TOMMANNUUTTILIMINATIONUS009862693B2 (12 ) United States Patent ( 10 ) Patent No

TOMMANNUUTTILIMINATIONUS009862693B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 862, 693 B2 Pietras et al. (45 ) Date of Patent : Jan . 9 , 2018 (54 ) COMPOUNDS AND METHODS OF ( 56 ) References Cited TREATING CANCER U . S . PATENT DOCUMENTS (71 ) Applicant: The Regents of the University of 4 , 574 ,123 A * 3 / 1986 Edwards ...... C07C 279/ 28 California , Oakland , CA (US ) 162 / 161 4 , 861, 760 A 8 / 1989 Mazuel et al. (72 ) Inventors : Richard J . Pietras , Los Angeles , CA 4 ,911 , 920 A 3 / 1990 Jani et al . (US ) ; Michael E . Jung, Los Angeles , 5 ,212 , 162 A 5 / 1993 Missel et al. CA (US ) ; Diana C . Marquez -Garban , 5 ,403 ,841 A 4 / 1995 Lang et al . 6 ,699 ,989 B1 * 3 / 2004 Shetty CO7D 215 / 56 Los Angeles, CA (US ) ; Gang Deng, 540 /474 Los Angeles, CA (US ) 7 , 285 ,681 B2 * 10 /2007 Moinet ...... CO7D 295/ 215 564 /233 ( 73 ) Assignee : The Regents of the University of 7 ,671 , 019 B2 * 3 /2010 Tobia A61K 8 /44 California , Oaklnad , CA (US ) 514 / 1 . 1 8 , 853, 259 B2 10 /2014 Mylari Subject to any disclaimer, the term of this 2010 / 0087544 A1 4 / 2010 Kim et al. ( * ) Notice : 2011 /0196015 A1 8 / 2011 Kim et al . patent is extended or adjusted under 35 2011/ 0207810 Al 8 / 2011 Kim et al . U . S .C . 154 (b ) by 40 days. 2015 /0126518 Al 5 /2015 Kim et al. (21 ) Appl. No. : 14 /566 ,055 FOREIGN PATENT DOCUMENTS ( 22 ) Filed : Dec . 10 , 2014 WO WO - 96 /05309 A2 2 / 1996 WO WO - 96 /05309 A3 2 / 1996 (65 ) Prior Publication Data WO WO - 2011 /083998 A2 7 / 2011 WO WO - 2011 /083998 A3 7 / 2011 US 2015 /0158832 A1 Jun . 11, 2015 WO WO - 2011 / 147528 Al 12 / 2011 Related U . S . Application Data OTHER PUBLICATIONS (63 ) Continuation of application No . CAPLUS on STN , accession No . 2010 :923694 , Abstract of PCT/ US2013 /045250 , filed on Jun . 11, 2013 . CN101781273 Jul. 21 , 2010 . * Registry No . 793641 -52 - 8 , CAPLUS on STN , Dec . 7 , 2004. * (60 ) Provisional application No . 61/ 658 ,238 , filed on Jun . Alimova I. N . et al. (Mar . 15 , 2009) . “ Metformin inhibits breast 11 , 2012 . cancer cell growth , colony formation and induces cell cycle arrest in vitro , ” Cell Cycle 8 ( 6 ) : 909 - 915 . ( 51 ) Int. Cl. Berstein , L . M . ( Aug. 2010 ). “ Modern approach to metabolic reha CO7D 295 /215 ( 2006 .01 ) bilitation of cancer patients : biguanides (phenformin and CO7D 203 /20 ( 2006 .01 ) metformin ) and beyond ,” Future Oncol 6 ( 8 ) : 1313 - 23 . CO7D 211 / 16 ( 2006 . 01 ) Carey, L . A . et al . ( Jun . 7 , 2006 ). “ Race , breast cancer subtypes , and survival in the Carolina Breast Cancer Study ," JAMA 295 (21 ) : 2492 C07D 213 / 78 ( 2006 .01 ) 2502 . C07D 239 /28 ( 2006 .01 ) Currie C . J. et al. ( Feb . 2012 , e - published Jan . 20 , 2012 ). " Mortality C07D 401/ 12 ( 2006 . 01 ) after incident cancer in people with and without type 2 diabetes : A61K 31/ 155 ( 2006 .01 ) impact of metformin on survival, ” Diabetes Care 35 ( 2 ): 299 - 304 . C07C 279 / 26 ( 2006 . 01 ) Dowling , R . J . et al . (Apr . 6 , 2011 ) . “ Understanding the benefit of metformin use in cancer treatment, ” BMC Med : 9 : 33 . A61K 31/ 4025 ( 2006 . 01 ) Dilman , V . M . et al . ( 1982 ) . “ Metabolic immunodepression and A61K 31 /445 ( 2006 .01 ) metabolic immunotherapy : an attempt of improvement in immuno A61K 31/ 4545 ( 2006 .01 ) logic response in breast cancer patients by correction of metabolic A61K 31/ 496 ( 2006 .01 ) disturbances , ” Oncology 39 ( 1 ) : 13 - 19 . A61K 31/ 5377 ( 2006 .01 ) Evans , J . M . et al . (Jun . 4 , 2005 ) . " Metformin and reduced risk of cancer in diabetic patients ,” BMJ 330 ( 7503 ) :1304 - 1305 . C07C 279 / 22 ( 2006 .01 ) Foulkes, W .D . et al . (Nov . 11, 2010 ). " Triple -negative breast can (52 ) U . S . CI. cer, " N Engl J Med . 363 ( 20 ) : 1938 - 1948 CPC ...... CO7D 295 /215 ( 2013 .01 ); A61K 31 / 155 International Search Report dated Nov . 1 , 2013 , for PCT Applica ( 2013 .01 ); A61K 31 /4025 ( 2013 .01 ) ; A61K tion No . PCT /US2013 /045250 , filed on Jun . 11 , 2013 , 4 pages . 31 /445 ( 2013 . 01 ) ; A61K 31/ 4545 ( 2013 .01 ) ; James , J. W . et al . (Sep . 1968 ). “ The synthesis of some heterocyclic A61K 31/ 496 ( 2013 . 01 ) ; A61K 31 /5377 derivatives of biguanide with antibacterial activity ," J Med Chem (2013 . 01 ) ; C07C 279/ 22 ( 2013 . 01) ; C07C 11 ( 5 ): 942 - 945 . 279 / 26 ( 2013 .01 ) ; C07D 203 /20 ( 2013 . 01 ) ; (Continued ) CO7D 211/ 16 (2013 . 01 ); C07D 213/ 78 Primary Examiner — Rebecca L Anderson ( 2013. 01 ) ; C07D 239 / 28 (2013 .01 ) ; C07D ( 74 ) Attorney , Agent, or Firm - Zachary L . Terranova ; 401 / 12 (2013 .01 ) Mintz , Levin , Cohn , Ferris , Glovsky and Popeo , P . C . ( 58 ) Field of Classification Search (57 ) ABSTRACT CPC ...... CO7D 295 /215 ; C07D 203 / 20 ; CO7D Presented herein inter alia are novel compounds and meth 211710211 / 16 ; COLCO7D 213 / 78 ; CO7D 239 /28 ; CO7D 401/ 12 ods of using the same for the treatment of cancers . See application file for complete search history. 7 Claims, 10 Drawing Sheets US 9 , 862, 693 B2 Page 2

