represented by the formula 5 C(O)N(R) 7 in which R is H, hydroxyl, alkoxy, alkyl, a carbocycle, a heterocycle, carbocycle substituted alkyl or alkoxy, or heterocycle-subsiituted alkyl or alkoxy wherein the alkyl, alkoxy, carbocycle and heterocycle are as herein defined. Carbamoyl groups include alkylaminoccarbonyl (e.g. ethylaminocarbonyl, El-NH-CO-), arylaminocarbonyl (e.g. phenylaminocarbonyl), aralkylaminocarbonyl (e.g. benzoylaminocarbonyl) a 10 heterocycleaminocarbonyl (e.g. piperizinylaminocarbonyl), and in particular a heteroarylaminocarbonyl (e.g. pyridylaminocarbonyl). "Carbocyclyl", "carbocyclic", "carbocycle" and "carbocyclo" alone and when used as a moiety in a complex group such as a carbocycloalkyl group, refers to a mono-, bi-, or tricyclic aliphatic 15 ring having 3 to 14 carbon atoms and preferably 3 to 7 carbon atoms which may be saturated or unsaturated, aromatic or non-aromatic. Preferred saturated carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl groups and more preferred are cyclopropyl and cyclohexyl and most preferred is cyclohexyl. Preferred unsaturated carbocycles are aromatic e.g. aryl groups as previously defined, the most preferred being plienyl. The terms "substituted 20 carbocyclyl", "substituted carbocycle" and "substituted carbocyclo" unless otherwise specified mean these groups substituted by the same substituents as the "substituted alkyl" group. "Carboxy-protecting group" as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are 25 carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4 dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbcnzyl, 3,4 methylenedioxybenzyl, benzhydryl, 4,4'-dimethoxybenzhydryl, 2,2%4,4' tetramethoxybenzhydryl, alkyl such as t-butyl or t-amyl, trityl, 4-methoxytrityl, 4,4' 30 dimethoxytrityl, 4,4',4"-trimethoxytrityl, 2-phenylprop-2-yl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, beta-(trimethylsilyl)ethyl, beta-(di(n-butyl)mcthylsilyl)ethyl, p toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)prop-1 en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the condition of subsequent reaction(s) on 35 other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. In particular, it is important not to subject a carboxy-protected 8 molecule to strong nucleophilic bases, such as lithium hydroxide or NaOH, or reductive conditions employing highly activated metal hydrides such as LiAIH. (Such harsh removal conditions are also to be avoided when removing amino-protecting groups and hydroxy-protecting groups, discussed below.) Preferred carboxylic acid protecting groups are the alkyl (e.g. methyl, 5 ethyl, t-butyl), allyl, benzyl and p-nitrobenzyl groups. Similar carboxy-protecting groups used in the cephalosporin, penicillin and peptide arts can also be used to protect a carboxy group substituents. Further examples of these groups are found in T. W, Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2" ed., John Wiley & Sons, Inc., New York, N.Y., 1991, chapter 5; E. Haslam, "Protective Groups in Organic Chemistry", J. G. W. McOmie, Ed., 10 Plenum Press. New York, N.Y., 1973, Chapter 5, and T.W. Greene, "Protective Groups in Organic Synthesis", John Wiley and Sons, New York, NY, 1981, Chapter 5. The term "protected carboxy" refers to a carboxy group substituted with one of the above carboxy-protecting groups. "Guanidine" means the group -NH-C(NH)-NHR wherein R is H, alkyl, a carbocycle, a 15 heterocycle, a carbocycle-substituted alkyl, or a heterocycle-substituted alkyl. A particular guanidine group is -NH-C(NH)-NH. "Heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "helerocyclo" alone and when used as a moiety in a complex group such as a heterocycloalkyl group, are used 20 interchangeably and refer to any mono-, bi-, or tricyclic, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic ring having the number of atoms designated, generally from 5 to about 14 ring atoms, where the ring atoms are carbon and at least one heteroatom (nitrogen, sulfur or oxygen) and preferably I to 4 heteroatoms. "Heterocyclosulfonyl" means a -SO 2 -hctcocycle group; "heterocyclosulfinyl" means a -SO-heterocycle group. Typically, a 5-membered ring has 25 0 to 2 double bonds and 6- or 7-membered ring has 0 to 3 double bonds and the nitrogen or sulfur heteroatoms may optionally be oxidized (e.g. SO, SO,), and any nitrogen heteroatom may optionally be quaternized. Preferred non-aromatic heterocycles include morpholinyl (morpholino), pyrrolidinyl, oximnyl, oxetanyl, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2H-pyranyl, tetrahydropyranyl, thiiranyl, thietanyl, tetrahydrothietanyl, aziridinyl, azetidinyl, 1-methyl-2 30 pyrrolyl, piperazinyl and piperidinyl, A "lieterocycloalkyl" group is a heterocycle group as defined above covalently bonded to an alkyl group as defined above. Preferred 5-membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms include thiazolyl, in particular thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, in particular 1,3,4 thiadiazol-5-yl and 1,2,4-thiadiazol-5-yI, oxazolyl. preferably oxazol-2-yl, and oxadiazolyl. such 35 as l,3,4-oxadiazol-5-yl, and 1,2,4-oxadiazol-5-yl. Preferred 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, preferably imidazol-2-yl; triazolyl, 9 preferably 1.3,4-triazol-5-yl: 1,2,3-triazol-5-yl, 1.2,4-triazol-5-yl, and tetrazolyl, preferably IH terrazol-5-yl. Preferred benzo-fused 5-membered heterocycles are benzoxazol-2-yl, benzthiazol 2-yl and benzimidazol-2-yl. Preferred 6-meiibered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, 5 and pyrid-4-yl; pyrimidyl. preferably pyrimid-2-yl and pyrimid-4-yl; triazinyl, preferably 1,3,4 triazin-2-yl and 1,3,5-triazin-4-yl; pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the 1,3,4-triazin-2-yl groups, are a preferred group. Substituents for optionally substituted heterocycles, and further examples of the 5- and 6-membered ring systems discussed 10 above can be found in W. Druckheimer er a, U.S. Patent No. 4,278,793. "Heteroaryl" alone and when used as a moicty in a complex group such as a heteroaralkyl group, refers to any mono-, bi-, or tricyclic aromatic ring system having the number of atoms designated where at least one ring is a 5-, 6- or 7-membered ring containing from one to four heteroatoms 15 selected from the group nitrogen, oxygen, and sulfur, and preferably at least one heteroatom is nitrogen (Lang's Handbook qf Chemistry, supra). Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to a benzene ring. Heteroaryls in which nitrogen or oxygen is the heteroatom are preferred. The following ring systems are examples of the heteroaryl (whether substituted or unsubstituted) groups denoted by the term "heteroaryl": 20 thienyl, fiuryl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrabydropyrimidyl, tetrazolo[1,5-b]pyridazinyl and purinyl, as well as benzo-fused derivatives. 25 for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl. A particularly preferred group of "heteroaryl" include; 1,3-thiazol 2 -yl, 4-(carboxymethyl)-5-mcthyl-1,3-thiazol-2-yl, 4-(carboxyiethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,2,4-thiadiazol-5-yl, 3-methyl-1,2,4-thiadiazol-5-yl, 1,3,4-triazol-5-yl. 2-methyl 1,3,4-triazol-5-yl, 2-hydroxy-1,3,4-triazol-5-yl, 2-carboxy-4-methyl-I,3,4-triazol-5-yl sodium salt, 30 2-carboxy-4-iethyl-1,3,4-triazol-5-yl, 1,3-oxazol-2-yl, 1,3,4-oxadiazol-5-yl, 2-methyl-1,3,4 oxadiazol-5-yl, 2-(hydroxymethyl)-1,3,4-oxadiazol-5-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-thiadiazol-5 yl, 2-thiol-1,3,4-thiadiazol-5-yl, 2-(methylthio)-1,3,4-thiadiazol-5-yl, 2-amino-1,3,4-thiadiazol-5 yl, IH-tetrazol-5-yl, I-methyl-lH-tetrazol-5-yl, 1-(l-(dimcthylamino)eth-2-yl)-IH-tetrazol-5-yl, 1 (carboxymethyl)-1H-tetrazol-5-yI, 1-(carboxynethyl)-1H-tetrazol-5-yI sodium salt, 1 35 (methylsulfonic acid)-lH-tetrazol-5-yl, 1-(iethylsulfonic acid)-IH-tetrazol-5-yl sodium salt, 2 methyl-IH-tetrazol-5-yl, 1,2,3-triazol-5-yl, 1-methyl-I,2,3-triazol-5-yl, 2-methyl-1,2,3-triazol-5 10 yl, 4-methyl-1,2,3-triazol-5-yl, pyrid-2-yl N-oxide, 6-methoxy-2-(n-oxide)-pyridaz-3-yl, 6 hydroxypyridaz-3-yl, 1 -methylpyrid-2-yl, I-methylpyrid-4-yl, 2-hydroxypyrimid-4-yl, 1,4,5,6 tetraliydro-5,6-dioxo-4-metliyl-as-triazin-3-yl, 1,4,5.6-tetrahydro-4-(formylmethyl)-5,6-dioxo-as triazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-astriazin-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-as-triazin 5 3 -yl sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-astriazin-3-yl sodium salt, 2,5-dihydro-5 oxo-6-hydroxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-6-methoxy-2-methyl-as-triazin-3-yl, 2,5-dihydro-5-oxo-as-triaziii-3-yl, 2,5-dihydro-5-oxo-2-metliyl-as-triazin-3-yl, 2,5-dihydro-5-oxo 2,6-dimethyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl and 8-aminotetmzolo[1,5-b]-pyridazin 6-yl. An alternative group of "heteroaryl" includes; 4-(carboxymethyl)-5-methyl-1,3-thiazol-2 10 yl, 4-(carboxymethyl)-5-methyl-1,3-thiazol-2-yl sodium salt, 1,3,4-triazol-5-yl, 2-methyl-1,3,4 triazol-5-yI, I H-tetrazol-5-yI, I-methyl-I H-tetrazol-5-yl, l-(l-(dimethylamino)eth-2-yl)-l H tetrazol-5-yl, 1-(carboxymethyl)-IH-tetrazol-5-yl, 1-(carboxymetbyl)-IH-tetrazol-5-yI sodium salt, 1-(methylsulfonic acid)-1 H-tetrazol-5-yl, 1-(methylsulfonic acid)-] H-tetirazol-5-yl sodium salt, 1,2,34riazol-5-yl, 1,4,5,6-tetrahydro-5,6-dioxo-4-methyl-as-triazin-3-yl, I,4,5,6-tetrahydro-4 15 (2-formylImetiyl)-5,6-dioxo-as-triaziii-3-yl, 2,5-dihydro-5-oxo-6-hydroxy-2-rethyl-as-triazin-3-y sodium salt, 2,5-dihydro-5-oxo-6-hydroxy-2-methyl-as-triazin-3-yl, tetrazolo[1,5-b]pyridazin-6-yl, and 8-aminotetrazolo[1,5-b]pyridazin-6-yl. "Hydroxy-protecting group" as used herein refers to a derivative of the hydroxy group commonly 20 employed to block or protect the hydroxy group while reactions are carried out on other functional groups on the compound. Examples of such protecting groups include tetrahydropyranyloxy, benzoyl, acetoxy, carbamoyloxy, benzyl, and silylethers (e.g. TBS, TBDPS) groups. Further examples of these groups are found in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 2" ed., John Wiley & Sons, Inc., New York, NY, 25 1991, chapters 2-3; E. Haslam, "Protective Groups in Organic Chemistry". J. G. W. McOmie, Ed., Plenum Press, New York. NY, 1973, Chapter 5, and T.W. Greene. "Protective Groups in Organic Synthesis", JolIn Wiley and Sois, New York, NY, 1981. The tenn "protected hydroxy" refers to a hydroxy group substituted with one of the above hydroxy-protecting groups. 30 "Pharmaceutically acceptable salts" include both acid and base addition salts. "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid and the like, and organic acids may be selected from aliphatic, 35 cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid,

II

pyruvic acid. oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fiumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, niethanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicyclic acid and the like. "Pharmaceutically acceptable base addition salts" include those derived from inorganic bases such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc. copper, manganese, aluminum salts and the like. Particularly preferred are the ammonium, potassium, sodium, calcium and magnesium salts. Salts derived from phanraceutically acceptable organic 10 nontoxic bases includes salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted anines, cyclic amines aid basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, TEA, tripropylamine, ethanolamine, 2 diethylaminoethanol, trimethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, bydrabamine, choline, belaine, ethylenediamine, glucosamine, methylglucamine, 15 theobronine, purines, piperizine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, trimethamine, dicyclohexylamine, choline, and caffeine. "Phosphinate" means -P(O)R-OR wehrein each R is independently H, alkyl, carbocycle, 20 heterocycle, carbocycloalkyl or heterocycloalkyl. Particular phosphinate groups arc alkylphosphinate (i.e. -P(O)R-O-alkyl), for example -P(O)Me-OEt. "Sulfamoyl" means -SO-N(R)2 wherein each R is independently H, alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfamoyl groups are alkylsulfamoyl, 25 for example methylsulfamoyl (-SO-NHMe); arylsulfamoyl, for example phenylsulfamoyl; aralkylsulfanoyl, for example benzylsulfamoyl. "Sulfinyl" means a -SO-R group wherein R is alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfinyl groups are alkylsulfinyl (i.e. -SO-alkyl), for example 30 methylsulfinyl; arylsulfiryl (i.e, -SO-aryl) for example phenylsulfinyl; aralkylsulfinyl, for example benzylsulfinyl. "Sulfonamide" means -NR-SO-R wherein each R is independently .H, alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl), a carbocycle or a heterocycle. Particular 35 sulfonamide groups are alkylsulfonamide (e.g. -NH-SO 2 -alkyl), for example methylsulfonamide; 12 arylsulfonamdie (i.e. -NH-SO-aryl) for example phenylsulfonamide; aralkylsulfonamide, for example benzylsulfonamide. 5 "Sulfonyl" means a -SO-R group wherein R is alkyl, carbocycle, heterocycle, carbocycloalkyl or heterocycloalkyl. Particular sulfonyl groups are alkylsulfonyl (i.c. -SO-alkyl), for example methylsulfonyl; arylsulfonyl, for example phenylsulfonyl; aialkylsulfonyl, for example benzylsulfonyl. 10 The phrase "and salts and solvates thereof' as used herein means that compounds of the inventions may exist in one or a mixture of salts and solvate forms, For example a compound of the invention may be substantially pure in one particular salt or solvate form or else may be mixtures of two or more salt or solvate forms. 15 The present invention provides novel compounds having the general formula I: (R3)m xsR N A wherein A, X, Y, R, R 2 . and R, are as defined herein. 20 A is a carbocycle or heterocycle ring substituted with 0 to 3 (e.g. n is 0-3) R 2 groups selected from the group consisting of halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy;. In a particular embodiment, A is optionally substituted aryl or heteroaryl. In particular embodiment A is optionally substituted 25 benzene, thiophene, thiazole, imidazole, pyrrole, N-alkyl pyrrole, pyridine, pyrazole or N-alkyl pyrazole. In a particular embodiment A is a ring selected from the group consisting of AK A2 A-,

A

4 A- A 6 and A': Z1 N Z2 N R2' (R2)n R2' A' A' A A 4 13 Ny A' A 6 A7 wherein Zi is 0, S or NR wherein R, is H or alkyl; Z, is CH, CR, or N; R, is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, 5 alkylsulfonyl or alkoxy; R, is H, halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; and n is 0-3, In a particular embodiment A is the ring of formula A'. In a particular embodiment, A is the ring of formula A' wherein ZI is S and Z, is CH or N. in another embodiment, A is the ring of formula A' wherein ZI is S and Z 2 is CH, i.e. thiophene. In another embodiment, A is the ring of formula 10 A' wherein Z, is S and Z 2 is N, i.e. thiazole. In another embodiment, A is the ring of formula A' wherein R, is H. In embodiment, A is the ring of formula A' wherein R, is methyl. In another embodiment, A is the ring A' wherein R, is methyl. In a particular embodiment A is ring A. In another embodiment, A is the ring of fonrula A' wherein R 2 may be absent, i.e. n is 0. In another embodiment, n is I and R, is Cl. fi another particular embodiment A is the ring of fonnula A'. In 15 an embodiment, A is a ring of formula A 3 wherein Z1 is S and Z is N, i.e. a thiazole. In another embodiment, A is a ring of formula A 3 wherein Z, is S, Z 2 is N and R' is CL In another embodiment, A is a ring of formula A 3 wherein ZI is S, Z2 is CH (i.e. thiophene) and R 2 ' is Cl. 20 In a particular embodiment A is the ring A A", A2", A A-l, A 4 , A A, A": Ala Au' A 2 a N N C Cl

A

3 " Ab A' 25 14 Cl Cl Cl N A5- A6 A7 In a particular embodiment A is the ring of formula A". In another embodiment A is the ring of formula A". In another embodiment A is the ring of formula A>. In another embodiment A is the I ring of formula A". In another embodiment A is the ring of formula A". In another embodiment A is the ring of formula A". X is alkylene, NR 4 C(O), NR4C(S), N(C(O)RI)C(O), NR 4 SO, NR 4

SO

2 , NR 4 C(O)NH, NR 4 C(S)NH,

C(O)NR

4 , C(S)NR 4 , NRAPO or NR 1 PO(OH) wherein R 4 is H or alkyl. In a particular embodiment 10 X is NR 4 C(O) which forms an amide linkage between ring A and R. In another embodiment, X is

N

4 C(S), which forms a thioamide linkage between ring A and R1. In another embodiment, X is

NR

4 C(O)NH which forms a urea linkage between ring A and R1 In another embodiment X is

NR

4 C(S)NH which with NR forms a thiourea linkage between ring A and R 1 . In another embodiment X is N(C(O)RI)C(O) i.e. a nitrogen with two -C(O)RI groups pending therefrom. 15 Y is absent, CHR 4 , 0, S, SO, SO2 or Ni, wherein l, is as defined herein. In a particular embodiment Y is CHR 4 . In a particular embodiment Y is Nit. In a particular embodiment Y is 0. In a particular embodiment Y is S. In a particular embodiment Y is SO. In a particular embodiment Y is SO2. In another embodiment Y is absent i.e. ring A is directly attached to the 20 pyridyl ring at the 2-position. Rt is selected from the group consisting of alkyl, a carbocycle or a heterocycle each of which is optionally substituted with hydroxyl, halogen, amino, carboxyl, amidino, guanidino, carbonyl (i.e. 25 =O), nitro, cyano, acyl, aikyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, a carbocycle or a heterocycle; wherein said amino, amidino, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, alkylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, carbocycle and heterocycle substituent is optionally substituted with, halogen, haloakyl, hydroxyl, carboxyl, carbonyl, or an amino, alkyl, alkoxy, acyl, sulfonyl, sulfiniyl, phosphinate, carbocycle or 30 heterocycle that is optionally substituted with hydroxyl, carboxyl, carbonyl, amino, halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl, a carbocycle or a heterocycle. 15 In another embodiment R1 is selected from the group consisting of alkyl, a carbocycle or a heterocycle each of which is optionally substituted with hydroxyl, halogen, amino, carbonyl, nitro, cyano, acyl, alkyl, haloalkyl. alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl (i.e. -CONR alkyl wherein R is H or alkyl), alkanoylamine (i.e. -NRCO-alkyl wherein R is H or alkyl), 5 alkylsulfwnoyl (i.e. -SO 2 NR-alkyl wherein R is H or alkyl), alkylsulfonamide (i.e. -NR-SO-alkyl wherein R is H or alkyl), a carbocycle or a heterocycle; wherein said amino, alkyl, acyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfamoyl, alkylsulfonamide, carbocycle and heterocycle substituent is optionally substituted with amino, halogen, hydroxyl, carbonyl, or a carbocycle or heterocycle that is optionally substituted with 10 hydroxyl, amino, halogen, haloalkyl, alkyl, alkoxy or acyl. In a particular embodiment R, is an optionally substituted aryl or heteroaryl. In a particular embodiment R, is an optionally substituted phenyl group. In another particular embodiment Ri is an optionally substituted pyridine group. In a particular embodiment R, is of formula Ila, Ilb, Ic, 15 lid, Ile, Iff, 11g, Ih, Ili, IIj, Ilk, III, Ilm, In or Ilo: Ila Ulb Ilc

(R

6 ). (Re). 0 20 CC-o .. o Ild lie lif (Re). (R)() x~ N N /N H H IPg IIlh Iii 25 (Rs). (R6)0 (Rs)-1 /Nw Ilj Ilk fIt 16 (R6). N (RNO. (R3). -/ -. /A Ny un Tiln lo 5 wherein W is 0, S or NR 7 wherein R7 is H, alkyl, acyl, a carbocycle or a heterocycle wherein said alkyl, acyl, carbocycle and heterocycle are each optionally substituted with 1-3 amino, halogen, hydroxyl and haloalkyl; o is 0-3. In a particular embodiment W is S.

R

6 in each instance is independently hydroxyl, halogen, amino, carboxyl, amidino, guanidino, 10 carbonyl, nitro, cyano, acyl, alkyl, haloalkyl, sulfonyl, sulfinyl, alkoxy, akylthio, carbamoyl, acylamino, sulfamoyl, sulfonamide, a carbocycle or a heterocycle; wherein said amino, amidino, alkyl, acyl, sulfonyl, sulfinyl, alkoxy, alkylthio, carbanoyl, acylanino, sulfanoyl, sulfonamide, carbocycle and heterocycle substituent is optionally substituted with, halogen, haloakyl, hydroxyl, carboxyl, carbonyl, or an amino, alkyl, alkoxy, acyl, sulfonyl, sulfinyl, phosphinate, carbocycle or 15 heterocycle that is optionally substituted with hydroxyl, carboxyl, carbonyl, amino, halogen, haloalkyl, alkyl, alkoxy, alkylthio, sulfonyl, sulfinyl, acyl, a carbocycle o a heterocycle. In a particular embodiment R 6 in each instance is independently hydroxyl, halogen, amino, carbonyl, nitro, cyano, acyl, alkyl, sulfonyl, alkylsulfonyl. alkylsulfinyl, alkoxy, alkylcarbamoyl, 20 alkanoylamine, alkylsulfamoyl, alkylsulfonamide, a carbocycle or a heterocycle; wherein said amino, alkyl, carbonyl, acyl, sulfonyl, alkylsulfonyl, alkylsulfinyl, alkoxy, alkylcarbamoyl, alkanoylamine, alkylsulfanoyl, alkylsulfonamide, carbocycle and heterocycle substituent is optionally substituted with amino, halogen, hydroxyl, carbonyl, or a carbocycle or heterocycle that is optionally substituted with hydroxyl, amino, halogen, haloalkyl, alkyl, alkoxy or acyl. 25 In a particular embodiment R is independently in each instance optionally substituted alkyl (e.g. methyl, trifluoromethyl, dinethylaminomethyl, piperidinylmethyl. morpholinomethyl, thiomorpholinomethyl); halogen (e.g. chloro); alkoxy (e.g. inethoxy): carbonyl (e.g. morpholinocarbonyl, acetyl); a heterocycle (e.g. morpholino, N-methyl-piperazin-4-yl, N-acetyl 30 piperazin-4-yl, 1H-1,2,4-triazole); alkylamino (e.g. i-butylamino, benzylamino, hydroxyethylamino, methoxyethylamino, dimethylaminoethylanino, norpholinoethylamino, morpholinopropylamino, pyrrolidin-2-one-substituted propylanino, imidazole-ethylamino, imidazole-propylamino); arylamino (e.g. phenylamino); alkylcarbamoyl (e.g. dimethylcarbamoyi, 17 i-butylaminocarbonyl); alkylsulfanoyl (e.g. propylaminosulfonyl, i-butylaminosulfonyl, dimethylaminosulfonyl, dimcthylaminoethyl hydroxyethylaminosulfonyl, methoxyethylaminosulfonyl. methoxypropylaminosulfonyl, methylsulfonylethylaminosulfonyl, imidazole-substituted propylaminosulfonyl, hydroxypropylaminosulfonyl, 2 5 hydroxypropylaminosulfonyl ); or sulfonyl (e.g. methylsulfonyl, ethylsulfonyl, aminosulfonyl, dimethylaminopropylsulfonyl, N-methyl-piperazin-4-yl-sulfonyl, morpholino-4-yl-sulfonyl, trifluoronethylsulfonyl). In a particular embodiment R, is H. In another particular embodiment R, is optionally substituted 10 acyl. In another particular embodiment R, is optionally substituted alkyl (e.g. methyl). In another particular embodiment R? is optionally substituted acyl (e.g. acetyl, benzoyl). In another particular embodiment R 7 is an optionally substituted aryl group (e.g. phenyl, benzyl). In a particular embodiment R, is the group of formula Ila. In such embodiment R6 may be alkoxy 15 and o is 1, 2 or 3. Particular Ila groups are Tla - Ila,: OMe OMe OMe OMe OMe OMe OMe -k N - OMe & OMe OMe Ila' 11a2 IIa Ila 4 Iha' CI O M e O E t O P r N O 20 Ia Ila' lIa 1.

9 .Ia 18 OPr CI u.," llaB 134 1a Ha1 NHN IlaN' N'a N la l NH(CH2)SNH2 CF, NO2 NOt CF3 lae 11.22 Ila 11.24 I.a5 CIC OMe In another particular embodiment R, is the group of formula lib. In such embodiment R, may be alkyl orlhaloalkyl (e.g. CF3). Particular Ib groups are Ij4- : 15 bN lb 2 HNb 19 In a particular embodiment R, is the group of formula lIe. In such embodiment W may be S and o is 0. In another particular embodiment R, is the group of formula lid. In such embodiment o may be 0. In another particular embodiment R, is the group of formula lie. In such embodiment o may 5 be 0. In another particular embodiment R, is the group of formula Ilf. In such embodiment o may be 0. In another particular embodiment R, is the group of formula lin. In such embodiment o may be 0 or 2 and R, may be alkyl or aiyl. In a particular embodiment, group fin has the formula Iain: 10 Ph"] lhi' ]n another particular embodiment R is the group of formula l1o. In such embodiment o may be 0 15 or 2 and R, may be alkyl or aryl. In a particular embodiment, group lo has the fonnula 1101: N \/ F flo' 20 .R is halogen, hydroxyl, alkyl, acyl or alkoxy each optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy. n is 0-3, for example 0 or 1. In a particular embodiment R, is hydroxyl. In a particular embodiment R2 is alkyl or alkyl substituted with halogen, methyl or trifluoromethyl. In a particular embodiment R 2 is acyl, for example alkanoyl e.g. acetyl. In a particular embodiment R, is halogen, for example Cl or F. In another particular 25 embodiment R2 is alkoxy, for example methoxy or ethoxy. R is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, sulfinyl, sulfonyl, a carbocycle or a heterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide. sulfinyl, sulfonyl, carbocycle and heterocycle is optionally substituted 30 with hydroxyl, halogen, amino, nitro, alkyl, acyl, sulfonyl or alkoxy. In a particular embodiment R, is halogen, hydroxyl, carboxyl, alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, alkylsulfinyl, alkylsulfonyl, a carbocycle or a heterocycle wherein each alkyl, acyl, alkoxy, alkoxycarbonyl, carbamoyl, alkylsulfide, alkylsulfinyl, alkylsulfonyl, carbocycle and heterocycle is 20 optionally substituted with hydroxyl, halogen, amino, nitro, alkyl, acyl, alkylsulfonyl or alkoxy; while m is 0 to 3. In a particular embodiment, R 3 is halogen (e.g. F), carboxyl, or optionally substituted alkyl (e.g. methyl, hydroxymethyl, dimethylaminormethyl), alkoxycarbonyl (e.g. methoxycarbonyl) or carbanoyl (e.g. dimcthylaminocarbonyl). In a particular embodiment m is 0, 5 i.e. R 3 is absent. In another particular embodiment m is 1-3. In a particular embodiment, compounds of the invention are represented by the general formula Ib: (R3 (a N 10 lb wherein X, Ri, R 3 and in are as defined herein and R 8 is halogen. In an embodiment, compounds of the invention have the general formula lb and X is NR 4 CO. In further embodiment, compounds are of formula lb and R, is H or methyl. 15 In another particular embodiment, compounds of the invention are represented by the general formula Ib: 'N (R3). N 'N x 'B lb' 20 wherein X, R3, Rc, in and o are as defined herein; R, is a halogen; and ring B is a carbocycle or heterocycle. In a particular embodiment Rs is Cl. hi a particular embodiment ring B is phenyl or pyridyl. In a particular embodiment X is NR 4 C(O) and R 4 is as defined herein. 25 In another particular embodiment, compounds of the invention have the general formula Ic: 21 (R13 Cl N c

N-

Ic wherein X, R,, R and m are as defined herein, In an embodiment, compounds of the invention have the general formula lb and X is NRtCO. In a farther embodiment, compounds are of formula S Ic and R 3 is H or methyl and m is 0 or 1. In another particular embodiment, compounds of the invention have the general fonula id:

(R

3 m& <N X-R, I0 Id wherein X, R,, R 3 and m are as defined herein. In an embodiment, compounds of the invention have the general formula lb and X is NR 4 CO. In a further embodiment, compounds are of formula Id and R 3 is H, Cl or trifluoromethyl and m is 0 or 1. 15 Particular compounds of the invention include, but are not limited to the following: 22 NN 0 HN 0 N-a N N- N CF, \ FC CF 3 3 ~ I~4 cI N -OMe HN MeO 0 5 6 C/ HNN CN o 0 HN HN

CFF

3 7 8 c \/ \/N 0 o HN

N

0 CF, 9 10 cI HNN O"N N-CF, 23 11 12 C cI

RN

N 13 14 cI cI \ N 0 HN HN- /\N

NN

15 16 cI cI N 0 HN N NH HN0 0 17 is N 0 N 0N HN- RN N NH0 NH H HO 19 20 CI N 0\/ / HN N0 HNI N/ 24 21 22 N cI N\N NH 23 24 cI cI NN 0 \ / 0 HN NNf0 / N N N N N N 25 26 cI \/ \/ \ N 0 HN N N 0 V2J 27 28 C cI HN NN N 29 30 C cI \ /- -/ \\// 0 N HN HN-/ 2 N 25 31 32 cl cI N 0 N 0 HN HN - H H N 0Ol~ 0 0 37 38 HN C N O 39cl 4() I"N O 00 OH 35 36 ci cI N N 0 HN / 0 c / 0o- -H N /S O 0 Me 37 38 cI CI \\\ \/ "N

HN

/ N 110 N-N N 39 CI 401 \ N 0 /N aN 0 11

HN

s=O ,Me NH, 0 26 41 42 NN C NN 0 [43 C1 [44C1 / ~N HN- FIlII HNH 47 48 c HN F HS NN 45 46 cI cI \' /N 0 N 0N H ci FaCMC 04 CN HN C~a Oe 47 48 cI Ch \ N I H [IN NH 2 /\'N 49 50 CIN /IZ NH N 0 51 52 F3CN C N N -NNy HN -- HN M.0

F

3 0 27 53 F3,a l5 F, N cI NJ NN N 0 N I N NN

F

3 F 55 56 HN-N 0 H N O28-N\_/4Me 57 CI 584 cI "N / N H N 02 N HN Me 59 cI 60 cI 02 0 NN H2N 61 cI 62 cI '0 HNH (N 63 cl64 cI N HN HN HN

O

2 & NH 65 cl 66 cl HN- HN MeQ,, NH "eiH 67 cl 68 cl X N0N 0 HN- HN so,00 Me, NHI 0 29 69 cI 701 cI H HN HN-_OMe 0 HO NH 71 GI72 cI N0 \N/ 0 HN H N-N N H 73 cI 74 cI / 0/ HN HN NH N NN HW HN HN 0 N 02, H0~yNI NH 30 77 cI 78 cl \\ "N H HN N 79 8l 0 cI \/\ N 0 HN-

HN

HN-

C\I-OH 8 82 cI N - HN N\ 2S-N ~HN-\_M 83 cl 84 Oce / \ "N 0 H HN HN 85 c 6CI N 0 NJ 0 I-IN-

HN

Nil 31 87 cI 88 cI HN HN CF, cI X9 cI 90 CI N0 \/N NN 0I H HN CI CI NH 91 ci 92 ci HN- N0 NH / N CI NH HCJ o's HO NHI go CF3 '00 32 97 \ / 0 98 HO / C 1 HNN HNN / N /\N CF3

CF

3 99 t00 CCI CI lp /0 C\N/ 0 HN HN NN CI CCF, 105 0 10 1 N 0 102 F 3 C N -H N H N

CF

3 CF, cI cI 104 F 103 N\ 0C HNN HN N 33 NN CF,

CF

3 105 106 \' / N0 \ N 0 HN- HIN N /\N CF, N NH 107 \ N 0 \ N 0 HN- HIN / N \ N N IN NH $NH 33 109 N HN N HN HN HN NH NH o 0 HNN HN'N 0 115116CI "/ 0 /1 HN HN NHNH NH, 0 113 11 \ "N /01 HN

-

I

NH NH N / 0 NHN C3 11 \N 0 116 cI HN- \/ "N 0 HN NH 0 117 "\-/\ UI \ "N/ HIN 'I HN- CI 34 119 N CC NN - N 0 121 122 C I HN CI/ HN\/ 0 N \ N O -- N N - \-N N- eol a 123 0 124 NN C O NN N0N HN4CI IIN3CI N 0H N 0H o 0 127 HN CI FIN-/ Q N H N q NH N0 N o \0 35 N N 130 12HN\' \/HN N HN CI IN CI NN N IN . c I I N NH N N 03 00 I-IN CI I- CI N 0 o o o CI C 135 N0 136 \/ \ N 0 HN CI I-N CI NH NH o 0 13 N 0 13 N 0 HN4C -IN/ 'C -As NH NH 139 "\/ \/ 140 \' "N\ / HN4 CIHN CI1 / N N NH N\ O 0 36 N4 0 N42 HN CIHN 4 NH N\ o NH0 ~ \/ \/ '44\/ /0 HN- 'CI H-N NtNH N H o 0_ 145 N' 14 \ "/ 0 HN- CIl I-N C I _NH -No o 'oH 0 147 \ / 0148 N~ / H N -- C H N -4 cl- 0 149 \'50 0 HN-- 01 HN CI4 NH 0 NH ra 0 0 37 151 0 152 \/ / HN CI HN CI qNHH 0 OH0 153 154 N 00 HN C1 HN C1 qNH qH OH 0 155 N 0 156 0 HN/ I CI I-HN CI NH NH Nl NH C CI 157 N 0 160 HN CI HN cI NH N 3 8 159 \' "N/16 \' "N/ HN iHN- C NH OH NH 0 0 38 C1 CI 161 0 162 HN HN C N/\ N Nil NH o 0 C1 C1 163 \/ \\ 164 \' / N HN NN HN HI-N CI HN NoH NH NH CI CI 165 16N 0 N HN CI HN C / \ OH NH2 NH o 0 CI C1 167 \N 0 170\/6\ " / 0 HN CI HN C

NH

2 N1 N0 N N H C1 CI 1N 0 170 \' \/ HN CI HN- CI 4 N N-"NN 171 N0 172 \' \ IIF -N H NH F HN N 39 173 174 HN\N HN \N H HN HN N HN N N HN 175 178 N 0 HN HN N N ON 179 N \\0180 HN NH H HN C NHO OH 18 182 HN N C HN- Nl 179 \ /D / \ / /40 400 183 \84 N"-, 0 184 \' \ HN HN I o o 185 N 0 186 HN HN N HN I OH HN IN C\ \ / NH N 187 \N 0 l0 HNO HN / N NH

NN

189 \N\/ 0 190 \/\ HN ,CI HN 0I OH NH. NH o oo 191 \N 192 \ /\ \/ HN- 0I I-N CI 0o~ 41 193 194 \' \/ H N H N -N N N NH 19N N 00 197 \/2010 \/ \ 95\N\/ 0 19 \ N 0 HN HNO NH -NH N o 0 cI CI 199 \ 200 2 -0 HN CI HNO N \ NH NH 0 0 N 0 CQ/-0 0 NI-I pH 00 42 CI CI 203 204 \' 0 HN CI HN CI qNH NH o N N 0- NH 2 N 0N 0 205 '\"/ ' 1206 HN / I HN C1 NH NH o 0N c I 207 N 0 208 \ HN CI HN CI NH- NIH O N NH 0 N N CI CI 209 \ 210 HN N 211 CN 0212 \"N0 HN I HN I oS- -N\_ N0 0_N O \0 43 213 0 214 \ / HN I HN CI _0 - '0 _N 0 0 O_ O 0 215 N 0 216 HNO HN 10 &O N-O -0 -0 217 "N 0 218 N 0 HN-Z HN-Z HNNH N N 219, 220 219 \/ \/ 0 22 / 0 tNH -NH H NH N N H 221 \ / 222 \ / HN- O HN O -0 0 SN N 44 223 \ / 224 N HN Br HN--O 00 s HN N 225 226 2HN/ 0 N 0 HN HN HN HN HN,N -N~N 22 N F 0 228 \ 'l - 0 HN HI-N - ) 04A S-0-p 229 \ / 0 230 \ "N/ 0 HN, \0- IAN 0 -0 23 N 0 232 H-IC N 0 HN - HN - -0 -0 P-0 S=O 45 _ ' N/ 234\/ / 233 N HO N 0 HNF HNF / \N F F F F F F 237 Nl \-) 238 :/ \ C 0 - N- 235NNN NN HN HN C N N F 243 244 237 \N 0 238 / \ HIN pi HNN

HN

4 OH 4N 239 \ \-/ 240 \0 N0 N H HN

-

N _N 241 \"N24 Q/\/0 0 N- 4 H N

-

Z N/K 243 \'/ \/ 0 244 \' "N/ 0 NN 00 ! NH HN OH 46 cI HO cI 245 ' 246 N 0 HN N

HN

/ N N H F HN 0- FF 247 N 0 N 0 HN IHN - 0 - 0

N-SI-IN

249 \N 0 250 \' "N/ NO N- H 0 o 0 251 N 0 252 \' / HN- H o 0OH o 0 253 \'/ 0/ 254 \ "/\/ 0 HN- I &N 0 NH on 01'" 255 \' "N\/ 250 \'0 HN- AN \N-j /--NH 47 257 \ " 2580 259260 \' \ HNI HN I /-+ S-NH FH 0" 0 261 " 260 \/ / HN2 HN I OH HN IHN C HNNI HN I 267 \ 262 \' / HNI HN C cl CI 263 \' "N// 264 \' "N/ HN - I IO-IN C ) 261 \' "N/ 266 \ "/ 0 HN CI HN C / \HO / HO 0 0 04 269 \" 0 27 N 0 - HN O 0 271 \ \ 272 \' / HN- HN- CI 0~ NH HO N0 HN

-

N

/\HO - O 0-" 0 So CI C 275 \ / 0 276 \/~0 HN

-

N

-N 00 GI CI 277 \N 0 27 /o 0 HN- HN _N 279 N02O \' / "\-N' / 8 I- HN / \ OH 0 S o 49 ci ci N8 c"q 282 \"/\ \/ HN-- HN- CI OH _ti C) 23\N \ ) 284 \' / HN- Ci HN / \ OH o 0 285 /1N 0 286\/ / / 'QI 0 HN- CI HN- C0 281 '\ 288\/ / I- a HN 00 289 \' 0/ 290 \N/ 0 HN- AN- Ci 291 \/ \/292 \/ / 0 N/ HN- CI AN O, 0 50 293 / 294 \ H N H N 295 / 296 CI C\ 299 3000 HN HN 297 \N/ 0 28 \' / NN 0 I- HN N HO /0 \NH /N 0 11 \"N HN- N 0 51 303 \' "N/ \N HN- IN /_\N HO N $ HN-/ N 0 305 \' "N/ 0 300 \ / 0 HN- I-IN \N \NN OH 307 Q\N -- / 0 38 \ N' 0 I- HN N0 NH N H 309 N 0 310 \/ \/ NN N cI 312 cl 311 ' ~ C-N 0 ~' "0 HN- HN-\4 HN I 00 52 CI CI /l \ / 313 \ 0 314 \ N 0 HN HN / N /\N N N NH NH CI CI 315 \ / \ 316 \/ \ HNN HN 0 N N HN HN N N NH N CI CI \ / 31O/\ 317 \ NM 0 38No 0 HN HN N N N OHN 2-AF CI CI 319 Q 0 0\"/ 0 HN- ' HN 5N HN- NN 53 CI CI 323 \ / 3240 HN- HN N N-N 0 _N< Cl CI 325 \/ \/ 326 / 0 HN- HN /N /N N-N N-N CI CI 327 \' 0 328 \/"N/0 HN HN /NHO N HN Cl C 329 \ 330 HN HN HN HN NH 331 332 \/ \ HN HN N N

