US007973161B2

(12) United States Patent (10) Patent No.: US 7,973,161 B2 Bruncko et al. (45) Date of Patent: *Jul. 5, 2011

(54) APOPTOSIS PROMOTERS (60) Provisional application No. 60/519,695, filed on Nov. 13, 2003. (75) Inventors: Milan Bruncko, Green Oaks, IL (US); Hong Ding, Gurnee, IL (US); Steven (51) Int. Cl. Elmore, Northbrook, IL (US); Aaron C07D 24I/02 (2006.01) Kunzer, Arlington Heights, IL (US); C07D 403/02 (2006.01) WAFS E.W. E. w (US); (52) U.S. C...... 544/393; 54.4/121 (US);an Cheol-Min cellan, Park, waukegan, Singapore (SG); (58) Field of Classification Search ...... None Andrew Petros, Mundelein, IL (US); See application file for complete search history. Xiaohong Song, Grayslake, IL (US); (56) References Cited Xilu Wang, Grayslake, IL (US); Noah Tu, Gurnee, IL (US); Michael Wendt, U.S. PATENT DOCUMENTS Vernon Hills, IL (US); Alexander 5,138,069 A 8, 1992 Carini et al. Shoemaker, Green Oaks, IL (US); 6,410,584 B1 6/2002 Pamukcu et al. Michael Mitten, Beach Park, IL (US) 6,720,338 B2 4/2004 Augeri et al. (73) Assignee: Abbott Laboratories, Abbott Park, IL (Continued) (US) FOREIGN PATENT DOCUMENTS (*) Notice: Subject to any disclaimer, the term of this NZ 230 136 12/1991 patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 1010 days. This patent is Subject to a terminal dis- OTHER PUBLICATIONS claimer. Thomas H. Corbett, et al., “Discovery and Preclinical Antitumor Efficacy Evaluations of LY32262 and LY33169. Investigational (21) Appl. No.: 11/600,445 New Drugs, Feb. 21, 2003, vol. 31: pp. 33-45. (22) Filed: Nov. 16, 2006 (Continued) (65) Prior Publication Data Primary Examiner — Zinna N Davis US 2007/0072860A1 Mar. 29, 2007 (74) Attorney, Agent, or Firm — Jones Day Related U.S. Application Data (57) ABSTRACT (63) Continuation-in-part of application No. 1 1/491,851, Disclosed are compounds which inhibit the activity of anti filed on Jul. 24, 2006, which is a continuation-in-part apoptotic protein family members, compositions containing of application No. 11/202,827, filed on Aug. 12, 2005, the compounds and uses of the compounds for preparing now Pat. No. 7,642,260, which is a medicaments for treating diseases during which occurs continuation-in-part of application No. 1 1/127,940, expression one or more than one of an anti-apoptotic protein filed on May 12, 2005, now Pat. No. 7,767,684, which family member. is a continuation-in-part of application No. 10/988,338, filed on Nov. 12, 2004, now abandoned. 5 Claims, 7 Drawing Sheets

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U.S. PATENT DOCUMENTS ISA, PCT International Preliminary Report on Patentability dated 7,030,115 B2 4/2006 Elmore et al. May 15, 2006, in International Application No. PCT/US2004/ 7,358,251 B2 4/2008 Elmore et al. 037911, filed Nov. 12, 2004. 7,390,799 B2 6, 2008 Bruncko et al. ISA, PCT International Search Report dated May 13, 2005, in Inter 7,449,485 B2 11/2008 Elmore et al. national Application No. PCT/US2004/036770, filed Nov. 3, 2004. 7,504,512 B2 3/2009 Augeri et al. ISA, PCT International Search Report dated May 13, 2005, in Inter 7,585,858 B2 9, 2009 Elmore et al. 7,642,260 B2 1/2010 Bruncko et al. national Application No. PC1/US2004/037911, filed Nov. 12, 2004. 2002fOO86887 A1 7/2002 Augeri et al. Kutzki, et al., “Development of Potent Bcl-Xl Antagonist Based on 2003/01 19894 A1 6/2003 Murthy et al. O-Helix Mimicry,” J. Am. Chern. Soc., 2002, 124, 11838-11839. 2006/0258657 A1 11/2006 Bruncko et al. Tse et al., “ABT-263: A Potent and Orally Bioavailable Bcl-2 Family 2007, OO15787 A1 1/2007 Bruncko et al. Inhibitor.” May 1, 2008, Cancer Research 68(9):3421-3428. 2008/0076779 A1 3/2008 Elmore et al. Wang, et al., “Structure-based discovery of an organic compound that 2008/0287419 A1 11/2008 Bruncko et al. binds Bcl-2 protein and induces apoptosis of tumor cells.” PNAS, Jun. 20, 2000, vol.97, No. 13, pp. 7124-7129. FOREIGN PATENT DOCUMENTS Wang, et al., “A novel Small molecule inhibitor of Bcl-X inhibits WO O224636 A1 3, 2002 tumor growth in a human head and neck squamous cell carcinoma WO 02098.848 A1 12/2002 Xenograft model.” Proceedings of the American Association for Can WO O3040 107 A1 5, 2003 cer Research, vol. 44, 2" Ed., Jul. 2003, p. 942, #4740. WO WOO3O80586 A1 10, 2003 Amendment and Response filed on Oct. 8, 2009 in U.S. Appl. No. WO 2004.043950 A1 5, 2004 WO 2004.0483.29 A1 6, 2004 1 1/600,445. WO WO 2005/049594 6, 2005 Banker, Gilbert S. et al., “Modem Pharmaceutics, Marcel Dekker', 1996. WO WO2005049593 A2 6, 2005 Final Office Action dated Aug. 12, 2009 for U.S. Appl. No. OTHER PUBLICATIONS 12/120,914. Hattori et al., CAS Accession No. 2006: 298664, 2006. Degterev, et al., “Identification of small-molecule inhibitors of inter Non-final Office Action dated Nov. 28, 2008 for U.S. Appl. No. action between the BH3 domain and Bcl-X.” Nature Cell Biology, 12/120,914. vol. 3, Feb. 2001, pp. 173-182. Oltersdorf et al., “An inhibitor of Bcl-2 family proteins induces Enyedy, et al., “Discovery of Small-Molecule inhibitors of Bcl-2 regression of solid tumours.” Nature, 2005, 435. through Structure-Based Computer Screening.” J. Med. Chem. Wang G. et al., “An Efficient Synthesis of ABT-263, a Novel Inhibi 2001, 44, 4313-4324. tor of Antiapoptotic Bcl-2 Proteins”. Synthesis, 2008, 15, 2398-2404. ISA, PCT International Preliminary Report on Patentability dated Wolff, Mandred E. "Burger's Medicinal Chemistry and Drug Dis May 15, 2006, in International Application No. PCT/US2004/ covery.” Principles and Practice, 1995,975-977, 5th Ed, vol. 1, John 036770, filed Nov. 3, 2004. Wiley & Sons. U.S. Patent Jul. 5, 2011 Sheet 1 of 7 US 7,973,161 B2

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0"| (uu) bulleMS pDd 100 US 7,973,161 B2 1. APOPTOSIS PROMOTERS (I) This application is a continuation-in-part of U.S. patent V/ application Ser. No. 1 1/491,851, filed Jul. 24, 2006, now ly N Yl pending, which is a continuation-in-part of U.S. patent appli 5 cation Ser. No. 1 1/202,827, filed Aug. 12, 2005, now U.S. Pat. i | No. 7,642,260, which is a continuation-in-part of U.S. patent D1 Al B', application Ser. No. 11/127,940, filed May 12, 2005, now U.S. Pat. No. 7,767,684, which is a continuation-in-part of 10 wherein A' is N or C(A): U.S. patent application No. 10/988,338, filed Nov. 12, 2004, one or two or three or each of A, B, D" and E' are now abandoned, which claims priority to U.S. Provisional independently selected R', OR', SR', S(O)R', SOR', C(O) Application No. 60/519,695, filed Nov. 13, 2003. R", C(O)OR', OC(O)R', NHR', N(R'), C(O)NHR', C(O) The specifications of U.S. patent application Ser. Nos. N(R'), NHC(O)R', NHC(O)OR', NRC(O)NHR', NRC 11/202,827, U.S. patent application Ser. No. 11/127,940 and 15 (O)N(R'), SONHR', SON(R'), NHSOR', U.S. Provisional Application No. 60/519,695, are hereby NHSONHR' or N(CH)SON(CH)R', and the remainder incorporated by reference into this application. are independently selected H, F, Cl, Br, I, CN, CF, C(O)OH, C(O)NH, or C(O)OR'; and Y' is H, CN, NO, C(O)OH, F, Cl, Br, I, CF. OCF, FIELD OF THE INVENTION 2O CFCF. OCFCF, R7, OR'7, C(O)R'7, C(O)OR'7, SR'7, NH, NHR'7, N(R7), NHC(O)R'7,C(O)NHC(O)NHR'7, This invention pertains to compounds which inhibit the C(O)N(R'7). NHS(O)R7 or NHSOR'7; activity of anti-apoptotic protein family members, composi O tions containing the compounds, and methods of treating B' and Y', together with the atoms to which they are diseases during which are expressed of one or more than one attached, are imidazole or triazole; and of an anti-apoptotic protein family member. one or two or each of A, D" and E' are independently selected R', OR', SR', S(O)R, SOR', C(O)R', C(O)OR', BACKGROUND OF THE INVENTION OC(O)R', NHR', N(R'), C(O)NHR', C(O)N(R'), NHC 30 (O)R', NHC(O)OR, NHC(O)NHR', N(CH)C(O)N(CH.) R', SONHR', SON(R'). NHSOR, NHSONHR' or Anti-apoptotic protein family members are associated with N(CH)SO.N(CH)R', and the remainder are independently a number of diseases. There is therefore an existing need in selected H. F. Cl, Br, I, CF, C(O)OH, C(O)NH, or C(O) the therapeutic arts for compounds which inhibit the activity OR of one of more than one of an anti-apoptotic protein family 35 R" is R, R, R or R: member. R'' is C1-Co-alkyl, Cs-Co-alkenyl or Cs-Co-alkynyl: R’ is phenyl which is unfused or fused with arene, het BRIEF DESCRIPTION OF THE FIGURES eroarene or R'; R is or heterocycloalkane; R is heteroaryl which is unfused or fused with benzene, heteroarene or R'; R is cycloalkane or heterocycloalkane; FIG. 1 shows comparative antitumorigenesis of 40 R" is cycloalkyl, cycloalkenyl, heterocycloalkyl or hetero EXAMPLE 2, etoposide (EPOSINR) and combinations cycloalkenyl, each of which is unfused or fused with arene, thereof. heteroarene or R'; R' is cycloalkane, cycloalkene, hetero FIG. 2 shows comparative antitumorigenesis of cycloalkane or heterocycloalkene; EXAMPLE 2, vincristine (ONCOVINR) and combinations as R is alkyl, alkenyl or alkynyl, each of which is unsubsti thereof. tuted or substituted with one or two or three independently FIG. 3 shows comparative antitumorigenesis of selected R, NC(R) (R), R7, OR7, SR 7, S(O)R7, SOR7, EXAMPLE 2, CHOP and combinations thereof. NHR'. N(R7), C(O)R’, C(O)NHC(O)NHR'. NHC(O)R’, FIG. 4 shows comparative antitumorigenesis of NHSOR7, NHC(O)OR7, SONH, SONHR', SON(R7), NHC(O)NH NHC(O)NHR'. NHC(O)CH(CH)NHC(O) EXAMPLE 2. (RITUXANR) and combinations thereof. 50 CH(CH)NH, NHC(O)CH(CH)NHC(O)CH(CH)NHR'. FIG. 5 shows comparative antitumorigenesis of OH, (O), C(O)OH, (O), NCN, NH, CF, CFCF, F, Cl, Br EXAMPLE 2, rapamycin and combinations thereof. or I substituents; FIG. 6 shows comparative percent survival of EXAMPLE R is C-C-spiroalkyl, each of which is unsubstituted or 2, VCP and combinations thereof. 55 substituted with OH, (O), N, CN, CF, CFCF, F, Cl, Br, I, FIG. 7 shows duration of action of EXAMPLE 2 (ABT NH, NH(CH) or N(CH): 737) during treatment in an autoimmune antiinflammation R'' and Rare independently selected alkyl or, together model. with the N to which they are attached, R: R is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-yl or pip 60 eridin-1-yl, each having one CH moiety unreplaced or SUMMARY OF THE INVENTION replaced with O, C(O), CNOH, CNOCH, S, S(O), SO, or NH; One embodiment of this invention, therefore, pertains to R7 is R. R. R0 or R's compounds or therapeutically acceptable salts, prodrugs or R is phenyl which is unfused or fused with arene, het salts of prodrugs thereof, which are useful as inhibitors one or 65 eroarene or R': more than one anti-apoptotic protein family member, the R is cycloalkane, cycloalkene, heterocycloalkane or het compounds having formula (I) erocycloalkene; US 7,973,161 B2 3 4 R is heteroaryl which is unfused or fused with arene, R’ is heteroarene which is unfused or fused with arene or heteroarene or R'; R is cycloalkane, cycloalkene, hetero heteroarene; cycloalkane or heterocycloalkene; R’ is phenyl which is unfused or fused with arene, het R" is Cs-Co-cycloalkyl or Ca-Cio-cycloalkenyl, each eroarene or R'; R is cycloalkane, cycloalkene, hetero having one or two CH2 moieties unreplaced or replaced with cycloalkane or heterocycloalkene independently selected O, C(O), CNOH, CNOCH, S, S(O), R’ is heteroarylor R'; R’ is cycloalkane, cycloalkene, SO or NH and one or two CH moieties unreplaced or heterocycloalkane or heterocycloalkene; replaced with N, and each of which is unfused or fused with R" is cycloalkyl or cycloalkenyl, each having one or two arene, heteroarene or R'; R' is cycloalkane, cycloalkene, CH moieties unreplaced or replaced with independently heterocycloalkane or heterocycloalkene; 10 selected O, C(O), CNOH, CNOCH, S, S(O), SO, or NH and R'' is alkyl, alkenyl or alkynyl, each of which is unsubsti one or two CH moieties unreplaced or replaced with N, and tuted or substituted with one or two or three independently each of which is unfused or fused with arene, heteroarene or selected R', OR, NHR', N(R'), C(O)NH, C(O) R'; R' is cycloalkane, cycloalkene, heterocycloalkane or NHR'. C(O)N(R'), OH, (O), C(O)OH, N, CN, NH, CF, 15 heterocycloalkene; CFCF, F, Cl, Br or I substituents: R" and R'' are independently F, Cl, Br or alkyl or are R’ is R13, R14, R or R16, taken together and are C-C-Spiroalkyl; R" is phenyl which is unfused or fused with arene, het R2 is R., C(O)R’ or C(O)OR:: eroarene or R'': R'' is cycloalkane, cycloalkene, hetero R3 is R or Rs. cycloalkane or heterocycloalkene; R is phenyl which is unfused or fused with aryl, het R" is heteroaryl, each of which is unfused or fused with eroaryl or R'; R is cycloalkane, cycloalkene, heterocy arene, heteroarene or R'': R'' is cycloalkane, cycloalkene, cloalkane or heterocycloalkene; heterocycloalkane or heterocycloalkene; R is alkyl which is unsubstituted or substituted with R: R" is cycloalkane, cycloalkene, heterocycloalkane or het R is phenyl which is unfused or fused with arene, het erocycloalkene, each of which is unfused or fused with arene, 25 eroarene or R'; R' is cycloalkane, cycloalkene, hetero heteroarene or R'': R'' is cycloalkane, cycloalkene, het cycloalkane or heterocycloalkene; erocycloalkane or heterocycloalkene; R7 is R, R or R', each of which is substituted with F. R" is alkyl, alkenyl or alkynyl: C1, Br, I, R, OR, NHR', N(R). NHC(O)OR', SR, R7 is R18, R19, R’ or R21; S(O)R' or SOR'; R" is phenyl which is unfused or fused with arene, het 30 R is phenyl which is unfused or fused with arene, het eroarene or R'': R'' is cycloalkane, cycloalkene, hetero eroarene or R'; R is cycloalkane, cycloalkene, hetero cycloalkane or heterocycloalkene; cycloalkane or heterocycloalkene; R" is heteroaryl which is unfused or fused with arene, R is heteroaryl which is unfused or fused with arene, heteroarene or R'; R' is cycloalkane, cycloalkene, het heteroarene or R'; R is cycloalkane, cycloalkene, het erocycloalkane or heterocycloalkene; 35 erocycloalkane or heterocycloalkene; R" is Cs-Co-cycloalkyl or Ca-Cio-cycloalkenyl, each R" is Cs-Cs-cycloalkyl or C-Cs-cycloalkenyl, each hav having one or two CH2 moieties unreplaced or replaced with ing one or two CH2 moieties unreplaced or replaced with independently selected O, C(O), CNOH, CNOCH, S, S(O), independently selected O, C(O), CNOH, CNOCH, S, S(O), SO or NH and one or two CH moieties unreplaced or SO or NH and one or two CH moieties unreplaced or replaced with N, and each of which is unfused or fused with 40 replaced with N, and each of which is unfused or fused with arene, heteroarene or R'; R' is cycloalkane, cycloalkene, arene, heteroarene or R'; R' cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; heterocycloalkane or heterocycloalkene; R’ is alkyl, alkenyl or alkynyl, each of which is unsubsti R is R42, R-43, R or R45. tuted or substituted with one or two or three independently R" is phenyl which is unfused or fused with arene, het selected R, OR, NHR, N(R), C(O)NH, C(O) 45 eroarene or R'; R'' is cycloalkane, cycloalkene, hetero NHR’, C(O)N(R), OH, (O), C(O)CH, N, CN, NH, CF, cycloalkane or heterocycloalkene; CFCF, F, Cl, Br or I substituents; R" is heteroaryl which is unfused or fused with arene, R22 is R23, R’ or R25. heteroarene or R'': R'' is cycloalkane, cycloalkene, het R’ is phenyl which is unfused or fused with arene, het erocycloalkane or heterocycloalkene; eroarene or R'; R is cycloalkane, cycloalkene, hetero 50 R" is Ca-Ca-cycloalkyl or Ca-Ca-cycloalkenyl, each hav cycloalkane or heterocycloalkene; ing one or two CH2 moieties unreplaced or replaced with R is heteroarene which is unfused or fused with arene, independently selected O, C(O), CNOH, CNOCH, S, S(O), heteroarene or R'; R' is cycloalkane, cycloalkene, het SO or NH and one or two CH moieties unreplaced or erocycloalkane or heterocycloalkene; replaced with N, and each of which is unfused or fused with R is Ca-Ca-cycloalkyl or Ca-Ca-cycloalkenyl, each hav 55 arene, heteroarene or R'; R' is cycloalkane, cycloalkene, ing one or two CH moieties unreplaced or replaced with heterocycloalkane or heterocycloalkene; independently selected O, C(O), CNOH, CNOCH, S, S(O), R" is alkyl, alkenyl or alkynyl, each of which is unsubsti SO or NH and one or two CH moieties unreplaced or tuted or substituted with one or two independently selected replaced with N, and each of which is unfused or fused with R, OR, NHR, N(R), C(O)NHC(O)NHR, C(O)N arene, heteroarene or R'; R is cycloalkane, cycloalkene, 60 (R), OH, (O), C(O)OH, N, CN, NH, CF, CFCF, F, Cl, heterocycloalkane or heterocycloalkene; Br or I substituents; Z' is R or R7, each of which is substituted with R. R’ R is R17, R8 or R19. or R, each of which is substituted with F, Cl, Br, I, CHR7, R7 is phenyl which is unfused or fused with arene, het CH(R)(R-7), C(R)(R31) (R7), C(O)R7, OR7, SR 7, eroarene or R'; R' is cycloalkane, cycloalkene, hetero S(O)R7, SOR7, NHR7 or N(R)R7; 65 cycloalkane or heterocycloalkene; R’ is phenyl which is unfused or fused with arene or R" is heteroarylor R'': R'' is cycloalkane, cycloalkene, heteroarene; heterocycloalkane or heterocycloalkene;

US 7,973,161 B2 9 10 isothiazole, isoxazole, 1.2.3-oxadiazole, 1,2,5-oxadiazole, Zolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimi Zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of dine, pyrrole, thiazole, thiophene, triazine or 1.2.3-triazole; which is unfused or fused with benzene, furan, imidazole, R" is C3-cycloalkyl, Ca-cycloalkyl, Cs-cycloalkyl, Co-cy isothiazole, isoxazole, 1.2.3-oxadiazole, 1,2,5-oxadiazole, cloalkyl, C7-cycloalkyl, Cs-cycloalkyl, Co-cycloalkyl, Co- 5 oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimi cycloalkyl, C-cycloalkyl, C-cycloalkyl, C-cycloalkyl, dine, pyrrole, thiazole, thiophene, triazine or 1.2.3-triazole; C-cycloalkyl, C-cycloalkenyl, Cs-cycloalkenyl, C-cy R" is C-cycloalkyl, C-cycloalkyl, Cs-cycloalkyl, C-cy cloalkenyl, C7-cycloalkenyl, Cs-cycloalkenyl, Co-cycloalk cloalkyl, C-cycloalkenyl, Cs-cycloalkenyl or C-cycloalk enyl or Co-cycloalkenyl, each having one or two CH moi enyl, each having one or two CH moieties unreplaced or eties unreplaced or replaced with independently selected O. 10 replaced with independently selected O. C(O), CNOH, C(O), S, S(O), SO, or NH and one or two CH moieties CNOCH, S, S(O), SO, or NH and one or two CH moieties unreplaced or replaced with N: unreplaced or replaced with N, and each of which is unfused R" and R'' are independently F, Cl, Br, C-alkyl, or fused with benzene, furan, imidazole, isothiazole, isox C-alkyl, C-alkyl, C-alkyl, C-alkyl or C-alkyl or are taken azole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, together and are C-Spiroalkyl, C-Spiroalkyl, C-Spiroalkyl 15 pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, or Cs-spiroalkyl: thiophene, triazine or 1,2,3-triazole; R2 is R., C(O)R or C(O)OR; R" is C-alkyl, C2-alkyl, C-alkyl, C-alkyl, Cs-alkyl R3 is R or R5; Co-alkyl, C-alkenyl, C-alkenyl, C-alkenyl, Cs-alkenyl R is phenyl which is unfused or fused with benzene, Co-alkenyl, C-alkynyl, C-alkynyl, C-alkynyl, Cs-alkynyl furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, 20 or C-alkynyl, each of which is unsubstituted or substituted 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, with one or two independently selected R, OR, NHR'. pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or N(R), C(O)NH, C(O)NHR', C(O)N(R), OH, (O), 1,2,3-triazole; C(O)OH, N, CN, NH, CF, CFCF, F, Cl, Br or I substitu R is C1-alkyl, C2-alkyl, C-alkyl, C-alkyl, Cs-alkyl or ents; C-alkyl, each of which is unsubstituted or substituted with 25 R is R17, R8 or R19. R36; R7 is phenyl which is unfused or fused with benzene, R is phenyl which is unfused or fused with benzene, furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or 30 1,2,3-triazole; 1,2,3-triazole; R" is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3- R7 is R, R or R', each of which is substituted with F. oxadiazoyl, 1,2,5-oxadiazolyl, oxazolyl pyrazinyl, pyra C1, Br, I, R, OR, NHR'', N(R). NHC(O)OR', SR, Zolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra S(O)R' or SOR'; Zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of R is phenyl which is unfused or fused with benzene, 35 which is unfused or fused with benzene, furan, imidazole, furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, isothiazole, isoxazole, 1.2.3-oxadiazole, 1,2,5-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimi pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or dine, pyrrole, thiazole, thiophene, triazine or 1.2.3-triazole; 1,2,3-triazole; R is C-cycloalkyl, Ca-cycloalkyl, Cs-cycloalkyl, Co-cy R is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1.2.3- 40 cloalkyl, C-cycloalkenyl, Cs-cycloalkenyl or C-cycloalk oxadiaZoyl, 1,2,5-oxadiazolyl, oxazolyl pyrazinyl, pyra enyl, each having one or two CH2 moieties unreplaced or Zolyl pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra replaced with independently selected O, C(O), S, S(O), SO Zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of or NH and one or two CH moieties unreplaced or replaced which is unfused or fused with benzene, furan, imidazole, with N: isothiazole, isoxazole, 1.2.3-oxadiazole, 1,2,5-oxadiazole, 45 wherein the moieties represented by B' andY' together are oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimi Substituted with C-alkyl, C-alkyl, C-alkyl, C-alkyl, dine, pyrrole, thiazole, thiophene, triazine or 1.2.3-triazole; Cs-alkyl or C-alkyl, each of which is substituted with one or R" is C3-cycloalkyl, Ca-cycloalkyl, Cs-cycloalkyl, Co-cy two independently selected SR or N(R), substituents, cloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C-cycloalkenyl, wherein R is independently selected phenyl, C-alkyl, Cs-cycloalkenyl, C-cycloalkenyl, C7-cycloalkenyl or Cs-cy- 50 C2-alkyl, C-alkyl, C-alkyl, C-alkyl or C-alkyl; cloalkenyl, each having one or two CH2 moieties unreplaced the moieties represented by R. RandR are unsubstituted or replaced with independently selected O. C(O), S, S(O), or substituted with one or two independently selected R', SO or NH and one or two CH moieties unreplaced or OR', SR, SOR, CO(O)R’ or OCF, substituents, replaced with N: wherein R' is phenyl, C-alkyl, C-alkyl, C-alkyl, C-alkyl, R!! is R-2, R1, R* or R's, 55 Cs-alkyl or C-alkyl, R" is phenyl which is unfused or fused with benzene, the moieties represented by R. R. and R'' are unsubsti furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, tuted or substituted with one or two independently selected 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, R, OR, C(O)NHSOR, CO(OR, C(O)R, C(O)OH, pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine, C(O)NHOH, OH, NH, F, Cl, Br or I substituents, wherein 1,2,3-triazole or R'': 60 R" is phenyl, tetrazolyl or R', wherein R is C-alkyl, R'' is C-cycloalkane, Cs-cycloalkane, C-cycloalkane, C-alkyl, C-alkyl, C-alkyl, Cs-alkyl or C-alkyl, each of C-cycloalkene, Cs-cycloalkene or C-cycloalkene, each which is unsubstituted or substituted with phenyl: having one or two CH2 moieties unreplaced or replaced with the moieties represented by Rand R7 are further unsub independently selected O. C(O), S, S(O), SO or NH and one stituted or substituted with one or two independently selected or two CH moieties unreplaced or replaced with N: 65 F, Br, C1 or I substituents: R" is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3- the moieties represented by R. R. and Rare further oxadiaZoyl, 1,2,5-oxadiazolyl, oxazolyl pyrazinyl, pyra unsubstituted or substituted with OR, wherein R is

US 7,973,161 B2 13 14 R’ is phenyl which is unfused or fused with benzene, Zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, which is unfused or fused with benzene: 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, R" is C-cycloalkyl, Ca-cycloalkyl, Cs-cycloalkyl, Co-cy pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or cloalkyl, C-cycloalkenyl, Cs-cycloalkenyl or C-cycloalk 1,2,3-triazole; 5 enyl, each having one or two CH moieties unreplaced or R’ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3- replaced with independently selected O. C(O), CNOH, oxadiaZoyl, 1,2,5-oxadiazolyl, oxazolyl pyrazinyl, pyra CNOCH, S, S(O), SO, or NH and one or two CH moieties Zolyl pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra unreplaced or replaced with N, and each of which is unfused Zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of or fused with benzene, furan, imidazole, isothiazole, isox which is unfused or fused with benzene: 10 azole, 1,2,3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, R is phenyl which is unfused or fused with benzene, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, thiophene, triazine or 1,2,3-triazole; pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or R" is C-alkyl, C2-alkyl, C-alkyl, C-alkyl, Cs-alkyl 1,2,3-triazole; 15 C-alkyl, C-alkenyl, C-alkenyl, C-alkenyl, C-alkenyl R’ is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3- Co-alkenyl, C-alkynyl, C-alkynyl, C-alkynyl, Cs-alkynyl oxadiaZoyl, 1,2,5-oxadiazolyl, oxazolyl pyrazinyl, pyra or C-alkynyl, each of which is unsubstituted or substituted Zolyl pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra with one or two independently selected R, OR, NHR'. Zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of N(R), C(O)NH, C(O)NHR', C(O)N(R), OH, (O), which is unfused or fused with benzene: C(O)OH, N, CN, NH, CF, CFCF, F, Cl, Br or I substitu R" is C-cycloalkyl, C-cycloalkyl, Cs-cycloalkyl, C-cy ents; cloalkyl, C7-cycloalkyl, Cs-cycloalkyl, Co-cycloalkyl, Co R is R17, R8 or R19. cycloalkyl, C-cycloalkyl, C-cycloalkyl, C-cycloalkyl, R" is phenyl which is unfused or fused with benzene, Ca-cycloalkyl, C-cycloalkenyl, Cs-cycloalkenyl, C-cy furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, cloalkenyl, C7-cycloalkenyl, Cs-cycloalkenyl, Co-cycloalk 25 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, enyl or Co-cycloalkenyl, each having one or two CH2 moi pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or eties unreplaced or replaced with independently selected O. 1,2,3-triazole; C(O), S, S(O), SO, or NH and one or two CH moieties R" is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3- unreplaced or replaced with N: oxadiaZoyl, 1,2,5-oxadiazolyl, oxazolyl, pyrazinyl, pyra R" and R'' are independently F, Cl, Br, C-alkyl, 30 Zolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra C2-alkyl, C-alkyl, C-alkyl, Cs-alkyl or C-alkyl or are taken together and are C-spiroalkyl, C-spiroalkyl, C-spiroalkyl zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of which is unfused or fused with benzene: or Cs-spiroalkyl: R is C-cycloalkyl, Ca-cycloalkyl, Cs-cycloalkyl, Co-cy R7 is R, R or R', each of which is substituted with F. cloalkyl, C-cycloalkenyl, Cs-cycloalkenyl or C-cycloalk C1, Br, I, R, OR, NHR'', N(R). NHC(O)OR', SR, 35 S(O)R' or SOR'; enyl, each having one or two CH moieties unreplaced or R is phenyl which is unfused or fused with benzene, replaced with independently selected O. C(O), S, S(O), SO furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, or NH and one or two CH moieties unreplaced or replaced 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, with N: pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine or 40 wherein the moieties represented by B' andY' together are 1,2,3-triazole; substituted with C-alkyl, C-alkyl or C-alkyl, each of which R is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3- is substituted with one or two independently selected SR or oxadiaZoyl, 1,2,5-oxadiazolyl, oxazolyl pyrazinyl, pyra N(R) substituents, wherein R is independently selected Zolyl pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra phenyl or C-alkyl; Zolyl, thiazolyl, thienyl, triazinyl or 1,2,3-triazolyl, each of 45 the moieties represented by R. RandR are unsubstituted which is unfused or fused with benzene: or substituted with one or two independently selected R', R" is C-cycloalkyl, C-cycloalkyl, Cs-cycloalkyl, C-cy OR', SR, SOR, CO(O)R’ or OCF, substituents, cloalkyl, C7-cycloalkyl, Cs-cycloalkyl, C-cycloalkenyl, wherein R' is phenyl, C-alkyl, C-alkyl, C-alkyl or Cs-cycloalkenyl, C-cycloalkenyl, C7-cycloalkenyl or Cs-cy C-alkyl: cloalkenyl, each having one or two CH2 moieties unreplaced 50 the moieties represented by R, R and R'' are unsubsti or replaced with independently selected O. C(O), S, S(O), tuted or substituted with one or two independently selected SO or NH and one or two CH moieties unreplaced or R50, OR50, C(O)NHSORSO, CO(O)R50, C(O)R50, C(O)OH, replaced with N: C(O)NHOH, OH, NH, F, Cl, Br or I substituents, wherein R41 is R42, R43, R44 O R45. R is phenyl, tetrazolyl or R, wherein R is C-alkyl, R" is phenyl which is unfused or fused with benzene, 55 C-alkyl or C-alkyl, each of which is unsubstituted or sub furan, imidazole, isothiazole, isoxazole, 1.2.3-oxadiazole, stituted with phenyl: 1,2,5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, the moieties represented by RandR are further unsub pyridine, pyrimidine, pyrrole, thiazole, thiophene, triazine, stituted or substituted with one or two independently selected 1,2,3-triazole or R'': F, Br, C1 or I substituents: R" is Ca-cycloalkane, Cs-cycloalkane, Co-cycloalkane, 60 the moieties represented by R. R. and Rare further C-cycloalkene, Cs-cycloalkene or C-cycloalkene, each unsubstituted or substituted with OR, wherein R is having one or two CH2 moieties unreplaced or replaced with C-alkyl or C-alkyl, each of which is unsubstituted or sub independently selected O, C(O), S, S(O), SO, or NH and one stituted with N(R), or R, wherein R is C-alkyl, or two CH moieties unreplaced or replaced with N: C2-alkyl, C-alkyl, Ca-alkyl, Cs-alkyl or Co-alkyl, and R is R" is furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,2,3- 65 Cs-cycloalkyl or C-cycloalkyl, each having one or two CH2 oxadiaZoyl, 1,2,5-oxadiazolyl, oxazolyl pyrazinyl, pyra moieties replaced with independently selected O or NH and Zolyl pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetra one CH moiety unreplaced or replaced with N:

US 7,973,161 B2 67 68 N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- istering to the patient a therapeutically effective amount of a yl)-1,2-benzisoxazol-3-yl)-4-(((1R)-3-(dimethylamino)- compound having formula (I). 1-((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenze Still another embodiment pertains to compositions for nesulfonamide, treating diseases during which are expressed one or more than 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 pro propyl)amino)-N-(6-(4.4-dimethylpiperidin-1-yl)-1,2- tein or antiapoptotic Bcl-W protein, said compositions com benzisoxazol-3-yl)-3-nitrobenzenesulfonamide, prising an excipient and a therapeutically effective amount of N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- N-(4-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- yl)-1-methyl-1H-indazol-3-yl)-3-nitro-4-((2-(phenylsul yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-(phenylsulfa fanyl)ethyl)amino)benzenesulfonamide, 10 nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, or a N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- therapeutically acceptable salt, prodrug or salt of a prodrug yl)-1-methyl-1H-indazol-3-yl)-4-((1,1-dimethyl-2-(phe thereof. nylsulfanyl)ethyl)amino)-3-nitrobenzenesulfonamide, Still another embodiment pertains to methods of treating N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- disease in a patient during which is expressed one or more yl)-1-methyl-1H-indazol-3-yl)-4-(((1R)-3-(dimethy 15 than one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 lamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-ni protein or antiapoptotic Bcl-W protein, said methods com trobenzenesulfonamide, prising administering to the patientatherapeutically effective N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- amount of N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl) yl)-1-methyl-1H-indazol-3-yl)-4-(((1R)-3-(morpholin-4- piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1- yl)-1-((phenylsulfanyl)methyl)propyl)amino)-3-nitroben ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene Zenesulfonamide, Sulfonamide, or a therapeutically acceptable salt, prodrug or N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- salt of a prodrug thereof. yl)-1H-indazol-3-yl)-3-nitro-4-((2-(phenylsulfanyl)ethyl) Still another embodiment pertains to compositions for amino)benzenesulfonamide, 25 treating bladder cancer, brain cancer, breast cancer, bone N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- marrow cancer, cervical cancer, chronic lymphocytic leuke yl)-1H-indazol-3-yl)-4-(((1R)-3-(dimethylamino)-1- mia, colorectal cancer, esophageal cancer, hepatocellular ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene cancer, lymphoblastic leukemia, follicular lymphoma, lym Sulfonamide, and phoid malignancies of T-cell or B-cell origin, melanoma, N-(6-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- 30 myelogenous leukemia, myeloma, oral cancer, ovarian can yl)-1H-indazol-3-yl)-4-(((1R)-3-(morpholin-4-yl)-1- cer, non-Small cell lung cancer, prostate cancer, Small cell (phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene lung cancer or spleen cancer, said compositions comprising Sulfonamide, an excipient and a therapeutically effective amount of N-(4- or therapeutically acceptable salts, prodrugs or salts of pro (4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl) drugs thereof. 35 benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) Still another embodiment pertains to compositions for methyl)propyl)amino)-3-nitrobenzenesulfonamide, or a treating diseases during which are expressed one or more than therapeutically acceptable salt, prodrug or salt of a prodrug one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 pro thereof. tein or antiapoptotic Bcl-W protein, said compositions com Still another embodiment pertains to methods of treating prising an excipient and a therapeutically effective amount of 40 bladder cancer, brain cancer, breast cancer, bone marrow the compound having formula (I). cancer, cervical cancer, chronic lymphocytic leukemia, col Still another embodiment pertains to methods of treating orectal cancer, esophageal cancer, hepatocellular cancer, disease in a patient during which is expressed one or more lymphoblastic leukemia, follicular lymphoma, lymphoid than one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 malignancies of T-cell or B-cell origin, melanoma, myelog protein or antiapoptotic Bcl-W protein, said methods com 45 enous leukemia, myeloma, oral cancer, ovarian cancer, non prising administering to the patientatherapeutically effective Small cell lung cancer, prostate cancer, Small cell lung cancer amount of a compound having formula (I). or spleen cancer in a patient, said methods comprising admin Still another embodiment pertains to compositions for istering to the patient a therapeutically effective amount of treating bladder cancer, brain cancer, breast cancer, bone N-(4-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- marrow cancer, cervical cancer, chronic lymphocytic leuke 50 yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-(phenylsulfa mia, colorectal cancer, esophageal cancer, hepatocellular nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, or a cancer, lymphoblastic leukemia, follicular lymphoma, lym therapeutically acceptable salt, prodrug or salt of a prodrug phoid malignancies of T-cell or B-cell origin, melanoma, thereof. myelogenous leukemia, myeloma, oral cancer, ovarian can Still another embodiment pertains to compositions for cer, non-small cell lung cancer, prostate cancer, Small cell 55 treating diseases during which are expressed one or more than lung cancer or spleen cancer, said compositions comprising one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 pro an excipient and a therapeutically effective amount of the tein or antiapoptotic Bcl-W protein, said compositions com compound having formula (I). prising an excipient and a therapeutically effective amount of Still another embodiment pertains to methods of treating the compound having formula (I) and a therapeutically effec bladder cancer, brain cancer, breast cancer, bone marrow 60 tive amount of one additional therapeutic agent or more than cancer, cervical cancer, chronic lymphocytic leukemia, col one additional therapeutic agent. orectal cancer, esophageal cancer, hepatocellular cancer, Still another embodiment pertains to methods of treating lymphoblastic leukemia, follicular lymphoma, lymphoid disease in a patient during which is expressed one or more malignancies of T-cell or B-cell origin, melanoma, myelog than one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 enous leukemia, myeloma, oral cancer, ovarian cancer, non 65 protein or antiapoptotic Bcl-W protein, said methods com Small cell lung cancer, prostate cancer, Small cell lung cancer prising administering to the patientatherapeutically effective or spleen cancer in a patient, said methods comprising admin amount of a compound having formula (I) and a therapeuti US 7,973,161 B2 69 70 cally effective amount of one additional therapeutic agent or thereof, and a therapeutically effective amount of one addi more than one additional therapeutic agent. tional therapeutic agent or more than one additional therapeu Still another embodiment pertains to compositions for tic agent. treating bladder cancer, brain cancer, breast cancer, bone Still another embodiment pertains to methods of treating marrow cancer, cervical cancer, chronic lymphocytic leuke bladder cancer, brain cancer, breast cancer, bone marrow mia, colorectal cancer, esophageal cancer, hepatocellular cancer, cervical cancer, chronic lymphocytic leukemia, col cancer, lymphoblastic leukemia, follicular lymphoma, lym orectal cancer, esophageal cancer, hepatocellular cancer, phoid malignancies of T-cell or B-cell origin, melanoma, lymphoblastic leukemia, follicular lymphoma, lymphoid myelogenous leukemia, myeloma, oral cancer, ovarian can malignancies of T-cell or B-cell origin, melanoma, myelog cer, non-small cell lung cancer, prostate cancer, Small cell 10 enous leukemia, myeloma, oral cancer, ovarian cancer, non lung cancer or spleen cancer, said compositions comprising Small cell lung cancer, prostate cancer, Small cell lung cancer an excipient and a therapeutically effective amount of the or spleen cancer in a patient, said methods comprising admin compound having formula (I) and a therapeutically effective istering to the patient a therapeutically effective amount of amount of one additional therapeutic agent or more than one N-(4-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- additional therapeutic agent. 15 yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-(phenylsulfa Still another embodiment pertains to methods of treating nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, or a bladder cancer, brain cancer, breast cancer, bone marrow therapeutically acceptable salt, prodrug or salt of a prodrug cancer, cervical cancer, chronic lymphocytic leukemia, col thereof, and a therapeutically effective amount of one addi orectal cancer, esophageal cancer, hepatocellular cancer, tional therapeutic agent or more than one additional therapeu lymphoblastic leukemia, follicular lymphoma, lymphoid tic agent. malignancies of T-cell or B-cell origin, melanoma, myelog Still another embodiment of this invention pertains to com enous leukemia, myeloma, oral cancer, ovarian cancer, non positions to be co-administered for treating lymphoma in a Small cell lung cancer, prostate cancer, Small cell lung cancer mammal with measurably additive antitumorigenesis, one or spleen cancer in a patient, said methods comprising admin 25 composition comprising atherapeutically effective amount of istering to the patientatherapeutically effective amount of the N-(4-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- compound having formula (I) and a therapeutically effective yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-(phenylsulfa amount of one additional therapeutic agent or more than one nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, or a additional therapeutic agent. salt thereof, and the other comprising a therapeutically effec Still another embodiment pertains to compositions for 30 tive amount of etoposide. treating diseases during which are expressed one or more than Still another embodiment pertains to methods for treating one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 pro lymphoma in a mammal with measurably additive antitum tein or antiapoptotic Bcl-W protein, said compositions com origenesis, said methods comprising co-administering a prising an excipient and a therapeutically effective amount of therapeutically effective amount of N-(4-(4-((4'-chloro(1,1- N-(4-(4-(4-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1- 35 biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1-(phenylsulfa (dimethylamino)-1-(phenylsulfanyl)methyl)propyl)amino)- nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, or a 3-nitrobenzenesulfonamide, or a salt thereof, at least once per therapeutically acceptable salt, prodrug or salt of a prodrug day for a schedule of at least twenty-one days and a therapeu thereof, and a therapeutically effective amount of one addi tically effective amount of etoposide on at least days one, five, tional therapeutic agent or more than one additional therapeu 40 and nine of the twenty-one day treatment schedule. tic agent. Still another embodiment pertains to compositions to be Still another embodiment pertains to methods of treating co-administered for treating lymphoma in a mammal with disease in a patient during which is expressed one or more measurably additive antitumorigenesis, one composition than one of antiapoptotic Bcl-X protein, antiapoptotic Bcl-2 comprising a therapeutically effective amount of N-(4-(4- protein or antiapoptotic Bcl-W protein, said methods com 45 ((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)ben prising administering to the patientatherapeutically effective Zoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me amount of N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl) thyl)propyl)amino)-3-nitrobenzenesulfonamide, or a salt piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1- thereof, and the other comprising a therapeutically effective ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene amount of Vincristine. Sulfonamide, or a therapeutically acceptable salt, prodrug or 50 Still another embodiment pertains to methods for treating salt of a prodrug thereof, and a therapeutically effective lymphoma in a mammal with measurably additive antitum amount of one additional therapeutic agent or more than one origenesis, said methods comprising co-administering a additional therapeutic agent. therapeutically effective amount of N-(4-(4-((4'-chloro(1,1'- Still another embodiment pertains to compositions for biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- treating bladder cancer, brain cancer, breast cancer, bone 55 (dimethylamino)-1-(phenylsulfanyl)methyl)propyl)amino)- marrow cancer, cervical cancer, chronic lymphocytic leuke 3-nitrobenzenesulfonamide, or a salt thereof, at least once per mia, colorectal cancer, esophageal cancer, hepatocellular day for a schedule of at least twenty-one days and a therapeu cancer, lymphoblastic leukemia, follicular lymphoma, lym tically effective amount of Vincristine on at least days one, phoid malignancies of T-cell or B-cell origin, melanoma, eight, and fifteen of the twenty-one treatment schedule. myelogenous leukemia, myeloma, oral cancer, ovarian can 60 Still another embodiment pertains to compositions to be cer, non-small cell lung cancer, prostate cancer, Small cell co-administered for treating lymphoma in a mammal with lung cancer or spleen cancer, said compositions comprising measurably additive antitumorigenesis, one composition an excipient and a therapeutically effective amount of N-(4- comprising a therapeutically effective amount of N-(4-(4- (4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl) ((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)ben benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) 65 Zoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me methyl)propyl)amino)-3-nitrobenzenesulfonamide, or a thyl)propyl)amino)-3-nitrobenzenesulfonamide, or a salt therapeutically acceptable salt, prodrug or salt of a prodrug thereof, and the other comprising a mixture of therapeutically US 7,973,161 B2 71 72 acceptable amounts of cyclophosphamide, doxorubican, Vin day for a schedule of at least twenty-one days and therapeu cristine and prednisone (CHOP). tically acceptable amounts of cyclophosphamide on days one, Still another embodiment pertains to methods for treating five, and nine of the twenty-one day Schedule, Vincristine on lymphoma in a mammal with measurably additive antitum days one, eight, and fifteen of the twenty-one day schedule origenesis, said methods comprising co-administering a and prednisone on days one to five, inclusive, of the twenty therapeutically effective amount of N-(4-(4-((4'-chloro(1,1'- one day treatment schedule. biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- Still another embodiment pertains to treating inflammation (dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)- related to autoimmune hypersensitivity. 3-nitrobenzenesulfonamide, or a salt thereof, at least once per day for a schedule of at least ten days and a mixture compris 10 DETAILED DESCRIPTION OF THE INVENTION ing therapeutically acceptable amounts of cyclophospha mide, doxorubican, Vincristine and prednisone (CHOP) for at Variable moieties herein are represented by identifiers least the first day of the ten day treatment schedule. (capital letters with numerical and/or alphabetical Super Still another embodiment pertains to compositions to be Scripts) and may be specifically embodied. co-administered for treating lymphoma in a mammal with 15 It is meant to be understood that proper Valences are main measurably additive antitumorigenesis, one composition tained for all moieties and combinations thereof, that comprising a therapeutically effective amount of N-(4-(4- monovalent moieties having more than one atom are drawn ((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)ben from left to right and are attached through their left ends, and Zoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me that divalent moieties are also drawn from left to right. thyl)propyl)amino)-3-nitrobenzenesulfonamide, or a salt It is also meant to be understood that a specific embodiment thereof, and the other comprising a therapeutically effective of a variable moiety herein may be the same or different as amount of rituximab. another specific embodiment having the same identifier. Still another embodiment pertains to methods for treating The term "cyclic moiety, as used herein, means arene, lymphoma in a mammal with measurably additive antitum aryl, cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, het origenesis, said methods comprising co-administering a 25 eroarene, heteroaryl, heterocycloalkane, heterocycloalkyl, therapeutically effective amount of N-(4-(4-((4'-chloro(1,1'- heterocycloalkene, heterocycloalkenyl, spiroalkyl, spiroalk biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- enyl, spiroheteroalkyl and spiroheteroalkenyl. (dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)- The term “arene, as used herein, means benzene. 3-nitrobenzenesulfonamide, or a salt thereof, at least once per The term “aryl, as used herein, means phenyl. day for a schedule of at least twenty-one days and a therapeu 30 The term “cycloalkane, as used herein, means C-cycloal tically effective amount of rituximab on at least day one of the kane, C-cycloalkane, Cs-cycloalkane, C-cycloalkane, twenty-one treatment schedule. C7-cycloalkane, Cs-cycloalkane, Co-cycloalkane, Co-cy Still another embodiment pertains to compositions to be cloalkane, C-cycloalkane, C-cycloalkane, C-cycloal co-administered for treating lymphoma in a mammal with kane and Ca-cycloalkane. measurably additive antitumorigenesis, one composition 35 The term "cycloalkyl, as used herein, means C-cy comprising a therapeutically effective amount of N-(4-(4- cloalkyl, Ca-cycloalkyl, Cs-cycloalkyl C-cycloalkyl, C7-cy ((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)ben cloalkyl, Cs-cycloalkyl, Co-cycloalkyl, Co-cycloalkyl, C Zoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me cycloalkyl, C-cycloalkyl, C-cycloalkyl and C thyl)propyl)amino)-3-nitrobenzenesulfonamide, or a salt cycloalkyl. thereof, and the other comprising a therapeutically effective 40 The term “cycloalkene, as used herein, means C-cy amount of rapamycin. cloalkene, Cs-cycloalkene, C-cycloalkene, C7-cycloalkene, Still another embodiment pertains to methods for treating Cs-cycloalkene, Co-cycloalkene, Co-cycloalkene, C-cy lymphoma in a mammal with measurably additive antitum cloalkene, C2-cycloalkene, C-cycloalkene and C-cy origenesis, said methods comprising co-administering a cloalkene. therapeutically effective amount of N-(4-(4-((4'-chloro(1,1'- 45 The term "cycloalkenyl as used herein, means C-cy biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- cloalkenyl, C-cycloalkenyl, Cs-cycloalkenyl, C-cycloalk (dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)- enyl, C7-cycloalkenyl, Cs-cycloalkenyl, Co-cycloalkenyl, 3-nitrobenzenesulfonamide, or a salt thereof, and a Co-cycloalkenyl, C-cycloalkenyl, C-cycloalkenyl, C therapeutically effective amount of rapamycin at least once cycloalkenyl and C-cycloalkenyl. per day for a schedule of at least twenty-one days. 50 The term "heteroarene, as used herein, means furan, imi Still another embodiment pertains to compositions to be dazole, isothiazole, isoxazole, 1.2.3-oxadiazole, 1,2,5-oxa co-administered for treating lymphoma in a mammal with diazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, measurably additive antitumorigenesis, one composition pyrimidine, pyrrole, thiazole, thiophene, triazine and 1.2.3- comprising a therapeutically effective amount of N-(4-(4- triazole. ((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)ben 55 The term "heteroaryl as used herein, means furanyl, imi Zoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me dazolyl, isothiazolyl, isoxazolyl, 1.2.3-oxadiaZoyl, 1.2.5- thyl)propyl)amino)-3-nitrobenzenesulfonamide, or a salt oxadiazolyl, oxazolyl pyrazinyl, pyrazolyl, pyridazinyl, thereof, and the other comprising a mixture of therapeutically pyridinyl, pyrimidinyl, pyrrolyl, tetrazolyl, thiazolyl, acceptable amounts of cyclophosphamide, Vincristine and thiophenyl, triazinyl and 1,2,3-triazolyl. prednisone (VCP). 60 The term "heterocycloalkane, as used herein, means Still another embodiment pertains to methods for treating cycloalkane having one or two or three CH moieties replaced lymphoma in a mammal with measurably additive antitum with independently selected O, C(O), CNOH, CNOCH, S, origenesis, said methods comprising co-administering a S(O), SO, or NH and one or two CH moieties unreplaced or therapeutically effective amount of N-(4-(4-((4'-chloro(1,1'- replaced with N and also means cycloalkane having one or biphenyl)-2-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3- 65 two or three CH moieties unreplaced or replaced with inde (dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)- pendently selected O, C(O), CNOH, CNOCH, S, S(O), SO 3-nitrobenzenesulfonamide, or a salt thereof, at least once per or NH and one or two CH moieties replaced with N.

