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(12) Patent Application Publication (10) Pub. No.: US 2010/0022773 A1 Bruncko Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2010/0022773 A1 Bruncko Et Al US 2010.0022773A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0022773 A1 Bruncko et al. (43) Pub. Date: Jan. 28, 2010 (54) APOPTOSIS PROMOTERS (22) Filed: Feb. 23, 2009 (76) Inventors: Milan Bruncko, Green Oaks, IL Related U.S. Application Data (US); Hong Ding, Gurnee, IL (US); (63) Continuation of application No. 1 1/127,940, filed on Steven Elmore, Gurnee, IL (US); May 12, 2005, which is a continuation-in-part of appli Aaron Kunzer, Schaumburg, IL cation No. 10/988,388, filed on Nov. 12, 2004, now (US); Christopher L. Lynch, abandoned. Trevor, WI (US); William McClellan, Waukegan, IL (US); (60) Provisional application No. 60/519,695, filed on Nov. Cheol-Min Park, Gurnee, IL (US); 13, 2003. Andrew Petros, Mundelein, IL (US); Xiaohong Song, Grayslake, Publication Classification IL (US); Noah Tu, Gurnee, IL (US); (51) Int. C. Xilu Wang, Oakwood, IL (US); C07D 24I/04 (2006.01) Michael Wendt, Vernon Hills, IL (US) (52) U.S. Cl. ........................................................ 544/392 Correspondence Address: (57) ABSTRACT PAUL. D. YASGER Disclosed are compounds which inhibit the activity of anti ABBOTT LABORATORIES apoptotic protein family members, compositions containing 100 ABBOTT PARK ROAD, DEPT. 377/AP6A the compounds and uses of the compounds for preparing ABBOTT PARK, IL 60064-6008 (US) medicaments for treating diseases during which occurs expression one or more than one of an anti-apoptotic protein (21) Appl. No.: 12/390,945 family member. US 2010/0022773 A1 Jan. 28, 2010 APOPTOSIS PROMOTERS or N(CH)SO.N(CH) R', and the remainder are indepen dently selected H, F, Cl, Br, I, CF, C(O)OH, C(O)NH2 or 0001. This application is a continuation of U.S. Ser. No. 0009 R is R. R. R. or R: 11/127,940 filed on May 12, 2005, which is a continuation 10010) R' is C1-Co-alkyl, C-C-alkenyl or C-C-alky in-part of and claims priority to U.S. Ser. No. 10/968,368 filed nyl: on Nov. 12, 2004, which claims priority to U.S. Provisional 10011) R' is phenyl which is unfused or fused with arene, Patent Application Ser. No. 60/519,695, filed Nov. 13, 2003, heteroarene or R'; R is cycloalkane or heterocycloalkane; I0012 R is heteroaryl which is unfused or fused with ben each of which is hereby incorporated by reference. Zene, heteroarene or R'; R is cycloalkane or heterocy cloalkane; FIELD OF THE INVENTION (0013 R' is cycloalkyl, cycloalkenyl, heterocycloalkyl or 0002 This invention pertains to compounds which inhibit heterocycloalkenyl, each of which is unfused or fused with the activity of anti-apoptotic protein family members, com arene, heteroarene or R'; R' is cycloalkane, cycloalkene, positions containing the compounds, and methods of treating heterocycloalkane or heterocycloalkene; diseases during which are expressed of one or more than one I0014 R is alkyl, alkenyl or alkynyl, each of which is of an anti-apoptotic protein family member. unsubstituted or substituted with one or two or three indepen dently selected R, NC(R)(R), R7, OR7, SR 7, S(O)R7, BACKGROUND OF THE INVENTION SOR7, NHR'. N(R7), C(O)R’, C(O)NH, C(O)NHR'. NHC(O)R’, NHSOR7, NHC(O)OR7, SONH, SONHR'. 