 Benzofuran- 2
专利摘要:
The present invention relates to novel benzofuran-2-sulfonamide pyridine derivatives of formula (1), processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors. 公开号:AU2013225815A1 申请号:U2013225815 申请日:2013-03-01 公开日:2014-09-25 发明作者:Richard L. Beard；John E. Donello；Michael E. Garst；Xiaoxia Liu；Veena Viswanath；Haiqing Yuan 申请人:Allergan Inc； IPC主号:C07D405-12
专利说明:
WO 2013/130962 PCT/US2013/028607 BENZOFURAN- 2 - SULFONAMIDE DERIVATIVES AS CHEMOKINE RECEPTOR MODULATORS 5 RELATED APPLICATION This application claims the benefit of U.S. Provisional Application Serial No. 61/605,300, filed March 1, 2012, which is incorporated herein by reference in its 10 entirety. FIELD OF THE INVENTION The present invention relates to novel benzofuran-2-sulfonamide pyridine derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals as modulators of chemokine receptors. The 15 invention relates specifically to the use of these compounds and their pharmaceutical compositions to treat disorders associated with chemokine receptor modulation. BACKGROUND OF THE INVENTION Chemokines are a group of 7- to 14-kd peptides that play an important role in orchestrating leukocyte recruitment and migration during inflammation, and therefore 20 represent an important target for anti-inflammatory therapies (Wells et al., 2006). They act by binding to seven-transmembrane, G protein-coupled receptors, the chemokine receptors. The chemokine system is complex, with about 50 chemokines and 20 chemokine receptors identified in humans, often acting with redundancy, making selection of specific antagonists difficult (Gerard and Rollins, 2001). Genetic 25 knockout strategies have confirmed the importance of chemokines as regulators of immune function, but the deletion of specific chemokines has led to only specific and relatively mild defects in the inflammatory response further emphasizing the complex redundancy of the system. Selectivity is crucial for use of chemokine receptor antagonists in systemic diseases where a single chemokine-receptor system is 30 implicated such as atheroscelorsis where the macrophage/monocyte system is the major player in order to allow a subtle and specific control over immune function (Weisberg et al., 2006; Feria and Diaz Gonzalez et al., 2006). 1 WO 2013/130962 PCT/US2013/028607 Many ocular conditions are characterized by inappropriate migration and infiltration of cells such as leukocytes and endothelial cells into the eye with deleterious effects to ocular structures (Wallace et al., 2004). Chemokines have been identified in such diseases and misregulation of the chemokine system is 5 apparent in corneal graft rejection, diabetic retinopathy, age-related macular degeneration (ARM D), chronic inflammatory diseases such as uveitis, dry eye etc. Mice lacking CCR2 or MCP-1 develop features of ARMD with age, including drusen deposits, choroidal neovascularization and photoreceptor atrophy indicating a crucial role for this chemokine and its receptor signaling (Amabati et al., 2003). Thus CCR2 10 receptor-specific inhibitor might have potential therapeutic benefit in ocular diseases like ARMD. In contrast, various human and animal studies have identified several chemokines in different forms of uveitis, produced both by resident and infiltrating cells, that strongly suggests a prominent role for these molecules in its pathogenesis. Studies in rat and mice models of uveitis have demonstrated up-regulation of 15 monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1 (MIP-1), RANTES, stromal derived factor-1 (SDF-1) which are powerful chemoattractants for monocytes and T-cells (Fang et al., 2004; Keino et al., 2003). Similar findings have been reported in peripheral blood mononuclear cells in patients with acute anterior uveitis (AAU), the most common form of human uveitis (Klitgaard 20 et al., 2004). MCP-1 knockout mice and CCR5 knockout mice show reduced endotoxin-induced uveitis, which is the animal model for AAU (Takeuchi et al., 2005; Tuallion et al., 2002). It has also been demonstrated that blocking the chemokine system upstream with the use of NF-KB blockers significantly attenuates experimental AAU in rats (Yang et al., 2005). Blockage of NF-KB results in 25 transcriptional inhibition of multiple chemokines. Given the complexity of pathogenesis in uveitis it is unlikely that a selective inhibition of a chemokine receptor in monotherapy will offer therapeutic benefit. A similar role of multiple chemokines have been shown to be correlated with clinical stage of disease in diabetic retinopathy and dry eye (Meleth et al., 2005; Yamagami et al., 2005). In 30 these ocular diseases the use of broad spectrum chemokine receptor inhibitor which inhibits the function of a wide range of chemokines may be beneficial. The first broad spectrum chemokine inhibitor (BSCI) to be reported was termed Peptide 3, which was derived from the sequence of human chemokine MCP 2 WO 2013/130962 PCT/US2013/028607 1 and was shown to block the migration of monocytes in response to MCP-1, MIP-1, RANTES and SDF-1 (Reckless and Grainger. 1999). A cyclic retro inverse analogue of Peptide 3, constructed of D-amino acids in the reverse sequence, called NR58 3.14.3 was observed to be a more potent chemokine inhibitor (Beech et al., 2001). 5 NR58-3.14.3 has been used to test for anti-inflammatory activities in animal models of atherosclerosis, lung inflammation, irritable bowel syndrome etc (Beech et al., 2001; Grainger and Reckless. 2003; Tokuyama et al., 2005). However there are several disadvantages to using these BSCI as a long-term therapeutic strategy. The known BSCIs which are peptides which have relatively low potency, poor 10 pharmacokinetics, and are unstable in vivo. In addition, systemic use of broad spectrum chemokine receptor inhibitors could potentially lead to deleterious side effects due to their systemic anti-inflammatory activity. However in ocular diseases, a local or topical application would prevent the broad spectrum inhibitor to be taken up systemically. Identification of a small molecule inhibitor of several chemokine 15 receptors could be very useful for treatment of inflammatory ocular diseases. Given the evidence for the role of multiple chemokines in several ocular diseases and these results, we propose that the use of small and large molecule broad spectrum chemokine receptor inhibitors will have utility in the local treatment of ocular inflammatory diseases including, but not limited to, uveitis, dry eye, diabetic 20 retinopathy, allergic eye disease and proliferative retinopathies. Manipulation of multiple chemokines therefore represents a novel therapeutic approach in treating ocular diseases. W02008008374 discloses CCR2 inhibitors and methods of use thereof. W003/099773 discloses CCR9 inhibitors and methods of use thereof. 25 US2012014997 discloses CCR9 inhibitors and methods of use thereof. US7622583 discloses heteroaryl sulfonamides as antagonists of the CCR2 receptor. US20110118248 discloses heteroaryl sulfonamides as antagonists of the CCR2 receptor. 30 US78841 10 discloses CCR2 inhibitors and methods of use thereof. US 2008/0293720 discloses pyridinyl sulfonamide modulators of chemokine receptors. 3 WO 2013/130962 PCT/US2013/028607 US7393873 discloses arylsulfonamide derivatives. SUMMARY OF THE INVENTION A group of novel benzofuran-2-sulfonamide pyridine derivatives which are potent and selective chemokine receptor modulators, has been now discovered. As 5 such, the compounds described herein are useful in treating a wide variety of disorders associated with modulation of chemokine receptors. The term "modulator" as used herein, includes but is not limited to: receptor agonist, antagonist, inverse agonist, inverse antagonist, partial agonist, partial antagonist. This invention describes compounds of Formula I, which have chemokine 10 receptor biological activity. The compounds in accordance with the present invention are thus of use in medicine, for example in the treatment of humans with diseases and conditions that are alleviated by chemokine receptor modulation. In one aspect, the invention provides a compound having Formula I or a pharmaceutically acceptable salt thereof or stereoisomeric forms thereof, or the 15 individual geometrical isomers, enantiomers, diastereoisomers, tautomers, zwitterions and pharmaceutically acceptable salts thereof: R5 R 4 R3 R6 S02 R 7 O ~ 1 R2 N RR 8 N (R)a Formula I wherein: 20 R 1 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 2 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; 4 WO 2013/130962 PCT/US2013/028607 R 3 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 4 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; 5 R is hydrogen, halogen, CN, substituted or unsubstituted C16 alkyl, OR, NRR 4, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 10 NR 1 R 14 , or COR; R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 0NRR4, or COR; R 9 is 0, C(O), S, S(O), S(O) 2 , -C(=NOR 1 6 )_; a is 0 or 1; 15 R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl, substituted or unsubstituted C2-6 alkyne, substituted or unsubstituted C2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; 20 R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C610 aryl or can from an optionally substituted heterocycle with R 13 ; 25 R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C610 aryl or substituted or unsubstituted C1. 6 alkyl; R 16 is hydrogen or substituted or unsubstituted C1.6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. 30 In another aspect the invention provides a compound having Formula I wherein: R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 2 is hydrogen, halogen or substituted or unsubstituted C1-6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1-6 alkyl; R 4 is hydrogen, halogen or substituted or unsubstituted C1-6 alkyl; 5 WO 2013/130962 PCT/US2013/028607 R 5 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 6 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 5 NR 1 R 14 , or COR; R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; R 9 is S, S(O) or S(O) 2 ; a is 0 or 1; 10 R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl, substituted or unsubstituted C2-6 alkyne, substituted or unsubstituted C2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; 15 R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C610 aryl or can from an optionally substituted heterocycle with R 13 ; 20 R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C610 aryl or substituted or unsubstituted C1. 6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. 25 In another aspect the invention provides a compound having Formula I wherein: R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 2 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 4 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 30 R 5 is hydrogen, halogen or substituted or unsubstituted C1-6 alkyl; R 6 is hydrogen, halogen, CN, substituted or unsubstituted C1-6 alkyl, OR, NRR 4, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1-6 alkyl, OR, NRR 4, or COR; 6 WO 2013/130962 PCT/US2013/028607 R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 9 is 0; a is 0 or 1; 5 R 11 is hydrogen, CN, substituted or unsubstituted C 1 . 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl, substituted or unsubstituted C2-6 alkyne, substituted or unsubstituted C2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; 10 R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C610 aryl or can from an optionally substituted heterocycle with R 13 ; 15 R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C610 aryl or substituted or unsubstituted C1. 6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. In another aspect the invention provides a compound having Formula I wherein: 20 R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 2 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 4 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 5 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 25 R 6 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1-6 alkyl, OR, 30 NR 1 R 14 , or COR; R 9 is C(O); a is 0 or 1; R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted 7 WO 2013/130962 PCT/US2013/028607 heterocycle, substituted or unsubstituted C3-8 cycloalkyl, substituted or unsubstituted C 2-6 alkyne, substituted or unsubstituted C2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an 5 optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C 1 . 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C610 aryl or can from an optionally substituted heterocycle with R 13 ; R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted 10 or unsubstituted C610 aryl or substituted or unsubstituted C 1 . 6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. In another aspect the invention provides a compound having Formula I wherein: R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 15 R 2 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 4 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 5 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 6 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, 20 NRR 13 1 4 , or OR 15 ; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; 25 R 9 is -C(=NOR 16 )-; a is 0 or 1; R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl, substituted or 30 unsubstituted C 2-6 alkyne, substituted or unsubstituted C2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1-6 alkyl; R 13 is hydrogen or substituted or unsubstituted C1-6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; 8 WO 2013/130962 PCT/US2013/028607 R 1 4 is hydrogen, substituted or unsubstituted C 1 . 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C6.10 aryl or can from an optionally substituted heterocycle with R 13 ; R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted 5 or unsubstituted C6.10 aryl or substituted or unsubstituted C 1 . 6 alkyl; R 16 is hydrogen or substituted or unsubstituted C1.6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. 10 In another aspect the invention provides a compound having Formula I wherein: R 1 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 2 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; 15 R3 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; R 4 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; R 5 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 20 NRR 13 1 4 , or OR 15 ; R 6 is hydrogen, halogen, ON, substituted or unsubstituted 01.6 alkyl, OR 12 , 0NRR4, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; 25 R is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; R 9 is 0, C(O), S, S(O), S(O) 2 , -C(=NOR 1 6 )_; a is 1; R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, 30 NR 1 R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl, substituted or unsubstituted C2-6 alkyne, substituted or unsubstituted C2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; 9 WO 2013/130962 PCT/US2013/028607 R 13 is hydrogen or substituted or unsubstituted C1-6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C 1 . 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C610 aryl or can from 5 an optionally substituted heterocycle with R 13 ; R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C610 aryl or substituted or unsubstituted C 1 . 6 alkyl; R 16 is hydrogen or substituted or unsubstituted C1.6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. 10 In another aspect the invention provides a compound having Formula I wherein R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; 15 R4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is hydrogen, halogen, substituted or unsubstituted C1.6 alkyl; R 8 is hydrogen; 20 R 9 is 0, C(O), S, S(O) or S(O) 2 ; a is 1; R" is substituted or unsubstituted C 1 . 6 alkyl, NR R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl; 25 R 13 froms an optionally substituted heterocycle with R 1 4 ; R 1 4 froms an optionally substituted heterocycle with R 13 ; and R 18 is hydrogen. In another aspect the invention provides a compound having Formula I wherein 30 R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; 10 WO 2013/130962 PCT/US2013/028607 R 6 is hydrogen; R 7 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; R 8 is hydrogen; R 9 is 0, C(O), S, S(O) or S(O) 2 ; 5 a is 1; R" is substituted or unsubstituted C 1 . 6 alkyl, NR R 14 , substituted or unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl; R 13 froms an optionally substituted heterocycle with R 1 4 ; 10 R 1 4 froms an optionally substituted heterocycle with R 13 ; and R 18 is hydrogen. In another aspect the invention provides a compound having Formula I wherein R 1 is hydrogen; 15 R 2 is hydrogen; R 3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; 20 R 7 is hydrogen, halogen, substituted or unsubstituted C1.6 alkyl; R 8 is hydrogen; R 9 is C(O); a is 1; R" is substituted or unsubstituted C 1 . 6 alkyl, NR R 14 , substituted or 25 unsubstituted C610 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C3.8 cycloalkyl; R 13 froms an optionally substituted heterocycle with R 1 4 ; R 1 4 froms an optionally substituted heterocycle with R 1 ; and R 1 4 is hydrogen. 30 In another aspect the invention provides a compound having Formula I wherein RI is hydrogen; R 2 is hydrogen; R 3 is hydrogen; 11 WO 2013/130962 PCT/US2013/028607 R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is hydrogen, halogen, substituted or unsubstituted C1-6 alkyl; 5 R 8 is hydrogen; R 9 is S, S(O) or S(O) 2 ; a is 1; R" is substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted heterocycle; and 10 R 18 is hydrogen. In another aspect the invention provides a compound having Formula I wherein R 1 is hydrogen; R 2 is hydrogen; 15 R3 is hydrogen; R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is hydrogen, halogen, substituted or unsubstituted C1.6 alkyl; 20 R 8 is hydrogen; R 9 is 0, C(O); a is 1; R" is substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted heterocycle; and 25 R 18 is hydrogen. In another aspect the invention provides a compound having Formula I wherein R 1 is hydrogen; R 2 is hydrogen; R 3 is hydrogen; 30 R 4 is hydrogen; R 5 is hydrogen; R 6 is hydrogen; R 7 is hydrogen, halogen, substituted or unsubstituted C1.6 alkyl; R 8 is hydrogen; 12 WO 2013/130962 PCT/US2013/028607 R 9 is 0, C(O); a is 1; R 11 is substituted or unsubstituted C 6-10 aryl or substituted or unsubstituted heterocycle; and 5 R 18 is hydrogen. The term "alkyl", as used herein, refers to saturated, monovalent or divalent hydrocarbon moieties having linear or branched moieties or combinations thereof and containing 1 to 6 carbon atoms. One methylene (-CH 2 -) group, of the alkyl can 10 be replaced by oxygen, sulfur, sulfoxide, nitrogen, carbonyl, carboxyl, sulfonyl, or by a divalent C3-6 cycloalkyl. Hydrogen atoms on alkyl groups can be substituted by groups including, but not limited to: halogens, -OH, C3.8 cycloalkyl, non-aromatic heterocycles, aromatic heterocycles, -OC1.6 alkyl, -NH 2 , -NO 2 , amides, carboxylic acids, ketones, ethers, esters, aldehydes, or sulfonamides. 