US 7,973,161 B2 75 76 pent-2-yl, 2-methylpent-3-yl 3-methylpent-1-yl, 3-methyl cyclononadiene, 1.3.5-cyclononatriene, 1.3.6-cyclonon pent-2-yl, 3-methylpent-3-yl 4-methylpent-1-yland 4-meth atriene, 1,3,7-cyclononatriene and 1.3.5.7-cyclononatet ylpent-2-yl. a. The term “C-alkynyl as used herein, means ethynyl The term "Co-cycloalkene, as used herein, means cyclo (acetylenyl). decene, 1.3-cyclodecadiene, 1,4-cyclodecadiene, 1,5-cyclo The term "C-alkynyl, as used herein, means 1-propyn-1- decadiene, 1.6-cyclodecadiene, 1,3,5-cyclodecatriene, 1.3.6- y1 and 2-propyn-1-yl (propargyl). cyclodecatriene, 1,3,5,7-cyclodecatetraene, 1,3,5,8- The term “C-alkynyl,” as used herein, means 1-butyn-1- cyclodecatetraene and 1.3.6.8-cyclodecatetraene. yl, 1,3-butadiyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl and 3-bu The term "C-cycloalkene, as used herein, means 10 cycloundecene, 1.3-cycloundecadiene, 1,4-cycloundecadi tyn-2-yl. ene, 1,5-cycloundecadiene, 1.6-cycloundecadiene, 1,3,5-cy The term "Cs-alkynyl,” as used herein, means 2-methyl-3- cloundecatriene, 1.3.6-cycloundecatriene, 1,3,7-cycloundec butyn-1-yl, 2-methyl-3-butyn-2-yl, 3-methyl-1-butyn-1-yl, atriene, 1.4.7-cycloundecatriene, 1.4.8-cycloundecatriene, 1,3-pentadiyn-1-yl, 1,4-pentadiyn-1-yl, 1.4-pentadiyn-3-yl, 1.3.5.7-cycloundecatetraene, 1,3,5,8-cycloundecatetraene, 2.4-pentadiyn-1-yl, 1-pentyn-1-yl, 1-pentyn-3-yl 2-pentyn 15 1.3.6.8-cycloundecatetraene and 1.3.5.7.9-cycloundecapen 1-yl, 3-pentyn-1-yl, 3-pentyn-2-yl 4-pentyn-1-yland 4-pen taene. tyn-2-yl. The term "C2-cycloalkene as used herein, means The term "Ce-alkynyl. as used herein, means 2.2-dim cyclododecene, 1.3-cyclododecadiene, 1,4-cyclododecadi ethyl-3-butyn-1-yl, 3.3-dimethyl-1-butyn-1-yl, 2-ethyl-3-bu ene, 1,5-cyclododecadiene, 1.6-cyclododecadiene, 1.7-cy tyn-1-yl, 2-ethynyl-3-butyn-1-yl, 1-hexyn-1-yl, 1-hexyn-3- clododecadiene, 1,3,5-cyclododecatriene, 1.3.6-cyclododec yl, 1.3-hexadiyn-1-yl, 1.3.5-hexatriyn-1-yl, 1.4-hexadiyn-1- atriene, 1.3.7-cyclododecatriene, 1.3.8-cyclododecatriene, yl, 1.4-hexadiyn-3-yl, 1.5-hexadiyn-1-yl, 1.5-hexadiyn-3-yl, 1.4.7-cyclododecatriene, 1.4.8-cyclododecatriene, 1.5.9-cy 2-hexyn-1-yl, 2.5-hexadiyn-1-yl, 3-hexyn-1-yl, 3-hexyn-2- clododecatriene, 1,3,5,7-cyclododecatetraene, 1,3,5,8-cy y1, 3.5-hexadiyn-2-yl 4-hexyn-1-yl 4-hexyn-2-yl 4-hexyn clododecatetraene, 1.3.5.9-cyclododecatetraene, 1,3,6,8-cy 3-yl, 5-hexyn-1-yl, 5-hexyn-2-yl, 5-hexyn-3-yl, 2-methyl-3- 25 clododecatetraene, 1.3.6.9-cyclododecatetraene, 1.3.6.10 pentyn-1-yl, 2-methyl-3-pentyn-2-yl, 2-methyl-4-pentyn-1- cyclododecatetraene, 1.3.7.9-cyclododecatetraene, 1,4,7,10 y1. 2-methyl-4-pentyn-2-yl, 2-methyl-4-pentyn-3-yl, cyclododecatetraene, 1.3.5.7.9-cyclododecapentaene, 1.3.5. 3-methyl-1-pentyn-1-yl, 3-methyl-4-pentyn-1-yl, 3-methyl 7,10-cyclododecapentaene and 1,3,5,8,10 4-pentyn-2-yl, 3-methyl-1,4-pentadiyn-1-yl, 3-methyl-1,4- cyclododecapentaene. pentadiyn-3-yl 3-methyl-4-pentyn-1-yl, 3-methyl-4-pentyn 30 The term “C-cycloalkene, as used herein, means 1,3- 3-yl 4-methyl-1-pentyn-1-yl and 4-methyl-2-pentyn-1-yl. cyclotridecadiene, 1,4-cyclotridecadiene, 1,5-cyclotrideca The term "Ca-cycloalkane,” as used herein, means diene, 1.6-cyclotridecadiene, 1.7-cyclotridecadiene, 1,3,5- . cyclotridecatriene, 1.3.6-cyclotridecatriene, 1,3,7- The term "Cs-cycloalkane, as used herein, means cyclo cyclotridecatriene, 1.3.8-cyclotridecatriene, 1,4,7- pentane. 35 cyclotridecatriene, 1.4.8-cyclotridecatriene, 14.9- The term "Ce-cycloalkane, as used herein, means cyclo cyclotridecatriene, 1.5.9-cyclotridecatriene, 1,3,5,7- hexane. cyclotridecatetraene, 1,3,5,8-cyclotridecatetraene, 1.3.5.9- The term "C-cycloalkane, as used herein, means cyclo cyclotridecatetraene, 1.3.6.8-cyclotridecatetraene, 1.3.6.9- heptane. cyclotridecatetraene, 1,3,6,10-cyclotridecatetraene, 1.3.6. The term "Cs-cycloalkane, as used herein, means 40 11-cyclotridecatetraene, 1.3.7.9-cyclotridecatetraene, 1.3.7, . 10-cyclotridecatetraene, 1,4,7,10-cyclotridecatetraene, 1.3, The term "Co-cycloalkane, as used herein, means 6,11-cyclotridecatetraene, 1.3.5.7.9-cyclotridecapentaene, . 1,3,5,7,10-cyclotridecapentaene, 1,3,5,8,10-cyclotridecap The term “Co-cycloalkane, as used herein, means cyclo entaene, 1,3,5,8,11-cyclotridecapentaene, 1.3.6.8, 11-cyclot decane. 45 ridecapentaene and 1,3,5,7,9,11-cyclotridecahexaene. The term "C-cycloalkane, as used herein, means The term "Ca-cycloalkene as used herein, means cycloundecane. cyclotetradecene, 1.3-cyclotetradecadiene, 1,4-cyclotet The term "C2-cycloalkane, as used herein, means radecadiene, 1,5-cyclotetradecadiene, 1.6-cyclotetradecadi . ene, 1.7-cyclotetradecadiene, 1,8-cyclotetradecadiene, 1.3.5- The term "C-cycloalkane, as used herein, means cyclo 50 cyclotetradecatriene, 1.3.6-cyclotetradecatriene, 1,3,7- tridecane. cyclotetradecatriene, 1.3,8-cyclotetradecatriene, 1.3.9- The term "Ca-cycloalkane, as used herein, means cyclotetradecatriene, 1.4.7-cyclotetradecatriene, 1.4.8- . cyclotetradecatriene, 14.9-cyclotetradecatriene, 1.5.9- The term "Ca-cycloalkene.” as used herein, means cyclotetradecatriene, 1,5,10-cyclotetradecatriene, 1,3,5,7- cyclobutene and 1.3-cyclobutadiene. 55 cyclotetradecatetraene, 1,3,5,8-cyclotetradecatetraene, 1,3,5, The term "Cs-cycloalkene, as used herein, means cyclo 9-cyclotetradecatetraene, 1,3,5,10-cyclotetradecatetraene, pentene and 1.3-cyclopentadiene. 1,3,6,8-cyclotetradecatetraene, 1.3.6.9-cyclotetradecatet The term "Ce-cycloalkene as used herein, means cyclo raene, 1,3,6,10-cyclotetradecatetraene, 1.3.6.11-cyclotet hexene, 1.3-cyclohexadiene and 1.4-cyclohexadiene. radecatetraene, 1.3.6.12-cyclotetradecatetraene, 1.3.7.9-cy The term "C-cycloalkene as used herein, means cyclo 60 clotetradecatetraene, 1,3,7,10-cyclotetradecatetraene, 1.3.7, heptene and 1.3-cycloheptadiene. 11-cyclotetradecatetraene, 1.3,8,10-cyclotetradecatetraene, The term "Cs-cycloalkene, as used herein, means 1,4,7,10-cyclotetradecatetraene, 1,4,7,1 1-cyclotetradecatet cyclooctene, 1.3-cyclooctadiene, 1.4-cyclooctadiene, 1,5-cy raene, 14.8.11-cyclotetradecatetraene, 1,3,5,7,9-cyclotet clooctadiene, 1,3,5-cyclooctatriene and 1.3.6-cyclooc radecapentaene, 1,3,5,7,10-cyclotetradecapentaene, 1.3.5.7. tatriene. 65 11-cyclotetradecapentaene, 1,3,5,8,10 The term "Co-cycloalkene, as used herein, means cyclotetradecapentaene, 1,3,5,8,11-cyclotetradecapentaene, cyclononene, 1.3-cyclononadiene, 1,4-cyclononadiene, 1.5- 1,3,5,8,12-cyclotetradecapentaene, 1,3,5,9,11-cyclotetrade

US 7,973,161 B2 87 88 The term "C-spiroalkenyl as used herein, means but-1- The term “Co-spiroalkyl, as used herein, means non-19 en-14-ylene, but-2-en-1,4-ylene and buta-1,3-dien-1,4- ylene, both ends of which replace hydrogenatoms of the same ylene, both ends of which replace hydrogenatoms of the same CH moiety. CH moiety. The term “lymphoma, as used herein, means malignant The term “Cs-spiroalkenyl as used herein, means pent-1- neoplasms of lymphatic or reticule endothelial tissues that en-1.5-yl-ene, pent-2-en-1.5-ylene, penta-1,3-dien-1.5-ylene occur as circumscribed solid tumors and are composed of and penta-1,4-dien-1.5-ylene, both ends of which replace cells resembling lymphocytes, plasma cells or histocytes. hydrogen atoms of the same CH moiety. Specific examples of lymphoma include, but are not limited The term "Ce-spiroalkenyl as used herein, means hex-1- to, B-cell lymphoma, Hodgkin’s lymphoma, non-Hodgkin’s en-1,6-ylene, hex-2-en-1,6-ylene, hexa-1,3-dien-1,6-ylene, 10 lymphoma and disseminated lymphoma. The term “measurably additive antiangiogenic effect as hexa-1,4-di-en-1,6-ylene and hexa-1,3,5-trien-1,6-ylene, used herein means greater antitumorigenesis than obtained both ends of which replace hydrogen atoms of the same CH from use of N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl) moiety. piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1- The term "C-spiroalkenyl,” as used herein, means hept-1- 15 ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene en-17-yl-ene, hept-2-en-17-ylene, hept-3-en-17-ylene, Sulfonamide, or a salt thereof, alone or greater hepta-1,3-dien-17-ylene, hepta-1,4-dien-17-ylene, hepta-1, antitumorigenesis than obtained from use of etoposide, 5-dien-17-ylene, hepta-2,4-dien-17-ylene, hepta-2,5-dien Vinchristine, CHOP, VCP. rituximab or rapamycin alone. 17-ylene, hepta-1,3,5-trien-17-ylene and hepta-1,3,6-trien The term “antitumorigenesis,” as used herein, means 17-ylene, both ends of which replace hydrogen atoms of the reduction of tumor growth. same CH moiety. Compounds of this invention contain asymmetrically Sub The term "Cs-spiroalkenyl as used herein, means oct-1- stituted carbonatoms in the R or S configuration, in which the en-18-ylene, Oct-2-en-18-ylene, oct-3-en-18-ylene, octa-1, terms “R” and “S” are as defined by the IUPAC 1974 Rec 3-dien-18-ylene, octa-1,4-dien-18-ylene, octa-1,5-dien-1, ommendations for Section E, Fundamental Stereochemistry, 8-ylene, octa-1,6-dien-18-ylene, octa-2,4-dien-18-ylene, 25 Pure Appl. Chem. (1976) 45, 13-10. Compounds having octa-2,5-dien-18-ylene, octa-3,5-dien-18-ylene, octa-1,3,5- asymmetrically Substituted carbon atoms with equal amounts trien-18-ylene, octa-1,3,6-trien-18-ylene and octa-2,4,6-tri of R and S configurations are racemic at those carbon atoms. en-18-ylene, both ends of which replace hydrogen atoms of Atoms with an excess of one configuration over the other are the same CH moiety. assigned the configuration present in the higheramount, pref The term "Co-spiroalkenyl as used herein, means nona 30 erably an excess of about 85%-90%, more preferably an 1-en-1.9-yl-ene, nona-2-en-1.9-ylene, nona-3-en-1.9-ylene, excess of about 95%-99%, and still more preferably an excess nona-4-en-1.9-ylene, nona-1,3-dien-1.9-ylene, nona-1,4- greater than about 99%. Accordingly, this invention includes dien-19-ylene, nona-1,5-dien-19-ylene, nona-1,6-dien-19 racemic mixtures, relative and absolute stereoisomers, and ylene, nona-1,7-dien-1.9-ylene, nona-1,8-dien-1.9-ylene, mixtures of relative and absolute stereoisomers. 35 Compounds of this invention may also contain carbon nona-2,4-dien-1.9-ylene, nona-2,5-dien-1.9-ylene, nona-2,6- carbon double bonds or carbon-nitrogen double bonds in the dien-19-ylene, nona-2,7-dien-19-ylene, nona-3,5-dien-19 Z or E configuration, in which the term “Z” represents the ylene, nona-3,6-dien-1.9-ylene, nona-4,6-dien-1.9-ylene, larger two Substituents on the same side of a carbon-carbon or nona-1,3,5-trien-19-ylene, nona-1,3,6-trien-1.9-ylene, carbon-nitrogen double bond and the term “E” represents the nona-1,3,7-trien-19-ylene, nona-1,3,8-trien-19-ylene, 40 larger two Substituents on opposite sides of a carbon-carbon nona-1,4,6-trien-1.9-yl-ene, nona-1,4,7-trien-1.9-ylene, or carbon-nitrogen double bond. The compounds may also nona-1,4,8-trien-1.9-ylene, nona-1,5,7-trien-19-ylene, exist as an equilibrium mixture of Z or E configurations. nona-2,4,6-trien-1.9-ylene, nona-2,4,7-trien-1.9-ylene, Compounds of this invention containing NH, C(O)OH, OH nona-1,3,5,7-tetraen-19-ylene, nona-1,3,5,8-tetraen-19 or SH moieties may have attached thereto prodrug-forming ylene and nona-1,3,6,9-tetraen-1.9-ylene, both ends of which 45 moieties. The prodrug-forming moieties are removed by replace hydrogen atoms of the same CH2 moiety. metabolic processes and release the compounds having the The term "C-spiroalkyl,” as used herein, means eth-1,2- freed hydroxyl, amino or carboxylic acid in vivo. Prodrugs ylene, both ends of which replace hydrogenatoms of the same are useful for adjusting such pharmacokinetic properties of CH moiety. the compounds as solubility and/or hydrophobicity, absorp The term "C-spiroalkyl as used herein, means prop-1,3- 50 tion in the gastrointestinal tract, bioavailability, tissue pen ylene, both ends of which replace hydrogenatoms of the same etration, and rate of clearance. For example, examples of CH moiety. prodrug-forming moieties for compounds having C(O)CH The term "Ca-spiroalkyl as used herein, means but -1,4- moieties are pivalate (CHOC(O)C(CH)) orphosphonooxy ylene, both ends of which replace hydrogenatoms of the same (CHOP(O)(OH)) esters. CH moiety. 55 Metabolites of compounds having formula (I), produced The term “Cs-spiroalkyl as used herein, means pent-1,5- by in vitro or in vivo metabolic processes, may also have ylene, both ends of which replace hydrogenatoms of the same utility for treating diseases associated with expression of an CH moiety. anti-apoptotic protein family member Such as of BC1-X. The term "C-spiroalkyl, as used herein, means hex-1,6- protein, and Bcl-2 protein or Bcl-w protein. ylene, both ends of which replace hydrogenatoms of the same 60 Certain precursor compounds which may be metabolized CH moiety. in vitro or in vivo to form compounds having formula (I) may The term “C7-spiroalkyl as used herein, means hept-1,7- also have utility for treating diseases associated with expres ylene, both ends of which replace hydrogenatoms of the same sion of an anti-apoptotic protein family member Such as of CH moiety. BC1-X protein, and Bcl-2 protein or Bcl-w protein. The term "Cs-spiroalkyl, as used herein, means oct-1.8- 65 Compounds having formula (I) may exist as an acid addi ylene, both ends of which replace hydrogenatoms of the same tion salts, basic addition salts or Zwitterions. Salts of the CH moiety. compounds are prepared during their isolation or following US 7,973,161 B2 89 90 their purification. Acid addition salts of the compounds are and mixtures thereof. Excipients for preparation of composi those derived from the reaction of the compounds with an tions comprising a compound of this invention having for acid. For example, the acetate, adipate, alginate, bicarbonate, mula (I) to be administered osmotically include, for example, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, chlorofluorohydrocarbons, ethanol, water and mixtures butyrate, camphorate, camphorsulfonate, digluconate, for thereof. Excipients for preparation of compositions compris mate, fumarate, glycerophosphate, glutamate, hemisulfate, ing a compound of this invention having formula (I) to be heptanoate, hexanoate, hydrochloride, hydrobromide, administered parenterally include, for example, 1,3-butane hydroiodide, lactobionate, lactate, maleate, mesitylene diol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, Sulfonate, methanesulfonate, naphthylenesulfonate, nicoti groundnut oil, liposomes, oleic acid, olive oil, peanut oil, nate, oxalate, pamoate, pectinate, persulfate, phosphate, 10 Ringer's Solution, Safflower oil, sesame oil, soybean oil, picrate, propionate. Succinate, tartrate, thiocyanate, trichlo U.S.P. or isotonic sodium chloride solution, water and mix roacetic, trifluoroacetic, para-toluenesulfonate, and unde tures thereof. Excipients for preparation of compositions canoate salts of the compounds and prodrugs thereof are comprising a compound of this invention having formula (I) contemplated as being embraced by this invention. Basic to be administered rectally or vaginally include, for example, addition salts of the compounds are those derived from the 15 cocoa butter, polyethylene glycol, wax and mixtures thereof. reaction of the compounds with the hydroxide, carbonate or Compounds having formula (I) may also be administered bicarbonate of cations such as lithium, sodium, potassium, with one or more than one additional therapeutic agents, calcium, and magnesium. wherein additional therapeutic agents include radiation or The compounds having formula (I) may be administered, chemotherapeutic agents, wherein chemotherapeutic agents for example, bucally, ophthalmically, orally, osmotically, include, but are not limited to, carboplatin, cisplatin, cyclo parenterally (intramuscularly, intraperintoneally intraster phosphamide, dacarbazine, dexamethasone, docetaxel, nally, intravenously, Subcutaneously), rectally, topically, doxorubicin, etoposide, fludarabine, irinotecan, CHOP (C: transdermally, or vaginally. Cytoxan R (cyclophosphamide); H: Adiamycin R (hydroxy Therapeutically effective amounts of compounds having doxorubicin). O: Vincristine (OncovinR); P: prednisone), formula (I) depend on recipient of treatment, disorder being 25 paclitaxel, rapamycin, Rituxin R (rituximab) and Vincristine. treated and severity thereof, composition containing it, time For example, as shown in FIG. 1, administration of 75 of administration, route of administration, duration of treat mg/kg of N-(4-(4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl) ment, its potency, its rate of clearance and whether or not piperazin-1-yl)benzoyl)-4-(((1R)-3-(dimethylamino)-1- another drug is co-administered. The amount of a compound ((phenylsulfanyl)methyl)propyl)amino)-3-nitrobenzene of this invention having formula (I) used to make a composi 30 sulfonamide (EXAMPLE 2) once per day for fourteen days tion to be administered daily to a patient in a single dose or in and 75 mg/kg of etoposide on days one, five and nine resulted divided doses is from about 0.03 to about 200 mg/kg body in measurably additive tumor volume reduction (p<0.005) weight. Single dose compositions contain these amounts or a compared to the monotherapies. combination of submultiples thereof. As shown in FIG. 2, administration of 75 mg/kg of N-(4- Compounds having formula (I) may be administered with 35 (4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl) or without an excipient. Excipients include, for example, benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) encapsulating materials or additives Such as absorption accel methyl)propyl)amino)-3-nitrobenzenesulfonamide once per erators, antioxidants, binders, buffers, coating agents, color day for twenty-one days and 0.25 mg/kg of Vincristine on ing agents, diluents, disintegrating agents, emulsifiers, days one, eight and fifteen resulted in measurably additive extenders, fillers, flavoring agents, humectants, lubricants, 40 tumor volume reduction (p<0.05, Wilcoxon Rank Sum perfumes, preservatives, propellants, releasing agents, steril Analysis) compared to the monotherapies and about 30% izing agents, Sweeteners, solubilizers, wetting agents and complete tumor regressions compared to no tumor regres mixtures thereof. sions for the monotherapies. Excipients for preparation of compositions comprising a As shown in FIG. 3, administration of 75 mg/kg of N-(4- compound having formula (I) to be administered orally in 45 (4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl) Solid dosage form include, for example, agar, alginic acid, benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3- methyl)propyl)amino)-3-nitrobenzenesulfonamide at least butylene glycol, carbomers, castor oil, cellulose, cellulose once per day for a schedule of at least ten days and a mixture acetate, cocoa butter, corn starch, corn oil, cottonseed oil, comprising cyclophosphoramide (25 mg/kg), doxorubicin (3 cross-povidone, diglycerides, ethanol, ethyl cellulose, ethyl 50 mg/kg), Vincristine (0.25 mg/kg) and prednisone (0.5 laureate, ethyl oleate, fatty acid esters, gelatin, germ oil, glu mg/kg)) for at least the first day of the schedule resulted in cose, glycerol, groundnut oil, hydroxypropylmethylcellulose, measurably additive tumor volume reduction (p<0.0005, Wil isopropanol, isotonic saline, lactose, magnesium hydroxide, coxon Rank Sum Analysis) compared to the monotherapies magnesium Stearate, malt, mannitol, monoglycerides, olive and about 40% complete tumor regressions compared to no oil, peanut oil, potassium phosphate salts, potato starch, povi 55 tumor regressions for the monotherapies. done, propylene glycol, Ringer's Solution, safflower oil, As shown in FIG. 4, administration of 75 mg/kg of N-(4- sesame oil, Sodium carboxymethyl cellulose, sodium phos (4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl) phate salts, Sodium lauryl Sulfate, Sodium Sorbitol, soybean benzoyl)-4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) oil, Stearic acids, Stearyl fumarate, Sucrose, Surfactants, talc, methyl)propyl)amino)-3-nitrobenzenesulfonamide once per tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, 60 day for twenty-one days and 10 mg/kg of rituximab on day and mixtures thereof. Excipients for preparation of composi one resulted in measurably additive tumor volume reduction tions comprising a compound of this invention having for (p<0.05, Wilcoxon Rank Sum Analysis) from day 20 com mula (I) to be administered ophthalmically or orally in liquid pared to the monotherapies and about 100% complete tumor dosage forms include, for example, 1,3-butylene glycol, cas regressions compared to about 50% tumor regressions for tor oil, corn oil, cottonseed oil, ethanol, fatty acid esters of 65 rituximab alone. Sorbitan, germ oil, groundnut oil, glycerol, isopropanol, olive As shown in FIG. 5, administration of 75 mg/kg of N-(4- oil, polyethylene glycols, propylene glycol, Sesame oil, water (4-((4'-chloro(1,1'-biphenyl)-2-yl)methyl)piperazin-1-yl)