References Cited Kelarev, V. I . et al. (Sep . 1993 ). “ Synthesis and properties of (56 ) derivatives of sym - triazines. 11 . Synthesis of 2 - amino - sym - triazines containing alkyl radicals , ” Chemistry of Heterocyclic Compounds OTHER PUBLICATIONS 29 ( 9 ) : 1087 - 1092 . Jiralerspong , S . et al. ( Jul. 10 , 2009 , e - published Jun . 1 , 2009 ) . Koh , M . et al. ( Apr. 2013 , e -published Feb . 22 , 2013 ) . “ A novel metformin derivative , HL010183 , inhibits proliferation and inva “ Metformin and pathologic complete responses to neoadjuvant sion of triple -negative breast cancer cells ,” Bioorg Med Chem chemotherapy in diabetic patients with breast cancer ,” J Clin Oncol. 21( 8 ) : 2305 - 2313 . 27 (20 ): 3297 -3302 . Liu , B . et al. ( Jul. 1, 2009 , e -published Jul. 21, 2009 ) . " Metformin Jiralerspong, S . et al . ( Sep . 1 , 2009 ) . " Expanding the arsenal : induces unique biological and molecular responses in triple negative metformin for the treatment of triple -negative breast cancer ? ” Cell breast cancer cells , " Cell Cycle 8 ( 13 ) :2031 - 2040 . Cycle : 8 ( 17 ) : 2681 - 2684 . Nagasaka , H . et al. Yuki Gosei Kagaku Kyokaishi ( 1967 ). Kihara, Y . et al. ( 1990 ) . Journal of Heterocyclic Chemistry 27 : 1213 25 (9 ): 802 -807 . (English translation of Abstract only ) . 1216 . Sahra , I. B . et al. (May 2010 , e - published May 4 , 2010 ) . “ Metformin Kelarev, V . I. et al . (May 1988 ). “ Synthesis and properties of in cancer therapy : a new perspective for an old antidiabetic drug ? ” sym - triazine derivatives . 7 . Synthesis of pyridyl- substituted Mol Cancer Ther 9 ( 5 ) : 1092 - 1099 . 2 -amino - and 2, 4 -diamino - sym -triazines , ” Chemistry of Heterocy Taubes, G . ( Jan . 6 , 2012 ) . " Cancer research . Unraveling the obesity clic Compounds 24 ( 5 ) :550 - 555. cancer connection ,” Science 335 (6064 ): 28 , 30 - 32 . Kelarev , V . I. et al. (Sep . 1992) . " Synthesis and properties of Written Opinion dated Nov. 1 , 2013 , for PCT Application No . sym - triazine derivatives 9 . Synthesis of 2 - amino - and 2 , 4 -diamino PCT/ US2013 /045250 , filed on Jun . 11, 2013 , 7 pages. sym - triazines containing furan fragments ,” Chemistry of Heterocy clic Compounds 28 ( 9 ) : 1060 - 1065 . * cited by examiner U . S. Patent Jan. 9 , 2018 Sheet 1 0f10 US 9 , 862 , 693 B2