ON

0 54 333 \ / 334 \/>\/ HNN HNN HN _\ I _\ CN N HN OH 335 336 N N 33 338 HN CO / \N_ HN 0 -N 337 33 H 0 0 341\"N 342 N HN- HN 55/ o 0= 05 343 \' "W/ 0 NH 0 4 \ / \/ HN _JN7 HN-4 0 0 345 \ \/346\/ /0 N 0 _N 0 I-N4 N HN s0 S~0 347 \I \N/ 0 348\' / N o QC; 0 No / ~0 o 0 "N HN N 2 HN -4/ \ NH 0 ~0 351 \ / \/52 N0 HN4 0 -N F I- C H F F o 00 GI c 353 \ \ / 0' 354 "4~ 0 HN HH HN N H H - N / NH HN 56 355 0 356 \N " HN HN / \N H- 0 NH NH HN HN 35 358 \/ / ~ 0 N O0 N NHH HN HN NH NH 363 364 ~ \ HN N H N 359 /\/ 366 HN

-

HN N 0 NH HN HN 361 0 3N H- HN NH NH HN HN 363 /YN 0 -3N4 F I N - H N N N- NH HN HN N 0N 0 HN- HN I-N N ]HN N 57 Ci Cl 367 \ \/368 \' / HN HN / / \ -- / \ HN \-" HN Compounds of the invention may contain one or more asymmetric carbon atoms. Accordingly, the compounds may exist as diastercomers, enantiomers or mixtures thereof. The syntheses of the compounds may employ racemates, diastereomers or enantiomers as starting materials or as 5 intermediates. Diastereomeric compounds may be separated by chromatographic or crystallization methods. Similarly, enantiomeric mixtures may be separated using the same techniques or others known in the art. Each of the asymmetric carbon atoms may be in the R or S configuration and both of these configurations are within the scope of the invention. 10 The invention also encompasses prodrugs of the compounds described above. Suitable prodrugs include known amino-protecting and carboxy-protecting groups which are released, for example hydrolyzed, to yield the parent compound under physiologic conditions. A particular class of prodrugs are compounds in which a nitrogen atom in an amino, amidino, aminoalkyleneamino, iminoalkylencamino or guanidino group is substituted with a hydroxy (OH) group, an 15 alkylcarbonyl (-CO-R) group, an alkoxycarbonyl (-CO-OR), an acyloxyalkyl-alkoxycarbonyl (-CO O-R-O-CO-R) group where R is a monovalent or divalent group and as defined above or a group having the formula -C(O)-O-CP1P2-haloalkyl, where P1 and P2 are the same or different and are H, lower alkyl, lower alkoxy, cyano, halo lower alkyl or aryl. Prodrug compounds may be prepared by reacting the compounds of the invention described above with an activated acyl 20 compound to bond a nitrogen atom in the compound of the invention to the carbonyl of the activated acyl compound. Suitable activated carbonyl compounds contain a good leaving group bonded to the carbonyl carbon and include acyl halides, acyl amines, acyl pyridinium salts, acyl alkoxides, in particular acyl phenoxides such as p-nitrophenoxy acyl, dinitrophenoxy acyl, fluorophenoxy acyl, and difluorophenoxy acyl. The reactions are generally exothermic and are 25 carried out in inert solvents at reduced temperatures such as -78 to about 50 'C. The reactions are usually also carried out in the presence of an inorganic base such as potassium carbonate or sodium bicarbonate, or an organic base such as an amine, including pyridine, TEA, etc. One manner of preparing prodrugs is described in USSN 08/843,369 filed April 15. 1997 58 (corresponding to PCT publication W09846576) the contents of which are incorporated herein by reference in their entirety. SYNTHESIS Compounds of the invention are prepared using standard organic synthetic techniques from commci-cially available starting materials and reagents. 11 will be appreciated that synthetic procedures employed in the preparation of compounds of the invention will depend on the particular substituents present in a compound and that various protection and deprotection 10 procedures may be required as is standard in organic synthesis. Compounds of the invention in which Y is absent may prepared by a Negishi coupling procedure according to the following general scheme 1: scheme 1 15 1, BXsR Pd(lhk (R3) A + (R3). N A R, N" ZnBr (R~tri(R2)n la in which the pyridyl zinc bromide (or alternatively pyridylzinc chloride) is reacted with all iodo or bromo substituted ring A to give the final compound [a. Alternatively, compounds la of the invention may be prepared using a Suzuki coupling reaction of a borylated ring A to provide direct 20 linkage between the appropriate pyridyl and ring A according to scheme 2. scheme 2 R x R1 I|dl (R3 0 N A (RB (RY n-iA1 a.-- (R2) (R N Br 0 0I 25 A halogen-substituted ring A is reacted with a boron ester such as pinacol diborane in the presence of palladium catalyst such as PdClz(dppf) and the resulting boronate ester is heated with a 2 halogen-substituted pyridine and a palladium catalyst to give a final compound la of the invention. 59 Compounds of the invention in which Y is NR may prepared by palladium catalyzed amination of halogen-substituted ring A with the desired 2-aminopyridine according to scheme 3. 5 scheme 3 (R~ i+ A Pd1 N N- A (R3 NR4H + RRR (3XR lb Compounds of the invention in which X is NR 4 CO may be prepared by the general scheme 4 in which amine-substituted ring A is reacted with the desired acid chloride Cl-C(O)-R 1 , In scheme 4 (RA NR 4 H C R (R 3

R

1 " ' N Y -Y Alternatively, such compounds may be prepared from by EDC catalyzed coupling of a carboxy 15 substituted ring A with an amine-substituted R, group, i.e. RI-NR4H. The same scheme may be used to prepare thioamide compounds of the invention, i.e. X is NR 4 C(S), by employing an appropriate thio acid chloride Cl-C(S)-R, in the acylation step. Compounds of the invention in which X is C(O)NR4 may be similarly prepared by reacting an 20 amine-substituted ring A with a carboxy-substituted R, group and EDC catalyst according to scheme 5. scheme 5 0 EDC0 25 (R2) (R 60 A similar scheme may be used to prepare thioamide compounds of the invention, i.e. X is

C(S)NR

4 , by employing an appropriate thioic acid-substituted ring A (e.g. -C(S)OH) or by converting the amide with Lawesson's reagent.. 5 Compounds of the invention in which X is NR 4 C(O)NH may be prepared according to the general scheme 6 by reacting amine-substituted ring A with the appropriate isocyanate R 1 -NCO. Scheme 6 R4 H (R3m 4 NR 4 H RNCO (R3rn A N , N Y-- A N Y R 0 10 The same scheme may be used to prepare thiourea compounds of the invention, i.e. X is NR4C(S)Ni, by employing an appropriate isothiocyanate R 1 -NCS in place of the isocyanate R, NCO. 15 Compounds of the invention in which X is NIKSO may be prepared according to the general scheme 7 by reacting an amine-substituted ring A with the appropriate sulfonyl chloride Rr S(0 2 )Ci in the presence of a non-nucleophilic base such as TEA or diisopropylethylamine to form the desired sulfonamide . Scheme 7 20

(R

3

NR

4 H CI-SO-R 1 ,base (R3A R Compounds of the invention in which X is NR 4 SO are similarly prepared using the appropriate sulfinyl chloride R 1 -SO-Cl instead of the sulfonyl chloride R,-S(O2)Cl. 25 Compounds of the invention having the structure of formula lb' in which X is NHCO (i.e. formula lb") may be prepared according to the general scheme 8 in which R, R6, m and o are as defined herein and Q is CI, Br or ; ' is halogen, OH, OR wherein R is an activating group: L is Br, I or OTf (e.g. O-SO2-CF,): 61 Scheme 8 L N (R3)r |I c (R3 N N Zn-Q

NO

2 NOz (a) (b) (C) (R) NN NHz0 HN $ (d) B (e)Ib 5 The zinc halide pyridine reagent (a) is reacted with 2-chloro-5-nitro-benzene reagent (b) in a Negishi coupling reaction in the presence of a suitable catalyst such as palladium tetrakis(triphenylphosphine) complex (Pd(PPh)4). In a particular embodiment, the palladium In tetrakis(triphenylphosphine) catalyst is stablized with triphenylphosphino (PPh 3 ). In a particular embodiment Q is Br. In a particular embodiment L is 1. In a particular embodiment, the coupling reaction is performed from about 504C to about 60"C. The nitrobenzene reagent (b) may be obtained from activating the corresponding amine (i.e. 2 15 chioro-5-nitroaniline) in an aqueous sulfuric acid solution with sodium nitrite and displacing with an L group (e.g. with KI, KBr). In a particular embodiment. L is 1. In a particular embodiment the reaction is performed at less than about 15"C. The resulting intermediate (c) is reduced, for example with Fe, Zn or SnCL 2 in presence of acid to 20 give the amine intermediate (d). In a particular embodiment, intermediate (c) is reduced with Fe, for example, in the presence of AcOH in EtOH. In a particular embodiment, intermediate (c) is reduced with Zn, for example in the presence of AcOH in EtOH. In a partiuclar embodiment, intermediate (c) is reduced with SnCI 2 , for example in the presence of HCI in EtOH. In a particular embodiment the reduction reaction is performed at about 60"C. 25 62 Finally, intennediate (d) is reacted with an activated acid (e) to yield final compound b". In a particular embodiment, the activated acid (e) is an acid halide (e.g. Q' is chloride) or activated ester (e.g. Q' is O-EDC). In a particular embodiment the final reaction is performed at about "C. The compounds of the invention inhibit the hedgehog signaling and are useful for the treatment of cancers associated with aberrant hedgehog signaling, for example when Patched fails to, or inadequately, represses Smoothened (Ptc loss-of function phenotype) and/or when Smoothened is active regardless of Patched repression (Smo gain-of-firmction phenotype). Examples of such 10 cancer types include basal cell carcinoma, neuroectodermal tumors such as medullablastoma, meningionia, hemangioma, glioblastoma, pancreatic adenocarcinoma, squamous lung carcinoma, small-cell lung carcinoma, non-small cell lung carcinoma, chondrosarcoma, breast carcinoma, rhabdonyosarcoma, oesophageal cancer, stomach cancer, biliary tract cancer, renal carcinoma, thyroid carcinoma. Compounds of the invention may be administered prior to, concomitantly 15 with, or following administration of other anticancer treatments such as radiation therapy or chemotherapy. Suitable cytostatic chemotherapy compounds include, but arc not limited to (i) antimetabolites, such as cytarabine, fludarabine, 5-fluoro-2'-deoxyuiridine, gemcitabine, hydroxyurea or methotrexate; (ii) DNA-fragmenting agents, such as bleomycin, (iii) DNA crosslinking agents, such as chlorambucil, cisplatin. cyclophosphamide or nitrogen mustard; (iv) 20 intercalating agents such as adriamycin (doxorubicin) or mitoxantrone; (v) protein synthesis inhibitors, such as L-asparaginase, cycloheximide, puromycin or diphteria toxin; (Vi) topoisonerase 1 poisons, such as camptothecin or topotecan; (vii) topoisomerase U1 poisons, such as etoposide (VP-16) or teniposide; (viii) microtubule-directed agents, such as colcecmid, colchicine, paclitaxel, vinblastine or vincristine; (ix) kinase inhibitors such as flavopiridol 25 staurosporin, STi571 (CPG 57148B) or UCN-01 (7-hydroxystaurosporine); (x) miscellaneous investigational agents such as thioplatin, PS-341, phenylbutyrate, ET-18- OCH, or farnesyl transferase inhibitors (L-739749, L-744832); polyphenols such as quercetin, resveratrol, piceatannol, epigallocatechine gallate, theaflavins, flavanols, procyanidins, betulinic acid and derivatives thereof; (xi) hormones such as glucocorticoids or fenretinide; (xii) hormone 30 antagonists, such as tamoxifen, finasteride or LHRH antagonists. In a particular embodiment, compounds of the present invention are coadministered with a cytostatic compound selected from the group consisting of cisplatin, doxorubicin, taxol, taxotere and mitomycin C. Another class of active compounds which can be used in the present invention are those which are 35 able to sensitize for or induce apoptosis by binding to death receptors ("death receptor agonists"). 63 Such agonists of death receptors include death receptor ligands such as tumor necrosis factor a (TN.F-a), tumor necrosis factor B (TNF-B, lymphotoxin-a) , LT- (lymphotoxin-B), TRAIL (Apo2L, DR4 ligand), CD95 (Fas, APO-1) ligand, TRAMP (DR3, Apo-3) ligand, DR6 ligand as well as fragments and derivatives of any of said ligands. In a particular embodiment, the death 5 receptor ligand is TNF-a. In another particular embodiment the death receptor ligand is Apo2L/TRAIL. Furthermore, death receptors agonists comprise agonistic antibodies to death receptors such as anti-CD95 antibody, anti-TRAIL-RI (DR4) antibody, anti-TRAJL-R2 (DR5) antibody, anti-TRAIL-R3 antibody, anti-TRAIL-R4 antibody, anti-DR6 antibody, anti-TNF-R antibody and anti-TRAMP (DR3) antibody as well as fragments and derivatives of any of said 10 antibodies. For the purpose of sensitizing cells for apoptosis, the compounds of the present invention can be also used in combination with radiation therapy. The phrase "radiation therapy" refers to the use of electromagnetic or particulate radiation in the treatment of neoplasia. Radiation therapy is based on the principle that high-dose radiation delivered to a target area will result in the death of 15 reproducing cells in both tumor and normal tissues. The radiation dosage regimen is generally defined in terms of radiation absorbed dose (rad), time and fractionation, and must be carefully defined by the oncologist. The amount of radiation a patient receives will depend on various consideration including the location of the tumor in relation to other organs of the body, and the extent to which the tumor has spread. Examples of radiotherapeutic agents are provided in. but not 20 limited to, radiation therapy and is known in the art (Hellman, Principles of Radiation Therapy. Cancer, in Principles I and Practice of Oncology, 24875 (Devita et al., 4th ed., vol 1, 1993). Recent advances in radiation therapy include three-dimensional conformal external beam radiation, intensity modulated radiation therapy (IMRT), stereotactic radiosurgery and brachythcrapy (interstitial radiation therapy), the latter placing the source of radiation directly into the tumor as 25 implanted "seeds". These newer treatment modalities deliver greater doses of radiation to the tumor, which accounts for their increased effectiveness when compared to standard external beam radiation therapy. Ionizing radiation with beta-emitting radionuclides is considered the most useful for radiotherapeutic applications because of the moderate linear energy transfer (LET) of the ionizing 30 particle (electron) and its intermediate range (typically several millimeters in tissue). Gamma rays deliver dosage at lower levels over much greater distances. Alpha particles represent the other extreme, they deliver very high LET dosage, but have an extremely limited range and must, therefore, be in intimate contact with the cells of the tissue to be treated. In addition, alpha emitters are generally heavy metals, which limits the possible chemistry and presents undue hazards from 35 leakage of radionuclide from the area to be treated. Depending on the tumor to be treated all kinds 64 of emitters are conceivable within the scope of the present invention. Furthermore, the present invention encompasses types of non-ionizing radiation like e.g. ultraviolet (IJV) radiation, high energy visible light, microwave radiation (hyperthermia therapy). infrared (IR) radiation and lasers. In a particular embodiment of the present invention UV radiation is applied. 5 Compounds of the invention inhibit angiogenesis 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, ovarian, breast and glioma. Furthermore, compounds of the invention are useful for treating macular degeneration e.g. wet age-related macular degeneration. Compounds of 10 the invention are also useful for treating inflammatory/immune diseases such as Crohn's, inflammatory bowel disease, Sjogren's syndrome, asthma, organ transplant rejection, systemic lupus erythmatoses, rheumatoid arthritis, psoriatic arthritis, psoriasis and multiple sclerosis. Compounds of the invention are also useful as a depilatory. 15 The invention also includes pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carder, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. Typically, the compounds of the invention used in the methods of the invention are formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with 20 physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but may range from about 3 to about S. A particular formulation is an acetate buffer at pH 5. The compounds for use herein may be in a sterile formulation. The compound may be stored as a solid composition, although 25 lyophilized formulations or aqueous solutions are acceptable. The composition of the invention will be formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of 30 the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The "effective amount" of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to decrease hedgehog pathway signaling or else is the minimum amount necessary to cause reduction in size, volume or mass of 65 a tumor that is responsive to hedgehog signaling, or a reduction in the increase in size, volume or mass of such a tumor relative to the increase in the absence of administering the compound of the invention. Alternatively "effective amount" of the compound means the amount necessary to reduce the number of malignant cells or the rate in increase of the number of malignant cells. 5 Alternatively, "effective amount" is the amount of the compound of the invention required to increase survival of patients afflicted with an anti-hedgehog pathway sensitive tumor. Such amount may be below the amount that is toxic to normal cells, or the mammal as a whole. With respect to non-malignant indications, "effective amount" means the amount of compound of the invention required to decrease severity of the particular indication or symptoms thereof. 10 Generally, the initial pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01 to about 100 mg/kg, for example about 0.1 to about 20 mg/kg of patient body weight per day, for example about 0.3 to about 15 mg/kg/day. Oral unit dosage forms, such as tablets and capsules, may contain from 15 about 25 to about 1000 mg of the compound of the invention. The compound of the invention may be administered by any suitable means, including oral, topical, transdermal, parenteral, subcutaneous, rectal, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions 20 include intramuscular, intravenous, intraarterial, intraperitoncal, or subcutaneous administration. An example of a suitable oral dosage form is a tablet containing about 25mg, 50mg, 100mg, 250mg, or 500mg of the compound of the invention compounded with about 90-30 ng anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and 25 then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An aerosol formulation caln be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution is typically filtered, e.g. using a 0.2 micron filter, to 30 remove impurities and contaminants. Topical formulations include ointments, creams, lotions, powders, solutions, pessaries, sprays, aerosols and capsules. Ointments and creams may be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such bases may include water and/or an oil such a liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol. 35 Thickening agents which may be used include soft paraffin, aluminum stearate, cctostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax. Lotions may be formulated with 66 an aqueous or oily base and may contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents, Powders for extenal application may be formed with the aid of any suitable powder base e.g. talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, 5 solubilizing agents or suspending agents. EXAMPLES 10 The invention will be more fully understood by reference to the following examples. They should not. however, be construed as limiting the scope of the invention. Abbreviations used herein are as follows: BuOH: butanol; 15 DI PEA: diisopropylethylamine; DMA: NN-dimethylacetanide; DMAP: 4- dimethylaminopyridine; DME: 1,2-dimethoxyethane; DMF: dimethylformamide; 20 EDC: I-ethyl-3-(3-dimctlylaninopropyl)carbodiimide HATU: O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate; HPLC: high pressure liquid chromatography MPLC: medium pressure liquid chromatography NBS: N-Bromosuccinimide; 25 TEA: Triethylamine; TASF: tris(dimethyl amino)sulfonium difluorotriiethylsilicate; THF: tetrahydrofiran; EtOH: Ethanol: MeOH: Methanol; 30 L: microlitre All reagents were obtained commercially unless otherwise noted. Reactions were performed using 35 oven-dried glassware under an atmosphere of nitrogen. Air and moisture sensitive liquids and solutions were transferred via syringe or stainless steel cannula. Organic solutions were 67 concentrated under reduced pressure (ca. 15 ,m Hg) by rotary evaporation. Unless otherwise noted all solvents used were obtained commercially. Chromatographic purification of products was accomplished by use of anl Isco Combiplash Companion and media. Reaction times are given for illustration only. The course of reactions was followed by thin-layer chromatography (TLC) and 5 liquid chromatography-mass spectrometry (LC-MS). Thin-layer chromatography (TLC) was performed on EM Science silica gel 60 F 2 54 plates (250 4m). Visualization of the developed chromatogran was accomplished by fluorescence quenching. LC-MS were acquired with a Shimadzu lOAD LC on a Phenomenex column (50 x 4.6 ma, 5 pm) operating at 3 nIL/min. A Shimadzu SPD-IOA detector monitoring at 214 and 254 nm was used. Single quadrupole mass 10 spectrometry was performed on an Applied Biosystems mass spectrometer. Nuclear magnetic resonance (NMR) spectra were acquired on a Varian Tnova spectrometer operating at 400 MHz for H and are referenced internally to tetramethylsilanc (TMS) in parts per million (ppm). Data for 'H NMR are recorded as follows: chemical shift (8, ppm), multiplicity (s, singlet: bs, broad singlet; d, doublet; t, triplet; q, quartet; quint, quintet; sext, sextet: hept, heptet; m, multiplet; bin, broad 15 multiplet), and integration. The structure and purity of all final products were assessed by at least one ofthe following techniques: LC-MS, NMR. TLC. Example I General Procedures 20 Compounds of examples 2-51 were prepared according to the following general procedures. A: Suzuki Coupling Procedure R ci 0 ci c 01 NA N PdCiz(dppf) R Pd(PPha)4 HN 0 rBB HN 0 HN 0 Ar Ar N Ar 25 2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene:ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh)4 (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 'C for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted 30 with ethyl acetate (2 x 20 mL), dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. 68 B: Negishi Coupling Procedure C1 X- CI Pd(PP1hI 4 N HN 0 R Ar ZnBr H O X=lorBr R = H, 3-Me, 4-Me, 5-Me, 6-Me Aryl zinc bromide (0.5 M in THF, 2.5 eq) was added to an oven-dried microwave vial charged 10 with the appropriate aryl halide (1.0 eq) and Pd(PPh 3

)

4 (0.04 eq). The vial was scaled and heated with stirring in the microwave to 140 *C for 10 minutes. The crude reaction mixture was concentrated and purified by chromatography on silica gel (conditions given below) to afford the desired product. 15 C: Iron Reduction of Aryl Nitro Group C1 CI R R Fe. AcOHl.

NO

2 EtHNH 2 R = I or pyridin-2-yl 20 The appropriate nitro aryl (1 minol, I eq) in AcOHi/EtOH (1:1, 0.42 M) was added slowly to a solution of Iron powder (6.0 eq) in AcOH/EtOH (1:2, 2 M) at 60 "C. The solution was stirred at 70 "C for 30-60 minutes. The reaction mixture was cooled to 23 *C, filtered through celite, washed with ethyl acetate, and concentrated. The oily residue was dissolved in ethyl acetate (30 25 mL), washed with saturated aq. NaHCO, (2 x 15 miL) and water (2 x 10 mL), dried (MgSO4), and concentrated. The oily residue was used with out further purification. 69 D: Amide Bond Formation CI ArCOCI

NH

2 EtN. Cl6Ck HN O Ar R = I or pyridin-2-yl 5 Acid chloride (1.05-1.1 cq) was added to a solution of aniline (1.0 eq) and TEA (1.1-1.5 eq) in methylene chloride at the indicated temperature. The solution was stirred for 0.5-3 hours, poured onto saturated aq. NaHCO 3 , extracted twice with methylene chloride, dried (MgSO 4 ), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product, I0 E: EDC Amide Bond Fonnation I c - HO Ar

NIH

4 C, H0

NH

2 CHJCextraction HN 15 R= I or pyridin-2-y Carboxylic acid (1.1 eq) was added to a solution of aniline (1.0 eq) and EDC (1.4 eq) in methylene chloride (0.7 M in aniline). The solution was stirred at 23 'C for 2 hours, poured onto a 1:H mixture of saturated aq. N.H 4 C1 and water, extracted twice with methylene chloride, dried 20 (MgSO4, and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. 70 F: addition of amines to 2-chloropyridine ci ci F -N0 _N__ _ __ HN R H HN R RNR BuOHN R=H, CH 3 ] NHRR' = ethanolamine, analine, benzylaminc, 2-methylpropylamine, N-methylpiperazine, 5 morpholine, 2-morpholinoethylamine Primary or secondary amine (5 eq) in either BuOH or a mixture of BuOH/ethylene gylcol was heated to 170 to 220 'C for 20 min in a scaled lube. The BuOH was removed under reduced pressure. In cases where ethylene glycol was used, the reaction was diluted with water, and the 10 product was extracted into ethyl acetate, dried (MgSO 4 ), and concentrated. The crude residue was purified by reverse phase HPLC to afford the desired product. G: Amide bond coupling with HATU 15 CI N H r N NH O IIATIl. DIlPA, DMF Ar NaOIor NaICO NH2 ehl acetale extraction HN O Ar Aniline (1.0 eq) was added to a mixture of carboxylic acid (1.I eq), HATU (1.1 eq) and DIPEA (2 eq) in DMF (0.1 - 0.2 M). After stirring overnight, the reaction mixture was diluted with 0.1 N sodium hydroxide or saturated NaHCO 3 . extracted into ethyl acetate and the combined organic 20 layers were washed with brine. The organic layer was dried (MgSO 4 ), concentrated and the crude mixture was purified by reverse phase HPLC. 71 H: Preparation of sulfonamide benzoic acids HO 0 HO 0 HNR DPEA/M O I O WNR' Chlororsulfonylbenzoic acid (1.0 eq) was added to a solution of amine (1.1 eq) in 10-20% 5 DIPEA/methanol (I M) at 4 'C. After I h, the reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC. I : Stannylation of 2-pyridyl triflates Pd(PPh 3

)

4 (Me 3 Su), Lid (R3)m---hl~ N OTf Dioxane/Toluene N SnMe 3 A solution of tetmkis-triphonylphosphincpalladium (0.04 eq.) in toluene (J mL) was added to degassed solution of aryltriflate (I eq), bis-trialkyltin (1.05 eq), and lithium chloride (3 eq) in dioxane. Heated to reflux for 2 hours, cooled to 23 'C, diluted with ethyl acetate, washed with 10% NH 4 OH, and brine, dried (MgSO 4 ) and concentrated. The crude material was used without 15 further purification. J: Stannylation of substituted pyridines L dinethylaminoethanol nBuLi, hexanc m ,y (R 3)m4 N 2. McSnCI N SnMe 3 20 n-Butyl lithium (6 eq, 2.5 M in hexanes) was added dropwise to a solution of dimethylaminoethanol (3 eq) in hexane at 0 *C. The solution was stirred at 0 0 C for thirty minutes before dropwise addition of the substituted pyridine (1 eq). The solution was stin-ed at 0 "C for an additional hour, then cooled to -78 "C. A solution of trialkyllin in hexane was added dropwise. The solution was stirred at -78 *C for thirty minutes, warmed to 0 *C, quenched with water, 25 extracted twice with ether, dried (MgSO 4 ), and concentrated. 72 K: Still Coupling Cl Pd 2 (dba), CI (R3)m PP , NMP (R3)m N N SnMe 3 microwave HN O HNrO R1 R1 Palladium catalyst (0.02 eq) was added to a degassed solution of aryliodide (I eq), arvistannanc (2 eq), and triphenylphosphine (0.16 eq) in NMP. Heated in the microwave to 130 0 C for 15 minutes. 5 The reaction mixture was diluted with ethylacetate, washed with 10% NH40H,q) and brine, dried (MgSO4). concentrated and purified by silica gel chromatography. L: Synthesis of alkylethers HO Cl RO CI N N alkyl iodide I N Cs 2 CO;, NMP microwave HN tO HNyO 10 R1 R1 A solution of hydroxypyridine (I eq), alkyliodide (excess), and cesium carbonate in NMP was heated in the microwave to 100 *C for ten minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NHOHnq, and brine, dried (MgSO 4 ), concentrated and purified by silica gel chromatography. 15 M: Methyl Ester Saponification 0 R R R R

-

LiOH 1: ITHF/H20 0 0 O O O HO 20 The methyl ester (lcq) was hydrolyzed with LiOH (2eq) in 50/50 THF/water mix. Upon completion of the reaction the THF was evaporated under reduced pressure and the solution is acidified with HCI to pH 2. The resultant solid was filtered and dried to give the pure acid. 73 N: Bromination in the presence of a free acid functionality 0 0 HO R HO R Benzoyl Peroxide - nbs, AcOH Benzene A Br 5 The parmethylbenzoic acid (Ieg) was combined with Benzoyl Peroxide (0.!eq) and N Bromosuccininde (0.9eq) in a solution of 5%AcOH in Benzenc and heated in the microwave at 120"C for 5-15minutes. The product was separated from the starting material and di-bromo product via ISCO flash chromatography with an ethyl acetate (with 1% AcOH) and hexanes solvent system. IO 0: Sodium Methanesulfinate displacement of Bromine o O R R R R NaSOCH 3 // Br To the bromine starting material (leq) was added sodium methanesulfinate (2eq) in DMF and 15 heated to 120'C in the microwave for 5 minutes. Alternatively, the reaction was heated to 60*C in an oil bath for several hours until completed. Reaction mixture was concentrated under reduced pressure and extracted in ethyl acetate and water. The organic layer was dried over Magnesium Sulfate, filtered and concentrated in vacuo to yield generic methylsulfone. 20) P: Amine displacement of Bromine o O Y R Y R RRNH - R Br N R To the brono starting material (leg) was added appropriate amine (3vg) in either DMSO or BuOH and stirred at room temperature until complete. For less nuclcophilic amines or anilines, the 25 reactions were forced to completion using microwave conditions ranging from 150"-170"C for 15 74 minutes. Crude reactions were concentrated to dryness and either extracted with ethyl acetate and saturated bicarbonate if the reaction resulted in an intermediate or purified via HPLC if the reaction resulted in a final product. 5 Q: Thiol displacement of halogen o O R R

-

RSH

/ eKCO, \ / Br DMF R The paramethylbrono benzoate (leq) was treated with Potassium (or Cesium) Carbonate (1.5eq) and appropriate thiol derivative (I,leq) in DMF (or CH 3 CN) and stirred overnight at room 10 temperature. The DMF was evaporated in vacuo and the reaction was extracted with ethyl acetate and water. The organic layer was dried over Magnesium Sulfate , filtered and concentrated to yield the thiol or derivatized thiol compound. 15 R: Oxone Oxidation R R oxone \ / 2:1 MCOH/HO R R Derivatized thiol (I eq) was dissolved in MeOH while Oxone (2eq) was seperately dissolved in half the amount of water. Once all the oxone was dissolved, the solution was added to the thiol in McOH solution at once and stirred until complete. The MeOH was evaporated in vacuo and the 20 remaining water was extracted twice with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate and concentrated to yield the sulfone. 25 S: Thiolysis of epoxides at alumina surfaces 75 R R R0 RR SH R OH A mixture of epoxides (1.0 eq), thiophenol (1.5 eq) and neutral aluminum oxide (-70 eq) in diethyl ether was stirred for 3 h at room temperature while being monitored by TLC. The reaction mixture was filtered through Celite, washed with ethyl acetate and concentrated. Purified by silica gel 5 chromatography (0-40% ethyl acetate/hexane) to yield ,6 -hydroxysulfide product. T: Conversion of nitrile group to carboxylic acid NC R HO R NaOl 119 If( S-R S-R 10 A solution of benzonitrile (1.0 eq) and sodium hydroxide (2.0 eq) in .HO was heated to 120 " C for 2h. The reaction mixture was cooled to room temperature and acidified with HCI to pH 2. The resulting solid was filtered to afford the pure acid product. 15 U. Alkylationofphenols R 0 R R-1 or R-Br OH Cs 2

CO

3 , DMF \ $ R The phenol was dissolved in DMF (1.0 ml). Cesium carbonate (1.0 eq.) and an alkyl bromide or 20 alkyl iodide (1.0 to 2.0 eq.) were added, and the reaction was stirred at room temperature for 18 hrs or 50*C for I to 24 hours. The reaction was quenched in water, and extracted with ethyl acetate twice. The organic extracts were washed with water once, brine once, dried with MgSO 4 , and evaporated to a crude oil which was purified on reverse phase HPLC. 76 V. Amide bond formation with an acid chloride and an aniline RO RO MP-Carbonate O THF, CH 2 Cl 2 0 CAR-N R NH2 Cl R 0H 5 The aniline was dissolved in THF (1.5 ml) and dichloromethane (1.5 ml). MP-Carbonate (1.5 eq.) and an acid chloride (1.1 eq.) were added, and the solution was stirred at room temperature for 18 hours. The reaction was diluted with methanol and dichloromethane, and filtered to remove the MP-Carbonate. The mother liquors were evaporated to a solid and purified by reverse phase 10 HPLC. W. Amidine formation from an inidate R 0 R 0 R R H N 0A HMN i'R 15 R A solution of freshly formed imidate in methanol was treated with a primary or secondary amine (1.5 eq,) at room temperature for 18 hours. The methanol was removed on a rotary evapoi-ator and the residue purified by reverse phase HPLC. 20 X. 4-(2-hydroxy-2-metliylpropylsulfonyl)-2-methylbenzoic acid 77 H 0 0 H 0 0 0 H Step1. Preparation of methyl 4-bromo-2-methylbenzoate - A IL 3 neck flask with mechanical stirrer, reflux condenser, internal temperature probe and a nitrogen bubbler was charged with 4 5 brono-2-methylbenzoic acid (50.35 g, leq., Hongda) and methanol (350 mL). and the reactor contents were cooled to 0 C. Acetyl chloride (2 7

.

6 g, leq.) was slowly added at a rate which maintained an internal temperature of less than 30 C. The reaction mixture was heated to reflux for 16 hours, until starting material was no longer detected by LC. Once reaction was complete, the reactor contents were cooled to room temperature and the reaction mixture was concentrated 10 to an oil via rotary evaporator. The oil was then diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (100 mL). The organic layer was concentrated via rotary evaporator to afford methyl 4-bromo-2-methylbenzoate (5 1.

22 g, 95.5 %) as a yellow oil. Step 2. 4-(2-hydroxy-2-methylpropylthio)-2-methylbenzoic acid - A 12 L 3 neck round bottom 15 flask with mechanical stirrer, reflux condenser, internal temperature probe and a nitrogen bubbler was charge with methyl 4-bromo-2-methylbenzoate (500 g), toluene (4,000 mL), 2-ethylhexyl 3 mercaptopropanoate (715 g), and diisopropylethylamine (564 g). Reactor contents were degassed by repeating a cycle of vacuum/nitrogen 3 times. The reactor was then charged with Pd (dba) (59.97 g), and Xantphos (63.15 g) and degassed by repeating a cycle of vacauu/itrogen I time. 20 Reactor contents were then heated to 95-100 C for 16 hours, until starting material was no longer detected by LC. Once the reaction was complete, the reactor contents were cooled to 45 C. The reactor was then charged with Florisil (1000 g) and the contents of reactor were stirred at 50 C for 2 hours, until intermediate material was no longer detected by LC. Once reaction was complete, reactor contents were cooled to room temperature and filtered over celite pad. The filter cake was 25 washed with ethyl acetate (4000 mL) and the filtrate was concentrated to an oil via rotary evaporator. The oil was then transferred back to the reactor with methanol (9000 mL) and the reactor was charged with sodium methoxide (327 g). (exothermic addition, AT- 10 C). Reactor contents were then heated to 50 C for I hour, until intermediate material was no longer detected by LC. Reactor was then charged with 2,2-dimethyloxirane (236 g), (exothermic addition, AT- 10 30 C) and contents were continued heating at 50 C for I hour, until intermediate material was no 78 longer detected by LC. Reactor was then charged with water (500 mL) and lithium hydroxide monohydrate (91 g) and then heated to 60 C for 12 hours, until intermediate material was no longer detected by LC. Once reaction was complete, reactor contents were cooled to room temperature and concentrated to an oil via rotary evaporator followed by dilution with water (18 5 L), extraction with dichloromethane (2 x 4 L), washing aqueous fraction with heptane (2 x 4 L), acidifying aqueous fraction with cone. HCI ( maintaining a temperature of less than 35 C, and extracting with dichloromethane (2 x 16 L). Each organic fraction was washed with water ( I x 8L) and concentrated to dryness to obtain 4-(2-hydroxy-2-methylpropylthio)-2-methylbenzoic acid

(

4 7 2 g, 90 % yield) as a yellow solid. I0 Step 3. Synthesis of 4-(2-hydroxy-2-methylpropylsulfonyl)-2-methylbenzoic acid - A 2000 mL reactor with mechanical stirrer, internal temperature probe and a nitrogen bubbler was charged with 4-(2-hiydroxy-2-iethylpropyltliio)-2-methylbenzoic acid (52 g), methanol (370 mL), water (370 mL) and Oxone (146 g). (slight exotherm observed, AT -15 C) and stirred at room 15 temperature for 18 hrs, until starting material was no longer present by LC. Methanol was removed via rotary evaporator and reactor contents were dissolved in 5% sodium bicarbonate solution (3L) and ethyl acetate (2L) was added followed by acidification with conc. HCI to pH 1. Organics were concentrated to dryness via rotary evaporator to obtain 4-(2-hydroxy-2 methylpropylsulfony)-2-methylbenzoic acid (52 g, 88 % yield, 96.47 area % by LC) as a white 20 solid. Example 2 6-(2-morpholinoetlhylamino)-N-(4-chloro-3-(pyidin-2-yl)phenyl)pyridine-3 carboxamide 25 CI HN NH 0 79 Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxanide (50 mg) and 2-morpholinoethylamine in butanol (0.5 mL). The crude reaction was purified by reverse phase HPLC to yield 6-(2-morpholinoethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3 carboxamide as a white solid. MS (Q1) 438.3 (M) . Example 3 N.N-(4-Chloro-3-(pyridin-2-yl)phenyl)-bis[6-(trifluoromethyl)-2-iethylpyridine 3]-carboxamide S C1 N o N O N\ / N

F

3 C CFa 10 Procedure B was performed with 2-pyridylzine bromide (4 mL, 2.0 mmol, 0.5 M in THF) and 3 bromo-4-chloro-nitrobenzenc (236 mg, 1.0 mmol). Purified by chromatography on silica gel (10% ethyl acetate/hexanes) to yield 2-(2-chloro-5-nitrophenyl)pyridine as a light yellow solid. Procedure C was performed with 2-(2-chloro-5-nitrophenyl)pyridine (122 ing, 0.52 mrol) to yield 15 4-chloro-3-(pyridin-2-yl)aniline as a light yellow solid, which was used without further purification. Procedure D was performed using 4-chloro-3-(pyridin-2-yl)aniline (40 mg, 0.2 mnol), The crude residue was purified by silica gel chromatography (15-60% ethyl acetate/hexanes) to yield N,N-(4 20 Cbloro-3-(pyridin-2-yl)phenyl)-bis[6-(trifluoromethyl)-2-methylpyridine-3]-carboxamide as an oily residue: TLC Rr= 0.42 (35% ethyl acetate/hexanes); H NMR (CDC 3 , 400 MHz) 6 8.72 (in, IH), 7.84 (d, 2HO, 7.77 (dd, IH), 7.68 (in, 1-1), 7.57 (d, IH), 7.51 (m, 3H), 7.33 (in, 1H), 7.12 (dd, 1H), 2.78 (s, 6H); MS (QI) 579 (M)". 80 Example 4 N-(4-Chloro-3-(pyridin-3-yl)phenyl)-3,5-dimethoxybenzamide C1 HN OMe Me 4-Chloro-3-(pyridin-2-yl)aniline (40 mg, 0.2 mmol) was used in procedure D with 3,5 5 dimethoxybenzoyl chloride (43 mug, 0.216 mmol) at 23 *C for 2 hours. The crude residue was purified by crystallization (CH 2 C,/hexanes) to yield N-(4-chloro-3-(pyridin-3-yl)phenyl)-3,5 dimethoxybenzamide as an off-white solid: TLC R, = 0.30 (15% ethyl acetate/hexanes); 'H NMR (CDCbI, 400 MHz) 8 8.72 (m, lH), 7.91 (in, 1H). 7.88 (dd, IH), 7.78 (in, 2H), 7.74 (dd, IH), 748 (d, IlH), 7.35 (in, In). 6.96 ( d, 2H), 6.62 (t, 1IH), 3.82 (s, 6H); MS (Q1) 369 (M)'. 10 Example 5 5-Acetyl-N-(4-ciloro-3-(pyridin-2-yl)phenyl)thiophene-2-carboxaiide CI N HN IS 4-Chloro-3-iodoaniline (2.5 g, 9.88 mmol) was used in Procedure E with 5-acetylthiophene-2 carboxylic acid (1.