US 7,973,161 B2 95 96 Accordingly, compounds having formula (I) are expected It is also expected that compounds having formula (II) to have utility in treatment of diseases during which anti would inhibit the growth of cells derived from a pediatric apopotic Bcl-X protein, anti-apopotic Bcl-2 protein, anti cancer or neoplasm such as embryonal rhabdomyosarcoma, apopotic Bcl-W protein or a combination thereof, are pediatric acute lymphoblastic leukemia, pediatric acute expressed. myelogenous leukemia, pediatric alveolar rhabdomyosar Diseases during which anti-apopotic protein family mem coma, pediatric anaplastic ependymoma, pediatric anaplastic bers such as BC1-X, protein, Bcl-2 protein and Bcl-w protein large cell lymphoma, pediatric anaplastic medulloblastoma, are expressed include cancer, neoplastic disease and autoim pediatric atypical teratoid/rhabdoid tumor of the central ner mune disorders, wherein cancer and neoplastic disease Vous system, pediatric biphenotypic acute leukemia, pediat include, but are not limited to, cancer and autoimmune dis 10 ric Burkitts lymphoma, pediatric cancers of Ewing's family orders, wherein cancer includes, but is not limited to, acoustic of tumors such as primitive neuroectodermal rumors, pediat neuroma, acute leukemia, acute lymphocytic leukemia, acute ric diffuse anaplastic Wilm's tumor, pediatric favorable his myelocytic leukemia (monocytic, myeloblastic, adenocarci tology Wilm's tumor, pediatric glioblastoma, pediatric noma, angiosarcoma, astrocytoma, myelomonocytic and pro medulloblastoma, pediatric neuroblastoma, pediatric neuro myelocytic), acute t-cell leukemia, basal cell carcinoma, bile 15 blastoma-derived myelocytomatosis, pediatric pre-B-cell duct carcinoma, bladder cancer, brain cancer, breast cancer, cancers (such as leukemia), pediatric psteosarcoma, pediatric bronchogenic carcinoma, cervical cancer, chondrosarcoma, rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and chordoma, choriocarcinoma, chronic leukemia, chronic lym pediatric T-cell cancers such as lymphoma and skin cancer phocytic leukemia, chronic myelocytic (granulocytic) leuke (commonly-owned U.S. application Ser. No. 10/988.338), mia, colorectal cancer, craniopharyngioma, cystadenocarci Cancer Res., 2000, 60, 6101-10); autoimmune disorders noma, diffuse large B-cell lymphoma, dysproliferative include, but are not limited to, acquired immunodeficiency changes (dysplasias and metaplasias), embryonal carcinoma, disease syndrome, autoimmune lymphoproliferative Syn endometrial cancer, endotheliosarcoma, ependymoma, epi drome, hemolytic anemia, inflammatory diseases, and throm thelial carcinoma, erythroleukemia, esophageal cancer, estro bocytopenia (Current Allergy and Asthma Reports 2003, gen-receptor positive breast cancer, essential thromb 25 3:378-384; Br. J. Haematol. 2000 September: 110(3): 584 ocythemia, Ewing's tumor, fibrosarcoma, follicular 90; Blood 2000 Feb. 15:95(4): 1283-92; and New England lymphoma, germ cell testicular cancer, glioma, heavy chain Journal of Medicine 2004 September; 351 (14): 1409-1418). disease, hemangioblastoma, hepatoma, hepatocellular can A representative compound having formula (I), cer, hormone insensitive prostate cancer, leiomyosarcoma, EXAMPLE 2. displayed therapeutic utility against human liposarcoma, lung carcinoma, lymphagioendotheliosarcoma, 30 tumor cell lines derived from Small cell lung carcinomas and lymphangiosarcoma, lymphoblastic leukemia, lymphoma lymphoid malignancies of both T-cell and B-cell origin. (Hodgkin’s and non-Hodgkin’s), malignancies and hyper EXAMPLE 2 also displayed therapeutic utility against proliferative disorders of the bladder, breast, colon, lung, acute lymphoblastoid leukemia, Small cell lung cancerpros ovaries, pancreas, prostate, skin and uterus, lymphoid malig tate cancer, non-Small cell lung cancer, and follicular lym nancies of T-cell or B-cell origin, leukemia, lymphoma, med 35 phoma tumors (RS11380, DoHH2 and SuDHL-4) in ullary carcinoma, medulloblastoma, melanoma, menin Xenograft models. gioma, mesothelioma, multiple myeloma, myelogenous EXAMPLE 2 also demonstrated anti-tumor activity in two leukemia, myeloma, myxosarcoma, neuroblastoma, non murine models (H146 and SCLC xenograft) from human Small cell lung cancer, oligodendroglioma, oral cancer, osteo derived Small cell lung cancer isolated from Smokers and genic sarcoma, ovarian cancer, pancreatic cancer, papillary 40 nonsmokers, defective for Rb/p53 gene function, and expres adenocarcinomas, papillary carcinoma, pinealoma, poly sive of moderately high levels of Bcl-2. In the H146 model, cythemia Vera, prostate cancer, renal cell carcinoma, retino treatment with EXAMPLE 2 resulted in complete regression blastoma, rhabdomyosarcoma, sarcoma, sebaceous gland of an established tumor with, in Some cases, tumor disappear carcinoma, seminoma, Small cell lung carcinoma, Solid ance after prolonged therapy. tumors (carcinomas and sarcomas), Small cell lung cancer 45 EXAMPLE 2 also prolonged survival in a systemic model squamous cell carcinoma, synovioma, Sweat gland carci of acute lymphoblastic leukemia and inhibited tumor growth noma, Waldenström's macroglobulinemia, testicular tumors, in a model of follicular lymphoma (DOHH-2). Therapeutic uterine cancer and Wilms tumor, (Cancer Res., 2000, 60, utility was also observed in a prostate cancer model. 6101-10 and Medicine, 2d Ed., J.B. Lippincott Co., Philadel Without being limited by theory, the genetic link between phia (1985)); autoimmune disorders include, but are not lim 50 Bcl-2 and cancer comes from the observation that tC14:18) ited to, acquired immunodeficiency disease syndrome, chromosomal translocations in B-cell lymphomas lead to autoimmune lymphoproliferative syndrome, hemolytic ane overexpression of the protein. Aberrant Bcl-2 and Bcl-X, mia, inflammatory diseases, and thrombocytopenia (Current expression is also seen in other lymphoid malignancies Such Allergy and Asthma Reports 2003, 3:378-384; Br. J. Haema as chronic lymphocytic leukemia and acute lymphocytic leu tol. 2000 September: 110(3): 584-90; Blood 2000 Feb. 15; 55 kemia. EXAMPLE 2 exhibited significant activity in a 95(4): 1283-92; and New England Journal of Medicine 2004 CCRF-CEMT-cell acute lymphoblastoid leukemia model as September; 351 (14): 1409-1418). well as in SuDHL4 and RS11380, two models of B-cell It is also expected that compounds having formula (II) follicular lymphoma. would inhibit the growth of cells derived from a cancer or CCRF-CEM is a p53-mutant acute lympoblastoid leuke neoplasm such as breast cancer (including estrogen-receptor 60 mia line of T-cell origin used as an animal (mouse) model of positive breast cancer), colorectal cancer, endometrial cancer, systemic leukemia involving intravenous inoculation of lung cancer (including Small cell lung cancer), lymphoma tumor cells. If left untreated, the mice succumb to disease (including follicular or Diffuse Large B-cell), lymphoma (in within about 34 days post inoculation, at which time exten cluding non-Hodgkin’s lymphoma), neuroblastoma, ovarian sive tumor infiltration of spleen, liver, and bone marrow has cancer, prostate cancer (including hormone-insensitive pros 65 occured. Administration of EXAMPLE 2 increased the aver tate cancer), testicular cancer (including germ cell testicular age Survival of the mice and showed a significant decrease in cancer). average spleen weight relative to vehicle controls (indicative US 7,973,161 B2 97 98 of a lower tumor burden in this organ). Subsequent histopah morbidity. EXAMPLE 2 was administered i.p. in a vehicle of tological assessments revealed lower tumor infiltration in 5% Tween 80, 30% propylene glycol, 65% D5W (5% dex both the liver and spleen relative to controls. trose in water), less than 1% DMSO. Cyclophosphamide was The therapeutic effect of EXAMPLE 2 on other human obtained from the Bristol-Myers Squibb Company (Princ tumor cell lines is shown in TABLE 1 for which the ECso's are eton, N.J.). Prednisolone was obtained from Aero Pharma the effective concentrations which cause a 50% reduction in ceuticals (Pompano Beach, Fla.). Etoposide was obtained cell viability. from Bedford Laboratories (Bedford, Ohio). Adriamycin was obtained from Sicor Pharmaceuticals (Irvine, Calif.). Vinc TABLE 1. ristine was obtained from Faulding Pharmaceuticals (Para 10 mus, N.J.). Rituximab was obtained from Genetech, Inc. (San Cell Line Tumor Type ECso (M) Francisco, Calif.). Each was administered according to the Calu-6 Non-Small Cell Lung 0.18 + 0.07(6) manufacturers guidelines. Rapamycin was administered i.p. NCI-EH460 Non-Small Cell Lung 2.3 + 1.5(6) in a vehicle of 4% ethanol, 10% solutol and 86% phosphate NCI-EH226 Non-Small Cell Lung 2.6+ 1.1(2) buffered saline. NCI-EH322M Non-Small Cell Lung 4.1 + 0.8(2) 15 The therapeutic effect of paclitaxel on A549 human non AS49 ATCC Non-Small Cell Lung 5.2 + 0.2(2) HOP-62 Non-Small Cell Lung 6.3 + 6.7(2) Small cell lung carcinoma cells was about 4.4-fold more effi NCI-EH23 Non-Small Cell Lung 7.4 + 0.6(2) cacious when administered with EXAMPLE 2. A similar COLO 205 Colorecta 0.51 + 0.07(4) increase (4.7-fold) in efficacy was demonstrated against PC-3 HCT-15 Colorecta 0.60 + 0.34(4) prostate carcinoma cells. The enantiomer of EXAMPLE 2 HCT-15 Colorecta >11(2) SW-62O Colorecta 0.69 + 0.07(2) was less efficacious, indicating that the therapeutic effect of DLD-1 Colorecta 0.99 + 0.45(4) EXAMPLE 2 was the direct result of binding to anti-apop HT-29 Colorecta 1.1 + 1.1 (6) totic Bcl-2 family proteins. The anti-tumor activity of KM12 Colorecta 1.7 + 0.2(2) EXAMPLE 2 was equivalent to slightly better than paclitaxel HCT-116 Colorecta 2.1 + 1.8(6) MCF7 Breast 2.0 + 0.8(2) near the maximum tolerated dose in a small cell lung cancer MDA-MB-435 Breast 2.4(1) 25 Xenograft tumor model and Superior to cisplatin and etopo MDA-MB-436 Breast 3.9 + 2.6(2) side. In a PC3 derived murine model of prostate cancer, BT-549 Breast 6.5 + 2.3(2) EXAMPLE 2 exhibited about 40-50% inhibition of tumor HS-578T Breast 7.2 + 8.2(2) T47D Breast >10(2) growth rate. NCIADR-RES Breast >10(2) Studies pertaining to the efficacy of EXAMPLE 2 in com U251 CNS 3.8 + 2.0(2) 30 bination with etoposide, Vincristine, modified CHOP, doxo SF-539 CNS 4.1 + 0.6(2) rubicin, rapamycin and Rituxin R) demonstrated that SF-295 CNS 7.7 it 2.3(2) SF-268 CNS 8.3 + 0.4(2) EXAMPLE2 synergistically enhanced efficacy of these cyto U87MG Glioma 2.7 + 1.8(2) toxic agents during combination therapy. In particular, com DS4MG Glioma 3.1 + 2.5(2) binations comprising EXAMPLE 2 and rapamycin and LOX IMVI Melanoma 1.7 + 0.4(2) 35 EXAMPLE 2 and Rituxin R resulted in complete regression MALME-3M Melanoma 1.9 + 0.8(2) SK-MEL-5 Melanoma 3.7 + 0.8(2) of a significant percentage of established DoHH2 follicular SK-MEL-28 Melanoma 9.3 + 0.1(2) lymphoma flank tumors for a Sustained period of time. OVCAR-S Ovarian 1.1 + O(2) These data demonstrate the utility of compounds having IGROV-1 Ovarian 1.7 + 0.6(2) formula (I) for treatment of diseases which are caused or OVCAR-3 Ovarian 1.9 + 0.3(2) 40 OVCAR-8 Ovarian 3.4 + 0.8(2) exascerbated by expression of one or more than one of an SK-OV-3 Ovarian 5.6+ 1.0(2) anti-apoptotic protein family member. Furthermore, experi OVCAR-4 Ovarian 22 + 3(2) ments with representative Bcl-X-selective compounds dem MiaPaca Pancreas 1.4 + 0.6(2) onstrated Synergistic therapeutic effects with multiple che PC3 Prostate 0.96 + 0.38(4) DU-145 Prostate 8.2 + 1.1(2) motherapeutic agents against cell lines representative of ACHN Renal 1(1) 45 diverse tumor types. Accordingly, the compounds having for 786-0 Renal 2.9 + 0.1(2) mula (I) are expected to be useful as chemotherapeutic agents RXF-393 Renal 2.9 + 0.4(2) alone or in combination with additional therapeutic agents SN12C Renal 3.2 + 0.2(2) including, but not limited to, angiogenesis inhibitors, antipro Serum-free conditions, 48 hour treatment, liferative agents, kinase inhibitors, receptor tyrosine kinase Meant SEMOn). 50 inhibitors, aurora kinase inhibitors, polo-like kinase inhibi tors, bcr-abl kinase inhibitors, growth factor inhibitors, Animal studies were conducted following the guidelines of COX-2 inhibitors, non-steroidal anti-inflammatory drugs the Institutional Animal Care and Use Committee. Immuno (NSAIDS), antimitotic agents, alkylating agents, antimetabo compromised male scid mice (C.B-17-Prkdc') were lites, intercalating antibiotics, platinum containing agents, obtained from Charles River Laboratories (Wilmington, 55 growth factor inhibitors, ionizing radiation, cell cycle inhibi Mass.) at 6-8 weeks of age. DoHH-2 cells were obtained from tors, enzymes, topoisomerase inhibitors, biologic response the German National Resource Centre for Biological Mate modifiers, immunologicals, antibodies, hormonal therapies, rial (Braunschweig, Germany). 2x10 DoHH-2 cells in 50% retinoids/deltoids plant alkaloids, proteasome inhibitors, Matrigel (BD Biosciences, Bedford, Mass.) were inoculated HSP-90 inhibitors, histone deacetylase inhibitors (HDAC) subcutaneously into the flank. Mice were sorted into therapy 60 inhibitors, purine analogs, pyrimidine analogs, MEK inhibi groups approximately 7-14 days after inoculation with an tors, CDK inhibitors, ErbB2 receptor inhibitors, mTOR average tumor size of 200-250 mm per group (N=10 mice inhibitors as well as other antitumor agents. per group). Tumor size was evaluated by twice weekly mea Angiogenesis inhibitors include, but are not limited to, Surements with digital calipers. Tumor Volume was estimated EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, using the formula: V-LXW. For systemic tumor studies, 65 TIE2 inhibitors, IGF1R inhibitors, matrix metalloproteinase 2x10 cells were inoculated into the lateral tail vein without 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) matrigel. Disease progression was recorded as the onset of inhibitors and thrombospondin analogs. US 7,973,161 B2 99 100 Examples of EGFR inhibitors include, but are not limited (trastuzumab), Omitarg (2C4, petuzumab), TAK-165, to, Iressa (gefitinib), Tarceva (erlotinib or OSI-774), Erbitux GW-572016 (Ionafarnib), GW-282974, EKB-569, PI-166, (cetuximab), EMD-7200, ABX-EGF, HR3, IgA antibodies, dHER2 (HER2 Vaccine), APC8024 (HER2 Vaccine), anti TP-38 (IVAX), EGFR fusion protein, EGF-vaccine, anti HER/2neu bispecific antibody, B7.her2IgG3, AS HER2 tri EGFr immunoliposomes and Tykerb (lapatinib). functional bispecific antibodies, maB AR-209 and mAB Examples of PDGFR inhibitors include, but are not limited 2B-1. to, CP-673,451 and CP-868596. Examples of alkylating agents include, but are not limited Examples of VEGFR inhibitors include, but are not limited to, nitrogen mustard N-oxide, cyclophosphamide, ifosfa to, Avastin (bevacizumab), Sutent (sunitinib, SU 11248), 10 mide, trofosfamide, chlorambucil, melphalan, buSulfan, Nexavar (sorafenib, BAY43-9006), CP-547,632, axitinib mitobronitol, carboquone, thiotepa, ranimustine, nimustine, (AG 13736), Zactima (vandetanib, ZD-6474), AEE788, Cloretazine (VNP 4010.1M), temozolomide, AMD-473, AZD-2171, VEGF trap, Vatalanib (PTK-787, ZK-222584), altretamine, AP-5280, apaziquone, brostallicin, bendamus Macugen, IM862, Pazopanib (GW786034), ABT-869 and tine, carmustine, estramustine, fotemustine, glufosfamide, angiozyme. 15 KW-2170, mafosfamide, and mitolactol, carmustine Examples of thrombospondin analogs include, but are not (BCNU), lomustine (CCNU), Busulfan, Treosulfan, Decar limited to, TSP-1, ABT-510, ABT-567 and ABT-898. bazine and Temozolomide. Examples of aurora kinase inhibitors include, but are not Examples of antimetabolites include but are not limited to, limited to, VX-680, AZD-1152 and MLN-8054. methotrexate, 6-mercaptopurine riboside, mercaptopurine, An example of a polo-like kinase inhibitor includes, but is 5-fluorouracil (5-FU) alone or in combination with leucov not limited to BI-2536. orin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cyt Examples of bcr-abl kinase inhibitors include, but are not arabine ocfosfate, enocitabine, S-1, Alimta (premetrexed limited to, Gleevec (imatinib) and Dasatinib (BMS354825). disodium, LY231514, MTA), Gemzar (gemcitabine, Eli Examples of platinum containing agents includes, but are 25 Lilly), fludarabine, 5-azacitidine, capecitabine, cladribine, not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, clofarabine, decitabine, eflornithine, ethnylcytidine, cytosine lobaplatin, medaplatin, Eloxatin (oxaliplatin) and satraplatin. arabinoside, hydroxyurea, TS-1, melphalan, nelarabine, Examples of mTOR inhibitors includes, but are not limited nolatrexed, ocfosate, disodium premetrexed, pentostatin, to, CCI-779, rapamycin, temsirolimus, everolimus, RAD001, 30 pelitrexol, raltitrexed, triapine, trimetrexate, Vidarabine, and AP-23573. mycophenolic acid, tiazofurin, Ribavirin, EICAR, hydrox Examples of HSP-90 inhibitors includes, but are not lim yurea and deferoxamine. ited to, geldanamycin, radicicol, 17-AAG, KOS-953, Examples of antibiotics include intercalating antibiotics 17-DMAG, CNF-101, CNF-1010, 17-AAG-nab, NCS but are not limited to, aclarubicin, actinomycin D, amrubicin, 683664, Mycograb, CNF-2024, PU3, PU24FC1, VER49009, 35 annamycin, adriamycin, bleomycin, daunorubicin, doxorubi IPI-504, SNX-2112 and STA-9090. cin, elsamitrucin, epirbucin, glarbuicin, idarubicin, mitomy Examples of histone deacetylase inhibitors (HDAC) cin C, nemorubicin, neocarzinostatin, peplomycin, pirarubi includes, but are not limited to, Suberoylanilide hydroxamic cin, rebeccamycin, stimalamer, Streptozocin, valrubicin, acid (SAHA), MS-275, Valproic acid, TSA, LAQ-824, Zinostatin and combinations thereof. Trapoxin, and Depsipeptide. 40 Examples of topoisomerase inhibiting agents include, but Examples of MEK inhibitors include, but are not limited to, are not limited to, one or more agents selected from the group PD325901, ARRY-142886, ARRY-438162 and PD98059. consisting of aclarubicin, amonafide, belotecan, camptoth Examples of CDK inhibitors include, but are not limited to, ecin, 10-hydroxycamptothecin, 9-aminocamptothecin, flavopyridol, MCS-5A, CVT-2584, seliciclib (CYC-202, 45 Amsacrine, Cardioxane (DexraZOXine), diflomotecan, irino R-roscovitine), ZK-304709, PHA-690509, BMI-1040, GPC tecan HCL (Camptosar), edotecarin, epirubicin (Ellence), 286199, BMS-387,032, PD0332991 and AZD-5438. etoposide, exatecan, Becatecarin, gimatecan, lurtotecan, Examples of useful COX-2 inhibitors include, but are not orathecin (Supergen), BN-80915, mitoxantrone, pirarbucin, limited to, CELEBREXTM (celecoxib), parecoxib, deracoxib, pixantrone, rubitecan, Sobuzoxane, SN-38, tafluposide and ABT-963, MK-663 (etoricoxib), COX-189 Lumiracoxib), 50 topotecan. BMS347070, RS57067, NS-398, Bextra (valdecoxib), para Examples of antibodies include, but are not limited to, coxib, Vioxx (rofecoxib), SD-8381,4-Methyl-2-(3,4-dimeth Rituximab, Cetuximab, Bevacizumab, Trastuzimab, specific ylphenyl)-1-(4-sulfamoyl-phenyl-1H-pyrrole, T-614, JTE CD40 antibodies and specific IGF1 Rantibodies, chTNT-1/B, 522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia 55 Denosumab, Panorex (Edrecolomab), Rencarex (WXG250), (etoricoxib). Zanolimumab, LintuZumab, Ticilimumab. Examples of non-steroidal anti-inflammatory drugs Examples of hormonal therapies include, but are not lim (NSAIDs) include, but are not limited to, Salsalate (Amige ited to, exemestane (Aromasin), leuprolide acetate, Buser sic), Diflunisal (Dolobid), Ibuprofen (Motrin), Ketoprofen elin, Cetrorelix, Deslorelin, Vantas, anastrozole (Arimidex), (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), 60 foSrelin (Zoladex), goserelin, Degarelix, doxercalciferol, Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), fadrozole, formestane, tamoxifen citrate (tamoxifen), Arzox Indomethacin (Indocin), Sulindac (Clinoril), Tolimetin ifene, Casodex, Abarelix, Trelstar, finasteride, fulvestrant, (Tolectin), Etodolac (Lodine), Ketorolac (Toradol) and toremifene, raloxifene, Trilostane (Modrastane, Desopan), Oxaprozin (Day pro). 65 lasofoxifene, letrozole, flutamide, bicalutamide, megesterol, Examples of ErbB2 receptor inhibitors include, but are not mifepristone, nilutamide, dexamethasone, predisone and limited to, CP-724-714, CI-1033 (canertinib), Herceptin other glucocorticoids. US 7,973,161 B2 101 102 Examples of retinoids/deltoids include, but are not limited posome muramyl tripeptide phophatidylethanolamine, Juno to, seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), Van), Dimericine (Liposome T4 endonuclase V). Onconase, fenretinide, Panretin (aliretinoin), Atragen, Bexarotene and BEC2, Xcytrin, CeaVac, NewTrexin, OvaRex, Osidem, LGD-1550. Advexin, RSR13 (efaproxiral, Cotara, NBI-3001 (IL-4), Examples of plant alkaloids include, but are not limited to, Canvaxin, GMK vaccine, PEG Interferon A, Taxoprexin, Vincristine, vinblastine, vindesine and vinorelbine. gene therapy agents such as TNFerade (GeneVac) or GVAX, Examples of proteasome inhibitors include, but are not Interferon-alpha, Interferon-gamma, Gardasil, Eniluracil limited to, bortezomib (Velcade), MG132, NPI-0052 and (GW 776C85), Lonafarnib, ABT-100, Tumor necrosis factor, PR-171. 10 Lovastatin, staurosporine, dactinomycin, Zorubicin, Bosen Examples of immunologicals include, but are not limited tan, OncoVAX, Cervarix, Cintredekin besudotox (IL-13 to, interferons and numerous other immune enhancing PE38, IL-13-PE38QQR, Interleukin 13-pseudomonas exo agents. Interferons include interferon alpha, interferon alpha toxin). Oncophage (HSPPC96), Phenoxodiol (NV 06), IGN 2a, interferon alpha-2b, interferon beta, interferon gamma 101, PANVAC (CEA, MUC-1 vaccinia), ampligen, iban 1a, interferon gamma-1b (Actimmune), or interferon gamma 15 dronic acid, miltefosine, L-asparaginase, procarbazine, Tra n1 and combinations thereof. Other agents include Alfaferone bectedin (ET-743, Ecteinascidin 743, Yondelis), 5,10-meth (Leukocyte alpha interferon, Cliferon), filgrastim, lentinan, ylenetetrahydrofolate, hydroxycarbamide, pegaspargase, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtu pentostatin, tazarotne, TransMID 107R (KSB 311), Trisenox, Zumab, BAM-002, decarbazine, daclizumab, denileukin, Telcyta, tretinoin, acitretin, Zometa (Zolendronic acid), Pan gemtuzumab ozogamicin, ibritumomab, imiquimod, dimex (Aglycon protopanaxadiol, PBD-2131), Talabostat lenograstim, lentinan, melanoma vaccine (Corixa), molgra (PT100), Tesmilifene, Tetrandrine, halofuginone, rebimastat, mostim, OncoVAC-CL, sargaramoStim, tasonermin, tecleu removab, squalamine, ukrain, paditaxel, Zinecard and kin, thymalasin, to situmomab, Virulizin, Z-100, epratu Vitaxin. Zumab, mitumomab, oregovomab, pemtumomab 25 Compounds having formula (I) may be made by Synthetic (Y-muHMFG1), Provenge (Dendreon), CTLA4 (cytotoxic chemical processes, examples of which are shown herein. It is lymphocyte antigen 4) antibodies and agents capable of meant to be understood that the order of the steps in the blocking CTLA4 such as MDX-010. processes may be varied, reagents, solvents, and reaction Examples of biological response modifiers are agents that 30 conditions may be substituted for those specifically men modify defense mechanisms of living organisms orbiological tioned, and Vulnerable moieties may be protected and depro responses, such as survival, growth, or differentiation of tis tected, as necessary, by NH, C(O)OH, OH, SH protecting sue cells to direct them to have anti-tumor activity. Such groups. agents include krestin, lentinan, sizofuran, picibanil The following abbreviations have the meanings indicated. PF-3512676 (CpG-8954) and ubenimex. 35 ADDP means 1,1'-(azodicarbonyl)dipiperidine; AD-mix-f Examples of pyrimidine analogs include, but are not lim means a mixture of (DHQD),PHAL, KFe(CN), KCO, ited to, 5-Fluorouracil, Floxuridine, Doxifluridine, Ratitr and KSO): 9-BBN means 9-borabicyclo[3.3.1 nonane; exed, cytarabine (ara C), Cytosine arabinoside, Fludarabine, Boc means tert-butoxycarbonyl: (DHQD)PHAL means triacetyluridine Troxacitabine (Troxatyl) and Gemcitabine. hydroquinidine 1,4-phthalazinediyl , DBU Examples of purine analogs include but are not limited to, 40 means 1,8-diazabicyclo5.4.0]undec-7-ene; DIBAL means Mercaptopurine and thioguanine. disobutylaluminum hydride; DIEA means diisopropylethy Examples of antimitotic agents include, but are not limited lamine; DMAP means N,N-dimethylaminopyridine; DMF to, N-(2-((4-hydroxyphenyl)amino)pyridin-3-yl)-4-meth means N,N-dimethylformamide; dimpe means 1,2-bis(dim oxybenzenesulfonamide, paclitaxel, docetaxel, epothilone D 45 ethylphosphino)ethane; DMSO means dimethylsulfoxide: (KOS-862), PNU100940 (109881), Batabulin, Ixabepilone dppb means 1,4-bis(diphenylphosphino)butane; dippe means (BMS 247550), Patupilone, XRP-9881, Vinflunine and ZK 1.2-bis(diphenylphosphino)ethane; dippf means 1,1'-bis EPO. (diphenylphosphino)ferrocene; dippm means 1,1-bis(diphe Compounds of the present invention are also intended to be nylphosphino)methane; EDAC.HCl means 1-(3-dimethy used as a radiosensitizer that enhances the efficacy of radio 50 laminopropyl)-3-ethylcarbodiimide hydrochloride; Fmoc therapy. Examples of radiotherapy include but are not limited means fluorenylmethoxycarbonyl: HATU means O-(7-aza to, external beam radiotherapy (XBRT), or teletherapy, benzotriazol-1-yl)-N,N'N'N'-tetramethyluronium hexafluo brachtherapy or sealed source radiotherapy, unsealed Source rophosphate: HMPA means hexamethylphosphoramide; IPA radiotherapy. 55 means isopropyl alcohol; MP BH means macroporus tri Additionally, compounds having formula (II) may be com ethylammonium methylpolystyrene cyanoborohydride; TEA bined with other antitumor agents selected from the following means triethylamine: TFA means trifluoroacetic acid; THF agents, Genasense, Panitumumab, Zevalin, BeXXar (Corixa). means tetrahydrofuran: NCS means N-chlorosuccinimide: Arglabin, Abarelix, Alimta, EPO906, discodermolide, Neov NMM means N-methylmorpholine; NMP means N-meth astat, enzastaurin, Combrestatin A4P ZD-6126, AVE-8062, 60 ylpyrrolidine: PPh means triphenylphosphine. DMXAA, Thymitaq, Temodar, Revlimid, Cypat, Histerelin, The term “NH protecting group, as used herein, means Plenaizis, Atrasentan, Celeuk (celmoleukin), Satraplatin, tha trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzy lomide (Thalidomide), theratope, Temilifene, ABI-007, loxycarbonyl, para-nitrobenzylcarbonyl, ortho-bromobenzy Evista, Atamestane, Xyotax, Targretin, TriaZone, Aposyn, 65 loxycarbonyl, chloroacetyl, dichloroacetyl, trichloroacetyl, Nevastat, Ceplene, Lanreotide, Aredia (pamidronic acid), trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert Orathecin, Virulizin, Gastrimmune, DX-8951f. Mepact (Li amyloxycarbonyl, tert-butoxycarbonyl, para-methoxybenzy US 7,973,161 B2 103 104 loxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-(pheny para-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylm lazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl, ethyl, triphenylmethyl, tetrahydrofuryl, tetrahydropyranyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, tetrahydrothiopyranyl, methoxymethyl, methylthiomethyl, isopropoxycarbonyl, phthaloyl. Succinyl, alanyl, leucyl. benzyloxymethyl, 2-methoxyethoxymethyl, 2.2.2-trichloro 1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, benzyl, 5 ethoxymethyl, 2-(trimethylsilyl)ethoxymethyl, 1-ethoxy ethyl, methanesulfonyl, para-toluenesulfonyl, trimethylsilyl, diphenylmethyl, triphenylmethyl 2-nitrophenylthio, meth triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-bu anesulfonyl, para-toluenesulfonyl, N,N-dimethylaminom tyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsi ethylene, benzylidene, 2-hydroxybenzylidene, 2-hydroxy-5- lyl, and tert-butylmethoxyphenylsilyl. chlorobenzylidene, 2-hydroxy-1-naphthylmethylene, 10 3-hydroxy-4-pyridylmethylene, cyclohexylidene, 2-ethoxy carbonylcyclohexylidene, 2-ethoxycarbonylcyclopentyl SCHEME 1. idene, 2-acetylcyclohexylidene, 3.3-dimethyl-5-oxycyclo Fl hexylidene, diphenylphosphoryl, dibenzylphosphoryl, 15 5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl, trimethylsilyl, H Yl triethylsilyl, and triphenylsilyl. N The term “C(O)OH protecting group, as used herein, 2 means methyl, ethyl, n-propyl, isopropyl, 1,1-dimethylpro El Al Bl pyl. n-butyl, tert-butyl, phenyl, naphthyl, benzyl, diphenylm ethyl, triphenylmethyl, para-nitrobenzyl, para-methoxyben (1) Zyl. bis(para-methoxyphenyl)methyl, acetylmethyl, benzoylmethyl, para-nitrobenzoylmethyl, para-bromoben 'V' HN Y N Yl -3- Zoylmethyl, para-methanesulfonylbenzoylmethyl 2-tetrahy 25 dropyranyl 2-tetrahydrofuranyl, 2.2.2-trichloroethyl 2-(tri 2 methylsilyl)ethyl, acetoxymethyl, propionyloxymethyl, El Al Bl pivaloyloxymethyl, phthalimidomethyl, Succinimidomethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, meth (2) oxymethyl, methoxyethoxymethyl, 2-(trimethylsilyl) 30 Q O O. F. ethoxymethyl, benzyloxymethyl, methylthiomethyl, 2-meth \/ Y1 ylthioethyl, phenylthiomethyl, 1,1-dimethyl-2-propenyl, Zl N1 N 3-methyl-3-butenyl, allyl, trimethylsilyl, triethylsilyl, triiso i 2 propylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, El Al Bl tert-butyldiphenylsilyl, diphenylmethylsilyl, and tert-butyl 35 methoxyphenylsilyl. (I) The term “OH or SH protecting group, as used herein, means benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, Compounds having formula (1) may be converted to com 4-bromobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 40 pounds having formula (2) by reacting the former, chlorosul 3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, fonic acid, and ammonia. ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxy carbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphe Compounds having formula (2) may be converted to com nylmethoxycarbonyl, 2.2.2-trichloroethoxycarbonyl, 2.2.2- pounds having formula (I) by reacting the former and com tribromoethoxycarbonyl, 2-(trimethylsilyl)ethoxycarbonyl, 45 pounds having formula Z-COH and a coupling agent, with 2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio) or without a first base. Examples of coupling agents include ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxycar EDCI, CDI, and PyBop. Examples of first bases include TEA, bonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocar bonyl, 4-ethoxy-1-naphthyloxycarbonyl, DIEA, DMAP, and mixtures thereof. 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichlo Compounds having formula (2) may be converted to com roacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phe 50 pounds having formula (I) by reacting the former and com noxyacetyl, pivaloyl, benzoyl, methyl, tert-butyl, 2.2.2- pounds having formula Z-COCl and the first base.

SCHEME 2

O O O Fl O O O Fl O O O Fl

Zl ls N1\/ N NH 2 Zl ls N1\/ S-N Zl l N1\/ S-NH

fi 2I - 2 y . . . . . 2. ) El A NH El Al N El YA1 N (4) (I) (I)

65 trichloroethyl, 2-trimethylsilylethyl, 1,1-dimethyl-2- Compounds having formula (4) may be converted to com propenyl, 3-methyl-3-butenyl, allyl, benzyl (phenylmethyl), pounds having formula (I), wherein B and Y together are US 7,973,161 B2 105 106 imidazole, by reacting the former, Sodium nitrite, hydrochlo EXAMPLE 1B ric acid, and . Compounds having formula (I), wherein B and Y' together are imidazole, may be reacted EXAMPLE 1A (200 mg) in dioxane at 40°C. (4 mL) was with a second base and the appropriate electrophile to provide treated with 2-(bromomethyl)-1,1'-biphenyl (232 mg) and compounds having formula (I), wherein B and Y' together DIEA (165 mg) and concentrated. The concentrate was flash are substituted imidazole. Examples of second bases include chromatographed on silica gel with 20% ethyl acetate/hex Sodium hydride, potassium hydride, lithium diisopropyla aS. mide and sodium bis(trimethylsilyl)amide. EXAMPLE 1C 10 EXAMPLE 1 B (340 mg) in 3:1:1 THF/methanol/water (4 SCHEME3 mL) at 25°C. was treated with LiOH.water (143 mg), stirred for 16 hours, and treated with 4M HCl (850 uL) and dichlo Q O O Fl romethane. The extract was dried (NaSO), filtered, and l \/ NO concentrated. The concentrate was flash chromatographed on Zl iN1 | N 2 He 15 silica gel with 20% methanol/dichloromethane. 2 El Al NH2 EXAMPLE 1D (3) EXAMPLE 1 C (112 mg) in dichloromethane (2.5 mL) at O O O Fl 25°C. was treated with 4-(((1R)-3-(dimethylamino)-1-((phe \/ NH nylsulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfona Zl N1 N 2 mide, prepared as described in commonly-owned Interna i || -- tional Application No. PCT/US01/29432, published as WO 2 02/24636, (115 mg), EDAC.HCl (109 mg), and DMAP (49 El Al NH2 25 mg), stirred for 16 hours, and concentrated. The concentrate (4) was flash chromatographed on silica gel with 20% methanol/ Q O O Fl dichloromethane. "H NMR (300 MHz, DMSO-d) & 8.45 (d. 1H), 8.28 (d. 1H), 7.78 (dd. 1H), 7.72 (d. 2H), 7.54 (dd. 1H), Y\/ N 7.45-7.41 (m, 4H), 7.40-7.28 (m, 6H), 7.25 (td, 2H), 7.17 (tt, Zl N N V 30 1H), 6.88 (d. 1H), 6.78 (d. 2H), 4.10-4.01 (m. 1H), 3.41 (s, N 2H), 3.33 (d. 2H), 3.14 (m, 4H), 2.82-2.62 (m, 2H), 2.44-2.35 El % N (m. 10 H), 2.09-1.91 (m, 2H). (I) EXAMPLE 1E 35 EXAMPLE 1 C (112 mg) in dichloromethane (2.5 mL) at 25°C. was treated with EXAMPLE 1D (115 mg), EDAC.HCl 9 O O Fl (109 mg), and DMAP (49 mg), stirred for 16 hours, and concentrated. The concentrate was flash chromatographed on 40 Zl l N1\/ N NH silica gel with 20% methanol/dichloromethane. "H NMR H N (300 MHz, DMSO-d) & 8.45 (d. 1H), 8.28 (d. 1H), 7.78 (dd. 2N 4 1H), 7.72 (d. 2H), 7.54 (dd. 1H), 7.45-741 (m, 4H), 7.40-728 El Al N (m, 6H), 7.25 (td, 2H), 7.17 (tt, 1H), 6.88 (d. 1H), 6.78 (d. 2H), 4.10-4.01 (m, 1H), 3.41 (s. 2H), 3.33 (d. 2H), 3.14 (m, 4H), (I) 45 2.82-2.62 (m, 2H), 2.44-2.35 (m, 10H), 2.09-1.91 (m, 2H). Compounds having formula (3), may be converted to com EXAMPLE 2A pounds having formula (4) by reacting the former, hydrogen A mixture of EXAMPLE 1A (23.43 g), 2-bromobenzyl and a hydrogenation catalyst. Examples of hydrogenation 50 catalysts include Pd on carbon, platinum on carbon, and bromide (26.24g), and DIEA (20.94 mL) in acetonitrile (200 Raney nickel. mL) at 25°C. was stirred for 2 hours and filtered. Compounds having formula (4) may be converted to com EXAMPLE 2B pounds having formula (I), wherein B and Y' together are triazole, by reacting the former, sodium nitrite, hydrochloric 55 A mixture of EXAMPLE 2A (13.83 g), 4-chlorophenyl acid, and acetic acid. Compounds having formula (I), wherein boronic acid (7.04 g), bis(triphenylphosphine)palladium B' and Y together are triazole, may be reacted with the dichloride (481 mg) and 2M sodium carbonate (22.5 mL) in second base and the appropriate electrophile to provide com 7:3:2 DME/water/ethanol (200 mL) at 90° C. was stirred for pounds having formula (I), wherein B and Y' together are 4.5 hours and extracted with ethyl acetate. The extract was substituted triazole. 60 dried (MgSO), filtered, and concentrated. The concentrate was flash chromatographed on silica gel with 5%-40% ethyl EXAMPLE 1A acetate/hexanes. A mixture of piperazine (129.2 g), ethyl-4-fluorobenzoate EXAMPLE 2C (84g), and KCO (103.65 g) in DMSO (200 mL) at 120° C. 65 was stirred for 6 hours, poured into water, stirred for 30 A mixture of EXAMPLE 2B (13 g) and lithium hydroxide minutes, and filtered. hydrate (3.78 g) in dioxane (250 mL) and water (100 mL) at US 7,973,161 B2 107 108 95° C. was stirred for 16 hours and concentrated. The con EXAMPLE 5A centrate in water was heated at 80°C. and filtered. The filtrate This example was prepared by Substituting 4-(methylsul was treated with 1M HCl (90 mL) and filtered. fanyl)phenylboronic acid for 4-chlorophenylboronic acid in EXAMPLE 2D EXAMPLE 2B. A mixture of EXAMPLE 2C (3.683 g), 4-(((1R)-3-(dim EXAMPLE SB ethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3- This example was prepared by substituting EXAMPLE5A nitrobenzenesulfonamide (3.53 g), EDAC.HCl (3.32 g) and for EXAMPLE 2B in EXAMPLE 2C. DMAP (2.12 g) in dichloromethane (500 mL) at 25°C. was 10 stirred for 8 hours, washed with saturated NHCl (330 mL), EXAMPLE SC and dried (MgSO), filtered, and concentrated. The concen trate was flash chromatographed on silica gel with 1%, 2%, This example was prepared by substituting EXAMPLE 5B 5%, 10%, and 15% methanol/NH-saturated dichlo for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 15 DMSO-d) & 12.10 (s, 1H), 9.9 (brs, 1H), 9.54 (s, 1H), 8.53 romethane. HNMR (DMSO-d) & 12.10(brs, 1H), 11.18 (br (d. 1H), 8.27 (d. 1H), 7.85 (dd. 1H), 7.76 (d. 2H), 7.72 (m, s, 1H), 10.40 (brs, 1H), 8.54 (s, 1H), 8.29 (d. 1H), 8.10 (brs, 1H), 7.51 (dd, 2H), 7.33 (d. 2H), 7.31 (m, 1H), 7.29 (d. 2H), 1H), 7.85 (d. 1H), 7.77 (d. 2H), 7.52 (d, 4H), 7.40-7.36 (m, 7.21 (d. 2H), 7.16 (d. 1H), 7.10 (m,3H), 6.92 (d. 2H), 4.32 (br 2H), 7.35-7.32 (m. 1H), 7.26-7.21 (m, 2H), 7.16-7.09 (m, s, 2H), 4.17 (m. 1H), 3.85 (brs, 4H), 3.38 (d. 2H), 3.11 (m, 3H), 6.93 (d. 2H), 4.34 (brs, 2H), 4.35-4.23 (m. 1H), 3.88 (br 5H), 2.90 (brs, 1H), 2.73 (s, 6H), 2.49 (s.3H), 2.14 (m, 2H). s, 2H), 3.42-3.36 (m, 4H), 3.17-3.07 (m, 2H), 2.90-2.78 (m, 2H), 2.50 (s, 6H), 2.20-2.15 (m, 2H). EXAMPLE 6A EXAMPLE 3A This example was prepared by substituting 1,1'-biphenyl 25 4-ylboronic acid for 4-chlorophenylboronic acid in This example was prepared by Substituting 4-methoxyphe EXAMPLE 2B. nylboronic acid for 4-chlorophenylboronic acid in EXAMPLE 6B EXAMPLE 2B. This example was prepared by substituting EXAMPLE 6A EXAMPLE 3B 30 for EXAMPLE 2B in EXAMPLE 2C. This example was prepared by substituting EXAMPLE3A EXAMPLE 6C for EXAMPLE 2B in EXAMPLE 2.0. This example was prepared by substituting EXAMPLE 6B EXAMPLE 3C 35 for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.10 (brs, 1H), 9.9 (brs, 1H),9.56 (s, 1H), 8.54 This example was prepared by substituting EXAMPLE3B (d. 1H), 8.28 (d. 1H), 7.86 (dd. 1H), 7.75 (m, 7H), 7.56 (m, for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 2H), 7.48 (m, 4H), 7.39 (m, 2H), 7.22 (dd, 2H), 7.17 (d. 1H), DMSO-d) & 12.10 (brs, 1H),9.9 (brs, 1H),9.57 (s, 1H), 8.54 7.11 (m,3H), 6.93 (d. 2H), 4.42 (brs, 2H), 4.18 (m, 1H), 3.83 40 (brs, 2H), 3.39 (d. 2H), 3.25 (brs, 2H), 3.13 (m, 4H), 2.91 (m, (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.72 (m, 2H), 2.74 (s, 6H), 2.14 (m, 2H). 1H), 7.50 (m, 2H), 7.33 (m, 1H), 7.29 (d. 2H), 7.23 (dd, 2H), 7.18 (d. 1H), 7.11 (m, 2H), 7.03 (d. 2H), 6.93 (d. 3H), 4.36 (br EXAMPLE 7A s, 2H), 4.18 (m, 1H), 3.80 (brs, 2H), 3.79 (s.3H), 3.39 (d. 2H), 3.07 (m, 6H), 2.75 (s, 3H), 2.74 (s.3H), 2.14 (q, 2H). This example was prepared by Substituting 4-phenoxyphe 45 nylboronic acid for 4-chlorophenylboronic acid in EXAMPLE 4A EXAMPLE 2B. This example was prepared by Substituting 4-fluorophe EXAMPLE 7B nylboronic acid for 4-chlorophenylboronic acid in 50 EXAMPLE 2B. This example was prepared by substituting EXAMPLE 7A for EXAMPLE 2B in EXAMPLE 2C. EXAMPLE 4B EXAMPLE 7C

This example was prepared by substituting EXAMPLE 4A 55 This example was prepared by substituting EXAMPLE 7B for EXAMPLE 2B in EXAMPLE 2.0. for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.09 (brs, 1H), 10.10 (brs, 1H), 9.64 (s, 1H), EXAMPLE 4C 8.55 (d. 1H), 8.29 (d. 1H), 7.87 (dd. 1H), 7.78 (d. 2H), 7.73 (m. 1H), 7.51 (m, 2H), 7.38 (m, 5H), 7.23 (m, 2H), 7.14 (m, This example was prepared by substituting EXAMPLE 4B 60 5H), 7.07 (d, 4H), 6.95 (d. 2H), 4.33 (brs, 2H), 4.20 (m, 1H), for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 3.86 (brs, 2H), 3.39 (d. 2H), 3.25 (brs, 2H), 3.12 (m, 4H), DMSO-d) & 12.10 (brs, 1H), 10.00 (brs, 1H), 9.65 (s, 1H), 2.92 (m, 2H), 2.74 (s, 6H), 2.15 (m, 2H). 8.54 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.74 (m. 1H), 7.52 (m, 2H), 7.41 (m, 2H), 7.34 (m. 1H), 7.29 (t, EXAMPLE 8 2H), 7.23 (dd, 2H), 7.18 (d. 1H), 7.12 (m, 3H), 6.93 (d. 2H), 65 4.29 (brs, 4H), 4.19 (m. 1H), 3.84 (brs, 2H), 3.39 (d. 2H), This example was prepared by Substituting 4-(1,1-dim 3.13 (m, 4H), 2.92 (m, 2H), 2.74 (s, 6H), 2.15 (m, 2H). ethyl-2-(phenylsulfanyl)ethyl)amino)-3-nitrobenzene