FIC , 1

; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

?? ? ? . 282 ??????etw ? ?????? ? ? ? ? ? ? ? ?? ? ?? ? ? ? ? ? ? ? ? ? ? ? ? ???????????? 8944???????V9?????????} 8 ??????????????????? ????? ????3 % 8385 ? ???i " " ? ; : ? ? ?? •••H•• ? ? ? ? ? ? , : 383 ; ????????????????????????????????????????????????????????????? ? 8_ 8A % ?

? 8_ ? ??? w & gt ; ? ? ?? ? ffx ?( ???????????????????????????????????????e

8_ ? { ACFT ???????????????????????????? e ????????????????????? cont _com = inopinion f { Y388 U . S . Patent Jan. 9 , 2018 Sheet 2 of 10 US 9, 862 , 693 B2

FIG. 2A

MANNNNNNN N NNNNNNNN

=-= - = - = -= - = =-= -= - ?????????????STYLE =-= - - - = ??????? whithinninnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnitinin ?? , “ ? ??????? ?

?? | FIG . 2B

FYMVIT -AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAMAHAMMMMMMMMMMMMMMMMMMMMMP MMMMMMMMMMMMMMMMMM

www .www . www . riversinaimagaine .www .www wwwronmentNows… …… …… … …… … … … …… … Newmwww “ ? AirHANNAHAH ????????????????????? ManasoniaMainstationa IPH55974???????????????????AHAN ????????? ????? ??????, ? ????????????????????????? HANN U . S . Patent Jan . 9 , 2018 Sheet 3 of 10 US 9 , 862 ,693 B2

FIG . 2C

* 3000 * 30002 w W10003 (QUODWuongelafjord 30004 NVNV. w jg005 * ** NENOVSMANN page

WWWWWWWWWWWWWWWWWWWWWHCC1937

FIG . 2D

theBE Pe V0002 waganiningi n isinesuivalenten imon 0005 (PQXudoX)dodelajoidja . n wwwwwwwwwwwwwwww HCC1806 wy 2 BV U . S . Patent Jan . 9 , 2018 Sheet 4 of 10 US 9 , 862 ,693 B2

FIG . 3A

- * * * * ** * ** * * X60

Segweiserovi -

- ???????????????????????????????????????????m - lozo3xodisada - optoutoni se sitreba primeraintegrado * * * * * * * * * * * * * * * * * * * * A549 00 .. 1

FIG . 3B

wwwwwww

wwwww CelProliferation(control) trandapihtimentointer spretrgarnir eru potapetate * * * 0004 operas stranurecorded

wwvini winniiiiiiiiiiiiiiiiiiiiiinnin MDAMB435 WWWWWWWWWWWWWWWWWWWWWWWWWW 110 . 5 U . S . Patent Jan. 9 , 2018 Sheet Sof 10 US 9, 862 , 693 B2

FIG. 44

… ?MAMAWAIWANNINAWAIWANNNNNNNNNNNNNNNNNNINeeweller trif; firsterferrary Ferrer Firsterferrary Ferrer , :: …: : : … …. … … :: … … * , … ** * * * *, * * , ? … “ ? ???? MAMAMAHANNERY ?3????? SPENTENTRAVERSITEM* ** * ** * * ** * * * ** * ??????? wowowowuwuwuwuwuinountum MEC ?????????????????????????????????????????????