8 5 g, 10.8 mmol) at 23 *C for 2 hours. The crude material was purified by silica gel chromatography (20-100% ethyl acetate/hexanes) to yield 5-Acetyl-N-(4-chloo-3 iodophenyl)thiophcne-2-carboxamnidc as a yellow solid. 20 5-Acetyl-N-(4chloro-3-iodophenyl)thiophene-2-carboxamide (202 mg, 0.5 mmol) was used in Procedure B with 2-pyridylzincbromide (2.5 mL, 1.25 mmol, 0.5 M in THE). Purified by silica gel chromatography (10-100% ethyl acetate/hexanes) to yield 5-acetyl-N-(4-chloro-3-(pyridin-2 yl)phenyl)thiophene-2-carboxamide as a yellow solid: TLC R, = 0.19 (50% ethyl acetate/hexanes); 'H NMR (CDCl 3 , 400 MHz) 6 8.96 ( bs, 1H). 8.67 ( d, IH), 7.79 (dt, 1H), 7.68 25 (m, 3H), 7.61 (d,1 H), 7.58 (d, IF), 7.37 (d, I H), 7.32 (in, 1 H), 2.58 (s, 3H); MS (Q1) 357.0 (M). 81 Example 6 N-(4-Chloro-3-(3-methylpyridin-2-yl)phenyl)-6-(trifluoronethyl)-2 methylpyridine-3oarboxamide HN

CF

3 5 N-(4-Chloro-3-iodophcnyl)-6-(trifluoroicthyl)-2-nethylpyridine-3-carboxamide (142 mg, 0.32 mmol) was used in Procedure B with 6-methyl-2-pyridylzinc bromide (1.75 mL, of a 0.5 M in TFHF). Purified by silica gel chromatography (5-100% Ethyl acetate/Hexanes) to yield N-(4-chloro 3-(3-methylpyridin-2-yl)phenyl)-6-(trifluoromethyl)-2-netbylpyridine-3-carboxamiide as a white solid: TLC R 1 = 0.23 (30% ethyl acetate/hexanes); 'H NMR (CDCI, 400 MHz) 6 8.81 (bs, 1 H), 10 7.95 ( dd, I H), 7.67 (m, 3H), 7.53 (t, 211), 7.38 (d, IH), 7.07 (d, 1-1), 2.71 (s, 3H), 2.43 (s, 3H); MS (Q 1) 406.1 (M)'. Example 7 N-(4-Chloro-3-(5-methylpyridin-2-yl)phcnyl)-6-(trifluoromethyl)-2 methylpyridine-3-carboxamide Cl N0 HN /\ 15 CF, N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridinc-3-carboxamide (150 mg, 0.34 mmol) was used in Procedure B with 4-methyl-2-pyiidylzinc bromide (1.7 niL of a 0.5 M in THF). Purified by silica gel chromatography (5-75% Ethyl acetate/Hexanes) to yield N-(4-chloro-3-(5 metlylpyridin-2-yl)phenyl)-6-(trifluorometlhyl)-2-methylpyridine-3-carboxamide as a white solid: 20 TLC Rr= 0.23 (35% ethyl acetate/hexanes); H NMR (CDCI, 400 MHz) 6 10.62 (bs, IH), 8.12 (dd, 11), 7.89 (d, 1H), 7.58 (d. I H), 7.47 (in, 3H), 7.18 (d, 1 H), 6.89 (d, 1N), 2.62 (s, 3H), 2.38 (s, 3H); MS (Q1) 406.3 (M). Example 8 5-Acetyl-N-(4-chloro-3-(5-methylpyridin-2-yl)phenyl)thiopliene-2<arboxamide 82 C I HN 5-Acetyl-N-(4-chloro-3-iodophenyl)thiophene-2-carboxamide (203 mg, 0.5 mmol), was used in Procedure B with 4-methyl-2-pyridylzinc bromide (2.5 mL, 1.25 mmol, 0.5 M in THF). Purified by silica gel chromatography (30-100% ethyl acetate/hexanes) to yield 5-acetyl-N-(4-chloro-3-(5 5 methylpyridin-2-yl)phenyl)thiophene-2-caboxamide as a yellow solid: TLC Rr= 0.25 (50% ethyl acetate/hexanes): 'H NMR (CDC,, 400 MHz) 8 9.52 (bs, I H), 8.51 (d, IIH), 7.60 (m, 4H), 7.39 (s, IH), 7.29 (d, IH), 7.14 (d, 1H), 2.55 (s, 3H), 2.42 (s, 3H); MS (QI) 371 (M)'. Example 9 N-(4-Chloro-3-(4-methylpyridin-2-yl)plienyl)-6-(trifluorometbyl)-2 10 methylpyridine-3-carboxamide cl H N

CF

3 Procedure B was performed with N-(4-Chloro-3-iodophenyl)-6-(trifluoromethyl)-2-methylpyridine 3-carboxamide (440 mug, 1.0 mmol) and 4-methyl-2-pyridylzinc bromide (5 mL of a 0.5 M 15 solution in THF). The crude residue was purified silica gel chromatography (5-100% Ethyl acetate/Hexanes) to yield N-(4-chloro-3-(4-methylpyridin-2-yl)phenyl)-6-(trifluoronetliyl)-2 methylpyridine-3-carboxamide as a white solid: TLC R,= 0.43 (35% ethyl acetate/hexanes); 'H NMR (CDCI 3 400 MHz) 6 10.39 (bs, IH), 8.11 (dd. IH), 7.87 (s, IH), 7.61 (d, IH), 7.59 (d, I H), 7.49 (m, 3H), 2.66 (s, 3H), 2.21 (s, 3H): MS (QI) 406.1 (M)-. 20 Example 10 N-(4-chloro-3-(6-methylpyridin-2-yl)phenyl)-3,5-dimetliylisoxazole-4 carboxamide 83 CI YO~k HN 4-Chloro-3-iodoanilinc (1.01 g, 4 mmol) was used in procedure E with 3,5-dimethyl-4 isoxazolecarboxylic acid (0.565 g, 4 mmol), EDC (1.32 g, 6.8 mmol), TEA (0.5 mL), DMAP (50 mg, 0.4 mmol) at 23 0 C for overnight. The crude reaction was purified by silica gel 5 chromatography (0-15% ethyl acetate/CH 2 Cl,) to yield 3,5-dimethyl-N-(4-chloro-3 iodophenyl)isoxazolc-4<arboxamidc as a white solid. Procedure B was performed with 3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide (190 mg, 0.5 mmol) and 3-methyl-2-pyridylzinc bromide (2.5 mL of a 0.5 M solution in THF). The In crude reaction was purified by silica gel chromatography (5-100% Ethyl acetatc/Hexanes) to yield N-(4-chloro-3-(6-nethylpyridin-2-yl)phenyl)-3,5-dimethylisoxazole-4-carboxamide as a white solid: TLC Rr= 0.43 (50% ethyl acetate/hexanes); 'H NMR (CDCl, 400 MHz) 6 8.52 (bs, 1H), 7.68 (m, 2H), 7.48 (m, 3H), 2.70 (s, 3H), 2.49 (s, 3H), 2,21 (s, 3H); MS (Q1) 342.3 (M), 15 Example II N-(4-chloro-3-(pyridin-2-vamino)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3 carboxamide CI HNH N HNI

N~

CF

3 N-(4-Chloro-3-iodoplienyl)-6-(trifluoronethyl)-2-nietliylpyridine-3-carboxamide (220 mg, 0.5 20 mmol), 2-aminopyridine (40 mg, 0.42 mnnol), potassium t-butoxide (66 mg, 0.59 unmol), Pd (dba) (20 mg, 0.21 mmol), dppf (24 ing, 0.042 nunol) in toluene (2.1 nL) were heated to 100 "C for 1.5 days. The solution was cooled to 23 *C, diluted with ether, filtered through celite, washed with ethyl acetate, and concentrated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2 ylamino)phenyl)-6-(trifluoromethyl)-2-methylpyridine-3-carboxainide as a white solid: H NMR 25 (CDCI 3 , 400 MHz) 6 11.53 (s, 1H), 9.68 (s, IH), 8.05 (m, 2H), 7.85 (m, 2H), 7.55 (d, 1H), 7.26 (d, IH), 7.13 (dd, I H:), 6.91 (1, tH), 6.88 (d, I H), 2.75 (s, 3H); IS (Q 1) 407.0 (M)-. 84 Example 12 N-(4-chloro-3-(pyridin-2-vl)phenyl)-6-(4-methylpiperazin-1-yl)pyridine-3 carboxamide CI N 0 HN N Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxanide (50 mg) and N-methylpiperazine in butanol (0.5 mL). The crude reaction was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-y1)phenyl)-6-(4-nethiy1piperazin-1-yl)pyridine-3 carboxamide as a white solid. MS (Q1) 408.4 (M). Example 13 N-(4-chloro-3-(pyridiii-2-yl)plhenyl)-6-(isobutylamino)pyridine-3-carboxamide Cl HN / \N

HN

Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)6-chloro-3-carboxamide (50 15 mg) and 2-methylpropylarnine in butanol (0.5 mL). The crude reaction was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)pyridine-3 carboxamide as a white solid. MS (QI) 381.1 (M)'. 20 Example 14 N-(4-cltoro-3-(pyridin-2-yl)phcnyl)-6-morpholinopyridine-3-carboxanide 85 CI N 0 HN N Procedure F was performed using N-(4-chlioro-3-(pyridin-2-yl)phenyl)-6-chloro-3<arboxamide (50 ng) and morpholine in butanol (0.5 nL). The crude reaction was purified by reverse phase HPLC 5 to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-morpholinopyridine-3-carboxamide as a white solid. MS (QI) 401.3 (M)'. Example 15 6-(benzylamnino)-N-(4-chlIor-3-(pyridin-2-yl)phenyl)pyridine-3-carboxanide 10 ci \ N 0 HN / \N HN Procedure F was performed using N-(4<hloro-3-(pyridin-2-yl)phenvl)-6-chloro-3-carboxamide (50 mg) and benzylamine in butanol (0.5 mL). The crude reaction was purified by reverse phase HPLC 15 to yield 6-(benzylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide as a white solid. MS (Q1) 415.1 (M)f. Example 16 N-(4-chloro-3-(pyridin-2-yl)phonyl)-6-(phonylainio)pyridine-3-carboxamidc CI \ N 0 HN / \N 20 HN 86 Procedure F was perfonned using N-(4-hloro-3-(pyridin-2-yl)phenyl)-6-chloro-3<arboxamide (50 rug) and analine in butanol (0.5 mL). The crude reaction was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(phcnylmnino)pyridine-3-carboxainde as a white 5 solid. MS (QI) 401.0 (M)*. Example 17 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-6-(tiifluoromethyl)-2-methylpyridine-3 carboxamide ci N H

CF

3 10 Procedure C was performed with 1-chloro-2-iodo-4-nitrobenzene (283 mg, I mmol) to produce 4 chloro-3-iodoaniline which was used without further purification. Procedure D was performed with 4-chloro-3-iodoaniline (225 mg, 0.889 mmol) and 6 (trifluoromethyl)-2-mcthylpyridine-3-carbonyl chloride (237 mg, 0/93 mmol, 1.05 eq) at 0 'C for 15 30 minutes. The crude residue was purified by silica gel chromatography (2-50% ethyl acetate/liexanes) to yield N-(4-chloro-3-iodophenyl)-6-(trifluoroiethyl)-2-methylpyridine-3 carboxamide as a white solid. Procedure B was performed using N-(4-Chloro-3-iodoplheny1)-6-(trifluoroietliyl)-2 20 methylpyridinc-3-carboxamidc (88 mng, 0.2 nmol) with 2-pyridylzinc bromide (1 nL, 0.5 mmol, 0.5 M in THF). Purified by silica gel chromatography (10-80% ethyl acetate/hexanes) to yield N (4-chloro-3-(pyridiin-2-y1)pbenyl)-6-(tritfuoromethyl)-2-methylpyridine-3-carboxamide as a yellow solid: TLC Rr= 0.28 (35% ethyl acetate/hexanes); TLC Rr= 0.28 (35% ethyl acetate/hexanes); 'H NMR (CDCls. 400 MHz) 8.88 (bs, IH), 8.41 (d, 1H), 7.96 (dd, IH), 7.74 (in, 4H), 7.52 (d, 1H), 25 7.22 (in, 1H), 2.75 (s, 3H); MS (QI) 392 (M). An alternative synthetic procedure is as follows. 75g (435 mmol) of 2-chloro-5-nitroaniline was added to a solution of water (600 muL) and conc. sulfuric acid (60 mL) in a 3L 3-neck flask equipped for mechanical stirring. The solution was cooled to 0 *C and a solution of sodium nitrite 30 (34.2 g, 496 mmol) in water (130 mL) was added slowly. The mixture was stirred for W hr. and then a solution of potassium iodide ( 1 30 g, 783 mmol) in water (520 mL) was added dropwise over 87 %z hr keeping the temperature below 5"C. The solution was stirred for 2 hr, then extracted with EtOAc (3 x 500 mL). The combined organic extracts were washed with sat. Na 2 S2O 3 (2x 500 nL), dried (Na 2 SO4), and concentrated. The crude iodide was dissolved in hot iPrOH (500 mL) and hexanes (200 ml-) were added. The reaction was allowed to cool with stirring and the product was 5 collected by suction filtration after stirring at 0 C for 2hr yielding 9 0g (318 mmol, 73%) 2-chloro 5-nitro-iodobenzene as a light tan crystalline solid. The 2-chloro-5-nitro-iodobenzene (5g, 17.6 mmol) was dissolved in 5 mL DMA in an oven dried flask and a 0.5M solution of 2-pyridylzincbromide (53 niL, 26.5 mmol, 0.5 M in THF) was added. 10 The solution was degassed with N, for '% hr., the PPh 3 (0.1 8 5g, 0.7 mmol) and Pd(PPh) 4 (0.

8 2 5g, 0.7 mmol) were added, rinsed in with several mLs THF and the solution was degassed for a further 10 min before heating to 60*C under N, The reaction was complete by TLC in -8h, cooled to RT, and poured into a 1:1 mixture of EtOAc/2.5N NaOH (500 mL). This solution was stirred for 10 mim, passed through a course fitted filter containing celite to remove the solid, and then extracted. 15 The organics were washed with brine and concentrated to a brown solid. The combined aqueous layers were backextracted with Et2O (I x 200 mL). This was used to suspend the crude product, which was extracted with IN HCI (I x 200 mL, 3 x 100 mL). The combined aqueous extracts were cooled to 0*C, diluted with E10Ac (250 mL), and made basic with 1ON NaOH (100 mL). This solution was separated, the aqueous layer extracted with EtOAc, and the combined organics were 20 dried over Na 2

SO

4 and charcoal with stirring. This solution was filtered through celite and concentrated to yield pure 4-chloro-3-(pyridin-2-yl)nitrobenzene ( 2

.

4 7g, 10.5 mmol, 60% yield) which was used in the next reaction without further purification. 4-chloro-3-(pyridin-2-yl)nitrobenzene (1.

4 7g, 6.26 mmol) was suspended in EtOH (35 mL), and 25 the SnCL ( 3 .87g; 20.4 mmol) and conc. HCl (5 mL) were added and rinsed in with a further 5 mLs EtOH. The solution was placed in a 40 0 C oil bath and heated to 60 0 C. The solution was stirred at 60*C for 1 '/ hr., cooled to RT and diluted with I N HCi (100 mL). This solution was poured into an Et0/1 N HCI solution (100 mL:150 mL) and extracted. The aqueous layer was diluted with EtOAc (250 mL), cooled to 0 0 C. and made basic with 10 N NaOH (50 mL). This solution was 30 extracted (EtOAc, 2x), and the combined organics were washed with brine and dried over NaS0 4 and charcoal. Suction filtration through elite gave a clear colorless solution which was concentrated to yield 4-chloro-3-(pyridine-2-yl)aniline (1.21g, 5.93 mmol, 94% yield) as a cream colored crystalline solid which was used in the next reaction without further purification. 88 6-(trifluoromnethyl)-2-methylpyridine-3-carbonyl chloride (1.68g, 7.51 mmol) in 3 mL THF was added dropwise to a solution of 4-hloro-3-(pyridine-2-yl)aniline (1.

2 1g, 5.93 mmol) in THF (15 mL) at 0*C. The solution was stirred for 10 min., poured into EtOAc and washed with saturated aq. NaHCOs (2x), and brine. The organics were dried (NaSO0 4 ) and concentrated. The crude product 5 was suspended in iPrOAc/Et 2 O (10 mL, 1:1), stirred at 0C for !/z hr, and collected by suction filtration to yield N-(4-chloro-3-(pyidin-2-yl)phenyl)-6-(tifluoromethyl)-2-methylpyridine-3 carboxamide ( 2 .0 4 g, 5.21 mmol, 88% yield) as a white solid: TLC Rr= 0.28 (35% EtOAc/Hex); H NMR (CDCl,, 400 MHz) 6 8.88 (bs, iH), 8.41 (d, IH), 7.96 (dd, IH), 7.74 (m, 4H), 7.52 (d, 1WH, 7.22 (m, 1H), 2.75 (s, 3H); MS (QI) 392 (M)*. 10 Example 18 6-(2-hydroxyethylamino)-N-(4-chloro-3-(pyridin-2-yl )pbenyl)pyridine-3 carboxamide CI N 0 HN

N-

H H Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-hloro-3<arboxamide (50 15 mg) and ethanolamine in butanol (0.5 mL). The crude reaction was purified by reverse phase HPLC to yield 6-(2-iydroxyetbylamino)-N-(4-cbloro-3-(pyridin-2-yl)phenyl)pyridine-3 carboxamide as a white solid. MS (Q1) 369.0 (M)-. Example 19 N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(trifluoromcthylsulfonyl)benzamide CI \//\\

HN

L0 20

F

3 0 4-(trifluorometbylthio)bcnzoic acid (200 ing, 0.9 nmmol) was dissolved in water (2 mL) and acetic acid (4 mL) and treated with potassium permanganate (711 mg. 4.5 mmul) at room temperature. The reaction was allowed to stir for 16 h, diluted with ethyl acetate and washed with water. The organic layer was dried (MgSO 4 ) and concentrated to yield 4-(trifluoroniethylsulfone)benzoic acid. 25 89 General procedure G was performed using 4-(trifluoromethylsulfone)benzoic acid and 4-chloro-3 (pyridin-2-yl)aniline. The crude reaction mixture was purified by reverse phase HPLC to yield N (4-chlioro-3-(pyridin-2-yl)phenyl)-4-(trifluoronethylsulfonyl)benzaiide. MS (Q1) 440.95 (M) 5 Example 20 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide C1 N 0 HN / \ General procedure G was performed using 4-(ethylthio)bcnzoic acid and 4-chloro-3-(pyridin-2 10 yl)aniline to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylthio)benzamide. A solution of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethyltliio)benzamide (40 mg, 0.11 mnol) in MeOH (3 nL), cooled to 0' C was treated with oxone (133 mg, 0.22 mnol), and the ice bath was removed. After lh of stirring, the reaction mixture was concentrated, and the residue was 15 dissolved in ethyl acetate. The organic solution was washed with water, dried (MgSO 4 ) and concentrated. The crude reaction mixture was purified by reverse phase HPLC to ycild N-(4 chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzanide. MS (Q1) 401.0 (M)*. 20 N-4-chloro-3-(pyridin-2-yl)phcnyl)-4-(2-hydroxy-2-methylpropylsulfonyl)-2-methylbcnzamide C I H N 0 J 0 H 2-Chloro-5-nitroiodobcnzene: The reactor used was purged with nitrogen and kept under nitrogen throughout the synthesis. Reactor was charged with USP purified water (400.0 L), agitated and 25 charged with 2-chloro-5-nitroaniline (50.0 kg) and then the contents were cooled to 0 - 5 "C. To the stirring reactor was charged concentrated sulfuric acid (40.0 L), maintaining the temperature at 90 S 10 *C (addition time -3-4 hr) and the contents were stirred at 0 - 5 'C for at least 15 minutes. In a separate vessel a solution of sodium nitrite (25.0 kg) and USP purified water (100.0L) was prepared. The sodium nitrite solution was slowly charged to the stir-ed reactor maintaining the temperature at 5 5 "C (exotherm and caused gas evolution, addition time -2 hours) and then the 5 contents were stirred at < 5 "C for at least 1 hour. In a separate vessel a solution of potassium iodide (60.0 kg) and USP purified water (240.0 L) was prepared and slowly charged to the stirred reactor maintaining the temperature at <5 "C (exothernm, caused gas evolution and foaming, addition time -7 hi). Cooling was turned off gradually allowing reaction to reach room temperature (-20 "C) and then the contents were stirred for at least 18 hours at 15 - 25 "C, and 10 then sampled reaction mass by HPLC analysis (dissolved sample in acetonitrile), when S 5% of 2 chloro-5-nitroaniline remained then continued to next step. however when the level of starting material was > 5% then sampled every hour until the reaction was complete. In a separate vessel a solution of sodium thiosulfate (30.0 kg) and USP purified water (600.0 L) was prepared and slowly charged - 1/2 of the sodium thiosulfate solution to the stirred reactor, maintaining the temperature 15 at 20 - 30 "C and then stirred reactor contents at 20 - 30 *C for at least 20 minutes. Cyclohexane (300.0 L) was charged to the reactor and the contents were heated to 55 - 60 "C and stirred for at least 20 minutes at 55 - 60 "C. Agitation was stopped to allow the layers to settle for at least 10 minutes and then were separated (setting aside organic layer) and returned the aqueous layer back into reactor. Cyclohexane (200.0 L) was charged to the reactor and stirred at 55 - 60 "C for at least 20 20 minutes and then agitation was stopped to allow the layers to settle for at least 10 minutes and then separating the layers (held aqueous layer for yield check) and combined both the organic layers from previous steps back into the reactor. The remaining -1/2 of the sodium thiosulfate solution was charged to the stirred reactor, maintaining temperature at 55 - 60 "C and stirred for at least 20 minutes at 55 - 60 "C. Agitation was stopped to allow the layers to settle for at least 10 25 minutes and the the aqueous layer was drained from the reactor. USP purified water (300.0 L) was then charged to the reactor and stirred for at least 20 minutes at 55 - 60 "C and then agitation was stopped to allow the layers to settle for at least 10 minutes and the aqueous layer was drained to waste. The reactor contents were heated at -45 "C and removed -65% of the solvent by vacuum distillation. Reactor contents were then cooled to 0 - 5 "C and allowed to stir for at least 5 hours 30 and then the solids were filtered and the product was washed with cold cyclohexane (100.0 L). The product was collected and dried in a hot air drier at 45 +/- 5 "C until LOD was < 1.0%. The process yielded 50.0 kg (61 % yield) of 2-chloro-5-nitroiodobenzene as a yellow solid. 35 Crude 2-(2-pyridyl)-4-nitrochlorobenzene: Reactor was purged with nitrogen and kept under nitrogen throughout the synthesis. Toluene (375.0 L) was charged to the reactor and agitation was 91 begun and zinc chloride (19.56 kg) was charged to the reactor. Using atmospheric distillation reactor contents was stripped to -50% of the original volume and then cooled to < 30 *C. THF (100.0 L) was slowly charged to the reactor (addition was exothermic). 5 Preparation of Grignard reagent in reactor 2: Reactor was purged with nitrogen and kept under nitrogen throughout the synthesis. Agitation was begun and THF (50.0 L) was charged to reactor. Isopropyl magnesium chloride (89.0 kg, adjusted after titration) was drum rolled to mix and then was slowly added, maintaining the temperature at S 30 (exothermic, addition time 30-40 mm). 2-bromopyridine (22.3 kg) was slowly charged to the reactor maintaining the temperature at < 30 10 oC (exothermic, addition time 50-60 min). The reactor contents were then heated to 50 +/- 5 'C and maintained for at least I hour. The Grignard solution (from Reactor 2) was slowly charged to the reactor (from earlier step) maintaining the temperature at < 55 *C (exothermic addition caused foaming, addition time -20 min). The reactor was then stirred at 50 +/- 5 "C at least 1 hour while maintaining the temperature. Dichlorobistriphenylphosphifne palladium (2.0 kg) was charged to 15 the reactor and stir-ed for -15 minutes. Triphenylphosphine (2.75 kg) was charged to the reactor and stirred for -15 minutes, 2-chloro-5-nitroiodobenzene (25.0 kg) was slowly charged to the stirred reactor (15 minute addition time). The reactor contents were heated to 60 +/- 5 *C and stirred for at least 14 hours at 60 +/- 5 *C, then sampled the reaction mass for HPLC analysis. When amount of starting material was > 4% continued heating and sampled again every hour until 20 the level of starting material fell below 4%. The reaction mixture was cooled to -55 *C and then the reactor contents were heated to reflux under vacuum and 75-90 L of solvent was removed. Toluene (120.0 L) was charged to the reactor while stirring. In a separate tank, the ammonium chloride (25.0 kg) was dissolved in USP purified water (250.0 L) and the solution was slowly charged into the reactor and stir for at least 30 minutes. The mixture was filtered through a 25 Nutsche filter (prepared with Celite (6.25 kg) and USP purified water (12.5 L)) and the filter cake was washed with toluene (75.0 L) and the filtrate was added and washed into a clean reactor. The layers were allowed to settle for at least 10 minutes and then separated (organic layer contained product) and returned the aqueous layer to the reactor. Toluene (75.0 L) was charged to the reactor and stirred for at least 15 minutes and then the layers were allowed to settle for at least 10 30 minutes before separating (organic layer contained product). The organic layers from previous steps were charged to a clean reactor. USP purified water (125.0 L) was charged to the reactor and stir for at least 15 minutes and then the layers were allowed to settle for at least 10 minutes before draining the aqueous layer and holding for yield check. 35 In a separate tank, a 3N hydrochloric acid solution was prepared by mixing concentrated hydrochloric acid (127.5 L) and USP purified water (272.5 L). Approximately 1/3 of the 3N 92 hydrochloric acid (133.3 L) was charged to the reactor and stir for at least 30 minutes. The layers were allowed to settle for at least 15 minutes and then the aqueous layer was drained and transferred to a separate vessel (product was in aqueous layer). Approximately 1/3 of the 3N hydrochloric acid (133.3 L) was charged to the reactor and stirred for at least 30 minutes. The 5 layers were allowed to settle for at least 15 minutes and then the aqueous layer was drained and transferred to a separate vessel (product was in aqueous layer). Aproximately 1/3 of the 3N hydrochloric acid (133.3 L) was charged to the reactor and stirred for at least 30 minutes. The layers were allowed to settle for at least 15 minutes and then the aqueous layer was drained and transferred to a separate vessel (product was in aqueous layer). The aqueous layers from previous 10 steps were transferred into a clean reactor to which was charged activated carbon (1.0 kg) and then heated to 50 +/- "C and stirred for at least 30 minutes. The mixture was filtered through a Nutsche filter (prepared with Celite (5.0 kg) and USP purified water (12.5 L) and the filter cake was washed with 3N hydrochloric acid (40.0 L) and the filtrate was added and washed into a clean reactor. The combined aqueous solutions were polish filtered through a I micron filter into a clean 15 reactor and cooled to 10 'C. Ammonium hydroxide (115,0 L) was slowly charged to the reactor, adjusting the pH to between 8.5 and 9.0 (addition time 4.25 hours). The reaction temperature was adjusted to 25-30 "C and the mixture was allowed to stir for 30 minutes. Reaction mixture was then centrifuged and the product washed with USP purified water (300.0 L) and dried in a hot air dryer at 50 - 60 'C. Process yielded 15.0 kg (72%) of crude 2-(2-pyridyl)-4-nitrochlorobenzene. 20 Purification of 2-(2-pyridyl)-4-nitrochlorobenzene - The reactor was purged with nitrogen and kept under nitrogen throughout the synthesis. Dichlioromethane (400.0 L) was charged to the reactor and stirring was begun. Crude 2-(2-pyridyl)-4-nitroclilorobenzene (40.0 kg) was charged to 25 the reactor and stirred at 20 - 30 "C for at least 30 minutes and checked to see if all solids were dissolved. Silica gel (20.0 kg) was charged to the reactor and stirred for at least 2 hours. The mixture was filtered through a Nutsche filter (prepared with Celite (14.8 kg) and dichlommethane (14.8 L)) and the filter cake was washed with dichloromethane (80.0 L) and the filtrate was added and washed into a clean reactor. The reactor contents were heated to reflux under vacuum and 80 30 90% of the solvent was removed and the cooled to 20 - 30 "C and then n-hexane (240.0 L) was charged to the reactor which was stirred for at least 2 hours at 20 - 30 *C. The reaction mixture was filted and washed with n-hexane (80.0 L) and the product dried in a hot air dryer at 50 - 55 "C. Process yields 34.5 kg (86% recovery) of 2-(2-pyridyl)-4-nitrochlorobenzenc as a beige solid. 93 4-chloro-3-(pyridin-2-yl)aniline: 2-(2-pyridyl)-4-nitrochlorobenzene was charged to a suitably sized reactor under nitrogen. Platinum on carbon (5%, -50% wet) (0.10 wt) was added with stirring, followed by tetrahydrofuran (9.68 wt). The reactor was pressurized with nitrogen to 40psi, then the pressure was released. This process was repeated two additional times. The 5 reactor was then pressurized with hydrogen to 50psi while maintaining the internal temperature at 20-26*C. After the hydrogen uptake subsided (1-2 hours), the pressure was held at 50psi and the reactor was heated to 504C for 2-3 hours. The reaction was checked by HPLC and once complete, cooled to 30*C. Next, the reactor was pressurized with nitrogen to 4 0 psi, then the pressure was released. This process was repeated two additional times. To a separate tank, Celite (0.1 wt) and 10 tetrahydrofuran (0.9 wt) were added. This slurry was then transferred to the reactor and stirred for a minimum of 30 minutes. The reaction mixture was filtered through a filter press and 0.2 micron filter, the cake was washed with tetrahydrofiran (2.2 wt) and all the organics were combined. Thiol silica gel (0.05 wt) was charged to the reactor and stirred for at least 30 minutes. This mixture was then filtered through a filter press into an adjacent, nitrogen purged, reactor. The 15 filter cake was washed with tetrahyrdofuran (2.2 wt) and the wash was added back to the reactor. With stirring, heptancs (6.8 wt) were added to the reactor and the contents were heated to reflux under vacuum. Approximately two thirds of the solvent was removed by vacuum distillation. The reactor was cooled to 20-26*C and stirred for 2-3 hours. The reactor contents were centrifuged and washed with heptanes (1.0 wt) and dried in a vacuum oven at 20-25"C until a constant weight of 4 20 chloro-3-(pyridin-2-yl)aniline was obtained (typical yield -80%). N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide - Tetrahydrofuran (10.24 wt) was charged to a suitably sized reactor under nitrogen. While stirring, 4-(2-hydroxy-2 methylpropylsulfonyl)-2-mietlhylbenzoic acid (1.265 wt) and 2-chloro-4,6-dinmethoxy-1,3,5-triazine 25 (0.815 wt) were added and stirred until dissolved. 4-methylmorpholine (0.564 wI) was slowly charged to the reactor while maintaining the internal temperature at < 30"C. The mixture was allowed to stir at room temperature for at least 30 minutes then sampled by TLC. Once all of the 4-(2-hydroxy-2-methylpropylsulfony)-2-metliylbenzoic acid was consumed, 4-chloro-3-(pyridin-2 yl)aniline (1.0 wt) was added. The reactor was heated to 50*C and stirred for at least 6 hours, at 30 which time the reaction was sampled by HPLC. Once the reaction was complete by HPLC, a sodium bicarbonate solution (sodium bicarbonate (0.506 wt) and USP purified water (24.8 wt), stirred until all solids were dissolved) was added to the reaction. The reaction mixture wa heated to reflux (-70*C) and solvent (5.7 wt.) was distilled from the reactor. The reactor was cooled to K 30"C and stirred for at least 20 hours. The reactor contents were centrifuged, washed with USP 94 purified water (3.47 wt) and dried in a vacuum oven at 45 "C until a constant weight of crude N-(4 chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)bnzamide was obtained (typical yield -90%). Methyl isobutyl ketone (20.0 wt) was charged to a suitably sized reactor under nitrogen. While stirring, crude N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide (1.0 wt) was added 5 and the reactor was heated to 60 "C and stirred for at least one hour. The solution was polish filtered through a filter press into an adjacent, nitrogen purged, reactor and the cake was washed with methyl isobutyl ketone (2.56 wi.). The filtered solution was then heated to reflux (-115 'C) and distilled to remove -2/3 of the solvent ( 14.5 wt). The reactor was cooled to 100 "C and stirred for at least 15 minutes. The reactor was then cooled to 80 "C and the tip speed of the In agitator was set to 2.0 in/s. A seed slurry was prepared by mixing N-(4-chloro-3-(pyridin-2 yl)phenyl)-4-(ethylsulfonyl)benzainide Form A (0.001 wt) and methyl isobutyl ketone (0.008 wtt. This seed slurry was added to the reactor at 80 *C and stirred for at least 2.5 hours. The bath temperature was set to 70 "C and the contents were stirred until the internal temperature reached 70 "C. The bath temperature was set to 50 "C and the contents wee stirred until the internal 15 temperature reached 50 "C. The bath temperature was set to 25 "C and the contents were stirred until the internal temperature reached 15-30 *C. Once this temperature was obtained, the mixture wa stirred for at least 12 hours. In a separate tank, a solution was prepared by charging methyl isobutyl ketone (3.0 wt) and heptanes (2.6 wt). The reactor contents were centrifuged, washed with the methyl isobutyl ketone/heptanes mixture (all) and dried in a vacuum oven at 60 "C until a 20 constant weight of purified N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide was obtained. The solids were milled using a Fitzmill grinder utilizing an 18 mesh screen, hammers forward on low speed. (typical yield ~80%). Example 21 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheny1)-4-((dimethylamino)mctliyl) 25 benzamide CI HN N General procedure G was used to couple 4-(BOC-aninomethyl)-2-chloro-benzoic acid and 4 chloro-3-(pyridin-2-yl)aniline to yield 2-cliloro-N-(4-chloro-3-(pyridin-2-yl)-phenyl)-4-(BOC 95 aminomethyl)-benzamide with . The crude reaction mixture was treated to TFA and trace water for I h prior to concentrating to dryness to yield 2-chloro-N-(4-chloro.3-(pyridin-2-yl)-phenyl)4 (aminomethyl)-benzanide. 5 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminomethyl)benzamide (80 mg, 0.20 mmol) was dissolved in DMF (5 mL) and treated with AcOH (10 uL), parafonnaldehyde (43 mg, 0.47 nnnol), and sodium triacetoxyborohydride (125 mg, 0.59 mmol). After stirring for 16 h, the solvent was evaporated and the residue was dissolved in ethyl acetate. The organic layer was washed with I N Sodium hydroxide, dried (MgSO 4 ) and concentrated. The crude product was purified by reverse 10 phase HPLC to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheinyl)4((dimethylanino)mehyl) benzamide. MS (Q1) 400.0 (M)'. Example 22 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(morpholinomethyl)pyridine-3-carboxanide N 0 HN \ ~N N 0 15 6-methylnicotinic acid (100 mg 0.14 mmod) was dissolved in 10% AcOH/benzene (I mL) and treated with NBS (117 mg, 0.18 mmol) and benzoylperoxide (18 mg, 0.07 mmol). The reaction mixture was heated in a sealed microwave reactor at 120' C for I min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous NaHCO, dried (MgSO4), concentrated 20 and purified by silica gel chromatography to yield 6-(bromoinethyl)pyridine-3-carboxylic acid. 6-(bromomethvl)pyridine-3-carboxylic acid was coupled to 4-chloro.3-(pyridin-2-yl)aniline as described in general procedure E to yield 6-(broiiomethyl)-N-(4-chloro-3-(pyridin-2 yl)phenyl)pyridine-3-carboxamide. 25 6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxainide was dissolved in DMSO (1 nL) treated with morpholine (33 uL) for I I. The reaction was concentrated, and the crude residue was purified by reverse phase HPLC to produce N-(4-chloro-3-(pyridin-2-yl)phenyl) 6-(morpholinomethyl)pyridine-3-carboxamide. MS (Q1) 409.3 (M) 30 96 Example 23 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyrimidin-2-ylamino)methyl)benzanide Ci N 0 HN 4-(bromomethyl)benzoic acid was coupled to 4-chloro-3-(pyridin-2-yl)aniline as described in 5 general procedure E to yield 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 4-(bronomethyl)-N-(4-chloro-3-(pyridin-2yl)phenyl)benzanide (85 mg) was dissolved in DMSO (0.5 mL) and treated with 2-aminopyridine (59 mg) at 150" C in a sealed microwave reactor for 5 min. The reaction mixture was concentrated, and the crude residue was purified by reverse phase I0 HPLC to produce pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyrimidin-2 ylamino)methyl)benzamide. MS (Q 1) 416.3 (M)-. Example 24 N-(4-chloro-3-(pyridii-2-yl)phenyl)-6-((4-methylpiperazin- I -yl)methyl)pyridine-3 carboxamide C1 A 0 HN / \_N 6-(bromomcthyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxanidc was dissolved in I mL of DMSO and tied for I h with N-methylpiperazine. The reaction was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyidin-2-yl)phenyl)-6 20 ((4-methylpiperazin-l-yl)metliyl)pyridiiie-3-carboxamide as a pure product. MS (QI) 422.3 (M)' Example 25 4-((4-acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)pheny) benzamide 97 CI \//\\ N 0 6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide (85 Ing) was dissolved in DMSO (1 niL) and stin-ed for 1 h) with N-acetylpiperazine. The reaction mixture was 5 concentrated, and the crude residue was purified by revered phase HPLC to yield 4-((4 acetylpiperazin-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl) benzamide. MS (Ql) 449.1 (M). Example 26 N-(4-cliloro-3-(pyridin-2-vl)phenyl)-4-(thiomorpholinomcthyl)benzamide CI "N 0 HN N S In1 4-(bromometliyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (I iL) and stirred for I h with thiomorpholine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 15 (thiomorpholinomethiyl)benzamide. MS (Q 1) 424.0 (M)". Example 27 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(morpliolinomethyl)bcnzamide C1 /-O 0 HN N 0 20 4-(bromonethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide (85 mg) was dissolved in DMSO (I mL) and stirred for I h with morpholine. The reaction mixture was concentrated, and the crude 98 residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (morpholinomcthyl)bcnzamide. MS (QI) 408.4 (M). Example 28 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((piperidin-1-yl)methyl)benzamnidc cl /\ NQ 4-(bromometiyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)beiizamide (85 mg) was dissolved in DMSO (I inL) and stirred for I h with piperdine. The reaction mixture was concentrated, and the crude I0 residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 ((piperidin-1-yl)methyl)benzamide. MS (QI) 406.4 (M)-. Example 29 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-((4-methylpiperazin- I yl)nethyl) benzamide cI HN 15 N N 15 4-(bromoncthyl)-N-(4-chloro-3-(pyiidin-2-yl)phenyl)benzanide (85 mg) was dissolved in DMSO (1 mL) and stirred for I h with methylpiperazine. The reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)pheny)-4 ((4-methylpiperazin- I-yl)methyl) benzamide. MS (Q1) 421.3 (M)'. 20 Example 30 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-((dimethylamino)methyl)benzamide Cl HN // N 99 Procedure G was used to couple BOC-4-(aminomethyl)benzoic acid (48 mg) with 4-chloro-3 (pyridin-2-yl)aniline (35 mg). The crude reaction mixture was treated with TFA (I mL) containing trace amounts of water for I h. The reaction mixture was concentrated to yield 4-(aminomethyl)-N 5 (4-chloro-3-(pyridin-2-yl)phenyl)benzamide. 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)plienyl)benzamide (80 mg) was dissolved in DMF (5 mL) and treated with AcOH (10 L), parmformaldehyde (48 mg), and sodium triacetoxyborohydride (125 mg) for 16 h. The reaction mixture was concentrated, and the crude 10 residue was dissolved in ethyl acetate and washed with I N sodium hydroxide, dried (MgSO 4 ) and concentrated. The crude product was purified by reverse phase HPLC to yield N-(4-chloro-3 (pyridin-2-yl)phcnyl)-4-((dimethylamino)mcthyl)bcnzamide. MS (QI) 365.0 (M)*. Example 31 N-(4-chlIoro-3-(pyridin-2-yl)phcnyl)-3-((2-methylpropyl)aminosulfonyl) 15 benzamide cl \ N 0 HN HN Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid with sec-butyl amine to 20 produce 3-(sec-butylsulfamoyl)bcnzoic acid which was purified by reverse phase HPLC. Procedure G was used to couple 3-(sec-butylsulfamoyl)benzoic acid with 4-chloro-3-(pyridin-2 yl)aniline (28 mg) to yield N-(4-chloro-3-(pyridin-2-vl)phenyl)-3-[(2 methyipropyl)aminosulfonyl]-bcnzamide. MS (Q I) 444.0 (M)*. 25 Example 32 N-(4-chloro-3-(pyridin-2-yl)plieyl)-4-(4-morpliolinylsulfonyl)-benzamide CI \//\\ N0 HN0 0 IaO Procedure It was performed to couple 4-(chlorosulfonyl)benzoic acid with morpholine to produce 4-(morpholinosulfamoyl)benzoic acid which was purified by reverse phase HIPLC. 5 Procedure G was used to couple 4-(morpholinosulfamoyl)benzoic acid with 4-chloro-3-(pyridin-2 yl)aniline (34 mg) to yield N-(4-chloro-3-(pyidin-2-yl)phenyl)-4-(4-mopholinylsulfony) benzamide. MS (Ql) 458.1 (M)'. Example 33 N-(4-chloro-3-(pyidin-2-y)phenyl)-3-(4-morpholinylsulfonyl)-benzamide 10 cl C\N HN 0 / \ 'o