15 The term "cycloalkyl", as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cyclic hydrocarbon. Cycloalkyl groups can be monocyclic or polycyclic. Cycloalkyl can be substituted by groups including, but not limited to: halogens, -OH, C3.8 cycloalkyl, non-aromatic heterocycles, aromatic heterocycles, -OC1.6 alkyl, -NH 2 , -NO 2 , amides, ethers, 20 esters, carboxylic acids, aldehydes, ketones, sulfonamides groups. The term "cycloalkenyl", as used herein, refers to a monovalent or divalent group of 3 to 8 carbon atoms, derived from a saturated cycloalkyl having one or more double bonds. Cycloalkenyl groups can be monocyclic or polycyclic. Cycloalkenyl groups can be substituted by groups including, but not limited to: 25 halogens, -OH, C3.8 cycloalkyl, non-aromatic heterocycles, aromatic heterocycles, OC1.6 alkyl, -NH 2 , -NO 2 , amides, ethers, esters, aldehydes, ketones, carboxylic acids, sulfonamides groups. The term "halogen", as used herein, refers to an atom of chlorine, bromine, fluorine, iodine. 30 The term "alkenyl", as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, 13 WO 2013/130962 PCT/US2013/028607 having at least one double bond. Q2-6 alkenyl can be in the E or Z configuration. Alkenyl groups can be substituted by C1-6 alkyl. The term "alkynyl", as used herein, refers to a monovalent or divalent hydrocarbon radical having 2 to 6 carbon atoms, derived from a saturated alkyl, 5 having at least one triple bond. The term "heterocycle" as used herein, refers to a 3 to 10 membered ring, which can be aromatic or non-aromatic, saturated or unsaturated, containing at least one heteroatom selected from 0 or N or S or combinations of at least two thereof, interrupting the carbocyclic ring structure. The heterocyclic ring can be interrupted by 10 a C=O; the S heteroatom can be oxidized. Heterocycles can be monocyclic or polycyclic. Heterocyclic ring moieties can be substituted by groups including, but not limited to: halogens, -OH, C3.8 cycloalkyl, non-aromatic heterocycles, aromatic heterocycles, -OC1.6 alkyl, -NH 2 , -NO 2 , amides, ethers, esters, aldehydes, carboxylic acids, ketones, sulfonamides groups. 15 The term "aryl" as used herein, refers to an organic moiety derived from an aromatic hydrocarbon consisting of a ring containing 6 to 10 carbon atoms by removal of one hydrogen. Aryl can be monocyclic or polycyclic Aryl can be substituted by groups including, but not limited to: halogens, -OH, C3.8 cycloalkyl, non-aromatic heterocycles, aromatic heterocycles, -OC1.6 alkyl, -NH 2 , -NO 2 , amides, 20 ethers, esters, carboxylic acids, ketones, aldehydes, sulfonamides groups. The term "amide" as used herein, represents a group of formula "-C(O)NRR" or wherein Rxand RY are the same or independently H or C 1-6 alkyl. The term "ketone" as used herein, represents a group of formula "-C(O)R" wherein Rx is C 1-6 alkyl. 25 The term "ester" as used herein, represents a group of formula "-C(O)OR" wherein Rx is C 1-6 alkyl. The term "ether" as used herein, represents a group of formula "-OR" wherein Rx is C 1-6 alkyl. The term "aldehyde" as used herein, represents a group of formula "-C(O)H". . 30 The term "sulfonamide" as used herein, represents a group of formula " S(O) 2 NRWRY" wherein Rxand RY are the same or independently H or C 1-6 alkyl. 14 WO 2013/130962 PCT/US2013/028607 The term "hydroxyl" as used herein, represents a group of formula "-OH". The term "amino" as used herein, represents a group of formula "-NH 2 ". The term "carbonyl" as used herein, represents a group of formula "-C(O)-". The term "carboxyl" as used herein, represents a group of formula "-C(0)0-". 5 The term "sulfonyl" (sulfone) as used herein, represents a group of formula S02-". The term "sulfate" as used herein, represents a group of formula "-O-S(0)2-0 The term "carboxylic acid" as used herein, represents a group of formula 10 C(O)OH". The term "sulfoxide" as used herein, represents a group of formula "-S(O)-". The term "phosphonic acid" as used herein, represents a group of formula P(O)(OH) 2 ". The term "phosphoric acid" as used herein, represents a group of formula "-0 15 P(O)(OH) 2 ". The term "sulphonic acid" as used herein, represents a group of formula S(O) 2 0H". The formula "H ", as used herein, represents a hydrogen atom. The formula "0 ", as used herein, represents an oxygen atom. 20 The formula "N ", as used herein, represents a nitrogen atom. The formula "S ", as used herein, represents a sulfur atom Compounds of the invention are: N-[2-(benzylsulfanyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; 25 N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfanyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; 30 N-(5-chloro-2-{[(1 -oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1 -benzofuran-2 sulfonamide; N-[2-(benzylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 15 WO 2013/130962 PCT/US2013/028607 N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; tert-butyl {3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfonyl)methyl]phenyl}carbamate; 5 N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfanyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; 10 N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; 15 N-{5-chloro-2-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; 2-({3-[(l-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoic acid; methyl 2-({3-[(l-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoate; N-[5-chloro-2-(morpholin-4-ylcarbonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(4-oxopiperidin-1 -yl)carbonyl]pyridin-3-yl}-1 -benzofuran-2 20 sulfonamide; N-[5-chloro-2-(phenylcarbonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 25 N-{5-ch loro-2-[(2-methyl pyrid in-3-yl)methoxy] pyrid in-3-yl}- 1 -benzofuran-2 sulfonamide; N-[5-chloro-2-(phenylacetyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfanyl)methyl]benzoate; 30 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfinyl)methyl]benzoate; 16 WO 2013/130962 PCT/US2013/028607 methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfonyl)methyl]benzoate; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoic acid; 5 N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoic acid; 10 N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 3-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 15 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoic acid; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoic acid; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2 yl}sulfanyl)methyl]benzoic acid; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoic 20 acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfanyl)methyl]benzoate; 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate; 25 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfonyl)methyl]benzoate; 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoic acid. 30 Some compounds of Formula I and some of their intermediates have at least one stereogenic center in their structure. This stereogenic center may be present in an R or S configuration, said R and S notation is used in correspondence with the rules described in Pure Appli. Chem. (1976), 45, 11-13. 17 WO 2013/130962 PCT/US2013/028607 The term "pharmaceutically acceptable salts" refers to salts or complexes that retain the desired biological activity of the above identified compounds and exhibit minimal or no undesired toxicological effects. The "pharmaceutically acceptable salts" according to the invention include therapeutically active, non-toxic base or acid 5 salt forms, which the compounds of Formula I are able to form. The acid addition salt form of a compound of Formula I that occurs in its free form as a base can be obtained by treating the free base with an appropriate acid such as an inorganic acid, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; or an organic acid such as for example, 10 acetic, hydroxyacetic, propanoic, lactic, pyruvic, malonic, fumaric acid, maleic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, citric, methylsulfonic, ethanesulfonic, benzenesulfonic, formic acid and the like (Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- ZOrich, 2002, 329-345). 15 The base addition salt form of a compound of Formula I that occurs in its acid form can be obtained by treating the acid with an appropriate base such as an inorganic base, for example, sodium hydroxide, magnesium hydroxide, potassium hydroxide, calcium hydroxide, ammonia and the like; or an organic base such as for example, L-Arginine, ethanolamine, betaine, benzathine, morpholine and the like. 20 (Handbook of Pharmaceutical Salts, P.Heinrich Stahal& Camille G. Wermuth (Eds), Verlag Helvetica Chemica Acta- ZOrich, 2002, 329-345). Compounds of Formula I and their salts can be in the form of a solvate, which is included within the scope of the present invention. Such solvates include for example hydrates, alcoholates and the like. 25 With respect to the present invention reference to a compound or compounds, is intended to encompass that compound in each of its possible isomeric forms and mixtures thereof unless the particular isomeric form is referred to specifically. Compounds according to the present invention may exist in different polymorphic forms. Although not explicitly indicated in the above formula, such forms 30 are intended to be included within the scope of the present invention. 18 WO 2013/130962 PCT/US2013/028607 The compounds of the invention are indicated for use in treating or preventing conditions in which there is likely to be a component involving the chemokine receptors. In another embodiment, there are provided pharmaceutical compositions 5 including at least one compound of the invention in a pharmaceutically acceptable carrier. In a further embodiment of the invention, there are provided methods for treating disorders associated with modulation of chemokine receptors. Such methods can be performed, for example, by administering to a subject in need 10 thereof a pharmaceutical composition containing a therapeutically effective amount of at least one compound of the invention. These compounds are useful for the treatment of mammals, including humans, with a range of conditions and diseases that are alleviated by chemokine receptor modulation. 15 Therapeutic utilities of chemokine receptor modulators are skin inflammatory diseases and conditions, including, but are not limited to: rosacea (dilation of the blood vessels just under the skin), sunburn, chronic sun damage, discreet erythemas, psoriasis, atopic dermatitis, menopause-associated hot flashes, hot flashes resulting from orchiectomyatopic dermatitis, photoaging, seborrheic 20 dermatitis, acne, allergic dermatitis, irritant dermatitis, telangiectasia (dilations of previously existing small blood vessels ) of the face, rhinophyma (hypertrophy of the nose with follicular dilation), red bulbous nose, acne-like skin eruptions (may ooze or crust), burning or stinging sensation of the face, irritated and bloodshot and watery eyes, cutaneous hyperactivity with dilation of blood vessels of the skin, Lyell's 25 syndrome, Stevens-Johnson syndrome, erythema multiforme minor, erythema multiforme major and other inflammatory skin diseases, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, wound healing. Therapeutic utilities of chemokine receptor modulators are ocular 30 inflammatory diseases including, but not limited to, uveitis, dry eye, keratitis, allergic eye disease and conditions affecting the posterior part of the eye, such as 19 WO 2013/130962 PCT/US2013/028607 maculopathies and retinal degeneration including non-exudative age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; 5 uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, 10 Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/ exudative diseases such as retinal arterial occlusive disease, central retinal vein occlusion, disseminated intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal 15 artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, and Eales disease; traumatic/ surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal detachment, trauma, conditions caused by laser, conditions caused by 20 photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular toxocariasis, presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, 25 retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic disorders such as retinitis pigmentosa, systemic disorders with accosiated retinal 30 dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, and pseudoxanthoma elasticum; retinal tears/ holes such as retinal detachment, macular hole, and giant 20 WO 2013/130962 PCT/US2013/028607 retinal tear; tumors such as retinal disease associated with tumors, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of 5 the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors; and miscellaneous other diseases affecting the posterior part of the eye such as punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigement epitheliitis. In still another embodiment of the invention, there are provided methods for 10 treating disorders associated with modulation of chemokine receptors. Such methods can be performed, for example, by administering to a subject in need thereof a therapeutically effective amount of at least one compound of the invention, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual isomers, enantiomers, and diastereomers thereof. 15 The present invention concerns the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of ocular inflammatory diseases including, but not limited to, uveitis, dry eye, Keratitis, allergic eye disease and conditions affecting the posterior part of the eye, such as maculopathies and retinal degeneration including non-exudative 20 age related macular degeneration, exudative age related macular degeneration, choroidal neovascularization, diabetic retinopathy, acute macular neuroretinopathy, central serous chorioretinopathy, cystoid macular edema, and diabetic macular edema; uveitis, retinitis, and choroiditis such as acute multifocal placoid pigment epitheliopathy, Behcet's disease, birdshot retinochoroidopathy, infectious (syphilis, 25 lyme, tuberculosis, toxoplasmosis), intermediate uveitis (pars planitis), multifocal choroiditis, multiple evanescent white dot syndrome (mewds), ocular sarcoidosis, posterior scleritis, serpiginous choroiditis, subretinal fibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome; vasuclar diseases/ exudative diseases such as retinal arterial occlusive disease, central retinal vein occlusion, disseminated 30 intravascular coagulopathy, branch retinal vein occlusion, hypertensive fundus changes, ocular ischemic syndrome, retinal arterial microaneurysms, Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion, papillophlebitis, central retinal 21 WO 2013/130962 PCT/US2013/028607 artery occlusion, branch retinal artery occlusion, carotid artery disease (CAD), frosted branch angiitis, sickle cell retinopathy and other hemoglobinopathies, angioid streaks, familial exudative vitreoretinopathy, and Eales disease; traumatic/ surgical conditions such as sympathetic ophthalmia, uveitic retinal disease, retinal 5 detachment, trauma, conditions caused by laser, conditions caused by photodynamic therapy, photocoagulation, hypoperfusion during surgery, radiation retinopathy, and bone marrow transplant retinopathy; proliferative disorders such as proliferative vitreal retinopathy and epiretinal membranes, and proliferative diabetic retinopathy; infectious disorders such as ocular histoplasmosis, ocular toxocariasis, 10 presumed ocular histoplasmosis syndrome (POHS), endophthalmitis, toxoplasmosis, retinal diseases associated with HIV infection, choroidal disease associate with HIV infection, uveitic disease associate with HIV infection, viral retinitis, acute retinal necrosis, progressive outer retinal necrosis, fungal retinal diseases, ocular syphilis, ocular tuberculosis, diffuse unilateral subacute neuroretinitis, and myiasis; genetic 15 disorders such as retinitis pigmentosa, systemic disorders with accosiated retinal dystrophies, congenital stationary night blindness, cone dystrophies, Stargardt's disease and fundus flavimaculatus, Best's disease, pattern dystrophy of the retinal pigmented epithelium, X-linked retinoschisis, Sorsby's fundus dystrophy, benign concentric maculopathy, Bietti's crystalline dystrophy, and pseudoxanthoma 20 elasticum; retinal tears/ holes such as retinal detachment, macular hole, and giant retinal tear; tumors such as retinal disease associated with tumors, congenital hypertrophy of the retinal pigmented epithelium, posterior uveal melanoma, choroidal hemangioma, choroidal osteoma, choroidal metastasis, combined hamartoma of the retina and retinal pigmented epithelium, retinoblastoma, vasoproliferative tumors of 25 the ocular fundus, retinal astrocytoma, and intraocular lymphoid tumors; and miscellaneous other diseases affecting the posterior part of the eye such as punctate inner choroidopathy, acute posterior multifocal placoid pigment epitheliopathy, myopic retinal degeneration, and acute retinal pigement epitheliitis. The actual amount of the compound to be administered in any given case will 30 be determined by a physician taking into account the relevant circumstances, such as the severity of the condition, the age and weight of the patient, the patient's general physical condition, the cause of the condition, and the route of administration. 22 WO 2013/130962 PCT/US2013/028607 The patient will be administered the compound orally in any acceptable form, such as a tablet, liquid, capsule, powder and the like, or other routes may be desirable or necessary, particularly if the patient suffers from nausea. Such other routes may include, without exception, transdermal, parenteral, subcutaneous, 5 intranasal, via an implant stent, intrathecal, intravitreal, topical to the eye, back to the eye, intramuscular, intravenous, and intrarectal modes of delivery. Additionally, the formulations may be designed to delay release of the active compound over a given period of time, or to carefully control the amount of drug released at a given time during the course of therapy. 10 In another embodiment of the invention, there are provided pharmaceutical compositions including at least one compound of the invention in a pharmaceutically acceptable carrier thereof. The phrase "pharmaceutically acceptable" means the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 15 Pharmaceutical compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a patch, a micelle, a liposome, and the like, wherein the resulting composition contains one or more compounds of the present invention, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications. Invention 20 compounds may be combined, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, 25 urea, medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form. In addition auxiliary, stabilizing, thickening and coloring agents and perfumes may be used. Invention compounds are included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or disease condition. 