US 2014020O250A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0200250 A1 Peng et al. (43) Pub. Date: Jul. 17, 2014 (54) ANTI-CANCERAGENTS (60) Provisional application No. 61/503,957, filed on Jul. 1, 2011. (71) Applicant: UWM Research Foundation, Inc., Milwaukee, WI (US) Publication Classification (72) Inventors: Xiaohua Peng, Milwaukee, WI (US); (51) Int. Cl. Yunyan Kuang, Shanghai City (CN); C07D 207/50 (2006.01) Sheng Cao, Milwaukee, WI (US); A6II 45/06 (2006.01) Wenbing Chen, Milwaukee, WI (US); A613 L/478 (2006.01) Yibin Wang, Milwaukee, WI (US) (52) U.S. Cl. CPC .......... CO7D 207/50 (2013.O1): 46K 3/478 (73) Assignee: UWM Research Foundation, Inc., ( ); Milwaukee, WI (US (2013.01); A61K 45/06 (2013.01) ilwaukee, WI (US) USPC ......................... 514/397: 548/313.7; 435/375 (21)21) Appl. NoNo.: 14/136,0259 (57) ABSTRACT (22) Filed: Dec. 20, 2013 Described herein are compounds that may be selectively acti Related U.S. Application Data vated to produce active anti-cancer agents in tumor cells. Also disclosed are pharmaceutical compositions comprising the (62) Division of application No. 13/539,471, filed on Jul. 1, compounds, and methods of treating cancer using the com 2012, now Pat. No. 8,637,490. pounds. Patent Application Publication Jul. 17, 2014 Sheet 1 of 13 US 2014/0200250 A1 Compound 6 6 7 7 17a 17a 8 8 9 9 10 10 5 5 Ho - + - + - + - + - + - + - + DNA Cross-link <" ssDNA 1 2 3 4 5 6 7 8 9 O 11 12 13 14 FG. Patent Application Publication Jul. 17, 2014 Sheet 2 of 13 US 2014/0200250 A1 Fate:is: if: Gigi Pisces: is is Farsist - Sifyi. Festigi 8 & 3rces : 3:83.3 38: 838 i8::::: 3. S: S. FIG. 2A Patent Application Publication Jul. 17, 2014 Sheet 3 of 13 US 2014/0200250 A1 8:38: s s &&E st & ex: 888: 8::::: & 8 88: FEG 2B Patent Application Publication Jul. 17, 2014 Sheet 4 of 13 US 2014/0200250 A1 3888:8:3& s as es: 8:33; S3888 & 28. 38:::::::::: FG. 2C Patent Application Publication Jul. 17, 2014 Sheet 5 of 13 US 2014/0200250 A1 & 88: waaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaXaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa 8-8-8-8-8-8-8-8-8-8 838 FIG. 2D Patent Application Publication Jul. 17, 2014 Sheet 6 of 13 US 2014/0200250 A1 88: 88: 8: &: 8883: 88: 888 &&. 8:888&&. so 888 88 .338 88 FIG. 2E Patent Application Publication Jul. 17, 2014 Sheet 7 of 13 US 2014/0200250 A1 H2O2 + - + + + + + + + r - - - - - - - Drug - + + + + + + 4 + h - - 3 4 5 8 9 O 1 2 3 1: S 6 FIG 3 Patent Application Publication Jul. 17, 2014 Sheet 8 of 13 US 2014/0200250 A1 1 2 5 A. 100 75 50 25 sR NC-H460 CAK-1 SN12C 100- B. 75 50 25 Donor 1 Donor 2 DOnor 3 FG. 4 Patent Application Publication Jul. 17, 2014 Sheet 9 of 13 US 2014/0200250 A1 DOrl Dr. DOrr 3 DOOf DOOr - DOr 3 A. Patent Application Publication Jul. 17, 2014 Sheet 10 of 13 US 2014/0200250 A1 irg Wr ". -- w w v. • sk. & ". s . it aw xx sa & . a- a & Patent Application Publication Jul. 17, 2014 Sheet 11 of 13 US 2014/0200250 A1 Patent Application Publication Jul. 17, 2014 Sheet 12 of 13 US 2014/0200250 A1 1 2 3 4 5, 6 f 8 9 1 O 1112 13 14 15 -- CL TTT TXT GXG AXA CXC AAA AAA CAC TAT GAG 14 6 7 8 9 FIG. 8 Patent Application Publication Jul. 17, 2014 Sheet 13 of 13 US 2014/0200250 A1 FG, 9 US 2014/020O250 A1 Jul. 17, 2014 ANT-CANCERAGENTS 10010 each R is independently selected from: CROSS-REFERENCE TO RELATED APPLICATIONS 0001. This application is a divisional of U.S. patent appli cation Ser. No. 13/539,471, filed Jul. 1, 2012, which applica X. X N e tion claims priority to U.S. Provisional Patent Application No. 61/503,957, filed on Jul. 1, 2011. The entire contents of each of these applications are hereby incorporated by refer R4a ?h Rb and Ra ?il R4b; CCC. STATEMENT REGARDING FEDERALLY 10011 each R“ and R' is independently selected from SPONSORED RESEARCH halo and OSOR: 0002 This invention was made with United States govern 0012 each Y is independently a bond or —CH2—, ment support awarded by the National Cancer Institute, Grant No. 1R15CA152914-01. The United States Government has (0013 each R is independently C-C alkyl: certain rights in this invention. 0014 n is 0, 1 or 2: SEQUENCE LISTING (0015 p is 1 or 2: 0016 each R is independently selected from optionally 0003. The instant application contains a Sequence Listing substituted alkyl: which has been submitted in text format via EFS-Web and is hereby incorporated by reference in its entirety. Said text 0017 wherein if the compound of formula (I) bears a copy, created on Oct. 30, 2012, is named ASFILED Se positive charge, it further comprises at least one counterion quenceListing-Text and is 2.270 bytes in size. Ze. 0018. In another aspect, the disclosure provides a com BACKGROUND pound of formula (Ia): 0004. Many cancer cells exhibit a disturbed intracellular redox balance, making them distinctively different from their (Ia) “healthy counterparts. Among these differences, some can cer cells are hypoxic and have an increase in bioreductive processes, while others have high intracellular concentrations of reactive oxygen species due to oxidative stress. 