-

N) Procedure 1H was performed to couple 3-(chlorosulfonyl)benzoic acid with morpholine to produce 3-morpholinosulfamoyl)benzoic acid which was purified by reverse phase HPLC 15 Procedure G was used to couple 3-(morpholinosulfaioyl)bcnzoic acid with 4-chloro-3-(pyridin-2 yl)aniline (25 mg) to yield N-(4-chlioro-3-(pyridin-2-yl)phenyl)-3-(4-morpholinvlsulfonyl). benzamide. MS (QI) 458.1 (M). Example 34 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-[(2-hydroxyethyl)amino]sulfonyl] 20 benzamide CI HN SHNH 0 Procedure H was performed to couple 4-(chlorosulfonyl)benlzoic acid with ethanolamiic to produce 4-(2-hydroxyethylsulfamoyl)benzoic acid which was purified by reverse phase HPLC. 25 l01 Procedure G was used to couple 4-(2-liydroxyethylsulfamoyl)benzoic acid with 4-chloro-3 (pyridin-2-yl)anilinc (42 mg) to yield N-(4-cl.oro-3.-(pyridin-2-yl)phenyl)-4-[(2 hydroxyethyl)amino]sulfonyl]-benzanide. MS(QI)431.9(M). 5 Example 35 N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-[(2-hydroxyethyl)amino]sulfonyl] benzamide CI \/\/O \/0

HN

HN OH 10 Procedure H was performed to couple 3.(chlorosulfonyl)benzoic acid with ethanolarnine to produce 3-(2-iydroxyethylsulfamoyl)benzoic acid which was purified by reverse phase HPLC. Procedure G was used to couple 3-(2-hydroxyethylsulfamoyl)benzoic acid with 4-chloro-3 (pyridin-2-yl)atiinc (42 mg) to yield N-(4-cloro-3-(pyridin-2-yl)phenyl)-3-[(2 15 bydroxyethyl)amino]sulfonyl]-benzanide. MS (Ql) 432.0 (M). Example 36 N-(4-chloro-3-(pyridin-2-yl)phcnyl)-3-(4-morpholinysulfony)-benzamide CI HN 0 "0 20 Procedure H was performed to couple 3-(chlorosulfonyl)benzoic acid with piperazine to produce 3-(N-methylpiperazinosulfanoyl)bcinzoic acid which was purified by reverse phase HPLC. Procedure G was used to couple 3-(N-methylpiperazinosulfamoyl)benzoic acid with 4-chloro-3 25 (pyridin-2-yl)aniline (50 mg) to yield N-(4-chloro-3-(pyridin-2-yl)pbenyl)-3-(4 norpholinylsulfonyl)-bcnzaniide. MS (QI) 471.0 (M). 102 Example 37 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide C HN ci -'o s5=0 Me 5 Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4 methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (methylsulfonyl)bcnzamidc. MS (QI) 421.0 (M). The product was then dissolved in 1 N HCI solution followed by freebasing with 0.5 N NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry. 10 Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-clhloro-4 (methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyidin-2-yl)phcnyl)-4 (methylsulfonyl)benzamide which is collected by suction filtration and the HCI salt is washed with Et 2 O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO, and the 15 organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone:EtOAc (80:20, approx lOmL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4<hloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)bcnzamide HCI salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate. 20 Example 38 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1H-1,2,4-triazol-l -yl)pyridine-3 carboxamide CI HNN \N N--N N 25 103 Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (40 mg) and 6-(lH-1,2,4-triazol 1-yl)pyridine-3-carboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(lH-1,2,4 triazol-1-yl)pyridine-3-carboxamide. MS (Qi) 377.0 (M) Example 39 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-[(dimethylamino)sulfonyl]-benzamide CI HN / \ s=o Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 4 10 [(dimethylamino)sulfonyl]bcnzoic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 [(dimotlylamino)sulfonyl]-benzamide. MS (QI) 416.0 (M)-. Example 40 N-(4-chloro-3-(pyridin-2-yl)phcnyl)-5-(mcthylsulfonyl)thiophene-2-carboxamide C N 0

N

0 S=0 Me 15 Procedure G was used to couple 4-cliloro-3-(pyridin-2-yl)aniline (40 mug) and 5 (mctliylsulfonyl)thiophene-2-carboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-5 (methylsulfonyl)thiophene-2-carboxamide. MS (QI) 393.0 (M)'. 20 Example 41 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(aminosulfonyl)-benzamide CI \//\\ NN H 0 104 Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (30 mg) and 4 carboxybenzenesulfonamide to produce N-(4-chloro-3-(pyiidin-2-yl)phenyl)-4-(amiinosulfonyl) benzamide. MS (QI) 388.0 (M). 5 Example 42 2,6-dichloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)pyridinc-3-carboxamide C1 HN CI / \N C In Procedure G was used to couple 4-chloro-3-(pyridin-2-yi)anilinc (50 ing) and 2,6-dichloonicotinic acid to produce 2,6-dichloro-.N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide. MS (QI) 378.1 (M)-. Example 43 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzaimide 15 CI N 0 HN Cl Procedure 0 was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chlorobenzoic acid 20 to produce 2-cliloro-N-(4-chloro-3-(pyiidin-2-yl)phenyl)beiizamide. MS (Ql) 343.1 (M)'. Example 44 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-fluoropyridine-3-carboxamide CI \/ \O \N 0 HN F / N 25 105 Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-fluoronicotinic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-fluoropyridine-3<arboxamide. MS (QI) 328.1 (M) . 5 Example 45 N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methylthiophene-2-carboxamide CI HN Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 3-methyl-2 1o thiophenecarboxylic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-methylthiophene-2 carboxamide. MS (Q1) 329,0 (M)'. Example 46 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-5-(metlhylsulfonyl)benzamide CI \ N 0 HN 15 M cMe Procedure G was used to couple 4-clIoro-3-(pyridin-2-yl)anilinc and 2-chloro-5 (methanesulfonyl)benzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheny)-5 (methylsulfonyl)benzamide. MS (QI) 420.95 (M)'. 20 Example 47 N-(4-cltoro-3-(pyridin-2-yl)phenyl)-3-inethylsulfonyl)benzamide CI HNN 0 10Me 106 Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and 3-(methanesulfonyl)benzoic acid to produce N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(methylsulfonyl)benzamide. MS (Ql) 387.2 (M), 5 Example 48 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide CI \N"N HN NH, / N Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)anilinc (50 mg) and 2-aminonicotinic 10 acid to produce 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide. MS (Ql) 325.2 (M). Example 49 N-(4-chloro-3-(pyridin-2-yl)phcnyl)4-methoxybenzamide 15 ci HN4 \/ /\ 0 Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline and 4-methoxylbenzoic acid to produce N-(4-chloro-3-(pyidiin-2-yl)penyl)4-methoxybenzamide. MS (Ql) 341.2 (M) 20 Example 50 N-benzyl-5-chloro-4-(pyridin-2-yl)thiazol-2-amine C1 N N H 25 A solution of 2-(Bromoacetyl)pyridine hydrobromide (100 mg, 0.36 mmol) in ethanol (2 mL) was treated with 1-benzyl-2-thiourea (90 ng, 0.54 mmol). The resulting yellow solution was 107 concentrated, and the crude residue was purified on reverse phase HPLC to produce N-benzyl-4 (pyridin-2-yl)thiazol-2-amine. A solution of N-benzyl-4-(pyridin-2-yl)thiazol-2-aminc (60 mg, 0.23 mmol) in DMF (2 mL) was 5 cooled to 0 "C and treated with N-chlorosuccinimide (33 mg, 0.25 mmol), and the reaction mixture was allowed to wann to room temperature. The solvent was evaporated, and the product was purified on reverse phase HPLC to produce N-benzyl-5-chloro-4-(pyridin-2-yl)thiazol-2-amine. MS (Q1) 302.2 (M)'. 10 Example 51 4-chloro-N-(3,5-dimethoxyphenyl)-3-(pyridin-2-yl)benzamide Cl N NH -o A solution of 3-brono-4-chlorobenzoic acid (250 mg, 1.1 nunol) in DMF (2 mL) was treated with 15 PyBop (550 mg, 1. 1 mmol) and DIPEA (370 uL, 2.1 mmol). After stirring the reaction mixture for 5 min. 3,5-dimethoxy analine (105 mg, 0.69 nnol) was added and the reaction was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and washed with 0.1 N HCI, 0.1 N sodium hydroxide and Brine, successively. The organic layer was dried (MgSO 4 ) and concentrated, and crude 3-bromo-4-chloro-N-(3,5-dimethoxyphenyl)benzanide was used without further purification. 20 3-bromo-4-chloro-N-(3,5-dimethoxyphenyl)benzamide was dissolved in 0.5 M 2 pyridylzincbromide (2.5 mL) and treated with Pd(PPh) 3 )4 (20 mg, 0.02 mrmol). The reaction mixture was heated to 155" C in a sealed tube for 20 min. in a microwave reactor. The resultant solution was diluted with Ethyl acetate and washed with 0.1 N sodium hydroxide and then brine. 25 The organic layer was dried (MgSO 4 ) and concentrated, and the crude residue was partially purified by silica gel chromatography. Pure 4-chloro-N-(3,5-dimethoxyphncuyl)-3-(pyridin-2 yl)benzamide was obtained by a second purification on reverse phase HPLC. MS (Ql) 369.1 (M)*. L08 Example 52 N-(3-(3,5-bis(trifluoromethyl)phenyl)propyl)4-chloro-3-(pyridin-2 yl)benzenamine C1 cFi F3C 5 A solution of 3,5-bis(trifluoromethyl)hydrocinnamic acid (1.0 g, 3.5 mmol) and TEA (0.46 g, 4.5 mnol) in THF (16 mL) was cooled to -40 0 C (ethanol-water/dry ice bath). To this mixture was dropwise added isobutyl chloroformate (0.56 g, 4,1 mmol) and stining was continued for another 1.5 hours while the temperature of the cooling bath was maintained between -40 *C and -20 C. Solid NaBH 4 (0.53 g, 14 mmol) was added, followed by H 2 0 (1.3 mL). The cloudy mixture was 10 stirred overnight while warming to room temperature. After concentrating in vacuo, the residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 1 with 37% HCI and extracted with ethyl acetate. The combined organic layers were washed sequentially with saturated NaHCOI. and brine, then dried (MgSO 4 ) and concentrated. The resulting oil was purified by flash silica gel chromatography (6:4 ethyl ether-hexane) to yield 3-[3',5' 15 bis(trifluoromethyl)phenyl]-I-propanol. 3-[3',5'bis(trifluoromethyl)phenyl]--propanol (0.88 g, 3.2 mmol) and CBr 4 (1.3 g, 4.0 mmol) were dissolved in CH2C 2 (5 mL) and cooled to OQC. Triphenylphosphine (1.3 g, 4.8 mmol) was added in three portions over 0.5 h. The mixture was stirred at 0 "C for 10 mit, then diluted with 20 pentane (30 mIL) and sat. NaHCO3 (30 mL). The aqueous layer was separated and washed with ethyl ether, and the combined organic layers were dried (MgSO 4 ) and concentrated. The residue was purified by silica gel flash chromatography (99:1 ethyl ether-bexane) to yield 0.8 g, (74%) of the 3-[3',5'-bis(trifluoromethyl)phcnyl}-l-bromopropane. 25 4-chloro-3-(2'-pyridyl)aniline (10 mg, 0.05 mmol), 3-[3',5'-bis(trifluoromethyl)phenyl]-l bromopropane (34 mg, 0.1 ninol) and K2CO 3 (14 mg, 0.1 mmol) in DMF (I mL) was stirred at 100 0 C overnight. The reaction mixture was acidified with IN HCI (aq.) and extracted with ethyl acetate. The combined organic layers were washed with brine. dried (MgSO 4 ) and concentrated. The crude was purified by preparative HPLC to yield N-(3-(3,5 30 bis(trifluoromethyl)phenyl)popyl)-4-chloro-3-(pyridin-2-y)benzenamine, 109 Example 53 N-(4-chloro-3-(5-(trifluorometliyl)pyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide c HN / \N N-(4-chloro-3-(4,4,5,5-tetrametbyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-metliyl-6 5 (trifluoronethyl)nicotinamide (- 0.5 nnnol) was used in Procedure A with 5-trifluornethyl-2 bromopyridine (113 mg, 0.5 mmol). Purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to yield N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyi)nicotiiiaimide as a white foam: TLC Rr= 0.30 (15% ethyl acetate/hexanes); MS (Q1) 460 (M). 10 Example 54 N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-4 (methylsulfonyl)benzamide Cl HN 15 N-(4-chloro-3-(4,4,5,5-tetranediyl-1,3,2-dioxaborolan-2-yl)pheiyl)-4-(methylsuIlfonyl)bcnzamide (- 1.0 mmol) was used in Procedure A with 5-tiifluoromethyl-2-bromopyridine (226 mg, I mnol). Purified by silica gel chromatography (0-10% acetone/dichloromethane) to yield N-(4-chloro-3-(5 (trifluoronethyl)pyridin-2-yl)phenyl)-4-(netliylsulfonyl)benzaniide as a white solid: MS (Ql) 455 (M). 20 Example 55 N-(4-clloro-3-(5-chloropyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide I 10 CI CI HN0 N CFa 5-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mmol) was used in Procedure I with trimethyltin chloride to yield 5-chloro-2-(timethylstannyl)pyridine. The crude material (~4 mmol) was used in Procedure K with N-(4-cbloro-3-iodophenyl)-2-imethyl-6 5 (trifluoroincthyl)nicotinamide (2 mnmol). Purified by silica gel chromatography (0-50% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-chloropyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide as a white solid: TLC Rf 0.48 (25% ethyl acetate/iexanes); MS (Q1) 427 (M) 10 Example 56 N-(4-chloro-3-(6-chloropyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide CI CI HNN SNN CF, 6-chloropyridin-2-yl trifluoromethanesulfonate (4.12 mnmol) was used in Procedure I with 15 trimethyltin chloride to yield 2-chloro-6-(trimethylstannyl)pyridinc. The crude material (~4 mmol) was used in Procedure K with N-(4-chloro-3-iodopheiyl)-2-nethyl-6 (trifluoromethyl)nicotinamide (2 mmol). Purified by silica gel chromatography (5-45% ethyl acetate/hexane) to yield N-(4-chloro-3-(6-chloropyridin-2-yl)phenyl)-2-imetliyl-6 (trifluoromethyl)nicotinanide as a white solid: TLC R 1 = 0-45 (25% ethyl acetate/hexanes); MS 20 (Q1) 426 (M). Example 57 N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-inethyl-6 (trifluoromethyl)nicotinamide Itl CI HO O HN

F

3 3-(triisopropylsilyloxy)pyridine (2.66 mmol) was used in Procedure J with hexamethyldistannane to yield 5-(triisopropylsilyloxy)-2-(trinethylstannyl)pyridine. The crude material (-0.55 mnol) was used in Procedure K with N-(4-cliloro-3-iodophenyl)-2-methyl-6 5 (trifluoromcthyl)nicotinainide (0.17 mmol). Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-(triisopropylsilyloxy)pyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide as a yellow oil. N-(4-clioro-3-(5-(triisopropylsilyloxy)pyridin-2 yl)plienyl)-2-methyl-6-(trifluorometliyl)nicotinamide (I mmol) was treated with TBAF (2 mL, I M in THF) in THF (1 mL) at 23 'C for thirty minutes, concentrated, redissolved in ethyl acetate, 10 washed with brine, dried (MgSO4), and concentrated. The crude solid was purified by silica gel chromatography (0-10 % isopropanol/dichloromethane) to yield N-(4-chloro-3-(5-lydroxypyrdiin 2-yl)phenyl)-2-methyl-6-(trifluorometliyl)nicotinanmide as a white solid: TLC R,= 0.59 (10% ethyl acetate/hexanes); MS (Q1) 408 (M)'. 15 Example 58 N-(4-chloro-3-(5-mcthoxypyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide CI

HN

/ \N

CF

3 N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.12 20 mmol) was used in Procedure L with excess iodomethane. Purified by silica gel chromatography (0-100% ethyl acctatc/hexanc) to yield N-(4-chloro-3-(5-methoxypyridin-2-yl)phcnyl)-2-methyl-6 (trifluoromethyl)nicotinamide as a white solid: TLC Rf= 0.57 (50% ethyl acetate/hexanes): MS (Q1) 423(M) 25 112 Example 59 N-(4-chloro-3-(5-ethoxypyridin-2-yl)phenyl)-2-methyl-6 (Irifluoromethyl)nicotinamide CI HN / "N CF, N-(4-chlIoro-3-(5-hydroxypyridin-2-yl)phenyl)-2-nethyl-6-(trifluoromethyl )nicotinamide (0.05 5 mmol) was used in Procedure L with excess iodoethane. Purified by silica gel chromatography (0 100% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-ethoxypyridin-2-yl)phenyl)-2-methvl-6 (trifluoromethyl)nicotinamide as a white solid: TLC Rf= 0.64 (50% ethyl acetate/hexanes); MS (Q1) 436 (M)'. 10 Example 60 N.-(4-chloro-3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)phenyl)-2-methyl-6 (trifluoronetlhyl)nicoti namide CI HN / N

CF

3 N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.12 15 mmol) was used in Procedure L with excess trifluoroethyl iodide. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-(2,2,2 trifluoroethoxy)pyridin-2-yl)phenyl)2-methyl-6-(trifluoronethyl)nicotinanide as a white solid: TLC R,= 0.64 (40% ethyl acetate/hexanes); MS (QI) 490 (M)*. Example 61 N-(4-chloro-3-(4-ethylpyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide 113 CI N 0 HN N

CF

3 N-(4-chIloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6 (trifluoromcthyl)nicotinanide (- I mmol) was used in Procedure A with 4-ethyl-2-bromopyridine (1 mmol). Purified by silica gel chromatography (0-60% ethyl acetate/hexanes) to yield N-(4 5 chlioro-3-(4-ethylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: MS (Q1) 419 (M)'. Example 62 N-(4-chloro-3-(5-fluoropyridin-2-yl)phenyl)-2-mcthyl-6 0 (trifluoronethyl)nicotinaiide c F 0 HN N

CF

3 N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3.2-dioxaborolan-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicolinamide (~ I mmol) was used in Procedure A with 5-fluoro-2-bromopyridine 15 (1 mmol). Purified by silica gel chornatography (545% ethyl acetate/hexanes) to yield N-(4 chloro-3-(5-fluoropyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a tan solid: MS (Q1) 409 (M)'. 20 Example 63 N-(4-chloro-3-(5-phenylpyridin-2-yl)phenyl)-2-nethyl-6-(trifluoromethyl) nicotinamide 114 cI NN

HN

N

CF

3 5-phenylpyridin-2-yl trifluoromethanesulfonate (1.5 nmol) was used in Procedure J with trimethyltin chloride to yield 5-phciiyl-2-(trinethylstannyl)pyridine. The crude material (-1.25 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-niethyl-6 5 (trifluoromethyl)nicotiniamide (I mmol). Purified by silica gel chromatography (1% acetone/methylene chloride) to yield N-(4-chloro-3-(5-phenylpyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamideas a tan solid: TLC Rf= 0.15 (1% acetone/methylene chloride); MS (Q1) 467 (M). Example 64 (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide Cl HN0 \N Q N N NH 15 Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and 75 ing of (S)-2-methylpiperazine in 0.75 nL of butanol at 160CC for 60 min. Purification by reverse phase HPLC yielded (S)-N-(4-cliloro-3-(pyridin-2-yl)phcnyl)-6-(3-methylpipcrazin-l yl)nicotinamide. MS (QI) 408 (M)'. Example 65 (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide 115 C1 HN / "N N NH Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and 75 mg of (R)-2-methylpiperazine in 0.75 mL of butanol at 160 0 C for 60 min. Purification 5 by reverse phase HPLC yielded (R)-N-(4-cliloro-3-(pyridin-2-yl)phenyl)-6-(3-imetliylpiperazin-1 yl)nicotinamide. MS (QI) 408 (M) . Example 66 N-(4-chloro-3-(pyridin-2-yl)pbenyl)-6-((3S,5R)-3,5-dimiethylpiperazin-l 10 yl)nicotinamide C1 HN N NH Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (75 15 mg) and 11 4 mg of 2,6-dimethylpiperazine in I mL of butanol at 160*C for 60 min. Purification by reverse phase HPLC yielded N-(4-chloro-3-(pyridin-2-yl)pbenyl)-6-((3S,5R)-3,5 dimcthylpiperazin-1-yl)nicotinamidc. MS (Ql) 422.1 (M)-. 20 Example 67 N-(4-cliloro-3-(pyridin-2-yl)phenyl)-N-(pyridin-3-yl)terephthalamide 116 C1 N 0

HN

NH O / N 320 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4 00 mg of 4-(metlioxycarbonyl)benzoic acid via Procedure G to give methyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)bcnzoate. 4-(4 5 chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was then hydrolyzed via Prodedure M to give 550 mg of 4-(4-cloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid. 50 mg of 4-(4-chloro-3 (pyridin-2-yl)phenylcarbamoyl)beiizoic acid was coupled to 3-arninopyridine via Procedure G. The organic layer was evaporated to dryness and purified on reverse phase HPLC to yield N'-(4 chloro-3-(pyridin-2-yl)phenyl)-N 4 -(pyridin-3-yl)terephthalamide. MS (QI) 429 (M) 10 Example 68 N' (4-chloro-3-(pyridin-2-yl)pheiyl)-M-(6-mcthoxypyidin-3-yl)terephthalamide CI HNN NH / N 0 15 50 ng of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2-methoxy-5 aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield N'-(4 chloro-3-(pyridin-2-yl)phenyl)-NM-(6-methoxypyridin-3-yl)terephthalamide. MS (QI) 459 (M). Example 69 N' (6-aininopyidin-3-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)tercphthalamide 117 Cl \ / h/ HN NH O N NH, 50 ng of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)benzoic acid was coupled to 2.5 diaminopyridine via Procedure G. The prodcut was purified on reverse phase HPLC to yield N' 5 (6-aiiinopyridi-3-yl)-N-(4-chloro-3-(pyridin-2-y1)plienyl)terepithalamide. MS (QI) 444 (M)*. Example 70 N(4-chloro-3-(pyridin-2-yl)pheny)-N-.(pyridin-2-ylmethyl)terephthalamide CI HN NH N~ 10 N 50 mg of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 (aminomethyl)pyridinc via Procedure G. The product was purified oil reverse phase .HPLC to yield N'-(4-ciloro-3-(pyridin-2-yl)phenyl)-N'-(pyridin-2-ylnetliyl)terephthalamide. MS (QI) 443 15 (M) . Example 71 N'-(4-cliloro-3-(pyridint-2-yl)phenyl)-N-isopropylterepbtlialamide I 18 C1 0 HN NH 0 / 50 mg of 4-(4-chloro-3-(pyridin-2-yl)plienylcarbamoyl)benzoic acid was coupled to isopropylamine via Procedure G. The product was purified on reverse phase HPLC to yield N'-(4 5 chloro-3-(pyridin-2-yl)phenyl)-N4-isopropyltereplitlialamide. MS (Q1) 394 (M)'. Example 72 N-lert-butyl-N-(4-chloro-3-(pyridin-2-yl)phenyl)terephthaiamide C1

HN

\/ /\ NH 10 O 50 mug of 4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)benzoic acid was coupled to tert butylamine via Procedure G. The product was purified on reverse phase HPLC to yield N'-erl butyl-N 4 -(4-chloro-3-(pyridin-2-yl)plienyl)terephthalamnide. MS (Ql) 408 (M) . 15 Example 73 /Atert-butyl-2-chloro-N (4-cloro-3-(pyridin-2-yl)phenyl)terephthalamide C1 HN O 1 \/ /\ NH 19 67 mL of 2-chloro-l,4-dimethylbenzene and 356 g of Potassium Permanganate were refluxed in 1.5 L of H20 for several hours and monitored for disappearance of starting material by TLC. The Potassium Permanganate was filtered and the reaction mixture was acidified and filtered to yield 2 5 chloroterephthalic acid. 46.8 g of 2-chloroterephthalic acid was treated with a saturated HCI gas solution in MeOH overnight at room temperature. the reaction mixture was concentrated, subjected to basic workup and dried to yield the dimethyl 2-chloroterephthalate. 20 g of diiethyl 2-chloroterephthalate was cooled to O'C in DCM and 87 mL of a I M in DCM solution of BBr; was added dropwise over several hours. The reaction mixture was subsequently warmed to room 10 temperature and stirred until complete. Following basic workup, 2-chloro4 (methoxycarbonyl)benzoic acid was purified by ISCO Combi-Flash. 959 mg of 2-chloro-4 (methoxycarbonyl)bcnzoic acid was coupled to 750 mg of 4<hloro-3-(pyridin-2-yl)aniline via procedure G. 1 g of methyl 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoate was hydrolyzed via Procedure M to give 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic 15 acid. 50 ing of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to rerz-butylamine via Procedure G. The product was purified on reverse phase HPLC to yield /M tert-butyl-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS(QI)443.2(M)'. 20 Example 74 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(4-(2-hydroxyethyl)piprazinc-1 carbonyl)benzamide Cl HN Cl N N O 0 N\-/N\OH 25 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-(2 hydroxyethyl)piperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(4-(2-hydroxyethyl)pipcmzine- I carbonyl)benzamide. MS (Q 1) 499 (M)'. 30 120 Example 75 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-methylpiperazine-1 carbonyl)benzamide CI HN CI / \ N N 5 50 mg of 3<hloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to I methylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2 chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)A-(4-methylpiperazine--carbonyl)benzanide. MS (Q1) 469 (M). 10 Example 76 4-(4-acetylpiperazine-1-carbonyl)-2-chloro-N-(4-chloro-3-(pyridin-2 yl)phenyl)benzamide Cl HN CI is~~ \ 50 mg of 3-cliloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1 acetylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 4-(4 acetylpiperazine-l-carbonyl)-2hloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzaide. MS (QI) 20 497 (M)-. Example 77 2-chloro-U-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(mcthylsulfonyl)piperazine-1 carbonyl)benzamide 121 Cl HN Cl / / 50 mg of 3-chloro-4-(4-chloro-3-(pyidin-2-yl)phenylcarbamoyl)benzoic acid was coupled to I sulfonylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2 5 chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(4-(methylsulfonyl)pipcrazine-1 carbonyl)benzamide. MS (Q1) 533 (M), Example 78 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)4(morpholine-4 10 carbonyl)benzamide C1 HN ,C1 \//\\ NO N 0 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phcnylcarbamoyl)benzoic acid was coupled to 15 morpholine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro N-(4-chloro-3-(pyridin-2-yl)phenyl)4(morpholine-4carbonyl)benzaniide. MS (QI) 456 (M). Example 79 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3.5-dinethylpiperazine-1 20 carbonyl)benzamiide 122 C H \/ /\ N N H C H 50 mg of 3-chloro4-(4-cliloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,6 dinethylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2 5 chloro-N-(4-chloro-3-(pyridin-2-yl)peiiyl)4-(3,5-dimethylpiperazine--carbonyl)benzamide. MS (QI) 483 (M)-. Example 80 2-chloro-N-(4-chloro-3-(pyridiin-2-y1)phenyl)-N4-(pyridin-3 In yhnethyl)terephthalamide C1 HN C1 4NH N 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3 15 (aminomcthyl)pyridinc via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N'-(pyridin-3-ylmethyl)terephtlialamide. MIS (QI) 477 (M). 20 Example 81 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(pyridin-2 yhnethyl)terephthalanide 123 C1 HN CI NH N 0 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 (aminomethyl)pyridine via Procedure G. The product was purified on reverse phase .HPLC to 5 yield 2-cliloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-NM-(pyridin-2-ylmetlhy1)terephthalamide. MS (Q1) 477 (M)-. Example 82 2-chloro-N-(4-chloro-3-(pyridiin-2-y)phenyl)-N 4 -(pyridin-4-yl)tereplitialamide 10 C1 "N 0 HN CI N NH 0 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)bcnzoic acid was coupled to 4 aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2 15 chloro-N'-(4<hloro-3-(pyridin-2-yl)phenyl)-N-(pyridin-4-yl)terphthalanide. MS (Q1) 463 (M). Example 83 2-chlow-N-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pyridin-3-y1)terephthalamide CI HN 0 HN I / \ /N NH 20 0 124 50 mng of 3<hloro4-(4<hloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3 aminopyridine via Procedure G. The product was purified on reverse phase HPLC to yield 2 chloro-N'-(4-chloro-3-(pyridin-2-yl)phcnyl)-NM-(pyridin-3-yl)tcrcphthalamide. MS (QI) 463 (M)*. 5 Example 84 2-cliloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(tionorplioline-4 carbonyl)benzamide (S-oxidized thiomoirpholine) CI HN C \/ /\ N10 HN C < 100 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phcnylcarbanoyl)bcnzoic acid was coupled to thionorpholine via Procedure C. Crude 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (thiomorpholine-4-carbonyl)benzamidc was reacted via Procedure R to oxidize the thiomorpholine 15 sulfur and purified via reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl) 4-(thionorpboline-4-carbonyl)benzamide (in which the thiomorpholline sulfur is oxidized to SO 2 ). MS (Q1) 504 (M). 20 Example 85 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheunyl)-4-(thiazolidine-3 carbonyl)benzamide (S-oxidized thiazolidine) CI HN- CI O Or 0 125 100 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)benzoic acid was coupled to thiazolidine via Procedure G. Crude 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(hiazolidinc 3-carbonyl)benzamide was reacted via Procedure R and purified via reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide (in which the 5 thiazolidine sulfur is oxidized to SO2). MS (Q] ) 490 (M) . Example 86 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(1-methyl-1H-pyrazol-5 yl)terephthalanide 10 CI HN Cl / \N NH 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 5 amino-1I-methylpyrazole via Procedure G. The product was purified on reverse phase HPLC to 15 yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)plieiiyl)-N-( I -methyl-I H-pyrazol-5 yl)terephtlhalamide. MS (QI)466(M)'. Example 87 2-chloro-N -(4-chloro-3-(pyridin-2-yl)phenyl)-NM-(isoxazol-5-yl)tcrepbthalanidc 20 CI N 0 HN-4I / \ N

-

d NH 0 50 mg of 3-hloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 5 aninoisoxazole via Procedure G. The product was purified on reverse phase HPLC to yield 2 25 chloro-N'-(4-chloro-3-(pyridin-2-yl)hlienyl)-N 4 -(isoxazol-5-yl)tereptlialiamide. MS (Q1) 463 (M)'. 126 Example 88 2-chloro-N'-(4-chloro-3-(pyridin-2-y)pheny)-M-(4,5-dihydrothiazol-2 yl)tcrephthalanidc C1 HN CI N, NH 0 50 mg of 3chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 amino-4.5-dihydrothiazole via Procedure G. The product was purified on reverse phase HPLC to 10 yield 2-chloro-N'-(4-hloro-3-(pyridin-2-yl)phenyl)-M-(4,5-dihydrothiazol-2-yl)tcrcphthalamide. MS (Q1) 471 (M). Example 89 2-clloro-N' -(4-chloro-3-(pyridin-2-yl)plinyl)-N-(lIt-imidazol-2 15 yl)terephthalamide C1 HN- C1 N 0 NH NH 0 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 20 aminoimidazole via Procedure G. The produce was purified on reverse phase HPLC to yield 2 chloro-N'-(4-cliloro-3-(pyridin-2-yl)phenyl)-M-(1H-inidazol-2-yl)terepbthalamide. MS (Ql) 452 (M). 25 Example 90 2-chloro-N -(4-chloro-3-(pyridin-2-y1)pheny1)-N4-(4H-1,2,4-triazol4 yl)terephthalamide 127 CI HN- CI N N IN NH 0 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phcnylcarbamoyl)benzoic acid was coupled to 4 5 amino-1,2,4-triazole via Procedure G. The product was purified on reverse phase HPLC to yield 2 chloro-N'-(4-hloro-3-(pyridin-2-yl)phenyl)-N-(4H-1,2,4-triazol-4-yl)terephthalamide. MS (QI) 453 (M)'. 10 Example 91 2-chloro-N' (4-chloro-3-(pyridin-2-yl)phenyl)-Nt(thiazol-2-yl)terephthalamide CI N N C HN/ I NH 0 50 mg of 3chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 15 aminothiazole via Procedure G. The product was purified on reverse phase HPLC to yield 2 chloro-N'-(4<hloro-3-(pyridin-2-yl)phenyl)-N'-(thiazol-2-yl)terephthalanide. MS (QI) 469 (M). Example 92 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(I H-1,2,4-triazol-5 20 yl)terephthalamide 128 C1 HN CI / \ N"'N ~-NH NH a 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3 amino- l.2,4-triazole via Procedure G. The product was purified on reverse phase HPLC to yield 2 5 chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-NM-(IH-1,2,4-triazol-5-yl)terephtlialamide. MS (Ql) 453 (M)f. Example 93 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3 10 carbonyl)benzamide C1 HN C1 /_\ /r-s ONt) 50 ing of 3-chloro-4-(4-cliloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to thiazoline via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N 15 (4-chloro-3-(pyridin-2-yl)phenyl)-4-(thiazolidine-3-carbonyl)benzamide. MS (Ql) 459 (M)'. Example 94 2-chloro-N' -(4-chloro-3-(pyridin-2-yl)phcnyl)-NM-(4,5-dihydrooxazol-2 yl)terephthalamide 20 CI N 0 \ OO HN CI NH 0 129 50 ng of 3<hloro.4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 amino-4,5-diliydrooxazole via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-chloro-3-(pyiidin-2-yl)phenyl)--(4,5-dihydrooxazol-2-yl)tcrcphthalamide. 5 MS(Q1)456(M). Example 95 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(1,4,5,6-tctrahydropyrinidinc- 1 carbonvl)benzamide 10 C1 N 0 HN C1 -N 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1,4,5,6-tetrahydropyrimnidine via Procedure G. The product was purified on reverse phase HPLC 15 to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1,4,5,6-tetrahydropyrinidine-1 carbonyl)benzarnide. MS (Q 1) 454 (M) . Example 96 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)4-(3-oxopiperazine-1 20 carbonyl)benzamide C1 HN CI N NH 50 ng of 3<hloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 3 25 oxopiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2 130 chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-oxopiperazine- I -carbonyl)benzamide. MS (QI) 470 (M). 5 Example 97 2-chloro-N -(4-chloro-3-(pyridin-2-yl)phenyl)-N-nethoxyterephtlhalamide C1 HN CI NH o o 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N 10 methylhydroxylamine hydrociforide via Procedure G. The product was purified on reverse phase HPILC to yield 2-chloro-N-(4-clloro-3-(pyridin-2-yl)phenyl)-N4-metboxyerephthalanide. MS (Q1) 417 (M)*. 15 Example 98 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N 4 -hydroxyterephthalamide Cl HN C1 NH O OH 75 mg of 3-chloro4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 20 hydroxylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)pbenyl)-4-iydroxyerephtlalamide. MS (QI) 403 (M). 25 Example 99 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyrrolidine-l-carbonyl)benzamide 131 Ci HN CI No 75 mg of 3-chloro4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N 5 (4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyrrolidine-l-carbonyl)benzamide. MS (Ql) 441 (M) Example 100 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(cthylsulfonylmcthyl)benzamide 10 CI HNN Ethanesulfonyl chloride was reduced to sodium ethanesulfinate according to the procedure in J. Med. Chen. 1989, vol. 32, no. 11, p 24 36 . Briefly. 2.5 ml of ethanesulfonyl chloride was added 15 dropwise to a solution of 3.67 g of sodium carbonate and 5.51 g of sodium sulfate in 13 mL of water. After completion of the reaction the water was evaporated and the solids were suspended in ethanol and heated to 80* C for I h prior to filtering the solids. The filtrate was then evaporated to give 2.5 grams of the sodium ethanesulfinate. 293 mg of the sodium ethansulfinate was combined with 230 mg of methyl (4-bromoethyl)benzoate in 2 mL of DMF and heated to 120 C for 5 min in 20 a microwave reactor. The reaction was then extracted with Ethyl Acetate and Brine to give 250 mg of methyl 4-(ethylsulfonylmethyl)benzoate after evaporation of the organic layer. 200 mg of methyl 4-(ethylsulfonylimetyl)benzoate was hydrolyzed via Procedure M to give 119 ng of 4 (ethylsulfonylmethyl)benzoic acid. 50 mg of 4-(ethylsulfonylmethyl)benzoic acid was coupled with 67mg of 4-chloro-3 25 (pyridin-2-yl)anilinc via Procedure G. This product was recrystallized from methanol to yield N (4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide. MS (Q1) 415(M) 132 Example 101 N-(4-chloro-3-(pyridin-2-yl)pheinyl)-4-( isopropylsulfonylmethyl)benzamnide C1 N 0 HN - a 5 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(isopropylsulfonylmethyl)benzamide was prepared using the same procedure as N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethiylsulfonyhnethyl)bcnzamide except propane-2-sulfonyl chloride was substituted for ethanesulfonyl chloride. The product was jo purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)4 (isopropylsulfonylmethyl)benzamide. MS (QI) 429(M) . Example 102 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-ethyltcrephthalamide '5 Cl HN C1 0 \ 75 ng of 3-chloro-}(4-cloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to ethylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro 20 N'-(4-chloro-3-(pyridin-2-yl)phenyl)--N ethyltercphthalamide. MS (Ql) 415 (M) Example 103 (S)-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-((tetrahydrofurnn-2 yl)methyl)tcrephthalamidc 5 133 C H \/ /\ HN Cl S NH 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S) (+)-tetrahydrofirylarnine via Procedure G. The product was purified on reverse phase HPLC to 5 yield (5)-2-chloro-N -(4-chloro-3-(pyridin-2-yl)pheny1)-N4-((tetrahydrofuran-2 yl)methyl)terephthalarnide. MS (Ql) 471 (M)'. Example 104 2-chloro-M-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(3 0 nethoxypropyl)terephthalamide C1 HN C1 \~~ \N NH 0 75 ng of 3-chlioro-4-(4-chloro-3-(pyridin-2-yl)phcnylcarbarnoyl)benzoic acid was coupled to 3 15 methoxypropylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phcnyl)-N4-(3-methoxypropyl)terephthalamide. MS (QI) 459 (M)'. 20 Example 105 2-chloro-N'-(4-chloro-3-(pyridii-2-yl)phcnyl)-N'-(3 hydroxypropy1)terephthalamide 134 C H \'-/ \ N N0O qNH 0 \- OH 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)plhenylcarbamoyl)benzoic acid was coupled to 3 hydroxypropylaminie via Procedure G. The product was purified on reverse phase HPLC to yield 5 2-cIloro-N'-(4-chloro-3-(pyridin-2-y1)pieny1)-NM-(3-hvdroxypropyl)terephthalaride MS (Q1) 445 (M)*. Example 106 (S)-2-cIloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-( 1-hydroxypropaii-2 In yl)tcrephthalamide Cl \/ /\ NH $ OH 75 mg of 3-chloro4-(4-chloro-3-(pyridin-2-yl)plienylcarbainoyl)bcnzoic acid was coupled to (S)-2 15 amino-I-propanol via Procedure G. The product was purified on reverse phase HPLC to yield (S) 2-cloro-N'-(4-chloro-3-(pyridin-2-yl)pcnyl)-N$-(I-hydroxypropan-2-yl)tereplithalamide. MS (Ql) 445 (M)'. 20 Example 107 (S)-2-chloro-NI(4-chloro-3-(pyridin-2-yl)phenyl)-N*(1-methoxypropan-2 yl)terephthalamide 135 Cl HN Cl /NH 0 i 75 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (S)-1 methoxy-2-propylamine via Procedure G. The product was purified on reverse phase HIPLC to 5 yield (S)-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-NM-(1-metboxypropan-2 yl)tcrephthalamide. MS (Q1) 459 (M) 4 . Example 108 N'-(3-(1 H-imidazol-1-yl)propyl)-2-chloro-N'-(4-chloro-3-(pyridin-2 10 yl)phcnyl)tercphthalarnidc Cl HN CI NH NN \N 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1-(3 15 aminopropyl)imidazole via Procedure G. The product was purified on reverse phase HPLC to yield N'-(3-(] H-imidazol-1 -yl)propyl)-2-cliloro-N'-(4-cliloro-3-(pyridin-2 yl)phenyl)tercphthalainide. MS(QI)495(M)-. 20 Example 109 N-(2-(1H-imidazol-4-yl)ethyl)-2-chloro-N'-(4-chloro-3-(pyridin-2 yl)phenyl)tcrephthalanide 136 C1 HN CI NH 0 NINH 75 ng of 3-chloro4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)bcnzoic acid was coupled to hystamine via Procedure G. The product was purified on reverse phase HPLC to yield NM-(2-( IH 5 imidazol-4-yl)ethyl)-2-chloro-N (4-chloro-3-(pyridin-2-yl)pheny)terephthalamide. MS (QI) 481 (M) Example 110 2-chloro-N' -(4-chloro-3-(pyridin-2-yl)phcnyl)-N4-methylterephthalamide CI '-N 0 HN C1 NH 0 \ 75 mng of 3-cliloro-4-(4-cliloro-3-(pyridin-2-yl)phenylcarbamnoyl)benzoic acid was coupled to methylanine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to 15 yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-methyterephtlhalamide. MS (Q1) 401 (M). Example 11I 2-chloro- '-(4-chloro-3-(pyridin-2-yl)phenyl)-N4ft-diethylerephthalanide 20 137 C1 HN C HN/ N 0 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to diethylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to 5 yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-NNM-diethylterephthalamide. MS (QI) 443 (M), Example 112 (S)-2-chloro-NI-(4-chloro-3-(pyridin-2-yl)pheiiyl)-N4-(2-hydroxypropyl) 10 terephthalamide CI HN CI NH tH O 4 "O 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)bcnzoic acid was coupled to (S)- 15 anino-2-propanol via Procedure G. The product was puified on reverse phase HPLC to yield (S) 2-chloro-NI -(4<hloro-3-(pyridin-2-yl)phenyl)-N4-(2-hydroxypropyl)terephthalamidc. MS (Ql) 444 (M). 20 Example 113 2-chlioro-N' -(4-chloro-3-(pyridin-2-yl)phcnyl)-A4-(2 metloxyethyl)terephthalamide 138 C1 HN CI NH 0 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 methoxycthananine via Procedure G. The product was purified on reverse phase HPLC to yield 2 5 chloMo-N'-(4-chloro-3-(pyridin-2-yl)Ihenyl)-N-(2-methoxyethyl)terephthalamide. MS (Q1) 444 (M) Example 114 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(1-methylpiperidin-4 10 yl)terephthalamide C1 \'\/ N 0 HN CI N NH 75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 4 15 amino-I -metliylpiperidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N' (4-chl.oro-3-(pyridin-2-yl)phenyl)-N"-(I-methylpiperidin-4-yl)tcrephthalamide. MS (Q1) 483 (M)'. 20 Example 115 2-chloro-N' -(4-chloro-3-(pyridin-2-yl)phcnyl)-N-(3 (diethylamino)propyl)terephtlialanide 139 C1 HN CI / \ N NH 0 75 mg of 3-cliloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N,N diethylpropyleiediamine via Procedure G. The product was purified onl reverse phase HPLC to 5 yield 2-chloro-N'-(4-chlIoro-3-(pyridin-2-yl)phenyl)-N-(3-(diethylamino)propyl)terephthalamide. MS(Q1)499(M)I. Example 116 2-chloro-N'-(4-chlIoro-3-(pyridin-2-yl)phenyl)-N4-(2-(pyrrolidin- I 10 yl)ethyl)terephthalamide C1 N 0 IN C N NH 0 75 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)bcnzoic acid was coupled to N-(2 15 aminoethyl)pyrrolidine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N' (4-chloro-3-(pyridin-2-yl)phenyI)-N-(2-(pyrrolidin-I-yl)cthyl)tcrephthalamide. MS (Q1) 483 (M). 20 Example 117 N'(4-chloro-3-(pyridin-2-yl)phenyl)-NNY,2-trinethylerephthalamide 140 C1 HN / \ In a scaled tube, 1.94 g of dimethyl 2-bromotcrephthalate was dissolved in 4 mL of HMPA and 5 degassed with nitrogen prior to adding 1.1 mL of tetramethyl tin and 0.077 g of palladium tetrakistriphenylphosphene. After scaling the tube, the reaction was heated to 65* C for 16 h. The reaction was then partitioned into ethylether and water and extracted, The organic layers were washed with 5% ammonium hydroxide, IN HCI, again with 5% ammonium hydroxide, and finally with water. Filtration of the solvent through sodium sulfate and evaporation gave 1.44 g of crude 10 dimethyl 2-methylterophthalate. 210 mg of dimethyl 2-methylterephthalae was hydrolyzed via Procedure M to give 4-(methoxycarbonyl)-3-nethylbenzoic acid. Silica gel chromatography was performed (0% to 70% EtOAc gradient in Hexancs) to yield 115 ing of 4-(methoxycarbonyl)-3 methylbenzoic acid. 4-(methoxycarbonyl)-3-methylbenzoic acid was then coupled to dimethylanine hydrochloride via Procedure G. The crude methyl 4-(dimethylcarbamoyl)-2 15 methylbenzoate was then hydi-olyzed via Procedure M to give 110 mg of 4-(dimetliylcarbamoyl)-2 methylbenzoic acid. 4-cliloro-3-(pyridin-2-yl)aniline was coupled to 110 mg of 4 (dimethylcarbamoyl)-2-nethylbenzoic acid via Procedure G to yield N' (4-chlioro-3-(pyridin-2 yl)phenyl)-N,2-trimetlhyltereplitlialamide. MS (QI)394(M). 20 Example 1 18 2-chloro-N' (4-chloro-3-(pyridin-2-yl)phenyl)N-propylterephthalamide C1 HN CI NH 0 l41 50 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to propylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro N -(4-chlow-3-(pyridin-2-yl)phenyl)-N-propylterephthalanide. MS (QI) 430 (M)'. 5 Example 119 2-chlom-N (4-chloro-3-(pyidin-2-yl)phenyl)--(2-hydroxyethyl)tcrephthalanide CI HN Cil OH NH 0 10 50 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to propanolamine via Procedure G. The product was purified on reverse phase HPLC to yield 2 chloro-N'-(4-chloro-3-(pyridin-2-yl)phcnyl)-NM-(2-hydroxyethyl)tcrcphthalamide. MS (Ql) 428 (M) . 15 Example 120 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)erephthalamide C1 HN C1 NH, 20 50 mg of 3-chloro4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to amrmonium chloride via Procedure G. The product was purified on reverse phase HPLC to yield 2 chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)tercphthalaridc. MS (Q1) 386 (M)'. 25 Example 121 N-(4-cliloro-3-(pyridin-2-yl)phenyl)4-(IH-tetrazol-1-yl)benzamide 142 C1 HN Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 4-(1H-tetrazol-1 yl)bcnzoic acid to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(IH-tetazol- I-yl)benzamide. MS 5 (QI)421.0(M)'. Example 122 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheny)-4-(4-cthylpiperazine-l carbonyl)benzamide la C1 HN C1 N N 0 \ 50 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)benzoic acid was coupled to I ethylpiperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2 15 chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(4-cthylpiperazinc- -carboinyl)bcnzamide. MS (Ql) 483 (M)'. Example 123 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl k4-(piperazine-1-carbonyl)bcnzamiIe 20 143 NCC HN CI "N//\ SNYJNH 50 mg 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)beinoic acid was coupled to Boc piperazinc via Procedure G. The organic layer was evaporated to dryness and treated with TFA. 5 After I h the TFA was removed and the crude was purified on reverse phase HPLC to yield 2 chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(piperazine-1-carbonyl)beinzaide. MS (Ql) 455 (M) 10 Example 124 2-chlioro-N' (4-chloro-3-(pyridin-2-yl)phenyl )-A"(2,2.2 trifluoroethyl)tereplithalamide C1 HN CI F NH F 0 15 75 mg of 3-chloro-4-(4-chloro-3-(pyiidin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2,2,2 trifluoroethylamine via Procedure G. The product was purified on reverse phase HPLC to yield 2 chloro-N'-(4-cliloro-3-(pyridin-2-yl)phenyl)-M'-(2,2,2-trifluoroethyl)tereplitlialamide. MS (QI) 469 (M) . 20 Example 125 6-(2-(I H-inidazol-5-yl)ethiylamino)-N-(4-hloio-3-(pyridin-2 yl)phenyl)nicotinanide 144 Cl \"N iI 0