30 Pharmaceutical compositions containing invention compounds may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or 23 WO 2013/130962 PCT/US2013/028607 syrups or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of a sweetening agent such as sucrose, lactose, or saccharin, flavoring 5 agents such as peppermint, oil of wintergreen or cherry, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets containing invention compounds in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods. The excipients used may be, for example, (1) inert diluents such as 10 calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents such as corn starch, potato starch or alginic acid; (3) binding agents such as gum tragacanth, corn starch, gelatin or acacia, and (4) lubricating agents such as magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and 15 absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. In some cases, formulations for oral use may be in the form of hard gelatin capsules wherein the invention compounds are mixed with an inert solid diluent, for 20 example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the invention compounds are mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil. The pharmaceutical compositions may be in the form of a sterile injectable suspension. This suspension may be formulated according to known methods using 25 suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 butanediol. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic 30 mono- or diglycerides, fatty acids (including oleic acid), naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty 24 WO 2013/130962 PCT/US2013/028607 vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required. Invention compounds and their pharmaceutically-acceptable salts may be administered through different routes, including but not limited to topical eye drops, 5 direct injection, application at the back of the eye or formulations that may further enhance the long duration of actions such as a slow releasing pellet, suspension, gel, or sustained delivery devices such as any suitable drug delivery system (DDS) known in the art. While topical administration is preferred, this compound may also be used in an intraocular implant as described in U.S. Patent 7,931,909. 10 Invention compounds may also be administered in the form of suppositories for rectal administration of the drug. These compositions may be prepared by mixing the invention compounds with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols, which are solid at ordinary temperatures, but liquefy and/or dissolve in the rectal cavity to release the drug. 15 Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration and dosage employed for each subject is left to the discretion of the practitioner. The compounds and pharmaceutical compositions described herein are 20 useful as medicaments in mammals, including humans, for treatment of diseases and/or alleviations of conditions which are responsive to treatment by agonists or functional antagonists of chemokine receptors. Thus, in further embodiments of the invention, there are provided methods for treating a disorder associated with modulation of chemokine receptors. Such methods can be performed, for example, 25 by administering to a subject in need thereof a pharmaceutical composition containing a therapeutically effective amount of at least one invention compound. As used herein, the term "therapeutically effective amount" means the amount of the pharmaceutical composition that will elicit the biological or medical response of a subject in need thereof that is being sought by the researcher, veterinarian, medical 30 doctor or other clinician. In some embodiments, the subject in need thereof is a mammal. In some embodiments, the mammal is human. 25 WO 2013/130962 PCT/US2013/028607 The present invention concerns also processes for preparing the compounds of Formula 1. The compounds of formula I according to the invention can be prepared analogously to conventional methods as understood by the person skilled in the art of synthetic organic chemistry. The described benzofuran-2-sulfonamide derivatives 5 were prepared by methods as shown in Scheme 1. Those skilled in the art will be able to routinely modify and/or adapt Scheme 1 to synthesize any compounds of the invention covered by Formula 1. Scheme 1 R5 R4 R 3 C102S R5 R4 O R 2 R3 R 6 H R1 R 6 So 2 N7 R 7N 0 R2 R ,R18 R ,R18 R 1R 1 R 8 N/l, R1 pyridine R1 10 R N R9a R8 N R9 DETAILED DESCRIPTION OF THE INVENTION It is to be understood that both the foregoing general description and the 15 following detailed description are exemplary and explanatory only and are not restrictive of the invention claimed. As used herein, the use of the singular includes the plural unless specifically stated otherwise. It will be readily apparent to those skilled in the art that some of the compounds of the invention may contain one or more asymmetric centers, such that 20 the compounds may exist in enantiomeric as well as in diastereomeric forms. Unless it is specifically noted otherwise, the scope of the present invention includes all enantiomers, diastereomers and racemic mixtures. Some of the compounds of the invention may form salts with pharmaceutically acceptable acids or bases, and such pharmaceutically acceptable salts of the compounds described herein are also 25 within the scope of the invention. 26 WO 2013/130962 PCT/US2013/028607 The present invention includes all pharmaceutically acceptable isotopically enriched compounds. Any compound of the invention may contain one or more isotopic atoms enriched or different than the natural ratio such as deuterium 2H (or D) in place of protium 1H (or H) or use of 13 C enriched material in place of 12C and 5 the like. Similar substitutions can be employed for N, 0 and S. The use of isotopes may assist in analytical as well as therapeutic aspects of the invention. For example, use of deuterium may increase the in vivo half-life by altering the metabolism (rate) of the compounds of the invention. These compounds can be prepared in accord with the preparations described by use of isotopically enriched reagents. 10 As will be evident to those skilled in the art, individual isomeric forms can be obtained by separation of mixtures thereof in conventional manner. For example, in the case of diasteroisomeric isomers, chromatographic separation may be employed. Compound names were generated with ACD version 12.0 and some 15 intermediates' and reagents' names used in the examples were generated with software such as Chem Bio Draw Ultra version 12.0 or Auto Nom 2000 from MDL ISIS Draw 2.5 SP1. In general, characterization of the compounds is performed according to the following methods: NMR spectra are recorded on Varian 600 or Varian 300, in the indicated 20 solvent at ambient temperature; chemical shifts in [pm], coupling constants in [Hz]. All the reagents, solvents, catalysts for which the synthesis is not described are purchased from chemical vendors such as Sigma Aldrich, Fluka, Bio-Blocks, Combi-blocks, TCI, VWR, Lancaster, Oakwood, Trans World Chemical, Alfa, Fisher, Maybridge, Frontier, Matrix, Ukrorgsynth, Toronto, Ryan Scientific, SiliCycle, 25 Anaspec, Syn Chem, Chem-Impex, MIC-scientific, Ltd; however some known intermediates were prepared according to published procedures. Solvents were purchased from commercial sources in appropriate quality and used as received. Air and/or moisture-sensitive reactions were run under an Ar- or N 2 - atmosphere. Usually the compounds of the invention were purified by chromatography: 30 CombiFlash Companion and RediSep Rf silica gel 60 (0.04-0.063 mm); Preparative thin layer chromatography (PTLC): Analtech (silica gel 60 F 254 , 500 or 1000 pm). 27 WO 2013/130962 PCT/US2013/028607 The following abbreviations are used in the examples: CH 2 CI 2 dichloromethane AcOH acetic acid 5 NaOH sodium hydroxide MeOH methanol CD 3 0D deuterated methanol HCI hydrochloric acid DMF dimethylformamide 10 EtOAc ethyl acetate CDCl 3 deuterated chloroform CHCl 3 chloroform DMSO-d 6 deuterated dimethyl sulfoxide THF tetrahydrofuran 15 K 2 CO 3 potassium carbonate Et 3 N triethylamine Na 2 SO 4 sodium sulfate iPr 2 NEt N, N'-diisopropylethylamine MPLC medium pressure liquid chromatography 20 NH 4 CI Ammonium chloride mCPBA 3-Chloroperoxybenzoic acid KOH potassium hydroxide Et 2 O diethylether EDCI I -ethyl-3-(3-dimethylaminopropyl)carbodiimide) 25 POCl 3 Phosphoryl chloride TFA 2,2,2-Trifluoroethanoic acid K 2 CO 3 potassium carbonate Na 2 S-9H 2 O Sodium Sulfide Nonahydride 30 Example 1 Intermediate 1 5-chloro-3-nitropyridine-2-thiol CI NO 2 N SH 28 WO 2013/130962 PCT/US2013/028607 To a solution of 2,5-dichloro-3-nitropyridine (524 mg, 2.70 mmol) in dioxane (5 ml) and water (1 ml) was added Na 2 S-9H 2 0 and the reaction was stirred at rt for 2 hours. The reaction was quenched with 1 N HCI and then extracted with EtOAc (2 x 30 ml). 5 The organic layer was washed with water, brine and dried over Na 2 SO 4 anhydride and concentrated in vacuo. The crude residue was purified by silica gel column chromatography (30% EtOAc in Hexane) to give Intermediate 1 (378 mg,74%). H NMR (600 MHz, CDCI 3 ) 5 8.54 (d, J = 2.05 Hz, 1 H), 8.51 (d, J = 2.05 Hz, 1 H). Example 2 10 Intermediate 2 2-(benzvlthio)-5-chloro-3-nitropyridine CI NO 2 N S A mixture of Intermediate 1 (332 mg, 1.74 mmol), (bromomethyl)benzene (299 mg, 15 1.74 mmol) and K 2 CO 3 (1.2 g, 8.74 mmol) in DMF (10 ml) was stirred at room temperature over night. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 anhydride, concentrated in vacuo and purified by column chromatography (0 - 30 % ethyl acetate in hexane) to give Intermediate 2 20 (417 mg, 85%). 1 H NMR (600 MHz, acetone) 5 8.88 (d, J = 2.35 Hz, 1 H), 8.65 (d, J = 2.05 Hz, 1 H), 7.41 - 7.52 (m, 2H), 7.29 - 7.34 (m, 2H), 7.23 - 7.28 (m, 1 H), 4.50 (s, 2H). Example 3 Intermediate 3 25 2-(benzvlthio)-5-chloropyridin-3-amine CI NH 2 N S 29 WO 2013/130962 PCT/US2013/028607 Intermediate 2 (417 mg, 1.49 mmol) was dissolved in MeOH (30 ml). Zn (2.4 g, 37.23 mmol) and NH 4 CI (1 ml) was added to the solution. After the mixture was stirred for 10 min at room temperature, the solid was filtered and the filtrate was concentrated in vacuo and then the crude residue was purified by column 5 chromatography (0 - 30 % EtOAc in hexane) to afford Intermediate 3 (326 mg, 88%). 1 H NMR (600 MHz, acetone) 6 7.82 (d, J = 2.05 Hz, 1 H), 7.40 (d, J = 7.63 Hz, 2H), 7.28 (t, J = 7.48 Hz, 2H), 7.18 - 7.24 (m, 1H), 7.03 (s, 1H), 4.44 (s, 2H). Example 4 10 Compound 1 N-[2-(benzvlthio)-5-chloropyridin-3-vil-1 -benzofuran-2-sulfonamide 0 aI NH 0 ci N S A mixture of Intermediate 3 (326 mg, 1.30 mmol) and benzofuran-2-sulfonyl chloride 15 (281 mg, 1.30 mmol) in pyridine (3 ml) was heated at 100 OC overnight. Pyridine was removed by reduced pressure and the residue was loaded on silica gel column directly and isolated Compound 1 with 30% EtOAc in Hexane ( 277 mg, 50%). 1 H NMR (600 MHz, acetone) 5 9.25 (br. s., 1H), 8.40 (d, J = 2.35 Hz, 1H), 7.71 - 7.79 (m, 2H), 7.50 - 7.61 (m, 2H), 7.44 (d, J = 0.88 Hz, 1H), 7.38 - 7.42 (m, 1H), 7.12 20 7.19 (m, 3H), 6.98 - 7.07 (m, 2H), 4.18 (s, 2H). Example 5 Compound 2 N-[2-(benzvlsulfinyl)-5-chloropyridin-3-vil-1 -benzofuran-2-sulfonamide 0 11S / K1:Z K- C1 N S 25 N 30 WO 2013/130962 PCT/US2013/028607 To a solution of Compound 1 (219 mg, 0.509 mmol) in CH 2 CI 2 (10 ml) at 00C was added mCPBA (102 mg, 0.509 mmol). After it was stirred for 30 min at 00C, the mixture was separated into two portions. One portion (5 ml) was concentrated in vacuo and purified by silica gel column chromatography (0 - 100 % EtOAc in hexane 5 followed by 0 - 10% MeOH in CH 2 CI 2 ) to give Compound 2 as a solid (92 mg). 1 H NMR (300 MHz, CD 3 OD) 6 7.88 (s, 1H), 7.81 (br. s., 1H), 7.62 - 7.71 (m, 1H), 7.03 - 7.45 (m, 9H), 4.52 (d, J = 12.89 Hz, 1H), 4.25 (d, J = 12.89 Hz, 1H). Example 6 10 Compound 3 N-[2-(benzvlsulfonyl)-5-chloropyridin-3-vil-1 -benzofuran-2-sulfonamide 0S CI CI N H 0 N S To the other portion (5 ml) of the reaction from Example 5 was added mCPBA (110 15 mg, 0.548 mmol) and the reaction was stirred at rt for 2 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0 - 100 % EtOAc in hexane) to give Compound 3 as a solid (63 mg). 1 H NMR (600 MHz, CD 3 OD) 5 8.18 (d, J = 2.05 Hz, 1H), 7.63 - 7.72 (m, 2H), 7.32 7.45 (m, 3H), 7.23 - 7.30 (m, 1H), 7.08 - 7.15 (m, 3H), 6.95 - 7.04 (m, 2H), 4.83 (s, 20 2H). Example 7 Intermediate 4 25 5-chloro-3-nitro-2-((Dvridin-3-vimethvl)thio)Dvridine CI NO 2 In N S N 31 WO 2013/130962 PCT/US2013/028607 To a solution of Intermediate 1 (416 mg, 2.19 mmol) in DMF (10 ml) was added 3 (bromomethyl)pyridine hydrobromide(554 mg, 2.19 mmol) and K 2 CO 3 (1.5 g, 10.95 mmol) and stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was 5 washed with brine and then dried over Na 2 SO 4 , concentrated in vacuo and purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give Intermediate 4 (462 mg, 75%). 1 H NMR (600 MHz, CD 3 OD) 5 8.80 (d, J = 2.35 Hz, 1 H), 8.65 (d, J = 2.35 Hz, 1 H), 8.64 (d, J = 2.05 Hz, 1 H), 8.39 (dd, J = 1.32, 4.84 Hz, 1 H), 7.94 (ddd, J = 1.61, 1.91, 10 8.22 Hz, 1H), 7.37 (dd, J = 5.14, 7.48 Hz, 1H), 4.52 (s, 2H). Example 8 Intermediate 5 5-chloro-2-((Dvridin-3-vimethvl)thio)Dyridin-3-amine CI NH 2 N S N 15 To a solution Intermediate 4 (460 mg, 1.64 mmol) in MeOH (20 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (2.7 g, 41.07 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and 20 concentrated in vacuo. The crude Intermediate 5 (314 mg, 76%) was used in the next reaction without further purification. 1 H NMR (600 MHz, CD 3 OD) 5 8.47 (d, J = 1.76 Hz, 1 H), 8.35 (dd, J = 1.47, 4.99 Hz, 1 H), 7.81 (dt, J = 1.91, 7.92 Hz, 1 H), 7.77 (d, J = 2.05 Hz, 1 H), 7.23 - 7.41 (m, 1 H), 6.98 (d, J = 2.35 Hz, 1 H), 4.38 (s, 2H). 25 Example 9 Compound 4 N-{5-chloro-2-[(Dyridin-3-vlmethvl)thiolDyridin-3-vil-1 -benzofuran-2 sulfonamide 32 WO 2013/130962 PCT/US2013/028607 0 CI H N S N To Intermediate 5 (310mg, 1.24 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (268 mg, 1.24 mmol) and the reaction was stirred at 100 C for 16 5 hours, then additional benzofuran-2-sulfonyl chloride (268 mg, 1.24 mmol) was added and the mixture was heated for another 24 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 4 (201 mg, 38%). 'H NMR (600 MHz, CD 3 OD) 5 8.47 (s, 1H), 8.29 (d, J = 4.70 Hz, 1H), 7.87 (d, J = 10 1.47 Hz, 1 H), 7.66 (d, J = 7.63 Hz, 1 H), 7.59 (d, J = 7.63 Hz, 1 H), 7.50 (d, J = 2.35 Hz, 1H), 7.46 (d, J = 8.22 Hz, 1H), 7.36 (td, J = 1.03, 7.85 Hz, 1H), 7.17 - 7.29 (m, 2H), 7.08 (s, 1 H), 4.23 (s, 2H). Example 10 15 Compound 5 N-{5-ch loro-2-4hyrid in-3-vimethvl)su IfinvilDyridin-3-vIl-1 -benzofuran-2 sulfonamide 0 0I SH CI C1 N N N S' N To a solution of Compound 4 (77 mg, 0.18 mmol) in CH 2 CI 2 (10 ml) at 0 0C was 20 added mCPBA (36 mg, 0.18 mmol). After it was stirred for 30 min at 0 0C, the mixture was concentrated in vacuo and purified by silica gel column chromatography (0 - 100 % EtOAc in hexane followed by 0 - 10% MeOH in CH 2 CI 2 ) to give Compound 5 (50 mg, 62%). 1 H NMR (600 MHz, CD 3 OD) 5 8.32 (dd, J = 1.17, 4.99 Hz, 1H), 8.05 (d, J = 1.47 Hz, 25 1H), 7.87 (d, J = 1.47 Hz, 1H), 7.76 (d, J = 1.76 Hz, 1H), 7.68 (d, J = 7.63 Hz, 1H), 7.39 - 7.45 (m, 2H), 7.30 - 7.37 (m, 2H), 7.24 - 7.29 (m, J = 7.63 Hz, 1H), 7.18 (dd, J = 4.99, 7.63 Hz, 1H), 4.59 (d, J = 13.21 Hz, 2H), 4.45 (d, J = 13.50 Hz, 1H). 33 WO 2013/130962 PCT/US2013/028607 Example 11 Compound 6 N-45-chloro-2-[(Dvridin-3-vimethvl)sulfonvllDyridin-3-vl}-1 -benzofuran-2 5 sulfonamide 0 / S. C1 NH N S N and Compound 7 N-(5-chloro-2-{[ (-oxidopyridin-3-vl)methvllsulfonvl}Dyridin-3-vl)-1 -benzofuran 10 2-sulfonamide O O=S CI NH NS N+-O To a solution of Compound 4 (79 mg, 0.18 mmol) in CH 2 CI 2 (10 ml) was added mCPBA (92 mg, 0.46 mmol), and the solution was stirred at room temperature for 2 15 hours. It was concentrated in vacuo and purified by silica gel column chromatography (0 - 100 % EtOAC in hexane followed by 0 - 10% MeOH in CH 2 CI 2 ) to isolate Compound 6 (11 mg) and Compound 7 ( 15 mg). Compound 6: 1 H NMR (600 MHz, CD 3 OD) 5 8.44 (d, J = 1.47 Hz, 1H), 8.35 (dd, J = 1.17, 4.99 Hz, 1H), 8.14 (d, J = 2.05 Hz, 1H), 7.72 (d, J = 2.05 Hz, 1H), 7.68 20 (d, J = 7.92 Hz, 2H), 7.45 (d, J = 8.22 Hz, 1 H), 7.33 - 7.40 (m, 2H), 7.23 - 7.32 (m, 1H), 7.17 (dd, J = 4.99, 7.92 Hz, 1H), 5.15 (s, 2H). Compound 7 : 1 H NMR (600 MHz, CD 3 OD) 5 8.40 (s, 1H), 8.19 (d, J = 6.46 Hz, 1H), 8.13 (d, J = 2.05 Hz, 1H), 7.86 (s, 1H), 7.68 (d, J = 7.34 Hz, 1H), 7.50 (d, J = 8.51 Hz, 1H), 7.46 (d, J = 7.92 Hz, 1H), 7.34 - 7.42 (m, 2H), 7.26 - 7.33 (m, 2H), 5.15 25 (s, 2H). 34 WO 2013/130962 PCT/US2013/028607 Example 12 Intermediate 6 2-(benzylthio)-3-nitropyridine NO2 N S 5 To a solution of 3-nitropyridine-2-thiol (1.0 g, 6.41 mmol) in DMF (30 ml) was added (bromomethyl)benzene (1.10 g, 6.41 mmol) and K 2 CO 3 (4.4 g, 32.05 mmol), and the reaction was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 , concentrated in vacuo and 10 purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give Intermediate 6 (1.49 g, 94%). 1 H NMR (600 MHz, CD 3 OD) 5 8.70 - 8.79 (m, 1 H), 8.55 (dd, J = 1.17, 8.22 Hz, 1 H), 7.39 - 7.44 (m, 2H), 7.33 (dd, J = 4.55, 8.36 Hz, 1H), 7.29 (t, J= 7.63 Hz, 2H), 7.19 7.25 (m, 1 H), 4.48 (s, 3H). 15 Example 13 Intermediate 7 2-(benzylthio)pyridin-3-amine NH 2 N S 20 To a solution Intermediate 6 (1.49 g, 6.06 mmol) in MeOH (100 ml) was added saturated aqueous NH 4 CI (4 ml) and zinc dust (7.8 g, 121.1 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude Intermediate 7 (1 g, 76%) was used 25 in the next reaction without further purification. H NMR (600 MHz, CD 3 OD) 6 7.80 - 7.84 (m, 1H), 7.25 - 7.30 (m, 2H), 7.20 - 7.24 (m, 2H), 7.15 - 7.19 (m, 1H), 6.95 - 7.02 (m, 2H), 4.30 (s, 2H). Example 14 Compound 8 35 WO 2013/130962 PCT/US2013/028607 N-[2-(benzvlthio)pvridin-3-vIl-1 -benzofuran-2-sulfonamide 0 o=S ~NH 0 N S To Intermediate 7 (553mg, 2.56 mmol) in pyridine (5 ml) was added benzofuran-2 5 sulfonyl chloride (553 mg, 2.56 mmol), and the reaction was stirred at 100 C for 16 hours, then additional benzofuran-2-sulfonyl chloride (553 mg, 2.56 mmol) was added, and the reaction was heated for another 24 hours, and the mixture was concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 8 (800 10 mg, 79%). H NMR (600 MHz, CD 3 OD) 5 8.29 (dd, J = 1.61, 4.84 Hz, 1 H), 7.65 (d, J = 7.92 Hz, 1 H), 7.60 (dd, J = 1.61, 7.78 Hz, 1 H), 7.41 - 7.51 (m, 2H), 7.33 (ddd, J = 2.20, 5.94, 8.00 Hz, 1H), 7.24 (s, 1H), 7.01 - 7.14 (m, 4H), 6.92 (dd, J = 1.47, 7.63 Hz, 2H), 4.11 (s, 2H). 15 Example 15 Compound 9 N-[2-(benzvlsulfinvl)pvridin-3-vil-1 -benzofuran-2-sulfonamide 0 036/ ~NH 0 N SK 200 To a solution of Compound 8 (228 mg, 0.58 mmol) in CH 2 CI 2 (10 ml) at 0 00 was added mCPBA (116 mg, 0.58 mmol). After it was stirred for 30 min at 0 00, the mixture was separated into two portions. One portion (5 ml) was concentrated in 25 vacuo and purified by silica gel column chromatography (0 - 100 % EtOAC in hexane followed by 0 - 10% MeGH in CH 2 CI 2 ) to give Compound 9 (205 mg, 86%). 36 WO 2013/130962 PCT/US2013/028607 'H NMR (600 MHz, CD 3 OD) 5 8.42 (dd, J = 1.03, 4.55 Hz, 1 H), 7.86 (dd, J = 1.03, 8.36 Hz, 1H), 7.73 (d, J = 9.10 Hz, 1H), 7.56 (d, J= 8.51 Hz, 1H), 7.47 - 7.52 (m, 2H), 7.44 - 7.47 (m, 1 H), 7.32 - 7.38 (m, 1 H), 7.11 - 7.22 (m, 3H), 7.05 (d, J = 7.04 Hz, 2H), 4.34 (d, J = 12.91, 1H), 4.25 (d, J = 13.21, 1H). 5 Example 16 Compound 10 N-[2-(benzvlsulfonyl)pyridin-3-yll-1 -benzofuran-2-sulfonamide 0 ~NH 0 NS 10 To a solution of Compound 8 (360 mg, 0.91 mmol) in CH 2 CI 2 (10 ml) at room temperature was added mCPBA (365 mg, 1.82 mmol). After it was stirred for 2 hours at room temperature, the mixture was concentrated in vacuo and purified by silica gel column chromatography (0 - 100 % EtOAc in hexane) to give Compound 10 15 (124 mg, 32%). 