0003 Anti-apoptotic protein family members are associ SON(R7). NHC(O)NH, NHC(O)NHR', NHC(O)CH ated with a number of diseases. There is therefore an existing (CH)NHC(O)CH(CH)NH, NHC(O)CH(CH)NHC(O) need in the therapeutic arts for compounds which inhibit the CH(CH,)NHR', OH, (O), C(O)OH, (O), N, CN, NH, CF, activity of one of more than one of an anti-apoptotic protein CFCF, F, Cl, Br or I substituents: family member. I0015 R is C-C-spiroalkyl, each of which is unsubsti tuted or substituted with OH, (O), N, CN, CF, CFCF, F, SUMMARY OF THE INVENTION Cl, Br, I, NH, NH(CH) or N(CH): (0016 R'' and R are independently selected alkyl or, 0004 One embodiment of this invention, therefore, per together with the N to which they are attached, R: tains to compounds or therapeutically acceptable salts, pro I0017 R is aziridin-1-yl, azetidin-1-yl, pyrrolidin-1-ylor drugs or salts of prodrugs thereof, which are useful as inhibi piperidin-1-yl, each having one CH2 moiety unreplaced or tors one or more than one anti-apoptotic protein family replaced with O, C(O), CNOH, CNOCH, S, S(O), SO, or member, the compounds having formula (I) NH; 0018 R7 is R. R. R' or R'': I0019 R is phenyl which is unfused or fused with arene, (I) heteroarene or R': O O. O El (0020) R' is cycloalkane, cycloalkene, heterocycloalkane ls \/ Yl or heterocycloalkene; Zl N1 N s (0021) R' is heteroaryl which is unfused or fused with i | 2 arene, heteroarene or R'; R is cycloalkane, cycloalkene, D1 Al Bl heterocycloalkane or heterocycloalkene; (0022) R' is Cs-Co-cycloalkyl or C-Co-cycloalkenyl, each having one or two CH moieties unreplaced or replaced wherein A' is N or C(A): with independently selected O, C(O), CNOH, CNOCH, S, 0005 one or two or three or each of A, B, D" and E' are S(O), SO, or NH and one or two CH moieties unreplaced or independently selected R', OR', SR', S(O)R', SOR", C(O) replaced with N, and each of which is unfused or fused with R", C(O)OR', OC(O)R', NHR', N(R'), C(O)NHR', C(O) arene, heteroarene or R'; R' is cycloalkane, cycloalkene, N(R'), NHC(O)R', NHC(O)OR', NRC(O)NHR', NRC heterocycloalkane or heterocycloalkene; (O)N(R'), SONHR', SON(R'), NHSOR', (0023 R'' is alkyl, alkenyl or alkynyl, each of which is NHSONHR' or N(CH)SON(CH)R', and the remainder unsubstituted or substituted with one or two or three indepen are independently selected H, F, Cl, Br, I, CN, CF, C(O)OH, dently selected R, OR, NHR'. N(R'), C(O)NHC(O) C(O)NH, or C(O)OR'; and NHR'. C(O)N(R'), OH, (O), C(O)CH, N, CN, NH, CF, 0006 Y is H, CN, NO, C(O)OH, F, Cl, Br, I, CF. OCF, CFCF, F, Cl, Br or I substituents: CFCF, OCFCF, R7, OR7, C(O)R'7, C(O)OR7, SR 7, 0024) R'? is R', R, R or R'; NH, NHR'7, N(R'7), NHC(O)R'7,C(O)NHC(O)NHR'7, I0025) R' is phenyl which is unfused or fused with arene, C(O)N(R7), NHS(O)R7 or NHSOR'7; heteroarene or R'': R'' is cycloalkane, cycloalkene, het O erocycloalkane or heterocycloalkene; 0007 B' andY', together with the atoms to which they are I0026 R'' is heteroaryl, each of which is unfused or fused attached, are imidazole or triazole; and with arene, heteroarene or R'': R''' is cycloalkane, 0008 one or two or each of A, D and