HN

/ \N H HN N Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and 100 mg of hystamine in butanol (0.5 mL). The crude reaction was purified by reverse 5 phase HPLC to yield 6-(2-(IH-imiidazol-5-yl)ethylamino)-N-(4-cliloro-3-(pyridin-2 yl)phenyl)nicotinaride. MS (Q1) 419 (M). Example 126 6-(4-acetylpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide CI \N 0 HN /\ N 0 ~N N Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxamide (50 mg) and 0.12 mL of acetylpiperazine in butanol (0.5 mL). The crude reaction was purified by 15 reverse phase HPLC to yield 6-(4-acetylpiperazin-1-yI)-N-(4-chloro-3-(pyridin-2 yl)phcnyl)nicotinanide. MS (QI) 436 (M). Example 127 6-(3-(1H-inidazol-1-yl)propylamino)-N-(4-chloo-3-(pyridin-2 20 yl)phenyl)nicotinamidc 145 CI

HN

/'\N N HN IN Procedure F was performed using N-(4-chloro-3-( pyridin-2-yl)pheiyl)-6-hloro-3<arboxamide (50 mg) and 125 mg of 1-(3-aminopropyl)imidazole in butanol (0.5 mL). The crude reaction was 5 purified by reverse phase HPLC to yield 6-(3-(lH-imidazolI-yl)propylamino)-N-(4-chloro-3. (pyridin-2-yl)phenyl)nicotinamide. MS (QI) 433 (M)'. Example 128 N-(4-cbloro-3-(pyridin-2-yl)phcnyl)-6-(3-(2-oxopyrrolidin- 1 1n yi)propylamino)nicotinamide CI HN / "N HN Procedure F was performed using N-(4<hloro-3-(pyridin-2-yl)phenyl)-6-chloro-3<arboxamide (50 15 rug) and 0.42 mL of 1-(3-aminopropyl)-2-pyrrolidinone in butanol (0.5 mL). The crude reaction was purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-(2 oxopyrrolidin-1-yl)propylamino)nicatinanide. MS (QI) 450 (M). 20 Example 129 N-(4-chloro-3-(pyridin-2-yl)pheny)-6-(3-morpholinopropylamino)nicolinamide 146 C1 \N 0 HN / NN HN Procedure F was performed using N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-chloro-3-carboxanide (50 mg) and 0.14 mL of N-(3-aminopropyl)morpholine in butanol (0.5 mL). The crude reaction was 5 purified by reverse phase HPLC to yield N-(4-clloro-3-(pyridin-2-yl)phenyl)-6-(3 morpholinopropylamino)nicotinamnide. MS (QI) 452 (M)'. Example 130 N-(4-clloro-3-(pyridin-2-yl)plienyl)benzo[d][I,2.3]thiadiazole-5-carboxamide 10 CI N Y 0 HN 50 mg of 4-chloro-3-(pyridin-2-yI)aniline was coupled to benzo-1,2,3-thiadiazole-5-carboxylic acid 15 via Procedure G. The crude product was purified via reverse phase HPLC to yield N-(4-chloro-3 (pyridin-2-yl)phenyl)benzo[d][1,2,3]thiadiazole-5-carboxamide. MS (QI) 367 (M)*. Example 131 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(( IS,2R)-2-hydroxy-2,3-dihydro 20 1H--inden-1-yl)1ereplhthalamide 147 C1 HN CI NH OH 0 60 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (IS,2R)-l-amino-2,3-dihydro-lH-inden-2-o via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-cIoro-3-(pyridin-2-yl)phenyl)-N-((1S.2R)-2 hydroxy-2,3-dihydro-lH-inden-1-yl)tcrphthalanidc. MS (QI)518.2(M)*. Example 132 2-chloro-N'-(4-chloro-3-(pyridin-2-y)pheny)-N 4 -((R,25)-2-iydroxy-2,3-dihydro 10 1H-inden-1-yl)tcrephthalanide C1 N 0 HN CI NH H 0 60 ng of 3-cbloro4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (IR,2S)-l-amino-2,3-dihydro-H-inden-2-o via Procedure G. The crude product was purified on 15 reverse phase HPLC to yield 2-chlow-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N4((IR,2S)-2 hydroxy-2,3-dihydro-IH-inden-1-yl)terephthalamide. MS (QI) 518.2(M)'. Example 133 N-benzyl-2-chloro-N-(4-chloro-3-(pyridiwn2-yl)phenyl)-N -(2-hydroxyethyl) 20 terephthalamide 148 CI N 0 HN CI N OH 40 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 (benzylamino)elhanol via Procedure G. The crude product was purified on reverse phase HPLC to 5 yield V-benzyl-2-chloro-N-(4-chloro-3-(pyridin-2-yl)plienyl)-N 4 -(2 hydroxyethyl)tcrcphthalainidc. MS (Q1) 520 (M). Example 134 2-chloro-N'-(4-chloro-3-(pyridin-2-y)pheny1)-4-nethyl-'-(pyridiii-2 I0 ylmcthyl)terephthalamide C1 N 0 HN C1 N N 40 ng of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)benzoic acid was coupled to N methyl-I-(pyridin-2-yl)mcthanaminc via Procedure G. The crude product was purified on reverse 15 phase HPLC to yield 2-clIoro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-imetliyl-N-(pyridin-2 yhmethyl)terephthalamide. MS (Q1) 491 (M)'. Example 135 N-benzyl-2-cliloro-N'-(4-chloro-3-(pyridiii-2-yl)phenyl)-N 20 methyltcrcphthalamide 149 CI HN CI 40 mg of 3-chloro-4-(4-cliloro-3-(pyridin-2-yl)plienylcarbamoyl)benzoic acid was coupled to N methyl- I -phcnylmethanamine via Procedure G. The crude product was purified on reverse phase 5 HPLC to yield N-benzyl-2-chloro-N'-(4-cbloro-3-(pyridin-2-yl)phenyl)-N-methylterephthalamide. MS (Q1) 490.1 (M)f. Example 136 N-(2-aminobenzyl)-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamnide 10 CI HN CI / \ H 2 N NH / 0 60 mg of 3-cliloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoy)benzoic acid was coupled to N' phenylethane-1,2-diamine via Procedure G. The crude product was purified on reverse phase 15 HPLC to yield N 4 -(2-aminobenzyl)-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phcnyl)terephtlhalamide. MS (Q1) 491 (M)'. Example 137 N-benzyl-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide 20 150 CI HN CI / \H oNH " 0 60 mng of 3-chloro-4-(4-cliloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to benzylamine via Procedure G. The crude product was purified on reverse phase HPLC to yield NM 5 benzyl-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (QI) 476(M). Example 138 (R)-2chloro-N'-(4-chloro-3-(pyridin-2-yl)phcnyl)-N-(2-hydroxyphenylethyl)terephthalamide 10 CI \ \ / \ N NH HN4PI N/ IOH 0 60 ng of 3-chloio-4-(4-chloro-3-(pyridii-2-yl)plhenylcarbaiioyl)benzoic acid was coupled to (R) 2-amino-2-plienylethanol via Procedure G. The crude product was purified on reverse phase 15 HPLC to yield (R)-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N'-(2-hydroxy-1 phenylethyl)tcrcphthalamide. MS (QI) 506 (M). Example 139 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yl)nicotinumide 20 151 C1 HN / N N, 50 ing of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)nicotinamide was reacted with 1-methyl-1,4 diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase 5 HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-methyl-1,4-diazepan-1-yI)nicotinamidc. MS (Q1) 422 (M)'. Example 140 N-(4-chloro-3-(pyridin-2-yl)phcnyl)-6-(1,4-diazepan- I -yl)nicotinamide 10 CI CNF 0

FIN

C N NH 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)nicotinamide was reacted with 1,4 diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase 15 HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1,4-diazepan-1-yl)nicotinamide. MS (Q1) 408 (M)". Example 141 2-clIoro-N' -(4-chloro-3-(pyridin-2-l)pheicnyl)-M-(2 20 (plenylaiino )ethyl)terephthalamide 152 CI HNNC NH 0 \ HN -O 62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N' phenylethane-1,2-diamine via Procedure G. The crude product was purified on reverse phase 5 HPLC to yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N'-(2 (phenylamino)ethyl)terephthalamide. MS (Q1) 505.1 (M)-. Example 142 (S)-2-chloro-N'-(4-cbloro-3-(pyridin-2-yl)phenyl)-NM-(2-hydroxy-1 10 phcnylethyl)tcrephthalamide C HN CI OH 0 62 mg of 3-chlIoro-4-(4-clhloro-3-(pyridin-2-yl)phenylcarbamioyl)benzoic acid was coupled to (S)-2 15 amino-2-phenylethanol via Procedure 0. The crude product was purified on reverse phase HPLC to yield (S)-2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-NM-(2-hydroxy-1 phenylethyl)terephthalamide. MS (QI) 506 (M) . 20 Example 143 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(I-phenylethyl)terephthalamide 153 C1 HN C1 qNH 0 G 62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 1 phenylethanamine via Procedure G. The crude product was purified on reverse phase HPLC to 5 yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-NV-(1-pienylethyl)terephtlhalamide. MS (QI) 490.1 (M). Example 144 2-chloro-N'-(4-chloro-3-(pyridiin-2-yl)pheinyl)-N-(4-(nethylsulfonyl)benzyl) In terephthalamride CI N H C1 H N I 0 NH_ 0 62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)plienylcarbamoyl)benzoic acid was coupled to (4 15 (methylsulfonyl)phenyl)mcthanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N'-(4 (methylsulfonyl)benzyl)terephthalamide. MS (Q1) 554 (M). 20 Example 145 N-(3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide 154 Cl \N 0 HN Cl NH N 0O 75 ing of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((tert-butoxycarbonylamino)methyl)-2 chlorobenzoic acid via Procedure G to yield ter-butyl 3-chloro-4-(4-chloro-3-(pyridin-2 5 yl)plienylcarbamoyl)benzylcarbamate. Tert-butyl 3-chloro-4-(4-clhloro-3-(pyridin-2 yl)phenylcarbamoyl)benzylcarbamate was subsequently treated with 4N HCI in Dioxane to remove the Boe protecting group and form the HCI salt of 4-(aninomethyl)-2-chloro-N-(4-chloro-3 (pyridin-2-yl)phcnyl)bcnzamide. 54 mg of the crude HCI salt of 4-(aminomethyl)-2-chloro-N-(4 chloro-3-(pyridin-2-yl)phenyl)benzamnide was coupled to picolinic acid via Procedure G. The I0 crude product was purified by reverse phase HPLC to yield N-(3-chloro-4-(4-chloro-3-(pyridin-2 yl)phenylcarbamoyl)benzyl)picolinamide. MS (Q1) 477.3 (M) . Example 146 N-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)picolinamide 15 CI \N 0 HN NH N 0T 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-((teri butoxycarbonylamino)methyl)benzoic acid via Procedure G to yield tert-butyl 4-(4-chloro-3 20 (pyridin-2-yl)plh.enylcarbamoyl)benzylcarbamate. Tert-butyl 4-(4-chloro-3-(pyridin-2 yl)plieiiylcarbanoyl)benzylcarbamate was subsequently treated with 4N HCI in Dioxane to remove the Boc protecting group and form the HCI salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2 yl)phenyl)benzamide. 50 mg of the crude HCI salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2 yl)phcnyl)benzamidc was coupled to picolinic acid via Procedure G. The crude product was 155 purified by reverse phase HPLC to yield N-(4-(4-chloro-3-(pyridin-2 yl)phcnylcarbamoyl)benzyl)picolinamide. MS (QI) 443.3 (M)*, 5 Example 147 N-(4-chloro-3-(pyridin-2-yl)phenyl)-N 2 -isopropylpyridine-2,5-dicaboxamide C1 HN NH 0 250 mg of 5-(metlioxycarbonyl)picolinic acid was coupled to isopropylamine via Procedure G. p) Crude methyl 6-(isopropylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 227 mg of 6-(isopropylcabamoyl)nicotinic acid. 60 ng of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(isopropylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N-(4-chloio-3-(pyidin-2-yl)phenyl)-N 2 -isopropylpyridine-2,5 dicarboxamide. MS (QI) 395.1 (M). 15 Example 148 N 2 -er-butyl[N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide CI N 0J HN / ~N N, 20 250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to iert-butylamine via Procedure G. Crude methyl 6-(tert-butylcarbamoy1)nlicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(tert-butylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)anilinc was coupled to 6-(tert-butylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse 156 phase HPLC to yield N2-tert-butyl-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2.5 dicarboxamide. MS (QI) 409 (M) . 5 Example 149 N-(4-chloro-3-(pyridin-2-yl)phenyl)-N 2 -(pyridin-2-ylmethyl)pyridine-2,5 dicarboxamide cl HN / \N NH N 0 O 250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to pyridin-2-ylnethanamine via 10 Procedure G. Crude methyl 6-(pyridin-2-ylnethylcarbamoyl)nicotinate was hydrolyzed via Procedure M to yield 250 mg of 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid. 60 mg of 4 chloro-3-(pyridin-2-yl)aniline was coupled to 6-(pyridin-2-ylmethylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N'-(4-chloro-3 (pyridin-2-y)phenyl)-N 2 -(pyridin-2-ylmcthyl)pyidine-2,5-dicarboxamidc. MS (QI) 444.1 (M)'. 15 Example 150 N 2 -benzyl-M-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxanidc CI HN NH 20 250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to benzylarnine via Procedure G. Crude methyl 6-(benzylcarbamoyl)nicotinate was hydrolyzed via Procedure M. to yield 300 mg of 6 (benzylcarbamoyl)nicotinic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6 (benzylcarbamoyl)nicotinic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield N 2 -benzyl-NM-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-2,5-dicarboxamide. 25 MS (Q1) 443.1 (M)f. 157 Example 151 N 5 -(4-chlow-3-(pyridin-2-yl)phenyl)-N-(6-netIoxypyridin-3-yl)pyridine-2,5 dicarboxamiidc CI HW N NH / NN 0 -Q/ 0 250 mg of 5-(methoxycarbonyl)picolinic acid was coupled to 6-methoxypyridin-3-amine via Procedure G. Crude methyl 6-(6-iiietlioxypyridin-3-ylcarbaioyl)nicotinate was hydrolyzed via I0 Procedure M to yield 196 mg of 6-(6-methoxypyridin-3-ylcarbamoyl)nicolinic acid. 60 mg of 4 chloro-3-(pyridin-2-yl)aniline was coupled to 6-(6-nethoxypyridin-3-ylcarbamoyl)nicotinic acid via Procedure G. The crude product was recrystallized to yield pure N 5 -(4-chloro-3-(pyridin-2 yl)pheny1)-N2-(6-methoxypyridin-3-yl)pyrdine-2,5-dicarboxamide. MS (QI) 460 (M) . 15 Example 152 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-((6-methylpyridin-2-yl)mnetliyl) terephthalamide HN CI ONH 20 2.5 mL of Diisopropylazodicarboxylate in 1.5nL of THF was added dropwise to a solution of 250 mg of (6-methylpyridin-2-yl)methanol, 2.8g of Triphenylphosphine and 1.6 g of isoindoline-1,3 dione in anhydrous THF at room temperature. The reaction was stirred for 2 hours and monitored 158 by TLC. Upon complection, the solvent was concentrated, the crude material was extracted in water and Chloroform 3 times and dried over Magnesium Sulfate. The crude was purified via ISCO Combi-Flash to yield 2-((6-methylpyridin-2-yl)methyl)isoindoline-1,3-dione. 350 mg of 2 ((6-methylpyridin-2-yl)mcthyl)isoindolinc-1,3-dione was treated with 440 aL of Hydrazine 5 Monohydrate in EtOH and refluxed for several hours to yield (6-methylpyridin-2-yl)methanamine. The crude (6-methylpyridin-2-yl)mcthanamine was evaporated and directly coupled to 50mg of 3 chloro-4-(4-chloro-3-(pyridin-2-y)phenylcabamoyl)benzoic acid via Procedure G. The crude product was purified on reverse phase HPLC to yield 2<hloro-N'-(4-chloro-3-(pyridin-2 yl)plhenyl)-N-((6-metbylpyridin-2-yl)methyl)terephthalamide. MS (Ql) 491.1 (M). 10 Example 153 N-(4<hloro-3-(pyridin-2-yl)phcnyl)4-((2 hydroxypropylsulfonyl)methyl)benzamide C1 -0 0 O OH 15 I g of methyl 4-(bromomcthyl)benzoate was reacted with I -mercaptopropan-2-ol via Procedure Q. I g of methyl 4-((2-hydroxypropylthio)methyl)benzoate was oxidized with 2g of MCPBA in DCM at -78"C to form crude methyl 4-((2-hydroxypropysulfonyl)methyl)benzoate. The reaction was 20 evaporated and purified by ISCO Combi-Flash to yield 567 mg of pure methyl 4-((2 hydroxypropylsulfonyl)methyl)benzoate which was subsequently hydrolyzed via Procedure M to give 328 mg of 4-((2-hydroxypropylsulfonyl)methyl)benzoic acid. 50 mg of 4-chloro-3-(pyridin 2-yl)anilinc was coupled to 4-((2-iydroxypropylsulfonyl)methyl)benzoic acid via Procedure G. The crude product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2 25 yl)phenyl)-4-((2-hydroxypropylsulfonyl)methyl)bcnzamide. MS (Q1) 445.3 (M)-. Example 154 (R)-2-chloro-N t -(4-chloro-3-(pyridin-2-yl)phenyl)-N-(2 hydroxypropyl)terephthalamide 30 159 C1 H CI NH PH 0 100 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)pheinylcarbamoyl)benzoic acid was coupled to (R) 2-amino-2-phenylethanol via Procedure G. The crude product was purified on reverse phase 5 HPLC to yield (R)-2-chloio-N'-(4-chloro-3-(pyridin-2-yl)plienyl)-N'-(2 hydroxypropyl)terephthalamide. MS (Q1) 444.3 (M)-. Example 155 N-(4-chloro-3-(pyridin-2-vl)pheny1)-4-((2-(dimethylamino)ethiylsulfonyl)methyl) 10 benzamide CI HN -0 -- 0

N

500 mg of 4-cliloro-3-(pyridin-2-yl)aniline was coupled to 4-(bromomethyl)benzoic acid via Procedure E. 170 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was 15 reacted with 2-(dimethylaino)ethanethiol hydrochloride via Procedure Q. 140mg of crude N-(4 chloro-3-(pyridin-2-yl)phenyl)4-((2-(dimcthiylamino)cthylthio)methyl)benzamide was reacted with oxone via Procedure R. The crude product was purified by reverse phase HPLC to yield N (4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-(dimetIylamino)cthylsulfonyl)mcthyl)bcnzamide. MS (Q1) 458.3 (M). 20 Example 156 2-chloro-N (4-chloro-3-(pyidin-2-yl)phenyl)-N-(6-methoxypyidin-3 yl)terephtlialamide 160 Cl HN Cl NH 0 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 6 methoxypyridin-3-amine via Procedure G. The crude product was purified on reverse phase HPLC 5 to yield 2-cliloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-M-(6-methoxypyridin-3-y)terephthalamide. MS (QI) 493 (M). Example 157 M-(6-aninopyridin-3-yl)-2-cliloro-N-(4-chloro-3-(pyridin-2-y)phenyl) 10 terephthalamide Cl HNI C \/ /\ NH 0 -Q NH2 50 ng of 3-chloro-4-(4-clhloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 15 pyridinc-2,5-diainiiie via Procedure G. The crude product was purified on reverse phase HPLC to yield N-(6-aminopyridin-3-yl)-2-chloro-N 1 -(4-chloro-3-(pyridin-2-yl)phenyl)terephthalamide. MS (QI) 478 (M). 20 Example 158 2-chloro-4'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(6-chloropyridin-3 yl)terephthalamide 161 C1 HN CI NH 0 CI 50 mrig of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 6 chloropyridin-3-amine via Procedure G. The crude product was purified on reverse phase HPLC 5 to yield 2-chloro-N'-(4-cliloro-3-(pyridin-2-yl)phenyl)-N-(6-clhloropyridin-3-yl)terephthalamide. MS (Q 1) 497 (M). Example 159 2-chloro-N'-(4-ciioro-3-(pyridin-2-y)peny)-N 4 -(pyridin-2-yl)terephthalamide C N10 HN C NH o N 50 mg of 3-clloro-4-(4-chloro-3-(pyridim-2-yl)phenylcarbamoyl)benzoic acid was coupled to pyridin-2-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 15 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(pyridin-2-yl)terephthalamide. MS (Ql) 463 (M). Example 160 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(pipeidin-4 20 ylmethyl)terephthalamide 162 C1 HN CI NH 0 N NH 50 mg of 3-chloro-4-(4-cbloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to piperidin-4-ylmethanaminc via Procedure G. The crude product was purified on reverse phase 5 HPLC to yield 2-cliloro-N'-(4<hloro-3-(pyridin-2-yl)plieny)-N 4 -(piperidin-4 ylmethyl)tcrephthalamide. MS (Q1) 483 (M) . Example 161 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)pheinyl)-N-(1,3-dinietliyl-1 H-pyrazol-5 10 yl)tcrephthalamide C1 HN C1 NH 0 N N 50 mg of 3-chloro4-(4-chloro-3-(pyridin-2-yl)phenylcarbanoyl)benzoic acid was coupled to 1,3 15 dimethyl-IH-pyrazol-5-amine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-(1,3-dimethyl-1H-pyrazol-5 yI)terephthalamide. MS (Q]) 480 (M). 20 Example 162 2-chloro-N' -(4-chloro-3-(pyridin-2-yl)phcnyl)-N'-(2-(methylsulfonyl)cthyl) terephthalamide 163 C H \/ /\ HN CI NH 0 \ o 50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to 2 (methylsulfonyl)cthanamnine via Procedure G. The crude product was purified on reverse phase 5 HPLC to yield 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N'-(2 (methylsulfonyl)cthyl)terephthalanide. MS (QI)492(M). Example 163 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-N-isopropylterephthalamide 10 Cl HN C 0 50 mg of 3-chloro4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to isopropylamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 15 2-chloro-N'-(4-chloro-3-(pyridin-2-yl)phenyl)-Nisopropylterephthalanide. MS (QI) 428 (M). Example 164 2-chloro-N-(4-chloro-3-( pyridin-2-yl)phenyl)-4-(N-(2-methoxyethyl)methyl sulfoinamido)benzamide 20 164 CI \N 0 HN CI To 5 g of methyl 2-chloro-4-nitrobenzoate in 100 mL of EtOH was added 20 g of Tin (11) Chloride in portions. The reaction was heated to 55"C and monitored by TLC until complete. Solvent was concentrated and extraction was performed in Ethyl Acetate and water with TEA to reduce 5 emulsions. The organic layer was dried over Magnesiun Sulfate, filtered and concentrated to give 3.9 g of methyl 4-amino-2-chlorobenzoate. I g of methyl 4-amino-2-chlorobenzoate was cooled to O"C in DCM with 485 pL of Pyridine before Methanesulfonyl Chloride was added dropwise. The reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was dissolved in Ethyl Acetate and extracted with saturated bicarbonate 10 solution and then brine. The crude material was dried over Magnesium Sulfate, filtered and concentrated to give 1.54 g of methyl 2-chloro-4-(methylsulfonanido)benzoate. 107 pL of 1 bromo-2-methoxyethane and 556 mg of Cesium Carbonate were added to 150 tug of methyl 2 chloro-4-(methylsulfonamido)benzoate in DMF and stired at room temperature for 16 hows. The action mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with 15 brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-(N-(2 methoxyethyl)methylsulfonamido)benzoate. 182 mg of methyl 2-cliloro-4-(N-(2 methoxycthyl)methylsulfonamido)bcnzoate was hydrolyzed via Procedure M to yield 169 mg of crude 2-chloro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic acid. 65 mg of 4-chloro-3 (pyridin-2-yl)aniline was coupled to 2-chioro-4-(N-(2-methoxyethyl)methylsulfonamido)benzoic 20 acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N (4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-methoxycthyl)mcthylsulfonamido)benzamide. MS (Ql) 494 (M)'. 25 Example 165 4-(N-(2-(lH-pyrrol-1-yl)ethyl)mthylsulfonamido)-2-chloro-N-(4hloro-3 (pyridin-2-yl)phenyl)benzamide 165 CI HN CI \~~ \N N N 200 iL of 1-(2-bromoethyl)-IH-pyrrole and 556 ug of Cesium Carbonate were added to 150 mg of methyl 2-chlioro4-(methylsulfonamido)benzoate in DMF and stirred at room temperature for 16 5 hours. The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N-(2 (IH-pyrrol-I-yl)ethyl)methylsulfonamido)-2-chlorobenzoate. 230mg of methyl 4-(N-(2-(IH pyrrol-1-yl)thyl)mthylsulfonamido)-2-chlorobenzoate was hydrolyzed via Procedure M to yield 221 mg of crude 4-(N-(2-(] H-pyrrol-1-yl)ethyl)nethylsulfonamido)-2-chlorobenzoic acid. In 64 mg of 4-chloro-3-(pyiidin-2-yl)aniline was coupled to 4-(N-(2-(IH-pyrrol-l yl)ethyl)methylsulfonamido)-2-chlorobenzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 4-(N-(2-IH-pyrrol-1-yl)ethyl)methylsulfonamido)-2 chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 529 (M) 15 Example 166 2-clloro-.N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-isobutylnethylsulfonamido) benzamide CI \/ \ N20 200 175 pL of 1-iodo-2-methylpropane and 740 mg of Cesium Carbonate were added to 200 mg of methyl 2-cliloro-4-(methylsulfonamido)benzoate in 2 mL of DMF and stirred in the microwave at 140'C for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated and purified on ISCO Combi-Flash to give methyl 166 2-chloro-4-(N-isobutylmethylsulfonanido)benzoate 120 mg of methyl 2-chloro-4-(N isobutylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 110 mg of crude 2 chloro-4-(N-isobutylmetbylsulfonanido)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro4-(N-isobutylmcthylsulfonamido)benzoic acid via Procedure G. The 5 crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2 yl)phenyl)-4-(N-isobutylmethylsulfonamido)benzamide. MS (Q 1) 492 (M) . Example 167 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-morpholinoethyl)methyl 10 sulfonaimido)benzatnide CI \//\/ \N 0 og N\N H I " 0 1.2 g of 4-(2-chloroethyl)inorpholine and 2.5 g of Cesium Carbonate were added to 334 mg of 15 methyl 2-chloro-4-(methylsulfonamido)benzoate in 7 mL of DM F and stirred in the microwave at 15()C for 30 minutes. The reaction mixture was extracted in Ethyl Acetate twice with water, dried over Magnesium Sulfate, filtered, concentrated to give crude methyl 2-chloro-4-(N-(2 morpholinoethyl)methylsulfonamido)bcnzoate. 476 mg of methyl 2-chloro-4-(N-(2 morpholinoethyl)methylsulfonamido)benzoate was hydrolyzed via Procedure .M and purified by 20 reverse phase HPLC to yield 460 mg of crude 2-chloro-4-(N-(2 norpholinoethyl)mcthylsulfonanido)bcnzoic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3 (pyridin-2-yl)phenyl)-4-(N-(2-morpbolinoethyl)methylsulfonamido)benzamide. MS (QI) 549 25 (M) . Example 168 N-(4-clhloro-3-(pyridin-2-yl)plieny1)-2-methyl-4-(methylsulfonylmetiyl)benzamide 167 CI \' /\ \N 0 0