1 H NMR (600 MHz, CD 3 OD) 5 8.13 (dd, J = 1.03, 8.95 Hz, 1 H), 7.74 (dd, J = 0.73, 4.26 Hz, 1 H), 7.66 (d, J = 7.34 Hz, 1 H), 7.38 - 7.43 (m, 1 H), 7.32 - 7.37 (m, 2H), 7.23 - 7.31 (m, 2H), 7.08 - 7.17 (m, 3H), 6.95 - 7.05 (m, 2H), 5.06 (s, 2H). 20 Example 17 Intermediate 8 tert-butyl (3-(((3-n itroivrid in-2-vl)th io)methyl)Phenvl)carbamate NO 2 NHBoc N S' 25 To 3-nitropyridine-2-thiol (532 mg, 3.41 mmol) in DMF (10 ml) was added tert-butyl (3-(bromomethyl)phenyl)carbamate (976 mg, 3.41 mmol) and K 2 CO 3 (2.35g, 17.05 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction 37 WO 2013/130962 PCT/US2013/028607 mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 , concentrated in vacuo and purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give Intermediate 8 (1.22 g, 100%). 5 'H NMR (600 MHz, CD 3 OD) 5 8.76 (d, J = 4.70 Hz, 1 H), 8.55 (d, J = 8.22 Hz, 1 H), 7.50 (s, 1H), 7.33 (ddd, J = 1.17, 4.70, 8.22 Hz, 1H), 7.27 (d, J = 7.92 Hz, 1H), 7.14 7.22 (m, 1 H), 7.06 (d, J = 7.63 Hz, 1 H), 4.45 (s, 2H), 1.51 (s, 9H). Example 18 Intermediate 9 10 tert-butyl (3-(((3-aminopyridin-2-vI)thio)methyl)Phenvl)carbamate NH2 N S NHBoc N S" To Intermediate 8 (1.18 g, 3.27 mmol) in MeOH (50 ml) and CH 2 CI 2 (5 ml) was added saturated aqueous NH 4 CI (3 ml) and zinc dust (5.3 g, 81.72 mmol). The 15 suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude Intermediate 9 (908 mg, 84%) was used in the next reaction without further purification. 1 H NMR (600 MHz, acetone) 6 7.86 (d, J = 4.40 Hz, 1H), 7.59 - 7.67 (m, 1H), 7.41 20 (d, J = 7.92 Hz, 1H), 7.17 (t, J = 7.78 Hz, 1H), 7.03 (d, J = 7.34 Hz, 1H), 6.97 (d, J= 7.63 Hz, 1 H), 6.89 (dd, J = 4.70, 7.92 Hz, 1 H), 4.59 (br. s., 2H), 4.44 (s, 2H), 1.46 (s, 9H). Example 19 Intermediate 10 25 {3-[3-(benzofuran-2-sulfonylamino)-Pyridin-2-vlsulfanvlmethvll-Phenvll carbamic acid tert-butyl Ester 0 0 HocNH N S NHBoc 38 WO 2013/130962 PCT/US2013/028607 and Compound 11 N-{2-[(3-aminobenzvl)sulfanyllpyridin-3-vIl-1 -benzofuran-2-sulfonamide 0 o=S/ 01 N S NH 2 5 To Intermediate 9 (908 mg, 2.74 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (592 mg, 2.74 mmol) and the reaction was stirred at 100 C for 16 hours, then additional benzofuran-2-sulfonyl chloride (592 mg, 2.74 mmol) was 10 added and the mixture was further heated for 24 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-40% EtOAc in hexanes) to yield Intermediate 10 (760 mg, 54%) and Compound 11(129 mg, 11%). Intermediate 10 1 H NMR (600 MHz, CD 3 OD) 5 8.33 (dd, J = 1.17, 4.70 Hz, 1H), 15 7.66 (d, J = 7.63 Hz, 1 H), 7.60 (dd, J = 1.61, 7.78 Hz, 1 H), 7.46 - 7.51 (m, 2H), 7.30 7.38 (m, 1H), 7.25 (s, 1H), 7.16 - 7.22 (m, 2H), 7.09 (dd, J = 4.70, 7.92 Hz, 1H), 7.00 (t, J= 8.22 Hz, 1H), 6.57 (d, J= 7.63 Hz, 1H), 4.10 (s, 2H), 1.52 (s, 9H). Compound 11 1 H NMR (600 MHz, acetone) 5 8.37 (dd, J = 1.47, 4.70 Hz, 1 H), 7.75 (d, J = 7.92 Hz, 1H), 7.48 - 7.68 (m, 3H), 7.30 - 7.44 (m, 2H), 7.12 (dd, J = 4.70, 7.92 20 Hz, 1 H), 6.87 (t, J = 7.63 Hz, 1 H), 6.41 - 6.57 (m, 2H), 6.31 (d, J = 7.63 Hz, 1 H), 4.09 (s, 2H). Example 20 Intermediate 11 25 {3-[3-(benzofuran-2-sulfonvlamino)-pyridine-2-sulfinvimethvll-phenvll carbamic acid tert-butyl ester 39 WO 2013/130962 PCT/US2013/028607 0 0 S N SH o S NHBoc To a solution of Intermediate 10 (294 mg, 0.58mmol) in CH 2 CI 2 (5 ml) was added mCPBA (115 mg, 0.58 mmol) and the reaction was stirred at 0 OC for 30 mins and was concentrated. The residue was purified by flash column chromatography on 5 silica gel (100% EtOAc) to yield Intermediate 11(242 mg, 80%). 1 H NMR (600 MHz, CD 3 OD) 5 8.84 (br. s., 1 H), 8.43 (dd, J = 1.17, 4.40 Hz, 1 H), 7.85 (dd, J = 1.03, 8.07 Hz, 1 H), 7.73 (d, J = 7.92 Hz, 1 H), 7.57 (d, J = 8.51 Hz, 1 H), 7.47 - 7.52 (m, 2H), 7.45 (dd, J = 4.55, 8.36 Hz, 1 H), 7.35 (t, J = 7.63 Hz, 1 H), 7.26 (d, J = 7.92 Hz, 1 H), 7.22 (s, 1 H), 7.10 (t, J = 7.78 Hz, 1 H), 6.70 (d, J = 7.63 Hz, 1 H), 4.27 10 4.33 (d, J = 12.91 Hz, 1 H), 4.18 - 4.23 (d, J = 12.91 Hz, 1 H), 1.51 (s, 9H). Example 21 Compound 12 N-{2-[(3-aminobenzvl)sulfinyllpyridin-3-vil-1 -benzofuran-2-sulfonamide 0 o=s/ N ~ NH 2 15 Intermediate 11(240 mg, 0.455 mmol), TFA (1 ml) in CH 2 CI 2 (5 ml) was stirred overnight. The solvent was removed and the crude was purified by column chromatography (50% ethyl acetate in hexanes) to afford Compound 12 (186 mg, 96%). 20 1 H NMR (600 MHz, CD 3 OD) 5 8.41 (dd, J = 1.32, 4.55 Hz, 1H), 7.82 (dd, J = 1.17, 8.51 Hz, 1 H), 7.71 (d, J = 7.92 Hz, 1 H), 7.41 - 7.57 (m, 4H), 7.33 (t, J = 7.48 Hz, 1 H), 7.14 (t, J = 7.78 Hz, 1H), 6.93 (dd, J = 1.47, 7.92 Hz, 1H), 6.90 (s, 1H), 6.72 (d, J = 7.63 Hz, 1H), 4.33 (d, J = 13.21 Hz, 1H), 4.23 (d, J = 13.21 Hz, 1H). 25 Example 22 Compound 13 40 WO 2013/130962 PCT/US2013/028607 tert-butyl {3-[({3-[(1-benzofuran-2-vIsulfonvl)aminolDyridin-2 vIlsulfonvl)methvllphenvllcarbamate 0 o= / 'U 0 5 To a solution of Intermediate 10 (418 mg, 0.82mmol) in CH 2 CI 2 (10 ml) was added mCPBA (426 mg, 2.13 mmol) and the reaction was stirred at room temperature for 3 hours and was concentrated. The residue was purified by flash column 10 chromatography on silica gel (100% EtOAc) to yield Compound 13 (340mg, 76%). 1 H NMR (600 MHz, CD 3 OD) 5 8.80 (br. s., 1H), 8.46 (br. s., 1H), 8.15 (dd, J = 1.32, 8.66 Hz, 1 H), 7.73 (d, J = 7.92 Hz, 1 H), 7.61 (dd, J = 4.40, 8.22 Hz, 1 H), 7.44 - 7.57 (m, 3H), 7.35 (t, J = 7.63 Hz, 1H), 7.25 (s, 1H), 7.14 (d, J = 7.04 Hz, 1H), 7.00 (t, J = 7.92 Hz, 1 H), 6.70 (d, J = 7.63 Hz, 1 H), 4.65 (br. s., 2H), 1.50 (s, 9H). 15 Example 23 Compound 14 N-{2-[(3-aminobenzyl)sulfonyllpyridin-3-vil-1 -benzofuran-2-sulfonamide 0 o=s / N ~NH 2 20 Compound 13 (287 mg, 0.53 mmol), TFA (1 ml) in CH 2 CI 2 (5 ml) was stirred overnight. The solvent was removed and the crude was purified by column 25 chromatography (50% ethyl acetate) to afford Compound 14 (214 mg, 91%). 1 H NMR (600 MHz, CD 3 OD) 5 8.46 (d, J = 4.40 Hz, 1H), 8.18 (d, J = 8.80 Hz, 1H), 7.74 (d, J = 7.92 Hz, 1 H), 7.60 - 7.67 (m, 1 H), 7.54 - 7.59 (m, 2H), 7.47 - 7.53 (m, 1 H), 41 WO 2013/130962 PCT/US2013/028607 7.36 (t, J = 7.48 Hz, 1 H), 6.85 - 6.96 (m, 1 H), 6.55 - 6.71 (m, 2H), 6.42 - 6.53 (m, 1 H), 4.61 (d, J = 3.81 Hz, 2H). 5 Example 24 Intermediate 12 2-chloro-5-fluoro-3-nitropyridine F aNO 2 N C1 10 To a solution of 5-fluoro-3-nitro-pyridin-2-ol (2.0 g, 12.65 mmol), benzyltrimethylammonium chloride (1.2 g, 6.33 mmol) in CH 3 CN (20 ml) was added POCl 3 (5 ml) and the mixture was heated at 80 0C overnight. Another 2 ml POCl 3 was added to the mixture and the reaction was heated at 80 0C for another 2 hours more. The reaction mixture was quenched with water and extracted with EtOAc. The 15 organic layer was washed with brine, dried over Na 2 SO 4 anhydrous and concentrated in vacuo. The residue was purified by silica gel column chromatography (0 - 30 % EtOAc in hexane) to give Intermediate 12 (1.3 g, 59 %). 1 H NMR (600 MHz, CDCI 3 ) 5 8.55 (d, J = 2.64 Hz, 1 H), 8.03 (dd, J = 2.79, 6.60 Hz, 1 H). 20 Example 25 Intermediate 13 5-fluoro-3-nitropyridine-2-thiol F nNO 2 N SH 25 To a solution of Intermediate 12 (460 mg, 2.61 mmol) in dioxane (5 ml) and water (1 ml) was added Na 2 S-9H 2 0 and the reaction was stirred at rt for 5 hours. The reaction was quenched with 1 N HCI and then extracted with EtOAc (2 x 30 ml). The organic layer was washed with water, brine and dried over Na 2 SO 4 and concentrated in vacuo. The crude product was used in the next reaction without further purification. 30 Example 26 42 WO 2013/130962 PCT/US2013/028607 Intermediate 14 2-(benzvlthio)-5-fluoro-3-nitropyridine F NO 2 N S 5 To the crude Intermediate 13 in DMF (10 ml) was added (bromomethyl)benzene (477 mg, 2.61 mmol) and K 2 CO 3 (1.8 g, 13.07 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with 10 brine and then dried over Na 2 SO 4 , concentrated in vacuo and purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give Intermediate14 (420 mg, 22%). 1 H NMR (600 MHz, CDCI 3 ) 5 8.66 (d, J = 2.64 Hz, 1 H), 8.27 (dd, J = 2.64, 7.63 Hz, 1 H), 7.41 (d, J = 7.63 Hz, 2H), 7.31 (t, J = 7.48 Hz, 2H), 7.22 - 7.28 (m, 1 H), 4.45 (s, 15 2H). Example 27 Intermediate 15 2-(benzvlthio)-5-fluoropyridin-3-amine F NH 2 N S 20 To a solution Intermediate14 (420 mg, 1.60 mmol) in MeOH (20 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (2.5 g, 40 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude Intermediate 15 (288 mg, 77%) was used in the 25 next reaction without further purification. 1 H NMR (600 MHz, CD 3 OD) 6 7.69 (d, J= 2.35 Hz, 1H), 7.11 - 7.30 (m, 5H), 6.77 (dd, J = 2.64, 10.27 Hz, 1H), 4.25 (s, 2H). Example 28 Compound 15 43 WO 2013/130962 PCT/US2013/028607 N-[2-(benzvlsulfanyl)-5-fluoropyridin-3-vil-1 -benzofuran-2-sulfonamide F NH 0 FK N S 5 To Intermediate 15 (285mg, 1.22 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (264 mg, 1.82 mmol) and the reaction was stirred at 100 C for 16 hours , then additional benzofuran-2-sulfonyl chloride (264 mg, 1.82 mmol) was added and the reaction was further heated for 3 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% 10 EtOAc in hexanes) to yield Compound 15 (379 mg, 75%). 1 H NMR (600 MHz, CD 3 OD) 5 8.29 (d, J = 2.64 Hz, 1H), 7.71 (d, J = 7.92 Hz, 1H), 7.45 - 7.58 (m, 3H), 7.38 (ddd, J = 2.93, 4.99, 7.92 Hz, 1H), 7.32 (s, 1H), 7.04 - 7.15 (m, 3H), 6.93 (dd, J = 1.32, 7.48 Hz, 2H), 4.10 (s, 2H). 15 Example 29 Compound 16 N-[2-(benzvlsulfinvl)-5-fluoropyridin-3-vIl-1-benzofuran-2-sulfonamide F NH 0 F 20 N To a solution of Compound 15 (110 mg, 0.27 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (53 mg, 0.27 mmol) and the reaction was stirred at 0 0C for 30 min and was concentrated. The residue was purified by flash column chromatography on 25 silica gel (100% EtOAc) to yield Compound 16 (170 mg, 72%). 44 WO 2013/130962 PCT/US2013/028607 'H NMR (600 MHz, CD 3 OD) 5 8.05 (br. s., 1H), 7.67 - 7.77 (m, 2H), 7.45 - 7.52 (m, 2H), 7.39 - 7.45 (m, 1H), 7.27 - 7.36 (m, 1H), 7.08 - 7.17 (m, 3H), 6.96 - 7.04 (m, 2H), 4.47 (d, J = 12.91 Hz, 1H), 4.26 (d, J = 13.21 Hz, 1H). 5 Example 30 Compound 17 N-[2-(benzvlsulfonvl)-5-fluoropyridin-3-vIl-1-benzofuran-2-sulfonamide F SH NH Fn N S 10 To a solution of Compound 15 (167 mg, 0.40 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (203 mg, 1.01 mmol) and the reaction was stirred at room temperature for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 17 (127 mg, 71%). 1 H NMR (600 MHz, CD 3 OD) 5 8.35 (d, J = 2.35 Hz, 1H), 7.95 (dd, J = 2.35, 10.56 15 Hz, 1 H), 7.75 (d, J = 7.92 Hz, 1 H), 7.62 (d, J = 0.88 Hz, 1 H), 7.47 - 7.57 (m, 2H), 7.38 (td, J = 1.17, 7.48 Hz, 1H), 7.05 - 7.14 (m, 4H), 6.98 - 7.03 (m, 1H), 4.71 (s, 2H). Example 31 20 Intermediate 16 tert-butyl (3-(((5-chloro-3-nitropyridin-2-vl)thio)methyl)phenvl)carbamate CI N02 N S NHBoc To Intermediate 1 (590 mg, 3.10 mmol) in DMF (10 ml) was added tert-butyl (3 25 (bromomethyl)phenyl)carbamate (889 mg, 2.61 mmol) and K 2 CO 3 (2.1 g, 15.53 mmol) and the reaction was stirred at room temperature for 3 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 , concentrated 45 WO 2013/130962 PCT/US2013/028607 in vacuo and purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give Intermediate 16 (1.06 g, 88%). H NMR (600 MHz, acetone) 5 8.87 (d, J = 2.05 Hz, 1 H), 8.64 (d, J = 2.35 Hz, 1 H), 8.35 (br. s., 1 H), 7.72 (s, 1 H), 7.41 (d, J = 8.22 Hz, 1 H), 7.21 (t, J = 7.92 Hz, 1 H), 5 7.08 (d, J = 7.63 Hz, 1 H), 4.47 (s, 2H), 1.47 (s, 9H). Example 32 Intermediate 17 tert-butyl (3-(((3-amino-5-chloropyridin-2-yl)thio)methyl)Phenyl)carbamate CI NH 2 N S NHBoc 10 To a solution Intermediate 16 (1.06 g, 2.68 mmol) in MeOH (30 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (4.3 g, 67 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The Intermediate 17 (581 mg, 59%) was used in the next 15 reaction without further purification. 1 H NMR (600 MHz, CD 3 OD) 6 7.74 (d, J = 2.05 Hz, 1 H), 7.38 (s, 1 H), 7.22 (d, J = 7.92 Hz, 1 H), 7.08 (t, J = 7.92 Hz, 1 H), 6.92 (d, J = 1.76 Hz, 1 H), 6.89 (d, J = 7.63 Hz, 1 H), 4.23 (s, 2H), 1 .46 (s, 9H). Example 33 20 Intermediate 18 {3-[3-(Benzofuran-2-sulfonylam ino)-5-chloro-pyridin-2-ylsu Ifanylmethyll phenvl}-carbamic acid tert-butyl ester 0 0 CI NH N S NHBoc To Intermediate 17 (580mg, 1.59 mmol) in pyridine (5 ml) was added benzofuran-2 25 sulfonyl chloride (242 mg, 1.82 mmol) and the reaction was stirred at 100 C for 16 hours , then additional benzofuran-2-sulfonyl chloride (342 mg, 1.82 mmol) was added and the reaction was further heated for 24 hours and concentrated in vacuo. 46 WO 2013/130962 PCT/US2013/028607 The crude Intermediate 18 was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield (359 mg, 41 %). 1 H NMR (600 MHz, CD 3 OD) 6 7.81 - 7.90 (m, 1 H), 7.66 (d, J = 7.63 Hz, 1 H), 7.60 (dd, J = 1.61, 7.78 Hz, 1 H), 7.40 - 7.52 (m, 3H), 7.29 - 7.37 (m, 1 H), 7.18 (s, 1 H), 5 7.06 - 7.12 (m, 1H), 7.00 (t, J = 8.22 Hz, 1H), 6.57 (d, J = 7.63 Hz, 1H), 4.10 (s, 2H), 1.52 (s, 9H). Example 34 Compound 18 10 Benzofuran-2-sulfonic acid [2-(3-amino-benzvlsulfanyl)-5-chloro-pyridin-3-vIl amide 0 CI NH 0 N S N NH 2 Intermediate 18 (50 mg, 0.092 mmol), TFA (0.5 ml) in CH 2 CI 2 (5 ml) was stirred for 15 2 hours. The solvent was removed and the crude was purified by flash column chromatography on silica gel (50% ethyl acetate) to afford Compound 18 (40 mg, 97%). 1 H NMR (600 MHz, CD 3 OD) 5 8.34 (d, J = 2.05 Hz, 1 H), 7.69 (d, J = 7.92 Hz, 1 H), 7.61 - 7.65 (m, 1 H), 7.46 - 7.56 (m, 2H), 7.36 (td, J = 1.03, 7.26 Hz, 1 H), 7.32 (s, 20 1H), 7.13 (t, J = 7.92 Hz, 1H), 7.04 (s, 1H), 6.97 (dt, J = 1.03, 7.92 Hz, 1H), 6.78 (d, J = 7.63 Hz, 1H), 4.16 (s, 2H). Example 35 Intermediate 19 25 {3-[3-(benzofuran-2-su Ifonylam ino)-5-chloro-pyridine-2-sulfinvlmethyll phenvil-carbamic acid tert-butyl ester 47 WO 2013/130962 PCT/US2013/028607 0 CII 0I NHS N N NHBoc o To a solution of Intermediate 18 (133 mg, 0.24 mmol) in CH 2 CI 2 (5 ml) was added 5 mCPBA (49 mg, 0.24 mmol) and the reaction was stirred at 0 OC for 30 min and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Intermediate 19 (80 mg, 58%). 1 H NMR (600 MHz, CD 3 OD) 6 7.91 (d, J = 1.47 Hz, 2H), 7.68 (d, J = 7.92 Hz, 1 H), 7.42 (d, J = 8.22 Hz, 1 H), 7.32 - 7.39 (m, 2H), 7.17 - 7.31 (m, 3H), 7.00 (t, J = 7.78 10 Hz, 1H), 6.66 (d, J = 7.63 Hz, 1H), 4.55 (d, J = 12.91 Hz, 1H), 4.23 (d, J = 12.91 Hz, 1 H), 1.47 (s, 9H). Example 36 Compound 19 N-{2-[(3-aminobenzvl)sulfinyll-5-chloropyridin-3-yl}-1 -benzofuran-2 15 sulfonamide 0 CI NH 0 N S NH 2 Intermediate 19 (80 mg, 0.15 mmol), TFA (0.5 ml) in CH 2 CI 2 (5 ml) was stirred for 2 hours. The solvent was removed and the crude was purified by flash column 20 chromatography on silica gel (50% ethyl acetate) to afford Compound 19 (60 mg, 91%). 1 H NMR (600 MHz, CD 3 OD) 5 8.23 (s, 1 H), 7.86 (d, J = 1.76 Hz, 1 H), 7.72 (d, J = 7.92 Hz, 1H), 7.48 - 7.53 (m, 2H), 7.41 - 7.47 (m, 1H), 7.28 - 7.37 (m, 1H), 7.17 7.25 (m, 1H), 7.03 - 7.11 (m, 2H), 6.85 (d, J = 7.92 Hz, 1H), 4.43 (d, J = 13.21 Hz, 25 1 H), 4.27 (d, J = 13.21 Hz, 1 H). Example 37 48 WO 2013/130962 PCT/US2013/028607 Intermediate 20 {3-[3-(benzofuran-2-su Ifonylamino)-5-ch loro-pyrid ine-2-su Ifonylmethyll phenvil-carbamic acid tert-butyl ester 0 C I NH 0 0 N S NHBoc || 5 0 To a solution of Intermediate 19 (167 mg, 0.31 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (153 mg, 0.77 mmol) and the reaction was stirred at room temperature for 3 hours and was concentrated. The residue was purified by flash column 10 chromatography on silica gel (100% EtOAc) to yield Intermediate 20 (138 mg, 78%). 1 H NMR (600 MHz, CD 3 OD) 5 8.45 (d, J= 1.76 Hz, 1H), 8.12 (d, J = 2.05 Hz, 1H), 7.72 (d, J = 7.92 Hz, 1 H), 7.56 (s, 1 H), 7.44 - 7.53 (m, 2H), 7.29 - 7.38 (m, 1 H), 7.20 (s, 1 H), 6.95 - 7.06 (m, 2H), 6.77 (d, J = 6.75 Hz, 1 H), 4.63 (s, 2H), 1.48 (s, 9H). Example 38 15 Compound 20 N-(2-((3-aminobenzyl)su Ifonyl)-5-chloropyridin-3-vl)benzofuran-2-sulfonamide 0 CI N H 0 Kl N S NH 2 20 Intermediate 19 (138 mg, 0.24 mmol), TFA (0.5 ml) in CH 2 CI 2 (5 ml) was stirred for 2 hours. The solvent was removed and the crude was purified by flash column chromatography on silica gel (50% ethyl acetate) to afford Compound 20 (112 mg, 100%). 1 H NMR (600 MHz, CD 3 OD) 5 8.29 (d, J= 1.76 Hz, 1H), 8.15 (d, J = 2.05 Hz, 1H), 25 7.70 (d, J = 7.92 Hz, 1 H), 7.57 (s, 1 H), 7.47 - 7.51 (m, 1 H), 7.42 - 7.46 (m, 1 H), 7.28 49 WO 2013/130962 PCT/US2013/028607 - 7.35 (m, 1 H), 7.07 - 7.18 (m, 2H), 6.97 - 7.04 (m, 1 H), 6.89 (d, J = 7.63 Hz, 1 H), 4.77 (s, 2H). Example 39 5 Intermediate 21 5-methyl-3-nitropyridine-2-thiol NO 2 N SH To a solution of 2-chloro-5-methyl-3-nitropyridine (1 g, 5.80 mmol) in dioxane (5 ml) and water (1 ml) was added Na 2 S-9H 2 0 (1.39 g, 5.80 mmol) and the reaction was 10 stirred at rt for 3 hours. The reaction was quenched with 1 N HCI and then extracted with EtOAc (2 x 30 ml). The organic layer was washed with water, brine and dried over Na 2 SO 4 anhydride and concentrated in vacuo. Example 40 15 Intermediate 22 2-(benzvlthio)-5-methyl-3-nitropyridine IaNO 2 N S To the crude Intermediate 21 in DMF (10 ml) was added (bromomethyl)benzene 20 (991.mg, 5.80 mmol) and K 2 CO 3 (2.4 g, 17.39 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 , concentrated in vacuo and purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give 25 Intermediate 22 (660 mg, 44%). 1 H NMR (600 MHz, acetone) 5 8.71 (d, J = 0.88 Hz, 1 H), 8.42 (d, J = 0.59 Hz, 1 H), 7.45 (d, J = 7.34 Hz, 2H), 7.30 (t, J = 7.63 Hz, 2H), 7.21 - 7.26 (m, J = 7.34 Hz, 1 H), 4.49 (s, 2H), 2.45 (s, 3H). 30 Example 41 50 WO 2013/130962 PCT/US2013/028607 Intermediate 23 2-(benzvlthio)-5-methylpyridin-3-amine IaNH 2 N S 5 To a solution of Intermediate 22 (660 mg, 2.55 mmol) in MeOH (20 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (4.1 g, 63.71 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and 10 concentrated in vacuo. The crude Intermediate 23 (512 mg, 88%) was used in the next reaction without further purification. H NMR (600 MHz, acetone) 6 7.72 (s, 1 H), 7.38 (d, J = 7.34 Hz, 2H), 7.26 (t, J = 7.48 Hz, 2H), 7.18 - 7.22 (m, 1H), 6.81 (s, 1H), 4.53 (br. s., 2H), 4.42 (s, 2H), 2.16 (s, 3H). 15 Example 42 Compound 21 N-[2-(benzvlsulfanyl)-5-methylpyridin-3-vil-1 -benzofuran-2-sulfonamide / o=S NH 0 N S 20 To Intermediate 23 (51 0mg, 2.23 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (481 mg, 2.23 mmol) and the reaction was stirred at 100 C for 16 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 21 (466 mg, 51%). 25 1 H NMR (600 MHz, acetone) 5 9.03 (br.s, 1 H), 8.24 (d, J = 0.88 Hz, 1 H), 7.73 - 7.78 (m, 1 H), 7.53 - 7.62 (m, 2H), 7.49 - 7.51 (m, 1 H), 7.39 - 7.43 (m, 1 H), 7.37 (s, 1 H), 7.11 - 7.20 (m, 3H), 7.04 (dd, J = 2.79, 6.60 Hz, 2H), 4.17 (s, 2H), 2.28 (s, 3H). 51 WO 2013/130962 PCT/US2013/028607 Example 43 Compound 22 N-[2-(benzvlsulfinvl)-5-methylpyrid in-3-vil-1 -benzofuran-2-sulfonamide o=S I NH N S 0 5 To a solution of Compound 21 (143 mg, 0.349 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (70 mg, 0.349 mmol) and the reaction was stirred at room temperature for 3 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 22 (129 mg, 85%). 