US 7,973,161 B2 111 112 EXAMPLE 17C methanol (20 mL) was treated with HC1-saturated methanol (75 mL), stirred at reflux for 24 hours, concentrated, poured This example was prepared by substituting EXAMPLE into 1M NaOH, and extracted with ethyl acetate. The extract 17B for EXAMPLE 2B in EXAMPLE 2C. was washed with brine and dried (NaSO), filtered, and concentrated. The concentrate was flash chromatographed on EXAMPLE 17D silica gel with 0-5% TEA/ethyl acetate. This example was prepared by substituting EXAMPLE EXAMPLE 1.8G 17C for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.09 (brs, 1H), 9.61 (brs, 1H), 8.55 (d. 10 This example was prepared by substituting EXAMPLE 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.60 (bd, 1H), 18F for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me 7.52 (d. 2H), 7.37 (m, 4H), 7.23 (m, 2H), 7.18 (d. 1H), 7.12 thyl)propyl)amino)-3-nitrobenzenesulfonamide in (m,3H), 6.94 (d. 2H), 4.18 (m, 3H), 3.80 (brs, 4H), 3.39 (d. EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 7.94 (d. 2H), 3.14 (m, 3H), 2.89 (s.3H), 2.75 (s, 6H), 2.15 (m, 2H). 1H), 7.80 (dd. 1H), 7.73 (d. 2H), 7.53 (dd. 1H), 7.47 (AB q, 15 4H), 741-7.33 (m, 5H), 7.36 (dd, 2H), 7.32 (d. 2H), 7.27 (m, EXAMPLE 18A 4H), 7.19 (dd. 1H), 6.89 (d. 2H), 6.87 (d. 1H), 5.94 (d. 1H), 3.94 (m. 1H), 3.42 (m, 2H), 3.26 (m, 4H), 3.10 (m. 1H), 2.96 3-(R)-((carbobenzyloxy)amino)-y-butyrolactone, pre (m. 1H), 2.67 (s, 6H), 2.41 (m, 4H), 2.13 (m. 2H). pared as described in J. Am. Chem. Soc. 1986, 108, 4943 4952, (7.72 g) in THF (100 mL) at 25°C. was saturated with EXAMPLE 19A dimethylamine, stirred for 16 hours, and concentrated. The concentrate was filtered through a silica gel plug with 50% 3-(R)-((carbobenzyloxy)-y-amino)-y-butyrolactone, pre acetone/hexanes. pared as described in J. Am. Chem. Soc. 1986, 108, 4943 4952, (62 g) in dioxane (700 mL) was treated with morpho EXAMPLE 1.8B 25 line (46 mL), heated to 65° C. for 24 hours, cooled and concentrated. The concentrate was flash chromatographed on EXAMPLE 18A (8.45g) in toluene (15 mL) at 25°C. was silica gel with 10% methanol in ethyl acetate. treated with tributylphosphine (9.76 mL) and diphenyldisul fide (7.3 g), heated to 80° C. for 16 hours and concentrated. EXAMPLE 19B The concentrate was flash chromatographed on silica gel with 30 0-50% ethyl acetate/hexanes. This example was prepared by substituting EXAMPLE 19A for EXAMPLE 18A in EXAMPLE 18B. EXAMPLE 18C EXAMPLE 19C EXAMPLE 18B (10.60g) in 30%HBrfacetic acid (50 mL) 35 at 25°C. was stirred for 18 hours, concentrated, treated with This example was prepared by substituting EXAMPLE water (200 mL) and 5% HCl (100 mL), washed with diethyl 19B for EXAMPLE 18B in EXAMPLE 18C. ether, adjusted to pH 8-9 with NaCO, and extracted with dichloromethane. The extract was dried (MgSO), filtered, EXAMPLE 19D and concentrated. 40 EXAMPLE 19C (45.4 g) in THF (500 mL) at 55° C. was EXAMPLE 1.8D treated with 1Mborane.THF in THF (650 mL), stirred for 24 hours, cooled to 0°C., treated with methanol, poured into 1-fluoro-2-(trifluoromethyl)benzene (15 g) in chlorosul methanol, and concentrated. The concentrate in methanol fonic acid (50 mL) and 1,2-dichloroethane (50 mL) at 70° C. 45 (400 mL) was treated with saturated HCl in methanol (800 was stirred to for 2 hours, and concentrated. The concentrate mL), refluxed for 24 hours, concentrated, poured into 2M in THF (200 mL) at to 0°C. was treated with concentrated NaOH, and extracted with ethyl acetate. The extract was ammonium hydroxide (20 mL), stirred for 10 minutes, and washed with 1M NaOH and brine and dried (NaSO), fil poured into ethyl diethyl ether (500 mL). The extract was tered, and concentrated. The concentrate was flash chromato washed with brine and dried (NaSO), filtered, and concen 50 graphed on silica gel with ethyl acetate, 10% methanol/ethyl trated. The concentrate was flash chromatographed on silica acetate, and 10% methanol/10% acetonitrile/5% TEA/75% gel with 30% ethyl acetate/hexanes. ethyl acetate. EXAMPLE 18E EXAMPLE 19E 55 A mixture of EXAMPLE 18D (1.7g) and EXAMPLE 18C This example was prepared by substituting EXAMPLE (1.67 g) in DMSO (17 mL) was treated with DIEA (1.22 mL), 19D for EXAMPLE 18C in EXAMPLE 18E. heated at 110°C. for 24 hours, poured into ethyl acetate (400 mL), washed with water and brine, and dried (NaSO), fil EXAMPLE 1.9F tered, and concentrated. The concentrate was flash chromato 60 graphed on silica gel with 50% ethyl acetate/hexanes. This example was prepared by substituting EXAMPLE 19E for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me EXAMPLE 18F thyl)propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 7.92 (d. EXAMPLE 1.8E (2.5 g) in THF (20 mL) at 25° C. was 65 1H), 7.76 (dd. 1H), 7.72 (d. 2H), 7.50 (dd. 1H), 7.47 (s, 4H), treated with 1Mborane.THF (22 mL), stirred for 24 hours, 741-7.33 (m, 5H), 7.30 (d. 2H), 7.24 (dd. 1H), 7.19 (dd. 1H), treated with methanol and concentrated. The concentrate in 6.88 (d. 2H), 6.79 (d. 1H), 5.98 (d. 1H), 3.94 (m. 1H), 3.51 (m, US 7,973,161 B2 113 114 4H), 3.31-3.23 (m, 8H), 2.43 (m, 2H), 2.39 (m, 4H), 2.28 (m, mL) at 25°C. was stirred for 20 minutes, cooled to 0°C., 2H), 1.96 (m. 1H), 1.83 (m, 1H). treated with diisopropylazodicarboxylate (1.1 mL) in THF (6 mL), stirred at 25°C. for 3 days, treated with ethyl acetate, EXAMPLE 20A washed with water and brine, and dried (MgSO), filtered, and concentrated. The concentrate was flash chromato 3-(R)-((carbobenzyloxy)amino)-y-butyrolactone, pre graphed on silica gel with 2%-10% ethyl acetate/hexanes. pared as described in J. Am. Chem. Soc. 1986, 108, 4943 4952, (1.8 g) in THF (20 mL) at 25° C. was treated with EXAMPLE 21C pyrrolidine (3 mL), stirred for 3 days, and concentrated with a toluene azeotrope. EXAMPLE21B (410 mg) in diethyl ether (5 mL) at 25°C. 10 was treated with 4M HCl in 1,4-dioxane (5 mL), stirred for EXAMPLE 20B 2.5 hours, and filtered. This example was prepared by substituting EXAMPLE EXAMPLE 21D 20A for EXAMPLE 18A in EXAMPLE 18B. 15 A mixture of EXAMPLE 21C (300 mg) and 4-fluoro-3- EXAMPLE 20O nitrobenzenesulfonamide (300 mg), and DIEA (690 u) in DMSO (2 mL) at 25°C. was stirred for 18 hours, cooled to This example was prepared by substituting EXAMPLE 15° C., treated with water (25 mL), acidified with 1M HCl, 2OB for EXAMPLE 18B in EXAMPLE 18C. cooled to 0°C., stirred for 1 hour, and filtered. EXAMPLE 2.0D EXAMPLE 21E EXAMPLE 20C (1.8 g) in DMF (30 mL) at 25° C. was This example was prepared by substituting EXAMPLE treated with TEA (950 uL) and 4-fluoro-3-nitrobenzene 21D for 4-(((1R)-3-(dimethylamino)-1-(phenylsulfanyl) sulfonamide, prepared as described in WO 02/24636, (1.5 g), methyl)propyl)amino)-3-nitrobenzenesulfonamide in heated at 60° C. for 150 minutes, poured into water, and 25 EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 8.59 (d. extracted with ethyl acetate. The extract was washed with 1H), 8.49, (s, 1H), 7.90 (dd. 1H), 7.80 (d. 2H), 7.77 (s, 1H), water and brine and dried (NaSO), filtered, concentrated. 7.52 (d,3H), 7.48 (d. 2H), 7.45 (dd, 2H), 7.40 (d. 2H), 7.40 (d. The concentrate was flash chromatographed on silica gel with 1H), 6.93 (d. 2H), 4.24 (s. 2H), 3.86, (s. 2H), 3.35 (m, 6H), 2.85 (s. 2H), 1.58 (s, 6H). 50% ethyl acetate/hexanes. 30 EXAMPLE 2.0E EXAMPLE 22A EXAMPLE 2.0D (2.35 g) in THF (30 mL) at 25° C. was A mixture of 2-mercaptothiazole (4.6 g) and tetra-n-buty treated with 1Mborane.THF in THF (20 mL), stirred for 24 lammonium persulfate, prepared as described in Tetrahedron hours, cooled to 0°C., treated with methanol, poured into 6M 35 Lett. 1993, 34,3581–3584, (14.7g) in water (460 mL) at 25° HCl, stirred for 24 hours, cooled to 0°C., brought to pH 12 C. was stirred for 18 hours and extracted with diethyl ether. with KOH, and extracted with ethyl acetate. The extract was The extract was washed with brine and dried (MgSO), fil washed with brine and dried (NaSO), filtered, and concen tered, and concentrated. trated. The concentrate was flash chromatographed on silica gel with ethyl acetate, 10% methanol/ethyl acetate, and 10% 40 EXAMPLE 22B methanol/5% TEA/85% ethyl acetate. A mixture of EXAMPLE 18A (720 mg) and EXAMPLE 22A (770 mg) in toluene (9.1 mL) at 85°C. was treated with EXAMPLE 20F tributylphosphine (830 uD), heated to 85°C., stirred for 5.5 hours, treated with ethyl acetate, washed with water and This example was prepared by substituting EXAMPLE 45 brine, and dried (MgSO), filtered, and concentrated. The 20E for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me concentrate was flash chromatographed on silica gel with thyl)propyl)amino)-3-nitrobenzenesulfonamide in 30%-66% ethyl acetate/hexanes. EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.06 (br s, 1H), 9.73 (brs, 2H), 8.54 (d. 1H), 8.29 (d. 1H), 7.87 (dd. EXAMPLE 22C 1H), 7.77 (d. 2H), 7.74 (m. 1H), 7.52 (m, 4H), 7.39 (d. 2H), 50 7.34 (m. 1H), 7.23 (m, 2H), 7.18 (d. 1H), 7.12 (m, 3H), 6.92 This example was prepared by substituting EXAMPLE (d. 2H), 4.22 (m, 3H), 3.86 (s, 4H), 3.51 (m, 2H), 3.38 (m, 22B for EXAMPLE 18B in EXAMPLE 18C. 2H), 3.21 (m, 4H), 2.94 (m, 4H), 2.15 (m, 2H), 2.00 (m, 2H), 1.84 (m. 2H). EXAMPLE 22D 55 EXAMPLE 21 This example was prepared by substituting EXAMPLE 22C for EXAMPLE 19C in EXAMPLE 19D. 2-Amino-2-methyl-1-propanol (5 g) in dichloromethane (200 mL) at 0°C. was treated with di-tert-butyldicarbonate EXAMPLE 22E (3.5 g) stirred for 8 hours at 25°C., washed with water, 5% 60 aqueous citric acid, saturated NaHCO, and brine, and dried This example was prepared by substituting EXAMPLE (MgSO), filtered, and concentrated. 22D for EXAMPLE 21C in EXAMPLE 21D. EXAMPLE 21B EXAMPLE 2.2F 65 A mixture of EXAMPLE 21 A (980 mg), 2-mercaptothia This example was prepared by substituting EXAMPLE Zole (610 mg), and triphenylphosphine (1.5 g) in THF (12 22E for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me US 7,973,161 B2 115 116 thyl)propyl)amino)-3-nitrobenzenesulfonamide in water, and extracted with ethyl acetate. The extract was EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 8.50 (d. washed with brine and dried (NaSO), filtered, and concen 1H), 8.22 (d. 1H), 7.90 (dd. 1H), 7.72 (dd, 2H), 7.61 (d. 1H), trated. The concentrate was flash chromatographed on silica 7.51 (m, 2H), 7.47 (s.3H), 7.37 (m, 2H), 7.23, (m, 2H), 6.79 gel with 50% ethyl acetate/hexanes. (d. 2H), 4.28 (m. 1H), 3.60 (m, 2H), 3.39 (s. 2H), 3.14 (m, 4H), 3.00 (m, 2H), 2.62 (s, 6H), 2.40 (m, 4H), 2.10 (m, 2H). EXAMPLE 24D EXAMPLE 23A EXAMPLE 24C (1.65 g) in THF (10 mL) at 25° C. was treated with 1Mborane.THF (20 mL), stirred for 24 hours, This example was prepared by Substituting 2-thienyldisul 10 treated with 5M HCl (300 mL) and THF (300 mL), stirred for fide and THF for EXAMPLE 22A and toluene, respectively, 2 days, cooled to 0°C., adjusted to pH 12 with KOH and in EXAMPLE 22B. extracted with ethyl acetate. The extract was washed with brine and dried (NaSO), filtered, and concentrated. The EXAMPLE 23B concentrate in DMF (30 mL) was treated with 4-fluoro-3- 15 nitrobenzenesulfonamide (1 g) and TEA (627 uL), heated at This example was prepared by substituting EXAMPLE 55° C. for 90 minutes, poured into water, and extracted with 23A for EXAMPLE 18B in EXAMPLE 18C. ethyl acetate. The extract was washed with water and brine and dried (NaSO), filtered, and concentrated. The concen EXAMPLE 23C trate was flash chromatographed on silica gel with ethyl acetate, 10% methanol/ethyl acetate, and 10% methanol/10% This example was prepared by substituting EXAMPLE acetonitrile/80% ethyl acetate. 23B for EXAMPLE 19C in EXAMPLE 19D. EXAMPLE 24E EXAMPLE 23D 25 This example was prepared by substituting EXAMPLE This example was prepared by substituting EXAMPLE 24D for 4-(((1R)-3-(dimethylamino)-1-(phenylsulfanyl) 23C for EXAMPLE 21C in EXAMPLE 21D. methyl)propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 12.12 (s, EXAMPLE 23E 1H), 10.90 (m. 1H), 9.90 (m, 1H), 8.56 (d. 1H), 8.52 (d. 1H), 30 8.04 (m. 1H), 7.86 (dd. 1H), 7.76 (d. 2H), 7.53 (m, 4H), This example was prepared by substituting EXAMPLE 7.13-7.39 (m, 9H), 6.93 (d. 2H), 4.35 (m. 1H), 3.87-3.79 (m, 23D for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) 2H), 3.74 (m, 4H), 3.47 (m, 8H), 3.23 (m, 4H), 2.75 (m, 6H). methyl)propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 8.50 (d. EXAMPLE 25A 1H), 8.22 (d. 1H), 7.90 (dd. 1H), 7.82, (dd. 1H), 7.72 (d. 2H), 35 7.62 (dd. 1H), 7.51 (m, 1H), 7.47 (s.3H), 7.37 (m, 2H), 7.25 Diethylamine (4.15 mL) in THF (150 mL) at -78°C. was (dd. 1H), 7.14 (dd. 1H), 7.02 (dd. 1H), 6.80 (m,3H), 3.99 (m, treated with 2.5M n-butyllithium in hexanes (15.4 mL), 1H), 3.31 (m, 2H), 3.18 (m, 6H), 2.95 (m, 3H), 2.59 (s, 6H), stirred for 5 minutes at 0°C., cooled to -78°C., treated with 2.40 (t, 3H), 2.11 (m, 1H), 2.02 (m. 1H). (2R,4S)-3-((benzyloxy)carbonyl)-4-methyl-2-phenyl-1,3- 40 oxazolidin-5-one, prepared as described in Helv. Chim. Acta EXAMPLE 24A 1991, 74,800, (10 g) in THF (40 mL), stirred for 20 minutes, treated with allyl bromide (4.29 mL), stirred for 1 hour, stirred N-tert-butoxycarbonyl-L-serine methyl ester (30 g) in at 25°C. for 18 hours, poured into pH 7 buffer, and extracted dichloromethane (300 mL) at 0°C. was treated with DIEA with diethyl ether. The extract was washed with brine and (59.7 mL) and methanesulfonylchloride (11.65 mL), stirred 45 dried (NaSO), filtered, and concentrated. The concentrate for 20 minutes, treated with thiophenol (15.5 mL), stirred at was flash chromatographed on silica gel with 20% ethyl 25° C. for 24 hours, and concentrated. The concentrate was acetate/hexanes. flash chromatographed on silica gel with 10-30% ethyl acetate/hexanes. EXAMPLE 25B 50 EXAMPLE 24B EXAMPLE 25A (8.18 g) in methanol (200 mL) and water (20 mL) at 25° C. was treated with LiOH.water (1.95 g), EXAMPLE 24A (8.35 g) in dichloromethane (75 mL) was stirred for 30 minutes, poured into saturated NaH2PO (200 treated with 1MDIBAL in dichloromethane (94 mL) stirred mL), and extracted with ethyl acetate. The extract was washed for 2 hours, treated with methanol, poured into saturated 55 with 1M NaOH and brine and dried (NaSO), filtered, and NaH2PO (300 mL), stirred for 30 minutes, and extracted concentrated. The base wash was acidified with 12M HCl and with ethyl acetate. The extract was washed with brine and extracted with ethyl acetate. The extract was concentrated, dried (NaSO), filtered, and concentrated. The concentrate and the concentrate in 1:1 ethyl acetate/methanol (50 mL) at was flash chromatographed on silica gel with 50% ethyl 25°C. was treated with 2M (trimethylsilyl)diazomethane in acetate/hexanes. 60 THF (5 mL), stirred for 10 minutes, and concentrated. The concentrates were combined and flash chromatographed on EXAMPLE 24C silica gel with 10% ethyl acetate/hexanes. 60% Oily NaH (480 mg) in dioxane (30 mL) at 25°C. was EXAMPLE 25C treated with EXAMPLE 24B (1.7 g) in dioxane (10 mL), 65 stirred for 10 minutes, treated with N,N-dimethylchloroac EXAMPLE 25B (5.03 g) in THF (75 mL) at 25° C. was etamide (1.23 mL), heated at 70° C. for 24 hours, poured into treated with 1M LiBH(CHCH) in THF (38 mL), stirred for US 7,973,161 B2 117 118 2 hours, treated with methanol (30 mL), poured into water, EXAMPLE 2.6B and extracted with ethyl acetate. The extract was washed with brine and dried (NaSO), filtered, and concentrated. The This example was prepared by substituting EXAMPLE concentrate was flash chromatographed on silica gel with 26A for EXAMPLE 18A in EXAMPLE 18B. 30% ethyl acetate/hexanes. 5 EXAMPLE 26C EXAMPLE 2.5D This example was prepared by substituting EXAMPLE This example was prepared by substituting EXAMPLE 26B for EXAMPLE 18B in EXAMPLE 18C. 25C for EXAMPLE 18A in EXAMPLE 18B. 10 EXAMPLE 26D EXAMPLE 25E This example was prepared by substituting EXAMPLE EXAMPLE 25D (2.9 g) in diethyl ether (45 mL) and tert 26C for EXAMPLE 21C in EXAMPLE 21 D. butanol (45 mL) at 25°C. was treated with AD-mix-B (12.74 15 g), stirred for 18 hours, poured into saturated NaCOs, and EXAMPLE 26E extracted with ethyl acetate. The extract was washed with brine and dried (NaSO), filtered, and concentrated. The This example was prepared by substituting EXAMPLE concentrate was flash chromatographed on silica gel with 26D for EXAMPLE 18Ein EXAMPLE 1.8F. 20-50% ethyl acetate/hexanes. The product in THF (30 mL) and water (30 mL) at 25°C. was treated with NaIO (2.75 g), EXAMPLE 26F stirred for 20 minutes, poured into water, and extracted with ethyl acetate. The extract was washed with brine and dried EXAMPLE 26E (1.12 g) in THF (7 mL) and acetonitrile (7 (NaSO), filtered, and concentrated. 25 mL) at 25°C. was treated with di-tert-butyldicarbonate (572 mg) and TEA (276 mg), stirred for 16 hours, and concen EXAMPLE 25F trated. The concentrate was flash chromatographed on silica gel with 50% ethyl acetate/hexanes. EXAMPLE 25E (1.92 g) in dichloromethane (30 mL) at EXAMPLE 26G 25°C. was treated with dimethylamine hydrochloride (684 30 mg), sodium triacetoxyborohydride (1.9 g), and TEA (1.56 mL), stirred for 24 hours, treated with methanol and water, This example was prepared by substituting EXAMPLE and concentrated. The concentrate was flash chromato 26F for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me graphed on silica gel with 50% ethyl acetate/hexanes. thyl)propyl)amino)-3-nitrobenzenesulfonamide in 35 EXAMPLE 2D. EXAMPLE 2.5G EXAMPLE 26H This example was prepared by substituting EXAMPLE 25F for EXAMPLE 18B in EXAMPLE 18C. EXAMPLE 26G was flash chromatographed on silica gel 40 with dichloromethane, 1:1 dichloromethane/ethyl acetate, EXAMPLE 25H and 10% (7MNH in methanol) in methanol. A mixture of the free base in dichloromethane at 25°C. was treated with 1:1 A mixture of EXAMPLE 25G (600 mg) and 4-fluoro-3- 2M HCl/diethyl ether (10 mL), stirred for 18 hours and con nitrobenzene-sulfonamide (554 mg) in DMSO (7 mL) at 25° centrated. "H NMR (500 MHz, DMSO-d) & 12.11 (s, 1H), C. was treated with TEA (351 uL), heated at 60° C. for 90 45 10.94 (m, 1H), 8.71 (m, 1H), 8.53 (d. 1H), 8.28 (d. 1H), 8.05 minutes, poured into water (30 mL), and extracted with ethyl (m. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.53 (m, 4H), 7.37 (m, acetate. The extract was washed with water and brine and 4H), 7.23 (m, 2H), 7.11 (m, 3H), 6.93 (d. 2H), 4.34 (m. 1H), dried (NaSO), filtered, and concentrated. The concentrate 4.28 (m. 1H), 4.12 (m, 1H), 3.92-3.87(m, 2H), 3.39 (m, 8H), was flash chromatographed on silica gel with 0-10% metha 3.27 (m, 3H), 2.94 (m, 3H), 2.11 (m, 2H). nol/ethyl acetate. 50 EXAMPLE 27A EXAMPLE 25 This example was prepared by substituting EXAMPLE A mixture of Fmoc-D-Asp(O-tert-butyl)-OH (10.25 g) and 25H for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) 55 NMM (2.8 mL) in DME (30 mL) at -15°C. was treated with methyl)propyl)amino)-3-nitrobenzenesulfonamide in isobutyl chloroformate (4.1 mL), stirred for 10 minutes, and EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 12.14 (s, filtered. The filtrate was cooled to 0°C., treated with NaBH 1H), 10.90 (m. 1H), 10.22 (m. 1H), 8.50 (d. 1H), 8.32 (s, 1H), (2.84 g) in water (15 mL), stirred for 5 minutes, treated with 8.04 (m. 1H), 7.83 (m, 3H), 7.54 (m, 4H), 7.36 (m, 4H), 7.23 water, stirred at 25°C. for 3 hours, and filtered. (d. 2H), 6.98-6.85 (m, 5H), 4.35 (m, 2H), 3.92-3.87(m, 2H), 60 3.74 (m, 2H), 3.48 (m, 8H), 3.23 (m, 2H), 2.70 (m, 6H), 1.56 EXAMPLE 27B (s, 3H). A mixture of EXAMPLE 27A (9.5 g), diphenyl disulfide EXAMPLE 26A (7.86 g) and tributylphosphine (7.28 g) in toluene (200 mL) at 65 80°C. was stirred for 5 hours and concentrated. The concen This example was prepared by Substituting methylamine trate was flash chromatographed on silica gel with 5% to 20% for dimethylamine in EXAMPLE 18A. ethyl acetate/hexanes. US 7,973,161 B2 119 120 EXAMPLE 27C EXAMPLE 29D This example was prepared by substituting EXAMPLE This example was prepared by substituting EXAMPLE 27B for EXAMPLE 21C in EXAMPLE 21D. 29C for EXAMPLE 21C in EXAMPLE 21D.

EXAMPLE 27D EXAMPLE 29E This example was prepared by substituting EXAMPLE This example was prepared by substituting EXAMPLE 27C for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me 29D for 4-(((1R)-3-(dimethylamino)-1-(phenylsulfanyl) thyl)propyl)amino)-3-nitrobenzenesulfonamide in 10 methyl)propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 11.88 (s, 1H), 11.33 (s, 1H), 10.13 (s, 1H), 9.57 (s, 1H), 8.30 (d. 1H), EXAMPLE 27E 8.08 (d. 1H), 7.94 (m, 1H), 7.63 (dd. 1H), 7.55 (d. 2H), 7.30 (m, 4H), 7.15 (m, 2H), 7.09 (m. 1H), 6.99 (m, 3H), 6.89 (m, EXAMPLE 27D (1g) in dichloromethane (5 mL) at 25°C. 15 3H), 6.71 (d. 2H), 4.11 (m. 1H), 3.61 (m, 8H), 3.19 (m. 1H), was treated with TFA (5 mL), stirred for 3 hours, and con 3.17 (m, 2H), 2.94 (m, 1H), 2.77 (m, 4H), 2.62 (m. 1H), 2.05 centrated. "H NMR (500 MHz, DMSO-d) & 8.57 (d. 1H), (m. 1H), 1.53 (m, 2H), 1.09-0.75 (m, 12H). 8.52 (d. 1H), 7.84 (dd. 1H), 7.75 (d. 2H), 7.55-7.35 (m, 7H), 7.27-7.11 (m, 6H), 6.91 (d. 2H), 4.39 (m, 1H), 3.39 (2, 2H), EXAMPLE 3OA 3.31 (s, 8H), 3.26 (m, 2H), 2.81 (d. 2H). EXAMPLE 27C (2.2g) in dichloromethane (25 mL) at 0° EXAMPLE 28 C. was treated with TFA (25 mL) and water (2.5 mL), stirred at 25°C. for 2 hours, and concentrated with a toluene azeo trope. A mixture of EXAMPLE 27E (160 mg) and N-methyl 25 morpholine (27 uL) in DMF (1 mL) at 25°C. was treated with HATU (92 mg) and isopropylamine (50 uL), stirred for 5 EXAMPLE 3OB hours, treated with ethyl acetate (200 mL), washed with 1% EXAMPLE 30A (1 g) in DME (25 mL) at 25° C. was HCl, saturated NaHCO, water, and brine, and dried treated with NMM (280 uL), cooled to -10°C., treated with (NaSO), filtered, and concentrated. The concentrate was 30 isobutyl chloroformate (330 uL), stirred for 15 minutes, flash chromatographed on silica gel with dichloromethane, treated with sodium borohydride (277 mg) in water (10 mL), (1:1) dichloromethane/ethyl acetate, and 5% methanol/ stirred for 45 minutes, and concentrated. The concentrate was dichloromethane. "H NMR (500 MHz, DMSO-d) & 8.73 (d. treated with 0.5M HCl and extracted with ethyl acetate. The 1H), 8.52 (d. 1H), 7.93 (d. 1H), 7.83 (dd. 1H), 7.76 (d. 2H), extract was washed with brine and dried (NaSO), filtered, 7.52 (m, 2H), 7.38 (m,3H), 7.23 (m, 2H), 7.18-7.10 (m, 6H), 35 and concentrated. The concentrate was flash chromato 6.92 (d. 2H), 4.39 (m, 1H), 3.75 (m, 1H), 3.40 (m. 10H), 3.34 graphed on silica gel with 2% methanol/dichloromethane and (m. 2H), 2.54 (m, 2H), 0.98 (d. 3H), 0.91 (d. 3H). 4% methanol/dichloromethane. EXAMPLE 29A EXAMPLE 3OC 40 EXAMPLE 27B (500 mg) in dichloromethane (3 mL) at A mixture of EXAMPLE30B (705 mg) and TEA (740 uL) 25°C. was treated with TFA (3 mL), stirred for 3 hours, and in dichloromethane (8 mL) at 0° C. was treated with concentrated with a dichloromethane azeotrope. SOpyridine (850mg) in DMSO (6 mL), stirred at 25° C. for 30 minutes, treated 10% (w/v) aqueous citric acid, and EXAMPLE 29B 45 extracted with ethyl acetate. The extract was washed with brine and dried (NaSO), filtered, and concentrated. A mixture of EXAMPLE 29A (450 mg) and NMM (140 uL) in DMF (3 mL) at 25°C. was treated with HATU (464 EXAMPLE 3OD mg) and diisopropylamine (283 LL), stirred for 5 hours, 50 EXAMPLE30C (100mg) and azetidine hydrochloride (20 treated with ethyl acetate, washed with 1% HCl, saturated mg) in acetonitrile (2 mL) at 25°C. was treated with DIEA NaHCO, water, and brine, and dried (NaSO), filtered, and (44 uL) and sodium triacetoxyborohydride (67 mg), stirred concentrated. The concentrate was flash chromatographed on for 16.5 hours, absorbed onto silica gel, concentrated, and silica gel with dichloromethane, 1:1 dichloromethane/ethyl flash chromatographed on silica gel with 5% methanol/ acetate, 5% methanol/dichloromethane. 55 dichloromethane and 10% methanol/NH-saturated dichlo romethane. EXAMPLE 29C EXAMPLE 3OE EXAMPLE 29B (200 mg) in THF (5 mL) at 25° C. was treated with 2M borane.THF in THF (1 mL), stirred for 4 60 This example was prepared by substituting EXAMPLE hours, treated with methanol (3 mL) and concentrated HCl (1 30D for 4-(((1R)-3-(dimethylamino)-1-(phenylsulfanyl) mL), stirred for 2 hours, brought to pH 7 with saturated methyl)propyl)amino)-3-nitrobenzenesulfonamide in NaHCO, and extracted with dichloromethane. The extract EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 8.45 (d. was washed with water and brine and dried (Na2SO), fil 1H), 8.20 (d. 1H), 7.81 (dd. 1H), 7.71 (d. 2H), 7.35 (m. 14H), tered, and concentrated. The concentrate was flash chromato 65 6.88 (d. 1H), 6.78 (d. 2H), 4.05 (m. 1H), 3.79 (m, 4H), 3.33 graphed on silica gel with dichloromethane and 5% metha (m, 5H), 3.13 (m, 5H), 2.40 (m, 4H), 2.24 (m, 2H), 1.89 (m, nol/dichloromethane. 2H). US 7,973,161 B2 121 122 EXAMPLE 31A C. for 2 hours, treated with HMPA (3 mL) and methyl iodide (3.0 mL), stirred at reflux for 18 hours, cooled to 0°C., treated A mixture of 3,6-dioxa-bicyclo[3.1.0 hexane (3.44 g) and with aqueous NaHSO, and extracted with ethyl acetate. The sodium azide (5.2g) in water (10 mL) at 60°C. was stirred for extract was dried (NaSO), filtered, and concentrated. The 24 hours and extracted with ethyl acetate. The extract was dried (MgSO), filtered, and concentrated. The concentrate concentrate was flash chromatographed on silica gel with was flash chromatographed on silica gel with 0-40% ethyl 10%-15% ethyl acetate/hexanes. acetate/hexanes. EXAMPLE 32C (AND 25% (W/W) EXAMPLE EXAMPLE 31B 32B) 10 A mixture of EXAMPLE 31A (3.23g), di-tert-butyldicar A mixture of EXAMPLE 32B (640 mg), 4-chlorophenyl bonate (8.73 g), and 20 wt % palladium hydroxide on carbon boronic acid (465 mg), Pd(dppf)Cl. (122 mg), and cesium (200 mg) in ethanol (15 mL) at 25° C. was treated with carbonate (1.46 g) in DMF (15 mL) at 80°C. was stirred for triethylsilane (4.651 g), stirred at 50° C. for 16 hours, filtered, 2 days and treated with ethyl acetate and brine. The water and concentrated. The concentrate recrystallized from ethyl 15 layer was extracted with ethyl acetate, and the extract was acetate/hexanes. dried (NaSO), filtered, and concentrated. The concentrate was flash chromatographed on silica gel with 5%-15% ethyl EXAMPLE 3 1C acetate/hexanes. A mixture of EXAMPLE 31B (2.03 g) and diphenyldisul EXAMPLE 32D fide (2.401 g) in toluene (20 mL) at 25°C. was treated with tributylphosphine (2.224g), stirred for 16 hours at 80°C., and This example was obtained by substituting EXAMPLE concentrated. The concentrate was flash chromatographed on 32C for EXAMPLE 2B in EXAMPLE 2C. silica gel with 0%-40% ethyl acetate/hexanes. 25 EXAMPLE 32E EXAMPLE 31D This example was prepared by substituting EXAMPLE EXAMPLE 31C (590 mg) in 1:1 dioxane/dichloromethane 32D for EXAMPLE 2C in EXAMPLE 2D and purified by (8 mL) at 25°C. was treated with 4M HCl in dioxane (5 mL), high pressure liquid chromatography on a Waters Symmetry stirred for 16 hours, and concentrated. The concentrate tritu 30 Cs column (25 mmx100 mm, 7 um particle size) with rated with diethyl ether and filtered. 10-100% acetonitrile/0.1% aqueous TFA over 8 minutes at a flow rate of 40 mL/minute. "H NMR (400 MHz, DMSO-d) & EXAMPLE 31E 9.38 (s, 1H), 8.54 (d. 1H), 8.28 (d. 1H), 7.86 (dd. 1H), 7.69 (d. 2H), 7.46 (d. 2H), 7.28 (m, 7H), 7.15 (m, 4H), 6.82 (d. 2H), This example was prepared by substituting EXAMPLE 35 4.18 (m. 1H), 3.40 (m, 4H), 3.13 (m, 2H), 3.04 (s.3H), 2.86 31D for EXAMPLE 21C in EXAMPLE 21 D. (m, 4H), 2.74 (s, 6H), 2.14 (m. 2H), 1.47 (d. 2H), 1.18 (t, 2H). EXAMPLE 31F EXAMPLE 33 This example was prepared by substituting EXAMPLE 40 This example was prepared by substituting 4-(((1R)-3-(4- 31E for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)me morpholinyl)-1-((phenylsulfanyl)methyl)propyl)amino)-3- thyl)propyl)amino)-3-nitrobenzenesulfonamide in nitrobenzenesulfonamide, prepared as described in WO EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 12.09 (s. 02/24636, and EXAMPLE 32D for 4-(((1R)-3-(dimethy 1H), 9.70 (s, 1H), 8.69 (d. 1H), 8.54 (d. 1H), 7.87 (dd. 1H), lamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-ni 7.78 (d. 2H), 7.74 (brs, 1H), 7.52 (d, 4H), 7.39 (d. 2H), 7.34 45 trobenzene-sulfonamide and EXAMPLE 2C, respectively, in (bd, 1H), 7.27 (m,3H), 7.08 (t, 2H), 6.98 (t, 1H), 6.93 (d. 2H), EXAMPLE 2D and purified by high pressure liquid chroma 4.74 (quintet, 1H), 4.45 (q, 1H), 4.33 (dd. 1H), 4.17 (dd. 1H), tography ona Waters Symmetry Cs column (25mmx100mm, 3.86 (brs, 2H), 3.77 (t, 1H), 3.75 (t, 1H), 3.49 (brs, 4H), 3.12 7 um particle size) with 10-100% acetonitrile/0.1% aqueous (brs, 2H), 2.89 (s. 2H). TFA over 8 minutes at a flow rate of 40 mL/minute. "H NMR 50 (400 MHz, DMSO-d) & 9.71 (s, 1H), 8.54 (d. 1H), 8.29 (d. EXAMPLE 32A 1H), 7.87 (dd. 1H), 7.69 (d. 2H), 7.46 (d. 2H), 7.30 (m, 7H), 7.14 (m, 4H), 6.82 (d. 2H), 4.18 (m, 1H), 3.95 (m, 2H), 3.67 A mixture of magnesium turnings (432 mg) and one iodine (m, 4H), 3.39 (m, 4H), 3.19 (m, 2H), 3.03 (s.3H), 3.00 (m, crystal in diethyl ether (30 mL) at 25°C. was treated with 2H), 2.85 (m, 4H), 2.17 (m, 2H), 1.47 (d. 2H), 1.17 (t, 2H). 2-bromobenzyl bromide (4.5 g), stirred for 3 hours, cooled to 55 0° C., treated with 4-(4-oxo-piperidine-1-yl)benzoic acid EXAMPLE 34 ethyl ester, prepared as described in Synthesis 1981, 606-608, (3.7g) in 1:1 diethyl ether/THF (40 mL), stirred at 25°C. for EXAMPLE 27E (6.7 g) in DME (50 mL) at -15° C. was 18 hours, treated with aqueous NHCl and extracted with treated with NMM (920 uL) and isobutyl chloroformate (1.09 ethyl acetate. The extract was dried (NaSO), filtered, and 60 mL), stirred for 20 minutes, treated with sodium borohydride concentrated. The concentrate was flash chromatographed on (1.59 g) in water (10 mL), stirred for 30 minutes, treated with silica gel with 50% ethyl acetate/hexanes. water, and extracted with ethyl acetate. The extract was washed with water and brine and dried (NaSO), filtered, and EXAMPLE 32B concentrated. The concentrate was flash chromatographed on 65 silica gel with dichloromethane, 1:1 dichloromethane/ethyl EXAMPLE 32A (1.6 g) in THF (20 mL) at 25°C. was acetate, and 10% methanol/dichloromethane. "H NMR (500 treated with 60% oily sodium hydride (288 mg), heated at 50° MHz, DMSO-d) & 8.53 (d. 1H), 8.49 (d. 1H), 7.83 (dd. 1H), US 7,973,161 B2 123 124 7.74 (d. 2H), 7.47 (m, 4H), 7.53-7.36 (m, 3H), 7.25 (m 2H), (m, 4H), 7.47 (m, 2H), 7.35 (d. 1H), 7.24 (m, 3H), 7.18 (d. 7.19-7.07 (m, 4H), 6.91 (d. 2H), 4.69 (m, 1H), 4.21 (m, 1H), 2H), 7.12 (m, 2H), 6.88 (d. 2H), 4.19 (m, 1H), 3.75 (brs, 2H), 3.49 (m, 2H), 3.35 (t, 2H), 3.31 (m, 8H), 3.27 (m, 2H), 1.89 3.39 (d, 4H), 3.29 (m, 4H), 3.14 (m, 2H), 2.98 (m, 2H), 2.75 (m. 2H). (s, 6H), 2.15 (dd, 2H). EXAMPLE 35A EXAMPLE 38A EXAMPLE 34 (786 mg) indichloromethane (5 mL) at 25° This example was made by Substituting 3-cyanophenylbo C. was treated with para-toluenesulfonic anhydride (326 mg), ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. N,N-dimethylaminopyridine (122 mg), and DIEA (350 uL), 10 stirred for 18 hours, treated with ethyl acetate, washed with EXAMPLE 38B 1% HCl, saturated NaHCO, and brine, and dried (NaSO), filtered, and concentrated. This example was made by substituting EXAMPLE 38A for EXAMPLE 2B in EXAMPLE 2C. EXAMPLE 35B 15 EXAMPLE 38C EXAMPLE 35A (100 mg) in DMF (2 mL) at 25°C. was treated with DIEA (100 uL) and isopropylamine (60 uL), This example was made by substituting EXAMPLE 38B stirred at 50° C. for 18 hours, treated with ethyl acetate, for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, washed with saturated NaHCO, water, and brine, and dried DMSO-d) & 12.09 (brs, 1H), 9.47 (brs, 2H), 8.54 (d. 1H), (NaSO), filtered, and concentrated. The concentrate was 8.29 (d. 1H), 7.89 (d. 1H), 7.86 (dd, 2H), 7.77 (d. 2H), 7.69 flash chromatographed on silica gel with dichloromethane, (m, 3H), 7.56 (m, 2H), 7.37 (m. 1H), 7.24 (m, 2H), 7.14 (d. 1:1 dichloromethane/ethyl acetate, and 10% (7M NH in 5H), 6.93 (d. 2H), 4.18 (m. 1H), 4.04 (m, 2H), 3.75 (m, 2H), methanol) in dichloromethane. "H NMR (500 MHz, DMSO 25 3.39 (d. 4H), 3.15 (m, 4H), 3.06 (m, 2H), 2.75 (s.3H), 2.74 (s, d) & 8.45 (d. 1H), 8.09 (d. 1H), 7.84 (dd. 1H), 7.72 (d. 2H), 3H), 2.14 (dd, 2H). 7.47 (m, 4H), 7.40-7.31 (m, 4H), 7.25 (m3H), 7.17 (m, 2H), 6.94 (d. 1H), 6.78 (d. 2H), 4.11 (m. 1H), 3.37 (m, 2H), 3.30 EXAMPLE 39A (m, 8H), 3.12 (m, 2H), 2.99 (m, 2H), 2.40 (m, 2H), 2.05 (m, 2H), 1.16 (m, 6H). 30 This example was made by Substituting 3-methoxyphenyl boronic acid for 4-chlorophenylboronic acid in EXAMPLE EXAMPLE 36A 2B.