-

0 410 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M and purified by ISCO Combi-Flash to afford 4-(methoxycarbonyl)-3-methylbenzoic acid. 255 ng of 4 5 (methoxycarbonyl)-3-methylbenzoic acid was cooled to O"C in 2 mL of THF before a solution of 2.6 mL of IM BH-THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at -50% complete by TLC. The reaction was re-cooled to 0"C and another 2.6 mL of BH;-THF was added dropwise before the ice bath was removed. Upon completion, the reaction Was re-cooled to O'C 10 and quenched with 3N HCI dropwise. The aqueous layer was extracted 2 times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(hydroxymethyl)-2-methylbcnzoate. 220 mg of methyl 4-(hydroxymethyl)-2-methylbenzoate was cooled to 0"C in 5 mL of DCM before adding 260 mg of Triphenylphosphine and 395 mg of NBS. The reaction was concentrated and 15 directly purified via ISCO Combi-Flash to give pure methyl 4-(bromomethyl)-2-metbylbenzoate. 255 mg of methyl 4-(bromomethyl)-2-nethylbenzoate was reacted via Procedure 0 to give methyl 2-methyl-4-(methylsulfonylmethyl)benzoate. 250 mg of methyl 2-methyl-4 (methylsulfonylmethyl)benzoate was then hydrolyzed upon heating to 45"C for 1 hour via Procedure M to give 2-inethyl-4-(methylsulfonylmethyl)bcnzoic acid. 202 mg of 4-chloro-3 20 (pyridin-2-yl)aniline was coupled to 2-methyl-4-(methylsu[lfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase .HPLC to yield N-(4-chiloro.3-(pyridin-2 yl)plheny1)-2-methyl-4-(methylsulfonylmethyl)bcnzamiide. MS (QI) 415 (M). 25 Example 169 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheny)-4-(N-methylnethyl sulfonamido)benzamide 168 C H \'/ \/ N- I N N C 0 N-o / \ 78 sL of iodomethane and 447 mg of Cesium Carbonate were added to 300mg of methyl 2-chloro 4-(methylsulfonamido)benzoate in 3 mL of DMF and stirred at room temperature for 16 hours. 5 The reaction mixture was extracted in Ethyl Acetate twice with saturated bicarbonate and once with brine, dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-chloro 4-(N-methylmetliylsulfonamido)benzoate. 295 mg of methyl 2-chloro-4-(N methylmethylsulfonamido)benzoate was hydrolyzed via Procedure M to yield 249 mg of 2-chlioro 4-(N-methylmethylsulfonamido)benzoic acid. 10 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(N methylmethylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N methylmetliylsulfonamido)benzanide. MS (QI) 450 (M)'. 15 Example 170 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)methyl)benzamide CI \/ \\o NNNH 20 500 mg of methyl 4-(bromomethyl)benzoate was reacted with 480 mg of tert-butyl 3 oxopiperazine-1-carboxylate and I g of Cesium Carbonate in 9 mnL of DMF at 45'C. Upon completion, the reaction was extracted in Ethyl Acetate 2 times saturated bicarbonate, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 4-(4-(methoxycarbonyl)bcnzyl)-3 oxopiperazine-i-carboxylate. 613 mg of tert-butyl 4-(4-(nethoxycarbonyl)benzyl)-3 25 oxopiperazine-l-carboxylate was hydrolyzed via Procedure M to give 4-((4-(Iert-butoxycarbonyl) 2-oxopiperazin-1-yl)methyl)benzoic acid. 200 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled 169 to 4-((4-(tert-butoxycarbonyl)-2-oxopiperazin-1-yl)methyl)benzoic acid via Procedure G. The crude product was extracted twice with saturated bicarbonate in Ethyl Acetate, dried over Magnesium Sulfate, filtered and concentrated to give crude tert-butyl 4-(4-(4-chiloro-3-(pyridin-2 yl)phenylcarbanoyl)benzyl)-3-oxopiperazine-1-carboxylate. 4N HCI was subsequently added to 5 crude tert-butyl 4-(4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl)-3-oxopiperazinecarboxylate and concentrated to give the HCI salt of N-(4-chiloro-3-(pyridin-2-yl)phenyl)-4-((2 oxopiperazin-1-yl)methyl)benzamide. The reaction was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyiidin-2-yl)phenyl)-4-((2-oxopiperazin-1-yl)mcthyl)benzamide. MS (Q1) 421.3 (M)'. 10 Example 171 N-(4-chloro-3-(pyridin-2-yl)phcnyl)4-((4-ncthyl-2-oxopipcmzin-l yl)methyl)benzamide C1 \N 0 HN 15 To 200 mg of the HCI salt of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2-oxopiperazin-l yl)methyl)benzamide was added 55 mg of Paraformaldehyde and 185 mg of Sodium Triacetoxyborohydride in I mL of 2% AcOH in DMF. After completion, the reaction is extracted 20 once with bicarbonate and brine in Ethyl Acetate, dried over Magnesium Sulfate, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2yl)phenyl)-4-((4-methyl-2 oxopiperazin-1-yl)methyl)benzamide. MS (QI) 435.3 (M)', 25 Example 172 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheny)-4-((4,5-dihydro-1H-imidazol-2 ylarnino)methyl)benzamide 170 Cl \/ \ N 0 NH N$-NH 100 mg of the crude HCI salt of 4-(aminonethyl)-2chloro-N-(4-chlIoro-3-(pyridin-2. yl)phenyl)benzamide was reacted with 72 ng of 1-(4,5-diliydro-IH-imidazol-2-yl)-3,5-dimethyl 5 1 H-pyrazole and 100 sL of DIPEA in 500 sL of DMF in the microwave at 150*C for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield 2 chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-((4,5-dihydro-IH-inidazol-2 ylamino)miethy1)benzamide. MS(QI)440 (M). I0 Example 173 N-(4-chioro-3-(pyridin-2-yl)phcnyl)4((4,5-dihydro- IH-imidazol-2 ylamino)nethy1)benzamide CI \N 0 HN NH NH 15 100 mg of the crude HCI salt of 4-(aminomethyl)-N-(4-chloro-3-(pyridin-2-yl)phcnyl)bcnzamidc was reacted with 80 mg of 1-(4,5-dihydro-IH-inidazol-2-yl)-3,5-dimethyl-1H-pyrazole and 110 gL of DIPEA in I mL of DMF in the microwave at 150'C for 5 minutes. The crude product was concentrated to dryness and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2 20 yl)phcnyl)-4-((4,5-dihydro-lH-imidazol-2-ylamino)mcthyl)benzamide. MS (QI) 406 (M) . Example 174 N-(4-cloro-3-(pyridin-2-yl)pheny1)-4-((pyridin-2-ylsulfonyl)mctiyl)benzamide 171 Cl \N 0 HN 500 mg of methyl 4-(bromomethyl)benzoate was reacted with pyridine-2-thiol via Procedure Q. 260 mg of methyl 4-((pyridin-2-ylthio)nethyl)benzoate was reacted via Procedure R to give methyl 5 4-((pyridin-2-ylsulfonyl)nethyl)benzoate. 275 mg of methyl 4-((pyridin-2 ylsulfonyl)methyl)benzoate was hydrolyzed via Procedure M to give 4-((pyridin-2 ylsulfonyl)methyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4 ((pyridin-2-ylsulfonyl)methyl)bcnzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((pyridin-2 10 ylsulfonyl)methyl)benzamide. MS (Q1) 464.1 (M)-. Example 175 N-(4-clloro-3-(pyridin-2-yl)phenyl)-4-(N-nethylmethylsulfonamido)benzamide cl HNN - 0 15 \ 500 mg of methyl 4-(methylamino)benzoate was cooled to O'C in DCM with 270 pL of Pyridine before 260 pL Methanesulfonyl Chloride was added dropwise. Reaction was allowed to warm to room temperature and stir overnight. Solvent was concentrated and the crude material was 20 dissolved in Ethyl Acetate and extracted with 0.1N NaOH solution twice. Crude material was dried over Magnesium Sulfate, filtered and concentrated to give methyl 4-(N methylmethylsulfonanido)benzoate. 698 mg of methyl 4-(N-methylmetlylsulfonamido)benzoate was hydrolyzed via Procedure M to give 4-(N-methylmcthylsulfonamido)bcnzoic acid 100 ng of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(N-methylmethylsulfonamido)benzoic acid via 172 Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4-chloro-3 (pyridin-2-yl)phonyl)-4-(N-methylmethylsulfonamido)benzamide. MS (QI) 416.3 (M) 5 Example 176 2-brono-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide C1 HN Br - 0 0 1.2 g of 2-bromo-4-methylbenzoic acid was brominated via Procedure N. 100 mg of 4-chloro-3 10 (pyridin-2-yl)anilinc was coupled to 160 mg of 2-brono-4-(bromonethyl)benzoic acid via Procedure E. 213 ng of 2-bromo-4-(broniometliyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamnide was reacted via Procedure 0 to give 2-bromo-N-(4-hloro-3-(pyiidin-2-yl)phenyl)-4 (methylsulfonylmethyl)benzamide which was purified by reverse phase HPLC to afford pure 2 bromo-N-(4-chloro-3-(pyridin-2-yl)pheny)-4-(methylsulfonylmethyl)bcnzamide. MS (Q]) 481.2 15 (M),'. Example 177 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)-N-(4-chloro-3-(pyridin-2 yI)phenyl )bcnzamide 20 CI N 0 HN / 0 HN, N 500 ng of methyl 4-(broniomethyl)benzoate was reacted with 4H-1,2,4-triazole-3-thiol via Procedure Q. 542 ng of methyl 4-((4H- 1,2,4-triazol-3-yithio)nthyl)benzoate was subsequently 25 reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4H-1,2,4-triazol-3 173 ylsulfinyl)methyl)benzoate and methyl 4-((4H-1,2,4-triazol-3-ylsulfonyl)methvl)benzoate. The mixture of 467 mg was hydrolyzed via Procedure M to give 4-((4H-1,2,4-triazol-3 ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid. 107 mg of the mixture of 4-((4H- 1,2,4-triazol-3-ylsulfinyl)rethyl)bcnzoic acid and 4-((4H- 1,2,4-triazol-3 5 ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was seperated on reverse phase HPLC to give 4-((4H-1,2,4-triazol-3 ylsulfinyl)methyl)-N-(4-chloro-3-(pyridin-2-y)phenyl)benzamide. MS (Ql) 438.1 (M). 10 Example 178 4-((4H-1,2,4-triazol-3-ylsulfonyl)methyl)N-(4-chloro-3-(pyridin-2-y)pheny) benzamide Cl HN0 / 0 HN, N 15 107 mg of a mixture of 4-((4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoic acid and 4-((4H-1,2,4 triazol-3-ylsulfonyl)mcthyl)bcnzoic acid was coupled to 75 ng of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was seperated on reverse phase HPLC to give 4-((4H-1,2,4-triazol 3-ylsulfonyl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phcnyl)benzamide. MS (Ql) 454.3 (M)*. Example 179 N-(4-clloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H-1,2,4-triazol-3-vlsulfinyl) methyl)benzamide CI HN \/ \ N- N 174 500 mg of methyl 4-(broniomethyl)benzoate was reacted with 4-methyl-4H-1,2,4-triazole-3-thiol via Procedure Q. 804 mg of methyl 4-((4-imethiyl-4H-1,2,4-triazol-3-ylthio)metliyl)benzoate was subsequently reacted via Procedure R to give an approximate 1:9 mixture of methyl 4-((4-methyl 5 4H-1,2,4-triazol-3-ylsulfinyl)methyl)benzoate and methyl 4-((4-nethyl-4H-1,2,4-triazol-3 ylsulfonyl)methyl)benzoate. The mixture of 740 mg was hydrolyzed via Procedure M to give 4 ((4-methyl-4H-1,2,4-triazol-3-y1sulfinyl)miethy1)benzoic acid and 4-((4-methyl-4H-1,2,4-triazol-3 ylsulfonyl)methyl)benzoic acid. 114 mg of the mixture of 4-((4-methyl-4H-1,2,4-triazo-3 ylsulfinyl)methyl)benzoic acid and 4-((4-metliyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid 10 was coupled to 75 mg of 4-chloro-3-(pyridin-2-yl)aniline via Procedure G. The mixture was seperated on reverse phase HPLC to give N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((4-methyl-4H 1,2,4-triazol-3-ylsulfinyl)methyl)benzamide. MS (QI) 452.3 (M)*. 15 Example 180 N-(4-cloro-3-(pyridin-2-yl)pIeny1)-4-((4-metliyl-4H-1,2,4-triazol-3-ylsulfonyl) methyl)benzamide C1 \ N 0 HN / 0 S-:0 N 20 114 mg of the mixture of 4-((4-methyl-4H-1,2.4-triazol-3-ylsulfinyl)ncthyl)benzoic acid and 4-((4 methyl-4H-1,2,4-triazol-3-ylsulfonyl)methyl)benzoic acid was coupled to 75 mg of 4-chloro-3 (pyridin-2-yl)aniline via Procedure G The mixture was separated on reverse phase HPLC to give N-(4-chlioro-3-(pyridin-2-yl)pheny1)-4-((4-metiyl-4H- I 2,4-triazol-3-ylsulfonyl)methyl)beiizamide. MS (Q 1) 468.1 (M), 25 Example 181 N-(4-clIoro-3-(pyridin-2-yl)pIeiyl)-3-(methylsulfonylniethyl)benzamide 175 Cl \ N 0 HN 0 300 mg of methyl 3-(bromonethyl)benzoate was reacted via Procedure 0 to give methyl 3 (methylsulfonylmethyl)benzoate. 230 rng of methyl 3-(mnethylsulfoiiylmethyl)beiizoate was 5 acted via Procedure M to give 3-(mcthylsulfonylmcthyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 3-(methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield pure N-(4 chloro-3-(pyridin-2-yl)phenyl )-3-(methylsulfonylmethyl)benzamide. MS (QI) 401 (M). 10 Example 182 N-(4-ebloro-3-(pyridin-2-yl)pbenyl)-2-methoxy4 (methylsulfonylnethyl)benzamide Cl HN 0 / \ St-O 15 900 ng of 2-methoxy-4-mcthylbenzoic acid was brominated via Procedure N to afford 4 (bromomethyl)-2-methoxybenzoic acid. 100 mg of 4-clloro-3-(pyridin-2-yl)aniline was coupled to 132 mg of 4-(bromomethyl)-2-methoxybenzoic acid via Procedure E. 211 mg of 4-(bromomethyl) N-(4-chloro-3-(pyridin-2-yl)phyivl)-2-methoxybenzamide was reacted via Procedure 0 and 20 purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methoxy-4 (methylsulfonylmethyl)benzamide. MS (Q1) 431 (M)'. Example 183 N-(4-chloro-3-(pyridin-2-yl)phcnyl)4-(1 -(mcthylsulfonyl)cthyl)benzamide 25 176 CI HN / 0 s=o 75 mg of 4-chloro-3-(pyiidin-2-yl)aniline was coupled to 93 mg of 4-(1-bromoethyl)benzoic acid via Procedure E. 153 ing of 4-(I-bromocthyl)-N-(4-chloIo-3-(pyridin-2-yl)phoiiyl)benzanide was reacted via Procedure 0 and purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin 2-yl)phcnyl)-4-(1-(methiylsulfonyl)ethyl)bcnzamide. MS (QI) 415.3 (M)-. Example 184 ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzyl(methyl)phosphinatc 10 CI HNN P-0 I \ 90 mg of 4-(bromomethyl)-N-(4hloro-3-(pyridin-2-yl)phenyl)benzamide was reacted with 45 fL of diethyl methylphosphonite in the microwave at 120"C for 5 minutes. The reaction was 15 evaporated to dryness and purified by reverse phase HPLC to give pure ethyl 4-(4-chloro-3 (pyridin-2-yl)phenylcarbanoyl)benzyl(nethyl)phosphinate. MS(QI)429(M). Example 185 N-(4-chloro-3-(5-(hydroxymcthyl)pyridin-2-yI)phenyl)4-(mcthylsulfony 20 methyl)benzamide 177 cl HN / \ S=0 75 mL of (5-netliylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-cliloro-2-iodo-4 nitrobenzene via Procedure B, To 935 mg of 2-(2chloro-5-nitrophenyl)-5-methylpyridine in 5 ml, 5 of Sulfuric Acid was slowly added 2.25 g of Chromium (111) Oxide and the reaction was stirred for several hours at room temperature until complete, Icewater was added to dilute the reaction and the aqueous layer was ext-acted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 6-(2-chloro-5 nitrophenyl)nicotinic acid. 704 mg of 6-(2-chloro-5-nitrophenyl)nicotinic acid was esterified with 10 3.1 mL of 4N HCI in Dioxane in 20 mL of MeOH. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 6-(2-chloro 5-nitrophenyl)nicotinate. 681 mg of methyl 6-(2-chloro-5-nitrophenyl)nicotinatc was treated with 2.1 g of Tin (11) Chloride and I mL of HCI in 25 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease 15 emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 6-(5-anino-2-chlorophenyl)nicotinate. 296 mg of methyl 6-(5-amino-2 chlorophenyl)nicotinate was coupled to 266 mg of 4-(methylsulfonylmethvl)benzoic acid via Procedure G. To 518 mg of methyl 6-(2-chloro-5-(4 (methylsulfonylmethyl)bcnzamido)phenyl)nicotinate at O"C in 20 mL of EIOH was slowly added 20 640 mg of Sodium Borohydride. The reaction was subsquently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4 chloro-3-(5-(hydroxymcthyl)pyridin-2-yl)phenyl)4(mthylsulfonynethyl)benzamide. MS (Ql) 431.1 (M). 25 Example 186 6-(2-hloro-5-(2-mcthyl-6-(trifluoromcthyl)nicotinamido)phenyl)nicoinate 178 C1 -O~' O HN / \N F F F 200 mg of methyl 6-(5-amino-2-clilorophenyl)nicotinate was treated with 255 JAL of 2-methyl-6 (trifluoromethyl)nicotinoyl chloride via Procedure D and purified by reverse phase HPLC to give 5 pure 6-(2-clloro-5-(2-metlyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate. MS (Q1) 450 (M)I Example 187 N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-2-methyl-6 10 (trifluoromethyl)nicotinamide C HO O HN \ N F F F To 110 mg of methyl 6-(2-chloro-5-(2-methyl-6-(trifluoromethyl)nicotinamido)phenyl)nicotinate at 15 0"C in 5 mL of EtOH was slowly added 148 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxyinethyl)pyridin-2-yl)phenyl)-2 methyl-6-(trifluoromethyl)nicotinamide. MS (Ql) 422.1 (M)'. 20 Example 188 N-(4-chloro-3-(5-(nethylcarbamoyl)pyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotinamide 179 cl 0 - 0 HN / \N F F F 120 mg of 6-(2-chloro-5-(2-methyl-6-(trifluoroiiethy1)nicotinamido)pienyl)nicotinate was hydrolyzed via Procedure M. 112 mg of 6-(2-chloro-5-(2-mcthyl-6 5 (trifluoromethyl)nicotinamido)phenyl)nicotinic acid was coupled to Methylamine Hydrochloride via Procedure G and purified by reverse phase .HPLC to give pure N-(4-chloro-3-(5 (methylcarbamoyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoroiethyl)nicotinamide. MS (Ql) 449 (M). 10 Example 189 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,2,2 trifluoroethylamino)methyl)benzamide. CI HN C N 'H F -F F 15 To 24.9 g of 2-chloro4-(methoxycarbonyl)bcnzoic acid and 2 mL of Sulfuric Acid in 350 nlL of DCM was added isobutylene gas at -78"C until the solvent was saturated and capped off securely. Let go several days at room temperature and re-cool to -78"C before removing cap. Concentrate solvent, extract with Ethyl Acetate and bicarbonate, dry with Magnesium Sulfate, filter and 20 concentrate to give 31.4 g of 1-rert-butyl 4-methyl 2-chlorotercphthalate. 3.35 g of 1-rert-butyl 4 methyl 2-chloroterephthalate was hydrolyzed via Procedure M. 2.5 g of 4-(tert-butoxycarbonyl)-3 chlorobenzoic acid was was cooled to O'C in 25 mL of THF before a solution of 19.5 mL of IM

BH

3 -THF complex in THF was added dropwise. The ice bath was subsequently removed and the reaction was stirred at room temperature until reaction stalled out at -50% complete by TLC. The 25 reaction is re-cooled to O'C and another 19.5 mL of BH-THF is added dropwise before the ice Is bath is removed. Upon completion, the reaction is re-cooled to O"C and quenched with 3N HCI dropwise. The aqueous layer was extracted two times with Ethyl Acetate and the organic layer was then extracted once with bicarbonate solution and brine, dried over Magnesium Sulfate, filtered and concentrated to give tert-butyl 2-chloro-4-(hydroxyimethyl)benzoate. 564 ing of Jert 5 butyl 2-chloro-4-(hydroxymethyl)benzoate was cooled to O'C in 5 mL of DCM before adding 665 mg of Triphenylphosphine and 417 mg of NBS. Reaction was concentrated and directly purified via ISCO Conbi-Flash to give pure tert-butyl 2-chloro-4-(hydroxymethyl)benzoate. 147 rng of tert-butyl 4-(bromonethyl)-2-chlorobenzoate was reacted with 2,2,2-trifluoroethanamine in DMSO via Procedure P. 141 mg of iert-butyl 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)benzoate was 10 treated with 4N HCI in Dioxane at 45"C and concentrated to give 2-chloro-4-((2,2,2 trifluoroethylamino)methyl)benzoic acid. 50 mg of 4-cliloro-3-(pyridin-2-yl)aniline was coupled to 75 mg of 2-chloro-4-((2,2,2-trifluoroethylamino)methyl)bcnzoic acid via Procedure G . The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloro-3-(pyridin-2 yl)phcnyl)-4-((2,2,2-trifluoroethylamino)methyl)benzanide. MS (QI) 454.6 (M)-. 15 Example 190 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide CI HN Cl 0 20 3.01 g of teri-butyl 4-(broinomethyl)-2-chlorobenzoate was reacted via Procedure 0 to give tert butyl 2-chloro-4-(methylsulfonylmethyl)bcnzoate. 1.2 g of Ierl-butyl 2-chloro-4 (methylsulfonyliethy1)benzoate was treated with 10 mL of 4N HCI in Dioxane at 45"C and concentrated upon completion to give crude 2-chloro4-(mcthylsulfonylnethyl)benzoic acid. 775 ig of 4-chloro-3-(pyridin-2-yl)aniline was coupled to I g of 2-chloro-4 25 (methylsulfonylmethyl)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to give pure 2-chloro-N-(4-chloio-3-(pyidin-2-yl)phenyl)4 (methylsulfonyhncthyl)bnzamnide. MS (Q1) 435 (M)t 30 Example 191 N-(4-clloro-3-(pyridin-2-yl)pheny1)-6-(methylsulfonamido)nicotinaiide i81 C1 N N 0 / 'N

HN

100 mg of 6-clor-N-(4-chloro-3-(pyiidin-2-yl)phenyl)nicotinainide was reacted with methanesulfonamide and 108 ltL of 2-Ieri-Butylimino-2-diethylamino-1,3-dimcthyl-pcrhydro 5 1.3,2-diazaphosphorine via Procedure F. The crude reaction was concentrated to dryness and purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-6 (methylsulfonamido)nicotinanide. MS (Q1) 403 (M). 10 Example 192 4-((IH 1,2,4-triazol-1-yl)mcthyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzanide C1 \' / \ N 0 F\ = 88 mg of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 45 mg 15 of IH-1,2,4-triazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield 4-((IH-1,2,4-triazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2 yI)phcnyl)benzamidc. MS (QI) 390 (M)~. 20 Example 193 4-(( IH-1,2.3-triazol-1-yl)metiyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide 182 Ci \// \ NNN FII 88 ig of 4-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 40 pL of IH-1,2,3-triazole via Procedure P. The reaction was evaporated to dryness and purified by reverse 5 phase HPLC to yield 4-((IH-1,2,3-triazol-1-yl)metliyl)-N-(4-chloro-3-(pyridin-2 yl)phcnyl)benzanide. MS (QI) 390.1 (M). Example 194 N-(4-chloro-3-( pyridin-2-yl)phenyl)-4-((3,5-dimethyl-1H-pyrazol-1 10 yl)methyl)benzamide C1 N 0 HN N 70 mg of 4-(bronometliyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide was coupled to 50 mg of 15 3,5-dimethyl-lH-pyrazole via Procedure P. The reaction was evaporated to dryness and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((3,5-dimetliyl-] H-pyrazol 1-yl)ncthyl)benzamidc. MS (Ql) 417.3 (M)'. 20 Example 195 4-((1 H-pyrazol-l -yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide 183 C HN 70 Ing of 4-(bromonethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzanide was coupled to 36 Ing of 1H-pyrazole via Procedure P. The reaction was evaporated to dryness and purified by reverse 5 phase HPLC to yield 4-((IH-pyrazol-1-yl)methyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (Q1) 389.3 (M)-. Example 196 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonylmethyl)nicotinamide 1o C1 HN-J N 0 1.2 g of 6-methylnicotinic acid was brominated via Procedure N to give 6-(brornomcthyl)nicotinic acid. 75 mg of 4-cbloro-3-(pyridin-2-yl)aniline was coupled to 87 mg of 6-(bromiomethyl)nicotinic 15 acid via Procedure E. 145 mg of 6-(bromomethyl)-N-(4-chloro-3-(pyridin-2 yl)phenyl)nicotinainde was reacted via Procedure 0 and purified by reverse phase HPLC to yield pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(nethylsulfonylmethyl)nicotinamide. MS (Ql) 402 (M)". 20 Example 197 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(N-hydroxycarbamimidoyl)benzamide 184 C1 HN NH HN OH 240 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 207 ng of 4-cyanobcnzoic acid via 5 Procedure G. To 445 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide and 2.5 mL of DIPEA in 10 niL of EtOH was added 793 mg Hydroxylamine Hydrochloride and heated to 60"C until reaction was complete. The solvent was subsequently evaporated, extracted twice with water in Ethyl Acetate, dried with Magnesium Sulfate, filtered and concentrated. The crude product was purified by reverse phase HPLC to give pure N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N 10 hydroxycarbamimidoyl)benzamide. MS (QI)367.4 (M). Example 198 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-methoxycarbamimidoyl)benzamide C1 HN NH 15 HN 0 100 mg of N-(4-chloro-3-(pyridin-2-vl)plhenyl)-4-(N-hydroxycarbaimiidoyl)beiizamiide was cooled to 0"C in 1.5 ml- of Dioxanc. 5 mL of 2N NaOH was slowly added followed by dropwise addition of 33 piL of dimethylsulfate. The ice bath was removed and reaction was stined at room 20 temperature for I hour. The reaction was subsequently evaporated and extracted with water twice in Ethyl Acetate, dried with Magnesium Sulfate, filtered and concentrated to yield pure N-(4 chloro-3-(pyridin-2-yl)phenyl)-4-(N-methoxycarbamimnidoyl)bcnzamidc. MS (QI) 381 (M). 25 Example 199 N-(4-chloro-3-(4-(hydroxymetliyl)pyridin-2-yl)phenyl)-2-methyl-6 (trifluoromethyl)nicotin amide 185 HO0 Cl HN / N F F F 75 mL of (4-mcthylpyridin-2-yl)zinc(U) bromide was reacted with 4 g of 1-chloro-2-iodo-4 5 nitrobenzene via Procedure B. To 300 mg of 2-(2-cbloro-5-nitrophenyl)-4-methylpyridine in 1.5 mL of Sulfuric Acid was slowly added 362 mg of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 2-(2-chloro-5 10 nitrophenyl)isonicotinic acid. 300 mg of 2-(2-chloro-5-nitrophenyl)isonicotinic acid was esterified with 750 pL of 4N HCI in Dioxane in 10 mL of MeOH at 55"C for 16 hours. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 2-(2-chloro-5-nitrophenyl)isonicotinate. 259 mg of methyl 2-(2 chloro-5-nitrophenyl)isonicotinate was treated with 200 ing of Tin (11) Chloride and 500 pL of HCI 15 in 10 mL of EtOi. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 2-(5-amino-2 chloroplienyl)isonicotinate. 240 mg of methyl methyl 2-(5-amino-2-chlorophenyl)isonicotinate was treated with 204 pL of 2-methyl-6-(trifluoromethyl)nicotinoyl chloride via Procedure D. To 20 100 mg of methyl 2-(2-chloro-5-(2-metliyl-6-(trifluoromethyl)nicotinamido)phenyl)isonicotinate at O'C in 5 mL of EtOH was slowly added 135 mg of Sodium Borohydride. The reaction was subsquently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(4-(hydroxymethyl)pyridin-2-yl)phenyl)-2 25 methyl-6-(trifluoromethyl)nicotinamide. MS (QI) 422.1 (M). Example 200 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylamide)benzamide 186 cl N/ \

IN

- 0 N-kIO 300 ing of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 270 mg of 4-nitrobenzoic acid via Procedure G. To 520 mg of N-(4-chloro-3-(pyidin-2-yl)phenyl)4-nitrobenzamide in 2.5 mL of 5 HCI in 10 mL of EtOlH was added 1.3 g of Tin (11) Chloride and stirred at 55"C. Upon completion, the reaction was concentratd and extracted with Ethyl Acetate in water with TEA to reduce emulsions. The organic layer was dried over Magnesiun Sulfate, filtered and concentrated to give 4-amino-N-(4-chlow-3-(pyridin-2-yl)phcnyl)bcnzamide. 100 ng of 4-amiuoN-(4-chloro-3 (pyridin-2-yl)phenyl)benzamide was reacted with 30 sL of Methanesulfonyl Chloride and 90 pL 10 DIPEA in 500 pL DCM. The reaction mixture was evaporated, subjected to basic workup conditions and purified by reverse phase HPLC to yield N-(4-chloio-3-(pyridin-2-y1)pheny1)-4 (methylsulfonylamnidc)benzamidc. MS (Q1) 402 (M)-. 15 Example 201 N-(4-clloro-3-(pyridin-2-yl)plieny)-4-( I -methylethylsulfonamido)benzamide CI CNF 0 HN -- o HN-rC 151 mg of 4-amino-N-(4-cltoro-3-(pyridin-2-yl)pbenyl)benzanide was reacted with 105 pL of 20 propane-2-sulfonyl chloride and 205 pL DIPEA in 500 pL DCM. The reaction mixture was evaporated, subjected to basic workup conditions and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(1-nethylethylsulfonamido)benzamide. MS (QI) 430(M)'. 25 Example 202 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonymethyl)bcnzamide 187 Cl HN-4 \/ \/ \ -IN 0 I g of methyl 4-(bromomethyl)benzoate was reacted via Procedure 0. 2.77 g of methyl 4 S (methylsulfonylmethyl)benzoate was hydrolyzed via Procedure M. Ig of 4-chloro-3-(pyridin-2 yl)aniline was coupled to 1.15 g of 4-(methylsulfonylmethy1)benzoic acid via Procedure G. The crude product was subjected to basic workup and recrystallized with 1:1 Ratio of Isopropylacetate and Ether to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)bnzamide. MS (Q1) 401 (M). 10 Example 203 4-(4-acetylpiperazin-1-ylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide CI HNN I-IN 0 15 1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 646 pL of 1-(piperazin-1-yl)cthanone via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of 4-(4 acetylpiperazin-1-ylsulfonyl)bcnzoic acid via Procedure G and purified by reverse phase HPLC to yield 4-(4-acetylpiperazin-1-ylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS(QI) 20 499.4(M)-. Example 204 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazin-1 ylsulfonyl)benzamide 25 l 88 CI \/"N/ 0 HN -N OH I g of 4-(chlorosulfonyl)bcnzoic acid was reacted with 615 gL of 2-(pipcrazin-1-yl)ethanol via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of 4-(4-(3 5 hydroxypropyl)piperazin-1-ylsulfonyl)benzoic acid by Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazin-1 ylsulfonyl)benzamide. MS (Q1) 501.3 (M)'. 10 Example 205 N-(4-clloro-3-(pyridin-2-yl)plieny1)-4-(4-hydroxypiperidin-I ylsulfonyl)benzanide CI

HN

/'\ NN 0 15 1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 506 lL of piperidin-4-ol via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 114 mg of 4-(4-hydroxypiperidin-1 ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro 3-(pyridin-2-yI)phenyl)-4-(4-hydroxypiperidin-1-ylsulfonyl)benzamide. MS (Q1) 472.3 (M). Example 206 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(2,6 dinethylmorpholinosulfonyl)benzanide t89 Cl HN .-S--N 0 1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 616 pl, of 2,6-dimuethylmorpholine via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 120 mg of 4-(2,6 5 dimethylinorpholinosulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phcnyl)4-(2,6-dimcthylmorpliolinosulfonyl)benzamide. MS (QI) 486.3 (M). In Example 207 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3,5-dimethylpipcrazin-l ylsulfonyl)benzamide Cl HN O-N NH_ 0 15 1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of 2,6-dinethylpiperazinc via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 119 mg of 4-(3,5 dinethylpiperazin-1-ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-cliloro-3-(pyridin-2-yl)plienyl)-4-(3,5-diiethylpiperaziii-1-ylsulfonyl)benzainide. MS (QI) 485.4 (M) 20 Example 208 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazin-I -ylsulfonyl)benzamide 190 CI ' N 0 HN o<h-N N-/ I g of 4-(chlorosulfonyl)benzoic acid was reacted with 570 mg of 1-ethylpiperazine via Procedure H. 75 mg of 4-chlioro-3-(pyridin-2-yl)aniline was coupled to 4-(4-ethylpiperazin-1 5 ylsulfonyl)benzoic acid via Procedure G and purified by reverse phase HPLC to yield N-(4-chloro 3-(pyridin-2-yl)phenyl)-4-(4-ethylpiperazin-1-ylsulfony). MS (QI ) 485 (M)'. Example 209 N-(4-cbloro-3-(pyridin-2-yl)plicnyl)-4-(piperazin-1-ylsulfonyl)benzamide 10 CI HN OS-N NH 0 1 g of 4-(chlorosulfonyl)bcnzoic acid was reacted with 931 mg of ter-butyl pipcrazine-l carboxylate via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 150 mg of 15 4-(4-(Uer-butoxycarbonyl)piperazin- I -ylsulfonyl)bcnzoic acid via Procedure G. The crude product was subjected to basic workup conditions, treated with TFA to remove the Boc group and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pipcrazin- I ylsulfonyl)benzamide. MS (Ql) 457.1 (M)'. Example 210 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(N-(2,2,2 trifluoroethyl)sulfamoyl)benzamide 19t Cl N\ HN F S-NH F 0 1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 500 pL of 2,2,2-trifluoroethananine via Procedure H. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 92 mg of 4-(N-(2,2,2 5 trifluoroethyl)sulfamoyl)benzoic acid by Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)plheyl)-4-(N-(2,2,2-trifluoroethyl)sufamoy)benzamide. MS (Q1) 470 (M)-. 10 Example 211 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-sulfamoylbenzamide Cl HN- CI oS-NH 2 0 A solution of 818 mg of Sodium Nitrite in 13 mL of water was added dropwise to a solution of 2g 15 of methyl 4-amino-2-chlorobenzoate in 5 mL of HCI and 15 mL of AcOH at 0"C. The reaction was removed from the ice bath and stirred at room temperature for 15 minutes. Simultaneously a solution of 460 mg of Copper 11 Chloride Dihydrate in I mL of water was added to a saturated solution of sulfur dioxide gas in 10 mL of AcOH at 0"C. The cooled solution containing Copper II Chloride and sulfur dioxide gas was slowly added to the re-cooled initial solution containing 20 Sodium Nitrite. The reaction was wanted to room temperature and stirred until gas no longer evolved. The reaction was filtered through celite and poured into a beaker of stirred icewater until a yellow-orange solid crashed out. The icewater solution was filtered thru a Buchner funnel to collect the methyl 2-chloro4-(chllorosulfonyl)benzoate precipitate and was dried for 24 hours under vacuum. Ig of methyl 2-chloro-4-(chlorosulfonyl)benzoate was added to a solution of 2 niL 25 of 2M solution of Ammonia in MeOH and 970 dL DIPEA in 5 nL MeOH. Upon completion the 192 reaction was concentrated, extracted twice with saturated bicarbonate, dried with Magnesium Sulfate, filtered and concentrated to give methyl 2-chloro-4-sulfamoylbenzoate. 777 mg of methyl 2-clhloro-4-sulfamoylbenzoate was hydrolyzed via Procedure M to yield crude 2-chloro-4 sulfamoylbenzoic acid. 75 mg of 4<hloro-3-(pyridin-2-yl)aniline was coupled to 91 mg of crude 5 2-chloro-4-sulfamoylbernzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheny1)4sulfamoylbenzamide. MS (QI) 422 (M)'. 10 Example 212 N-(4-chloro-3-(pyridin-2-yl)phenyl)4(piperidin-4-ylmethyl)benzamide Cl HN NH 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 125 mg of 4-((1-(ter butoxycarbonyl)piperidin-4-yl)metlyl)benzoic acid via Procedure G. The crude product was treated with 4N HCI in Dioxane, evaporated and purified by reverse phase HPLC to yield N-(4 15 chloro-3-(pyridin-2-yl)phenyl)-4-(piperidin-4-ylmethyl)benzaiide. MS (QI) 406.1 (M)'. Example 213 2-chloro-.N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methy1sulfonamido)benzamiide C HN CI HN-4 20 0 4.2 g of methyl 2-chloro-4-(methylsulfonamido)benzoate was hydrolyzed via Procedure M. I g of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1.35 g of 2-chloro-4-(mcthylsulfonamido)benzoic acid via Procedure G. The crude product was purified by reverse phase HPLC to yield 2-chloro-N 25 (4<hloro-3-(pyridin-2-yl)phinyl)-4-(inethylsulfonamido)benzamide. MS (QI) 436.1 (M)-. 193 Example 214 N(4-chloro-3-(pyridin-2-yl)phenyl)-4-(IH-imidazol-1-yl)benzamide CI \//\\ N 0 N N 5 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 78 ng of 4-(IH-imidazol-l-yl)benzoic acid via Procedure G . The crude product was purified by reverse phase HPLC to yield N-(4 chloro-3-(pyridin-2-yl)phenyl)4-(IH-imidazol-1-yl)benzaniide. MS(QI)375.3(M)'. In Example 215 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2 methylpropylsulfonyl lbenzamide C1 \/ \4 - OH 0 15 8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 niL of concentrated hydrochloric acid and was then cooled to 0 C. A solution of 3.9 g of sodium nitrite in 15 mL of H 2 0 was added dropwise over 30 min. The reaction was stirred at 0 "C for an additional ih. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H 2 O at 50-60 "C. The reaction was heated to 65 "C for 2h and monitored by 20 TLC until complete. The mixture was cooled to 25 "C and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO 4 ), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetare/hexane) to afford methyl 2-chloro-4 (etlioxycarbonothioyltliio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of HoO was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The 25 action mixture was heated to 70 'C for lh. Upon completion, the mixture was cooled to 25 'C, 194 and then acidified to pH 3 by the addition of 10 N HCL. The solid was filtered and washed with HO to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3h. After concentration of the reaction mixture, 10 mL of HO was added and the resulting mixture was 5 made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4 mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4 mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2 methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2 10 methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2 methylpropylthio)benzoic acid. 160mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-mcthylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4- (2-hydroxy-2 methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase 15 :HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2 methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)t. Example 216 (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2 20 phenylethylsulfonyl)benzamide C1 HN C1 HN- I HO -i 1 04 150 mg of (R)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxy-2-penylethiylthio)benzoate. 190 mg of (R)-methyl 25 2-cliloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (R)-2 chloro-4-(2-hydroxy-2-phenylethylthio)bcnzoic acid. 170 mg of (R)-2-chloro-4-(2-hydroxy-2 phenylethylthio)beuzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2-hydroxy-2 phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R 2-cIloro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure G. The product was 30 purified on reverse phase HPLC to yield (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2 hydroxy-2-phenylethylsulfonyl)benzamide. MS (QI) 527.2 (M) 195 Example 217 (S)-2-cliloro-N-(4-cliloo-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-phenylethyl sulfonyl)bcnzamide C1 HN- Cl / HO 0 119 mg of (S)-styrene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (S)-methyl 24hloro-4-(2-iydroxy-2-phenylethylthio)bnzoate. 230 mg of (S)-methyl-2 10 chloro-4-(2-hydroxy-2-phenylethylthio)benzoate was hydrolyzed via Procedure M to give (S)-2 chloro-4-(2-hydroxy-2-phenylethylthio)benzoic acid. 180 ng of (S)-2-chloro-4-(2-hydroxy-2 phenylethylthio)benizoic acid was reacted via Procedure R to give (S)-2-chloro-4-(2-hydroxy-2 phenylethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S) 2-cIoro-4-(2-hydroxy-2-phenylethylsulfonyl)benzoic acid via Procedure 0. The product was 15 purified on reverse phase HPLC to yield (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2 hydroxy-2-phenylethylsulfonyl)benzamide. MS (QI) 527.0 (M). Example 218 (R)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl) 20 benzamide C1 \N 0 HN I HO