E' are indepen cycloalkene, heterocycloalkane or heterocycloalkene; dently selected R', OR', SR', S(O)R', SOR', C(O)R', C(O) 10027) R' is cycloalkane, cycloalkene, heterocycloalkane OR', OC(O)R', NHR', N(R'), C(O)NHR', C(O)N(R'), or heterocycloalkene, each of which is unfused or fused with NHC(O)R', NHC(O)OR', NHC(O)NHR', N(CH)C(O)N arene, heteroarene or R'': R'' is cycloalkane, cycloalkene, (CH) R', SONHR', SON(R'), NHSOR', NHSONHR' heterocycloalkane or heterocycloalkene; US 2010/0022773 A1 Jan. 28, 2010 0028) R' is alkyl, alkenyl or alkynyl: I0049 R is phenyl which is unfused or fused with arene, 0029 R7 is R', R, R20 or R2'; heteroarene or R'; R is cycloalkane, cycloalkene, het I0030) R' is phenyl which is unfused or fused with arene, erocycloalkane or heterocycloalkene; heteroarene or R'': R'' is cycloalkane, cycloalkene, het 0050 R7 is R, R or R', each of which is substituted erocycloalkane or heterocycloalkene; with F, C1, Br, I, R', OR, NHR', N(R'), NHC(O)OR', 0031) R' is heteroaryl which is unfused or fused with SR', S(O)R or SOR; arene, heteroarene or R'; R' is cycloalkane, cycloalkene, 0051 R is phenyl which is unfused or fused with arene, heterocycloalkane or heterocycloalkene; heteroarene or R'; R is cycloalkane, cycloalkene, het I0032) R' is Cs-Co-cycloalkyl or C-Co-cycloalkenyl, erocycloalkane or heterocycloalkene; each having one or two CH2 moieties unreplaced or replaced 0052 R is heteroaryl which is unfused or fused with with independently selected O, C(O), CNOH, CNOCH, S, arene, heteroarene or R'; R' is cycloalkane, cycloalkene, S(O), SOor NH and one or two CH moieties unreplaced or heterocycloalkane or heterocycloalkene; replaced with N, and each of which is unfused or fused with I0053 R' is C-Cs-cycloalkyl or C-Cs-cycloalkenyl, arene, heteroarene or R'; R' is cycloalkane, cycloalkene, each having one or two CH2 moieties unreplaced or replaced heterocycloalkane or heterocycloalkene; with independently selected O, C(O), CNOH, CNOCH, S, I0033 R’ is alkyl, alkenyl or alkynyl, each of which is S(O), SOor NH and one or two CH moieties unreplaced or unsubstituted or substituted with one or two or three indepen replaced with N, and each of which is unfused or fused with dently selected R, OR, NHR’, N(R), C(O)NHC(O) arene, heteroarene or R'; R' cycloalkane, cycloalkene, NHR’, C(O)N(R'), OH, (O), C(O)OH, N, CN, NH, CF, heterocycloalkane or heterocycloalkene; CFCF, F, Cl, Br or I substituents: 0054 R is R2, R, R or R5; 0034 R is R, R or R: 0055) R' is phenyl which is unfused or fused with arene, 0035 R’ is phenyl 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; erocycloalkane or heterocycloalkene; 0056 R is heteroaryl which is unfused or fused with 0036) R' is heteroarene which is unfused or fused with arene, heteroarene or R'': R is cycloalkane, cycloalkene, arene, heteroarene or R'; R' is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; heterocycloalkane or heterocycloalkene; I0057 R is C-C-cycloalkyl or Ca-Ca-cycloalkenyl, I0037 R’ is C-C-cycloalkyl or Ca-Ca-cycloalkenyl, each having one or two CH moieties unreplaced or replaced each having one or two CH moieties unreplaced or replaced with independently
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