10 1 H NMR (600 MHz, acetone) 5 11.12 (br. s., 1H), 8.16 (d, J = 1.17 Hz, 1H), 7.85 (d, J = 0.88 Hz, 1 H), 7.79 (s, 1 H), 7.67 (s, 1 H), 7.61 (s, 1 H), 7.47 - 7.54 (m, 1 H), 7.37 (t, J = 7.63 Hz, 1H), 7.12 - 7.26 (m, 3H), 6.98 - 7.08 (m, 2H), 4.35 (d, J= 13.21 Hz, 1H), 4.21 (d, J= 13.21 Hz, 1H), 2.36 (s, 3H). 15 Example 44 Compound 23 N-[2-(benzvlsulfonyl)-5-methylpyridin-3-vil-1 -benzofuran -2-sulfonamide 20 To a solution of Compound 21 (241 mg, 0.588mmol) in CH 2 CI 2 (5 ml) was added mCPBA (291 mg, 1 .47 mmol) and the reaction was stirred at room temperature for 3 hours, and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 23 (203 mg, 78%). 25 i NMR (600 MHz, acetone) 5 8.34 (d, J = 0.59 Hz, 1 H), 7.99 (s, 1 H), 7.76 (d, J = 7.92 Hz, 1 H), 7.70 (s, 1 H), 7.59 (s, 1 H), 7.51 (td, J = 1 .03, 7.85 Hz, 1 H), 7.35 (t, J = 7.63 Hz, 1 H), 7.11 - 7.24 (in, 5H), 4.75 (s, 2H), 2.40 (s, 3H). 52 WO 2013/130962 PCT/US2013/028607 Example 45 Intermediate 24 5-chloro-2-((2-methylDyridin-3-vl)oxv)-3-nitropyridine CI NO 2 N 0 5 To a solution of 2,5-dichloro-3-nitropyridine (655 mg, 3.41 mmol) in DMF (10 ml) was added 2-methylpyridin-3-ol (368 mg, 3.41 mmol) and K 2 CO 3 (2.35 g, 17.05 mmol) and the reaction was stirred at 900C for 3 hours, diluted with H 2 0, and the resulting 10 solution was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 24 as yellow solid (705 mg, 78%). 1 H NMR (600 MHz, acetone) 5 8.61 - 8.68 (m, 1 H), 8.34 - 8.46 (m, 2H), 7.61 (d, J = 8.22 Hz, 1H), 7.14 - 7.46 (m, 1H), 2.37 (s, 3H). 15 Example 46 Intermediate 25 5-chloro-2-((2-methvlovrid in-3-vI)oxv)Dvrid in-3-am ine CI NH 2 N 0 To a solution of Intermediate 24 (705 mg, 2.92 mmol) in MeOH (15 ml) was added 20 saturated aqueous NH 4 CI (2 ml) and zinc dust (4.7 g, 73 mmol). The suspension was stirred at room temperature for 0.5 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude Intermediate 25 (476 mg, 76%) was used in the next reaction without further purification. 25 1 H NMR (600 MHz, acetone) 5 8.31 (d, J = 4.40 Hz, 1 H), 7.45 (d, J = 7.92 Hz, 1 H), 7.21 - 7.28 (m, 2H), 7.16 (d, J = 2.05 Hz, 1H), 5.26 (br. s., 2H), 2.33 (s, 3H). Example 47 53 WO 2013/130962 PCT/US2013/028607 Compound 24 N-45-chloro-2-[(2-methylDyridin-3-vl)oxyloyridin-3-vil-1 -benzofuran-2 sulfonamide 0 0I SH C1 N N N 5 To Intermediate 25 (476 mg, 2.0 mmol) in pyridine (4 ml) was added benzofuran-2 sulfonyl chloride (437 mg, 2.0 mmol) and the reaction was stirred at room temperature for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) 10 followed by re-crystallization from 20% EtOAc/Hexane to yield Compound 24 (419 mg, 50%) as a yellow solid. 1 H NMR (600 MHz, CD 3 OD) 5 8.18 (dd, J = 1.32, 4.84 Hz, 1 H), 8.02 (dd, J = 1.03, 2.49 Hz, 1 H), 7.79 - 7.83 (m, 1 H), 7.73 (d, J = 7.92 Hz, 1 H), 7.45 - 7.53 (m, 3H), 7.33 - 7.40 (m, 1H), 7.10 (dd, J = 4.99, 8.22 Hz, 1H), 6.94 (d, J = 9.39 Hz, 1H), 1.99 (s, 15 3H). Example 48 Intermediate 26 20 methyl 2-((5-chloro-3-nitropyridin-2-yl)oxy)benzoate CI NO 2 N 0 COOMe To a solution of 2,5-dichloro-3-nitropyridine (1 g, 5.2 mmol) in DMF (10 ml) was added methyl 2-hydroxybenzoate (790 mg, 5.2 mmol) and K 2 CO 3 (3.6 g, 25.9 mmol) 25 and the reaction was stirred at 900C for 3 hours, diluted with H 2 0, and the resulting solution was extracted with EtOAc. The organic layer was washed with brine, dried 54 WO 2013/130962 PCT/US2013/028607 over Na 2 SO 4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 26 as clear oil (1.5 g, 93%). 1 H NMR (600 MHz, acetone) 5 8.59 - 8.64 (m, 1 H), 8.32 (d, J = 1.76 Hz, 1 H), 8.05 (dd, J = 1.61, 7.78 Hz, 1 H), 7.72 - 7.78 (m, 1 H), 7.45 - 7.50 (m, 1 H), 7.40 (d, J = 8.22 5 Hz, 1 H), 3.65 (s, 3H). Example 49 Intermediate 27 methyl 2-((3-amino-5-chloropyridin-2-yl)oxy)benzoate CI NH 2 N 0 COOMe 10 To a solution of Intermediate 26 (1.5 mg, 4.82 mmol) in MeOH (30 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (7.8 g, 121 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over 15 Na 2 SO 4 , and concentrated in vacuo. The crude Intermediate 27 (1.12 g, 83%) was used in the next reaction without further purification. 1 H NMR (600 MHz, acetone) 6 7.92 (dd, J = 1.47, 7.92 Hz, 1 H), 7.57 - 7.69 (m, 1 H), 7.28 - 7.38 (m, 2H), 7.19 (d, J = 1.76 Hz, 1H), 7.12 (dd, J = 0.59, 2.35 Hz, 1H), 5.18 (br. s., 2H), 3.66 (s, 3H). 20 Example 50 Compound 25 methyl 2-({3-(1 -benzofuran-2-ylsulfonyl)aminol-5-chloropyridin-2 viloxv)benzoate 0 C1 ' O N 0 COOMe 25 55 WO 2013/130962 PCT/US2013/028607 To Intermediate 27 (413 mg, 1.5 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (320 mg, 1.5 mmol) and the reaction was stirred at room temperature for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to 5 yield Compound 25 (627 mg, 92%) as a yellow solid. 'H NMR (600 MHz, CD 3 OD) 5 8.00 (d, J = 2.35 Hz, 1 H), 7.89 (dd, J = 1.32, 7.78 Hz, 1 H), 7.75 (d, J = 7.92 Hz, 1 H), 7.71 (d, J = 2.35 Hz, 1 H), 7.47 - 7.55 (m, 3H), 7.35 7.41 (m, J = 7.63 Hz, 2H), 7.26 (t, J = 7.63 Hz, 1H), 6.52 (d, J = 8.22 Hz, 1H), 3.47 (s, 3H). 10 Example 51 Compound 26 2-({3-[(1-benzofuran-2-vlsulfonyl)aminol-5-chloropyridin-2-vloxy)benzoic acid 0 C11 0I SH N O COOH 15 To Compound 25 (627 mg, 1.36 mmol) in MeOH (30 ml) was added NaOH (5N, 2 ml) and the reaction was stirred at room temperature for 3 hours. The mixture was acidified with 10% HCl, extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 26 20 (485 mg, 80%). 1 H NMR (600 MHz, acetone) 5 11.22 (br. s., 1 H), 9.66 (br. s., 1 H), 7.96 - 8.01 (m, 2H), 7.81 (d, J = 7.92 Hz, 1 H), 7.77 (d, J = 2.35 Hz, 1 H), 7.65 (s, 1 H), 7.58 - 7.61 (m, 1 H), 7.54 (ddd, J = 1.17, 7.26, 8.29 Hz, 1 H), 7.49 (td, J = 1.61, 7.70 Hz, 1 H), 7.38 7.43 (m, 1 H), 7.32 (t, J = 7.63 Hz, 1 H), 6.80 (d, J = 7.92 Hz, 1 H). 25 Example 52 Intermediate 28 (3-amino-5-chloropyridin-2-yI)(morpholino)methanone 56 WO 2013/130962 PCT/US2013/028607 CI ' NH 2 N 0 N A solution of 3-amino-5-chloropicolinic acid hydrogen chloride (226 mg, 1.08 mmol), morpholine (94 pl, 1.08 mmol), EDCI (308 mg, 1.61 mmol) and DMAP (394 mg, 3.23 5 mmol) in CH 2 CI 2 (5 ml) was stirred at room temperature overnight, diluted with H 2 0, and the resulting solution was extracted with CH 2 CI2. The organic layer was washed with brine, dried over Na 2 SO 4 and concerntrated in vacuo, followed by MPLC purification to yield Intermediate 28 as a yellow oil (173 mg, 66%). H NMR (600 MHz, acetone) 6 7.80 (d, J = 2.35 Hz, 1 H), 7.28 (d, J = 2.35 Hz, 1 H), 10 5.78 (br. s., 2H), 3.83 - 4.04 (m, 4H), 2.51 (d, J = 4.40 Hz, 4H). Example 53 Compound 27 N-[5-chloro-2-(morpholin-4-vlcarbonyl)pyridin-3-vil-1 -benzofuran-2 sulfonamide 0 C I N H 0 N 0 N 150 To Intermediate 28 (170 mg, 0.70 mmol) in pyridine (3 ml) was added benzofuran-2 sulfonyl chloride (152 mg, 0.70 mmol) and the reaction was stirred at room temperature for 16 hours. Solvent was removed in vacuo and the crude product was 20 purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 27 (78 mg, 26%). 1 H NMR (600 MHz, acetone) 6 7.85 - 7.94 (m, 1 H), 7.71 (d, J = 2.05 Hz, 1 H), 7.64 (d, J = 8.22 Hz, 1H), 7.46 (d, J = 8.22 Hz, 1H), 7.33 (ddd, J = 1.17, 7.26, 8.29 Hz, 1 H), 7.20 - 7.27 (m, 1 H), 7.14 (d, J = 0.59 Hz, 1 H), 3.67 (s, 4H), 3.47 - 3.57 (m, 2H), 25 3.09 - 3.18 (m, 2H). 57 WO 2013/130962 PCT/US2013/028607 Example 54 Intermediate 29 1-(3-amino-5-chloropicolinovl)piperidin-4-one CI ~ NH 2 C -'C 0 N N 5 0 A solution of 3-amino-5-chloropicolinic acid hydrogen chloride(303 mg, 1.44 mmol), piperidin-4-one (220 mg, 1.44 mmol), EDCI (413 mg, 2.16 mmol) and DMAP (528 mg, 4.33 mmol) in CH 2 CI 2 (5 ml) was stirred at room temperature overnight, diluted with H 2 0, and the resulting solution was extracted with CH 2 CI2. The organic layer 10 was washed with brine, dried over Na 2 SO 4 and concerntrated in vacuo, followed by MPLC purification to yield Intermediate 29 (255 mg, 79%). 1 H NMR (600 MHz, acetone) 6 7.80 (s, 1H), 7.28 (d, J= 2.35 Hz, 1H), 5.78 (br. s., 2H), 3.72 - 4.13 (m, 4H), 2.51 (d, J = 4.40 Hz, 4H). Example 55 15 Compound 28 N-{5-chloro-2-(4-oxopiperidin-1 -v)carbonvllovridin-3-vil-1 -benzofuran-2 sulfonamide 0 0 200 To Intermediate 29 (288 mg, 1.13 mmol) in pyridine (3 ml) was added benzofuran-2 sulfonyl chloride (245 mg, 1.13 mmol) and the reaction was stirred at room temperature for 16 hours. Solvent was removed in vacuo and the crude product was 58 WO 2013/130962 PCT/US2013/028607 purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 28 (52 mg, 10%). 'H NMR (300 MHz, CDCI 3 ) 5 8.24 (d, J = 2.05 Hz, 1 H), 8.14 (d, J = 2.05 Hz, 1 H), 7.65 (d, J = 7.62 Hz, 1 H), 7.42 - 7.55 (m, 2H), 7.29 - 7.41 (m, 2H), 3.86 (t, J = 6.15 5 Hz, 2H), 3.51 (t, J = 6.15 Hz, 2H), 2.50 (t, J = 6.30 Hz, 2H), 2.36 (t, J = 5.86 Hz, 2H). Example 56 Intermediate 30 5-chloro-3-nitropicolinic acid CI NO 2 10 N COOH To a suspension of 4-(5-chloro-3-nitropyridin-2-yl)-2-methylbut-3-yn-2-ol (2.1 g, 8.71 mmol) in H 2 0 (30 ml) was added KMnO 4 (4.55 g, 28.78 mmol) portion wise over 30 15 min at 75 C. After addition, the reaction was stirred at 75 OC for 2 hours, then cooled down to room temperature and adjusted pH to -9 by addition of 1 N NaOH and filtered away the solid. The filtrate was diluted with H 2 0, and extracted with EtOAc and discarded. The aqueous portion was acidified to pH 2- 3 with 1 N HCl, the resulting solution was extracted with EtOAc, washed with brine, dried over Na 2 SO 4 20 and concentrated in vacuo to yield Intermediate 30 as yellow solid (1.23 g, 71 %). 1 H NMR (300 MHz, acetone) 5 8.98 (d, J = 2.05 Hz, 1 H), 8.67 (d, J = 2.05 Hz, 1 H). Example 57 Intermediate 31 (5-chloro-3-n itropyridin-2-yl)(phenyl)methanone CI NO 2 N 0 N 25 To a solution of Intermediate 30 (724 mg, 3.62 mmol) in CH 2 CI 2 (5 ml) was added oxalyl chloride (3.6 ml,7.24 mmol) at room temperature followed by a drop of DMF. After stirring for 1.5 hours, the mixture was concentrated and dried under high vacuum. The crude acid chloride was dissolved in benzene (30 ml) and AICl 3 (499 59 WO 2013/130962 PCT/US2013/028607 mg, 3.75 mmol)was added. The resulting mixture was heated at 800C for 3.5 hours. The reaction was quenched with NaHCO 3 and extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% 5 EtOAc in hexanes) to yield Intermediate 31 (675 mg, 72%). H NMR (300 MHz, acetone) 5 9.05 (d, J = 2.34 Hz, 1 H), 8.83 (d, J = 2.05 Hz, 1 H), 7.85 - 7.99 (m, 2H), 7.66 - 7.80 (m, 1 H), 7.48 - 7.64 (m, 2H). Example 58 Intermediate 32 10 (3-amino-5-chloropyridin-2-yi)(phenvl)methanone CI NH 2 N 0 1 To a solution of Intermediate 31 (477 mg, 1.84 mmol) in EtOH (10 ml) was added SnCI 2 (1.95 g, 10.28 mmol). The mixture was stirred at 800C for 2 days. The solvent 15 was removed, NaOH (1 N) was added to adjusted the pH -11. The cloud mixture was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Intermediate 32 (308 mg, 73%). 20 1 H NMR (300 MHz, acetone) 6 7.89 - 7.97 (m, 1 H), 7.87 (d, J = 2.05 Hz, 1 H), 7.38 7.61 (m, 3H), 7.04 - 7.24 (m, 2H). Example 59 Compound 29 N-[5-chloro-2-(phenvlcarbonyl)pyridin-3-vil-1 -benzofuran-2-sulfonamide 0 O=S- /I CI NH 0 N O 25 60 WO 2013/130962 PCT/US2013/028607 To Intermediate 32 (300 mg, 1.29 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (288 mg, 1.29 mmol) and DMAP (cat.) and the reaction was stirred at 100 OC for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) 5 and further purified by preparative TLC to yield Compound 29 (118 mg, 22%). 1 H NMR (300 MHz, acetone) 5 8.46 (d, J = 2.05 Hz, 1 H), 8.28 (d, J = 2.05 Hz, 1 H), 7.71 - 7.83 (m, 4H), 7.54 - 7.63 (m, 1 H), 7.28 - 7.50 (m, 5H). Example 60 10 Intermediate 33 5-chloro-3-nitro-2-(phenvlthio)pvridine CI NO 2 N S 6 To a solution of 2,5-dichloro-3-nitropyridine (995 mg, 5.0 mmol) in MeOH (5 ml) was 15 added benzenethiol (0.51 ml, 5.0 mmol) and 4M NaOH (1.25 ml, 5.0 mmol) and the reaction was stirred at room temperature for 4 hours, diluted with 1 M NaOH, extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (0-5% EtOAc in hexanes) to yield Intermediate 33 as a yellow solid 20 (1.33 g, 100%). 1 H NMR (CHLOROFORM-d) 5 8.49 (d, J = 2.1 Hz, 1 H), 8.44 (d, J = 2.3 Hz, 1 H), 7.51 - 7.56 (m, 2H), 7.43 - 7.49 (m, 3H). Example 61 Intermediate 34 25 5-chloro-2-(phenvlthio)pvridin-3-amine CI NH 2 N S 6 61 WO 2013/130962 PCT/US2013/028607 To a solution of Intermediate 33 (0.65 g, 2.43 mmol) in HOAc (10 ml) was added iron powder (0.68 g, 12.2 mmol). The suspension was stirred at 70 0C for 1.5 hours and was concentrated, diluted with EtOAc, washed with 1M NaOH, brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by flash column 5 chromatography on silica gel (10% EtOAc in hexanes) to yield Intermediate 34 as a light brown solid (567 mg, 98%). 1H NMR (CHLOROFORM-d) 5: 7.96 (d, J = 2.3 Hz, 1H), 7.18 - 7.32 (m, 5H), 7.02 (d, J = 2.3 Hz, 1 H), 4.27 (br. s., 2H). Example 62 10 Compound 30 N-[5-chloro-2-(Phenvlsulfanyl)pyridin-3-vil-1 -benzofuran-2-sulfonamide 0 I- N S 6 To Intermediate 34 (551 mg, 2.32 mmol) in pyridine (10 ml) was added benzofuran 15 2-sulfonyl chloride (505 mg, 2.32 mmol) and DMAP (28 mg, 0.23 mmol). The reaction was stirred at 100 0C for 12 hours, when additional benzofuran-2-sulfonyl chloride (505 mg, 2.32 mmol) was added. The reaction was continued at 100 0C for 12 hours and was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10-30% EtOAc in hexanes) to yield Compound 30 as 20 a light brown solid (271 mg, 28%). 1H NMR (CHLOROFORM-d) 5: 8.23 (d, J = 2.1 Hz, 1H), 8.02 (d, J = 2.1 Hz, 1H), 7.70 (br. s., 1 H), 7.66 (dt, J = 7.8, 1.1 Hz, 1 H), 7.46 - 7.50 (m, 2H), 7.40 (s, 1 H), 7.31 - 7.38 (m, 1 H), 7.09 - 7.23 (m, 5H). 25 Example 63 Compound 31 N-[5-chloro-2-(phenvlsulfonvl)pvridin-3-vil-1 -benzofuran-2-sulfonamide 62 WO 2013/130962 PCT/US2013/028607 0 CI NH N To a solution of Compound 30 (200 mg, 0.48 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (173 mg, -0.72 mmol) and the reaction was stirred at room temperature for 2 hours and additional mCPBA (58 mg, -0.24 mmol) was added. The reaction was 5 continued for 1 hour and was diluted with saturated aqueous NaHCO 3 and saturated aqueous Na 2 CO 3 to -pH8, extracted with EtOAc (x3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexanes followed by 5% MeOH in EtOAc) to yield Compound 31 (119 mg, 55%). 10 1H NMR (METHANOL-d4) 5: 8.23 (d, J = 2.1 Hz, 1H), 8.19 (s, 1H), 7.82 (dd, J = 8.4, 1.0 Hz, 2H), 7.70 (d, J = 7.6 Hz, 1 H), 7.45 - 7.58 (m, 4H), 7.29 - 7.40 (m, 3H). Example 64 Compound 32 15 N-[5-chloro-2-(phenvlsulfinvl)pvridin-3-vIl-1-benzofuran-2-sulfonamide 0 CI NH 0 N S nc0 6 To a solution of Compound 30 (200 mg, 0.48 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (173 mg, -0.72 mmol) and the reaction was stirred at room temperature for 2 hours and additional mCPBA (58 mg, -0.24 mmol) was added. The reaction was 20 continued for 1 hour and was diluted with saturated aqueous NaHCO 3 and saturated aqueous Na 2 CO 3 to -pH8, extracted with EtOAc (x3). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50-100% EtOAc in hexanes followed by 5% MeOH in EtOAc) to yield Compound 32 (73 mg, 35%). 63 WO 2013/130962 PCT/US2013/028607 1 H NMR (METHANOL-d4) 5: 8.03 (s, 1 H), 7.88 (d, J = 1.8 Hz, 1 H), 7.70 - 7.76 (m, 2H), 7.60 (dt, J = 7.8, 0.9 Hz, 1 H), 7.35 - 7.39 (m, 2H), 7.21 - 7.29 (m, 4H), 7.01 (s, 1 H). 5 Example 65 Intermediate 35 5-chloro-2-((2-methylpyridin-3-vl)methoxy)-3-nitropyridine CI NO 2 N 0 N 10 To a solution of 5-chloro-2-fluoro-3-nitropyridine (520 mg, 2.96 mmol) in DMF (10 ml) was added (2-methylpyridin-3-yl)methanol (364 mg, 2.96 mmol) and K 2 CO 3 (2.00 g, 14.82 mmol) and the reaction was stirred at room temperature for 16 hours, diluted with H 2 0, and the resulting solution was extracted with EtOAc. The organic layer 15 was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, followed by MPLC purification to yield Intermediate 36 as a yellow solid (500 mg, 61 %). 'H NMR (600 MHz, CD 3 OD) 5 8.32 - 8.44 (m, 1 H), 7.87 - 7.98 (m, 2H), 7.65 (dd, J = 2.64, 9.10 Hz, 1H), 7.46 (d, J= 9.10 Hz, 1H), 5.31 (s, 2H), 2.58 (s, 3H). Example 66 20 Intermediate 36 5-chloro-2-((2-methylpyrid in-3-yl)methoxy)pyrid ine-3-am ine CI NH 2 N 0 N 25 To a solution of Intermediate 35 (490 mg, 1.76 mmol) in MeOH (20 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (2.9 g, 44 mmol). The suspension was 64 WO 2013/130962 PCT/US2013/028607 stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The Intermediate 36 (439mg, 100%) was used in the next reaction without further purification. 5 1 H NMR (300 MHz, acetone) 5 8.52 (d, J = 3.80, 1 H), 7.88 (d, J = 7.91 Hz, 1 H), 6.94 (d, J= 8.50 Hz, 1H), 6.77 (d, J= 2.64 Hz, 1H), 6.56 (dd, J= 2.64, 8.50 Hz, 1H), 5.16 (s, 2H), 2.62 (s, 3H). Example 67 Compound 33 10 N-{5-chloro-2-[(2-methylDyridin-3-vl)methoxylDyridin-3-vl}-1-benzofuran-2 sulfonamide 0 0I SH C1 N NON 15 To Intermediate 37 (439 mg, 1.77 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (382 mg, 1.77 mmol) and the reaction was stirred at 100 C for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to yield Compound 33 (350 mg, 46%) as a yellow solid. 20 1 H NMR (300 MHz, DMSO-d 6 ) 5 8.68 (dd, J = 1.32, 5.71 Hz, 1 H), 8.45 (d, J = 7.62 Hz, 1 H), 7.82 (dd, J = 5.71, 7.77 Hz, 1 H), 7.60 (d, J = 7.62 Hz, 1 H), 7.33 - 7.48 (m, 4H), 7.19 - 7.31 (m, 2H), 4.89 (s, 2H), 2.46 (s, 3H). Example 68 Intermediate 37 25 2-bromo-5-chloropyridin-3-amine CI NH 2 N Br 65 WO 2013/130962 PCT/US2013/028607 To a suspension of iron powder (1.3 g, 23.16 mmol) in AcOH (8 ml) at 80 C was added a solution of 2-bromo-5-chloro-3-nitropyridine (1 g, 4.21 mmol) in AcOH (8 ml) via addition funnel and the reaction was stirred at 80 0C for 30 min. The reaction was subsequently cooled to room temperature, diluted with EtOAc, filtered through a pad 5 of Celtite and concentrated in vacuo. The residue was dissolved in EtOAc, and washed with 1 N NaOH and brine, dried over Na 2 SO 4 and concentrated in vacuo to afford Intermediate 38 (861 mg, 99%) as a yellow solid which was used directly without further purification. H NMR (300 MHz, acetone) 6 7.62 (d, J = 2.34 Hz, 1 H), 7.22 (d, J = 2.34 Hz, 1 H), 10 5.40 (br. s., 2H). Example 69 Intermediate 38 N-(2-bromo-5-chloropyrid in-3-yi)benzofuran-2-sulfonamide 0 CI NH NH In N Br 15 To Intermediate 37 (861 mg, 4.16 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (900 mg, 4.16 mmol) and the reaction was stirred at 100 C for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to yield 20 Intermediate 38 (490 mg, 31%). 1 H NMR (300 MHz, DMSO-d 6 ) 5 8.32 (d, J = 2.34 Hz, 1 H), 7.86 (d, J = 2.34 Hz, 1 H), 7.73 - 7.78 (m, 1 H), 7.69 (dd, J = 0.88, 8.20 Hz, 1 H), 7.46 - 7.56 (m, 2H), 7.32 - 7.41 (m, 1 H). 25 Example 70 Intermediate 39 N-(2-bromo-5-chloropyrid in-3-yi)-N -(methoxymethyl)benzofuran-2-su Ifonam ide 66 WO 2013/130962 PCT/US2013/028607 CIn~ 2 N N Br To a solution of Intermediate 38 (377 mg, 0.974 mmol) in THF (10 ml) at 0 C was added NaH (37 mg, 95%, 1.46 mmol) and further stirred for 30 min. Then MOMCI 5 (81 ul, 1.07 mmol) was added into the mixture at 0 0C and further stirred for 1 hour more. Water was added to quenched the reaction, extracted with EtOAc (x2), washed with brine and dried over Na 2 SO 4 and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Intermediate 39 (350 mg, 83 %). 