This example was made by Substituting 2-napthalenebo EXAMPLE 39B ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. 35 EXAMPLE 36B This example was made by substituting EXAMPLE 39A for EXAMPLE 2B in EXAMPLE 2C. This example was made by substituting EXAMPLE 36A for EXAMPLE 2B in EXAMPLE 2.0. EXAMPLE 39C 40 EXAMPLE 36C This example was made by substituting EXAMPLE 39B for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, This example was made by substituting EXAMPLE 36B DMSO-d) & 12.10 (brs, 1H), 9.58 (brs, 1H), 8.55 (d. 1H), for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.72 (m, 1H), 7.50 DMSO-d) & 12.12 (brs, 1H), 9.98 (brs, 1H),9.60 (brs, 1H), 45 (m. 2H), 7.37 (m, 2H), 7.24 (m, 2H), 7.14 (d. 4H), 6.98 (m, 8.55 (d. 1H),8.29 (d. 1H), 7.87 (dd. 1H), 7.81 (d. 2H), 7.49 (tt, 1H), 6.92 (m, 4H), 4.31 (brs, 2H), 4.18 (m. 1H), 3.79 (s.3H), 2H), 7.41 (m, 3H), 7.35 (m, 3H), 7.23 (m, 3H), 7.18 (d. 2H), 3.39 (d. 3H), 3.15 (m, 5H), 2.75 (s, 6H), 2.14 (dd, 2H). 7.12 (m, 2H), 7.02 (d. 2H), 4.19 (m, 1H), 3.99 (brs, 2H), 3.39 (d, 4H), 3.29 (m, 4H), 3.14 (m, 2H), 2.98 (m, 2H), 2.75 (s, EXAMPLE 40A 6H), 2.14 (dd, 2H). 50 This example was made by substituting 3-chlorophenylbo EXAMPLE 37A ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. This example was made by Substituting 1-napthalenebo EXAMPLE 4OB ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. 55 This example was made by substituting EXAMPLE 40A EXAMPLE 37B for EXAMPLE 2B in EXAMPLE 2C. This example was made by substituting EXAMPLE 37A EXAMPLE 4OC for EXAMPLE 2B in EXAMPLE 2.0. 60 This example was made by substituting EXAMPLE 40B EXAMPLE 37C for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.09 (brs, 1H), 9.86 (brs, 1H),9.59 (brs, 1H), This example was made by substituting EXAMPLE 37B 8.55 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.70 for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 65 (m. 1H), 7.49 (m, 5H), 7.34 (m, 2H), 7.24 (m, 2H), 7.14 (d. DMSO-d) & 12.07 (brs, 1H), 9.59 (brs, 2H), 8.54 (d. 1H), 4H), 6.94 (d. 2H), 4.19 (m. 1H), 3.39 (d. 3H), 3.13 (m, 5H), 8.29 (d. 1H), 8.01 (dd, 2H), 7.85 (dd, 2H), 7.74 (d. 2H), 7.59 2.88 (m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H). US 7,973,161 B2 125 126 EXAMPLE 41A EXAMPLE 4.4B This example was made by Substituting 2-chlorophenylbo This example was made by substituting EXAMPLE 44A ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. for EXAMPLE 2B in EXAMPLE 2C. EXAMPLE41B EXAMPLE 44C This example was made by substituting EXAMPLE 41A This example was made by substituting EXAMPLE 44B for EXAMPLE 2B in EXAMPLE 2.0. for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 10 DMSO-d) & 12.08 (brs, 1H),9.99 (brs, 1H),9.66 (brs, 1H), EXAMPLE 41C 8.69 (dd. 1H), 8.54 (d. 1H), 8.29 (d. 1H), 7.95 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.59 (m, 3H), 7.40 (m, 1H), 7.24 (m, This example was made by substituting EXAMPLE 41B 2H), 7.14 (d, 4H), 6.93 (d. 2H), 4.19 (m. 1H), 3.39 (d. 3H), for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 3.14 (m, 5H), 2.92 (m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H). DMSO-d) & 12.12 (brs, 1H), 10.00 (brs, 1H),9.59 (brs, 1H), 15 8.55 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.76 EXAMPLE 45A (m. 1H), 7.58 (m, 3H), 7.45 (m, 3H), 7.28 (dd. 1H), 7.23 (m, 2H), 7.14 (d, 4H), 6.94 (d. 2H), 4.18 (m. 1H), 3.39 (d. 3H), This example was made by Substituting 8-quinolinebo 3.13 (m, 5H), 3.02 (m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H). ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. EXAMPLE 42A EXAMPLE 45B This example was made by Substituting 3.4-methylene This example was made by substituting EXAMPLE 45A for EXAMPLE 2B in EXAMPLE 2C. dioxybenzeboronic acid for 4-chlorophenylboronic acid in 25 EXAMPLE 2B. EXAMPLE 45C EXAMPLE 42B This example was made by substituting EXAMPLE 45B This example was made by substituting EXAMPLE 42A 30 for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, for EXAMPLE 2B in EXAMPLE 2.0. DMSO-d) & 12.10 (brs, 1H),9.84 (brs, 1H),9.61 (brs, 1H), 8.84 (dd. 1H), 8.54 (d. 1H), 8.48 (dd. 1H), 8.29 (d. 1H), 8.10 EXAMPLE 42C (td, 1H), 7.85 (dd. 1H), 7.80 (d. 1H), 7.73 (m, 4H), 7.56 (m, 3H), 7.35 (dd. 1H), 7.23 (m, 3H), 7.14 (m, 3H), 6.89 (d. 2H), This example was made by substituting EXAMPLE 42B 35 4.29 (m, 1H), 4.20 (m. 1H), 3.90 (d. 1H), 3.39 (d, 4H), 3.14 for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, (m,3H), 2.97 (m, 3H), 2.75 (s, 6H), 2.15 (dd, 2H). DMSO-d) & 12.08 (brs, 1H), 9.85 (brs, 1H), 9.55 (brs, 1H), EXAMPLE 46A 8.54 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.69 (m. 1H), 7.48 (brs, 2H), 7.31 (m. 1H), 7.23 (m, 2H), 7.14 (d. This example was made by Substituting benzofuran-2-bo 4H), 6.96 (m, 4H), 6.79 (dd. 1H), 6.06 (s. 2H), 4.18 (m, 1H), 40 ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. 3.39 (d. 3H), 3.12 (m, 5H), 2.86 (m, 2H), 2.75 (s, 6H), 2.14 (dd, 2H). EXAMPLE 46B EXAMPLE 43A This example was made by substituting EXAMPLE 46A 45 for EXAMPLE 2B in EXAMPLE 2C. This example was made by substituting thiophene-3-bo ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. EXAMPLE 46C EXAMPLE 43B This example was made by substituting EXAMPLE 46B 50 for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, This example was made by substituting EXAMPLE 43A DMSO-d) & 12.14 (brs, 1H), 9.81 (brs, 1H),9.63 (brs, 1H), for EXAMPLE 2B in EXAMPLE 2.0. 8.55 (d. 1H), 8.29 (d. 1H), 7.97 (d. 1H), 7.86 (dd. 1H), 7.81 (d. 2H), 7.69 (m, 3H), 7.60 (m, 2H), 7.46 (s, 1H), 7.38 (td, 1H), EXAMPLE 43C 7.32 (t, 1H), 7.22 (m, 2H), 7.15 (d, 4H), 7.01 (d. 2H), 4.19 (m, 55 1H), 3.39 (d. 3H), 3.27 (m, 2H), 3.15 (m, 5H), 2.75 (s, 6H), This example was made by substituting EXAMPLE 43B 2.15 (dd, 2H). for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.11 (brs, 1H),9.99 (brs, 1H),9.62 (brs, 1H), EXAMPLE 44A 8.55 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.78 (d. 2H), 7.69 (m. 2H), 7.63 (s, 1H), 7.48 (brs, 2H), 7.41 (m. 1H), 7.24 (m, 60 This example was made by Substituting 2-methylphenyl 2H), 7.14 (d. 5H), 6.95 (d. 2H), 4.18 (m. 1H), 3.39 (d. 3H), boronic acid for 4-chlorophenylboronic acid in EXAMPLE 3.14 (m, 5H), 2.89 (m, 2H), 2.75 (s, 6H), 2.15 (dd, 2H). 2B. EXAMPLE 44A EXAMPLE 4.4B 65 This example was made by Substituting pyridine-3-boronic This example was made by substituting EXAMPLE 44A acid for 4-chlorophenylboronic acid in EXAMPLE 2B. for EXAMPLE 2B in EXAMPLE 2C. US 7,973,161 B2 127 128 EXAMPLE 44C 2H), 4.23 (brs, 2H), 3.82 (brs, 4H), 3.67 (dd, 2H), 3.28 (m, 2H), 3.16 (brs, 2H), 2.97 (brs, 2H). This example was made by substituting EXAMPLE 44B for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, EXAMPLE SO DMSO-d) & 12.08 (brs, 1H), 9.94 (brs, 1H), 9.73 (brs, 1H), 8.55 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.74 This example was made by substituting EXAMPLE 49C (m. 1H), 7.50 (m, 2H), 7.31 (d. 2H), 7.22 (m, 9H), 6.94 (d. for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 2H), 4.19 (m. 1H), 3.39 (d. 4H), 3.16 (m, 4H), 2.92 (m, 2H), DMSO-d) & 12.12 (brs, 1H), 9.97 (brs, 1H),9.56 (brs, 1H), 2.75 (s, 6H), 2.15 (dd, 2H). 8.55 (d. 1H), 8.29 (d. 1H), 8.12 (d. 1H), 8.05 (d. 1H), 7.87 (d. 10 1H), 7.86 (d. 1H), 7.79 (d. 2H), 7.61 (m, 3H), 7.50 (m, 1H), EXAMPLE 48A 7.38 (d. 2H), 7.28 (d. 1H), 7.22 (m, 2H), 7.14 (m, 4H), 6.95 (d. 2H), 4.25 (brs, 2H), 4.19 (m. 1H), 3.39 (d. 3H), 3.14 (m, 5H), This example was made by Substituting 3-quinolinebo 2.94 (m, 2H), 2.75 (s, 3H), 2.74 (s.3H), 2.15 (dd, 2H). ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. 15 EXAMPLE 51 EXAMPLE 48B This example was made by substituting EXAMPLE 49C This example was made by substituting EXAMPLE 48A and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) for EXAMPLE 2B in EXAMPLE 2.0. propyl)amino)-3-nitrobenzenesulfonamide, prepared as described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- EXAMPLE 48C 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) amino)-3-nitrobenzenesulfonamide, respectively, in This example was made by substituting EXAMPLE 48B EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.11 (br for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 25 s, 1H), 9.89 (brs, 2H), 8.55 (d. 1H),8.29 (d. 1H),8.12 (d. 1H), DMSO-d) & 12.07 (brs, 1H), 9.93 (brs, 1H), 9.56 (brs, 1H), 8.04 (d. 1H), 7.86 (m, 2H), 7.78 (d. 2H), 7.62 (d. 2H), 7.60 (m, 8.53 (d. 1H), 8.42 (s, 1H), 8.28 (d. 1H),8.09 (d. 1H),8.04 (dd. 1H), 7.50 (t, 1H), 7.38 (d. 2H), 7.28(d. 1H), 7.15 (d, 4H), 6.95 1H), 7.85 (dd. 1H), 7.82 (m, 2H), 7.74 (d. 2H), 7.68 (td, 1H), (d. 2H), 4.19 (m, 1H), 3.95 (m, 4H), 3.62 (m3H), 3.41 (d. 5H), 7.50 (m, 2H), 7.23 (m, 2H), 7.14 (d, 4H), 6.90 (d. 2H), 4.19 3.18 (m, 5H), 3.01 (brs, 4H), 2.19 (dd, 2H). (m. 1H), 3.39 (d. 3H), 3.14 (m, 5H), 2.90 (m, 2H), 2.74 (s, 30 EXAMPLE 52A 6H), 2.13 (dd, 2H). A mixture of 6-oxa-bicyclo[3.1.0 hexane (1.68 g) and EXAMPLE 49A NaNs (2.6 g) in water (5 mL) at 60°C. was stirred for 3 days. The water layer was extracted with dichloromethane, and the A mixture of EXAMPLE 1 A (272 mg), 1-bromo-naphtha 35 extract was dried (MgSO), filtered, and concentrated. The lene-2-carbaldehyde (0.409 g), MP BHCN (2.47 mmol/g, concentrate was flash chromatographed on silica gel 0-40% 1.41 g) and acetic acid (0.14 g) in 1:1 methanol/dichlo ethyl acetate/hexanes. romethane (8 mL) was shaken for 1 day at 25°C., filtered, and concentrated. EXAMPLE 52B The concentrate was treated with Saturated aqueous 40 KCO and dichloromethane, and the organic layer was dried A mixture of EXAMPLE 52A (1.017 g), di(tert-butyl) (MgSO), filtered and concentrated. The concentrate was dicarbonate (2.619 g), Pd(OH) (100 mg) and triethylsilane flash chromatographed on silica gel with 5%-50% ethyl (1.395 g) in ethanol (15 mL) at 50° C. was stirred for 16 hours, acetate/hexanes. concentrated partially, and partitioned between ethyl acetate 45 and water. The extract was dried (MgSO), filtered, and con EXAMPLE 49B centrated. The concentrate was flash chromatographed on silica gel with 10-60% ethyl acetate/hexanes. This example was made by substituting EXAMPLE 49A for EXAMPLE 2A in EXAMPLE 2B. EXAMPLE 52C 50 EXAMPLE 49C A mixture of EXAMPLE 52B (0.201 g) and diphenyldis ulfide (262 mg) in toluene (2 mL) at 25°C. was treated with This example was made by substituting EXAMPLE 49B tri-n-butylphosphine (243 mg), stirred for 16 hours at 80°C., for EXAMPLE 2B in EXAMPLE 2.0. and concentrated. The concentrate was flash chromato 55 graphed on silica gel 0-30% ethyl acetate/hexanes. EXAMPLE 49D EXAMPLE 52D This example was made by substituting EXAMPLE 49C and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene A mixture of EXAMPLE 52C (0.325 g) and 4M HCl in sulfonamide, prepared as described in WO 02/24636, for 60 dioxane (2.5 mL) in dichloromethane (3 mL) at 25°C. was EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl stirred for 3 hours and partially concentrated. The concentrate Sulfanyl)-methyl)propyl)amino)-3-nitrobenzenesulfona was treated with diethyl ether and filtered. mide, respectively, in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.05 (brs, 1H), 9.87 (brs, 1H), 8.76 (t, 1H), EXAMPLE 52E 8.60 (d. 1H), 8.29 (d. 1H), 8.13 (d. 1H), 8.04 (d. 1H), 7.90 (dd. 65 1H), 7.86 (d. 1H), 7.77 (d. 2H), 7.62 (d. 2H), 7.60 (m, 1H), This example was prepared by substituting EXAMPLE 7.50 (t, 1H), 7.37 (m,3H), 7.28 (d. 2H), 7.19 (m, 2H), 6.94 (d. 52D for EXAMPLE 21C in EXAMPLE 21D.

US 7,973,161 B2 131 132 s, 1H), 9.99 (brs, 2H), 8.55 (d. 1H), 8.29 (d. 1H), 7.86 (dd. EXAMPLE 64B 1H), 7.83 (d. 2H), 7.79 (brs, 1H), 7.77 (d. 2H), 7.60 (d. 2H), 7.57 (m, 2H), 7.38 (m, 1H), 7.23 (m, 2H), 7.14 (m, 4H), 6.93 This example was made by substituting EXAMPLE 64A (d. 2H), 4.32 (brs, 2H), 4.19 (m, 1H), 3.95 (m, 2H), 3.62 (m, for EXAMPLE 2B in EXAMPLE 2C. 3H), 3.40 (m, 5H), 3.20 (m, 4H), 3.02 (brs, 4H), 2.18 (dd, 5 2H). EXAMPLE 64G, This example was made by substituting EXAMPLE 64B EXAMPLE 61A and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene sulfonamide, prepared as described in WO 02/24636, for This example was made by substituting 4-trifluo- 10 EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl romethoxyboronic acid for 4-chlorophenylboronic acid in Sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, EXAMPLE 2B. respectively, in EXAMPLE2D. "H NMR (400 MHz, DMSO d) & 12.05 (brs, 1H), 9.76 (brs, 1H), 8.76 (t, 1H), 8.60 (d. 1H), 7.91 (dd. 1H), 7.77 (d. 2H), 7.73 (brs, 1H), 7.52 (m, 2H), EXAMPLE 61B 15 7.38 (m,7H), 7.26 (t, 2H), 7.18 (m,3H), 7.07 (m, 4H), 6.94 (d. 2H), 4.36 (brs, 2H), 3.80 (brs, 4H), 3.67 (q, 2H), 3.28 (t, 2H), This example was made by substituting EXAMPLE 61A 3.15 (brs, 2H), 2.87 (brs, 2H). for EXAMPLE 2B in EXAMPLE 2.0. EXAMPLE 65 EXAMPLE 61C 2O This example was made by substituting EXAMPLE 64B and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) This example was made by substituting EXAMPLE 61B propyl)amino)-3-nitrobenzenesulfonamide, prepared as and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- sulfonamide, prepared as described in WO 02/24636, for 25 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl amino)-3-nitrobenzenesulfonamide, respectively, in Sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.07 (br respectively, in EXAMPLE2D. "H NMR (400 MHz, DMSO s, 1H), 9.98 (brs, 2H), 8.56 (d. 1H), 8.30 (d. 1H), 7.87 (dd. d) & 12.05 (brs, 1H), 9.78 (brs, 1H), 8.76 (t, 1H), 8.60 (d. 1H), 7.78 (d. 2H), 7.73 (brs, 1H), 7.51 (m, 2H), 7.38 (m, 5H), 1H), 7.90 (dd. 1H), 7.76 (d. 2H), 7.75 (brs, 1H), 7.54 (m, 2H), 7.23 (m, 2H), 7.15 (m, 5H), 7.07 (d, 4H), 6.95 (d. 2H), 4.31 (br 7.50 (d. 2H), 7.45 (d. 2H), 7.37 (m,3H), 7.26 (t, 2H), 7.18 (m, s, 2H), 4.20 (m, 1H), 3.94 (m, 2H), 3.63 (m, 3H), 3.40 (m, 2H), 6.93 (d. 2H), 4.30 (brs, 2H), 3.98 (brs, 4H), 3.67 (q, 2H), 5H), 3.19 (m, 4H), 3.02 (brs, 4H), 2.18 (dd, 2H). 3.28 (t, 2H), 3.11 (brs, 2H), 2.89 (brs, 2H). EXAMPLE 66A EXAMPLE 62 35 ADDP (11.43 g) in THF (100 mL) at 25°C. was treated with tributylphosphine (9.16 g), stirred for 10 minutes, This example was made by substituting EXAMPLE 61B treated with (S)-3-tert-butoxycarbonylamino-4-hydroxybu for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, tyric acid cyclohexyl ester (9.1 g), prepared as described in DMSO-d) & 12.10(brs, 1H), 10.05 (brs, 1H), 9.62 (brs, 1H), Tet. Lett. (1995), 36(8), 1223, in THF (20 mL) and thiophenol 8.54(d. 1H),8.29 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.76 (br 40 (6.61 g), stirred for 2 days, treated with diethyl ether, and s, 1H), 7.54 (m, 2H), 7.50 (d. 2H), 7.45 (d. 2H), 7.37 (m, 1H), filtered. The filtrate was concentrated, and the concentrate 7.23 (m, 2H), 7.14 (m, 4H), 6.93 (d. 2H), 4.31 (brs, 2H), 4.19 was flash chromatographed on silica gel with 0-15% ethyl (m. 1H), 3.82 (brs, 2H), 3.39 (d. 3H), 3.13 (m, 5H), 2.92 (m, acetate/hexane. 2H), 2.74 (s, 6H), 2.15 (dd, 2H). EXAMPLE 66B 45 EXAMPLE 63 A mixture of EXAMPLE 66A (7.1 g) and 4M HCl in dioxane (30 mL) was stirred for 5 hours and concentrated. This example was made by substituting EXAMPLE 61B and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) EXAMPLE 66C propyl)amino)-3-nitrobenzenesulfonamide, prepared as 50 described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- This example was made by substituting EXAMPLE 66B 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) for EXAMPLE 21C in EXAMPLE 21 D. amino)-3-nitrobenzenesulfonamide, respectively, in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.13 (br EXAMPLE 66D s, 1H), 9.99 (brs, 2H), 8.55 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 55 1H), 7.77 (d. 2H), 7.76 (brs, 1H), 7.54 (m, 2H), 7.51 (d. 2H), A mixture of EXAMPLE 66C (8.341 g) and lithium 7.45 (d. 2H), 7.37 (m, 1H), 7.23 (m, 2H), 7.14 (m, 4H), 6.93 hydroxide (1.426 g) in 1:1 THF/water (100 mL) was stirred (d. 2H), 4.30 (brs, 2H), 4.20 (m, 1H), 3.95 (m, 2H), 3.63 (m, for 18 hours at 25°C., partially concentrated, treated with 3H), 3.40 (m, 5H), 3.20 (m, 4H), 3.02 (brs, 4H), 2.18 (dd. water (250 mL), washed with dichloromethane/ethyl acetate, 60 acidified with 12M HCl to pH 2, and extracted with ethyl 2H). acetate. The extract was washed with water and brine and dried (MgSO), filtered, and concentrated. EXAMPLE 64A EXAMPLE 66E This example was made by Substituting 4-phenoxyphenyl- 65 boronic acid for 4-chlorophenylboronic acid in EXAMPLE A mixture of EXAMPLE 66D (6.42 g) and NMM (1.67 g) 2B. in DME (70 mL) at 0-5°C. was treated with isobutyl chloro US 7,973,161 B2 133 134 formate (2.14 mL), stirred for 5 minutes treated with 2M EXAMPLE 68A dimethylamine in THF (40 mL), stirred at 25°C., concen trated, and filtered. This example was made by Substituting 2,4-dichlorophe nylboronic acid for 4-chlorophenylboronic acid in EXAMPLE 66F EXAMPLE 2B. This example was made by substituting EXAMPLE 66E EXAMPLE 68B for EXAMPLE 1.8E in EXAMPLE 1.8F. This example was made by substituting EXAMPLE 68A 10 for EXAMPLE 2B in EXAMPLE 2C. EXAMPLE 66G EXAMPLE 68C This example was made by substituting EXAMPLE 66F for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) This example was made by substituting EXAMPLE 68B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 15 for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, 2D.' HNMR (400 MHz, DMSO-d) 89.69 (brs, 1H), 8.47 (d. DMSO-d) & 12.10 (brs, 1H), 9.89 (brs, 1H),9.56 (brs, 1H), 1H), 8.19 (d. 1H), 7.82 (dd. 1H), 7.72 (d. 2H), 7.51 (m, 1H), 8.54 (d. 1H), 8.28 (d. 1H), 7.85 (dd. 1H), 7.77 (d. 2H), 7.74 7.47 (s, 4H), 7.37 (m, 2H), 7.30 (m, 2H), 7.24 (t,3H), 7.16 (m, (m. 1H), 7.52 (m,3H), 7.43 (d. 1H), 7.26 (d. 1H), 7.22(d. 2H), 1H), 6.93 (d. 1H), 6.80 (d. 2H), 4.07 (brs, 2H), 3.39 (m, 2H), 7.13 (m, 4H), 6.94 (d. 2H), 4.26 (brs, 2H), 4.17 (m, 1H), 3.38 3.33 (m, 2H), 3.14 (m, 4H), 3.00 (m, 2H), 2.63 (s, 6H).2.40 (d. 3H), 3.13 (m, 7H), 2.74 (s, 6H), 2.14 (dd, 2H). (m, 4H), 2.08 (m. 2H). EXAMPLE 69A EXAMPLE 67A 25 This example was made by Substituting thiophene-2-bo ADDP (16.94 g) in THF (90 mL) at 25°C. was treated with ronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. tributylphosphine (13.55 g), stirred for 10 minutes, treated with (2-hydroxy-1,1-dimethylethyl)carbamic acid tert-butyl EXAMPLE 69B ester (8.47g), prepared as described in Synlett. (1997), (8), This example was made by substituting EXAMPLE 69A 893-894, in THF (30 mL) and thiophenol (7.38 g), stirred for 30 1 day, treated with diethyl ether, and filtered. The filtrate was for EXAMPLE 2B in EXAMPLE 2C. concentrated, and the concentrate was flash chromatographed EXAMPLE 69C on silica gel 0-15% ethyl acetate/hexanes. This example was made by substituting EXAMPLE 69B EXAMPLE 67B 35 for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.11 (brs, 1H), 9.95 (brs, 1H), 9.55 (brs, 1H), A mixture of EXAMPLE 67A (0.562 g) and 80% magne 8.54 (d. 1H), 8.29 (d. 1H), 7.85 (dd. 1H), 7.78 (d. 2H), 7.73 sium monoperoxypthalic acid (1.36 g) in THF (10 mL) was (m. 1H), 7.68 (d. 1H), 7.51 (m, 3H), 7.24 (m, 2H), 7.17 (m, stirred for 18 hours, treated with dichloromethane, and fil 40 2H), 7.14 (m, 4H), 6.96 (d. 2H), 4.41 (brs, 2H), 4.18 (m, 1H), tered. The filtrate was washed with brine and dried (MgSO), 3.38 (d. 3H), 3.13 (m, 7H), 2.75 (s, 6H), 2.15 (dd, 2H). filtered, and concentrated. The concentrate was flash chro matographed on silica gel 10-50% ethyl acetate/hexanes. EXAMPLE 70A This example was made by Substituting 4-chloro-2-meth EXAMPLE 67C 45 ylphenylboronic acid for 4-chlorophenylboronic acid in EXAMPLE 2B. This example was made by substituting EXAMPLE 67B for EXAMPLE 66A in EXAMPLE 66B. EXAMPLE 70B 50 This example was made by substituting EXAMPLE 70A EXAMPLE 67D for EXAMPLE 2B in EXAMPLE 2C. This example was made by substituting EXAMPLE 67C EXAMPLE 70C for EXAMPLE 21C in EXAMPLE 21 D. 55 This example was made by substituting EXAMPLE 70B for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, EXAMPLE 67 E DMSO-d) & 12.10 (m. 1H), 9.60 (s, 1H), 8.53 (d. 1H), 8.28 (d. 1H), 7.85 (dd. 1H), 7.77 (d. 3H), 7.52 (m, 2H), 7.41 (d. This example was made by substituting EXAMPLE 67D 1H), 7.31 (dd. 1H), 7.20 (m, 4H), 7.12 (m, 4H), 6.94 (d. 1H), for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 60 4.18 (m. 1H), 3.85 (m, 7H), 3.38 (d. 2H), 3.11 (m, 6H), 2.74 propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE (s, 6H), 2.14 (dd, 2H), 1.96 (s.3H). 2D. "H NMR (400 MHz, DMSO-d) & 12.11 (brs, 1H), 9.69 (brs, 1H), 8.44 (d. 1H),8.33 (s, 1H), 7.82 (d. 2H), 7.71 (dd. EXAMPLE 71A 2H), 7.64 (td, 2H), 7.52 (d. 3H), 7.40 (d. 2H), 7.32 (m. 1H), 7.25 (d. 1H), 7.23 (tt, 1H), 7.16 (tt, 2H), 6.95 (d. 2H), 4.30 (br 65 This example was made by Substituting 2,4-difluorophe s, 2H), 4.13 (s. 2H), 3.84 (brs, 2H), 3.13 (brs, 4H), 2.86 (br nylboronic acid for 4-chlorophenylboronic acid in s. 2H), 1.62 (s, 6H). EXAMPLE 2B.

US 7,973,161 B2 137 138 (500 MHz, DMSO-d) & 11.96 (brs, 1H), 10.46 (brs, 1H), concentrated. The concentrate flash chromatographed on 8.60 (d. 1H), 8.49 (d. 1H), 7.95 (dd. 1H), 7.76 (d. 2H), 7.69 silica gel with 10-30% ethyl acetate/hexanes. (m. 1H), 7.51 (m, 4H), 7.40 (t, 4H), 7.32 (m, 1H), 7.24 (m, 4H), 6.92 (d. 2H), 4.69 (brs, 1H), 4.25 (brs, 2H), 3.97 (brs, EXAMPLE 82C 2H), 3.68 (m, 2H), 3.29 (brs, 4H), 2.91 (s, 3H), 2.75 (brs, 2H). This example was made by substituting EXAMPLE 82B for EXAMPLE 2B in EXAMPLE 2C. EXAMPLE 79 EXAMPLE 82D This example was made by substituting EXAMPLE 10 83.7538C and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfa This example was made by substituting EXAMPLE 82C nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, pre for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, pared as described in WO 02/24636, for EXAMPLE 2C and DMSO-d) & 12.02 (brs, 1H), 9.49 (brs, 1H), 8.54 (d. 1H), 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 8.28 (d. 1H), 7.86 (dd. 1H), 7.73 (d. 2H), 7.47 (m, 5H), 7.38 propyl)amino)-3-nitrobenzenesulfonamide, respectively, in 15 (m. 2H), 7.23 (d. 2H), 7.14 (m, 5H), 6.89 (d. 2H), 4.18 (m, EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & H NMR 2H), 3.39 (d. 2H), 3.20 (m, 6H), 2.75 (s, 3H), 2.74 (s, 3H), (500 MHz, DMSO-d) & 8.50 (d. 1H), 8.36 (d. 1H), 7.79 (dd, 2.44 (brs, 4H), 2.13 (dd, 2H), 1.01 (brs, 2H), 0.82 (brs, 2H). 1H), 7.72 (d. 2H), 7.36 (d. 2H), 7.28(d. 2H), 7.21 (t, 2H), 7.15 (d. 1H), 7.12 (d. 2H), 7.03 (d. 1H), 6.84 (d. 2H), 4.13 (m, 1H), EXAMPLE 83A 3.52 (m, 4H), 3.38 (m, 4H), 3.21 (brs, 4H), 2.82 (brs, 2H), A mixture of 2M dimethylamine in THF (27 mL), (R)-2- 2.45 (m, 4H), 2.32 (brs, 4H), 2.20 (brs, 2H), 2.17 (brs, 2H), benzyloxycarbonylamino-3-phenylthiopropionic acid (5.8 2.00 (m. 1H), 1.86 (m, 1H), 1.67 (m, 4H). g), HoBT (2.67 g), and EDAC.HCl (5.2 g) in THF (50 mL) EXAMPLE 81A was stirred for 18 hours at 25° C., treated with water and 25 extracted with dichloromethane. The extract was dried (MgSO), filtered, and concentrated. The concentrate was This example was made by Substituting 4-bromophenyl flash chromatographed on silica gel with 15-50% ethyl boronic acid for 4-chlorophenylboronic acid in EXAMPLE acetate/hexanes. 2B. 30 EXAMPLE 83B EXAMPLE 81B This example was prepared by substituting EXAMPLE This example was made by substituting EXAMPLE 81A 83A for EXAMPLE 18B in EXAMPLE 18C. for EXAMPLE 2B in EXAMPLE 2.0. 35 EXAMPLE 83C EXAMPLE 81C This example was prepared by substituting EXAMPLE This example was made by substituting EXAMPLE 81B 83B for EXAMPLE 18E. in EXAMPLE 1.8F. for EXAMPLE 2C in EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 12.06 (brs, 1H), 9.79 (brs, 1H),9.47 (brs, 1H), 40 EXAMPLE 83D 8.54(d. 1H), 8.28 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.69 (br s, 1H), 7.64 (d. 2H), 7.50 (m, 2H), 7.35 (m,3H), 7.23 (m, 2H), This example was prepared by substituting EXAMPLE 7.14 (m, 4H), 6.93 (d. 2H), 4.29 (brs, 2H), 4.19 (m, 1H), 3.77 83C for EXAMPLE 21C in EXAMPLE 21D. (brs, 2H), 3.14 (m, 3H), 2.74 (s, 6H), 2.14 (dd, 2H). 45 EXAMPLE 83E EXAMPLE 82A This example was made by substituting EXAMPLE 4'-chloro-biphenyl-2-carbonitrile, prepared as described in 83.7538C and EXAMPLE 83D for EXAMPLE 2C and J. Org. Chem. (1984), 49(9), 1594-1603), (0.35 g) in diethyl 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) ether (25 mL) at -75° C. was treated with titanium isopro 50 propyl)amino)-3-nitrobenzenesulfonamide, respectively, in poxide (0.53 mL) and 3M ethyl magnesium bromide in EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 12.11 (br diethyl ether (1.2 mL), stirred for 10 minutes, stirred at 25°C. s, 1H), 9.46 (brs, 1H), 9.36 (brs, 1H), 8.52 (d. 1H), 8.28 (d. for 1 hour, treated with BF.diethyl etherate (0.41 mL), stirred 1H), 7.88 (dd. 1H), 7.79 (d. 2H), 7.41 (d. 2H), 7.35 (d. 2H), for 1 hour, treated with 1M HCl (5 mL) then 10% NaOH (15 7.17 (m, 4H), 7.09 (m, 2H), 6.96 (d. 2H), 4.67 (m. 1H), 3.89 mL), and extracted with diethyl ether. The extract was dried 55 (brs, 2H), 3.75 (m, 4H), 3.43 (m, 2H), 3.36 (m, 4H), 3.16 (br (MgSO), filtered, and concentrated. The concentrate was s, 2H), 2.82 (s, 3H), 2.75 (s, 3H), 2.26 (brs, 2H), 2.21 (brs, flash chromatographed on silica gel 10%-50% ethyl acetate/ 2H), 1.71 (brs, 4H). hexanes). EXAMPLE 84 EXAMPLE 82B 60 This example was made by substituting EXAMPLE 83D A mixture of 4-(bis(2-methanesulfonyloxyethyl)amino) for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) benzoic acid ethyl ester, prepared as described in J. Med. propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE Chem. (1977), 21 (1), 16-26, (80.6 mg), EXAMPLE 82A 2D. (58.5 mg), and potassium carbonate (69.1 mg) in acetonitrile 65 'HNMR (500 MHz, DMSO-d) & 12.12 (brs, 1H),9.94 (br (5 mL) in a microwave reactor at 160° C. was stirred for 30 s, 1H), 9.42 (brs, 1H), 8.51 (d. 1H), 8.28 (d. 1H), 7.87 (dd. minutes, treated with ethyl acetate (10 mL), filtered, and 1H), 7.78 (d. 2H), 7.73 (brs, 1H), 7.52 (d, 4H), 7.39 (d. 2H), US 7,973,161 B2 139 140 7.34 (m, 2H), 7.17 (m, 2H), 7.09 (m, 3H), 6.93 (d. 2H), 4.66 EXAMPLE 87 (m. 1H), 4.29 (brs, 2H), 3.85 (brs, 2H), 3.75 (t, 2H), 3.43 (d. 2H), 3.36 (m, 2H), 3.12 (brs, 4H), 2.87 (brs, 3H), 2.82 (s, This example was made by substituting EXAMPLE 3H). 83.7538C and EXAMPLE 85D for EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 85A propyl)amino)-3-nitrobenzenesulfonamide, respectively, in This example was prepared by Substituting diethylamine EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.16 (br for dimethylamine in EXAMPLE 83A. s, 1H), 9.67 (brs, 1H), 9.06 (brs, 1H), 8.52 (d. 1H), 8.33 (d. 10 1H), 7.87 (dd. 1H), 7.79 (d. 2H), 7.41 (d. 2H), 7.33 (d. 1H), EXAMPLE 85B 7.17 (m, 4H), 7.10 (m, 3H), 6.96 (d. 2H), 4.61 (m. 1H), 3.88 (brs, 2H), 3.76 (m, 4H), 3.59 (brs, 2H), 3.42 (m, 2H), 3.15 This example was prepared by substituting EXAMPLE (m, 4H), 2.80 (brs, 2H), 2.27 (brs, 2H), 2.22 (brs, 2H), 1.71 85A for EXAMPLE 18B in EXAMPLE 18C. (brs, 4H), 1.19 (dd, 6H). 15 EXAMPLE 85C EXAMPLE 88 This example was prepared by substituting EXAMPLE This example was made by substituting EXAMPLE 83.7538C and EXAMPLE 86D for EXAMPLE 2C and 85B for EXAMPLE 1.8E in EXAMPLE 1.8F. 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 85D propyl)amino)-3-nitrobenzenesulfonamide, respectively, in EXAMPLE 2D. This example was prepared by substituting EXAMPLE 'HNMR (400 MHz, DMSO-d) & 12.11 (brs, 1H),9.97 (br 85C for EXAMPLE 21C in EXAMPLE 21D. s, 1H), 9.55 (brs, 1H), 8.51 (d. 1H), 8.38 (d. 1H), 7.86 (dd. 1H), 7.79 (d. 2H), 7.41 (d. 2H), 7.25 (d. 1H), 7.17 (m, 5H), EXAMPLE 85E 25 7.09 (m, 2H), 6.96 (d. 2H), 4.58 (m, 1H), 3.90 (brs, 2H), 3.39 (m, 4H), 3.17 (brs, 4H), 2.80 (brs, 2H), 2.26 (brs, 2H), 2.22 This example was made by substituting EXAMPLE 85D (brs, 2H), 1.71 (brs, 4H). for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE EXAMPLE 89 2D. "H NMR (400 MHz, DMSO-d) & 12.15 (brs, 1H), 9.99 30 (brs, 1H), 9.02 (brs, 1H), 8.51 (d. 1H), 8.33 (d. 1H), 7.87 (dd. A mixture of EXAMPLE 833566 (44.9 mg) and 2.47 1H), 7.77 (d. 2H), 7.74 (brs, 1H), 7.52 (d, 4H), 7.39 (d. 2H), mmol/g MP-BHCN (0.81 g) in 1:1 dichloromethane/metha 7.33 (m, 2H), 7.18 (m, 2H), 7.10 (m, 3H), 6.93 (d. 2H), 4.60 nol at 25°C. (4 mL) was treated with DIEA and acetic acid to (m. 1H), 4.26 (brs, 2H), 3.85 (brs, 2H), 3.43 (m, 2H), 3.36 pH 5-6, shaken for 18 hours, filtered, and concentrated. The 35 concentrate was chromatographed on C-18 with 30-100% (dd, 2H), 3.15 (m, 6H), 2.92 (brs, 4H), 1.19 (m, 6H). acetonitrile/water/0.1% TFA. H NMR (500 MHz, DMSO EXAMPLE 86A d) & 12.13 (brs, 1H),9.76 (brs, 1H), 9.18 (brs, 1H), 8.54 (d. 1H), 8.32 (d. 1H), 7.87 (dd. 1H), 7.78 (d. 2H), 7.71 (brs, 1H), This example was prepared by Substituting morpholine for 7.53 (m, 4H), 7.41 (d. 2H), 7.34 (m, 1H), 7.23 (m, 3H), 7.14 dimethylamine in EXAMPLE 83A. 40 (m,3H), 6.93 (d. 2H), 4.33 (brs, 2H), 4.22 (m. 1H), 3.85 (br s, 2H), 3.12 (m, 4H), 2.82 (s.3H), 2.19 (m, 2H), 0.81 (m, 4H). EXAMPLE 86B EXAMPLE 90A This example was prepared by substituting EXAMPLE 86A for EXAMPLE 18B in EXAMPLE 18C. 45 A mixture of magnesium turnings (0.144 g) and one iodine crystal at 25°C. was treated with 2-phenylbenzyl bromide EXAMPLE 86C (1.48 g) in diethyl ether (10 mL), stirred for 3 hours, cooled to 0° C., treated with 4-(4-oxo-piperidine-1-yl)benzoic acid This example was prepared by substituting EXAMPLE ethyl ester, prepared as described in J. Het. Chem. 1969, 6, 86B for EXAMPLE 1.8E in EXAMPLE 1.8F. 50 941, (1.48 g) in diethyl ether (5 mL) and THF (5 mL), stirred at 25° C. for 18 hours, and treated with ethyl acetate and EXAMPLE 86D aqueous NHC1. The extract was extracted with ethyl acetate, and the combined extracts were dried (NaSO), filtered, and This example was prepared by substituting EXAMPLE concentrated. The concentrate was flash chromatographed on 86C for EXAMPLE 21C in EXAMPLE 21D. 55 silica gel with 25% ethyl acetate/hexane. EXAMPLE 86E EXAMPLE 9 OB This example was made by substituting EXAMPLE 86D EXAMPLE 90A (0.27 g) in THF (10 mL) at 25° C. was for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 60 treated with 60% oily NaH (0.24g), stirred for 2 hours at 50° propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE C., treated with HMPA (2 mL) and methyl iodide (2 mL), 2D. "H NMR (400 MHz, DMSO-d) & 12.13 (brs, 1H), 9.95 heated at reflux for 18 hours, cooled to 0°C, and treated with (brs, 1H), 8.51 (d. 1H), 8.33 (d. 1H), 7.86 (dd. 1H), 7.78 (d. ethyl acetate and aqueous NaHSO. The extract was extracted 2H), 7.74 (brs, 1H), 7.52 (d, 4H), 7.39 (d. 2H), 7.34 (m. 1H), with ethyl acetate, and the combined extracts were dried 7.25 (d. 1H), 7.19 (m, 2H), 7.09 (m,3H), 6.93 (d. 2H), 4.59 (br 65 (Na2SO4), filtered, and concentrated. The concentrate was s, 1H), 4.29 (brs, 2H), 3.39 (m, 4H), 3.12 (brs, 6H), 2.90 (br flash chromatographed on silica gel with 10% ethyl acetate/ s, 3H). hexanes. US 7,973,161 B2 141 142 EXAMPLE 90C 9.44 (s, 1H), 8.64 (d. 2H), 8.54 (d. 1H), 8.28 (d. 1H), 7.97 (dd. 1H), 7.86 (dd. 1H), 7.70 (d. 2H), 7.62 (m, 1H), 7.37 (m,3H), A mixture of EXAMPLE 90B (0.09 g) and 1M LiOH (1 7.23 (m, 3H), 7.13 (m, 4H), 6.83 (d. 2H), 4.19 (m. 1H), 3.45 mL) in dioxane (5 mL) at 60°C. was stirred for 18 hours, and (m. 2H), 3.39 (d. 2H), 3.13 (m, 2H), 2.99 (s.3H), 2.88 (m, concentrated. The concentrate in water was treated with 2M 5 4H), 2.74 (d. 6H), 2.14 (q, 2H), 1.49 (d. 2H), 1.20 (dt, 2H). HC1 and filtered. EXAMPLE 92 EXAMPLE 9 OD This example was prepared by Substituting 4-pyridinebo This example was made by substituting EXAMPLE 90C 10 ronic acid for 4-pyridineboronic acid in EXAMPLE 91. H for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, NMR (400 MHz, DMSO-d) & 9.47 (brs, 1H), 8.75 (d. 2H), DMSO-d) & 11.95 (brs, 1H), 9.38 (s, 1H), 8.54 (d. 1H), 8.28 8.53 (d. 1H), 8.28 (d. 1H), 7.86 (dd. 1H), 7.70 (d. 2H), 7.66 (d. (d. 1H), 7.86 (dd. 1H), 7.70 (d. 2H), 7.30 (m. 10H), 7.15 (m, 2H), 7.39 (m, 3H), 7.23 (d. 2H), 7.13 (m, 4H), 6.83 (d. 2H), 4H), 6.82 (d. 2H), 4.19 (m. 1H), 3.45 (m, 4H), 3.13 (m, 2H), 4.18 (m. 1H), 3.46 (m, 2H), 3.39 (d. 2H), 3.13 (m, 2H), 2.99 3.04 (s.3H), 2.88 (m, 4H), 2.74 (d. 6H), 2.14 (q, 2H), 1.47 (m, 15 (s.3H), 2.86 (m, 4H), 2.74 (d. 6H), 2.14 (q, 2H), 1.49 (d. 2H), 2H), 1.18 (m, 2H). 1.20 (dt, 2H). EXAMPLE 91A EXAMPLE 93 A mixture of magnesium turnings (0.432 g) and one iodide This example was prepared by Substituting thiophene-2- crystal at 25°C. was treated with 2-bromobenzyl bromide boronic acid for 4-pyridineboronic acid in EXAMPLE 91. H (4.5 g) in diethyl ether (30 mL), stirred for 3 hours, cooled to NMR (400 MHz, DMSO-d) & 8.44 (d. 1H), 8.26 (d. 1H), 0° C., treated with 4-(4-oxo-piperidine-1-yl)benzoic acid 7.79 (dd. 1H), 7.67 (d. 2H), 7.57 (dd. 1H), 7.3 (m, 8H), 7.17 ethyl ester, prepared as described in J. Het. Chem. 1969, 6, (d. 1H), 7.10 (m, 2H), 6.87 (d. 1H), 6.71 (d. 2H), 4.05 (m, 1H), 941, (3.7g) in diethylether (20 mL) and THF (10 mL), stirred 25 3.30 (m, 4H), 3.12 (s.3H), 3.03 (s. 2H), 2.74 (m, 4H), 2.43 (s, at 25° C. for 18 hours, and treated with ethyl acetate and 6H), 2.00 (m, 2H), 1.55 (d. 2H), 1.30 (dt, 2H). aqueous NHC1. The extract was extracted with ethyl acetate, and the combined extracts were dried (NaSO), filtered, and EXAMPLE 94. concentrated. The concentrate was flash chromatographed on silica gel with 50% ethyl acetate/hexane. 30 This example was prepared by Substituting thiophene-3- boronic acid for 4-pyridineboronic acid in EXAMPLE 91. EXAMPLE 91B "H NMR (400 MHz, DMSO-d) & 8.44 (d. 1H), 8.26 (d. 1H), 7.79 (dd. 1H), 7.67 (d. 2H), 7.59 (m, 1H), 7.44 (m. 1H), EXAMPLE 91A (1.6 g) in THF (20 mL) at 25°C. was 7.28 (m, 7H), 7.16 (m, 2H), 6.87 (d. 1H), 6.71 (d. 2H), 4.05 treated with 60% oily NaH(0.288 g), stirred for 2 hours at 50° 35 (m. 1H), 3.30 (m, 4H), 3.07 (s.3H), 2.94 (s.2H), 2.74 (m, 4H), C., treated with HMPA (3 mL) and methyl iodide (3 mL), 2.45 (s, 6H), 2.00 (m, 2H), 1.49 (d. 2H), 1.25 (dt, 2H). stirred at reflux for 18 hours, cooled to 0°C, and treated with ethyl acetate and aqueous NaHSO. The extract was extracted EXAMPLE 95A with ethyl acetate, and the combined extracts were dried (NaSO4), filtered, and concentrated. The concentrate was 40 N-methyl-2.2.2-trifluoroacetamide (6.35 g) in diethyl flash chromatographed on silica gel with 10-15% ethyl ether (25 mL) at -15°C. was treated with lithium aluminum acetate/hexanes. hydride (3.8g) in diethyl ether (25 mL) over 1 hour, stirred for 2 hours, stirred at 25°C. for 16 hours, cooled to 0°C., treated EXAMPLE 91C with water, and distillated at 34-36° C. The distillate was 45 treated with HCl and filtered. A mixture of EXAMPLE 91B (0.6 g) and 1M LiOH (5 mL) in dioxane (5 mL) at 60° C. was stirred for 18 hours and EXAMPLE 95B concentrated. The concentrate in water was treated with 2M HC, and filtered. This example was made by substituting EXAMPLE 95A 50 for isopropylamine in EXAMPLE 28. 'H NMR (400 MHz, EXAMPLE 91D DMSO-d) 88.67 (d. 1H),8.52 (d. 1H), 7.83 (dd. 1H), 7.74 (d. 2H), 7.52 (d. 1H), 7.47 (m, 4H), 7.38 (m, 2H), 7.24 (m, 2H), This example was made by substituting EXAMPLE 91C 7.14 (m, 4H), 6.82 (d. 2H), 4.46 (m, 1H), 4.12 (q, 2H), 3.35 for EXAMPLE 2C in EXAMPLE 2D. (m. 10H), 3.04 (s.3H), 2.42 (m, 4H). 55 EXAMPLE 91E EXAMPLE 96A A mixture of EXAMPLE 91D (0.08 g), 3-pyridineboronic This example was made by substituting 2.2.2-trifluoroet acid (0.04 g), Pd(dppf)C1 (0.01 g), and CSCO (0.1 g) in hylamine for isopropylamine in EXAMPLE 28. DMF (1 mL) at 80°C. was stirred for 2 days and treated with 60 ethyl acetate and brine. The extract was extracted with ethyl EXAMPLE 96 acetate, and the extracts were combined and dried (Na2SO4), filtered, and concentrated. The concentrate was purified by Borane.dimethyl sulfide (0.37 mL) was treated with high pressure liquid chromatography on a Waters Symmetry EXAMPLE 96A (110 mg) in THF (2 mL) at 25° C., for 5 Cs column (25 mmx100 mm, 7 um particle size) with 65 hours, treated with methanol, and concentrated. The concen 10-100% acetonitrile/0.1% aqueous TFA over 8 minutes at a trate was purified by HPLC with 0-70% acetonitrile/water/ flow rate of 40 mL/minute. "H NMR (400 MHz, DMSO-d) & 0.1% TFA. H NMR (400 MHz, DMSO-d) & 8.53 (d. 1H), US 7,973,161 B2 143 144 8.30 (d. 1H), 7.84 (dd. 1H), 7.76 (d. 2H), 7.52 (m, 3H), 7.35 diethyl ether (25 mL) over 1 hour, stirred for 2 hours then at (m, 4H), 7.15 (m, 6H), 6.92 (d. 2H), 4.46 (m. 1H), 3.75 (m, 25° C. for 16 hours, cooled to 0°C., treated with water (10 2H), 3.5 (m. 12H), 2.42 (m, 4H). mL), 15% NaOH (10 mL), and water (30 mL), stirred a for 30 minutes, and filtered. The filtrate was washed with water and EXAMPLE 97A brine, dried (NaSO), and filtered. The filtrate was treated This example was made by substituting methyl trifluoro with HCl, and filtered. acetamide for EXAMPLE 100A in EXAMPLE 10OB. EXAMPLE 1 OOC EXAMPLE 97B 10 This example was made by substituting EXAMPLE 100B This example was made by substituting EXAMPLE 97A and EXAMPLE 30A for isopropylamine and EXAMPLE and EXAMPLE 30A for isopropylamine and EXAMPLE 27E in EXAMPLE 28. 27E in EXAMPLE 28. EXAMPLE 1 OOD EXAMPLE 97C 15 This example was made by substituting EXAMPLE 97C This example was made by substituting EXAMPLE 100C for EXAMPLE 96A in EXAMPLE 96. for EXAMPLE 96A in EXAMPLE 96. EXAMPLE 97D EXAMPLE 1 OOE This example was made by substituting EXAMPLE 97C This example was made by substituting EXAMPLE 100D for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 8.72 (d. 1H), 8.59 (d. 2D. "H NMR (400 MHz, DMSO-d) & 11.90 (brs, 1H), 8.51 1H), 7.99 (dd. 1H), 7.95 (d. 2H), 7.71 (m,3H), 7.55 (m, 3H), 25 (d. 1H), 8.32 (d. 1H), 7.80 (dd. 1H), 7.74 (d. 2H), 7.46 (m, 7.41 (d. 2H), 7.29 (m, 5H), 7.11 (d. 2H), 4.46 (brs, 1H), 4.33 5H), 7.37 (m, 2H), 7.24 (d. 2H), 7.12 (m, 3H), 7.02 (d. 1H), (m. 1H), 3.75 (m, 12H), 3.31 (q, 2H), 2.78 (m, 2H), 2.68 (s, 6.89 (d. 2H), 4.12 (m, 1H), 3.42 (s.2H), 3.35 (m, 6H), 3.13 (q, 3H), 2.09 (m, 2H). 2H), 2.63 (t, 2H), 2.56(q,2H), 2.40 (s, 4H), 1.90 (m,2H), 0.88 (t, 3H). EXAMPLE 98 30 EXAMPLE 101 This example was made by substituting EXAMPLE 32D and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) This example was made by substituting 2-fluoroethy propyl)amino)-3-nitrobenzenesulfonamide, prepared as lamine for isopropylamine in EXAMPLE35B. "HNMR (400 described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- 35 MHz, DMSO-d) & 8.80 (s. 2H), 8.53 (d. 1H), 8.26 (d. 1H), 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) 7.86 (dd. 1H), 7.75 (m, 3H), 7.52 (m, 4H), 7.38 (d. 2H), 7.33 amino)-3-nitrobenzenesulfonamide, respectively, in (m. 1H), 7.15 (m, 5H), 6.92 (d. 2H), 4.71 (t, 1H), 4.61 (t, 1H), EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 9.71 (s, 4.30 (m, 2H), 4.21 (m. 1H), 3.38 (d. 2H), 3.25 (m, 12H), 2.11 1H), 8.54 (d. 1H), 8.29 (d. 1H), 7.87 (dd. 1H), 7.69 (d. 2H), (m. 2H). 7.46 (d. 2H), 7.30 (m, 7H), 7.14 (m, 4H), 6.82 (d. 2H), 4.18 40 (m. 1H), 3.95 (m, 2H), 3.67 (m, 4H), 3.39 (m, 4H), 3.19 (m, EXAMPLE 102 2H), 3.03 (s.3H), 3.00 (m, 2H), 2.85 (m, 4H), 2.17 (m, 2H), 1.47 (d. 2H), 1.17 (t, 2H). This example was made by substituting 2,2-difluoroethy lamine for isopropylamine in EXAMPLE35B. HNMR (400 EXAMPLE 99 45 MHz, DMSO-d) & 9.15 (s. 2H), 8.53 (d. 1H), 8.26 (d. 1H), 7.86 (dd. 1H), 7.77 (d. 2H), 7.74 (m. 1H), 7.52 (m, 4H), 7.38 This example was made by substituting EXAMPLE 32D (d. 2H), 7.33 (m, 1H), 7.15 (m,5H), 6.92 (d. 2H), 6.36 (tt, 1H), and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene 4.23 (m, 1H), 4.00 (m, 4H), 3.49 (t, 2H), 4.39 (d. 2H), 3.10 (m, sulfonamide, prepared as described in WO 02/24636, for 4H), 2.90 (m, 2H), 2.54 (s. 2H), 2.13 (m, 2H). EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl 50 Sulfanyl)methyl)propyl)-amino)-3-nitrobenzenesulfona EXAMPLE 103A mide, respectively, in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 8.74 (t, 1H), 8.53 (d. 1H), 7.90 (dd. 1H), 7.68 (d. A mixture of EXAMPLE 2 (250 mg) and 10% Pd on 2H), 7.46 (d. 2H), 7.46 (m, 3H), 7.28 (m, 6H), 7.16 (m, 3H), carbon (100 mg) in methanol (5 mL) and ethyl acetate (5 mL) 6.81 (d. 2H), 3.66 (q, 2H)3.41 (m, 2H), 3.03 (s.3H), 2.48 (m, 55 at 25°C. was stirred under H (balloon) for 18 hours, filtered 4H), 1.47 (m, 2H), 1.18 (dt, 2H). through diatomaceous earth (Celite(R), and concentrated. EXAMPLE 1 OOA EXAMPLE 103B