0005. There is a continuing need for new anti-cancer agents, particularly those that have fewer toxic side-effects. e SUMMARY / \ 0006. In one aspect, the disclosure provides a compound of formula (I): 0019 wherein: (I) (0020) R' is B(XR"), wherein each X is independently R1 selected from O and S, and each R" is independently selected from hydrogen and alkyl, or two Rare taken together to form 1N an optionally substituted 5- to 8-membered ring: (R)-Nux 0021 R is: (R), r 0007 wherein: 0008 each R" is independently —B(XR"), wherein each X is independently selected from O and S, and each R' is ul. independently selected from hydrogen and alkyl, or two R' are taken together to form an optionally substituted 5- to 8-membered ring; 0022 wherein each RandR is independently selected I0009 each R is independently selected from optionally from halo and —OSOR"; and substituted alkyl, alkoxy, amino, halo, and —CH N(R) 0023 each R is independently selected from optionally €e. 3 3 substituted alkyl. US 2014/020O250 A1 Jul. 17, 2014 0024. In another aspect, the disclosure provides a com I0038 each R is independently selected from: pound of formula (II): (II) (R'), A. A. rf and N(R): (R), R4a R4b 0025 wherein: 0039 each R* and R is independently selected from 0026 each R" is independently —B(XR"), wherein each halo and—OSOR: X is independently selected from O and S, and each R' is I0040 each R is independently optionally substituted independently selected from hydrogen and alkyl, or two R' alkyl: 0041 m is 1 or 2: are taken together to form an optionally substituted 5- to 0042 n is 0, 1 or 2: 8-membered ring; 0043 p is 2; and I0027 each R is independently selected from optionally 0044 wherein the compound further comprises at least Substituted alkyl, alkoxy, amino, halo and nitro: one counterion Z. 0028 each R is independently selected from: 0045. In another aspect, the disclosure provides a com pound of formula (III): (III) RI A. R2 ri and N(R): R4a l R4b 0029 each R" and R' is independently selected from halo and —OSOR: O R2 I0030) each R is independently optionally substituted alkyl: RI 0031 m is 1 or 2: 0046 wherein: 0032 n is 0, 1 or 2: I0047 each R" is independently selected from selected 0033 p is 2; and from the group consisting of 0034 wherein the compound further comprises at least one counterion Z. 0035. In another aspect, the disclosure provides a com pound of formula (IIa): d (IIa) R3 R2 rth RI ( ) ( ) R1 GE) R2 R3 N(R), 0048 wherein at least one R' is other than —CHO: I0036) each R' is independently —B(XR"), wherein each I0049 each R is independently selected from an electron X is independently selected from O and S, and each R' is withdrawing group; independently selected from hydrogen and alkyl, or two R' 0050 each X is independently halo: are taken together to form an optionally substituted 5- to 10051) each R“ and R' is independently selected from 8-membered ring; halo and OSOR'; and 0037 each R is independently selected from hydrogen, I0052 each R is independently selected from optionally optionally substituted alkyl, alkoxy, amino, halo and nitro: substituted alkyl: US 2014/020O250 A1 Jul. 17, 2014 0053 wherein if the compound of formula (III) bears a 0063 wherein: positive charge, it further comprises at least one counterion I0064) R' is selected from the group consisting of: Ze. 0054. In another aspect, the disclosure provides a com pound of formula (IIIa): A A R2 (IIIa)III Ns Y- R4 and R4 J)s N / y I0065 R is selected from the group consisting of Hand RI N a hydroxy protecting group; I0066 R is selected from the group consisting of Hand - P(N(CH(CH)))(OCHCHCN); and I0067 each R" is independently an electron withdrawing N RI group. 0068. In another aspect, the disclosure provides a com \ f pound of formula (Va), (Vb), (Vc), (Vd), (Ve) or (Vf): N R2 (Va) R1 0055 wherein: I0056 each R" is independently selected from selected N from the group consisting of (R2)-H 2 R4 GE) (Vb) X and N(R), I0057 each R is independently selected from an electron withdrawing group; 0058 each X is independently halo: (Vc) I0059) each R is independently selected from the group consisting of —H and —COO(alkyl), and 0060 each R is independently selected from optionally substituted alkyl: 0061 wherein if the compound of formula (III) bears a positive charge, it further comprises at least one counterion Ze.