10 'H NMR (600 MHz, CDCI 3 ) 5 8.37 (d, J = 2.35 Hz, 1 H), 7.76 (d, J = 2.64 Hz, 1 H), 7.67 (dt, J = 0.99, 7.70 Hz, 1 H), 7.59 (dd, J = 0.73, 8.36 Hz, 1 H), 7.51 (ddd, J = 1.32, 7.19, 8.51 Hz, 1H), 7.36 (td, J = 1.03, 7.56 Hz, 1H), 7.31 (d, J = 0.88 Hz, 1H), 5.35 (br. s., 1 H), 5.01 (br. s., 1 H), 3.50 (s, 3H). Example 71 15 Intermediate 40 N-methoxy-N -methyl-2-phenvlacetam ide To a mixture of 2-phenylacetyl chloride (1 g, 6.47 mmol) and N,O 20 dimethylhydroxylamin (757 mg, 7.76 mmol) in CH 2 CI 2 (30 ml) was added TEA (2.7 ml, 19.41 mmol) at 0 C. After the reaction was stirred for 15 min at 0 C, it was warmed up to room temperature for 1 hour under N 2 . The mixture was diluted with H 2 0, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na 2 SO 4 and concentrated in vacuo to yield Intermediate 40 crude (1.03 25 g, 85 %), which was used without further purification. 1 H NMR (600 MHz, acetone) 5 6.71 - 7.41 (m, 5H), 3.61 (s, 2H), 3.56 (s, 3H), 2.99 (s, 3H). Example 72 Intermediate 41 67 WO 2013/130962 PCT/US2013/028607 N-(5-chloro-2-(2-phenvlacetyl)pyridin-3-yi)-N-(methoxymethyl)benzofuran-2 sulfonamide 0 0i Sj0 CI 1.1 N 5 To a solution of Intermediate 39 (300 mg, 0.69 mmol) in THF (3 ml) under N 2 at -78 0C was added dropwise of i-PrMgCI (1 ml, 2.08 mmol, 2.0 M in THF). The reaction was stirred at -78 0C for 10 min, followed by warming to room temperature for 30 min. The mixture was cooled down to 0 0C and a solution of Intermediate 40 (248 mg, 1.39 mmol) in THF (1 ml) was added and stirred for 3 hour at room 10 temperature. The mixture was diluted with H 2 0, and the resulting solution was extracted with EtOAc and washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude Intermediate 41 was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield (69 mg, 21 %). 1 H NMR (600 MHz, acetone) 5 8.80 (t, J = 2.05 Hz, 1 H), 7.94 - 7.98 (m, 1 H), 7.81 (d, 15 J = 7.92 Hz, 1 H), 7.65 (d, J = 8.51 Hz, 1 H), 7.52 - 7.62 (m, 1 H), 7.37 - 7.50 (m, 2H), 7.12 - 7.27 (m, 3H), 7.02 (d, J = 7.63 Hz, 2H), 5.15 (br. s., 2H), 4.29 (br. s., 2H), 3.41 (s, 3H). Example 73 Compound 34 20 N-[5-chloro-2-(phenylacetyl)pyridin-3-vil-1 -benzofuran-2-sulfonamide 0 CI NH N O The mixture of Intermediate 42 (58 mg, 0.123 mmol) and 4M HCI in dioxane (5 ml) in H 2 0 (1 ml) was heated at 100 0C for 3 hours. The mixture was cooled down to 68 WO 2013/130962 PCT/US2013/028607 room temperature, and adjusted the pH to - 9 by NaHCO 3 (sat.), extracted with EtOAc (x2), The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo. The crude was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 34 (28 mg, 53%). 5 1 H NMR (600 MHz, acetone) 5 11.58 (br. s., 1 H), 8.32 (d, J = 2.05 Hz, 1 H), 8.09 (d, J = 2.05 Hz, 1 H), 7.72 (d, J = 0.88 Hz, 1 H), 7.63 - 7.68 (m, 1 H), 7.38 - 7.46 (m, 2H), 7.25 (ddd, J = 1.17, 6.75, 7.92 Hz, 1H), 7.10 - 7.15 (m, 4H), 7.05 - 7.10 (m, 1H), 4.39 (s, 2H). Example 74 10 Intermediate 43 methyl 2-(((5-chloro-3-nitropyridin-2-yl)thio)methyl)benzoate CI NO 2 COOMe N S 15 To the crude Intermediate 42 in DMF (10 ml) was added methyl 2 (bromomethyl)benzoate (1.47 g, 6.44 mmol) and K 2 CO 3 (2.7 g, 19.32 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 anhydride, concentrated in 20 vacuo and purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give Intermediate 43 (573 mg, 26%). 1 H NMR (300 MHz, CD 3 OD) 5 8.77 (d, J = 2.34 Hz, 1 H), 8.60 (d, J = 2.34 Hz, 1 H), 7.90 (d, J = 7.91 Hz, 1 H), 7.64 (d, J = 6.74 Hz, 1 H), 7.42 - 7.54 (m, 1 H), 7.27 - 7.39 (m, 1 H), 4.88 (s, 2H), 3.91 (s, 3H). 25 Example 75 Intermediate 44 methyl 2-(((3-amino-5-chloropyridin-2-yl)thio)methyl)benzoate CI NH 2 COOMe N S 69 WO 2013/130962 PCT/US2013/028607 To a solution of Intermediate 43 (575 mg, 1.70 mmol) in MeOH (20 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (2.8 g, 42.40 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and 5 concentrated in vacuo. The crude Intermediate 44 (430 mg, 82%) was used in the next reaction without further purification. 'H NMR (600 MHz, CD 3 OD) 6 7.87 (d, J = 7.92 Hz, 1H), 7.71 - 7.79 (m, 1H), 7.35 7.43 (m, 2H), 7.30 (t, J = 7.34 Hz, 1 H), 6.92 - 7.00 (m, 1 H), 4.71 (s, 2H), 3.89 (d, J = 0.88 Hz, 3H). 10 Example 76 Compound 35 methyl 2-[({3-(1 -benzofuran-2-visulfonvl)aminol-5-chloropyridin-2 VIlsulfanyl)methyllbenzoate 0 CI NH COOMe N S 15 To Intermediate 44 (430mg, 1.40 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (300 mg, 1.40 mmol) was added and the reaction was stirred at 1000C for 16 hours, then additional benzofuran-2-sulfonyl chloride (300 mg, 1.40 mmol) and the reaction was heated for another 24 hours and was concentrated in 20 vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 35 (341 mg, 50%). 1 H NMR (300 MHz, CD 3 OD) 5 8.32 (d, J = 2.34 Hz, 1H), 7.70 - 7.81 (m, 1H), 7.59 7.67 (m, 2H), 7.40 - 7.49 (m, 2H), 7.12 - 7.38 (m, 5H), 4.54 (s, 2H), 3.81 (s, 3H). 25 Example 77 Compound 36 2-[({3-(1 -benzofuran-2-VIsulfonvl)aminol-5-ch loropyridin-2 VIlsulfany)methyllbenzoic acid 70 WO 2013/130962 PCT/US2013/028607 0 O=S O CI NH COOH N S To Compound 35 (60mg, 0.12 mmol) in MeOH (5 ml) was added 5N NaOH (1 ml) and the reaction was stirred at room temperature for 3 hours. The mixture was 5 acidified with 10% HCI, extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 36 (47 mg, 80%). 'H NMR (300 MHz, CD 3 OD) 5 8.33 (d, J = 2.34 Hz, 1H), 7.74 - 7.85 (m, 1H), 7.56 10 7.69 (m, 2H), 7.46 (d, J = 3.52 Hz, 2H), 7.07 - 7.38 (m, 5H), 4.58 (s, 3H). Example 79 Compound 37 methyl 2-[({3-(1 -benzofuran-2-visulfonvl)aminol-5-chloropyridin-2 15 VIlsulfinvl)methyllbenzoate 0 CI NH COOMe N S 0 To a solution of Compound 35 (106 mg, 0.22 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (44 mg, 0.22 mmol) and the reaction was stirred at 0 0C for 30 mins and 20 was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 37 (82 mg, 75%). H NMR (300 MHz, CD 3 OD) 6 7.86 (d, J = 2.05 Hz, 1 H), 7.81 (d, J = 1.47 Hz, 1 H), 7.78 (d, J = 1.17 Hz, 1 H), 7.62 - 7.72 (m, 1 H), 7.41 - 7.48 (m, 1 H), 7.21 - 7.39 (m, 4H), 7.16 (td, J= 1.47, 7.47 Hz, 1H), 6.83 (d, J = 7.62 Hz, 1H), 5.17 (d, J = 12.60 Hz, 25 1 H), 4.79 (d, J = 12.60 Hz, 1 H), 3.84 (s, 3H). 71 WO 2013/130962 PCT/US2013/028607 Example 80 Compound 38 methyl 2-[({3-(1 -benzofuran-2-visulfonvl)aminol-5-chloropyridin-2 5 yllsulfonv)methyllbenzoate 0 O=S CI NH COOMe N S To a solution of Compound 35 (88 mg, 0.18 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (90 mg, 0.45 mmol) and the reaction was stirred at room temperature for 3 10 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 38 (55 mg, 59%). 1 H NMR (300 MHz, CD 3 OD) 5 8.18 (d, J = 2.05 Hz, 1 H), 7.83 (d, J = 8.20 Hz, 1 H), 7.62 - 7.73 (m, 2H), 7.20 - 7.49 (m, 5H), 6.93 - 7.09 (m, 2H), 5.67 (s, 2H), 3.88 (s, 3H). 15 Example 81 Compound 39 2-[({3-(1 -benzofuran-2-VIsulfonvl)aminol-5-ch loropyridin-2 20 yllsulfonyl)methyllbenzoic acid 0 COOH N S To Compound 38 (55mg, 0.11 mmol) in MeOH (5 ml) was added 5N NaOH (1 ml) and the reaction was stirred at room temperature for 3 hours. The mixture was 25 acidified with 10% HCI, extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude 72 WO 2013/130962 PCT/US2013/028607 product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 39 (36 mg, 43%). 'H NMR (300 MHz, CD 3 OD) 5 8.35 (s, 1 H), 8.21 (d, J = 1.76 Hz, 1 H), 7.82 (d, J= 7.33 Hz, 1 H), 7.78 - 7.78 (m, 1 H), 7.75 (s, 1 H), 7.62 (s, 1 H), 7.48 - 7.59 (m, 2H), 7.28 5 - 7.42 (m, 2H), 7.13 - 7.27 (m, 2H), 5.40 (s, 2H). Example 82 Intermediate 45 5-fluoro-3-nitro-2-(phenvlthio)pyridine F nNO 2 N S 10 To a solution of 2-bromo-5-fluoro-3-nitropyridine (1.17 g, 5.29 mmol) in DMF (10 ml) was added benzenethiol (0.54 ML, 5.29 mmol) and K 2 CO 3 (2.19 g, 15.88 mmol), and the reaction was stirred at room temperature for 16 hours, diluted with H 2 0, and the resulting solution was extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, followed by MPLC purification 15 to yield Intermediate 45 as yellow solid. 'H NMR (300 MHz, CD 3 OD) 5 8.42 - 8.54 (m, 2H), 7.36 - 7.49 (m, 5H). Example 83 Intermediate 46 5-fluoro-2-(phenvlthio)pyridin-3-amine F n NH 2 N S 20 To a solution of Intermediate 45 (1.3 g, 5.29 mmol) in MeOH (20 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (8.6 g, 132 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and 25 concentrated in vacuo. The crude Intermediate 46 (735 mg, 55%, 2-step yield) was used in the next reaction without further purification. 73 WO 2013/130962 PCT/US2013/028607 'H NMR (300 MHz, CD 3 OD) 6 7.72 (d, J= 2.64 Hz, 1H), 7.06 - 7.29 (m, 5H), 6.95 (dd, J = 2.64, 10.55 Hz, 1 H). Example 84 Compound 40 5 N-[5-fluoro-2-(phenvlsulfanvl)pvridin-3-yll-1 -benzofuran-2-sulfonamide o=s F NH N S b To Intermediate 46 (735 mg, 3.34 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (735 mg, 3.34 mmol) and the reaction was stirred at 100 C for 16 10 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to yield Compound 40 (150 mg, 11%). 1 H NMR (300 MHz, CD 3 OD) 5 8.12 (d, J = 2.64 Hz, 1H), 7.62 - 7.77 (m, 2H), 7.42 7.58 (m, 2H), 7.28 - 7.41 (m, 2H), 7.06 - 7.23 (m, 3H), 6.90 - 7.00 (m, 2H). 15 Example 85 Compound 41 N-[5-fluoro-2-(phenvlsulfinvl)pvridin-3-vil-1 -benzofuran-2-sulfonamide o=P F NH NH N S:-O 20 To a solution of Compound 40 (60 mg, 0.15 mmol) in CH 2 CI 2 (3 ml) was added mCPBA (30 mg, 0.15 mmol) and the reaction was stirred at 0 C for 20 min and was 74 WO 2013/130962 PCT/US2013/028607 concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 41 (44 mg, 73 %). 1 H NMR (300 MHz, CD 3 OD) 5 8.25 (br. s., 1 H), 7.89 (dd, J = 1.90, 10.11 Hz, 1 H), 7.68 - 7.77 (m, 1 H), 7.55 - 7.64 (m, 3H), 7.41 - 7.54 (m, 3H), 7.32 - 7.40 (m, 1 H), 5 7.21 - 7.30 (m, 3H). Example 86 Compound 42 N-[5-fluoro-2-(phenvlsulfonyl)pyridin-3-vI-1 -benzofuran-2-sulfonamide 0 NH 'P N 10 To a solution of Compound 40 (57 mg, 0.13 mmol) in CH 2 CI 2 (3 ml) was added 15 mCPBA (65 mg, 0.32 mmol) and the reaction was stirred at room temperature for hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 42 (38 mg, 62%). 1 H NMR (300 MHz, CD 3 OD) 5 8.24 (d, J = 2.34 Hz, 1 H), 8.07 (dd, J = 2.34, 10.26 Hz, 1 H), 7.73 - 7.86 (m, 3H), 7.68 (s, 1 H), 7.48 - 7.61 (m, 3H), 7.29 - 7.45 (m, 3H). 20 Example 87 Compound 43 2-[({3-(1 -benzofuran-2-visulfonvl)aminol-5-ch loropyridin-2 vllsulfinvl)methyllbenzoic acid 0 CI NH COOH N S 25 N 75 WO 2013/130962 PCT/US2013/028607 To Compound 37 (76mg, 0.15 mmol) in MeOH (5 ml) was added 5N NaOH (1 ml) and the reaction was stirred at room temperature for 3 hours. The mixture was 5 acidified with 10% HCI, extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 43 (67 mg, 90%). 'H NMR (300 MHz, CD 3 OD) 5 8.29 (d, J = 2.05 Hz, 1 H), 8.00 (d, J = 2.05 Hz, 1 H), 10 7.91 (dd, J = 1.76, 7.62 Hz, 1H), 7.75 (dd, J = 1.03, 7.77 Hz, 1H), 7.61 (s, 1H), 7.44 7.58 (m, 2H), 7.23 - 7.41 (m, 3H), 6.94 (dd, J = 1.32, 7.47 Hz, 2H), 4.94 (d, J = 12.60 Hz, 1H), 4.81 (d, J= 12.60 Hz, 1H). Example 88 15 Intermediate 47 5-methyl-3-nitro-2-(Dhenvithio)Dyrid ine n NO 2 N S 6 20 To a solution of 2-chloro-5-methyl-3-nitropyridine (1.05 g, 5.44 mmol) in MeOH (10 ml) was added benzenethiol (0.56 ML, 5.44 mmol) and NaOH (1.5 ml, 5N) and the reaction was stirred at room temperature for 1.5 hours, diluted with H 2 0, and the resulting solution was extracted.with EtOAc .The organic layer washed with brine, dried over Na 2 SO 4 and concentrated in vacuo, followed by MPLC purification to 25 yield Intermediate 47 (1.26 g, 88%) as a yellow solid. 'H NMR (300 MHz, CDCI 3 ) 5 8.29 - 8.36 (m, 2H), 7.50 - 7.59 (m, 2H), 7.37 - 7.49 (m, 3H), 2.36 (t, J = 0.73 Hz, 3H). Example 89 Intermediate 48 30 5-methyl-2-(Dhenvithio)Dvridin-3-amine 76 WO 2013/130962 PCT/US2013/028607 C NH 2 N S 6 To a solution of Intermediate 47 (1.26 g, 4.76 mmol) in MeOH (50 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (7.8 g, 119 mmol). The suspension 5 was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude Intermediate 49 (1.0 g, 91 %) was used in the next reaction without further purification. 'H NMR (300 MHz, CDCI 3 ) 6 7.90 (d, J = 1.47 Hz, 1 H), 7.08 - 7.28 (m, 5H), 6.86 (d, 10 J = 1.17 Hz, 1H), 4.18 (br. s., 2H), 2.27 (s, 3H). Example 90 Compound 44 N-[5-methyl-2-(phenvlsulfanvl)pvridin-3-vil-1 -benzofuran-2-sulfonamide 0 O=S- O,1 NH N S 15 To Intermediate 49 (548 mg, 2.54 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (548 mg, 2.54 mmol) and the reaction was stirred at 100 C for 16 hours. Solvent was removed in vacuo and the crude product was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to yield 20 Compound 44 (691 mg, 69%). 1 H NMR (300 MHz, CD 3 OD) 5 8.02 (dd, J = 0.73, 2.20 Hz, 1 H), 7.62 - 7.70 (m, 2H), 7.38 - 7.56 (m, 2H), 7.25 - 7.36 (m, 2H), 7.02 - 7.20 (m, 3H), 6.86 - 6.98 (m, 2H), 4.85 (br. s., 1 H), 2.25 (s, 3H). 25 Example 91 77 WO 2013/130962 PCT/US2013/028607 Compound 45 N-[5-methyl-2-(phenvlsulfinvl)pvridin-3-vil-1 -benzofuran-2-sulfonamide o=se NH N SsO 5 To a solution of Compound 44 (106 mg, 0.27 mmol) in CH 2 CI 2 (3 ml) was added mCPBA (54 mg, 0.27 mmol) and the reaction was stirred at 0 OC for 30 min and was concentrated. The residue was purified by flash column chromatography on silica gel 10 (100% EtOAc) to yield Compound 45 (59 mg, 81%). 1 H NMR (300 MHz, CD 3 OD) 5 8.19 (s, 1 H), 7.82 (s, 1 H), 7.70 (d, J = 7.62 Hz, 1 H), 7.55 - 7.63 (m, 2H), 7.53 (s, 1 H), 7.42 - 7.50 (m, 2H), 7.21 - 7.39 (m, 4H), 2.30 (s, 3H). 15 Example 92 Compound 46 N-[5-methyl-2-(phenvlsulfonvl)pvridin-3-vIl-1-benzofuran-2-sulfonamide 0 NH N O 20 To a solution of Compound 44 (204 mg, 0.52 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (222 mg, 1.29 mmol) and the reaction was stirred at room temperature for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 46 (141 mg, 64%). 78 WO 2013/130962 PCT/US2013/028607 'H NMR (300 MHz, CD 3 OD) 5 8.00 (d, J = 9.67 Hz, 2H), 7.84 (d, J = 7.62 Hz, 2H), 7.64 (d, J = 7.91 Hz, 1 H), 7.21 - 7.55 (m, 7H), 2.28 (s, 3H). Example 93 Intermediate 49 5 methyl 2-((5-chloro-3-nitropyridin-2-yl)thio)benzoate CI NO 2 N S 0 OMe To a solution of 2,5-dichloro-3-nitropyridine (1.0 g, 5.2 mmol) in MeOH (5 ml) was added methyl 2-mercaptobenzoate (0.71 ml, 5.2 mmol) and 4M NaOH (1.3 ml, 5.2 10 mmol) and the reaction was stirred at room temperature for 3 hours. The resulting suspension was diluted with H 2 0 and was filtered to give Intermediate 49 as yellow solid (1.74 g). The crude product was used in the next reaction without further purification. Example 94 15 Intermediate 50 methyl 2-((3-amino-5-chloropyridin-2-yl)thio)benzoate CI NH 2 In N S 0 ct l OMe To a solution of Intermediate 49 (1.7 g, 5.2 mmol) in HOAc (10 ml) was added iron 20 powder (1.5 g, 26 mmol). The suspension was stirred at 70 OC for 1 hour and was diluted with MeOH, treated with Celite and was filtered. The filtrate was concentrated, then taken up in EtOAc, washed with 4M NaOH, brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (10-40% EtOAc in hexanes) to yield Intermediate 50 25 as light yellow solid (1.4 g, 91%). 1 H NMR (METHANOL-d4) 5: 7.98 (dd, J = 7.8, 1.6 Hz, 1 H), 7.82 - 7.85 (m, 1 H), 7.30 - 7.37 (m, 1 H), 7.19 - 7.27 (m, 2H), 6.74 - 6.79 (m, 1 H), 3.92 (s, 3H). 79 WO 2013/130962 PCT/US2013/028607 Example 95 Intermediate 51 methyl 2-((3-(benzofu ran -2-su Ifonam ido)-5-ch loropyrid in -2-yl)th io)benzoate 0 cl1 o=S / N S O OMe 5 To Intermediate 50 (300 mg, 1.02 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (221 mg, 1.02 mmol) and a catalytic amount of DMAP. The reaction was stirred at 100 OC for a total of 42 hours, during which additional benzofuran-2 sulfonyl chloride (553 mg, 2.55 mmol) was added in three batches to drive the reaction toward completion. At the end the reaction was concentrated, acidified with 10 6M HCl, diluted with brine and extracted with EtOAc (x2). The combined organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (15-20% EtOAc in hexanes) to yield Intermediate 51 (182 mg, 38%). 1 H NMR (CHLOROFORM-d) 5: 8.36 (s, 1 H), 8.22 (d, J = 2.1 Hz, 1 H), 8.06 (d, J = 15 2.1 Hz, 1 H), 7.79 (dd, J = 7.9, 1.5 Hz, 1 H), 7.49 - 7.53 (m, 1 H), 7.29 - 7.36 (m, 2H), 7.17 - 7.25 (m, 2H), 6.99 (td, J = 7.6, 1.2 Hz, 1H), 6.81 - 6.86 (m, 1H), 6.50 (dd, J = 7.9, 0.9 Hz, 1H), 3.83 (s, 3H). Example 96 Compound 47 20 2-({3-(1 -benzofuran-2-vlsulfonvl)aminol-5-chloropyridin-2-yllsulfanyl)benzoic acid 0 CI NH 0 I- N S O - OH 80 WO 2013/130962 PCT/US2013/028607 To a solution of Intermediate 51 (60 mg, 0.13 mmol) in MeOH (5 ml) was added 4M NaOH (0.16 ml, 0.64 mmol) and the reaction was stirred at room temperature for 6 hours, when additional 4M NaOH (0.64 ml, 2.6 mmol) was added and the reaction was continued for 64 hours. The reaction was then acidified with HCl, and 5 concentrated. The crude product was triturated with MeOH to yield Compound 47 as an off-white solid (24 mg, 41%). 1 H NMR (METHANOL-d4) 5: 8.28 (d, J = 2.1 Hz, 1 H), 8.00 (d, J = 2.3 Hz, 1 H), 7.81 (dd, J = 7.8, 1.3 Hz, 1 H), 7.64 (d, J = 7.9 Hz, 1 H), 7.43 (d, J = 3.5 Hz, 2H), 7.37 (s, 1 H), 7.27 - 7.34 (m, 1 H), 7.12 (t, J = 7.6 Hz, 1 H), 6.99 (td, J = 7.6, 1.5 Hz, 1 H), 6.50 10 (d, J = 8.2 Hz, 1H). Example 97 Intermediate 52 methyl 3-((5-chloro 3-nitropyridin-2-yl)thio)benzoate 15 CI NO 2 In N S CO 2 Me To a solution of 2,5-dichloro-3-nitropyridine (1.15 g, 5.96 mmol) in MeOH (10 ml) was added methyl 3-mercaptobenzoate (1.0 g, 5.96 mmol) and 4M NaOH (1.5 ml, 6.0 mmol) and the reaction was stirred at room temperature for 2 hours. The 20 resulting suspension was diluted with H 2 0, and it was filtered to give Intermediate 52 as yellow solid (1.94 g). The crude product was used in the next reaction without further purification. Example 98 Intermediate 53 25 methyl 3-((3-amino-5-chloropyridin-2-yl)thio)benzoate CI NH 2 In N S CO 2 Me 81 WO 2013/130962 PCT/US2013/028607 To a solution of Intermediate 53 (324 mg, 1.0 mmol) in MeOH (15 ml) and THF (15 ml) was added saturated aqueous NH 4 CI (20 ml) and zinc dust (1.63 g, 25 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc. The organic layer was washed with brine, dried 5 over Na 2 SO 4 , and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (20-30% EtOAc in hexanes) to yield Intermediate 53 (250 mg, 85%). 'H NMR (METHANOL-d4) 5: 7.82 - 7.86 (m, 1 H), 7.79 (dt, J = 7.6, 1.5 Hz, 1 H), 7.73 (d, J = 2.1 Hz, 1H), 7.41 (dt, J = 8.0, 1.4 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 10 2.3 Hz, 1 H), 3.83 (s, 3H). Example 99 Intermediate 54 methyl 3-((3-(benzofu ran -2-su Ifonam ido)-5-ch loropyrid in -2-yl)th io)benzoate 0 C I N H 0 I N S CO 2 Me 15 To Intermediate 53 (222 mg, 0.76 mmol) in pyridine (4 ml) was added benzofuran-2 sulfonyl chloride (164 mg, 0.76 mmol) and a catalytic amount of DMAP. The reaction was stirred at 100 OC for a total of 42 hours, during which additional benzofuran-2 sulfonyl chloride (410 mg, 1.9 mmol) was added in three batches to drive the reaction toward completion. At the end the reaction was concentrated, acidified with 20 6M HCl, diluted with brine and extracted with EtOAc (x2). The combined organic layer was dried over Na 2 SO 4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (20% EtOAc in hexanes) to yield Intermediate 54 (275 mg, 77%). 'H NMR (CHLOROFORM-d) 5: 8.23 (d, J = 2.3 Hz, 1H), 8.01 (d, J = 2.3 Hz, 1H), 25 7.84 - 7.90 (m, 2H), 7.68 (s, 1 H), 7.65 (dt, J = 7.8, 1.1 Hz, 1 H), 7.44 - 7.48 (m, 2H), 7.41 (d, J = 0.6 Hz, 1 H), 7.30 - 7.37 (m, 1 H), 7.21 - 7.25 (m, 2H), 3.87 (s, 3H). Example 100 Compound 48 82 WO 2013/130962 PCT/US2013/028607 3-({3-(1 -benzofuran-2-ylsulfonyl)aminol-5-chloropyridin-2-yllsulfanyl)benzoic acid 0 CI H N S b I OH 0 5 To a solution of Intermediate 54 (96 mg, 0.20 mmol) in MeOH (8 ml) was added 4M NaOH (0.25 ml, 1.0 mmol) and the reaction was stirred at room temperature for 6 hours, when an additional 4M NaOH (1.0 ml, 4.0 mmol) was added and the reaction was continued for 64 hours. The reaction was then acidified with HCI, concentrated. The crude product was triturated with H 2 0 to yield Compound 48 as an off-white 10 solid (93 mg, 100%). 