Trifluoroacetic anhydride (15g) in diethyl ether (80 mL) at 60 A mixture of EXAMPLE 103A (0.06 g) in 80% -10° C. was treated with ethylamine for 40 minutes and (3 mL) at 100°C. was stirred for 3 hours and concentrated. distilled under vacuum at 68° C. The concentrate was purified by high pressure liquid chroma tography ona Waters Symmetry Cs column (25mmx100mm, EXAMPLE 1 OOB 7 um particle size) with 10-100% acetonitrile/0.1% aqueous 65 TFA over 8 minutes at a flow rate of 40 mL/minute. "H NMR EXAMPLE 100A (7.8 g) in diethyl ether (25 mL) at -15° (400 MHz, DMSO-d) & 12.01 (s, 1H), 9.64 (s, 1H), 8.56 (s, C. was treated with lithium aluminum hydride (4.17 g) in 1H), 8.22 (s, 1H), 7.83 (d. 1H), 7.75 (m, 4H), 7.52 (m, 4H), US 7,973,161 B2 145 146 7.40 (d. 2H), 7.33 (m, 1H), 7.14 (m, 3H), 7.07 (m. 1H), 6.92 EXAMPLE 106C (d. 2H), 4.76 (m. 1H), 3.85 (m, 6H), 3.66 (d. 2H), 3.15 (m, 4H), 2.71 (s, 6H), 2.45 (m, 2H). EXAMPLE 106B (0.3 g), 4-(N,N-dimethylamino)phenyl boronic acid (0.146 g), PdCl2(PPh) (0.03 g), and 2M EXAMPLE 104 NaCO, (0.4 mL) in 7:3:2 DME/water/ethanol (3 mL) at 150° C. in a 10 mL microwave reaction tube was stirred in a A mixture of EXAMPLE 103A (0.06 g) and 12M HCl microwave reactor for 20 minutes, filtered through diatoma (0.56 mL) in acetic acid (2 mL) at 0°C. was treated with ceous earth (Celite(R) and concentrated. The concentrate was NaNO (7.2 mg) in water (0.38 mL), stirred for 2 hours, and flash chromatographed on silica gel with 5-50% ethyl acetate/ concentrated. The concentrate was purified by high pressure 10 hexanes. liquid chromatography on a Waters Symmetry Cs column (25 mmx100mm, 7um particle size) with 10-100% acetonitrile/ EXAMPLE 106D 0.1% aqueous TFA over 8 minutes at a flow rate of 40 mL/minute. "H NMR (400 MHz, DMSO-d) & 9.50 (s, 1H), This example was made by substituting EXAMPLE 106C 8.57 (s, 1H), 8.06 (d. 1H), 7.99 (d. 1H), 7.77 (d. 2H), 7.74 (m, 15 for EXAMPLE 2B in EXAMPLE 2C. 1H), 7.52 (m, 4H), 7.40 (d. 2H), 7.33 (m, 1H), 7.04 (m, 5H), 6.92 (d. 2H), 5.24 (m, 1H), 3.74 (m, 2H), 3.45 (m, 6H), 3.15 EXAMPLE 106E (m, 4H), 2.71 (s, 6H). This example was made by substituting EXAMPLE 106D EXAMPLE 105A for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 12.01 (s, 1H), 9.29 (s.1H), 8.53 (d. 1H), 8.29 (d. 3-Cyano-4-fluorobenzenesulfonyl chloride (5 g) in dichlo 1H), 7.86 (dd. 1H), 7.30 (m, 11H), 6.80 (d. 2H), 6.73 (d. 2H), romethane (110 mL) at -78°C. was treated with 7MNH in 4.18 (m. 1H), 3.50 (m, 4H), 3.39 (m, 4H), 3.04 (m, 6H), 2.78 methanol (8.1 mL), stirred at -20°C., and acidified with 1M 25 (s, 6H), 2.74 (d. 6H), 2.14 (m. 2H). HC1. The water layer was separated and extracted with dichloromethane. The extract was dried (MgSO), filtered, EXAMPLE 107A and concentrated. The concentrate was recrystallized from hexane/ethyl acetate. This example was prepared by Substituting 4-(methylsul 30 fanyl)phenylboronic acid for 4-(N,N-dimethylamino)phe EXAMPLE 105B nylboronic acid in EXAMPLE 106C. This example was made by substituting EXAMPLE 18C EXAMPLE 107B with EXAMPLE 1.8E in EXAMPLE 18F. 35 This example was made by substituting EXAMPLE 107A EXAMPLE 105B for EXAMPLE 2B in EXAMPLE 2C. A mixture of EXAMPLE 105A (0.5 g), EXAMPLE 105B EXAMPLE 107C (0.5 g), and DIEA (0.8 mL) in THF (6 mL) at 80° C. was stirred for 16 hours and concentrated. The concentrate was 40 This example was made by substituting EXAMPLE 107B flash chromatographed on silica gel with 5% methanol/ for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, dichloromethane. DMSO-d) & 12.01 (s, 1H), 9.38 (s, 1H), 8.53 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.49 (m,3H), 7.33 (m, 5H), 7.17 (m, 5H), EXAMPLE 105C 6.83 (d. 2H), 4.18 (m, 1H), 3.65 (m, 2H), 3.39 (m, 4H), 3.11 45 (m, 4H), 2.97 (m, 1H), 2.85 (m, 1H), 2.73 (d. 6H), 2.39 (s. A mixture of EXAMPLE 105B (0.05 g) and KOH (0.031 g) 3H), 2.14 (m, 2H). in tert-butanol (2 mL) at reflux was stirred for 6 hours and concentrated. The concentrate was flash chromatographed on EXAMPLE 108A silica gel with 5-10% methanol/dichloromethane. 50 This example was prepared by Substituting 4-chlorophe EXAMPLE 105D nylboronic acid for 4-(N,N-dimethylamino)phenylboronic acid in EXAMPLE 106C. This example was made by substituting EXAMPLE 105C for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 108B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 55 2D. "H NMR (400 MHz, DMSO-d) & 11.82 (s, 1H), 9.63 (s, This example was made by substituting EXAMPLE 108A 1H),8.82 (d. 1H), 8.15 (s, 1H), 7.76 (d. 2H), 7.70 (d. 1H), 7.52 for EXAMPLE 2B in EXAMPLE 2C. (d, 4H), 7.39 (d. 2H), 7.33 (m, 2H), 7.27 (m, 2H), 7.19 (m, 1H), 6.92 (d. 2H), 6.69 (s, 1H), 4.14 (m. 1H), 3.86 (m, 2H), EXAMPLE 108C 3.45 (m, 6H), 3.15 (m, 4H), 2.74 (s, 6H), 2.10 (m, 1H), 1.96 60 (m. 1H). This example was made by substituting EXAMPLE 108B for EXAMPLE 2C in EXAMPLE 2D. "H NMR (400 MHz, EXAMPLE 106B DMSO-d) & 12.01 (s, 1H), 9.38 (s, 1H), 8.53 (d. 1H), 8.29 (d. 1H), 7.86 (dd. 1H), 7.74 (d. 2H), 7.49 (m, 8H), 7.17 (m, 5H), A mixture of EXAMPLE 1A (1.5 g), 2-bromobenzoyl 65 6.83 (d. 2H), 4.18 (m, 1H), 3.65 (m, 2H), 3.39 (m, 4H), 3.11 chloride (1.5 g), and DIEA (2 mL) in THF (20 mL) at 25°C. (m, 4H), 2.99 (m, 1H), 2.89 (m. 1H), 2.74 (d. 6H), 2.14 (m, was stirred for 16 hours, filtered, and concentrated. 2H). US 7,973,161 B2 147 148 EXAMPLE 109 H NMR (400 MHz, DMSO-d) & 10.29 (s, 1H), 8.54 (d. 1H), 8.29 (s, 1H), 7.86 (dd. 1H), 7.76 (d. 2H), 7.65 (m, 2H), This example was made by substituting EXAMPLE 105B 7.46 (m, 5H), 7.30 (m, 1H), 7.22 (d. 2H), 7.12 (m, 4H), 6.92 for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) (d. 2H), 4.14 (m. 1H), 3.54 (m, 4H), 3.40 (m. 10H), 2.18 (m, propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2H), 1.32 (s, 6H), 0.87 (n,2H). 2D. "H NMR (400 MHz, DMSO-d) & 11.70 (s, 1H), 9.60 (s, 1H), 7.68 (d. 1H), 7.52 (d. 2H), 7.27 (m, 43H), 7.14 (d. 2H), EXAMPLE 112 7.08 (m, 1H), 7.00 (m, 5H), 6.91 (m. 1H), 6.67 (d. 2H), 6.37 (m. 2H), 3.96 (m. 1H), 3.70 (m, 2H), 3.80 (m, 4H), 3.02 (m, This example was made by Substituting 1,4,5,6-tetrahydro 4H), 2.89 (m, 4H), 2.58 (s, 6H), 1.84 (m, 2H). 10 pyrimidine for isopropylamine in EXAMPLE35B. "H NMR (400 MHz, DMSO-d) & 12.09 (s, 1H), 9.62 (d. 1H), 8.53 (d. EXAMPLE 11 OA 1H), 8.27 (d. 1H), 8.02 (d. 1H), 7.85 (dd. 1H), 7.76 (d. 2H), 7.51 (m, 3H), 7.40 (m, 1H), 7.14 (m, 7H), 6.93 (d. 2H), 4.14 3,4-dihydroxy-butyric acid methyl ester, prepared as (m. 1H), 3.40 (m. 14H), 3.19 (m. 2H), 2.12 (m. 2H), 1.88 (m, described in Chem. Lett., 1984, 1389, (510 mg) in dimethy 15 2H). lamine in THF (19 mL) in a sealed tube at 80°C. was stirred for 12 hours and concentrated. The concentrate was flash EXAMPLE 113 chromatographed on silica gel with 0-20% methanol/dichlo romethane. This example was made by Substituting 2-methyl-4,5-di hydro-1H-imidazole for isopropylamine in EXAMPLE 35B. EXAMPLE 11 OB "H NMR (400 MHz, DMSO-d) & 10.06 (s, 1H), 8.56 (d. 1H), 8.32 (d. 1H), 7.90 (dd. 1H), 7.81 (d. 2H), 7.55 (m, 4H), 7.43 A mixture of EXAMPLE 110A (200 mg), benzenethiol (d. 2H), 7.37 (m. 1H), 7.26 (m, 3H), 7.14 (m, 3H), 6.97 (d. (153 uL), and tributylphosphine (372 uL) in THF (10 mL) at 2H), 4.28 (m. 2H), 3.85 (m. 14H), 3.42 (m. 2H), 2.14 (m. 2H), 0°C. was treated with 1,1'-(aZodicarbonyl)dipiperidine (377 25 2.08 (s.3H), 1.27 (m, 2H). mg), stirred at 25° C. for 12 hours, and treated with ethyl acetate and 1M NaOH. The extract was extracted with ethyl EXAMPLE 114 acetate, and the extract was dried (MgSO), filtered and con centrated. The concentrate was flash chromatographed on This example was made by substituting EXAMPLE silica gel with 0% to 80% ethyl acetate/dichloromethane. 30 842657F and 1,4,5,6-tetrahydro-pyrimidine for isopropy lamine and 35A in EXAMPLE 35B. "H NMR (400 MHz, EXAMPLE 11 OC DMSO-d) & 11.92 (s, 1H), 9.60 (s, 1H), 8.01 (d. 1H), 7.95 (d. 1H), 7.80 (dd. 1H), 7.73 (d. 2H), 7.68 (m, 1H), 7.49 (m,3H), EXAMPLE 110B (160mg) in THF (2.3 mL) at 25°C. was 7.41 (d. 2H), 7.27 (m, 5H), 7.17 (m. 1H), 6.90 (d. 2H), 6.82 (d. treated with borane.THF (1 mL), stirred for 5 hours, treated 35 1H), 6.00 (d. 1H), 3.83 (m, 2H), 3.40 (m, 16H), 2.08 (m, 2H), with saturated methanolic HCl (3 mL), heated at reflux for 2 1.285 (t, 2H). hours, and concentrated. The concentrate was flash chro matographed on silica gel with 0-10% NH-saturated metha EXAMPLE 115 nol (saturated NH)/dichloromethane. 40 This example was made by Substituting 2,4-dimethyl-4,5- EXAMPLE 11 OD dihydro-1H-imidazole for 1,4,5,6-tetrahydro-pyrimidine In EXAMPLE 114. "H NMR (400 MHz, DMSO-d) & 11.92 (s, EXAMPLE 110C (224 mg) in DMF (1 mL) at 0°C. was 1H), 10.02 (s, 1H), 7.95 (d. 1H), 7.82 (dd. 1H), 7.73 (d. 2H), treated with NaH (40 mg), stirred at 25°C. for 1 hour, cooled 7.70 (m, 1H), 7.50 (m, 3H), 7.40 (d. 2H), 7.27 (m, 5H), 6.92 to 0°C., treated with 15-crown-5 (146 uL), stirred for 15 45 (m, 3H), 6.04 (d. 1H), 4.08 (m, 2H), 3.90 (m, 4H), 3.40 (m, minutes, treated with 4-fluoro-3-nitrobenzenesulfonamide, 10H), 2.04 (m, 2H), 2.02 (s.3H), 1.10 (m, 3H). prepared as described in WO02/24636, (110 mg), stirred at 25°C. for 2 hours, treated with saturated NHCl (200LL), and EXAMPLE 116 concentrated. The concentrate was flash chromatographed on silica gel with 50-100% ethyl acetate/hexane then switching 50 This example was made by Substituting 2-methyl-4,5-di to 0-10% NH-saturated methanol/dichloromethane. hydro-1H-imidazole for 1,4,5,6-tetrahydro-pyrimidine In EXAMPLE 114. "H NMR (400 MHz, DMSO-d) & 11.92 (s, EXAMPLE 11 OE 1H), 9.82 (s, 1H), 7.88 (d. 1H), 7.75 (dd. 1H), 7.68 (d. 2H), 7.62 (m. 1H), 7.43 (m, 3H), 7.35 (d. 2H), 7.28 (m, 5H), 6.82 This example was made by substituting EXAMPLE 110D 55 (m, 3H), 5.98 (d. 1H), 3.90 (m, 2H), 3.70 (m, 4H), 3.40 (m, for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 12H), 2.00 (m, 2H), 1.95 (s.3H). propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (400 MHz, DMSO-d) & 9.70 (s, 1H), 8.38 (d. EXAMPLE 117 1H), 8.09 (dd. 1H), 7.78 (m,3H), 7.51 (m, 5H), 7.27 (m, 8H), 6.92 (d. 2H), 5.01 (m, 1H), 3.47 (m, 2H), 3.33 (m, 2H), 3.21 60 This example was made by Substituting 4.4-dimethyl-4,5- (m, 4H), 3.14 (m, 2H), 3.05 (s.2H), 2.76 (s, 6H), 2.23 (m,2H). dihydro-1H-imidazole for 1,4,5,6-tetrahydro-pyrimidine In EXAMPLE 114. "H NMR (400 MHz, DMSO-d) & 11.92 (s, EXAMPLE 111 1H), 10.22 (s, 1H), 8.25 (d. 1H), 7.95 (d. 1H), 7.80 (dd. 1H), 7.75 (d. 2H), 7.65 (m. 1H), 7.52 (m, 3H), 7.50 (d. 2H), 7.25 This example was made by Substituting 4,4-dimethyl-4,5- 65 (m,5H), 7.18 (m. 1H), 6.90 (d. 2H), 6.82 (d. 1H), 6.00 (d. 1H), dihydro-1H-imidazole for isopropylamine in EXAMPLE 3.88 (m,2H), 3.50 (m, 4H), 3.40 (m, 10H), 2.08 (m, 2H), 1.25 35B. (m, 6H). US 7,973,161 B2 149 150 EXAMPLE 118A d) 89.60 (s, 1H), 7.95 (d. 1H), 7.81 (dd. 1H), 7.76 (d. 2H), 7.41 (d. 2H), 7.28 (m, 4H), 7.12 (d. 2H), 6.94 (d. 2H), 6.87 (d. EXAMPLE 18D (200 mg), cesium carbonate (671 mg) and 1H), 6.02 (d. 1H), 3.91 (m, 3H), 3.63 (m, 2H), 3.40 (m, 2H), tetrabutylammonium iodide (61 mg) in DMF (4 mL) at 25°C. 3.28 (m, 2H), 3.15 (m, 4H), 3.00 (m, 2H), 2.73 (d. 6H), 2.46 was treated with 4-methoxybenzyl chloride (246 uL), stirred (m, 4H), 2.10 (m, 2H), 1.82 (m, 2H), 1.57 (m, 4H). for 12 hours, and treated with ethyl acetate and saturated EXAMPLE 120 NHC1. The extract was extracted with ethyl acetate, and the combined extracts were dried (MgSO), filtered, and concen This example was made by Substituting bis(2-methoxy trated. The concentrate was flash chromatographed on silica ethyl) for isopropylamine in EXAMPLE 35B. H gel with 0-50% ethyl acetate/hexane. 10 NMR (500 MHz, DMSO-d) & 12.02 (s, 1H), 9.50 (s, 1H), 8.54 (d. 1H), 8.27 (d. 1H), 7.87 (dd. 1H), 7.77 (m, 3H), 7.52 EXAMPLE 118B (m, 4H), 7.39 (d. 2H), 7.34 (m. 1H), 7.16 (m, 5H), 6.94 (d. 2H), 4.32 (m, 1H), 4.20 (m, 2H), 3.61 (m, 4H), 3.39 (m, 2H), EXAMPLE 110C (38 mg) in N-methyl-2-pyrrolidinone 3.30 (m. 12), 3.23 (s, 6H), 2.17 (m, 2H). (845 LL) at 25°C. was treated with NaH (8 mg), stirred for 20 15 minutes, treated with EXAMPLE 118A (122 mg), stirred for EXAMPLE 121 3 hours, treated with NaH (6.6 mg) and EXAMPLE 118A (76 mg), stirred for 3 hours, treated with saturated NaHCO, (1 This example was made by Substituting bis(2-methoxy mL), and partitioned between ethyl acetate and Saturated ethyl)amine for 1,4,5,6-tetrahydropyrimidine in EXAMPLE NaHCO. The extract was extracted with ethyl acetate, and 114. "H NMR (500 MHz, DMSO-d) & 12.02 (s, 1H), 9.50 (s, the combined extracts were dried (MgSO), filtered, and con 1H), 7.95 (d. 1H), 7.83 (dd. 1H), 7.75 (m,3H), 7.53 (m, 4H), centrated. The concentrate was flash chromatographed on 7.39 (d. 2H), 7.34 (m, 5H), 7.16 (m, 1H), 6.94 (m, 2H), 6.02 silica gel with 0-to 50% acetonitrile (1% NH-saturated (d. 1H), 4.32 (m, 1H), 3.96 (m, 2H), 3.61 (m, 4H), 3.39 (m, methanol)/1% NH-saturated ethyl acetate. 25 16H), 3.23 (s, 6H), 2.17 (m, 2H). EXAMPLE 118C EXAMPLE 122A EXAMPLE 118C (90 mg) in triethylsilane/TFA/dichlo A mixture of EXAMPLE 29C (0.5 g) and diethylamine (4 romethane (0.05 mL/0.45 mL/0.5 mL) at 25°C. was stirred mL) in THF (4 mL) at 25°C. was stirred for 2 hours and for 12 hours and concentrated. The concentrate was flash 30 concentrated. The concentrate was flash chromatographed on chromatographed on silica gel with 5% NH-saturated silica gel with 5% to 10% methanol/dichloromethane. methanol/dichloromethane. EXAMPLE 122B EXAMPLE 118D 35 This example was made by substituting EXAMPLE 122A This example was made by substituting EXAMPLE 118C for EXAMPLE 105B EXAMPLE 119B.HNMR (400 MHz, and EXAMPLE 83.7538C for EXAMPLE 2C and 4-(((1R)- DMSO-d) & 12.02 (s, 1H),9.60 (s, 1H), 8.50 (s, 1H), 7.95 (d. 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) 1H), 7.81 (dd. 1H), 7.76 (d. 2H), 7.41 (d. 2H), 7.28 (m, 4H), amino)-3-nitrobenzenesulfonamide (prepared according to 7.12 (d. 2H), 6.94 (m, 3H), 6.12 (d. 1H), 4.02 (m, 1H), 3.89 the procedure described in commonly owned WO02/24636, 40 (m. 2H), 3.63 (m, 4H), 3.42 (m, 4H), 3.17 (m, 2H), 2.93 (m, filed Sep. 20, 2001) in EXAMPLE 2D. "H NMR (400 MHz, 2H), 2.79 (m, 2H), 2.46 (m, 4H), 2.10 (m, 2H), 1.82 (m, 2H), DMSO-d) & 12.02 (s, 1H), 9.40 (s, 1H), 8.12 (d. 2H), 7.72 (d. 1.57 (m, 4H), 1.23 (m. 12H). 2H), 7.41 (m, 3H), 7.31 (d. 2H), 7.26 (m, 2H), 7.17 (m, 3H), 6.95 (d. 2H), 4.97 (m, 1H), 3.50 (m, 12H), 3.16 (m, 4H), 2.76 EXAMPLE 859948 (s, 6H), 2.23 (m, 4H), 1.70 (s, 4H). 45 This example was made by Substituting 4,4-difluoropiperi EXAMPLE 119A dine for isopropylamine in EXAMPLE 35B. "H NMR (400 MHz, DMSO-d) & 10.06 (s, 1H), 8.55 (d. 1H), 8.30 (d. 1H), A mixture of 4-bromo-3-(trifluoromethyl)benzene 7.87 (dd. 1H), 7.77 (d. 2H), 7.55 (m, 4H), 7.40 (d. 2H), 7.39 sulfonamide (0.121 g), EXAMPLE 847124C (0.17 g) EDAC 50 (m. 1H), 7.24 (m, 3H), 7.13 (m, 3H), 6.93 (d. 2H), 4.20 (m, (0.153 g), and DMAP (0.098 g) in dichloromethane (2 mL) at 2H), 3.86 (m, 4H), 3.42 (m, 4H), 3.17 (m, 8H), 2.28 (m, 4H), 25°C. was stirred for 16 hours, treated with ethyl acetate, 2.18 (m, 4H). washed with saturated NHCl solution and brine, and dried (NaSO), filtered, and concentrated. The concentrate was EXAMPLE 8.55996 flash chromatographed on silica gel with 5% methanol/ 55 dichloromethane. This example was made by Substituting 2-methylpyrroli dine for isopropylamine in EXAMPLE 35B. "H NMR (400 EXAMPLE 119B MHz, DMSO-d) & 9.42 (s, 1H), 8.54 (d. 1H), 8.32 (d. 1H), 7.87 (dd. 1H), 7.77 (d. 2H), 7.53 (m, 4H), 7.39 (d. 2H), 7.36 A mixture of EXAMPLE 119A (0.1 g), EXAMPLE 105B 60 (m. 1H), 7.23 (m, 3H), 7.14 (m, 3H), 6.94 (d. 2H), 4.05 (m, (0.038 g), Pd(dba), (0.011 g), BINAP (0.009 g), CsCO, 6H), 3.57 (m, 2H), 3.40 (m, 4H), 3.06 (m, 4H), 2.14 (m, 2H), (0.07 g) in toluene (1.5 mL) at 100° C. was stirred for 16 1.93 (m, 2H), 1.57 (m, 2H), 1.27 (m, 3H). hours, filtered, and concentrated. The concentrate was puri fied by high pressure liquid chromatography on a Waters EXAMPLE 123A Symmetry Cs column (25 mmx100 mm, 7 um particle size) 65 with 10-100% acetonitrile/0.1% aqueous TFA over 8 minutes 2.5 g/100 mL Rieke magnesium in diethyl ether (12.75 at a flow rate of 40 mL/minute. "H NMR (400 MHz, DMSO mL) at 25°C. was treated with 1-bromo-3-methyl-2-butene US 7,973,161 B2 151 152 (1.81 g), stirred for 1 hour, added to 2-methylpropane-2- 3.95-4.12 (m, 1H), 3.41 (m, 1H), 3.17-3.27 (m, 4H), 2.79 Sulfonic acid (2-benzyloxyethylidene)amide, prepared as 2.96 (m, 4H), 2.33–2.45 (m, 5H), 1.73 (m, 4H), 1.18-1.43 (m, described in J. Org. Chem. 2001, 26, 8772-8778, (1.85g) in 9H). toluene (30 mL) at -78° C., and treated, at 25° C., with saturated NHCl, ethyl acetate, and water. The extract was 5 EXAMPLE 125 washed with water and brine and dried (MgSO), filtered, and concentrated. The concentrate was flash chromatographed on EXAMPLE 124 (0.40 g) in dichloromethane (10 mL) was silica gel with 10-20% acetone/hexanes. treated with 4M HCl in dioxane (2 mL), stirred for 20 hours at 25°C., and concentrated to give the desired product as the EXAMPLE 123B 10 hydrochloride salt. "H NMR (300 MHz, DMSO-d) & 12.09 (s, 1H),9.76 (s, 1H), 8.53 (d. 1H), 8.30 (d. 1H), 7.85 (dd. 1H), EXAMPLE 123A (1.01 g) in methanol (20 mL) at 25°C. 7.77 (d. 3H), 7.62 (m, 4H), 7.52 (d. 2H), 7.40 (d. 1H), 7.34 (d. was treated with 4M HCl in dioxane (8 mL), stirred for 10 2H), 7.18-7.26 (m,3H), 7.03-7.18 (m, 2H), 6.93 (d. 2H), 4.33 minutes, treated with 10% Pd/C, stirred under H (balloon) (m. 2H), 4.08 (m, 3H), 3.28-3.42 (m, 4H), 3.11 (m, 4H), for 18 hours, filtered through diatomaceous earth (Celite(R). 15 2.81-2.96 (m. 1H), 2.64-2.81 (m, 4H), 1.66-1.85 (m, 2H), and concentrated. The concentrate was mixed with 1:1 2M 1.43-1.58 (m, 2H), 1.24-1.43 (m, 2H). NaCO/chloroform (60 mL), treated with benzylchlorofor mate (0.58 mL) and benzyltriethylammonium chloride (cata EXAMPLE 126 lytic), and stirred 3 hours. The extract was washed with water, dried (MgSO), filtered, and concentrated. The concentrate EXAMPLE 125 (0.075 g) in dichloromethane (7 mL) was was flash chromatographed on silica gel with 3:1-2:1 hex treated with DIEA (0.055 g), cooled to 0°C., treated with anes/ethyl acetate. methanesulfonylchloride (0.013 g), stirred for 1 hour, and treated with water. The extract was washed with water and EXAMPLE 123C 25 brine, and dried (MgSO), filtered, and concentrated. The A mixture of EXAMPLE 123B (0.52g), diphenyldisulfide concentrate was flash chromatographed on silica gel with (0.40 g), and tributylphosphine (0.81 g) in toluene (15 mL) at 0-2.5% methanol in dichloromethane. "H NMR (300 MHz, 85°C. was stirred for 18 hours, cooled to 25°C., and concen DMSO-d) & 12.00 (s, 1H), 8.52 (d. 1H), 8.30 (d. 1H), 7.84 trated. The concentrate was flash chromatographed on silica (dd. 1H), 7.74 (d. 2H), 7.43-7.57 (m, 1H), 7.47 (s. 2H), gel with 20:1 then 10:1 and 5:1 hexanes/ethyl acetate. 30 7.32-7.42 (m, 2H), 7.20-7.29 (m, 3H), 7.04-7.19 (m, 4H), 6.84-6.94 (m, 3H), 3.98-4.16 (m, 1H), 3.16-3.48 (m, 7H), EXAMPLE 123D 2.85-2.95 (m, 2H), 2.83 (s.3H), 2.41 (m, 3H), 1.67-1.83 (m, 2H), 1.28-1.50 (m, 4H). EXAMPLE 123C (0.52g) in 30% HBr in acetic acid (15 mL) at 25°C. was stirred for 2 hours, poured into 5% HCl (75 35 EXAMPLE 127 mL), washed with ethyl acetate, brought to pH 12 with 15% NaOH, and extracted with chloroform. The extract was dried EXAMPLE 125 (0.065 g) in dichloromethane (7 mL) at (MgSO4) and concentrated. 25° C. was treated with DIEA (0.048 g), cooled to 0°C., treated with trimethylsilylisocyanate (0.011 g), stirred at 25° EXAMPLE 123E 40 C. for 24 hours, treated with methanol (0.5 mL), and concen trated. The concentrate was purified by reverse phase HPLC This example was made by substituting EXAMPLE 123D (C-18) with 10-100% acetonitrile/water containing 0.1% for EXAMPLE 21C in EXAMPLE 21 D. TFA.'HNMR (300 MHz, DMSO-d) & 12.07 (s, 1H),9.56(s, 1H), 8.52 (s, 1H), 8.31 (d. 1H), 7.84 (dd. 1H), 7.77 (d. 3H), EXAMPLE 123F 45 7.52 (m, 3H), 7.28-7.44 (m,3H), 7.03-7.27 (m, 6H), 6.93 (d. 2H), 5.80-5.93 (m, 1H), 5.18-5.42 (m, 2H), 4.26-4.51 (m, This example was made by substituting EXAMPLE 123 E 2H), 4.08 (m, 2H), 3.75-3.98 (m, 2H), 2.99-3.20 (m, 3H), for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 2.79-2.98 (m, 4H), 1.63-1.89 (m, 2H), 1.24-1.44 (m, 4H). propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 12.07 (s, 1H), 9.61 (s, 50 EXAMPLE 128A 1H), 8.49 (d. 1H), 8.35 (d. 1H), 7.64-7.96 (m, 4H), 7.41-7.60 (m, 5H), 7.24-7.40 (m, 4H), 7.01-7.20 (m, 4H), 6.92 (d. 2H), A mixture of ethyl 4-fluorobenzoate (7.71 g), 1-(tert-bu 4.38 (m, 2H), 4.05 (m, 1H), 3.68-3.95 (m, 2H), 3.21-3.65 (m, toxycarbonyl)piperazine (9.31 g), potassium carbonate (13.8 1H), 2.96-3.25 (m, 2H), 2.61-2.95 (m, 2H), 1.17-1.50 (m, g), and 1-methyl-2-pyrrolidinone (20 mL) at 130° C. was 1H), 0.93 (d. 6H), 0.80 (t, 4H). 55 stirred for 16 hours, poured into water, and filtered. The filtrant was washed with water and dried in a vacuum oven at EXAMPLE 124 50° C. and 18 mmHg. This example was made by substituting tert-butyl (5R)-5- EXAMPLE 128B ((4-(aminosulfonyl)-2-nitrophenyl)amino)-6-(phenylsulfa 60 nyl)hexylcarbamate, prepared as described in WO 02/24636, This example was prepared by substituting EXAMPLE for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 128A for EXAMPLE 1 B in EXAMPLE 1 C. propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 11.96 (s, 1H), 8.51 (d. EXAMPLE 128C 1H), 8.28 (d. 1H), 7.83 (dd. 1H), 7.74 (d. 2H), 7.49-7.56 (m, 65 3H), 7.44-7.49 (m, 2H), 7.34-7.41 (m, 2H), 7.20-7.28 (m, This example was prepared by substituting EXAMPLE 3H), 7.03-7.19 (m, 4H), 6.89 (d. 2H), 6.66-6.77 (m, 1H), 128B for EXAMPLE 1 C in EXAMPLE 1D. US 7,973,161 B2 153 154 EXAMPLE 128D nylphosphino) ferrocene)palladium (II).dichloromethane (82 mg). The container was sealed, and the mixture was heated at EXAMPLE 128C (3.7g) in dichloromethane (10 mL) and 120° C. for 16 hours and concentrated. The concentrate was 4M HCl in dioxane (10 mL) at 25°C. was stirred for 5 hours, flash chromatographed on silica gel with 50% ethyl acetate/ concentrated, treated with diethyl ether (20 mL), and filtered. hexanes. The filtrant was washed with diethyl ether and dried in a vacuum oven at 50° C. and 18 mm Hg. EXAMPLE 13 OD EXAMPLE 128E EXAMPLE 128C (4.02 g) in dioxane (7 mL) at 25°C. was 10 treated with 4M HCl (7 mL), stirred for 16 hours, neutralized EXAMPLE 128D (110 mg) in dichloromethane (2 mL) at and extracted with dichloromethane. The extract was concen 25°C. was treated with 2-(methylsulfanyl)benzaldehyde (27 trated. The concentrate was chromatographed on Cs with 1:1 mg), N,N-DIEA (52 mg), and sodium triacetoxyborohydride acetonitrile/0.1% aqueous TFA. (38 mg), stirred for 16 hours, and concentrated. The concen trate was flash chromatographed on silica gel with 10% 15 EXAMPLE 13OE methanol/dichloromethane. "H NMR (300 MHz, DMSO-d) & 8.45 (d. 1H), 8.36 (d. 1H), 7.78 (dd. 1H), 7.73 (d. 2H), EXAMPLE 130C (50mg) in dichloromethane (2 mL) and 7.38-7.21 (m, 6H), 7.18 (d. 1H), 7.18-7.10 (m, 2H), 6.87 (d. methanol (0.4 mL) at 25° C. was treated with EXAMPLE 1H), 6.80 (d. 2H), 4.10-4.01 (m, 1H), 3.52 (s. 2H), 3.33 (d. 130D (130 mg) and 2.38 mmol/g MP-BHCN (118 mg), 2H), 3.18 (t, 4H), 2.65-2.40 (m, 6H), 2.44 (s, 3H), 2.27 (s, stirred for 16 hours, and concentrated. The concentrate was 6H), 2.07-1.82 (m, 2H). flash chromatographed on silica gel with 20% methanol/ dichloromethane. "H NMR (300 MHz, DMSO-d) & 8.42 (d. EXAMPLE 129A 1H), 8.26 (d. 1H), 7.79 (dd. 1H), 7.74 (dd, 2H), 7.62-7.44 (m, 2-(methylsulfanyl)benzaldehyde (1 g) in dichloromethane 25 2H), 7.40-7.35 (m, 2H), 7.32 (d. 2H), 7.25 (td, 2H), 7.17 (tt, (35 mL) was treated with 70% 3-chloroperoxybenzoic acid 1H), 6.88 (d. 1H), 6.82 (t, 2H), 4.10-4.01 (m, 1H), 3.78 (s, (3.32 g), stirred for 75 minutes, and concentrated. The con 2H), 3.49 (s. 2H), 3.34 (d. 2H), 3.23-3.14 (m, 6H), 2.90-2.62 centrate was flash chromatographed on silica gel with 1:1 (m, 4H), 2.43 (s, 6H), 2.10-1.90 (m, 2H), 1.50 (s, 6H). ethyl acetate/hexanes. 30 EXAMPLE 131A EXAMPLE 129B A mixture of 2-bromobenzaldehyde (4 g), butylamine EXAMPLE 128D (110 mg) in dichloromethane (2 mL) (1.58 g), and 4A sieves (3 g) in dichloromethane (75 mL) at was treated with EXAMPLE 129A (33 mg), 3.45 mmol/g 25°C. was stirred for 72 hours, filtered and concentrated. N,N-DIEA resin (116 mg), and sodium triacetoxyborohy 35 dride (38 mg), stirred at 25°C. for 16 hours, and concentrated. EXAMPLE 131B The concentrate was flash chromatographed on silica gel with 10% methanol/dichloromethane. "H NMR (300 MHz, EXAMPLE 131A (400 mg) in THF (5 mL) at 0°C. was DMSO-d) 88.45 (d. 1H),8.21 (d. 1H), 7.98 (d. 1H), 7.81 (dd. treated with MnCl2 (21 mg) and 2M cyclohexylmagnesium 1H), 7.73 (d. 2H), 7.70 (td, 1H), 7.61 (d. 2H), 7.32 (dd, 2H), 40 chloride in THF (1.67 mL), stirred for 25 minutes, treated 7.24 (tt, 2H), 7.17 (tt, 1H), 6.90 (d. 1H), 6.82 (d. 2H), 4.11 with saturated NHCl, and extracted with diethyl ether. The 4.01 (m. 1H), 3.93 (s. 2H), 3.42 (s.3H), 3.33 (d. 2H), 3.18 (t, extract was washed with brine, dried (Na2SO), filtered, and 4H), 3.00-2.80 (m, 2H), 2.62-2.48 (m, 4H), 2.56 (s, 6H), concentrated. The concentrate was flash chromatographed on 2.13-1.98 (m, 2H). silica gel with 5% ethyl acetate/hexanes. Relevant fractions 45 were combined and concentrated. The concentrate in 1:1 EXAMPLE 13OA 1,4-dioxane?water was stirred at 25° C. for 16 hours and extracted with diethyl ether. The extract was washed with N-(tertbutoxycarbonyl)glycine methyl ester (5 g) in THF brine and dried (NaSO), filtered, and concentrated. (60 mL) at 0°C. was treated with 1.4M methylmagnesium bromide in 3:1 toluene/THF (75.5 mL), stirred at 25°C. for 16 50 EXAMPLE 13 1C hours, cooled to 0°C., treated with saturated NHCl, and extracted with ethyl acetate. The extract was washed with This example was prepared by substituting EXAMPLE brine and dried (Na2SO), filtered, and concentrated. 131B for EXAMPLE 130C in EXAMPLE 13OD. H NMR (300 MHz, DMSO-d) 88.43 (d. 1H), 8.18 (d. 1H), 7.82 (dd. EXAMPLE 13OB 55 1H), 7.73 (d. 2H), 7.45-7.37 (m, 1H), 7.30 (d. 2H), 7.28-7.07 (m, 6H), 6.92 (d. 1H), 6.82 (d. 2H), 4.12-4.01 (m, 1H), 3.51 (s, EXAMPLE 130A (1g) in THF (27 mL) at OC was treated 2H), 3.33 (d. 2H), 3.17 (s, 4H), 3.05-2.88 (m, 3H), 2.70-2.52 with potassium tert-butoxide (663 mg), stirred for 30 min (m. 2H), 2.61 (s, 6H), 2.16-1.98 (m, 2H), 1.84-1.65 (m, 6H), utes, and concentrated. The concentrate was flash chromato 1.50-1.22 (m, 6H). graphed on silica gel with 5% methanol/ethyl acetate. 60 EXAMPLE 132 EXAMPLE 130C This example was prepared by Substituting 2-morpholi A mixture of EXAMPLE 130B (120 mg), 2-bromobenzal nobenzaldehyde for EXAMPLE 130C in EXAMPLE 130D. dehyde (289 mg), and sodium tert-butoxide (150mg) in tolu 65 "H NMR (300 MHz, DMSO-d) & 8.46 (d. 1H), 8.22 (d. 1H), ene (5 mL) in a sealable container was degassed/flushed with 7.81 (dd. 1H), 7.72 (d. 2H), 7.39 (dd. 1H), 7.32 (d. 2H), nitrogen three times and treated with dichloro(1,1'-bis(diphe 7.28-7.22 (m, 3H), 7.20-7.04 (m, 3H), 6.90 (d. 1H), 6.81 (d. US 7,973,161 B2 155 156 2H), 4.14-4.00 (m. 1H), 3.75 (t, 4H), 3.57 (s. 2H), 3.33 (d. EXAMPLE 135A 2H), 3.18 (s, 4H), 2.94 (t, 4H), 2.88-2.50 (m, 6H), 2.56 (s, 6H), 2.15-1.90 (m, 2H). This example was prepared by Substituting di-n-propy lamine for N-methylisopropylamine in EXAMPLE 134A. EXAMPLE 133A 5 EXAMPLE 135B 2-propanethiol (797mg) in 1-methyl-2-pyrrolidinone (20 mL) at 25°C. was treated with 60% sodium hydride (419 mg) This example was prepared by substituting EXAMPLE and 2-fluorobenzaldhyde (1 g), stirred for 10 minutes, treated 135A for EXAMPLE 18A in EXAMPLE 18B. with 1MNaOH (20 mL), and extracted with diethylether. The 10 extract was washed with water and brine and dried (Na2SO), EXAMPLE 135C filtered, and concentrated. This example was prepared by substituting EXAMPLE EXAMPLE 133B 135B for EXAMPLE 18B in EXAMPLE 18C. 15 This example was prepared by substituting EXAMPLE EXAMPLE 135D 133A for EXAMPLE 130C in EXAMPLE 13OD. "H NMR (300 MHz, DMSO-d) & 8.45 (d. 1H), 8.30 (d. This example was prepared by substituting EXAMPLE 1H), 7.78 (dd. 1H), 7.74 (d. 2H), 7.44 (dt, 2H), 7.33 (d. 2H), 135C for EXAMPLE 19C in EXAMPLE 19D. 7.28-7.22 (m, 4H), 7.17 (tt, 1H), 6.87 (d. 1H), 6.81 (d. 2H), 4.11-4.00 (m, 1H), 3.61 (s. 2H), 3.33 (d. 2H), 3.17 (t, 4H), EXAMPLE 135E 2.80-2.50 (m, 6H), 2.44-2.36 (m. 1H), 2.39 (s, 6H), 2.10-1.86 (m. 2H), 1.23 (d. 6H). This example was prepared by substituting EXAMPLE 13.5D for EXAMPLE 21C in EXAMPLE 21 D. EXAMPLE 134A 25 EXAMPLE 135F A mixture of 3-(R)-((carbobenzyloxy)amino)-y-butyrolac tone, prepared according to the procedure described in J. Am. This example was prepared by substituting EXAMPLE Chem. Soc. 1986, 108, 4943-4952, (15g) and N-methyliso 135E and EXAMPLE 83.7538C for 4-(((1R)-3-(dimethy propylamine (25 mL) in diglyme (200 mL) at 120° C. was 30 lamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-ni stirred for 48 hours, and concentrated. The concentrate was trobenzenesulfonamide, prepared as described in WO02/ flash chromatographed on silica gel with 5% methanol/ethyl 24636, and EXAMPLE 1C, respectively, in EXAMPLE 1D. acetate. H NMR (300 MHz, DMSO-d) & 8.44 (d. 1H), 8.18 (s, 1H), 7.78 (d. 1H), 7.71 (d. 2H), 7.38-7.29 (m, 4H), 7.24 (tt, EXAMPLE 134B 35 2H), 7.18 (dt, 1H), 7.12 (d. 2H), 6.93-6.84 (m. 1H), 6.77 (d. 2H), 4.12-3.98 (m, 1H), 3.32 (d. 2H), 3.12 (s, 4H), 2.76 (s, This example was prepared by substituting EXAMPLE 2H), 2.50-2.30 (m, 2H), 2.27 (s, 4H), 2.23-2.14 (m, 6H), 134A for EXAMPLE 18A in EXAMPLE 18B. 2.1.0-1.94 (m, 2H), 1.66 (s, 4H), 1.60-1.20 (m, 6H), 0.80 (s, 6H). EXAMPLE 134C 40 EXAMPLE 136 This example was prepared by substituting EXAMPLE 134B for EXAMPLE 18B in EXAMPLE 18C. This example was prepared by substituting EXAMPLE 135E for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) EXAMPLE 134D 45 methyl)propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 8.45 (d. This example was prepared by substituting EXAMPLE 1H), 8.18 (s, 1H), 7.89 (d. 1H), 7.72 (d. 2H), 7.51 (dd. 1H), 134C for EXAMPLE 19C in EXAMPLE 19D. 7.48 (s, 4H), 7.40-7.34 (m, 2H), 7.32 (dd, 2H), 7.27-7.21, (m, 3H), 7.16 (tt, 1H), 6.94-6.85 (m, 1H), 6.79 (d. 2H), 4.12-4.00 EXAMPLE 134E 50 (m. 1H), 3.38 (s. 2H), 3.33 (d. 2H), 3.13 (t, 4H), 3.00-2.85 (m, 2H), 2.40 (t, 4H), 2.08-1.93 (m, 2H), 1.60- 1.20 (m, 8H), 0.81 This example was prepared by substituting EXAMPLE (s, 6H). 134D for EXAMPLE 21C in EXAMPLE 21 D. EXAMPLE 137A EXAMPLE 134F 55 This example was prepared by Substituting diethylamine This example was prepared by substituting EXAMPLE for N-methylisopropylamine in EXAMPLE 134A. 855.0516E and EXAMPLE 83.7538C for 4-(((1R)-3-(dim ethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3- EXAMPLE 137B nitrobenzenesulfonamide, prepared as described in WO02/ 60 24636, and EXAMPLE 1C, respectively, in EXAMPLE 1D. This example was prepared by substituting EXAMPLE "H NMR (300 MHz, DMSO-d) & 8.43 (d. 1H), 8.16 (s, 137A for EXAMPLE 18A in EXAMPLE 18B. 1H), 7.79 (d. 1H), 7.70 (d. 2H), 7.39-7.28 (m, 4H), 7.25 (td, 2H), 7.18 (dt, 1H), 7.12 (dt, 2H), 6.90 (d. 1H), 6.76 (d. 2H), EXAMPLE 137C 4.13-4.01 (m, 1H), 3.34 (d. 2H), 3.12 (s, 4H), 2.76 (s. 2H), 65 2.67-2.49 (m, 2H), 2.27 (s, 4H), 2.23-2.00 (m, 8H), 1.66 (s, This example was prepared by substituting EXAMPLE 4H), 1.22-0.96 (m, 8H). 137B for EXAMPLE 18B in EXAMPLE 18C. US 7,973,161 B2 157 158 EXAMPLE 137D DMSO-d) & 12.15 (br. 1H), 10.11 (br. 1H), 9.46 (br. 1H), 8.55 (d. 1H), 8.30 (d. 1H), 7.89 (d. 1H), 7.82 (m, 4H), 7.70 (m, This example was prepared by substituting EXAMPLE 2H), 7.59 (t, 1H), 7.51 (m, 3H), 7.42 (m, 1H), 7.17 (m, 6H), 137C for EXAMPLE 19C in EXAMPLE 19D. 7.02 (d. 2H), 4.46 (m, 2H), 3.50 (m. 13H), 2.74 (d. 6H), 2.14 (q, 2H). EXAMPLE 137E EXAMPLE 141 This example was prepared by substituting EXAMPLE 137D for EXAMPLE 21C in EXAMPLE 21D. This example was made by substituting EXAMPLE 139C and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) EXAMPLE 137F 10 propyl)amino)-3-nitrobenzenesulfonamide, prepared as described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- This example was prepared by substituting EXAMPLE 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) 137E and EXAMPLE 83.7538C for 4-(((1R)-3-(dimethy amino)-3-nitrobenzenesulfonamide, respectively, in lamino)-1-((phenylsulfanyl)methyl)propyl)amino)-3-ni EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 12.17 (br. trobenzenesulfonamide, prepared as described in WO02/ 15 1H), 10.10 (br. 1H), 9.77 (br. 1H), 8.55 (d. 1H), 8.31 (d. 1H), 24636, and EXAMPLE 1C, respectively, in EXAMPLE 1D. 7.89 (dd. 1H), 7.80 (m, 4H), 7.70 (m, 2H), 7.59 (t, 1H), 7.51 H NMR (300 MHz, DMSO-d) & 8.44 (d. 1H), 8.18 (d. 1H), (m, 3H), 7.41 (m, 1H), 7.18 (m, 6H), 7.01 (d. 2H), 4.46 (m, 7.81 (dd. 1H), 7.71 (d. 2H), 7.37 (d. 2H), 7.31 (dd, 2H), 7.24 2H), 3.60 (m, 21H), 2.17 (q, 2H). (tt, 2H), 7.18 (dt, 1H), 7.12 (d. 2H), 6.92 (d. 1H), 6.77 (d. 2H), 4.17-4.04 (m, 1H), 3.34 (d. 2H), 3.12 (s, 4H), 2.95 (m, 6H), EXAMPLE 142A 2.76 (s. 2H), 2.27 (s, 4H), 2.19 (m, 4H), 2.06 (m, 2H), 1.66 (s, 4H), 1.08 (t, 6H). 3,4-Difluorobenzoic acid (1 g) in THF (6 mL) and metha nol (3 mL) at 25°C. was treated with 2M (trimethylsilyl) EXAMPLE 138 diazomethane in hexane (4 mL), stirred for 2 hours, and concentrated. The concentrate was flash chromatographed on This example was prepared by substituting EXAMPLE 25 silica gel with 5% ethyl acetate/hexane. 137E for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl) methyl)propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 142B EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 8.46 (d. 1H), 8.18 (s, 1H), 7.82 (dd. 1H), 7.72 (d. 2H), 7.52 (dd. 1H), EXAMPLE 142A in acetonitrile (6 mL) at 25° C. was 7.48 (s, 4H), 7.40-7.35 (m, 2H), 7.31 (dd, 2H), 7.27-7.22, (m, 30 treated with KCO (0.46 g) and piperazine (250 mg), 3H), 7.17 (tt, 1H), 6.94 (d. 1H), 6.79 (d. 2H), 4.15-4.04 (m, refluxed for 24 hours, cooled to 25°C., treated with KCO 1H), 3.38 (s. 2H), 3.35 (d. 2H), 3.14 (t, 4H), 3.13-2.95 (m, (0.40 g) and 2-phenylbenzyl bromide (0.53 mL), stirred for 6H), 2.40 (t, 4H), 2.15-2.00 (m, 2H), 1.10 (s, 6H). 18 hours, and concentrated. The concentrate was partitioned between ethyl acetate and brine. The extract was dried EXAMPLE 139A 35 (Na2SO4), filtered, and concentrated. The concentrate was This example was made by substituting 3-bromobenzyl flash chromatographed on silica gel with 5% acetone/hexane. bromide for 2-bromobenzyl bromide in EXAMPLE 2A. EXAMPLE 142C EXAMPLE 139B 40 This example was made by substituting EXAMPLE 142B This example was made by substituting EXAMPLE 139A for EXAMPLE 2B in EXAMPLE 2C. and phenylboronic acid for EXAMPLE 2A and 4-chlorophe nylboronic acid, respectively, in EXAMPLE 2B. EXAMPLE 142D EXAMPLE 139C 45 This example was made by substituting EXAMPLE 142C for EXAMPLE 2C in EXAMPLE 2D. "H NMR (300 MHz, This example was made by substituting EXAMPLE 139B DMSO-d) & 9.79 (br. 1H), 9.47 (br. 1H), 8.53 (d. 1H), 8.30 for EXAMPLE 2B in EXAMPLE 2.0. (d. 1H), 7.86 (dd. 1H), 7.69 (m, 3H), 7.43 (m, 8H), 7.14 (m, 8H), 3.65 (m. 15H), 2.74 (d. 6H), 2.14 (q, 2H). EXAMPLE 139D 50 EXAMPLE 143 This example was made by substituting EXAMPLE 139C and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene This example was made by substituting EXAMPLE 142C sulfonamide, prepared as described in WO 02/24636, for and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl 55 sulfonamide, prepared as described in WO 02/24636, for Sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl respectively, in EXAMPLE2D. "H NMR (300 MHz, DMSO Sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, d) & 12.12 (br. 1H), 9.92 (br. 1H), 8.78 (t, 1H), 8.60 (d. 1H), respectively, in EXAMPLE2D. "H NMR (300 MHz, DMSO 7.91 (dd. 1H), 7.81 (m, 4H), 7.70 (m, 2H), 7.59 (t, 1H), 7.51 d) & 12.28 (br. 1H), 9.66 (m. 1H), 8.78 (t, 1H), 8.58 (d. 1H), (m, 3H), 7.39 (m, 3H), 7.21 (m, 4H), 7.00 (d. 2H), 4.44 (m, 60 7.89 (dd. 1H), 7.74 (br. 1H), 7.68 (s, 1H), 7.64 (m, 1H), 7.48 2H), 4.07 (m, 2H), 3.67 (t, 2H), 3.39 (m, 4H), 3.28 (t, 2H), (m, 4H), 7.37 (m, 5H), 7.23 (m, 4H), 7.05 (t, 2H), 4.38 (m, 3.18 (m, 2H). 2H), 3.24 (m. 12H). EXAMPLE 140 EXAMPLE 1.44 65 This example was made by substituting EXAMPLE 139C This example was made by substituting EXAMPLE 142C for EXAMPLE 2C in EXAMPLE 2D. "H NMR (300 MHz, and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) US 7,973,161 B2 159 160 propyl)amino)-3-nitrobenzenesulfonamide, prepared as triacetoxyborohydride (368 mg), stirred for 1 hour, and described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- treated with dichloromethane and 1MNaOH. The extract was 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) washed with brine and dried (NaSO), filtered, and concen amino)-3-nitrobenzenesulfonamide, respectively, in trated. The concentrate was flash chromatographed on silica EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 9.74 (br. gel with 3-5% methanol/dichloromethane. 1H), 8.54 (d. 1H), 8.30 (d. 1H), 7.86 (dd. 1H), 7.68 (m, 3H), 7.48 (m, 9H), 7.13 (m, 6H), 3.63 (m, 23H), 2.18 (m, 2H). EXAMPLE 148C EXAMPLE 145A This example was made by substituting EXAMPLE 148B for EXAMPLE 2B in EXAMPLE 2C. This example was made by substituting 3,4,5-trifluoroben 10 Zoic acid for 3,4-difluorobenzoic acid in EXAMPLE 142A. EXAMPLE 148D EXAMPLE 145B This example was made by substituting EXAMPLE 148C and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene This example was made by substituting EXAMPLE 145A 15 sulfonamide, prepared as described in WO 02/24636, for for EXAMPLE 142A in EXAMPLE 142B. EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl Sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, EXAMPLE 145C respectively, in EXAMPLE2D. "H NMR (300 MHz, DMSO d) & 12.02 (br. 1H), 8.78 (t, 1H), 8.59 (d. 1H), 7.90 (dd. 1H), This example was made by substituting EXAMPLE 145B 7.80 (d. 1H), 7.77 (d. 2H), 7.60 (m, 6H), 7.35 (m, 2H), 7.21 for EXAMPLE 2B in EXAMPLE 2.0. (m, 4H), 6.95 (d. 2H), 4.10 (m,2H), 3.50 (m, 6H), 3.28 (t, 2H), 2.86 (m, 4H). EXAMPLE 145D EXAMPLE 149 This example was made by substituting EXAMPLE 145C for EXAMPLE 2C in EXAMPLE 2D. "H NMR (300 MHz, 25 This example was made by substituting EXAMPLE 148C DMSO-d) & 9.72 (br. 1H), 9.44 (br. 1H), 8.51 (d. 1H), 8.27 and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) (d. 1H), 7.84 (dd. 1H), 7.75 (m. 1H), 7.49 (m, 8H), 7.36 (m, propyl)amino)-3-nitrobenzenesulfonamide, prepared as 3H), 7.18 (m, 6H), 3.50 (m, 15H), 2.74 (d. 6H), 2.13 (q, 2H). described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) EXAMPLE 1.46 30 amino)-3-nitrobenzenesulfonamide, respectively, in EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 12.10 (br. This example was made by substituting EXAMPLE 145C 1H), 9.74 (br. 1H), 8.55 (d. 1H), 8.31 (d. 1H), 7.87 (dd. 1H), and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene 7.83 (d. 1H), 7.78 (d. 2H), 7.61 (m, 6H), 7.17 (m, 6H), 6.95 (d. sulfonamide, prepared as described in WO 02/24636, for 2H), 3.53 (m, 23H), 2.19 (m, 2H). EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl 35 Sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, EXAMPLE 15OA respectively, in EXAMPLE2D. "H NMR (300 MHz, DMSO d) & 9.55 (br. 1H), 8.72 (t, 1H), 8.55 (d. 1H), 7.87 (dd. 1H), This example was made by Substituting 1-phenylpyrazole 7.73 (br. 1H), 7.34 (m, 16H), 4.36 (m, 2H), 3.25 (m, 12H). for 1-phenylimidazole in EXAMPLE 148A. 40 EXAMPLE 1.47 EXAMPLE 15OB This example was made by substituting EXAMPLE 145C This example was made by substituting EXAMPLE 150A and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) for EXAMPLE 148A in EXAMPLE 148B. propyl)amino)-3-nitrobenzenesulfonamide, prepared as 45 described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- EXAMPLE 150C 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) amino)-3-nitrobenzenesulfonamide, respectively, in This example was made by substituting EXAMPLE 150B EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 9.70 (br. for EXAMPLE 2B in EXAMPLE 2C. 1H), 8.51 (d. 1H), 8.27 (d. 1H), 7.86 (dd. 1H), 7.75 (m, 1H), 50 7.49 (m, 7H), 7.35 (m, 3H), 7.25 (m, 2H), 7.16 (m, 4H), 4.40 EXAMPLE 15OD (m. 2H), 4.16 (m, 2H), 3.38 (m. 19H), 2.15 (m, 2H). This example was made by substituting EXAMPLE 150C EXAMPLE 148A and 3-nitro-4-((2-(phenylsulfanyl)ethyl)amino)benzene 55 sulfonamide, prepared as described in WO 02/24636, for 1-Phenylimidazole (0.44 mL) in THF at 0°C. was treated EXAMPLE 2C and 4-(((1R)-3-(dimethylamino)-1-((phenyl with 2.5M butyllithium in hexane (1.7 mL), stirred for 20 Sulfanyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide, minutes, treated with DMF (0.8 mL), stirred for 1.5 hours, respectively, in EXAMPLE 2D. and treated with saturated aqueous NHCl and ethyl acetate. "H NMR (300 MHz, DMSO-d) & 12.07 (br. 1H), 8.78 (t, The extract was washed with brine and dried (NaSO), fil 60 1H), 8.59 (d. 1H), 7.91 (dd. 1H), 7.76 (d. 2H), 7.75 (s, 1H), tered, and concentrated. The concentrate was flash chromato 7.52 (m, 5H), 7.36 (m, 2H), 7.21 (m, 4H), 6.95 (d. 2H), 6.67 graphed on silica gel with 15% acetone/hexane. (br. 1H), 3.28 (t, 2H), 3.22 (m, 12H). EXAMPLE 148B EXAMPLE 1.51 65 A mixture of EXAMPLE 1A and EXAMPLE 148A in This example was made by substituting EXAMPLE 150C 1,2-dichloroethane (2 mL) at 25°C. was treated with sodium and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) US 7,973,161 B2 161 162 propyl)amino)-3-nitrobenzenesulfonamide, prepared as was concentrated and the concentrate was flash chromato described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- graphed on silica gel with 35-40% ethyl acetate/hexane. 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) amino)-3-nitrobenzenesulfonamide, respectively, in EXAMPLE 153C EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 12.10 (br. 1H), 9.76 (br. A mixture of EXAMPLE 153A (28 mg) and EXAMPLE 1H), 8.55 (d. 1H), 8.31 (d. 1H), 7.87 (dd. 1H), 7.77 (d. 2H), 153B (34 mg) in DMF (0.4 mL) at 25°C. was treated with 7.74 (s, 1H), 7.54 (m, 5H), 7.17 (m, 6H), 6.95 (d. 2H), 6.64 DBU (0.031 mL), stirred for 20 hours, and concentrated. The (br. 1H), 3.25 (m, 23H), 2.17 (m, 2H). concentrate was flash chromatographed on silica gel with 5% 10 methanol/dichloromethane, 10% methanol/1% water/0.1% EXAMPLE 152A acetic acid/dichloromethane, and 20% methanol/20% water/ 2% acetic acid/dichloromethane. "H NMR (300 MHz, 3-Phenyl-3H-imidazole-4-carboxylic acid ethyl ester, pre DMSO-d) & 8.46 (d. 1H), 8.30 (br. 1H), 7.81 (dd. 1H), 7.72 pared as described in Tet. Lett. 2000, 41, 5453-5456, (150 (d. 2H), 7.46 (m, 5H), 7.26 (m, 7H), 6.93 (m, 1H), 6.81 (d. mg) in dichloromethane (2.5 mL) at -78°C. was treated with 15 2H), 4.06 (m, 2H), 2.99 (m, 16H), 1.65 (m, 4H). 1MDIBAL in dichloromethane (1.4 mL), stirred for 30 min utes, and treated with 25% aqueous potassium sodium tar EXAMPLE 154A trate, ethyl acetate (50 mL) and 25% aqueous potassium sodium tartrate (50 mL). The extract was washed with 25% This example was made by Substituting 1,1-dimethyletha aqueous potassium sodium tartrate (50 mL) and brine (50 nolamine for azetidine hydrochloride in EXAMPLE 30D. mL) and dried (NaSO), filtered, and concentrated. The con centrate was flash chromatographed on silica gel with 20-30 EXAMPLE 154B 50% acetone/hexane. This example was made by substituting EXAMPLE 154A EXAMPLE 152B 25 for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 MHz, DMSO-d) & 8.45 (d. 1H), 8.12 (d. 1H), 7.82 (dd. 1H), This example was made by substituting EXAMPLE 152A 7.72 (d. 2H), 7.51 (m, 5H), 7.26 (m, 7H), 6.93 (d. 1H), 6.78 (d. for EXAMPLE 148A in EXAMPLE 148B. 2H), 4.10 (m, 2H), 3.26 (m, 7H), 2.92 (m, 2H), 2.75 (m, 2H), EXAMPLE 152C 30 2.40 (m, 4H), 2.08 (m. 2H), 1.14 (s, 6H). EXAMPLE 155A This example was made by substituting EXAMPLE 152B for EXAMPLE 2B in EXAMPLE 2.0. This example was made by Substituting sarcosine for 3-azetidinecarboxylic acid in EXAMPLE 153A. EXAMPLE 152D 35 EXAMPLE 155B This example was made by substituting EXAMPLE 152C and 4-(((1R)-3-(4-morpholinyl)-1-((phenylsulfanyl)methyl) This example was made by substituting EXAMPLE 155A propyl)amino)-3-nitrobenzenesulfonamide, prepared as for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 described in WO 02/24636, for EXAMPLE 2C and 4-(((1R)- 40 MHz, DMSO-d) & 12.08 (br. 1H),9.76 (br. 1H), 8.52 (d. 1H), 3-(dimethylamino)-1-((phenylsulfanyl)methyl)propyl) 8.28 (d. 1H), 7.85 (dd. 1H), 7.77 (d. 2H), 7.69 (br. 1H), 7.43 amino)-3-nitrobenzenesulfonamide, respectively, in (m, 7H), 7.15 (m, 6H), 6.93 (d. 2H), 5.56 (br. 1H), 4.21 (m, EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 8.50 (d. 2H), 4.03 (m, 2H), 3.37 (m. 11H), 2.79 (s.3H), 2.19 (m, 2H), 1H), 8.36 (d. 1H), 7.88 (d. 1H), 7.80 (dd. 1H), 7.72 (d. 2H), 1.65 (m, 2H). 7.61 (m, 2H), 7.50 (m, 3H), 7.22 (m, 5H), 7.03 (m, 2H), 6.85 45 (d. 2H), 4.14 (m, 2H), 3.38 (m, 8H), 2.40 (m, 9H), 2.00 (m, EXAMPLE 156A 2H), 1.87 (n, 2H), 1.29 (m, 2H). This example was made by substituting D-proline for EXAMPLE 153A 3-azetidinecarboxylic acid in EXAMPLE 153A. 50 A mixture of EXAMPLE 30C (50.5 mg) and 3-azetidin EXAMPLE 156B ecarboxylic acid (13 mg) in methanol (1 mL) at 25°C. were treated with sodium cyanoborohydride (8.5 mg), stirred for 4 This example was made by substituting EXAMPLE 156A hours, treated with silica gel and concentrated. The concen for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 trate was flash chromatographed on silica gel with 5% metha 55 MHz, DMSO-d) & 12.15 (br. 1H),9.67 (br. 1H), 8.52 (d. 1H), nol/dichloromethane, 20% methanol/2% water/0.2% acetic 8.29 (d. 2H), 7.80 (m, 4H), 7.44 (m, 7H), 7.15 (m, 4H), 6.93 acid/dichloromethane and 40% methanol/10% water/1% (d. 2H), 5.56 (br. 1H), 4.30 (m, 3H), 2.33 (m, 21H). acetic acid/dichloromethane. EXAMPLE 157A EXAMPLE 153B 60 This example was made by Substituting isonipocotic acid A mixture of EXAMPLE 2C (1 g) and N-hydroxysuccin for 3-azetidinecarboxylic acid in EXAMPLE 153A. imide (296 mg) in ethyl acetate (9 mL) and THF (4 mL) at 25° C. was treated with 1,3-dicyclohexylcarbodiimide (556 mg), EXAMPLE 157B stirred at 40°C. for 6 hours and at 25°C. for 16 hours, cooled 65 to 0°C., treated with 40% ethyl acetate/hexane, and filtered This example was made by substituting EXAMPLE 157A through silica gel with 40% ethyl acetate/hexane. The filtrate for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 US 7,973,161 B2 163 164 MHz, DMSO-d) & 12.05 (br. 1H), 8.47 (d. 1H), 8.21 (m, 1H), mL) at reflux was stirred for 38 hours, treated with methanol, 7.81 (dd. 1H), 7.72 (d. 2H), 7.50 (m, 5H), 7.27 (m, 9H), 6.97 and concentrated twice from methanol. The concentrate was (m. 1H), 6.82 (d. 2H), 4.10 (m, 2H), 3.35 (m, 10H), 3.17 (m, treated with ethyl acetate and saturated NaHCO. The water 3H), 2.50 (m, 4H), 2.40 (m, 3H), 2.07 (m, 2H), 1.63 (m, 2H). layer was adjusted to pH less than 2 with 12M HCl and EXAMPLE 158A extracted with ethyl acetate. The extract was dried (MgSO), filtered, and concentrated. The concentrate was flash chro This example was made by Substituting 2-(methylamino) matographed on silica gel with 2% methanol/dichlo ethanol for azetidine hydrochloride in EXAMPLE 30D. romethane and 5% methanol/0.5% acetic acid/dichlo romethane. EXAMPLE 158B 10 EXAMPLE 16OE This example was made by substituting EXAMPLE 158A for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 A mixture of EXAMPLE 160D (224 mg) and palladium MHz, DMSO-d) & 8.45 (d. 1H), 8.18 (d. 1H), 7.81 (dd. 1H), black (0.20 g) at 25°C. was treated with a mixture of 96% 7.72 (d. 2H), 7.51 (m, 5H), 7.27 (m,8H), 6.93 (d. 1H), 6.79 (d. 15 2H), 5.10 (m, 1H), 4.09 (m, 2H), 3.61 (m, 4H), 3.39 (m, 2H), formic acid (0.19 mL) in methanol (4 mL), stirred for 30 3.14 (m, 4H), 2.97 (m, 3H), 2.62 (m,3H), 2.50 (m, 3H), 2.40 minutes, filtered, concentrated, and reconcentrated from (m, 4H), 2.09 (m. 2H). methanol. EXAMPLE 159A EXAMPLE 16OF This example was made by Substituting L-proline for This example was made by substituting EXAMPLE 160E 3-azetidinecarboxylic acid in EXAMPLE 153A. for 3-azetidinecarboxylic acid in EXAMPLE 153A. EXAMPLE 159B 25 EXAMPLE 16OG This example was made by substituting EXAMPLE 159A for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 This example was made by substituting EXAMPLE 160F MHz, DMSO-d) & 12.10(br. 1H),9.67 (br. 1H), 8.52 (d. 1H), for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 8.29 (d. 2H), 7.46 (m. 15H), 6.93 (d. 2H), 5.56 (br. 1H), 4.24 MHz, DMSO-d) & 8.48 (d. 1H), 8.36 (d. 1H), 7.82 (dd. 1H), 30 7.70 (m, 3H), 7.32 (m, 12H), 6.99 (d. 1H), 6.83 (d. 2H), 2.93 (m,3H), 2.35 (m, 21H). (m. 22H). EXAMPLE 16OA EXAMPLE 161A A mixture of 3-azetidinecarboxylic acid (251 mg) and 1M NaOH (6 mL) in dioxane (6 mL) at 25°C. was treated with 35 A mixture of EXAMPLE 832729 (25 mg), Boc-Ala-Ala 95% benzyl chloroformate (0.54 mL), stirred for 18 hours and OH (9 mg), EDAC.HCl (7 mg), and HoBT (6 mg) in dichlo concentrated. The concentrate was treated with water, and the romethane (0.5 mL) at 25°C. was treated with DIEA (0.009 mixture was adjusted to pH greater than 10, washed with mL), stirred for 16 hours, and treated with water and ethyl diethyl ether, adjusted to pH less than 3, and extracted with acetate. The extract was washed with 20% aqueous NHCl dichloromethane. The extract was dried (NaSO), filtered, 40 and brine (25 mL) and dried (NaSO), filtered, and concen and concentrated. trated. The concentrate was flash chromatographed on silica gel with 8% methanol/dichloromethane. EXAMPLE 16OB EXAMPLE 161B EXAMPLE 833294A (574 mg) indichloromethane (5 mL) 45 at 0°C. was treated with oxalyl chloride (0.75 mL) and DMF EXAMPLE 161A (15 mg) in dichloromethane (1 mL) at (2 drops), stirred for 1 hour, and concentrated twice from 25°C. was treated with water (0.08 mL) and TFA (0.6 mL), dichloromethane. The concentrate in ethyl acetate (5 mL) was treated with 30% aqueous ammonium hydroxide (1.3 mL) stirred for 1 hour, and concentrated twice from dichlo 50 romethane. HNMR (300 MHz, DMSO-d) & 12.09 (br. 1H), while cooling in a bath of cold water, stirred at 25°C. for 2 9.68 (br. 1H),8.52 (d. 1H),8.51 (d. 1H),8.29 (d. 1H), 8.05 (m, hours, and treated with water and dichloromethane. The water 3H), 7.77 (m, 4H), 7.52 (m,3H), 7.37 (m, 3H), 7.17 (m, 7H), layer was extracted with ethyl acetate, and the combined 6.93 (d. 2H), 3.55 (m. 17H), 1.92 (m, 2H), 1.30 (d. 3H), 1.18 extracts were dried (NaSO), filtered, and concentrated. (d. 3H). EXAMPLE 16OC 55 EXAMPLE 162A EXAMPLE 833294B (481 mg) in DMF (4 mL) at 25° C. was treated with cyanuric chloride (189 mg), stirred for 30 This example was made by substituting 5-pyrrolidin-2- minutes, and treated with water and ethyl acetate. The extract yltetrazole, prepared as described in J. Med. Chem. 1985, 28. was washed with 1MNaHCO and water and dried (Na2SO), 60 1067-1071, for 3-azetidinecarboxylic acid in EXAMPLE filtered, and concentrated. The concentrate was flash chro 153A. matographed on silica gel with 20% acetone/hexane. EXAMPLE 162B EXAMPLE 16OD 65 This example was made by substituting EXAMPLE 162A A mixture of EXAMPLE 160C (394 mg), azidotrimethyl for EXAMPLE 153A in EXAMPLE 153C. "H NMR (300 silane (0.52 mL), and dibutyltin oxide (45 mg) in toluene (3.5 MHz, DMSO-d) & 8.50 (d. 1H), 8.27 (d. 1H), 7.85 (dd. 1H), US 7,973,161 B2 165 166 7.73 (d. 2H), 7.43 (m, 7H), 7.17 (m, 7H), 6.88 (d. 2H), 4.11 matographed on silica gel with 5% methanol/dichlo (m,3H), 2.88 (m. 17H), 1.93 (m, 4H). romethane and 5-10% methanol/NH gas-saturated/dichlo romethane. EXAMPLE 163A EXAMPLE 164E This example was made by Substituting isonipecotic acid for 3-azetidinecarboxylic acid in EXAMPLE 160A. This example was made by substituting EXAMPLE 164D for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 163B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 10 2D. "H NMR (300 MHz, DMSO-d) & 7.71 (d. 2H), 7.57 (d. This example was made by substituting EXAMPLE 163A 2H), 7.48 (m, 5H), 7.29 (m, 8H), 6.86 (d. 2H), 6.51 (br. 1H), and methanesulfonamide for EXAMPLE 2C and 4-(((1R)-3- 6.47 (d. 2H). (dimethylamino)-1-((phenylsulfanyl)methyl)propyl)amino)- 3-nitrobenzenesulfonamide, respectively, in EXAMPLE 2D. EXAMPLE 165A 15 EXAMPLE 163C EXAMPLE 163A (0.50g) indichloromethane (5 mL) at 0° C. was treated with DMF (2 drops) and oxalyl chloride (0.58 This example was made by substituting EXAMPLE 163B mL), stirred for 10 minutes, stirred at 25°C. for 30 minutes, for EXAMPLE 16OD in EXAMPLE 16OE. and concentrated twice from dichloromethane. The concen trate in THF (5 mL) at 25°C. was treated with 50% aqueous EXAMPLE 163D hydroxylamine (0.46 mL), stirred for 17 hours and concen trated. The concentrate in ethyl acetate was washed with This example was made by substituting EXAMPLE 163C 0.5M HCl, water, and brine, dried (NaSO), filtered, and for 3-azetidinecarboxylic acid in EXAMPLE 153A. 25 concentrated.