S

0 140 mg of (R)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford (R)-methyl 2-chloro-4-(2-hydroxypropylthio)benzoate. 435 mg of (R) 25 metbyl-2-chloro-4-(2-hydroxypropylthio)benzoate was hydrolyzed via Procedure M to give (R)-2 196 chloro-4-(2-hydroxypropylthio)benzoic acid. 403 mg of (R)-2-chloro-4-(2 hydroxypropylthio)benzoic acid was reacted via Procedure R to give (R)-2-chloro-4-(2 hydroxypropylsulfonyl)benzoic acid. 298 img of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (R)-2-chloro-4-(2-hydroxypropylsulfonyl)bcnzoic acid via Procedure G. The product was purified 5 on reverse phase HPLC to yield (R)-2-chloro-.N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2 hydroxypropylsulfonyl)benzamide. MS (QI) 465.1 (M). Example 219 (S)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl) 10 benzamide C1 HN Cl / \ -l O 0 86 mg of (S)-propylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure 15 S to afford (S)-methyl 2-chloro4-(2-hydroxypropylthio)benzoate. 275 ing of (S)-inethyl-2-chloro 4-(2-lydroxypropylthio)bcnzoate was hydrolyzed via Procedure M to give (S)-2-chloro-4-(2 hydroxypropylthio)benzoic acid. 220 mg of (S)-2-chloro-4-(2-hydroxypropyltiio)benzoic acid was acted via Procedure R to give (S)-2-chloro-4-(2-hydroxypropylsulfonyl)beiizoic acid. 70 ng of 4-chloro-3-(pyridine-2-yl)aniline was coupled to (S)-2-chloro-4-(2-hydroxypropylsulfonyl)benzoic 20 acid via Procedure G. The product was purified on reverse phase HPLC to yield (S):2-chloro-N (4-clioro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamnide. MS (QI) 465.0 (M)' Example 220 (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hiydroxypropylsulfonyl)benzamide Cl HN HO 25 0 197 100 mg of (R)-propylene oxide was reacted with methyl 4-mercaptobeinzoate via Procedure S to afford (R)-methyl 4-(2-liydroxypropylthio)benzoate. 169 rug of (R)-methyl 4-(2 hydroxypropylthio)benzoatc was reacted via Procedure R to give (R)-methyl 4-(2 5 hydroxypropylsulfonyl)benzoate. 179 mg of (R)-methyl 4-(2-hydroxypropylsulfonyl)benzoate was hydrolyzed via Procedure M to give (R)4-(2-iydroxypropylsulfonyl)bcnzoic acid. 45 mg of 4 chloro-3-(pyridine-2-yl)aniline was coupled to (R)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (R)-N-(4-chloro-3 (pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzanide. MS (Ql) 431.2 (M)*. 10 Example 221 (S)-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(2-hydroxypropylsulfonyl)bcnzamide Cl \N 0 HN HO 0 15 150 mg of (S)-propyine oxide was reacted with methyl 4-mcrcaptobenzoate via Procedure S to afford (S)-methyl 4-(2-hydroxypropylthio)benzoate. 650 mg of (S)-methyl 4-(2 hydroxypropylthio)benzoate was reacted via Procedure R to give (S)-methyl 4-(2 hydroxypropylsulfonyl)benzoate. 350 mg of (S)-mcthyl 4-(2-hydroxypropylsulfonyl)bcnzoate was hydrolyzed via Procedure M to give (S)-4-(2-hydroxypropylsulfonyl)benzoic acid. 45 mg of 4 20 chloro-3-(pyridine-2-yl)aniline was coupled to (S)-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield (S)-N-(4-chloro-3 (pyridin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzaniide. MS (Ql) 431.3 (M)'. 25 Example 222 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide 198 CI N 0 HN N oog 0 Ig of 3-(bromorncthyl)pyridine hydrobronide was reacted with methyl 4-mercaptobenzoatc via Procedure Q to afford methyl 4-(pyridin-3-ylmethylthio)benzoate. 980 mg of methyl 4-(pyridin-3 5 ylmethylthio)bcnzoatc was reacted via Procedure R to give methyl 4-(pyridin-3 ylmethylsulfonyl)benzoate. 760 mg of methyl 4-(pyridin-3-ylnethylsulfony)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-3-ylmethylsulfonyl)benzoic acid. 60 mg of 4 chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-3-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2 10 yl)plienyl)-4-(pyridin-3-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)'. Example 223 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(pyridin-2-ylnethylsulfonyl)benzamide Cl \N 0 HN IS 0 Ig of 2-(bromorncthyl)pyridine hydrobromnide was reacted with methyl 4-mcrcaptobenzoate via Procedure Q to afford methyl 4-(pyridin-2-ylmethylthio)benzoate. 500 mg of methyl 4-(pyridin-2 ylmethylthio)benzoate was reacted via Procedure R to give methyl 4-(pyridin-2 20 ylmethylsulfonyl)benzoate. 470 mg of methyl 4-(pyridin-2-ylmethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(pyridin-2-ylmethylsulfonyl)bcnzoic acid. 70 mg of 4 chloro-3-(pyridin-2-yl)aniline was coupled to 4-(pyridin-2-ylmethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPILC to yield N-(4-chloro-3-(pyridin-2 yl)plienyl)-4-(pyridin-2-ylmethylsulfonyl)benzamide. MS (Q1) 464.1 (M)'. 25 199 Example 224 4-(2-amino-2-oxoethylsulfonyl)-N.(4.chloro-3-(pyridin-2-yl)phenyl)benzamide CI HN - NH 2 5 2.5 g of 2-bronioacetamide was reacted with methyl 4-mercaptobenzoate via Procedure Q to afford methyl 4-(2-amino-2-oxocthylthio)bcnzoatc. 2.6 g of methyl 4-(2-amino-2-oxocthylthio)beizoate was reacted via Procedure R to give methyl 4-(2-anino-2-oxoetliylsulfonyl)benzoate. I g of methyl 4-(2-amino-2-oxoethylsulfonyl)benzoate was hydrolyzed via Procedure M to give 4-(2 10 amino-2-oxoetiylsulfonyl)benzoic acid. 150 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-amino-2-oxoethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-amino-2-oxoetlhylsulfonyl)-N-(4-chloro-3-(pyridin-2 yl)phenyl)benzamidc. MS (QI) 430.2 (M). 15 Example 225 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2 hydroxypropylsulfonyl)benzamide C1 Q/ O HN CI HO 20 2 g of 2-chloro4-fluorobenzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 2-chloro-4-(2-hydroxypropylthio)benzonitrile. 2.5 g of 2-chloro-4-(2 hydroxypropylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2 hydroxypropylthio)benzoic acid. 2.1 g of 2-clloro-4-(2-hydroxypropylthio)benzoic acid was 25 acted via Procedure R to give 2-chloro-4-(2-hydroxypropylsulfonyl)bcuzoic acid. 70 mg of 4 200 chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro 3-(pyiidin-2-yl)phenyl)-4-(2-hydroxypropylsulfonyl)benzamide. MS (QI) 465.2 (M) . Example 226 N-(4-chlioro-3-(pyridin-2-yl)phcnyl)4(2-hydroxypropylsulfonyl)-2 methylbenzainde CI HN HO 0 10 2 g of 4-bromo-2-methylbcnzonitrile was reacted with 1-mercapto-2-propanol via Procedure Q to afford 4-(2-hydroxypropylthio)-2-methylbenzonitrile. 950 mg of 4-(2-hydroxypropylthio)-2 nethylbenzonitrile was reacted via Procedure T to give 4-(2-hydroxvpropylthio)-2-methylbenzoic acid. 1.0 g of 4-(2-hydroxypropyltliio)-2-methylbenzoic acid was reacted via Procedure R to give 15 4-(2-hydroxypropylsulfonyl)-2-methylbcnzoic acid. 100 mg of 4-chloro-3-(pyridin-2 yl)aniline was coupled to 4-(2-iydroxypropylsulfony)-2-mcthylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (2-hydroxypropylsulfonyl)-2-methylbenzamidc. MS (Q 1) 445.3 (M)'. 20 Example 227 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxyethylsulfony1)benzamide CI HN OH 0 5 g of 4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 4-(2 25 hydroxycthylthio)bcnzonitrile. 900 mg of 4-(2-hydroxycthylthio)bcnzonitile was reacted via 201 Procedure T to give 4-(2-hydroxyethylthio)benzoic acid. 1.0 g of 4-(2-hydroxyethylthio)benzoic acid was reacted via Procedure R 1o give 4-(2-hydroxyethylsulfonyl)bcnzoic acid. 80 mg of 4 chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2 5 yl)phenyl)-4-(2-hydroxyethylsulfonyl)benzamide. MS (QI) 417.0 (M)*. Example 228 4-(2-( lH-imidazol-l-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2 yl)phenyl)benzamide 10 CI HN o-N 0 4 g of 4-(2-hydroxyethylthio)benzonitrile was reacted via Procedure R to yield 4-(2 15 hydroxyethylsulfonyl)bcnzonitrile. 3.0 g of triphenylphosphine was added to a solution of 2 g of 4-(2-hydroxyethylsulfonyl)benzonitrile and 4.7 g of carbon tetrabromide in dichloromethane at 0 "C. The reaction mixture was allowed to warm to room temperature and stirred for 1ih. The mixture was diluted with dichloromethane, washed with H210, dried (MgSO 4 ) and evaporated. Purified by silica gel chromatography (0-70% ethyl acetate/hexane) to afford 4-(2 20 bromoethylsulfonyl)bcnzonitrile. 250 mg of 4-(2-bromoethylsulfonyl)bcnzonittile was used in Procedure P with imidazole to give 4-(2-(IH-imidazol-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(lH-inidazol-1-yl)cthylsulfonyl)bcnzonitrile was reacted via Procedure T to give 4-2-(1H imidazol-1-yl)ethylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(lH-imidazol-1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was 25 purified on reverse phase HPLC to yield 4-(2-(lH-imidazol-1-y)ethylsulfonyl)-N-(4-chloro-3 (pyridin-2-yl)phenyl)benzamide. MS (Q 1) 467.1 (M). Example 229 4-(2-(IH-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2 30 yl)phcnyl)benzamidc 202 Cl HN 0 250 ing of 4-(2-broioethylsulfonyl)benzonitrilc was used in Procedure P with pyrazole to yield 4 (2-(IH-pyrazole-1-yl)ethylsulfonyl)benzonitrile. 300 mg of 4-(2-(IH-pyrazole-1 5 yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(IH-pyrazole-l yl)ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2 (IH-pyrazole-l-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 4-(2-(IH-pyrazol-1-yl)ethylsulfonyl)-N-(4-chloro-3-(pyridin-2 yl)pbenyl)benzamide. MS (QI ) 467.0 (M). 10 Example 230 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(4-methyl-IH-imidazol-l yl)ethylsulfonyl)benzamide C1 HNN IN is 0 270 mg of 4-(2-bromnocthylsulfonyl)bcnzonitrile was used in Procedure P with 4-methylimidazole to yield 4-(2-(4-methyl-IH-imidazole-1-yl)ethylsulfonyl)benzonitrile. 320 mg of 4-(2-(4-methyl IH-imidazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(4-methyl 20 I H-imidazole-1-yl)ethylsulfonyl)benzoic acid. 70 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(4-methyl-lH-imidazole-I yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(4-methyl-IH-imidazol-I yl)ethylsulfonyl)benzamide. MS (QI) 481.0 (M)'. 25 203 Example 231 N-(4-cloro-3-(pyridin-2-yl)phenyl)-4-(2-(3-methyl-1H-1,2,4-triazol-1 yl)ethylsulfouyl)benzamide. C1 HN /

\

- N' 0 To a stirred suspension of 10 g of thiosenicarbazide in 100 mL of pyridine was slowly added 7.8 ml of acetyl chloride at 0 0 C. The temperature was maintained throughout the addition (0 "C - 4 'C). The reaction mixture was allowed to warn to room temperature and stirred for 16 h. 10 Evaporation gave I-acetyl thiosemicarbazide. The crude I-acetyl thiosemicarbazide was dissolved in 70 mL of MeOH and 12 g of sodium methoxide, and was refluxed for 10 h. The solvent was removed and the residue was dissolved in H,0, then acidified to pH 2 by the addition of IN HCl. The resulting solid was filtered and washed with H 2 0 to give 3-methyl-1,2,4-triazole-5-thiol. t g of 3-iethyl-1,2,4-triazole-5-tliiol was added to a solution of 61 mg of sodium nitrite in 3 il of 15 nituic acid and 6 mL of HO at 0 C. The reaction mixture was stirred for lh at 0 "C, and basified with saturated sodium carbonate and concentrated. The residue was dissolved with MeOH and filtered. The filtrate was evaporated to give 3-mnetiy1-1,2,4-triazole. 230 mg of 4-(2 bromocthylsulfonyl)benzonitrile was used in Procedure P with 3-methyl-1,2,4-triazole to yield 4 (2-(3-methyl-1IH-1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile. 310 mg of 4-(2-(3-methyl-IH 20 1,2,4-triazole-1-yl)ethylsulfonyl)benzonitrile was reacted via Procedure T to give 4-(2-(3-methyl IH-1,2,4-triazole-1-yl)ethylsulfonyl)benzoic acid. 60 mg of 4-hloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-(3-methyl-IH-1,2,4-triazole 1-yl)ethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-(3-methyl-IH- 1,2,4-triazol- I 25 yl)ethylsulfonyl)benzamide. MS (QI) 482.1 (M)'. Example 232 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide 204 CI \N 0 HN / \ H -$ 5 g of 4-fluorobcnzonitrilc was used in Procedure Q with 3-mercapto-l-propanol to afford 4-(3 hydroxypropylthio)benzonitrile. 1.8 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via 5 Procedure T to give 4-(3-hydroxypropylthio)benzoic acid. 1.2 g of 4-(3. hydioxypropylthio)benzoic acid was reacted via Procedure R to give 4-(3 hydroxypropylsulfonyl)benzoic acid. 50 ng of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4 (3-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-iydroxypropylsulfonyl)bnzamide 10 MS(Q1)431.3(M)'. Example 233 N-(4-chlIoro-3-(pyridin-2-yl)phcnyl)-4-(2-methoxyethylsulfonyl)benzaniide CI \N 0 HN /O \ -- o Is 0 A mixture of 500 mg of methyl 4-mercaptobenzoatc, 1.6 g of potassium carbonate, 1.2 g of 2 bromoethylethylether and 329 mg of tetrabutylammonium iodide in 10 mL of acetone was refluxed for 16 h1. The reaction mixture was diluted with ethyl acetate, washed with HO and 20 concentrated. Purified by silica gel chromatography (0-50% ethyl acetate/ hexane) to yield 4-(2 mcthoxyethylthio)benzoate. 240 ing of 4-(2-methoxyethylthlio)benzoatc was reacted via Procedure R to give 4-(2-methoxyethylsulfonyl)benzoate. 120 mg of 4-(2-methoxyethylsulfonyl)benzoate was hydrolyzed via Procedure M to yield 4-(2-methoxyethylsulfonyl)benzoic acid. 50 mg of 4 chloro-3-(pyridin-2-yl)aniline was coupled to 4-(2-methoxyetlwlsulfonyl)benzoic acid via 205 Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2 yl)phenyl)-4-(2-methoxyethylsulfonvl)benzamide. MS (QI) 431.0 (M). 5 Example 234 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide C1 HNO OA 0 1 g of 4-fluorobenzonitrile was used in Procedure Q with I-propanethiol to afford 4 10 (propylthio)benzonitrile. 860 mg of 4-(propylthio)benzonitrile was reacted via Procedure T to give 4-(propylthio)bcnzoic acid. 700 mg of 4-(propylthio)bcnzoic acid was reacted via Procedure R to give 4-(propylsulfonyl)benzoic acid. 60 ing of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4 (propylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-cliloro-3-(pyridin-2-yl)phenyl)-4-(propylsulfonyl)benzamide. MS (QI) 415.0 (M)', 15 Example 235 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2 hydroxyethylsulfonyl)bcnzamnidc Cl Q/ 0 20OH 4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-mercaptoethanol to afford 2 chloro4-(2-hydroxycthylthio)benzonitrile. I g of 2<hloro-4-(2-iydroxyethylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(2-hydroxyethylthio)benzoic acid. I g of 2-chloro-4-(2 25 hydroxyethylthio)bcnzoic acid was reacted via Procedure R to yield 2-chloro-4-(2 206 hydroxyethylsulfonyl)benzoic acid. 50 rmg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2 chloro-4-(2-hydroxyethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)plienyl)-4-(2 bydroxyethylsulfonyl)benzamnidc. MS (QI) 451 .O(M)-. Example 236 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3 hydroxypropylsulfonyl)bcnzamide CI HN CI OH 10 0 4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 3-nercapto-1 -propanol to afford 2-chloro-4-(3-hydroxypropylthio)benzonitrile. 1 g of 2-cbloro-4-(3. hydroxypropylthio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(3 15 hydroxypropylthio)benzoic acid. 1.2 g of 2-chloroA-(3-hydroxypropylthio)bcnzoic acid was reacted via Procedure R to yield 2-chloro-4-(2-bydroxypropysulfonyl)benzoic acid. 75 mg of 4 chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxypropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro 3-(pyridin-2-yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamide. MS (QI) 465.0 (M)'. 20 Example 237 4-(allylsulfonyl)-N-(4-chloro-3-(pyridin-2-yI)phenyl)benzamide CI HN O S 0 207 7.3 g of 4-(3-hydroxypropylthio)benzonitrile was reacted via Procedure R to yield 4-(3 hydroxypropylsulfonyl)benzonitrile. 1.9 g of NBS was added to a solution of 2 g of 4-(3 hydroxypropylsulfonyl)benzonitrile and 2.8 g of triphenylphosphine in 10 rmL of dichloromethane at 0 C. The reaction mixture was stirred at 0 -5 "C for li. The mixture was diluted with 5 dichloromethane, washed with HO, dried (MgSO 4 ) and evaporated. Purified by silica gel chromatography (10-70% ethyl acetate/hexane) to afford 4-(3-bromopropylsulfonyl)benzonitrile. 300 mg of 4-(3-bromnopropylsulfonyl)benzonitrile was reacted via Procedure T to give 4 (allylsulfonyl)benzoic acid. 40 mg of 4-chloro-3-(pyridin-2-yl)anilinc was coupled to 4 (allylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to 10 yield 4-(allylsulfonyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide. MS (QI) 413.2 (M). Example 238 4-(allylsulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)benzamide C1 N N C HN I 15 0 115 mg of NBS was added to a solution of 200 mg of 2-chloro-N-(4-chloro-3-(pyridin-2 yl)phenyl)-4-(3-hydroxypropylsulfonyl)benzamnide and 169 ng of triphcnylphosphinc in 3 mL of dichloromethane at 0 "C. The reaction mixture was stirred at 0 -5 "C for lh. The mixture was 20 diluted with dichloromethane, washed with H 1 0, dried (MgSO4) and evaporated. Purified by prep TLC plate (60% ethyl acetate/hexane) to afford 4-(3-biomopropylsulfonyl)-2-chloro-N-(4-chloro 3-(pyridin-2-yl)phenyl)bcnzamide. 60 mg of 4-(3-bromopropylsulfonyl)-2-chloro-N-(4-chloro-3 (pyridin-2-yl)phenyl)benzamide and 111 ng of cesium carbonate in 0.5 mL of DMF were heated to 100 *C in a sealed microwave reactor for 20 min. The reaction mixture was evaporated, and the 25 product was purified on reverse phase HPLC to yield 4-(allylsulfonyl)-2-chloro-N-(4-chloo-3 (pyridin-2-yl)phenyl)bcnzamide. MS (Q1) 448.0 (M). Example 239 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3-morpholinopropylsulfony I) 30 benzamide 208 C1 \N 0 HN CI 0 / \ N -s 10 120 mg of 4-(3-bromopopysulfonyl)-2-chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)bcnzamide was used in Procedure P with morpholine to yield 2-chloro-.N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(3 5 morpholinopropylsulfonyl)benzamide. MS (Q I) 534.0 (M)'. Example 240 2-chloro-M-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopyrrolidin-1-yl)benzamide C1 \N 0 HN CI In A mixture of 500 mg of 2-chloro-4-florobenzonitrile, 821 mg of 2-pyrrolidinone and 3 g of cesium carbonate in 5 mL of DMF was heated to 100 T in a scaled microwave reactor for 15 min. The reaction mixture was diluted with ethyl acetate, washed with H,0. dried (MgSO 4 ) and evaporated. 15 Purified by silica gel chromatography (20-80% ethyl acetaie/hexane) to afford 2-chloro-4-(2 oxopyrrolidin-1-yl)benzonitrile. 890 mg of 2-chloro-4-(2-oxopyrrolidin-1-yl)benzonitrile was macted via Procedure T to give 2<hilom-4-(2-oxopyrrolidin-1-yl)bcnzoic acid. 80mg of 4-chloro 3-(pyridin-2-yI)aniline was coupled to 2-chloro-4-(2-oxopyrrolidin-1-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2<hloro-N-(4-cli.oro-3-(pyridin-2 20 yl)phenyl)-4-(2-oxopyn-olidin-1-yl)benzamide. MS (Ql) 426.2 (M)'. Example 241 N-(4-chloro-3-(pyridin-2-yl)pbenyl)4-(2-oxooxazolidin-3-yl)benzamide 209 CI \' " HNN N A mixture of I g of methyl 4-iodobcnzoate, 399 mng of 2-oxozolidone, 1.1 g of potassium carbonate, 34 mg of N, N'-dimethylethylenediamine and 73 mg of copper iodide in 10 mL of 5 toluene was heated to 150 "C in a sealed microwave reactor for 2h. The reaction mixture was diluted with ethyl acetate, washed with HO, dried (MgSO 4 ) and evaporated. Purified by silica gel chromatography (20-70% ethyl acetate/hexane) to afford methyl 4-(2-oxooxazolidin-3-yl)benzoate. 530 mg of methyl 4-(2-oxooxazolidin-3-yl)benzoate was hydrolyzed via Procedure M to give 4-(2 oxooxazolidin-3-yl)benzoic acid. 70 mg of 4-chloro-3-(pyidin-2-yl)anilinc was coupled to 4-(2 10 oxooxazolidin-3-yl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(2-oxooxazolidin-3-yl)benzamide. MS (Ql) 394.2 (M). 15 Example 242 N-(4-chloro-3-(pyridin-2-yl)phenyl)4-(cthylsulfonyl)-2-mcthylbenzanide CI rjN 0 HN / \ 0 0 4 g of 4-bromo-2-methylbenzonitrile was used in Procedure Q with ethanethiol to afford 4 20 (ethylthio)-2-methylbenzonitrile. 2 g of 4-(ethylthio)-2-methylbeizonitrile was reacted via Procedure R to give 4-(ethylsulfonyl)-2-mcthylbcnzonitrilc. 2.5 g of 4-(ethylsulfonyl)-2 methylbenzonitrile was reacted via Procedure T to give 4-(ethylsulfonyl)-2-metliylbenzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(ethylsulfonyl)-2-methylbenzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3 25 (pyridin-2-yl)phenyl)A-(ethylsulfonyl)-2-methylbenzamide. MS (Q1) 415.0 (M)-. 210 Example 243 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonyl)benzamide CI O HN- CI O-S 0 4 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with cthancthiol to afford 2-chloro-4 (ethylthio)benzonitrile. 2 g of 2-chloro-4-(ethyltlhio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(ethythio)bcnzoic acid. 1.5 g of 2-chloro-4-(etiylthio)benzoic acid was reacted 10 via Procedure R to yield 2-chloro-4-(ethylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2 yl)anilinc was coupled to 2-chloro4-(cthylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)4 (ethylsulfinyl)benzamide. MS (Q1) 435.1 (M). 15 Example 244 2-chloro-N-(4-chloro-3-(pyridin-2-yl)pheny)-4-(isopropylsulfonyl)benzamide C H \/ /\ N 0 HNI CI 0 20 2 g of 2-cliloro-4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 2 chloro-4-(isopropylthio)bcnzonitrile. 1.6 g of 2-chloro-4-(isopropythio)bcnzonitrile was reacted via Procedure T to give 2-chloro-4-(isopropylthio)benzoic acid. I g of 2-chloro-4 (isopropylthio)benlzoic acid was reacted via Procedure R to give 2-chloro-4 (isopropylsulfonyl)benzoic acid. 75 ng of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2 25 chloro-4-(isopropylsulfonyl)bcnzoic acid via Procedure G. The product was purified on reverse 211 phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (isopropylsulfonyl)benzamide. MS (Q 1) 449.1 (M)'. 5 Example 245 N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide C1 N 0 HN 0 2 g of 4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 4 10 (isopropylthio)benzonitrile. 900 mg of 4-(isopropythitdo)benzonitrile was reacted via Procedure T to give 4-(isopropylthio)benzoic acid. 730 mg of 4-(isopropylthio)benzoic acid was reacted via Procedure R to give 4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-cliloro-3-(pyiidin-2-yl)phenyl)-4-(isopropylsulfonyl)benzanide. 15 MS IQ 1) 415.0 (M) Example 246 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-4-(methylsulfonyl)benzamid CI HN 20 0 A solution of 500 mg of 4-bromno-2-methylbenzonitrile and 268 mg of sodium thiomethoxide in 3 mL of DMF was stirred for Ih. The reaction mixture was diluted with ethyl acetate, washed with H0, dried (MgSO 4 ) and evaporated to afford 2-methyl-4-(nietliyltliio)benzonitrile. 400 ng of 2 25 metbyl-4-(imethylthio)benzonitrile was acted via Procedure T to give 2-methyl-4 212 (methylthio)benzoic acid. 430 mg of 2-imethyl-4-(methylthio)benzoic acid was reacted via Procedure R to yield 2-methyl4-(methylsulfonyl)benzoic acid. 60 mg of 4-cl.oro-3-(pyridin-2 yl)aniline was coupled to 2-metliyl-4-(nethylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phcnyl)-2-methyl-4 5 (methylsulfonyl)benzamide. MS (QI) 401.0 (M)'. Example 247 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonyl)nicotinanide CI \N 0 HN / \N 10 0 1 g of methyl 6-chloronicotinate was reacted via Procedure 0 to yield methyl 6 (iethylsulfony)iicotinate. I g of methyl 6-(nethylsulfonyl)nicotinate was hydrolyzed via Procedure M to give 6-(metliylsulfonyl)nicotinic acid. 100mg of 4-cliloro-3-(pyridin-2-yl)aniline 15 was coupled to 6-(ncthylsulfonyl)nicotinic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(nethylsulfonyl)nicotinamide. MS (Q1) 388.1 (M). 20 Example 248 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-miethyl-4-phenylpyrimidine-5-carboxamide Cl

NN-

/ N 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 4-methyl-2-phenyl-5-pyrimidine 25 carboxylic acid via Procedure G. The pi-oduct was purified on reverse phase HPLC to yield N-(4 chloro-3-(pyridin-2-yl)phenyl)-2-ncthyl-4-phenylpyrimidine-5-carboxamide. MS (Q1) 401.1 (M)-. 213 Example249 N-(4-chloro-3-(pyridin-2-vl)phenyl)-i-(4-fluorophenyl)-5-nethyl-H-pyrazole-4 carboxamide C1 \N 0 HN NWN 5 F 50 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 1-(4-fluorophenyl)-5-methyl-1H pyrazole-4-carboxylic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)- I -(4-fluorophcnyl)5-incthyl- I H-pyrazole-4 I0 carboxamide. MS (QI) 407.0 (M). Example 250 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicoinamide CI N 0 HN / \N 15 CI A mixture of 450 mg of 4<hloro-3-(pyridin-2-yl)aniline, 427 mg of 6-chloronicotinyl chloride and 1.9 g of PS-DIEA in 10 mL of dichloromethane was shook on the shaker for 3h. The reaction mixture was filtered and washed with dichloromethane. The filtrate was concentrated to yield 6 20 chloro-N-(4-chloro-3-(pyiidin-2-yl)phenyl)nicotinamide. MS (Q1) 344.2 (M)'. Example 251 N-(4-chloro-3-(pyridii-2-yl)phcnyl)-6-(4-ethylpiperazin- -yI)nicotinamide 214 CI \ N 0 HN N Procedure F was performed using 50 ng of 6-chloro-N-(4-chloro-3-(pyridin-2 yI)phenyl)nicotinamide and 93 pL of I-ethylpiperazine in 0.5 mL of BuOH. Purified by reverse 5 phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-ethylpipcrazin-1-yl)nicotinamide. MS (QI) 422.0 (M)'. Example 252 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyethyl)piperazin-1 10 yl)nicotinamide C1 \N 0 HN / \N N OH Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2 15 yl)pheny)nicotinamide and 90 AL of 1-(2-hydroxyethyI)piperazine in 0,5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2 hydroxyethyl)piperazin-1-yl)nicotinamide. MS (Ql) 438.0 (M)'. 20 Example 253 (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)nicotinamidc. 215 CI HN / N H HN Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2 yl)phcnyl)nicotinamide and 57 pL of R-1-Amino-2--propanol in 0.5 mL of BuOH. Purified by 5 reverse phase HPLC to yield (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2 hydroxypropylamino)nicotinamidc. MS (QI) 383.4 (M). Example 254 (S)-N-(4-chloro-3-(pyridin-2-y)plieiyl)-6-(2-hydroxypropylanino)nicotinamiide 10 CI "N 0 HN / NN HO HN Procedure F was performed using 50 mg of 6-chloro-N-(4-clhloro-3-(pyridin-2 yl)phcnyl)nicotinanide and 57 aL of S-1-Amino-2--propanol in 0.5 nL of BuOH. Purified by 15 reverse phase HPLC to yield (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2 hydroxypropylamino)nicotinamide. MS (QI) 383.4 (M)'. Example 255 N-(4-chloro-3-(pyiidin-2-yl)phenyl)-6-(2.6-dimethylmorpholino)nicotinamile 20 CI \N 0 HN / \N N 0 21.6 Procedure F was performed using 50 ng of 6-chloro-N-(4-chloro-3-(pyridin-2 yl)phienyl)uicotinamide and 90 tL of 2,6-dimethylmorpholine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4<hloro-3-(pyridin-2-yl)plieny)-6-(2,6 5 dimethylImopholino)nicotinamide. MS (QI) 423.4 (M)'. Example 256 N-(4-chloro-3-(pyridin-2-yl)pheny)-6-(4-hydroxypiperidin- I -yl)nicotinamide CI HN / N In OH Procedure F was performed using 50 ng of 6-chloro-N-(4-chloro-3-(pyridin-2 yl)phenyl)nicotinamide and 74 mg of 4-hydroxypiperidine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phcnyl)-6-(4-hydroxypiperidin-l 15 yl)nicotinamide. MS (Q1) 409.3 (M)t. Example 257 N-(4-clIoro-3-(pyridin-2-yl)plieny1)-6-(3,5-dimethyl- IH-pyrazol-1-yl)nicotinamide C1 \N 0 HN / \N N-N 20 21 mug of sodium hydride was added to a solution of 84 mg of 3,5-dimethylpyrazole in 2 mL of DMF. The reaction mixture was stirred for 10 min, and then added 100 mg of 6-chloro-N-(4 chloro-3-(pyridin-2-yl)phenyl)nicotinanide. The reaction was heated to 140 "C for 16h. The 217 mixture was quenched with MeOH and evaporated. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3,5-dimethyl-IlH-pyrazol- I -yl)nicotinamide. MS (Q1) 404.3 (M). 5 Example 258 N(4-chlioro-3-(pyridin-2-yl)phcnyl)-6-(3-oxopiperidi- I -yl)nicotinamide Cl HN N NH lo Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2 yl)phenyl)nicotinamide and 29 mg of piperazin-2-one in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(3-oxopiperidin-1-yl)nicotinamide. MS (Q1) 408.3 (M). 15 Example 259 N-(4-chloro-3-(pyridin-2-yl)phcny1)-4-(2-oxopiperazin--vl)benzamide Cl N 0 HN / NH NH 20 A mixture of I g of methyl 4-iodobenzoate, 920 mg of 4-Boc-piperazinone, I . g of potassium carbonate, 32 mg of N, N'-dimethylethylenediamine and 70 mg of copper iodide in 10 mL of toluene was heated to 150 C in a scaled microwave reactor for 3h. The reaction mixture was diluted with ethyl acetate, washed with H0, dried (MgSO 4 ) and evaporated. Purified by silica gel chromatography (20-80% ethyl acetate/hexane) lo afford tert-butyl 4-(4 218 (methoxycarbonyl)phenyl)-3-oxopiperazine-I-carboxylate. 500 mg of tert-butyl 4-(4 (methoxycarbonyl)phenyl)-3-oxopiperazine cI arboxylate was hydrolyzed via Procedure M to give 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)benzoic acid. 100 mg of 4-chloro-3-(pyridin-2 yl)aniline was coupled to 4-(4-(tert-buthoxycarbonyl)-2-oxopiperazin-1-yl)bcnzoic acid via 5 Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and brine, dried (MgSO 4 ) and evaporated to afford tert-butyl 4-(4-(4-chloro-3-(pyridin 2-yl)phenylcaibamoyl)pbenyl)-3-oxopiperazine-1-carboxylate. 300 mg of crude tert-butyl 4-(4-(4 chloro-3-(pyridin-2-yl)phenylcarbanoyl)phenyl)-3-oxopiperazinc-I-carboxylate was treated with TFA (2 mL) containing trace amounts of' H2O for lI. The reaction mixture was evaporated and 10 the crude product was purified by reverse phase HPLC to yield N-(4-chiloro-3-(pyridin-2 yl)phenyl)-4-(2-oxopiperazii-l-yl)benzamide. MS (Q l) 407.3 (M). Example 260 N-(4-chlIoro-3-(pyridin-2-yl)phcnyl)4-(4-methyl-2-oxopiperazin-I -yl)benzamide 15 C1 N 0 HN / \ 120 ng of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-oxopipcrazin-1-yl)benzanide was dissolved in 2 mL of DMF and then treated with 53 mg of paraformaldehyde, 187 mg of sodium 20 triacetoxyborohydride and 0.2 mL of AcOH. After stirring 16 h, the reaction mixture was evaporated and the crude product was purified by reverse phase HPLC to yield N-(4-chloro-3 (pyridin-2-yl)phenyl)4(4-methyl-2-oxopiperazin-1-yl)benzaniide. MS (Ql) 421.3 (M)-. 25 Example 261 2-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide 219 Cl H-N NI-I / \ 0 O 2.2 g of methyl 4-(mcthylsulfonyl)-2-nitrobenzoate was reacted via Procedure C to afford methyl 2-amino-4-(methylsulfonyl)benzoate. 500 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was 5 hydrolyzed via Procedure M to give 2-amino-4-(methylsulfonyl)bcnzoic acid, 100 mg of 4-chloro 3-(pyridin-2-yl)aniline was coupled to 2-anino-4-(methylsulfounyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-amino-N-(4-chloro-3-(pyridin-2 yl)phenyl)-4-(methylsulfonyl)benzanide. MS (Q1) 402.0 (M)*. 10 Example 262 2-acetamido-N-(4-hloro-3-(pyridin-2-yl)phcnyl)-4-(methylsulfonyl)bcnzanide CI HN HN 0 15 20 gL of acetyl chloride was added to a solution of 90 mg of 2-amino-N-(4-chloro.3-(pyridin-2 yl)pheny1)-4-(methylsulfoinyl)benzamide in 2 mL of pyridine at 0 C. The reaction mixture was allowed to warn to room temperature and stirred for 2h. The reaction was quenched with McOH and evaporated. The product was purified on reverse phase HPLC to yield 2-acetamido-N-(4 chloro-3-(pyridin-2-yl)phenyl)4-(methlylsulfonyl)benzamide. MS (Q1) 444.0 (M)-. 20 Example 263 N-(4-chloro-3-(pyiidin-2-yl)phenyl)-2-iodo-4-(methylsulfonyl)benzamide 220 Cl HN I / \ 0 600 mg of methyl 2-amino-4-(methylsulfonyl)benzoate was added to a solution of 4 mL of HO and I mL of concentrated sulfuric acid. The solution was cooled to 0 'C and a solution of 206 mg 5 of sodium nitrite in I mL of HO was added slowly. The reaction mixture was stirred for 2 h and then a solution of 782 mg of ponassium iodide in 2 mL of H20 was added dropwise at 0 "C, The reaction was allowed to warm to room temperature and stirred for 5 h. The mixture was extracted with ethyl acetate. The combined organic extracts were washed with saturated Na'S20t dried (MgSO4) and evaporated. Purified by silica gel chromatography (5-50% ethyl acetate/hexane) to 10 afford methyl 2-iodo-4-(methylsulfonyl)benzoate. 160 mg of methyl 2-iodo-4 (methylsulfonyl)benzoate was hydrolyzed via Procedure M to give 2-iodo-4 (methylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-iodo-4 (methylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-iodo-4-(methylsulfonyl)benzamide. MS (Q1) 513.0 15 (M). Example264 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5-dimethylpipcrazin-1-yl)2 methyinicotinamide CI NM - 0 HN / "N N NH 20 Stoichioictric amounts (0.04 mol) of methyl proplolate and ethyl 3-aminocrotonate were heated to 140 *C for I h. I g of the crude (2E,4Z)-methyl-4-(1-aminoethylidene)-5-oxooct-2-enoate in 4 mL of DMF was heated to 230 'C in a sealed microwave reactor for 40 min. The reaction mixture was 221 diluted with ethyl acetate, washed with HO, dried (MgSO4) and evaporated to afford crude ethyl 6-hydroxy-2-methylnicotinate. A mixture of 800 mg of crude ethyl 6-hydroxy-2-methylnicotinate in 4 mL of phosphorus oxychloride was heated to 150 "C in a sealed microwave reactor for 15 min. The reaction mixture was poured into ice/water, extracted with diethyl ether. The combined 5 organic layers were dried (MgSO 4 ) and evaporated. Purified by silica gel chromatograph (0-20% ethyl acetate/hexane) to yield ethyl 6-chloro-2-methylnicotinate. 400 mg of ethyl 6-chloro-2 methylnicotinate was hydirolyzed via Procedure M to give 6-chloro-2-methylnicotinic acid. 300 mg of 4-chloro-3-(pyridii-2-yI)aniline was coupled to 6-chloro-2-methylnicotinic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N sodium hydroxide and 10 brine, dried (MgSO) and evaporated to afford 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide. Procedure F was perfonned using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin 2-yl)phenyl)-2-methylnicotinamide and 128 mg of 2,6-dimethylpiperazinc in I mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((3S,5R)-3,5 dimethylpiperazin-1-yl)-2-methylnicotinamide. MS (QI) 436.3 (M) 15 Example 265 (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-mcthyl-6-(3-mcthylpiperazin-I yl)nicotinamide c1 N 0 HNN N NH 20 Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)plhenyl)-2 methylnicotinamide and 112 mg of S-(-)-2-methylpiperizine in I mL of BuOH. Purified by reverse phase HPLC to yield (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3 methylpiperazin-1-yl)nicotinaniide. M.S (QI) 422.3 (M)-. 25 Example 266 (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1 yl)nicotinamide. 222 C1 HN / N N NH Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide and 112 mg of R-(+)-2-methylpipcrizine in I mL of BuOH. Purified by 5 reverse phase HPLC to yield (R)-N-(4-chloro-3-(pyridin-2-v)phenyl)-2-metliyl-6-(3 methylpiperazin-l-yl)nicotinamide. MS (QI) 422.3 (M). Example 267 N-(4-chloro-3-(pyridin-2-vl)phenyl)-2-methyl-6-(3-methylpiperazin-1 10 yl)nicotinamide C1 \"N 0 HN N / N NH Procedure F was performed using 100 mng of 6-chloro-N-(4-chloro-3-(pyridin-2-y)pheniy1)-2 methylnicotinamide and 112 mg of 2-methylpiperizine in I mL of BuOH. Purified by reverse 15 phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(3-methylpiperazin-1 yI)nicotinamide. MS (Q1) 422.3 (M) . Example 268 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyacetyl)piperazin-1-yl)-2 20 methylnicotinamide 223 Cl H /_\N N N O OH 100 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(piperazin-1-yl)nicotinamide was coupled to glycolic acid via Procedure G. The product was purified on reverse phase HPLC to 5 yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyacetyl)piperazin-1 -yl)-2 methylnicotinamide. MS (Q1) 466.3 (M)f. Example 269 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-rethyl-6-(4-(methylsulfonyl)piperazin-I I0 yl)nicotinamide Cl \N 0 HN / \N N oS 1.3 mL of methanesulfonyl chloride was slowly added to a solution of 2 g of 1-Boc-piperazine and 1.3 miL of pyridine in 6 nmL of dichloromethane at 0 * C. The reaction mixture was allowed to 15 warn to room temperature and stirred for 2h while being monitored by TLC. Upon completion, the mixture was diluted with dichloromethane, washed with HO, dried (MgSO 4 ) and evaporated. Purified by silica gel chromatograph (20-100% ethyl acetate/hexane) to afford tert-butyl-4 (inethylsulfonyl)piperazine-1-carboxylate. 930 mg of tert-butyl-4-(methylsulfonyl)piperzine-1 carboxylate was treated with 4N HCI in dioxanc for 2h. The reaction mixture was evaporated to 20 give the HCI salt of 1-(methylsulfonyl)piperazine. Procedure F was performed using 50 mg of 6 chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-2-methylnicoinamide, 69 mg of I (methylsulfonyl)piperazine and DIEPA(1 eq) in 0.5 mL of BuOH. Purified by reverse phase 224 HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(4-(nethylsulfonyl)piperazinyl)nicotinamide. MS (Q1) 486.3 (M). 5 Example 270 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-thionorpholinonicotinamide C1 HN / \N S Procedure F was performed using 90 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)plienyl)-2 10 methylnicotinamide and 78 oL of thiomorpholine in I mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-thionorpholinonicotinamide. MS (Q 1) 4253 (M)". 15 Example 271 N-(4-cleoro-3-(pyridin-2-yl)phenyl)-2-methyl-6-sulfonylmorpholinonicotinamide c1 HNN N SO 0 100 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-nethyl-6-thiomoirpholioonicotinamiide was 20 reacted via produce R. The product was purified on reverse phase HPLC to yield N-(4-chloro-3 (pyridin-2-yl)phenyl)-2-methyl-6-sulfonylmorpholinonicotinamide. MS (Q1) 457.3 (M)'. 225 Example 272 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(2-(pynolidin-1-yl)ethylamino) nicotinamide C1 \ N 0 HN / N HN 5 Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)plienyl)-2 methylnicotinamide and 70 gL of I-(2-aninoethyl)pyrrolidine in I mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(2-(pyrrolidinyl)ethylamino)nicotinamnide. MS (QI) 436.0 (M). Example 273 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-((2-(dimethylamino)ethyl)(methyl)amino) 2-methylnicotinamide C1 \/ \/ HN N N/ N 15 Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phlinyl)-2 methylnicotinamide and 66 IL of N,NN'-trinetliylethylenediamine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)pheny)-6-((2 (dimethylamino)ethyl)(methyl)amino)-2-methylnicotinanide. MS (Q1) 424.0 (M). 20 Example274 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-mcthyl-6-(3-oxopiperazin-1-yl)nicotinanidc 226 Cl \N 0 HN NH Procedure F was performed using 100 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide and 84 mg of piperazine-2-one in I mL of BuOH. Purified by reverse phase 5 HPLC to yield N-(4-chloro-3-(pyridin-2-yl)plienyl)-2-metbyl-6-(3-oxopiperazin-1-yl)nicotinaimide. MS (Q1) 422.3 (M). Example 275 N-(4-chloro-3-(pyridin-2-vl)phenyl)-2-methyl-6-(3-methyl-1H-,2,4-triazol-I n yI)nicotinamide Cl \N 0 HN / N N-N N A mixture of 57 mg of 3-methyl-1,2,4-triazol and 16 mg of sodium hydride in 2 mL of DMF was stined for 10 min. 80 mg of 6-chloro-N-(4-chloio-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide 15 was added. The reaction was heated to 140 "C for 16h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2 yl)phcnyl)-2-methyl-6-(3-methyl-IH-,2,4-triazol-1-yl)nicotinamide. MS (Ql) 405.3 (M), 20 Example 276 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(1H-1,2,4-triazol-1 yI)nicotinamide 227 C1 HN / \N N--N N A mixture of 41 mg of 1,2,4-triazol and 14 mg of sodium hydride in 2 mL of DMF was stirred for 10 min. 70 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-y1)pheny1).2-methylnicotinamide was added. 5 The reaction was heated to 140 "C for 6h. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyiidin-2-yl)phnyl)-2 methyl-6-(IH-1.2,4-triazol-1-yl)nicotinamide. MS (QI) 391.4 (M)". In Example 277 N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(I H-pyrazol- I -y1)nicotinamide C1 \"/ 0/ N 0 H N / ~N _N A mixture of 52 mg of pyrazole and 18 mg of sodium hydride in 2 mL of DMF were stirred for 10 15 min. 90 mg of 6-chlow-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methylnicotinamide was added. The reaction was heated to 140 "C for Sh. The reaction mixture was quenched with MeOH and evaporated. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methyl-6-(1H-pyrazol-I-yl)nicotinamide. MS (QI) 390.0 (M). 20 Example 278 N-4-clloro-3-(pyiidin-2-yl)phenyl)-2-mnethyl-6-(piperazin-1-yl)nicotinamide 228 C1 N 0