1 H NMR (METHANOL-d4) 5: 8.18 (d, J = 2.1 Hz, 1H), 7.89 (d, J = 7.6 Hz, 1H), 7.80 (d, J = 2.3 Hz, 1 H), 7.67 - 7.75 (m, 2H), 7.52 - 7.59 (m, 1 H), 7.47 (t, J = 7.8 Hz, 1 H), 7.24 - 7.41 (m, 3H), 7.14 (d, J = 7.9 Hz, 1H). 15 Example 101 Compound 49 methyl 2-((3-(benzofuran-2-sulfonamido)-5-chloropyridin-2-yl)sulfinyl)benzoate 0 o=1 / CI NH ~0 N S 0 ctr OMe To a solution of Intermediate 51 (58 mg, 0.12 mmol) in CH 2 CI 2 (2 ml) was added 20 mCPBA (29 mg, -0.12 mmol) and the reaction was stirred at room temperature for 2 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 49 (56 mg, 93%). 83 WO 2013/130962 PCT/US2013/028607 H NMR (acetone) 5: 8.10 - 8.23 (m, 2H), 8.06 (d, J = 6.2 Hz, 1H), 7.54 - 7.71 (m, 4H), 7.46 - 7.54 (m, 1 H), 7.32 - 7.44 (m, 2H), 7.23 - 7.32 (m, 1 H), 3.61 (s, 3H). Example 102 Compound 50 5 2-({3-(1 -benzofuran-2-ylsulfonyl)aminol-5-chloropyridin-2-yllsulfinyl)benzoic acid / I < CI NH 0 ~0 N S " 0 ct OH 10 To a solution of Compound 49 (55 mg, 0.11 mmol) in MeOH (5 ml) was added 4M NaOH (0.7 ml, 2.8 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction was then acidified with HCI and was concentrated. The crude product was triturated with H 2 0 to yield Compound 50 as yellow solid (46 mg, 87%). 1H NMR (CHLOROFORM-d) 5: 9.54 (br. s., 1H), 8.37 (d, J = 8.2 Hz, 1H), 8.19 (d, J 15 = 2.1 Hz, 1H), 8.09 (d, J = 2.1 Hz, 1H), 8.04 (dd, J = 7.5, 1.0 Hz, 1H), 7.77 - 7.85 (m, 1 H), 7.65 (d, J = 7.9 Hz, 1 H), 7.52 - 7.61 (m, 2H), 7.49 (s, 1 H), 7.44 (td, J = 7.8, 1.3 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 1 H). Example 103 Compound 51 20 methyl 2-((3-(benzofuran-2-sulfonamido)-5-chloropyridin-2 vl)sulfonvl)benzoate 0 C I N H /0 CO 2 Me N S To a solution of Intermediate 51 (58 mg, 0.12 mmol) in CH 2 CI 2 (2 ml) was added mCPBA (59 mg, -0.25 mmol) and the reaction was stirred at room temperature for 2 25 hours and additional mCPBA (30 mg, -0.12 mmol) was added. The reaction was 84 WO 2013/130962 PCT/US2013/028607 continued for 4 hours and was diluted with saturated aqueous NaHCO 3 , extracted with EtOAc. The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (50% EtOAc in hexanes) to yield Compound 51 5 (45 mg, 73%). 1 H NMR (acetone) 5: 8.13 - 8.21 (m, 1 H), 8.08 (br. s., 1 H), 7.51 - 7.74 (m, 5H), 7.11 7.47 (m, 5H), 3.50 (br. s., 3H). Example 104 10 Compound 52 2-{3-[(1 -benzofuran-2-vlsulfonvl)aminol-5-ch loropyridin-2-vllsulfonyl)benzoic acid 0 C I N H 0 0 0 OH N S 15 To a solution of Compound 51 (45 mg, 0.089 mmol) in MeOH (5 ml) was added 4M NaOH (0.56 ml, 2.2 mmol) and the reaction was stirred at room temperature for 2 days. The reaction was then acidified with HCI and was concentrated. The crude product was triturated with H 2 0 and was further purified by PTLC (developed with 20 EtOAc) to yield Compound 52 as white solid (20 mg, 45%). 1 H NMR (CHLOROFORM-d) 5: 9.77 (s, 1H), 8.42 - 8.45 (m, 1H), 8.30 (d, J = 2.1 Hz, 1 H), 8.11 (d, J = 2.1 Hz, 1 H), 8.04 - 8.06 (m, 1 H), 7.76 - 7.79 (m, 2H), 7.68 - 7.70 (m, 1 H), 7.58 - 7.60 (m, 1 H), 7.55 (d, J = 0.9 Hz, 1 H), 7.49 (ddd, J = 8.5, 7.2, 1.3 Hz, 1 H), 7.35 (ddd, J = 7.9, 7.0, 0.9 Hz, 1 H). 25 Example 106 Intermediate 55 methyl 2-(((5-methyl-3-nitropyridin-2-yl)thio)methyl)benzoate 85 WO 2013/130962 PCT/US2013/028607 N0 2 COOMe N S To the crude Intermediate 54 in DMF (10 ml) was added methyl 2-(bromomethyl) 5 benzoate (1.4 g, 6.20 mmol) and K 2 CO 3 (2.5 g, 18.11 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 anhydride, concentrated in vacuo and purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to 10 give Intermediate 55 (555 mg, 31%). 'H NMR (300 MHz, CDCI 3 ) 5 8.53 (d, J = 1.47 Hz, 1 H), 8.28 (d, J = 1.47 Hz, 1 H), 7.92 (dd, J = 1.17, 7.91 Hz, 1H), 7.59 (d, J = 7.62 Hz, 1H), 7.42 (td, J = 1.32, 7.55 Hz, 1 H), 7.21 - 7.35 (m, 1 H), 4.88 (s, 2H), 3.93 (s, 3H), 2.39 (s, 3H). Example 107 15 Intermediate 56 methyl 2-(((3-amino-5-methylpyridin-2-yl)thio)methyl)benzoate NH 2 COOMe N S To a solution Intermediate 55 (555 mg, 1.94 mmol) in MeOH (20 ml) was added 20 saturated aqueous NH 4 CI (2 ml) and zinc dust (3.2 g, 63.71 mmol). The suspension was stirred at room temperature for 1 hour and was filtered, and the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude Intermediate 56 (406 mg, 81 %) was used in the next reaction without further purification. 25 1 H NMR (300 MHz, CD 3 OD) 6 7.83 (dd, J = 1.47, 7.62 Hz, 1H), 7.65 (d, J = 1.17 Hz, 1 H), 7.13 - 7.38 (m, 3H), 6.83 (d, J = 1.17 Hz, 1 H), 4.58 (s, 2H), 3.86 (s, 3H), 2.18 (s, 3H). Example 108 Intermediate 57 86 WO 2013/130962 PCT/US2013/028607 methyl 2-(((3-(benzofuran-2-sulfonamido)-5-methylpyridin-2 yl)th io)methyl)benzoate O=s NH COOMe N S 5 To Intermediate 56 (406mg, 1.41 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (305 mg, 1.41 mmol), and the reaction was stirred at 100 C for 16 hours and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Intermediate 57 (270 mg, 41%). 10 'H NMR (600 MHz, CDCI 3 ) 5 8.15 (dd, J = 0.59, 2.05 Hz, OH), 7.88 (dd, J = 1.61, 7.48 Hz, OH), 7.65 - 7.70 (m, 1 H), 7.63 - 7.65 (m, OH), 7.59 (ddd, J = 0.88, 1.03, 8.07 Hz, OH), 7.43 (dd, J = 1.17, 6.75 Hz, OH), 7.21 - 7.31 (m, 4H), 7.17 (dd, J = 1.61, 7.48 Hz, 1 H), 4.63 (s, 2H), 3.91 (s, 3H), 2.30 (s, 3H). Example 109 15 Compound 53 2-[({3-[(1-benzofuran-2-visulfonvl)aminol-5-methylDyridin-2 VIlsulfanyl)methyllbenzoic acid NH COOH N S 20 To Intermediate 57 (136 mg, 0.29 mmol) in MeOH (30 ml) was added 5N NaOH (2 ml) and the reaction was stirred at room temperature for 3 hours. The mixture was acidified with 10% HCl, extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 53 25 (108 mg, 82%). 87 WO 2013/130962 PCT/US2013/028607 'H NMR (600 MHz, CDCI 3 ) 5 8.05 (s, 1H), 7.80 (dd, J = 1.47, 7.63 Hz, 1H), 7.69 (s, 1 H), 7.62 (d, J = 7.92 Hz, 1 H), 7.52 - 7.56 (m, 1 H), 7.49 (td, J = 1.32, 7.85 Hz, 1 H), 7.33 - 7.37 (m, J = 7.48, 7.48 Hz, 1H), 7.28 (d, J = 0.88 Hz, 1H), 7.23 (td, J = 1.17, 7.48 Hz, 1H), 7.18 (td, J = 1.47, 7.48 Hz, 1H), 7.10 (d, J = 7.63 Hz, 1H), 7.03 (br. s., 5 1 H), 4.47 (s, 2H), 2.29 (s, 3H). Example 110 Compound 54 10 methyl 2-(((3-(benzofuran-2-sulfonamido)-5-methylpyridin-2 vl)sulfinvl)methvl)benzoate 0 0 NH COOMe N S 0 To a solution of Intermediate 57 (134 mg, 0.29mmol) in CH 2 CI 2 (5 ml) was added 15 mCPBA (57mg, 0.29 mmol) and the reaction was stirred at 0 OC for 30 mins and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 54 (82 mg, 59%). 1 H NMR (600 MHz, CDCI 3 ) 5 10.84 (br. s., 1H), 8.07 (d, J = 1.17 Hz, 1H), 7.98 (dd, J = 1.32, 7.78 Hz, 1 H), 7.87 (s, 1 H), 7.65 (d, J = 7.92 Hz, 1 H), 7.44 - 7.48 (m, 2H), 20 7.38 - 7.43 (m, 2H), 7.34 - 7.38 (m, 1 H), 7.27 - 7.32 (m, 1 H), 7.01 - 7.09 (m, 1 H), 4.98 (d, J= 12.32 Hz, 1H), 4.63 (d, J = 12.32 Hz, 1H), 3.87 (s, 3H), 2.36 (s, 3H). Example 111 25 Compound 55 2-[({3-[(1-benzofuran-2-visulfonvl)aminol-5-methylDyridin-2 VIlsulfinvl)methyllbenzoic acid 88 WO 2013/130962 PCT/US2013/028607 O O= S NH COOH N S 0 To Compound 54 (505 mg, 1.04 mmol) in MeOH (30 ml) was added 5N NaOH (2 ml) and the reaction was stirred at room temperature for 16 hours. The mixture was 5 acidified with 10% HCI, and extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 55 (454 mg, 93%). 'H NMR (600 MHz, CDCI 3 ) 5 8.05 - 8.16 (m, 2H), 7.90 (s, 1 H), 7.68 (dd, J = 0.73, 10 7.78 Hz, 1 H), 7.37 - 7.52 (m, 5H), 7.33 (td, J = 1.03, 7.56 Hz, 1 H), 7.04 (d, J = 7.34 Hz, 1H), 4.97 (d, J = 11.74 Hz, 1H), 4.63 (d, J = 12.03 Hz, 1H), 2.41 (s, 3H). Example 112 15 Intermediate 58 methyl 2-(((3-n itropyrid in -2-y)th io)methyl)benzoate NO2 COOMe N S 20 To 3-nitropyridine-2-thiol (1 g, 6.40 mmol) in DMF (10 ml) was added methyl 2 (bromomethyl)benzoate (1.5 g, 6.40 mmol) and K 2 CO 3 (2.6 g, 19.21 mmol) and the reaction was stirred at room temperature for 16 hours. The reaction mixture was poured into water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The organic layer was washed with brine and then dried over Na 2 SO 4 , concentrated in vacuo and 25 purified by flash column chromatography on silica gel (0 - 30 % ethyl acetate in hexane) to give Intermediate 58 (1.12 g, 57%). 1 H NMR (600 MHz, CDCI 3 ) 5 8.70 (dd, J = 1.61, 4.55 Hz, 1 H), 8.47 (dd, J = 1.47, 8.22 Hz, 1H), 7.95 (dd, J = 1.17, 7.63 Hz, 1H), 7.62 (d, J = 7.92 Hz, 1H), 7.44 (td, J= 89 WO 2013/130962 PCT/US2013/028607 1.32, 7.56 Hz, 1H), 7.29 - 7.36 (m, 1H), 7.19 (dd, J = 4.55, 8.36 Hz, 1H), 4.92 (s, 2H), 3.94 (s, 3H). Example 113 Intermediate 59 5 methyl 2-(((3-aminopyridin-2-yl)thio)methyl)benzoate NH2 COOMe N S To a solution of Intermediate 58 (555 mg, 3.68 mmol) in MeOH (20 ml) was added saturated aqueous NH 4 CI (2 ml) and zinc dust (4.8 g, 73.68 mmol). The suspension 10 was stirred at room temperature for 1 hour and was filtered, the filtrate was extracted with EtOAc (x2). The organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. Intermediate 59 (988 mg, 98%) was used in the next reaction without further purification. 1 H NMR (600 MHz, CDCI 3 ) 5 8.15 (dd, J = 0.59, 2.05 Hz, 1 H), 7.88 (dd, J= 1.61, 15 7.48 Hz, 1 H), 7.65 - 7.70 (m, 1 H), 7.63 - 7.65 (m, 1 H), 7.59 (ddd, J = 0.88, 1.03, 8.07 Hz, 1H), 7.43 (dd, J = 1.17, 6.75 Hz, 1H), 7.21 - 7.31 (m, 4H), 7.17 (dd, J 1.61, 7.48 Hz, 1 H), 4.63 (s, 2H), 3.91 (s, 3H), 2.30 (s, 3H). Example 114 20 Compound 56 methyl 2-[({3-(1 -benzofuran-2-visulfonyl)aminolDyridin-2 yllsulfanyl)methyllbenzoate o=s I0 COOMe N S 25 To Intermediate 59 (968mg, 3.53 mmol) in pyridine (5 ml) was added benzofuran-2 sulfonyl chloride (763 mg, 1.41 mmol) and the reaction was stirred at 100 C for 16 hours, then additional of benzofuran-2-sulfonyl chloride (763 mg, 1.41 mmol) and DMAP (cat.) was added and the reaction was further stirred at 100 C for 16 hours 90 WO 2013/130962 PCT/US2013/028607 and concentrated in vacuo. The crude product was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to yield Compound 56 (745 mg, 46%). 'H NMR (600 MHz, CDCI 3 ) 5 8.55 (br. s., 1 H), 8.24 (dd, J = 1.47, 4.70 Hz, 1 H), 7.81 5 (d, J = 7.92 Hz, 1 H), 7.71 (dd, J = 1.61, 8.07 Hz, 1 H), 7.50 - 7.53 (m, 1 H), 7.31 - 7.40 (m, 2H), 7.13 - 7.25 (m, 5H), 6.99 (dd, J = 4.70, 8.22 Hz, 1H), 4.62 (s, 2H), 3.83 (s, 3H). Example 115 10 Compound 57 2-({3-[(1 -benzofuran-2-visulfonvl)aminolDyridin-2-vllsulfanyl)methyllbenzoic acid o=s I0 ~NH COOH N S 15 To Compound 56 (170 mg, 0.37 mmol) in MeOH (30 ml) was added 5N NaOH (2 ml) and stirred at room temperature for 3 hours. The mixture was acidified with 10% HCI, extracted with EtOAc (x2). The combined organic layer was washed with brine, 20 dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 57(165 mg, 100%). 1 H NMR (600 MHz, CDCI 3 ) 5 8.33 (br. s., 1H), 7.89 (none, 1H), 7.86 - 7.91 (m, 1H), 7.78 (d, J = 7.92 Hz, 1 H), 7.60 (d, J = 7.92 Hz, OH), 7.42 - 7.48 (m, 2H), 7.29 - 7.35 (m, 2H), 7.22 - 7.26 (m, 3H), 7.16 - 7.20 (m, 1H), 7.13 (br. s., 1H), 4.64 (s, 2H). 25 Example 116 Compound 58 methyl 2-[({3-(1 -benzofuran-2-visulfonvl)aminolDyridin-2 30 vllsulfinvl)methyllbenzoate 91 WO 2013/130962 PCT/US2013/028607 O= I 0t NH COOMe N S 0 To a solution of Compound 56 (180 mg, 0.40 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (80 mg, 0.40 mmol) and the reaction was stirred at 0 OC for 30 mins and 5 was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 58 (180 mg, 96%). 'H NMR (600 MHz, CDCI 3 ) 5 8.22 (ddd, J = 1.32, 1.47, 4.55 Hz, 1 H), 8.03 - 8.08 (m, 1 H), 7.96 (dd, J = 1.47, 7.63 Hz, 1 H), 7.63 (dd, J = 0.59, 7.92 Hz, 1 H), 7.22 - 7.49 (m, 7H), 7.01 (d, J = 7.63 Hz, 1H), 5.02 (d, J= 12.32 Hz, 1H), 4.66 (d, J = 12.32 Hz, 10 1 H), 3.86 (s, 3H). Example 117 Compound 59 2-[{3-[(1 -benzofuran-2-vlsulfonvl)aminolovridin-2-vllsulfinvl)methvllbenzoic 15 acid O=s O 0 NH COOH N S To Compound 58 (189 mg, 0.40 mmol) in MeOH (30 ml) was added 5N NaOH (2 ml) and stirred at room temperature for 3 hours. The mixture was acidified with 10% 20 HCI, extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 59 (140 mg, 76%). 1 H NMR (600 MHz, CD 3 OD) 5 8.30 (d, J = 3.52 Hz, 1H), 7.95 - 8.02 (m, 1H), 7.84 (s, 1 H), 7.72 (d, J = 7.92 Hz, 1 H), 7.51 - 7.57 (m, 2H), 7.41 - 7.49 (m, 2H), 7.29 - 7.37 25 (m, 3H), 6.83 - 6.92 (m, 1 H), 4.96 (d, J = 12.32 Hz, 1 H), 4.80 (d, J = 12.32 Hz, 1 H). 92 WO 2013/130962 PCT/US2013/028607 Example 118 Compound 60 methyl 2-[({3-[(1 -benzofuran-2-visulfonvl)aminolDyridin-2 5 VIlsulfonv)methyllbenzoate I0 NH COOMe N'S To a solution of Compound 56 (180 mg, 0.40 mmol) in CH 2 CI 2 (5 ml) was added mCPBA (200mg, 0.99 mmol) and the reaction was stirred at room temperature for 2 10 hours and was concentrated. The residue was purified by flash column chromatography on silica gel (100% EtOAc) to yield Compound 60 (186 mg, 97%). 1 H NMR (600 MHz, CDCI 3 ) 5 9.62 (br. s., 1 H), 8.39 (d, J = 4.40 Hz, 1 H), 8.19 (d, J = 8.80 Hz, 1 H), 7.89 (d, J = 7.92 Hz, 1 H), 7.63 (d, J = 7.92 Hz, 1 H), 7.41 - 7.51 (m, 4H), 7.33 - 7.38 (m, 1H), 7.27 - 7.32 (m, 2H), 7.18 (d, J = 7.34 Hz, 1H), 5.31 (s, 2H), 15 3.86 (s, 3H). Example 119 Compound 61 20 2-[({3-(1 -benzofuran-2-vlsulfonyl)aminolPyridin-2-vllsulfonv)methyllbenzoic acid 0 NH COOH N S 0 25 93 WO 2013/130962 PCT/US2013/028607 To Compound 60 (119mg, 0.24 mmol) in MeOH (30 ml) was added 5N NaOH (2 ml) and the reaction was stirred at room temperature for 3 hours. The mixture was acidified with 10% HCI, extracted with EtOAc (x2). The combined organic layer was washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The crude 5 product was recrystallized from minimal MeOH and CH 2 CI 2 to yield Compound 61 (98 mg, 85%). 1 H NMR (600 MHz, CD 3 OD) 5 8.41 (dd, J = 1.17, 4.40 Hz, 1 H), 8.20 (dd, J = 1.32, 8.66 Hz, 1 H), 7.86 (dd, J = 1.32, 7.78 Hz, 1 H), 7.73 (d, J = 7.92 Hz, 1 H), 7.63 (dd, J = 4.40, 8.51 Hz, 1 H), 7.58 (d, J = 0.88 Hz, 1 H), 7.53 - 7.56 (m, 1 H), 7.48 - 7.53 (m, 10 1 H), 7.36 (td, J = 1.03, 7.56 Hz, 1 H), 7.29 - 7.33 (m, 1 H), 7.23 (td, J = 1.47, 7.63 Hz, 1H), 7.13 (dd, J= 0.88, 7.63 Hz, 1H), 5.39 (s, 2H). Biological Data HEK-Gqi5 cells stably expressing CCR2 were cultured in (DMEM high 15 glucose, 10% FBS, 1% PSA, 400 pg/ml geneticin and 50 pg/ml hygromycin. Appropriate positive control chemokines (MCP-1, MIP1A or RANTES) was used as the positive control agonist for screening compound-induced calcium activity assayed on the FLIPRTetra. The drug plates were prepared in 384-well microplates using the EP3 and the MultiPROBE robotic liquid handling systems. Compounds 20 were synthesized and tested for CCR2 activity. Table 1 shows activity: CCR2 receptor (IC50) nM 94 WO 2013/130962 PCT/US2013/028607 Table 1 IUPAC Name IC50 (nM) %ANTAGONISM N-[2-(benzylsulfanyl)-5-chloropyridin- 252 83 3-yl]-l -benzofuran-2-sulfonamide N-[2-(benzylsulfinyl)-5-chloropyridin- 31 94 3-yl]-l -benzofuran-2-sulfonamide N-[2-(benzylsulfonyl)-5-chloropyridin- 19 90 3-yl]-l -benzofuran-2-sulfonamide N-{5-chloro-2-[(pyridin-3 ylmethyl)sulfanyl]pyridin-3-yl}-1 - 32 95 benzofuran-2-sulfonamide N-{5-chloro-2-[(pyridin-3 ylmethyl)sulfinyl]pyridin-3-yl}-1 - 201 99 benzofuran-2-sulfonamide N-{5-chloro-2-[(pyridin-3 ylmethyl)sulfonyl]pyridin-3-yl}-1 - 2142 84 benzofuran-2-sulfonamide N-(5-chloro-2-{[(1 -oxidopyridin-3 yl)methyl]sulfonyl}pyridin-3-yl)-1 - 130 100 benzofuran-2-sulfonamide N-[2-(benzylsulfanyl)pyridin-3-yl]-1 - 3012 80 benzofuran-2-sulfonamide N-[2-(benzylsulfinyl)pyridin-3-yl]-1 - 27 100 benzofuran-2-sulfonamide N-[2-(benzylsulfonyl)pyridin-3-yl]-1 - 16 95 benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)sulfanyl]pyridin- 102 99 3-yl}-1 -benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)sulfinyl]pyridin- 255 100 3-yl}-1 -benzofuran-2-sulfonamide tert-butyl {3-[({3-[(1-benzofuran-2 ylsulfonyl)amino]pyridin-2- 497 102 yl}sulfonyl)methyl]phenyl}carbamate 95 WO 2013/130962 PCT/US2013/028607 N-{2-[(3-aminobenzyl)sulfonyl]pyridin- 71 102 3-yl}-1 -benzofuran-2-sulfonamide N-[2-(benzylsulfanyl)-5-fluoropyridin- 125 94 3-yl]-l -benzofuran-2-sulfonamide N-[2-(benzylsulfinyl)-5-fluoropyridin-3- 18 95 yl]-1 -benzofuran-2-sulfonamide N-[2-(benzylsulfonyl)-5-fluoropyridin- 43 101 3-yl]-l -benzofuran-2-sulfonamide N-{2-[(3-aminobenzyl)sulfanyl]-5 chloropyridin-3-yl}-1 -benzofuran-2- 95 98 sulfonamide N-{2-[(3-aminobenzyl)sulfinyl]-5 chloropyridin-3-yl}-1 -benzofuran-2- 101 97 sulfonamide N-{2-[(3-aminobenzyl)sulfonyl]-5 chloropyridin-3-yl}-1 -benzofuran-2- 142 100 sulfonamide N-[2-(benzylsulfanyl)-5-methylpyrid in- 194 80 3-yl]-l -benzofuran-2-sulfonamide N-[2-(benzylsulfinyl)-5-methylpyridin- 25 103 3-yl]-l -benzofuran-2-sulfonamide N-[2-(benzylsulfonyl)-5-methylpyrid in- 12 96 3-yl]-l -benzofuran-2-sulfonamide N-{5-ch loro-2-[(2-methyl pyrid in-3 yl)oxy]pyridin-3-yl}-1 -benzofuran-2- 34 90 sulfonamide 2-({3-[(1 -benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 157 97 yl}oxy)benzoic acid methyl 2-({3-[(1-benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 215 93 yl}oxy)benzoate N-{5-chloro-2-[(4-oxopiperidin-1 yl)carbonyl]pyridin-3-yl}-1 - 24 105 benzofuran-2-sulfonamide N-[5-chloro-2-(phenylcarbonyl)pyridin- 36 100 3-yl]-l -benzofuran-2-sulfonamide N-[5-chloro-2-(phenylsulfonyl)pyridin- 17 105 3-yl]-l -benzofuran-2-sulfonamide 96 WO 2013/130962 PCT/US2013/028607 N-[5-chloro-2-(phenylsulfinyl)pyridin- 7 99 3-yl]-l -benzofuran-2-sulfonamide N-{5-ch loro-2-[(2-methyl pyrid in-3 yl)methoxy]pyridin-3-yl}-1 - 251 102 benzofuran-2-sulfonamide methyl 2-[({3-[(1-benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 4252 91 yl}sulfanyl)methyl]benzoate 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 340 97 yl}sulfanyl)methyl]benzoic acid methyl 2-[({3-[(1-benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 191 95 yl}sulfinyl)methyl]benzoate methyl 2-[({3-[(1-benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 180 97 yl}su Ifonyl)methyl] benzoate 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 2691 32 yl}sulfonyl)methyl]benzoic acid N-[5-fluoro-2-(phenylsulfanyl)pyridin- 469 65 3-yl]-l -benzofuran-2-sulfonamide N-[5-fluoro-2-(phenylsulfinyl)pyridin-3- 68 97 yl]-l -benzofuran-2-sulfonamide 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- nd 90 yl}sulfinyl)methyl]benzoic acid N-[5-methyl-2-(phenylsulfinyl)pyridin- 455 105 3-yl]-l -benzofuran-2-sulfonamide N-[5-methyl-2-(phenylsulfonyl)pyridin- 1436 57 3-yl]-l -benzofuran-2-sulfonamide 2-({3-[(1 -benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 1230 102 yl}sulfanyl)benzoic acid 97 WO 2013/130962 PCT/US2013/028607 3-({3-[(1 -benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 786 96 yIlsulfanyl)benzoic acid 2-({3-[(l -benzofuran-2 ylsulfonyl)amino]-5-chloropyridin-2- 1951 5 yIlsulfinyl)benzoic acid methyl 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]pyridin-2- 1754 92 yIlsulIfanyl )m ethyl] benzoate 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]pyridin-2- 493 98 yIlsulIfanyl)m ethyl] benzoic acid methyl 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]pyridin-2- 198 102 yIlsuIfi nyl)m ethyl] benzoate 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]pyridin-2- nd 58 yIlsulfinyl)methyl]benzoic acid methyl 2-[({3-[(1 -benzofuran-2 ylsulfonyl)amino]pyridin-2- 86 101 yIlsu Ifonyl )m ethyl] benzoate 2-[({3-[(l -benzofuran-2 ylsulfonyl)amino]pyridin-2- nd 57 yIlsulIfonyl)m ethyl] benzoic acid ______ ___ ____________ 98