EXAMPLE 163E EXAMPLE 165B This example was made by substituting EXAMPLE 163D This example was made by substituting EXAMPLE 165A for EXAMPLE 153A in EXAMPLE 153C. 30 for EXAMPLE 16OD in EXAMPLE 16OE. MS (ESI) m/e 974.1 (M+H). EXAMPLE 165C EXAMPLE 164A This example was made by substituting EXAMPLE 165B This example was made by substituting EXAMPLE 18C 35 for 3-azetidinecarboxylic acid in EXAMPLE 153A. for 19C in EXAMPLE 19D. EXAMPLE 165D EXAMPLE 164B This example was made by substituting EXAMPLE 165C 4-Bromobenzenesulfonyl chloride (0.40 g) in dichlo 40 for EXAMPLE 153A in EXAMPLE 153C. romethane (10 mL) at 0°C. was treated with TEA (0.26 mL), bis(2,4-dimethoxybenzyl)amine, prepared as described in EXAMPLE 166A Synthesis, 1991, 703-708, (0.50 g) and DMAP (35 mg), stirred at 25°C. for 4.5 hours, and treated with water and ethyl This example was made by Substituting 4-bromo-2-chlo acetate. The extract was washed with brine and dried 45 robenzenesulfonyl chloride for 4-bromobenzenesulfonyl (NaSO), filtered, and concentrated. The concentrate was chloride in EXAMPLE 164B. flash chromatographed on silica gel with 20% ethyl acetate/ hexane. EXAMPLE 166B

50 EXAMPLE 164C This example was made by substituting EXAMPLE 166A for EXAMPLE 164B in EXAMPLE 164C.

A mixture of EXAMPLE 164A (356 mg), EXAMPLE EXAMPLE 166C 164B (151 mg), sodium tert-butoxide (91 mg), tris(diben Zylideneacetone)dipalladium(0) (32 mg) and rac-2,2'-bis 55 This example was made by substituting EXAMPLE 166B (diphenylphosphino)-1,1'-binaphthyl (42 mg) in toluene (3 for EXAMPLE 164C in EXAMPLE 164D. mL) at reflux was stirred for 3.5 hours, and treated with ethyl acetate and brine. The extract was dried (NaSO), filtered, EXAMPLE 166D and concentrated. The concentrate was flash chromato graphed on silica gel with 2-4% methanol/dichloromethane. 60 This example was made by substituting EXAMPLE 166C for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 164D propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 7.74 (d. 2H), 7.65 (d. A mixture of EXAMPLE 164C (0.34g) and triethylsilane 1H), 7.50 (m, 5H), 7.30 (m, 9H), 6.83 (d. 2H), 6.47 (m, 1H), (0.25 mL) in dichloromethane (5 mL) at 25°C. was treated 65 6.39 (m, 2H), 3.59 (m, 1H), 3.39 (s. 2H), 3.17 (m, 4H), 3.08 with TFA (0.5 mL), stirred for 1.25 hours, and concentrated (m,2H), 2.73 (m, 2H), 2.51 (s.3H), 2.49 (s.3H), 2.40 (m, 4H), twice from dichloromethane. The concentrate was flash chro 2.00 (m. 1H), 1.75 (m, 1H). US 7,973,161 B2 167 168 EXAMPLE 167A (m,3H), 3.13 (m, 4H), 2.97 (m, 2H), 2.40 (m, 4H), 2.09 (m, 3H), 1.85 (m, 4H), 1.58 (m, 4H). This example was made by Substituting 4-bromo-2,6- dichlorobenzenesulfonyl chloride for 4-bromobenzenesulfo EXAMPLE 17OA nyl chloride in EXAMPLE 164B. This example was made by Substituting 1-bromo-2-ni EXAMPLE 167B trobenze for 1-fluoro-2-(trifluoromethyl)benzene in EXAMPLE 1.8D. This example was made by substituting EXAMPLE 167A for EXAMPLE 164B in EXAMPLE 164C. 10 EXAMPLE 17OB This example was made by substituting EXAMPLE 170A EXAMPLE 167C for 4-bromobenzenesulfonyl chloride in EXAMPLE 164B. This example was made by substituting EXAMPLE 167B EXAMPLE 17OC for EXAMPLE 164C in EXAMPLE 164D. 15 EXAMPLE 170B (150 mg) at 25°C. was treated with a EXAMPLE 167D mixture of 95% sodium hydride (8 mg) and 2-(phenylsulfa nyl)ethanol (0.042 mL) in DMF (1.5 mL), stirred for 6 hours This example was made by substituting EXAMPLE 167C and treated with ethyl acetate and brine. The water layer was for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) extracted with ethyl acetate, and the extract was dried propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE (NaSO), filtered, and concentrated. The concentrate was 2D. "H NMR (300 MHz, DMSO-d) & 7.73 (d. 2H), 7.51 (m, flash chromatographed on silica gel with 25% acetone/hex 5H), 7.30 (m, 9H), 6.81 (d. 2H), 6.48 (m, 1H), 6.43 (s. 2H), a. 3.55 (m, 1H), 3.39 (s. 2H), 3.17 (m, 4H), 3.07 (m, 2H), 2.87 25 (m. 2H), 2.51 (s.3H), 2.49 (s.3H), 2.41 (m, 4H), 2.02 (m. 1H), EXAMPLE 17OD 1.75 (m, 1H). This example was made by substituting EXAMPLE 170C EXAMPLE 168A for EXAMPLE 164C in EXAMPLE 164D. Tropane in 1,2-dichloroethane (8 mL) at 0°C. was treated 30 EXAMPLE 17OE with 1-chloroethyl chloroformate (0.47 mL), stirred for 15 minutes, refluxed for 2 hours, and concentrated twice from This example was made by substituting EXAMPLE 170D dichloromethane. The concentrate in methanol (8 mL) was for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) refluxed for 2 hours and concentrated twice from dichlo propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE romethane. 35 2D. "H NMR (300 MHz, DMSO-d) & 8.32 (d. 1H), 8.08 (dd, 1H), 7.73 (d. 2H), 7.35 (m. 14H), 6.85 (d. 2H), 4.41 (t, 2H), EXAMPLE 168B 3.46 (m, 2H), 3.39 (t, 2H), 3.23 (m, 4H), 2.44 (m, 4H). This example was made by substituting EXAMPLE 168A EXAMPLE 171A for azetidine hydrochloride in EXAMPLE 30D. 40 This example was made by substituting 4-bromo-3-trifluo EXAMPLE 168C romethylbenzenesulfonyl chloride for 4-bromobenzene sulfonyl chloride in EXAMPLE 164B. This example was made by substituting EXAMPLE 168B for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 45 EXAMPLE 171B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 8.87(m, 1H), 8.44 (d. This example was made by substituting EXAMPLE 171A 1H), 8.09 (m. 1H), 7.82 (m, 1H), 7.71 (d. 2H), 7.50 (m, 5H), for EXAMPLE 17OB in EXAMPLE 17OC. 7.27 (m, 8H), 6.92 (m, 1H), 6.78 (d. 2H), 4.07 (m. 1H), 3.90 (m. 2H), 3.38 (m, 3H), 3.12 (m, 4H), 2.97 (m, 2H), 2.41 (m, 50 EXAMPLE 171C 4H), 2.09 (m, 4H), 1.83 (m, 4H), 1.61 (m, 4H), 1.48 (m, 1H). This example was made by substituting EXAMPLE 171B EXAMPLE 169A for EXAMPLE 164C in EXAMPLE 164D.