HN

\N NH Procedure F was performed using 80 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide and 209 mg of I -Boc-piperizine in I mL of BuOH. The reaction mixture 5 was evaporated to afford tert-butyl 4-(5-(4-cliloro-3-(pyridin-2-yl)plenylcarbamoyl)-6 methylpyridin-2-yl)piperazine-l-carboxylate. 150 ing of tert-butyl 4-(5-(4-chloro-3-(pyridin-2 yl)phenylcarbamoyl)-6-methylpyridin-2-yl)piperazine-l-carboxylate was treated with TFA (I mL) containing trace amounts of HO for 2 h. The reaction mixture was diluted with ethyl acetate, washed with 0.1N sodium hydroxide and brine, dried (MgSO 4 ) and evaporated. Purified by I0 reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-2-methyl-6-(pipcrazin-l yl)nicotinamide. MS (Q 1) 408.3 (M)'. Example 279 (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2 methylnicotinamide Cl HN N HO 15 HN Procedure F was performed using 60 mg of 6-chloro-N-(4-chloio-3-(pyridin-2-yl)pheny)-2 methylnicotinamide and 116 al of R-(-)-l-amrino-2-propanol in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield (R)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylanino) 20 2-methylnicotinamide. MS (QI) 397.4 (M)-. Example 280 (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-hydroxypropylamino)-2 methylnicotinamide 229 C1 HN N HO HN Procedure F was performed using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide and .116 pL of S.(+)-1-amino-2-propanol in 0.5 mL of BuOH. Purified by 5 reverse phase HPLC to yield (S)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2-iydroxypropylamino)-2 methylnicotinamide. MS (Ql) 397.4 (M). Example 281 6-(2-(1 H-imiidazol-4-y1)etliylamino)-N-(4-chloro-3-(pyridiii-2-y)pheniy1)-2 10 methylnicotinanide CI \' "N/ ' HN HN NH Procedure F was perfonied using 60 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)plienyl)-2 methylnicotinanide and 93 mg of histamine in 0.5 mL of BuOH. Purified by reverse phase HPLC 15 to yield 6-(2-(1H-imidazol-4-yl)ethylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide. M.S (QI) 433.0 (M) Example 282 6-(4-acetylpipemzin-1-yl)-N-(4-chloro-3-(pyridin-2-yI)phenyl)-2 20 methyInicotinamide 230 CI HNN \N Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-2 metlylnicotinaride and 99 mg of I-acetylpiperazine in 0.5 mL of BuOH. Purified by reverse 5 phase HPLC to yield 6-(4-acetyIpiperazin-1-yl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide. MS (Ql) 450.4 (M). Example 283 N-(4-clforo-3-(pyridin-2-yl)phenyl)-6-(2,6-dimethylnorpholino)-2 10 methylnicotinamide C1 \N 0 HN / \N N 0 Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)plienyl)-2 methylnicotinamide and 95 mg of 2,6-dimethylmorpholine in 0.5 mL of BuOH. Purified by 15 reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(2,6-diimethylmorpholino)-2 methylnicotinamide. MS (Q1) 436.2 (M). Example 284 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin- 1 -yl)- 2 20 methylnicotinamide 231 C1 \N 0 HN / "N NN OH Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)plienyl)-2 methylnicotinamide and 78 ng of 4-hydropiperidine in 0.5 mL of BuOH. Purified by reverse 5 phase HPLC to yield N-(4-chlIoro-3-(pyridin-2-yl)phenyl)-6-(4-hydroxypiperidin-1-yl)-2 methylinicotinamide. MS (QI) 422.! (M), Example 285 6-(3-(IH-imidazol-1 -yl)propylamino)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 10 methylnicotinamide CI HN N HN Procedure F was performed using 55 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide and 92 gL of 1-(3-aminopropyl)-imidazole in 0.5 mL of BuOH. Purified by 15 reverse phase HPLC to yield 6-(3-(1H-imidazol-1-yl)propylamino)-N-(4-cIloro-3-(pyridin-2 yl)phenyl)-2-methylnicotinamide. MS (Q1) 446.1 (M)-. Example 286 N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)-2-methylnicotinanide CI N 0 HN / \N 20 HN 232 Procedure F was performed using 50 ng of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-2 methylnicotinamide and 70 gL of isobutylamine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(isobutylamino)-2-mnetliylnicotinanide. MS (Q1) 395.4 (M)-. Example 287 2-chloro-N'-(4-cbloro-3-(pyridin-2-yl)phienyl)-N,N 4 -dinethylterephthalamide CI HN CI -N 290 ing of dimethylainine hydrochloride was coupled to I g of 4-(tert-butoxycarbonyl)-3 chlorobenzoic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with 0.1 N H.Cl, 0.1 N NaOH and brine, dried (MgSO 4 ) and evaporated to afford tert-butyl 2 chloro-4-(diiethylcarbamoyl)benzoate. I.1g of tert-butyl 2-chloro-4 15 (dimethylcarbamoyl)benzoate was treated with TFA (4 mL) containing trace amounts of H20 for 2 h. The reaction mixture was evaporated, and then added 0.1 N HC. The resulting solid was filtered and washed with H 2 0 to yield 2-chloro-4-(dimethylcarbanioyl)benzoic acid. 100 mg of 4 chloro-3-(pyidinc-2-yl)anilinc was coupled to 2-chloro-4-(dimethylcarbamoyl)bcnzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N'-(4-chloro-3 20 (pyridin-2-yl)phcnyl)-NtN 4 -dimethyterephthalamide. MS (Q1) 414.1 (M). Example 288 N-(4<hloro-3-(pyridin-2-yl)phenyl)-6-(morpholine4-carbonyl)nicotinamide 25 233 CI NO HN N 0 63 mg of morpholine was coupled to 120 mg of 5-(methoxycarbonyl)pyridine-2-carboxvlic acid via Procedure G. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate and brine, dried (MvgSO 4 ) and evaporated to afford methyl 6-(morpholine-4 carbonyl)nicotinate. 180 mg of methyl 6-(morpholine-4-carbonyl)nicotinate was hydrolyzed via Procedure M to give 6-(morpholine-4-carbonyl)nicotinic acid. 100 mg of 4-chloro-3-(pyridine-2 yl)aniline was coupled to 6-(morpholine-4<arbonyl)nicotinic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro- N-(4-chloro-3-(pyridin-2-yl)phenyl)-6 In (morpholinc4-carbonyl)nicotinamide. NS (QI) 423.4 (M). Example 289 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-iydroxy-4 (methylsulfonylmethyl )benzanide 15 C \N 0 HN / \ OH 0 3-Hydroxy-4-methylbenzoic acid (6.86 g, 45.1 nmol) was dissolved in methanol (200 ml). 4N HCI in 1,4-dioxane (34 ml, 0.135 mmol HCl) was added and the solution heated to 55 0 C for 18 20 hours. The solvent was concentrated on a rotary evaporator, and then partitioned between water and ethyl acetate. The aqueous portion was extracted with ethyl acetate once, and the ethyl acetate extracts were combined and washed with water once, brine once, dried with MgSOi, and evaporated to methyl 3-hydroxy-4-nethylbenzoate as a crude tan solid (6.66 g) which was used without purification. Methyl 3-hydroxy-4-methylbenzoatc (6,66 g, 40.1 mmol) was dissolved in 234 dichloromethane (200 ml), treated with pyridine (4.3 ml, 60.2 mmol), and cooled in an ice water bath. Acetyl chloride (3.6 ml, 50.1 mmol) was added dropwise. The solution was allowed to wam1 to room temperature, with stirring, over 18 hours. The solution was washed with I N aqueous HCI twice, water once, brine once, dried with MgSO 4 , and evaporated to methyl 3 5 acetoxy-4-methylbenzoate as a crude tan oil (6.93 g) which was used without purification. Methyl 3-acetoxy-4-methylbenzoate (6.38 g, 30.6 nnol) was dissolved in carbon tetrachloride (130 ml) and treated with benzoic peroxyanhydride (200 mng, 0.83 mmol) and NBS (5.45 g, 30.6 mrnol), then heated to 85"C for 3 hours. After cooling to room temperature, the solution was filtered through Celite 545 and evaporated to a crude yellow solid which was purified by silica gel flash 10 chromatography (5% dichloromethane/hexanes increasing to 35% dichloromethanc/hexancs) to yield methyl 3-acetoxy-4-(bromomethyl)benzoate as an off white solid (4.18 g). Methyl 3-acetoxy 4-(bromomethyl)benzoate (2.00 g, 6.97 mmol) was used in procedure 0 to afford methyl 3 aceioxy-4-(methylsulfonylmethyl)benzoate as a white solid (1.67 g) which was used without purification. Methyl 3-acetoxy-4-(methylsulfonylmethyl)benzoate (1.67 g, 5.83 mmol) was 15 saponified via procedure M to afford 3-hydroxy-4-(methylsulfonylmethyl)benzoic acid as a white solid (1.05 g) which was used without purification. 3-Hydroxy-4-(methylsulfonylnethyl)benzoic acid (860 mg, 3.74 mmol) was dissolved in 1,4-dioxane (25 ml) and treated with thionyl chloride (8 ml) and DMF (5 drops), then heated to 50*C for 2 hours. The reaction was cooled and evaporated to an oil. The oil residue was dissolved in dichloromethane (40 ml), cooled in an ice 20 water bath, and treated dropwise with a solution of 4-chloro-3-(pyridin-2-yl)aniline (767 ing, 3.74 mmol) in dichloromethane (30 md). The reaction was stirred 18 hours, allowing to warm to room temperature. The reaction was diluted with dichloromethane (40 ml) and stirred vigorously with water (50 ml) while acidifying to pH 6 with I M citric acid. The dichloromethane portion was separated, and enough methanol was added to dissolve precipitating solids. The solution was 25 washed with water once, brine once, dried with MgSO 4 , and evaporated to a solid which was triturated with dichloromethane, filtered, and air dried to yield 909 mg of crude product. A portion (20 mg) was purified on reverse phase HPLC to yield 16 mg of purified N-(4-chloro-3-(pyridin-2 yl)phenyl)-3-hydroxy-4-(methylsuifonylmethyl)benzamide as a white solid. MS (Q1) 417 (M). 30 Example 290 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-isobutoxy-4 (methylsulfonylmethyl)benzamide 235 CI \N 0 HN / / s=o 0 N-(4-chloro-3-(pyridin-2-yl)phcnyl)-3-hydroxy4-(methylsulfonylnethyl)benzamide (50 mg, 0.12 mmol) was treated with 1-bromo-2-methylpropane (26 pl, 0.24 mmOl) via procedure U to yield 19 5 mg of N-(4-chloro-3-(pyridin-2-yl)phinyl)-3-isobutoxy-4-(metihylsulfonylmethyl)bciizamide. MS (Q1)473(M)'. Example 291 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-methoxy-4 10 (methylsulfonylnetliyl)benzamide C1 \N 0 HN / \ 0 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (50 mg, 0.12 15 immol) was treated with iodomethane (7.5 pl. 0.12 mmol) via procedure U to yield 12 mg of N-(4 chloro-3-(pyridin-2-yl)phenyl)-3-methoxy-4-(methiylsulfonylmethyl)benzamnide. MS (Qi) 431 (MY. 20 Example 292 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-ethoxy-4 (methylsulfonyimethyl)benzaiide 236 Cl HN / \ -O 0 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmcthyl)benzamide (50 mg, 0.12 mmOl) was treated with iodoethane (10 pil, 0.12 mmol) via procedure U to yield 22 mg of N-(4 5 chloro-3-(pyridin-2-yl)pheny)-3-ethoxy-4-(mcthylsulfonylimethyl)benzamide. MS (Ql) 445 (M)'. Example 293 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-(2-(4-(methylsulfonyl)piperazin-1 yl)ethoxy)-4-(methylsulfonylmethyl)benzaniide 10 cI 0 0~,1 HN N /\o 0 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-3-hydroxy-4-(methylsulfonylmethyl)benzamide (1.00 g, 2.40 mmOl) was dissolved in DMF (20 ml). Cesium carbonate (1.56 g, 4.8 mmol) and 1,2 15 dibromoethane (0.83 ml, 9.6 mmol) were added, and the reaction was stirred at 50 0 C for 18 hours. The reaction was quenched with water, basified with 10% aqueous NaOH, and extracted with ethyl acetate twice. The ethyl extracts were washed with water once, brine once, dried with MgSO 4 , and evaporated to a crude oil which was purified by chromatography (25% hexanes in ethyl acetate) to yield 490 ng of 3-(2-bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 20 (methylsulfonylnietliyl)benzamide as a yellow solid. 3-(2-Bromoethoxy)-N-(4-cliloro-3-(pyridin-2 yl)phcnyl)-4-(methylsulfonylmethyl)benzamide (100 mg, 0.19 mmol) was dissolved in DMF (2.0 ml), and potassium carbonate (32 mg, 0.23 mnol) and tert-butyl piperazine-1-carboxylate (38 mg, 0.21 mmol) were added. The reaction was stirred for 18 hours at room temperature, quenched in water, and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water 25 once, brine once, dried with MgSO 4 , and evaporated to a crude oil. The oil was dissolved in 237 dichloromethane (I ml) and treated with trifluoroacetic acid (3 ml) for I hour. The reaction was evaporated to dryness, and the crude solid was purified on reverse phase HPLC to yield 63 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylinethyl)-3-(2-(piperazin-1 yl)ethoxy)benzamnidc as a white solid. N-(4-Chloro-3-(pyridin-2-yl)phonyl)-4 5 (nethylsulfonylmethyl)-3-(2-(piperazin-1-yl)ethoxy)benzamide (30 mg, 0.047 mml) was dissolved in dichloromethane (1.5 ml) and THF (1.0 ml). N-ethyl-N-isopropylpropan-2-amine (18 l, 0.10 mmol) and methanesulfonyl chloride (4 1t, 0.051 nol) were added, and the reaction stirred at room temperature for 72 hours. Additional N-cthyl-Nisopropylpropan-2-aminc (9 i, 0.051 mmol) and methanesulfonyl chloride (4 pl, 0.051 mmol) were added and the reaction stirred 10 for 2 hours. After a further addition of methanesulfonyl chloride (4 pl, 0.051 mmol), the reaction was stirred for 2 hours and evaporated to a crude solid which was purified on reverse phase HPLC to yield 8 mg of N-(4-chloro-3-(pyridin-2-yl)phcnyl)-3-(2-(4-(methylsulfonyl)piperazin-l yl)ethoxy)-4-(metliylsulfonylnethyl)benzamide. MS (QI) 607(M). 15 Example 294 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(3 oxopiperazin-1-yl)ethoxy)benzaimide Cl \/"N/ NH N 0 / HN N / 0 20 3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmetlhyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 nuol) and piperazin-2-one (II mg, 0.11 mme]) for 18 hours. The reaction was heated for2.0 hours at 50 0 C, then additional potassium carbonate (18 mg, 0.13 mmol) and piperazin-2-one (11 25 mg, 0. 11 mmol) was added. After 2 hours, the reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once. dried with MgSO 4 , and purified by reverse phase HPLC to yield 16 mg of N-(4-chloro-3-(pyridin 2-yl)phenyl)-4-(methylsulfonylmcthyl)-3-(2-(3-oxopiperazin-1-yl)ethoxy)benzamidce. MS (Ql) 558 (M) 30 238 Example 295 3-(2-(4-Acetylpiperazin-1-yl)ethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (methylsulfonylmethyi)benzamide C>0 HN N 0/ / sro 0 5 3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylnethyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 mmol) and 1-(piperazin-1-yl)ethanone (15 mg, 0.11 inmol) for 18 hours. The reaction was heated for 2.0 hours at 50*C, then additional potassium carbonate (18 mg, 0.13 mmol) and I 10 (piperazin-1-yl)ethanone (15 mg, 0.11 mmol) was added. After 2 hours, the reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO 4 , and purified by reverse phase IPLC to yield 18 mg of 3-(2-(4-acetylpiperazin-I -yl)ethoxy)-N-(4<hloro-3-(pyridin-2-yl)phenyl)-4 (methylsulfonylmethyl)benzamide. MS (Q1) 543 (M) 15 Example 296 N-(4-Chloro-3-(pyridiu-2-yl)phenyl)-3-(2-(2,6-dinethylmnorpholino)etlioxy)-4 (methylsulfonylncthyl) be nzamide CI \/ \/ N20 20 0 3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(nethylsulfonylmethyl)benzamide (50 mg, 0.095 nrol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 Ing, 0.13 mmol) aid 2,6-dimethylmorpholine (14 pl, 0.11 mmol). and stirred at room temperature for 25 18 hours. The reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The 239 ethyl acetate extracts were washed with water once, brine once, dried with MgSO 4 , and purified by reverse phase HPLC to yield 20 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(2,6 dimethylmorpholino)ethoxy)-4-(miethylsulfonylmethyl)beiizamide. MS (Ql) 571 (M). Example 297 N14-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmcthyl)-3-(2 morpholinoethoxy)benzamide C1 N 0 ) HN 0 100 3-(2-Bromocthoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)bcnzanide (50 mg, 0.095 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 m1), treated with potassium carbonate (16 mg, 0.12 mnmol) and morpholinc (10 pl, 0.11 mmol), and stirred 18 hours at room temperature. The reaction was heated to 50'C for 8 hours, and then was allowed to stir 18 hours at 15 room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO 4 , and evaporated to an oil which was purified by reverse phase HPLC to yield 30 mg of N-(4-chloio-3 (pyridin-2-yl)phenyl)-4-(methylsulfonylhcthyl)-3-(2-morpholinoethoxy)benzamide. MS (Ql) 530 (M) . 20 Example 298 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(nethylsulfonylmethyl)-3-(2-(piperidin-1 yl)ethoxv)benzamide Cl HN 25 240 3-(2-Bromoothoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyniethyl)benzamide (50 ing, 0.095 mmol) was dissolved in dichloromethane (1.0 ml), treated with triethylamine (20 lt, 0.15 mnol) and piperidine (11 gl, 0.11 nnnol), and stirred 2.0 hours at room temperature. 5 Acetonitrile (0.25 ml) and N-ethyl-N-isopopylpropan-2-amine (25 pI, 0.19 mmol) were added, and the reaction was stirred for an additional 45 hours. The reaction was quenched in water and extracted with dicbloromethane twice. The dichloronethane extracts were washed with water once, brine once, dried with MgSO, and evaporated to an solid which was purified by reverse phase HPLC to yield 17 ng N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2 10 (piperidin-1-yl)ethoxy)bcnzamide. MS (Q1) 528 (M). Example 299 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-I yl)ethoxy)benzamide 15 CI XN 0 HN / / s=o 0 3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phcnyl)-4-(methylsuIlfonylmethyI)benzaniide (40 mg, 0.076 mmol) was dissolved in acetonitrile (1.0 ml) and DMF (1.0 ml, treated with potassium 20 carbonate (16 mg, 0.12 mmol) and pyrrolidine (7 pI, 0.084 mnmol), and stirred 18 hours at room temperature. The reaction was quenched in water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO, and evaporated to an oil which was purified by reverse phase HPLC to yield 30 ing of N-(4-chloro-3-(pyridin-2 yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1-yl)ethoxy)benzamide. MS (QI) 514 (M)f. 25 Example 300 3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide 241 Cl \N 0 HN /\ NH2 S=o 0 4-(Bromomethyl)-3-nitrobenzoic acid (2.00 g, 7.69 nnnol) was dissolved in methanol (20 ml) and treated with I drop of concentrated sulfuric acid, then stirred 72 hours at room temperature. An 5 additional 3 drops ofconcentrated sulfuric acid was added, and the reaction stirred at 50 0 C for 24 hours. The solvent was concentrated on a rotary evaporator, diluted with ethyl acetate, and washed with water twice, saturated NaHCO once, water once, brine once, dried with MgSO, and evaporated to a 1.82 g of a yellow oil, methyl 4-(bromomnethyl)-3-nitrobenzoate and used without purification. Methyl 4-(bromomethyl)-3-nitrobenzoate (1.82 g, 6.64 mmol) was used in procedure 10 0 to afford 1.66 g of methyl 4-(methylsulfonylmethyl)-3-nitrobenzoate as a solid which was used without purification. Methyl 4-(methylsulfonylmethyl)-3-nitrobenzoate ( 1 .66 g, 6.07 mmol) was saponified via procedure M to afford 1.21 g of 4-(methylsulfonylmethyl)-3-nitrobenzoic acid as an orange solid, which was used without purification. 4-(.Methylsulfonyilmethyl)-3-nitrobenzoic acid (639 mg, 2.46 mmol) was dissolved in 1,4-dioxane (15 ml), treated with thionyl chloride (1.0 ml) 15 and DMF (1 drop), and stirred at room temperature for 18 hours, then at 50'C for 8 hours, then at room temperature for 18 hours. After an additional 4.0 hours at 50*C, the solvents and excess thionyl chloride were removed via rotary evaporator, and the residue was dissolved dichloromethanc (25.0 ml) and treated with N-ethyl-N-isopropylpropan-2-amine (1.7 ml, 9.8 mmol) and 4-chloro-3-(pyiidin-2-yl)aniline (503 ug, 2.46 mmol) and stirred for 20 min at room 20 temperature, over which time a solid precipitated. Water was added, and the mixture was filtered and air dried, to afford 797 mg ofN-(4-chloro-3-(pyridin-2-yl)plienyl)-4-(methylsulfonylnethyl)-3 nitrobenzamide as a tan-yellow solid. N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4 (metlylsulfonylmethyl)-3-nitrobenzamide (786 mug, 1.76 mmol) was dissolved in ethanol (74 ml) and concentrated HCI (12 ml). Tin(1l) chloride dihydrate (.1,31 g, 5.82 mol) was added and the 25 reaction was heated to 55"C for 2.5 hours. The reaction was cooled in an ice bath and triethylamine (10 ml) was added to basify the solution. The reaction was evaporated to a yellow solid which was slurried in ethyl acetate. The slurry was filtered through Celite 545, and the mother liquors were washed with water twice, brine once, dried with MgSO 4 , and evaporated to 552 mg of as a cmde yellow solid, 20 ng of which was purified by reverse phase HPLC to afford 30 13 mg of purified 3-amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)4 (imethylsulfonylmethyl)benzamide. MS (Q1) 416 (M) 242 Example 301 3-Acetamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (methylsulfonylinethyl)benzamide Cl HN O 0, NH 5 /O 3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(nethylsulfonylmethyl)benzanide (30 mg, 0.072 mmol) was reacted with acetyl chloride (5.6 1i, 0.079 mol via procedure V to afford 19 mg of 3 acetamido-N-(4-clIoro-3-(pyridin-2-yl)pienyl)-4-(nethylsulfonyliimethyl)benzanidc as a white 10 solid. MS (Q1) 458 (M). Example 302 N-(5-(4-Chloro-3-(pyridin-2-yl)pbenylcarbamoyl)-2 (methylsulfonylmethyl)plienyl)-2-methyl-6-(trifluoroncthyl)nicotinainide 15 Cl HN O ... N F F H F 0 3-Amino-N-(4<hloro-3-(pyridin-2-yl)phenyl)-4-(inethylsulfonylmethyl)benzamide (30 mg, 0.072 mmol) was reacted with 2-methyl-6-(trifluoromethyl)nicotinoyl chloride (19 mg, 0,079 mmol) via 20 procedure V to afford 16 mg of N-(5-(4-chloro-3-(pyridin-2-yl)phcnylcarbamoyl)-2 (imethylsulfonylnethyl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid. MS (Q1)603(M)-. 243 Example 303 3-Benzamido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4 (methylsulfonymethyl)benzamide Ci N N 0 HNH 0 5 3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (30 mg, 0.072 unmol) was reacted with benzoyl chloride (9 pd, 0.079 mmol) via procedure V to afford 17 mg of 3 benzanido-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(metlhylsulfonylmethyl)benzamide as a white solid. MS (Q 1) 520 (Mf. 10 Example 304 N-(4-ChIloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-I yl)acetamido)benzamide C1 HN 0 / \t s=o is 0 3-Amino-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmcthyl)benzamidc (100 mg, 0.24 mmcl) was dissolved in 1,4-dioxane (5.0 ml), treated with triethylamine (274 l, 1.97 mol) and 2-bromoacetyl bromide (121 p], 1.39 mmol). The reaction was heated to reflux for 10 minutes, 20 and stirred at room temperature for 18 hours. The reaction was quenched with water, and extracted twice with ethyl acetate. The ethyl acetate extracts were filtered, washed with water once, brine once, dried with MgSO 4 , evaporated to 158 mg of a crude brown oil, 3-(2 bromoacetamido)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ncthylsulfonymethyl)benzamide, which was used without further purification. Crude 3-(2-bromoacetamido)-N-(4-cliloro-3-(pyridin-2 25 yl)phenyl)-4-(methylsulfonyl-methyl)bcnzamide (158 mg) was dissolved in DMF, treated with N 244 ethyl-N-isopropylpropan-2-amine (61 pl, 0.35 numol) and pyrrolidine (27 pl, 0.32 mmol), and stirred at room temperature for 18 hours. The reaction was quenched with water and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO 4 , evaporated to a tan solid which was purified by reverse phase HPLC to afford 5 27 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)-3-(2-(pyrrolidin-1 yl)acetamido)benzamidc as a white powder. MS (QI) 527 (M)'. Example 305 4-(N-(3-(lH-midazol-4-y)piopyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2 10 yl)phenyl)benzamide Cl HN H NH HN 4-Chloro-3-(pyridin-2-yl)aniline (687 mg, 3.36 mmol) was dissolved in dichloromethane (8.0 l) 15 and TFIF (8,0 ml), treated with pyridine (0.33 ml, 4.0 mmol), and cooled to 0 0 C. 4-Cyanobcnzoyl chloride (612 mg, 3.7 nmol) was added and the reaction was stin-ed for 1.0 hour. The reaction was diluted with dichlioromethane and methanol was added to dissolve all solids. The solution was washed with water once, brine once, dried with MgSO 4 , and evaporated to an orange solid which was purified by silica gel flash column chromatography (50% ethyl acetate/50% hexancs) to afford 20 908 img of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-cyanobenzamide as a yellow solid. N-(4-Chloro 3-(pyridin-2-yl)phenyl)-4-cyanobenzamidce (500 mg, 1.5 mmol) was slurried in ethanol (75 ml) and heated until just dissolved. The solution was cooled in an ice bath, and saturated with HC1 gas. The solution was heated briefly to 70*C to dissolve precipitated solids, cooled in an ice bath, and resaturated with HCI gas. The solution was then stored at (WC for 18 hours. The solution was 25 saturated again with HCI gas, heated to 70*C until all solids dissolved, cooled to 0*C, resaturated with HCI gas, and stored at 0*C for 18 hours. Finally, nitrogen gas was bubbled through the solution for 1.0 hour, and the solution was evaporated to dryness. The residue was dissolved in methanol, treated with MP-carbonate (2.57 g) and stirred 30 min. The solution was filtered to afford a neutral, methanolic solution of ethyl 4-(4-chloro-3-(pyridin-2 30 yl)plenylcarbamoyl)benzimidate, which was diluted with enough methanol to make a 0.075 M solution. 245 Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 miol) was treated with 3-(1IH-imidazo1-4-yl)propan-l-amine (27 pl, 0.23 mmtol) via procedure W to afford 83 mg of 4-(N-(3-(lH-imidazol-4-yl)propyl)carbamimidoyl)-N-(4-chloro-3 5 (pyridin-2-yl)phenyl)benzamide. MS (Q1) 459 (M). Example 306 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-(pyrrolidin-2 yl)cthyl)carbamimidoyl)benzamide 10 Cl N\ 0 HN / \ NH NH HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2-(pyrrolidin-2-yl)cthananine (28 pI, 0.23 munol) via 15 procedure W to afford 90 mg of N-(4-cliloro-3-(pyridin-2-yl)phenyl)-4-(N-(2-(pyrrolidin-2 yl)ethyl)carbamimidoyl)benzamide. MS (QI) 448 (M). Example 307 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-((tetrahydrofiran-2 20 yl)methyl)carbamimidoyl)benzamide C1

HN

\/ \\O N 0 NH HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)bnzimidate (2.0 ml of a 0.075 M methanol 25 solution, 0.15 mmol) was treated with (tetrahydroftuan-2-yl)methanamine (23 p], 0.23 mmuol) via 246 procedure W to afford 76 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-((tetrahydrofuran-2 yl)methyl)carbamimidoyl)benzamide. MS (QI) 435 (M) 5 Example 308 4-(N-(2-(lH-Imidazol-4-ylethyl)carbamimidoyl)-N-(4-chloro-3-(pyridin-2 yl)phenyl)benzamide C1 N HN HN- N//NO NH HN 10 Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimiidate (2.0 ml of a 0.075 M methanol solution, 0.15 mumol) was treated with 2-(1H-iiiidazol-4-yl)etlianamine (25 mug, 0.23 immol) via procedure W to afford 90 mg of 4-(N-(2-(lH-imidazol-4-yl)ctbyl)carbanminidoy)-N-(4-chloro-3 (pyridin-2-yl)phenyl)benzamide. MS (Q1) 445 (M)'. 15 Example 309 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2 trifluoroethyl)carbamimidoyl)benzamide C1 HN NIH F HN 20 Ethyl 4-(4-chloio-3-(pyfldin-2-yl)phenylcarbaioyl)benzinidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2.2,2-trifluorocthanainine (18 al, 0.23 mmol) via procedure W to afford 56 ng of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2 trifluoroethyl)carbainmidoyl)benzamide. MS (QI) 433 (M)'. 25 247 Example 310 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-((2.6-dimethylmorpholino)(inino)methyl) benzamide CI HN HN 5 Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)bcnzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 rmmol) was treated with 2.6-dimethylmorpholine (28 pl, 0.23 mmol) via procedure W to afford 74 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-((2,6 dimethylmorpholino)(imiiino)metiyl)-benzamide. MS (QI) 449 (M). In Example 311 N-(4-Chloro-3-(pyridin-2-yl)pheny)-4-(N-(3-methoxypropyl)carbamimidoyl) benzamide CI HN / \ o/ NH 5 HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzimnidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 3-methoxypropan-l-amine (23 PI, 0.23 nmmol) via procedure W to afford 68 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(3-methoxypropyl)carbamimidoyl) 20 benzamide. MS (Q 1) 423 (M)'. Example 312 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2 methoxyethyl)carbamimidoyl)benzamide 25 248 C1 HN NH HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcaibaiiioyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with 2-methoxycthanamine (19 pl, 0.23 mmol) via procedure W 5 to afford 50 Ig of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2 methoxyethyl)carbamimidoyl)benzamide. MS (QI) 409 (M)-. Example 313 N-{4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-cyclohexylcarbamimidoyl)benzamide 10 CI HN NH HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)pbenylcarbanoyl)benzimidate (2.0 in] of a 0.075 M methanol solution, 0.15 mmol) was treated with cyclohexanamine (26 al, 0.23 mmol) via procedure W to 15 afford 30 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-cyclohexylcarbamimidoyl)benzamide. MS (Q1) 433 (M)'. Example 314 N-(4-Chloro-3-(pyridiii-2-yl)phenyl)-4-(imino(4-methylpiperazin-1 20 yl)methyl)benzamide 249 CI HN N N HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzinidate (2.0 ml of a 0.075 M methanol solution, 0.15 imnol) was treated with 1-methylpiperazine (23 mg, 0.23 mnol) via procedure W to 5 afford 35 mng of N-(4-cbloro-3-(pyridin-2-yl)phenyl)-4-(imino(4-methylpiperazin-l yI)methyl)benzamide. MS (Q1) 434 (M) . Example 315 N-{4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-propylcarbamimidoyl)benzamide 10 CI HN / \ e NH HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)pbenylcarbanoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0,15 mmol) was treated with propan-l-anine (18 pl, 0.23 mmol) via procedure W to 15 afford 39 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-propylcarbamimidoyl)benzamide. MS (Q 1) 393 (M)-. Example 316 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(imino(pyrrolidin-1-yl)mnethyl)benzanide 20 CI HN \' / \ HN 250 Ethyl 4-(4-chloro-3-(pyridin-2-yl)phcnylcarbamoyl)benzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with pyrrolidine (19 pd. 0.23 mmol) via procedure W to afford 25 mg of N-(4-chloro-3-( pyridin-2-yl)phenyl)-4-(imino(pytrolidin-1-yl)methyl)benzamnide. MS (Ql) 5 405 (M)*. Example 317 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(N-phenylcarbamimidoyl)benzamide Cl HN NH I0 HN Ethyl 4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)bcnzimidate (2.0 ml of a 0.075 M methanol solution, 0.15 mmol) was treated with aniline (21 pl, 0.23 mmol) via procedure W to afford 7 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-phenycarbamimidoyl)benzamide. M.S (QI) 427 (M)'. 15 Example 318 N-(4-Chloro-3-(pyridin-2-yl)phenyl)-4-(imino(morpholino)methyl)benzamide CI HN \/ /\ HN N 20 N-(4-chloro-3-(pyridin-2-yl)pheiiyl)-4-cyanobenzamide (300 mg, 0.899 iimol) was slurried in 45 ml ethanol and treated with 10 ml of ethanol saturated with HCL. The reaction was stored at 0 0 C for 3 days, then heated to 75*C for 3.0 hours, and cooled to room temperature for 18 hours. The reaction was cooled in an ice bath, and saturated with HC gas. After storing at 0*C for an 25 additional 3 days, N2 gas was bubbled through the solution for 1.0 hour, and the solution was diluted with enough ethanol to make a 0.0155 M solution of ethyl 4-(4-chloro-3-(pyridin-2 251 yl)phenylcarbamoyljbenzimidate. Ethyl 4-(4-chloro-3-(pyridin-2 yl)phcnylcarbamoyl)benzimidate (17.5 ml of a 0.0155 M ethanol solution, 0.27 mmol) was treated with morpholine (1.0 mfl, 11.4 mmol) for 3 days. The ethanol was evaporated, and the residue purified by reverse phase HPLC to afford 30 ng of N-(4-chloro-3-(pyridin-2-yl)phonyl)-4 5 (imino(morpholino)methyl)benzamide. MS (QI ) 421 (M) . Example 319 N-(4-chloro-3-(pyridi-2-yl)phenyl)A-(imino(piperidin-I yl)methyl)benzamide Cl HN I0 HN N Ethyl 4-(4vhloro-3-(pyridin-2-yl)phenylcarbamoyl)benzinidate (17.5 ml of a 0.0155 M solution, 0.27 mmol) was treated with piperidine (1.0 ml, 10.0 mmol) for 3 days. The ethanol was evaporated, and the residue purified by reverse phase HPLC to afford 26 mg of N-(4-chloro-3. 15 (pyridin-2-yl)phenyl)-4-(imino(piperidin-1-yl)methyl)benzamide. MS (Q1) 419 (M)'. Example 320 Hedgehog signalling inhibition assays 20 Mouse Reporter Cell lines - IOTI/2-GliLuc [S12] cells (derived from cell line C3H1IOT/2 ATCC #CCL-226); Mouse Embryonic Fibroblasts): Growth Medium: Dulbcoco's modified Eagles' Medium (DMEM) supplemented with 10% Fetal Bovine Serum (FBS), 10 units/mL penicillin, 100 ug/mL streptomycin, 2mM glutamine, and 10mM HEPES. 25 Human Reporter Cell lines - HEPM-GliLuc [MZ24] - cells (derived from HEPM, Human Embryonic Palatal Mesenchyme ATCC #CRL-1486); Growth Medium: Minimum Essential Medium (MEM; with Earle's salts) supplemented with 10-20% Fetal Bovine Serium (FBS), 10 units/ml, penicillin, 100ug/mL str-eptomycin, 2mM glutamine, and 10mM HEPES pH 7.2. 30 Sonic hedgehog - recombinant human SHh N-terminal octylated conjugate. 252 Microtiter Plates (MTPs) - For the Luciferase assay cells are plated in 96-well MTPs (White, Flat-bottom, Clear-View). 5 Luciferase-Assay Medium- DMEM supplemented with 0.5% FBS, 10 units/mL penicillin, 100ug/mL streptomycin, 2mM glutanine, and 10mM HEPES pH 7.2. PBS/Ca/Mg Mix - Phosphate Buffered Saline (PBS) supplemented with 0.5mM CaC 2 and 1mM MgC1 . 10 Assay Procedure S12 and MZ24 cells genetically modified to contain a luciferase reporter gene driven by the hedgehog-reseponsive Gli promoter were maintained on tissue culture dishes in Growth Medium 15 at 37"C and 5% CO. Cell cultures were passaged at sub-confluency at every 3-4 days. (1:20 to 1:40 for s12; 1:3 to 1:10 for MZ24). Cells were harvested and diluted in Growth Medium such that they could be plated in a microtitre plate at 10.000-20,000 cells (s]2), or 20,000-30,000 cells (MZ24), per 100ul, per well. Cells were further incubated for -24-48 hours at 37"C and 5% CO,. 20 After -24-48 hour incubation the Growth Medium in the microtitre plates was replaced by Luciferase-Assay Medium (100 ul per well), with and without Sonic hedgehog-octyl conjugate, at 0.1-0.3 ug/nl (S12) or 0.5-1.0 ug/ml (MZ24), and test compounds. Cells were then further incubated for and additional 24 hrs. 25 Microtitre plates were then subjected to the luciferase reporter gene assay kit (LucLite"), with modifications to the manufacturer's procedure wherein medium was removed and the substrate was reconstituted with 1:1 PBS/Ca/Mg: lysis buffer instead of straight lysis buffer. In brief, the PBS/Ca/Mg was mixed 1:1 with lysis buffer and I0mL were added to each substrate vial (of the 1000-assay kit). Then the assay media from the microtitre plate was discarded, and .1 00ul of this 30 substrate mix was added to each well, Plates were incubated at room tennperature for 20-30 minutes and then the Relative Light Units (RLUS) representing the relative expression level of the luciferase reporter gene were determined with a Topcount reader (Packard) or an Analyst reader (Molecular Devices). Compounds of the invention tested in the assays demonstrated reduced Gli expression in the reporter cell lines indicating hedgehog pathway signalling 35 inhibition. 253

Claims (9)

1. 2. Th ronjoapond of Noban ?, whecir A. Q; R: ris 0.iodfo lt piienit~go The Aomo. n of A A> h> andci 11W, >: Z " R AA nAl" The~ ~~ or x, e h 'NNA Co 3 .' 71 The enpadt ixnIwee Xis NtQICAt The ounk ofne ci
2. 9. The cuenpound of' clda 7, oerei 11 is 141 or M.~ fY 10. h en TO0(1 -febah .l 4.vherern is "I ii, Tha eOnwOund of Own)r 1, whewns R. i> At, or F 1 S. 'the enpounzd of cl-aims~ 1. wherch R iv M asid n".1is 1 r 2
3. 13. "Thc ccsnptlu36d Wn 1, Uareit; h; 1. anti in is I w 2.
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5. 19. The eon'afltsdu of hthn 16, whecin A is 1ing A op A, 2a 10 ngus ni 0.e 24, The m f Qpzind 5a Rh A is "
6. 23. he 24 whoeein ky is M orCO X
7. 24. The Jnpound elate 1 5, wheri ,. is hte t-otp of fnnnla 1iW 2 The compound of a . ereit i A 35 The compund of cin 24 henrha is Ri,
8. 31. The conpouad of ceim 24 whet X is NR A AN, 32 A compositta onsnce a omponnao cai n adm e a picul naptli
9. 32. 33, cto of ttctilt Cmoo~k ' ii1 U ni naCtl3l Bt d i)ittt~t adi~)U ia ertecoxeami.aoa cmpound of wan i4 The mnehd of Cain 33. whewin iad cancer i c ar nOh tulhas to ohhd snai oesophaIcancer Symalb cancer . iirtat cancor. 35 A uhadof iaiingiiens W a n CelnpamUsg atnt sa tdmail rt niffece amount Ctin~~d of claimn ci pin o eeipvpeg a o compound ondaM isRO Wi halogen, hydrxyl arboyL lky acsyLakxakycbnycrbmy alkybulfohr eyLtit coyle aind hef~trocycle sotoal usbue ihhdoy 206 acyL, aiky, vSutfi. alkylsulian , alkisulfinyt. alkoxy, alkycarbamoyi, alkanoylaminec alkylsualfamoyt alykulftonamidc, a carbocycle or ahercye whereinn said aamino. alkyl. carbo~nyl, acylx \ulfony, alkylsulfonyi. aikyisulfinyi 5 alkosv, aiv carbainov, aikanoxlarcit, aikyUl mo4 a lyv s tbnamnd carbocle and hetertcvle siustitusnt in ptionally subsTiuted ith amino, balogeni hydroxyil carbonyt or a cacyce or heteroccle1 that is optionally substitnud wth hydruxyl amn.. halogen haloikyt alkyl alkowy or acy': to 3 (MAO -rcaii m id tempd of f ula dhia a compound of fornna (() ilk whorcim m4 is fl AIV or P ihacmpudtli\Oi 21. a ( 13,~ K is ~rn ~ctiva~i~ q'vst~ to \~~rIA ssu.d $Wifl'~flC~Sfl4 Q~ is haloyjcn (HI * OR ~ ~. ~ ~ cJ ~rnuia %'> to