权利要求:
Claims (12) [1] 1. A compound having Formula I, its enantiomers, diastereoisomers, hydrates, solvates, crystal forms and individual isomers, tautomers or a pharmaceutically acceptable salt thereof: R5 R 4 R3 R6 S02 R~~ ~ 7 80 N R1R R N (R)a Formula I wherein: R 1 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; 10 R 2 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 3 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; R 4 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 15 NRR 13 1 4 , or OR 15 ; R 5 is hydrogen, halogen, ON, substituted or unsubstituted 01.6 alkyl, OR 12 , 5NRR4, or COR; R 6 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; 20R 8 is hydrogen, halogen, ON, substituted or unsubstituted 01-6 alkyl, OR 12 NR ,or 0OR 15 R 9 is 0, C(O), S, S(O), S(O) 2 , -C(=NOR 1 6 )-; 25 a is 0 or 1; 99 WO 2013/130962 PCT/US2013/028607 R 11 is hydrogen, CN, substituted or unsubstituted C 1 . 6 alkyl, CF 3 , OR, NRR 13 1 4 , substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3.8 cycloalkyl, substituted or unsubstituted C 2-6 alkyne, substituted or unsubstituted C 2-6 alkene or COR 15 ; 5 R1 2 is hydrogen or substituted or unsubstituted C1.6 alkyl; R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C 6-10 aryl or can from 10 an optionally substituted heterocycle with R 13 ; R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 610 aryl or substituted or unsubstituted C1. 6 alkyl; R 16 is hydrogen or substituted or unsubstituted C1.6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. 15 [2] 2. A compound according to calim 1 wherein: R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 2 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 20 R 4 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 5 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 6 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, 25 NR 1 R 14 , or COR; R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; R 9 is S, S(O), S(O) 2 ; a is 0 or 1; 30 R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3.8 cycloalkyl, substituted or unsubstituted C 2-6 alkyne, substituted or unsubstituted C 2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; 100 WO 2013/130962 PCT/US2013/028607 R 13 is hydrogen or substituted or unsubstituted C1-6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C 1 . 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C 6-10 aryl or can from 5 an optionally substituted heterocycle with R 13 ; R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 610 aryl or substituted or unsubstituted C 1 . 6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. [3] 3. A compound according to claim 2 selected from: 10 N-[2-(benzylthio)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)thio]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; 15 N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-(5-chloro-2-{[(1 -oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1 -benzofuran-2 sulfonamide; N-[2-(benzylthio)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 20 N-[2-(benzylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; tert-butyl {3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfonyl)methyl]phenyl}carbamate; 25 N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfanyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; 30 N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; 101 WO 2013/130962 PCT/US2013/028607 N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 5 methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfanyl)methyl]benzoate; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 10 yl}sulfinyl)methyl]benzoate; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfonyl)methyl]benzoate; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoic acid; 15 N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoic acid; 20 N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 3-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 25 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoic acid; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoic acid; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2 yl}sulfanyl)methyl]benzoic acid; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoic 30 acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfanyl)methyl]benzoate; 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate; 102 WO 2013/130962 PCT/US2013/028607 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfonyl)methyl]benzoate; and 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoic acid. 5 [4] 4. A compound according to claim 1 wherein: R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 2 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 10 R 4 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 5 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 6 is hydrogen, halogen, CN, substituted or unsubstituted C16 alkyl, OR, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, 15 NR 1 R 14 , or COR; R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; R 9 is 0; a is 0 or 1; 20 R 11 is hydrogen, CN, substituted or unsubstituted C 1 . 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3.8 cycloalkyl, substituted or unsubstituted C 2-6 alkyne, substituted or unsubstituted C 2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; 25 R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C 6-10 aryl or can from an optionally substituted heterocycle with R 13 ; 30 R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 610 aryl or substituted or unsubstituted C1. 6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. [5] 5. A compound according to claim 1 wherein: 103 WO 2013/130962 PCT/US2013/028607 R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 2 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 4 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 5 R5 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 6 is hydrogen, halogen, CN, substituted or unsubstituted C16 alkyl, OR, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; 10 R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1. alkyl, OR, NRR 4, or COR; R 9 is C(O); a is 0 or 1; R 11 is hydrogen, CN, substituted or unsubstituted C 1 . 6 alkyl, CF 3 , OR, 15 NR 1 R 14 , substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3.8 cycloalkyl, substituted or unsubstituted C 2-6 alkyne, substituted or unsubstituted C 2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an 20 optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C 6-10 aryl or can from an optionally substituted heterocycle with R 13 ; R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted 25 or unsubstituted C 610 aryl or substituted or unsubstituted C1. 6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. [6] 6. A compound according to claim 1 wherein: R 1 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 30 R 2 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 3 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 4 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; R 5 is hydrogen, halogen or substituted or unsubstituted C1.6 alkyl; 104 WO 2013/130962 PCT/US2013/028607 R 6 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; 5 R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; R 9 is -C(=NOR 16 )-; a is 0 or 1; R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, 10 NR 1 R 14 , substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3.8 cycloalkyl, substituted or unsubstituted C 2-6 alkyne, substituted or unsubstituted C 2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an 15 optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C 6-10 aryl or can from an optionally substituted heterocycle with R 13 ; R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted 20 or unsubstituted C 610 aryl or substituted or unsubstituted C1. 6 alkyl; R 16 is hydrogen or substituted or unsubstituted C1.6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. [7] 7. A compound according to claim 1 selected from: N-[2-(benzylsulfanyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; 25 N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfanyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; 30 N-(5-chloro-2-{[(1 -oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1 -benzofuran-2 sulfonamide; N-[2-(benzylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 105 WO 2013/130962 PCT/US2013/028607 N-[2-(benzylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; tert-butyl {3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 5 yl}sulfonyl)methyl]phenyl}carbamate; N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; 10 N-{2-[(3-aminobenzyl)sulfanyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; 15 N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; 2-({3-[(l-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoic acid; methyl 2-({3-[(l-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoate; N-[5-chloro-2-(morpholin-4-ylcarbonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 20 N-{5-chloro-2-[(4-oxopiperidin-1 -yl)carbonyl]pyridin-3-yl}-1 -benzofuran-2 sulfonamide; N-[5-chloro-2-(phenylcarbonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 25 N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-ch loro-2-[(2-methyl pyrid in-3-yl)methoxy] pyrid in-3-yl}- 1 -benzofuran-2 sulfonamide; N-[5-chloro-2-(phenylacetyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 30 yl}sulfanyl)methyl]benzoate; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoic acid; 106 WO 2013/130962 PCT/US2013/028607 methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfinyl)methyl]benzoate; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfonyl)methyl]benzoate; 5 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoic acid; N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 10 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoic acid; N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 15 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 3-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoic acid; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoic acid; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2 20 yl}sulfanyl)methyl]benzoic acid; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfanyl)methyl]benzoate; 25 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate; 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfonyl)methyl]benzoate; and 30 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoic acid. 107 WO 2013/130962 PCT/US2013/028607 [8] 8. A pharmaceutical composition comprising as active ingredient a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable adjuvant, diluents or carrier. 5 [9] 9. A pharmaceutical composition according to claim 8 wherein the compound is selected from: N-[2-(benzylsulfanyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-chloropyridin-3-yl]-1 -benzofuran-2-sulfonamide; [10] 10 N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfanyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(pyridin-3-ylmethyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-(5-chloro-2-{[(1 -oxidopyridin-3-yl)methyl]sulfonyl}pyridin-3-yl)-1 -benzofuran-2 sulfonamide; 15 N-[2-(benzylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfanyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; 20 tert-butyl {3-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfonyl)methyl]phenyl}carbamate; N-{2-[(3-aminobenzyl)sulfonyl]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfinyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; 25 N-[2-(benzylsulfonyl)-5-fluoropyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfanyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfinyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-{2-[(3-aminobenzyl)sulfonyl]-5-chloropyridin-3-yl}-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfanyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; 30 N-[2-(benzylsulfinyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[2-(benzylsulfonyl)-5-methylpyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(2-methylpyridin-3-yl)oxy]pyridin-3-yl}-1 -benzofuran-2-sulfonamide; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoic acid; 108 WO 2013/130962 PCT/US2013/028607 methyl 2-({3-[(l-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}oxy)benzoate; N-[5-chloro-2-(morpholin-4-ylcarbonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-chloro-2-[(4-oxopiperidin-1 -yl)carbonyl]pyridin-3-yl}-1 -benzofuran-2 sulfonamide; 5 N-[5-chloro-2-(phenylcarbonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-chloro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-{5-ch loro-2-[(2-methyl pyrid in-3-yl)methoxy] pyrid in-3-yl}- 1 -benzofuran-2 10 sulfonamide; N-[5-chloro-2-(phenylacetyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfanyl)methyl]benzoate; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)methyl]benzoic 15 acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfinyl)methyl]benzoate; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2 yl}sulfonyl)methyl]benzoate; 20 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)methyl]benzoic acid; N-[5-fluoro-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-fluoro-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 25 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)methyl]benzoic acid; N-[5-methyl-2-(phenylsulfanyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfinyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; N-[5-methyl-2-(phenylsulfonyl)pyridin-3-yl]-1 -benzofuran-2-sulfonamide; 30 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 3-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfanyl)benzoic acid; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfinyl)benzoic acid; 2-({3-[(1-benzofuran-2-ylsulfonyl)amino]-5-chloropyridin-2-yl}sulfonyl)benzoic acid; 109 WO 2013/130962 PCT/US2013/028607 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2 yl}sulfanyl)methyl]benzoic acid; 2-[({3-[(1 -benzofuran-2-ylsulfonyl)amino]-5-methylpyridin-2-yl}sulfinyl)methyl]benzoic acid; 5 methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfanyl)methyl]benzoate; 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfanyl)methyl]benzoic acid; methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoate; 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfinyl)methyl]benzoic acid; 10 methyl 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2 yl}sulfonyl)methyl]benzoate; and 2-[({3-[(1-benzofuran-2-ylsulfonyl)amino]pyridin-2-yl}sulfonyl)methyl]benzoic acid. 15 10. A method of treating a disorder associated with chemokine receptor modulation, which comprises administering to a mammal in need thereof, a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I R5 R 4 R3 R6 S02 R 7 O R2 R R" R RR 8 N (R)a 20 Formula I wherein: R 1 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 2 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 25 NR R 14 , or COR; 110 WO 2013/130962 PCT/US2013/028607 R 3 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, or COR; R 4 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, NRR 4, or COR; 5 R is hydrogen, halogen, CN, substituted or unsubstituted C16 alkyl, OR, NRR 4, or COR; R 7 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 10 NR 1 R 14 , or COR; R 8 is hydrogen, halogen, CN, substituted or unsubstituted C1.6 alkyl, OR, 0NRR4, or COR; R 9 is 0, C(O), S, S(O), S(O) 2 , -C(=NOR 1 6 )_; a is 0 or 1; 15 R 11 is hydrogen, CN, substituted or unsubstituted C1. 6 alkyl, CF 3 , OR, NR 1 R 14 , substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 3.8 cycloalkyl, substituted or unsubstituted C 2-6 alkyne, substituted or unsubstituted C 2-6 alkene or COR 15 ; R 12 is hydrogen or substituted or unsubstituted C1.6 alkyl; 20 R 13 is hydrogen or substituted or unsubstituted C1.6 alkyl or can from an optionally substituted heterocycle with R 1 4 ; R 1 4 is hydrogen, substituted or unsubstituted C1. 6 alkyl, substituted or unsubstituted heterocycle or substituted or unsubstituted C 6-10 aryl or can from an optionally substituted heterocycle with R 13 ; 25 R 15 is hydrogen, hydroxyl, substituted or unsubstituted heterocycle, substituted or unsubstituted C 610 aryl or substituted or unsubstituted C1. 6 alkyl; R 16 is hydrogen or substituted or unsubstituted C1.6 alkyl; and R 18 is hydrogen or substituted or unsubstituted C1.6 alkyl. 30 [11] 11. A method of claim 10, wherein the pharmaceutical composition is administered to the mammal to treat ocular inflammatory diseases and skin inflammatory diseases and conditions. [12] 12. The method of claim 10 wherein the mammal is a human. 111
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引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 NZ536504A|2002-05-24|2008-04-30|Millennium Pharm Inc|CCR9 inhibitors and methods of use thereof| US20070021466A1|2002-11-18|2007-01-25|Solomon Ungashe|CCR2 inhibitors and methods of use thereof| US7420055B2|2002-11-18|2008-09-02|Chemocentryx, Inc.|Aryl sulfonamides| US7393873B2|2003-07-02|2008-07-01|Merck & Co., Inc.|Arylsulfonamide derivatives| PT1651621E|2003-08-08|2008-09-30|Janssen Pharmaceutica Nv|2- -benzamide compounds as cck2 modulators| US8519135B2|2006-07-14|2013-08-27|Chemocentryx, Inc.|Heteroaryl sulfonamides and CCR2/CCR9| US7622583B2|2005-01-14|2009-11-24|Chemocentryx, Inc.|Heteroaryl sulfonamides and CCR2| US7931909B2|2005-05-10|2011-04-26|Allergan, Inc.|Ocular therapy using alpha-2 adrenergic receptor compounds having enhanced anterior clearance rates| GB0524786D0|2005-12-05|2006-01-11|Glaxo Group Ltd|Compounds| DE602007012552D1|2006-07-14|2011-03-31|Chemocentryx Inc|TRIAZOLYLPHENYLBENZENSULFONAMIDE| US20100234364A1|2006-07-14|2010-09-16|Arindrajit Basak|Ccr2 inhibitors and methods of use thereof| EP2175859B1|2007-07-12|2012-03-07|ChemoCentryx, Inc.|Fused heteroaryl pyridyl and phenyl benzenesulfonamides as ccr2 modulators for the treament of inflammation| TWI440638B|2007-10-30|2014-06-11|Otsuka Pharma Co Ltd|Heterocyclic compound and pharmaceutical composition thereof| BR112013015260B1|2010-12-16|2020-03-24|Allergan, Inc.|SULFUR DERIVATIVES AS CHEMOCCIN RECEPTOR MODULATORS, COMPOSITION UNDERSTANDING THE SAME AND ITS USE| US8580779B2|2010-12-16|2013-11-12|Allergan, Inc.|1,2-bis-sulfonamide derivatives as chemokine receptor modulators| US8524745B2|2011-12-12|2013-09-03|Allergan, Inc.|Benzisothiazol-3-one-5-sulfonyl derivatives as chemokine receptor modulators| HUE049728T2|2012-03-01|2020-10-28|Allergan Inc|Benzofuran-2-sulfonamide derivatives as chemokine receptor modulators| EP2970239B1|2013-03-12|2018-10-10|Allergan, Inc.|Sulfonamide derivatives as chemokine receptor modulators|HUE049728T2|2012-03-01|2020-10-28|Allergan Inc|Benzofuran-2-sulfonamide derivatives as chemokine receptor modulators| EP2970239B1|2013-03-12|2018-10-10|Allergan, Inc.|Sulfonamide derivatives as chemokine receptor modulators| AR098583A1|2013-12-02|2016-06-01|Allergan Inc|SULFONAMIDE COMPOSITE OF BENZOTIOPHENE, PHARMACEUTICAL COMPOSITION THAT INCLUDES IT AND ITS USE FOR THE PREPARATION OF SUCH COMPOSITION|
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2018-02-08| FGA| Letters patent sealed or granted (standard patent)|
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