This example was made by Substituting 7-aza-bicyclo 55 EXAMPLE 171D 2.2.1]heptane hydrochloride, prepared as described in Org. Lett. 2001, 3, 1371-1374, for azetidine hydrochloride in This example was made by substituting EXAMPLE 171C EXAMPLE 3OD. for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE EXAMPLE 169B 60 2D. "H NMR (300 MHz, DMSO-d) & 8.05 (m, 2H), 7.71 (d. 2H), 7.50 (m, 5H), 7.30 (m, 9H), 6.84 (d. 2H), 4.36 (t, 2H), This example was made by substituting EXAMPLE 169A 3.41 (s. 2H), 3.38 (t, 2H), 3.20 (m, 4H), 2.41 (m, 4H). for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE EXAMPLE 172A 2D. "H NMR (300 MHz, DMSO-d) & 9.20 (m, 1H), 8.44 (d. 65 1H), 8.13 (m, 1H), 7.82 (d. 1H), 7.71 (d. 2H), 7.51 (m, 5H), 2(S)-Hydroxymethyl-4(R)-(toluene-4-sulfonyloxy)pyrro 7.27 (m, 8H), 6.92 (d. 1H), 6.78 (d. 2H), 4.12 (m, 3H), 3.38 lidine-1-carboxylic acid tert-butyl ester, prepared as US 7,973,161 B2 169 170 described in J. Med. Chem. 1991, 34, 2787-2797), (467 mg) H NMR (300 MHz, DMSO-d) & 8.46 (d. 1H), 8.32 (m, in methanol (21 mL) at 25°C. was treated with 95% sodium 1H), 7.81 (dd. 1H), 7.71 (d. 2H), 7.24 (m. 10H), 6.94 (d. 1H), methoxide (74 mg) in ethanol (3.5 mL), refluxed for 9.5 6.79 (d. 2H), 4.45 (m, 1H), 4.11 (m, 1H), 3.87(m, 1H), 3.56 hours, and concentrated. The concentrate in water and diethyl (m. 1H), 3.32 (m, 4H), 3.15 (m, 5H), 2.97 (m, 2H), 2.78 (m, ether was washed with brine and dried (MgSO), filtered, and 4H), 2.22 (m, 6H), 1.96 (m, 4H), 1.66 (m, 4H). concentrated. The concentrate was flash chromatographed on silica gel with 20% acetone/hexane. EXAMPLE 175 EXAMPLE 172B This example was made by substituting EXAMPLE 10 83.7538C and EXAMPLE 173C for EXAMPLE 2C and EXAMPLE 172A (178 mg) was treated with 1M HCL in 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) methanol (20 mL), stirred for 21 hours, concentrated, and propyl)amino)-3-nitrobenzenesulfonamide, respectively, in reconcentrated from diethyl ether. EXAMPLE 2D. H NMR (300 MHz, DMSO-d) & 8.46 (d. 1H), 8.26 (m, EXAMPLE 172C 15 1H), 7.80 (dd. 1H), 7.71 (d. 2H), 7.24 (m. 10H), 6.94 (d. 1H), 6.79 (d. 2H), 4.45 (m, 1H), 4.13 (m, 1H), 3.86 (m, 1H), 3.57 This example was made by substituting EXAMPLE 172B (m. 1H), 3.32 (m, 4H), 3.15 (m, 5H), 2.94 (m, 2H), 2.78 (m, for azetidine hydrochloride in EXAMPLE 30D. 4H), 2.22 (m, 6H), 1.95 (m, 4H), 1.66 (m, 4H). EXAMPLE 172D EXAMPLE 176 This example was made by substituting EXAMPLE 172C This example was made by substituting EXAMPLE for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 83.7538C and EXAMPLE 169A for EXAMPLE 2C and propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 25 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 2D. "H NMR (300 MHz, DMSO-d) & 8.46 (d. 1H), 8.33 (m, propyl)amino)-3-nitrobenzenesulfonamide, respectively, in 1H), 7.79 (dd. 1H), 7.71 (d. 2H), 7.50 (m, 5H), 7.27 (m, 9H), EXAMPLE 2D. 6.92 (d. 1H), 6.80 (d. 2H), 4.43 (m. 1H), 4.09 (m, 1H), 3.85 (m. 1H), 3.54 (m, 1H), 3.39 (s. 2H), 3.33 (m, 2H), 3.15 (m, "H NMR (300 MHz, DMSO-d) & 9.18 (br. 1H), 8.44 (d. 5H), 2.94 (m, 2H), 2.40 (m, 5H), 1.94 (m, 4H), 1.72 (m. 1H). 1H), 8.14 (m, 1H), 7.80 (d. 1H), 7.71 (d. 2H), 7.24 (m, 9H), 30 6.93 (d. 1H), 6.78 (d. 2H), 4.09 (m, 2H), 3.35 (m, 4H), 3.14 EXAMPLE 173A (m, 6H), 2.76 (brs, 4H), 2.22 (m, 7H), 2.04 (m. 2H), 1.84 (m, 4H), 1.66 (m, 6H). This example was made by Substituting 2CR)-hydroxym ethyl-4-(S)-(toluene-4-sulfonyloxy)pyrrolidine-1-carboxylic EXAMPLE 177A acid tert-butyl ester, prepared as described in J. Med. Chem. 35 1991, 34, 2787-2797, for 2CS)-hydroxymethyl-4(R)-(tolu This example was made by Substituting 2.5-(cis)-dimeth ene-4-sulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ylpyrrolidine toluenesulfonate, prepared as described in A. R. ester in EXAMPLE 172A. Katritzky et al. J. Org. Chem. 1999, 64, 1979-1985) for aze tidine hydrochloride in EXAMPLE 30D. EXAMPLE 173B 40 EXAMPLE 177B This example was made by substituting EXAMPLE 173A for EXAMPLE 172A in EXAMPLE 172B. This example was made by substituting EXAMPLE 83.7538C and EXAMPLE 177A for EXAMPLE 2C and EXAMPLE 173C 45 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide, respectively, in This example was made by substituting EXAMPLE 173B EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 8.57 (br. for azetidine hydrochloride in EXAMPLE 30D. 1H), 8.45 (d. 1H), 8.15 (m. 1H), 7.81 (d. 1H), 7.71 (d. 2H), 7.24 (m, 9H), 6.96 (m, 1H), 6.78 (d. 2H), 4.11 (m. 1H), 3.49 EXAMPLE 173D 50 (m. 1H), 3.31 (m, 2H), 3.13 (m, 8H), 2.77 (m, 4H), 2.17 (m, 7H), 1.62 (m 6H), 1.29 (m, 6H). This example was made by substituting EXAMPLE 173C for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 178A propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (300 MHz, DMSO-d) & 8.46 (d. 1H), 8.25 (m, 55 A mixture of 205H)-furanone (1 mL) and N-(methoxym 1H), 7.81 (dd. 1H), 7.71 (d. 2H), 7.51 (m, 5H), 7.27 (m, 9H), ethyl)-N-(trimethylsilylmethyl)benzylamine (4.2 mL) in 6.94 (d. 1H), 6.80 (d. 2H), 4.46 (m. 1H), 4.14 (m, 1H), 3.87 dichloromethane (30 mL) at 0°C. was treated with TFA (0.10 (m. 1H), 3.56 (m, 1H), 3.39 (s. 2H), 3.33 (m, 2H), 3.16 (m, mL), stirred for 2.5 hours, and treated with dichloromethane 5H), 2.95 (m, 2H), 2.40 (m, 5H), 1.95 (m, 4H), 1.76 (m. 1H). and saturated aqueous NaHCO. The extract was washed with 60 brine and dried (NaSO), filtered, and concentrated. The EXAMPLE 174 concentrate was flash chromatographed on silica gel with 15% acetone/hexane. This example was made by substituting EXAMPLE 83.7538C and EXAMPLE 172C for EXAMPLE 2C and EXAMPLE 178B 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 65 propyl)amino)-3-nitrobenzenesulfonamide, respectively, in EXAMPLE 178A (2.76 g) in 1,2-dichloroethane (25 mL) EXAMPLE 2D. at 25°C. was treated with 95% benzyl chloroformate (3.8 US 7,973,161 B2 171 172 mL), refluxed for 24 hours and concentrated. The concentrate EXAMPLE 18OA was flash chromatographed on silica gel with 25% acetone/ hexane. This example was made by Substituting cyclohexylmetha nol for cyclohexanol in EXAMPLE 179A. EXAMPLE 178C EXAMPLE 18OB EXAMPLE 178B (2.26 g) in THF (40 mL) at -78°C. was treated with 1M DIBAL in dichloromethane (20 mL) then This example was made by substituting EXAMPLE methanol (40 mL), filtered at 25°C., and concentrated. The 779855A for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfa concentrate was flash chromatographed on silica gel with 10 nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide in 30% acetone/hexane. EXAMPLE 1D. "H NMR (300 MHz, DMSO-d) & 8.41 (d. 1H), 8.17 (dd. 1H), 7.77 (s, 1H), 7.74 (s. 2H), 7.58 (d. 1H), EXAMPLE 178D 7.53 (m, 2H), 7.46 (m, 3H), 7.37 (m, 3H), 6.93 (d. 2H), 4.31 (brs, 1H), 3.80 (brs, 4H), 3.19 (brs,3H), 2.83 (brs, 2H), 1.74 A mixture of EXAMPLE 178C (1.282 g) and triethylsilane 15 (m, 6H), 1.23 (m, 3H), 1.07 (m, 2H). (1.17 mL) in dichloromethane (25 mL) at 0°C. was treated with BFs-diethyl etherate (0.68 mL), stirred at 25° C. for 3 EXAMPLE 181A hours, and treated with ethyl acetate and Saturated aqueous NaHCO. The extract was washed with brine and dried This example was made by Substituting 2-cyclohexyletha (NaSO4), filtered, and concentrated. The concentrate was nol for cyclohexanol in EXAMPLE 179A. flash chromatographed on silica gel with 15% acetone/hex a. EXAMPLE 181B EXAMPLE 178E This example was made by substituting EXAMPLE 181A 25 for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) This example was made by substituting EXAMPLE 178D propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE for EXAMPLE 16OD in EXAMPLE 16OE. 1D. "H NMR (500 MHz, DMSO-d) & 8.41 (d. 1H), 8.17 (dd, 1H), 7.77 (s, 1H), 7.75 (s. 2H), 7.60 (d. 1H), 7.53 (m, 2H), EXAMPLE 178F 7.52 (t, 2H), 7.43 (t, 1H), 7.37 (m, 3H), 6.92 (d. 2H), 4.30 (t, 30 4H), 2.95 (brs, 4H), 1.71 (d. 2H), 1.65 (m, 8H), 1.46 (m, 1H), This example was made by substituting EXAMPLE 178E 1.18 (m, 4H), 0.94 (m. 2H). for azetidine hydrochloride in EXAMPLE 30D. EXAMPLE 182A EXAMPLE 178G 35 Ammonium formate (5.8 g) in water (2.9 mL) at 25°C. was This example was made by substituting EXAMPLE treated with tetrahydropyran-4-one (1 g) in methanol (26 83.7538C and EXAMPLE 178F for EXAMPLE 2C and mL), stirred for 5 minutes, treated with 10% Pd/C (1.2 g), 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) stirred for 18 hours, filtered through diatomaceous earth propyl)amino)-3-nitrobenzenesulfonamide, respectively, in (Celite(R), and concentrated. A mixture of the concentrate in EXAMPLE 2D. 40 ethanol (23 mL) was stirred at 0°C. as 12M HCl (1.7 mL) was H NMR (300 MHz, DMSO-d) & 8.46 (d. 1H), 8.23 (m, added dropwise, stirred for 1 hour, and filtered. 1H), 7.77 (d. 1H), 7.71 (d. 2H), 7.24 (m, 10H), 6.96 (d. 1H), 6.79 (d. 2H), 4.08 (m, 1H), 3.61 (m, 2H), 2.68 (m, 26H), 1.66 EXAMPLE 182B (m, 6H). 45 This example was made by substituting EXAMPLE 182A EXAMPLE 179A for EXAMPLE 21C in EXAMPLE 21 D. Cyclohexanol (880 mg) in DMF (2 mL) a 25° C. was EXAMPLE 182C treated with 60% oily NaH (400mg) and DMF (3 mL), stirred for 1.5 hours, treated with 15-crown-5 (0.6 mL), 4-fluoro-3- 50 This example was made by substituting EXAMPLE nitrobenzenesulfonamide, prepared as described in WO02/ 780431B for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfa 24636, (440 mg), and DMF (0.5 mL), stirred for 1.5 hours, nyl)methyl)propyl)amino)-3-nitrobenzenesulfonamide in and treated with water and ethyl acetate. The extract was dried EXAMPLE 1D. "H NMR (400 MHz, DMSO-d) & 8.62 (d. (MgSO), filtered, and concentrated. The concentrate was 1H), 8.27 (d. 1H), 7.93 (dd. 1H), 7.49 (d. 2H), 7.46 (d. 2H), flash chromatagraphed on silica gel with hexanes/ethyl 55 7.42 (d. 1H), 7.36 (m, 4H), 6.90 (d. 2H), 4.22 (brs, 1H), 3.93 acetate (10-30%). (m. 1H), 3.86 (d. 2H), 3.72 (brs, 2H), 3.46 (t,3H), 2.91 (brs, 4H), 2.49 (s. 2H), 1.91 (d. 2H), 1.62 (m, 2H). EXAMPLE 179B EXAMPLE 183A This example was made by substituting EXAMPLE 179A 60 for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) This example was made by Substituting 2-cyclohexylethy propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE lamine for EXAMPLE 21C in EXAMPLE 21 D. 1D.H NMR (500 MHz, DMSO-d) & 8.31 (d. 1H),8.07 (dd, 1H), 7.72 (d. 2H), 7.55 (t, 2H), 7.40 (m, 7H), 7.23 (dd. 1H), EXAMPLE 183B 6.85 (d. 2H), 6.73 (m, 1H), 3.51 (s. 2H), 3.23 (s, 4H), 2.44 (s, 65 4H), 1.85 (m, 2H), 1.66 (m, 2H), 1.55 (m, 2H), 1.46 (m, 1H), This example was made by substituting EXAMPLE 183A 1.28 (m, 3H). for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) US 7,973,161 B2 173 174 propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE (m, 4H), 3.35 (m, 2H), 3.17 (d, 4H), 2.41 (m, 4H), 1.87 (m, 1D. "H NMR (400 MHz, DMSO-d) & 12.20 (brs, 1H), 8.62 2H), 1.60 (m, 2H), 1.40 (s.9H). (d. 1H),8.52 (t, 1H), 7.94 (dd. 1H), 7.75 (d,3H), 7.52 (m, 2H), 7.47 (d. 1H), 7.42 (m, 1H), 7.37 (m,3H), 7.21 (d. 1H), 6.92 (d. EXAMPLE 1.87 2H), 4.28 (brs, 2H), 3.75 (brs, 4H), 3.44 (m, 2H), 3.17 (brs, 2H), 2.86 (brs, 2H), 1.73 (d. 2H), 1.65 (m, 2H), 1.52 (m, 2H), This example was made by substituting EXAMPLE 186C 1.36 (m, 1H), 1.18 (m, 4H), 0.95 (m, 2H). for EXAMPLE21B in EXAMPLE 21C.HNMR (400 MHz, DMSO-d) & 12.30 (brs, 1H), 11.58 (brs, 1H), 9.31 (s, 1H), EXAMPLE 184A 9.08 (s, 1H), 8.46 (d. 1H),8.19 (dd. 1H),8.18 (m. 1H), 7.76 (d. 10 2H), 7.71 (d. 1H), 7.52 (t, 2H), 7.46 (t, 2H), 7.42 (d. 1H), 7.35 This example was made by substituting N-methylcyclo (d,3H), 6.92 (d. 2H), 5.11 (m, 1H), 4.35 (s.2H), 3.84 (m, 2H), hexylamine for EXAMPLE 21C in EXAMPLE 21 D. 3.67 (s.3H), 3.38 (m, 2H), 3.12 (m, 2H), 2.73 (s. 2H), 2.72 (d. 1H), 2.15 (m, 2H), 1.98 (m, 2H). EXAMPLE 184B 15 EXAMPLE 1.88 This example was made by substituting EXAMPLE 184A for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) A mixture of EXAMPLE 187 (53 mg) and 37% formalin propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE (6.6 LL), in 1:1 dichloromethane/methanol (1.5 mL) at 25°C. 1D. "H NMR (400 MHz, DMSO-d) & 8.26 (d. 1H), 7.89 (dd, was treated with 2.47 mmol/g MP-NaCNBH (55 mg) and 1H), 7.75 (d. 3H), 7.52 (m, 2H), 7.47 (d. 2H), 7.43 (m, 2H), DIEA (1 drop), stirred for 18 hours, treated with 1:1 dichlo 7.37 (m, 3H), 6.92 (d. 2H), 4.27 (brs, 2H), 3.81 (brs, 3H), romethane/methanol (5 mL), and filtered through diatoma 3.56 (t, 1H), 3.15 (brs, 3H), 2.84 (brs, 2H), 2.65 (s.3H), 1.76 ceous earth (Celite(R). The filtrate was dried (MgSO), fil (t, 4H), 1.59 (m, 3H), 1.35 (m, 2H), 1.15 (m, 1H). tered, concentrated. The concentrate was flash 25 chromatographed on silica gel with dichloromethane/2-5% EXAMPLE 185A methanol/0.5-1% NHOH. 'H NMR (500MHz, DMSO-d) & 8.28 (d. 1H), 8.04 (dd. 1H), 7.72 (d. 2H), 7.54 (d. 1H), 7.45 (d. This example was made by Substituting 3.3-dimethylglu 2H), 7.46 (t, 2H), 7.42 (m, 3H), 7.36 (m, 3H), 7.24 (dd. 1H), tarimide for EXAMPLE 1.8E in EXAMPLE 18F. 6.79 (d. 2H), 4.91 (s, 1H), 4.42 (s. 2H), 3.14 (m, 8H), 2.74 (s, 30 3H), 2.39 (m, 4H), 2.10 (s. 2H), 1.96 (s. 2H). EXAMPLE 185B EXAMPLE 1.89 This example was made by substituting EXAMPLE 185A for EXAMPLE 21C in EXAMPLE 21 D. This example was made by Substituting 4-((cyclohexylm 35 ethyl)amino)-3-nitrobenzenesulfonamide for 4-(((1R)-3- EXAMPLE 185C (dimethylamino)-1-(phenylsulfanyl)methyl)propyl)amino)- 3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR This example was made by substituting EXAMPLE 185B (400 MHz, DMSO-d) & 8.64 (m, 2H), -7.93 (dd. 1H), 7.78 for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) (d. 2H), 7.72 (s, 1H), 7.52 (d. 4H), 7.40 (d. 2H), 7.33 (m, 1H), propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 40 7.24 (d. 1H), 6.92 (d. 2H), 4.22 (brs, 1H), 3.82 (brs, 2H), 3.29 1D. "H NMR (500 MHz, DMSO-d) 88.29 (d. 1H), 7.93 (dd, (t, 4H), 2.88 (brs, 2H), 1.70 (m, 8H), 1.18 (m, 4H), 0.98 (m, 1H), 7.74 (d. 3H), 7.51 (m, 2H), 7.47 (t, 2H), 7.42 (m, 2H), 2H). 7.35 (m, 3H), 6.91 (d. 2H), 4.29 (s. 2H), 3.79 (brs, 4H), 3.15 (m, 6H), 2.90 (brs, 2H), 1.42 (m, 4H), 0.96 (s, 6H). EXAMPLE 190A 45 EXAMPLE 186A Cyclohexanecarboxaldehyde (2 g) in methanol (20 mL) at A mixture of tert-butyl-4-oxo-1-piperidinecarboxylate (2 0° C. was treated with n-propylamine (0.77 mL) and NaC g) in methanol (50 mL) 0°C. was treated with NaBH (2 g), NBH (600 mg), stirred at 25°C. for 18 hours, treated with stirred for 0.5 hours, stirred for 2 hours at 25° C., concen 50 water, and extracted with diethyl ether. The extract was dried trated, treated with water, and extracted with dichlo (MgSO), filtered, and concentrated. romethane. The extract was washed with water and dried (MgSO), filtered, and concentrated. EXAMPLE 190B

EXAMPLE 186B 55 This example was made by substituting EXAMPLE 190A for EXAMPLE 21C in EXAMPLE 21 D. This example was made by substituting EXAMPLE 186A for cyclohexanol in EXAMPLE 179A. EXAMPLE 190C

EXAMPLE 186C 60 This example was made by substituting EXAMPLE 190B for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) This example was made by substituting EXAMPLE 186B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 2D. "H NMR (400 MHz, DMSO-d) & 8.24 (d. 1H), 7.89 (t, propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 1H), 7.76 (m, 2H), 7.70 (brs, 1H), 7.51 (m, 4H), 7.45 (d. 1H), 1D. "H NMR (300 MHz, DMSO-d) & 8.26 (d. 1H), 8.03 (dd, 65 7.39 (m, 2H), 7.32 (m, 1H), 6.91 (d. 2H), 3.15 (dd, 2H), 3.07 1H), 7.72 (d. 2H), 7.54 (m, 1H), 7.49 (m, 1H), 7.42 (m, 3H), (d. 2H), 2.05 (s. 2H), 1.61 (m, 6H), 1.48 (m, 3H), 1.11 (m, 7.36 (m, 3H), 7.24 (m, 1H), 6.81 (d. 2H), 4.92 (m. 1H), 3.44 4H), 0.78 (m, 5H). US 7,973,161 B2 175 176 EXAMPLE 191A 7.35 (m, 3H), 6.91 (d. 2H), 4.29 (brs, 2H), 3.27 (d. 4H), 2.81 (m,3H), 1.63 (m, 8H), 1.13 (m, 4H), 0.86 (m, 2H). This example was made by Substituting 1-N-Boc-4-cyan opiperidine for EXAMPLE 21B in EXAMPLE 21C. EXAMPLE 193A EXAMPLE 191B This example was made by Substituting 4-amino-1-ben Zylpiperidine for EXAMPLE 21C in EXAMPLE 21D. A mixture of EXAMPLE 191A (520 mg), KCO (1.7g), benzylbromide (0.62 mL), and acetone (7 mL) at reflux was EXAMPLE 193B stirred for 2.5 hours and concentrated. The concentrate was 10 treated with water and 1M HCl, washed with hexanes, made This example was made by substituting EXAMPLE 193A basic with 2.5MNaOH, and extracted with dichloromethane. for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) The extract was dried (MgSO), filtered, and concentrated. propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 1D. "H NMR (500 MHz, DMSO-d) & 9.95 (brs, 1H), 8.62 EXAMPLE 191C 15 (brs, 1H), 8.15 (brs, 1H), 7.95 (d. 1H), 7.73 (d, 4H), 7.50 (m, 10H), 7.41 (m, 1H), 7.34 (m, 5H), 6.90 (d. 2H), 4.46 (brs, A mixture of EXAMPLE 191B (420mg) and Raney nickel 1H), 4.34 (brs, 2H), 4.23 (brs, 1H), 3.92 (brs, 1H), 3.18 (m, (4.5 g) in 20% NH/methanol (100 mL) at 25°C. was stirred 2H), 3.06 (m, 3H), 2.20 (m, 2H), 1.83 (brs, 1H). under H at 60 psi for 16 hours, filtered, and concentrated. EXAMPLE 194A EXAMPLE 191D A mixture of tetrahydrothiopyran-4-one (1 g), hydroxy This example was made by substituting EXAMPLE 191C lamine hydrochloride (1.5 g), and TEA (3 mL) in absolute for EXAMPLE 21C in EXAMPLE 21 D. 25 ethanol (5 mL) was stirred at reflux for 3 hours, cooled to 25° C., treated with water, and extracted with dichloromethane. EXAMPLE 191E The extract was dried (MgSO), filtered, and concentrated. This example was made by substituting EXAMPLE 191D EXAMPLE 194B for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 30 propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE EXAMPLE 193A (300 mg) was treated with LiAlH (400 1D. mg) in THF (4 mL)/diethylether (11 mL), stirred at reflux for H NMR (400 MHz, DMSO-d) & 12.08 (brs, 1H), 11.50 5 hours, and processed as described in Fieser and Fieser, (brs, 1H), 10.68 (brs, 1H),8.69(m, 1H), 8.62 (s, 1H), 8.10(br Reagents for Organic Synthesis, Vol 1, p. 584. s, 1H), 7.91 (m. 1H), 7.74 (d. 3H), 7.57 (brs, 2H), 7.46 (m, 35 7H), 7.33 (m, 4H), 7.27 (d. 1H), 6.90 (d. 2H), 4.34 (brs, 2H), EXAMPLE 194C 4.20 (m, 2H), 3.81 (m, 2H), 3.26 (m, 7H), 3.15 (s. 2H), 2.79 (m, 5H), 2.49 (s. 1H), 1.87 (n, 4H), 1.60 (m. 2H), 1.24 (m, This example was made by substituting EXAMPLE 194B 1H), 0.85 (m, 1H). for EXAMPLE 21C in EXAMPLE 21 D. 40 EXAMPLE 192A EXAMPLE 194D Cyclohexanemethylamine (2 mL) in THF (8 mL) at 25°C. This example was made by substituting EXAMPLE 194C was treated with acetic , prepared as for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) described in Tet. Lett. 1982, 33,3315, (5.7g), stirred for 3.5 45 propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE hours, concentrated, cooled to 0° C., treated with 1M 1D. "H NMR (400 MHz, DMSO-d) & 12.01 (brs, 1H), 8.64 borane.THF (5.1 mL), stirred at reflux for 2.5 hours, concen (d. 1H), 8.31 (d. 2H), 7.94 (dd. 1H), 7.74 (d. 3H), 7.47 (m, trated, cooled to 0°C., treated with methanol (10 mL) and 4H), 7.34 (m,3H), 6.91 (d, 4H), 4.29 (brs, 1H), 3.79 (m,3H), 2.79 (m, 3H), 2.67 (m, 2H), 2.21 (m, 2H), 1.75 (m, 2H). methanolic HCl (50 mL), stirred at reflux for 1 hour, concen 50 trated, treated with water, and washed with diethyl ether. The EXAMPLE 195A water layer was made basic with 1MKOH and extracted with dichloromethane. The extract was dried (MgSO), filtered, This example was made by Substituting ethyl 4-amino-1- and concentrated. piperidinecarboxylate for EXAMPLE 21C in EXAMPLE 55 21D. EXAMPLE 192B EXAMPLE 195B This example was made by substituting EXAMPLE 192A for EXAMPLE 21C in EXAMPLE 21 D. This example was made by substituting EXAMPLE 195A 60 for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 192C propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 1D. "H NMR (500 MHz, DMSO-d) & 12.10 (brs, 1H), 8.64 This example was made by substituting EXAMPLE 192B (d. 1H), 8.29 (d. 1H), 7.95 (dd. 1H), 7.75 (d. 3H), 7.54 (m, for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 2H), 7.48 (m. 1H), 7.43 (m. 1H), 7.37 (m, 2H), 6.92 (d. 2H), propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 65 4.36 (brs, 2H), 4.05 (m, 2H), 3.94 (m, 3H), 3.77 (brs, 3H), 1D. "H NMR (500 MHz, DMSO-d) & 8.27 (d. 1H), 7.86 (dd, 3.01 (brs, 4H), 2.83 (brs, 2H), 1.94 (d. 2H), 1.55 (m, 2H), 1H), 7.74 (m, 3H), 7.52 (m, 2H), 7.47 (m, 2H), 7.42 (m, 2H), 1.19 (t, 5H). US 7,973,161 B2 177 178 EXAMPLE 196A 1D. "H NMR (400 MHz, DMSO-d) & 8.80 (t, 1H), 8.61 (d. 1H), 7.96 (dd. 1H), 7.73 (m, 4H), 7.62 (d. 1H), 7.51 (m, 2H), This example was made by Substituting 1-bromopropane 7.46 (d. 2H), 7.40 (m, 2H), 7.34 (m, 4H), 6.91 (d. 2H), 4.28 (br for benzyl bromide in EXAMPLE 191B. s, 2H), 3.81 (m, 4H), 3.50 (t, 4H), 2.06 (s. 2H).

EXAMPLE 196B EXAMPLE 199A This example was made by substituting EXAMPLE 196A This example was made by Substituting 4-phenyl-2-mer for EXAMPLE 191B in EXAMPLE 797 197C. captothiazole for 2-mercaptothiazole in EXAMPLE 198A. 10 EXAMPLE 196C EXAMPLE 199B This example was made by substituting EXAMPLE 196B for EXAMPLE 21C in EXAMPLE 21 D. This example was made by substituting EXAMPLE 199A 15 for EXAMPLE 21 B in EXAMPLE 21 C. EXAMPLE 196D EXAMPLE 199C This example was made by substituting EXAMPLE 196C for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) This example was made by substituting EXAMPLE 199B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE for EXAMPLE 21C in EXAMPLE 21 D. 1D. "H NMR (400 MHz, DMSO-d) & 8.51 (d. 1H), 8.43 (t, 2H), 7.90 (dd. 1H), 7.72 (d. 2H), 7.53 (m, 1H), 7.42 (m, 4H), EXAMPLE 199D 7.35 (m,3H), 7.24 (m, 1H), 7.10 (d. 1H), 6.78 (d. 2H), 3.41 (s, 2H), 3.36 (m, 5H), 3.13 (m, 4H), 2.77 (m,3H), 2.39 (m, 4H), This example was made by substituting EXAMPLE 199C 1.87 (d. 3H), 1.59 (m, 2H), 1.42 (m, 2H), 0.87 (t, 3H). 25 for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE EXAMPLE 197A 1D. "H NMR (400 MHz, DMSO-d) & 8.77 (m. 1H), 8.57 (d. 1H), 8.00 (s, 1H), 7.91 (m, 3H), 7.73 (d. 2H), 7.54 (m, 1H), This example was made by Substituting isopropylamine for 7.39 (m. 11H), 7.24 (m, 1H), 6.86 (d. 2H), 3.87(m, 2H), 3.57 EXAMPLE 21C in EXAMPLE 21 D. 30 (dd, 2H), 3.43 (s. 2H), 3.22 (m, 4H), 2.39 (m, 4H).

EXAMPLE 197B EXAMPLE 20OA This example was made by substituting EXAMPLE 197A for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 35 This example was made by Substituting 2-mercaptobenz propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE thiazole for 2-mercaptothiazole in EXAMPLE 198A. 1D. "H NMR (500 MHz, DMSO-d) & 8.64 (d. 1H), 8.24 (d. 1H), 7.95 (dd. 1H), 7.74 (m,3H), 7.50 (m, 4H), 7.42 (m. 1H), EXAMPLE 20OB 7.35 (m,3H), 7.27 (d. 1H), 6.91 (d. 2H), 4.25 (brs, 2H), 4.00 (m. 1H), 1.28 (d. 6H). 40 This example was made by substituting EXAMPLE 200A for EXAMPLE 21 B in EXAMPLE 21 C. EXAMPLE 198A A mixture of tributylphosphine (0.8 mL), (1,1'-azodicar EXAMPLE 200C bonyl)dipiperidine (0.8 g), and THF (5.1 mL) at 25°C. was 45 stirred for 10 minutes, treated with tert-butyl N-(2-hydroxy This example was made by substituting EXAMPLE 200B ethyl)carbamate (0.32 mL), 2-mercaptothiazole (500 mg), for EXAMPLE 21C in EXAMPLE 21 D. and THF (5 mL), stirred for 20 hours, treated with ethyl acetate (50 mL), washed with water, dried (MgSO), filtered, EXAMPLE 20OD and concentrated. The concentrate was flash chromato 50 graphed on silica gel with 5-30% ethyl acetate/hexanes. This example was made by substituting EXAMPLE 200C for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 198B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 1D. "H NMR (500 MHz, DMSO-d) & 8.86 (t, 1H), 8.59 (d. This example was made by substituting EXAMPLE 198A 55 1H), 7.76 (m, 4H), 7.54 (m, 2H), 7.48 (m, 2H), 7.43 (m, 2H), for EXAMPLE 21 B in EXAMPLE 21 C. 7.36 (m, 4H), 6.92 (d. 2H), 4.31 (brs, 2H), 3.91 (m, 2H), 3.66 EXAMPLE 198C (t, 4H), 2.97 (brs, 4H).

This example was made by substituting EXAMPLE 198B 60 EXAMPLE 2.01 for EXAMPLE 21C in EXAMPLE 21 D. This example was made by substituting EXAMPLE 198C EXAMPLE 1.98D for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE This example was made by substituting EXAMPLE 198C 65 2D. "H NMR (400 MHz, DMSO-d) & 8.80 (m. 1H), 8.61 (d. for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 1H), 7.95 (dd. 1H), 7.74 (m, 4H), 7.71 (d. 1H), 7.62 (d. 1H), propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 7.52 (m, 4H), 7.40 (m, 1H), 7.39 (m, 2H), 7.37 (m, 1H), 7.33 US 7,973,161 B2 179 180 (m. 1H), 6.91 (d. 2H), 3.81 (m, 4H), 3.50 (m, 4H), 3.32 (m, 7.72 (brs, 1H), 7.52 (m, 5H), 7.40 (d. 2H), 7.33 (m. 1H), 7.24 1H), 3.27 (m, 1H), 2.49 (m. 1H), 2.06 (s, 1H). (t, 1H), 6.92 (d. 2H), 4.29 (brs, 2H), 3.78 (m, 4H), 3.39 (t, 4H), 2.85 (brs, 2H). EXAMPLE 202A EXAMPLE 205A This example was made by Substituting 2-mercaptoben This example was made by Substituting 2-bromoethy Zoxazole for 2-mercaptothiazole in EXAMPLE 198A. lamine hydrochloride for EXAMPLE 21C in EXAMPLE 21D. EXAMPLE 202B 10 EXAMPLE 2.05B This example was made by substituting EXAMPLE 202A EXAMPLE 205A and 2-mercaptoimidazole were sub for EXAMPLE 21 B in EXAMPLE 21 C. jected to the procedure described in J. Med. Chem. 1995, 38. 1067. 15 EXAMPLE 202C EXAMPLE 205C This example was made by substituting EXAMPLE 205B This example was made by substituting EXAMPLE 202B for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) for EXAMPLE 21C in EXAMPLE 21 D. propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 8.73 (t, 1H), 8.63 (d. EXAMPLE 202D 1H), 7.94 (dd. 1H), 7.76 (d. 3H), 7.53 (m, 4H), 7.40 (d. 2H), 7.34 (m. 1H), 7.30 (m. 1H), 6.93 (d. 2H), 4.26 (brs, 2H), 3.72 This example was made by substituting EXAMPLE 202C (m, 4H), 3.42 (t, 4H), 2.98 (brs, 4H). for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 25 propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE EXAMPLE 2.06 2D. "H NMR (400 MHz, DMSO-d) & 8.84 (m, 1H), 8.58 (d. This example was made by substituting EXAMPLE 191D 1H), 8.00 (dd. 1H), 7.76 (d. 2H), 7.71 (brs, 1H), 7.57 (m, 2H), for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 7.50 (m, 4H), 7.39 (m, 2H), 7.29 (m, 3H), 6.91 (d. 2H), 4.22 propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE (brs, 2H), 3.92 (m, 2H), 3.60 (t, 4H), 2.97 (m, 4H). 30 2D. "H NMR (500 MHz, DMSO-d) & 12.11 (brs, 1H), 11.43 (brs, 1H), 10.67 (brs, 1H), 8.73 (t, 1H), 8.63 (d. 1H), 8.15 (m, EXAMPLE 203 1H), 7.92 (dd. 1H), 7.76 (d. 2H), 7.59 (m, 2H), 7.53 (m, 4H), 7.44 (m, 4H), 7.38 (d. 2H), 7.33 (m. 1H), 7.28(d. 1H), 6.93 (d. 2H), 4.34 (brs, 2H), 4.22 (d. 2H), 3.89 (d. 2H), 3.37 (m, 4H), This example was made by substituting EXAMPLE 200C 35 3.31 (d. 2H), 3.25 (d. 2H), 2.84 (m, 4H), 1.88 (d,3H), 1.61 (m, for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 2H). propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) & 12.06 (brs, 1H), 8.85 EXAMPLE 207 (t, 1H),8.58 (d. 1H), 8.01 (dd. 1H), 7.97 (d. 1H), 7.75 (m,3H), 7.71 (brs, 1H), 7.51 (m, 4H), 7.37 (m, 4H), 6.91 (d. 2H), 4.26 40 This example was made by substituting EXAMPLE 205A (brs, 2H), 3.90 (m, 2H), 3.64 (t, 4H), 2.96 (m, 6H) for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 1D. "H NMR (500 MHz, DMSO-d) & 12.12 (brs, 1H), 8.75 EXAMPLE 2.04A (m. 1H), 8.65 (d. 1H), 7.96 (dd. 1H), 7.75 (d. 3H), 7.53 (m, 2H), 7.48 (m, 2H), 7.43 (m. 1H), 7.36 (m, 4H), 6.92 (d. 2H), This example was made by Substituting 2-mercaptopyri 45 4.29 (brs, 2H), 3.88 (m, 4H), 3.82 (m, 2H), 3.72 (t, 2H), 3.03 midine for 2-mercaptothiazole in EXAMPLE 198A. (m, 4H). EXAMPLE 208A EXAMPLE 204B 50 This example was made by Substituting 4-methylthiazole This example was made by substituting EXAMPLE 204A 2-thiol for 2-mercaptoimidazole in EXAMPLE 205B. for EXAMPLE 21 B in EXAMPLE 21 C. EXAMPLE 208B

EXAMPLE 2.04C 55 This example was made by substituting EXAMPLE 208A for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) This example was made by substituting EXAMPLE 204B propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE for EXAMPLE 21C in EXAMPLE 21 D. 2D. "H NMR (500 MHz, DMSO-d) & 12.07 (brs, 1H), 8.81 (t, 1H), 8.63 (d. 1H), 7.95 (dd. 1H), 7.76 (d. 2H), 7.73 (brs, 60 1H), 7.52 (m, 3H), 7.39 (d. 2H), 7.34 (m. 1H), 6.93 (d. 2H), EXAMPLE 2.04D 4.25 (brs, 2H), 3.82 (m, 2H), 3.48 (m, 4H), 3.02 (m, 4H), 2.29 (s, 3H), 2.07 (s. 2H). This example was made by substituting EXAMPLE 204C for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) EXAMPLE 209A propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 65 2D. "H NMR (500 MHz, DMSO-d) & 12.07 (brs, 1H), 8.83 This example was made by Substituting benzylamine for (t, 1H), 8.66 (d. 2H), 8.63 (d. 1H), 8.04 (dd. 1H), 7.76 (d. 2H), 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) US 7,973,161 B2 181 182 propyl)amino)-3-nitrobenzenesulfonamide and 4-methoxy EXAMPLE 211B carboxylic acid for EXAMPLE 2C in EXAMPLE 2D. This example was made by substituting EXAMPLE 21 1A for EXAMPLE 21 B in EXAMPLE 21 C. EXAMPLE 209B EXAMPLE 211C This example was made by substituting EXAMPLE 209A for EXAMPLE 1.8E in EXAMPLE 1.8F. This example was made by substituting EXAMPLE 8O3O757B for EXAMPLE 21C in EXAMPLE 21 D. EXAMPLE 209C 10 EXAMPLE 21 1D EXAMPLE 209B (710 mg) and Pd(OH) (0.28 g) in methanol (70 mL) at 50° C. was stirred under H (60 psi) for This example was made by substituting EXAMPLE 211C 22 hours, cooled to 25°, filtered, and concentrated. for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 15 propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE EXAMPLE 209D 2D. "H NMR (500 MHz, DMSO-d) & 8.58 (d. 1H), 8.54 (s, 1H), 7.82 (dd. 1H), 7.79 (d. 2H), 7.72 (brs, 1H), 7.52 (m, 4H), This example was made by substituting EXAMPLE 209C 7.33 (d. 2H), 7.21 (dd. 1H), 6.96 (dd. 1H), 6.94 (d. 2H), 6.66 for EXAMPLE 21C in EXAMPLE 21 D. (dd. 1H), 4.19 (brs, 4H), 2.90 (brs, 6H), 1.54 (s, 6H). EXAMPLE 209E EXAMPLE 212A This example was made by substituting EXAMPLE 209D This example was made by sustituting EXAMPLE 19A for for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 25 Boc-2-amino-2-methylpropanol and EXAMPLE 22A for propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2-thienyldisulfide in EXAMPLE 21 1A. 2D. "H NMR (400 MHz, DMSO-d) & 8.55 (d. 1H), 8.48 (t, 1H), 7.90 (dd. 1H), 7.72 (d. 2H), 7.51 (m, 1H), 7.47 (s.3H), EXAMPLE 2.12B 7.37 (m, 2H), 7.25 (m, 1H), 7.14 (d. 1H), 6.84 (d. 2H), 3.39 (s. 2H), 3.36 (m. 1H), 3.27 (m, 4H), 3.19 (m, 5H), 2.40 (t, 4H), 30 This example was made by substituting EXAMPLE 212A 1.80 (m, 2H), 1.69 (m. 1H), 1.48 (m, 2H), 1.33 (m, 4H). for EXAMPLE 18B in EXAMPLE 18C. EXAMPLE 21 OA EXAMPLE 212C

This example was made by Substituting 2-mercap 35 This example was made by substituting EXAMPLE 212B tothiophene for 2-mercaptothiazole in EXAMPLE 198A. for EXAMPLE 1.8E in EXAMPLE 1.8F. EXAMPLE 21 2D EXAMPLE 21 OB This example was made by substituting EXAMPLE 212C This example was made by substituting EXAMPLE 210A 40 for EXAMPLE 21C in EXAMPLE 21 D. for EXAMPLE 21 B in EXAMPLE 21 C. EXAMPLE 212E EXAMPLE 21 OC This example was made by substituting EXAMPLE 212D This example was made by substituting EXAMPLE 210B 45 for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) for EXAMPLE 21C in EXAMPLE 21 D. propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 2D. "H NMR (500 MHz, DMSO-d) 89.97 (brs, 1H), 8.61 (d. EXAMPLE 21 OD 1H), 8.34 (d. 1H), 7.95 (dd. 1H), 7.75 (d. 2H), 7.72 (brs, 1H), 7.66 (d. 1H), 7.59 (d. 1H), 7.51 (d, 4H), 7.32 (m, 1H), 6.92 (d. This example was made by substituting EXAMPLE 210C 50 2H), 4.35 (m, 2H), 4.22 (brs, 2H), 3.95 (brs, 4H), 3.21 (m, for 4-(((1R)-3-(dimethylamino)-1-((phenylsulfanyl)methyl) 4H), 2.94 (m, 6H), 2.20 (m, 2H). propyl)amino)-3-nitrobenzenesulfonamide in EXAMPLE 1D. "H NMR (500 MHz, DMSO-d) & 8.74 (t, 1H), 8.62 (d. EXAMPLE 213A 1H), 7.90 (dd. 1H), 7.75 (m, 2H), 7.61 (dd. 1H), 7.54 (m, 2H), 7.49 (m, 2H), 7.43 (m, 1H), 7.36 (m, 2H), 7.21 (dd. 1H), 7.13 55 This example was prepared by Substituting 2-mercaptopy (d. 1H), 7.02 (dd. 1H), 6.92 (d. 2H), 4.36 (brs, 2H), 3.63 (m, rimidine for 2-mercaptothiazole in EXAMPLE 22A. 4H), 3.11 (t, 4H), 2.54 (s, 4H). EXAMPLE 213B EXAMPLE 21 1A 60 This example was made by sustituting EXAMPLE 18A for A mixture of Boc-2-amino-2-methylpropanol (633 mg) Boc-2-amino-2-methylpropanol and EXAMPLE 213A for and 2-thienyldisulfide (1 g) in THF (12 mL) at 25°C. was 2-thienyldisulfide in EXAMPLE 21 1A. treated with tributylphosphine (1.1 mL), heated at 85°C. for 2.5 hours, treated with ethyl acetate, washed with water, dried EXAMPLE 213C (MgSO), filtered, and concentrated. The concentrate was 65 flash chromatographed on silica gel with 30-70% ethyl This example was made by substituting EXAMPLE 213B acetate/hexanes. for EXAMPLE 18B in EXAMPLE 18C.