FIG . 48

? : … … … www SATA ???? ; “ ???33?????? Roweren ? sineserSTMENTERNET www ????s?? -Serview CMNAN ? * PATHERMAN * HUVEC …. MMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMMM U . S . Patent Jan . 9 , 2018 Sheet 6 of 10 US 9 , 862 ,693 B2

FIG . 5

what * sti Metformin residentiteroritrupini itthat the Barry

+ CellProliferation(%control) H 444444444444*

+ 4 + JD003

* 0 .01 0 . 1 1 . 0 Drug Dose (MM ) U . S . Patent Jan . 9 , 2018 Sheet 7 of 10 US 9 , 862 ,693 B2

FIG . 6A FIG . 6B FIG .6C

controlena !

* - * .... -

: - *

* - :

- HUEC * *000101011 * Callofwration(cokono *

- *

teren Celproliferation(%contron * : : * . : . : . : . : . : * : .. - 3

* -

: cellproliferation :

: * vy :

0 . 1 wwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwwww Oh0 . 1 1. 0 Metformin Dose (mto ) 0008 Dose (mt U . S . Patent Jan . 9 , 2018 Sheet 8 of 10 US 9 , 862 ,693 B2

FIG . 7 ?? ?? ??? ??:??? ? ????? * * ?????? ????? ?????? {? * ??? ? ?????? ??? ? ??? ?? ? ?? ???? ? ????????? - ????? ??? ? 43 ??????? ???? 4 ??? ?? ?? ????? ? " * ????? ?? ?? . * ?? ??? *?? * * * * U . S . Patent Jan . 9 , 2018 Sheet 9 of 10 US 9 , 862 ,693 B2

FIG . 8 wwwwwwwwwwwwwwwwwwwwwwwwwww wwwwwwwwwwwwwwwwwwwww Apoptosis(%)

aon Con| Met 8W U . S . Patent Jan . 9 , 2018 Sheet 10 of 10 US 9 ,862 ,693 B2

FIG . 9

MOAMB231 cells treated with metformin analogues

Voormi * 0007 J0033 my jo0 mener 0000 controlproliferationsforCell .. . JO009 . . . 30011 was 0012 *** * . 10013 *** weg 10014

01 ?? IM US 9 , 862 ,693 B2 COMPOUNDS AND METHODS OF L ' and L ? are independently a bond or — NH - C (NH ) . R ! TREATING CANCER is — NRARIB, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted CROSS -REFERENCES TO RELATED cycloalkyl, substituted or unsubstituted heterocycloalkyl, APPLICATIONS 5 substituted or unsubstituted aryl, or substituted or unsubsti This application is a continuation of PCT Application No. tuted heteroaryl, wherein R14 and RB are optionally joined PCT/ US2013 /045250 , filed Jun . 11 , 2013 which claims the together to form a substituted or unsubstituted heterocy benefit of U . S . Application No . 61/ 658 ,238 , filed Jun . 11, cloalkyl. R2 is — NR24R2B , substituted or unsubstituted 2012 which are incorporated herein by reference in their alkyl, substituted or unsubstituted heteroalkyl, substituted or entirety and for all purposes . 10 unsubstituted cycloalkyl, substituted or unsubstituted het erocycloalkyl, substituted or unsubstituted aryl , or substi BACKGROUND OF THE INVENTION tuted or unsubstituted heteroaryl, wherein R24 and R2B are optionally joined together to form a substituted or unsub Breast Cancer is the most common type of cancer that occurs in women in the US , and it ranks as the second 15 stituted heterocycloalkyl. R14 , R1B , R24 , and R2B are inde leading cause of cancer death after lung cancer. About pendently hydrogen , OR * , substituted or unsubstituted 15 -20 % of breast cancers are classified as “ triple negative ” alkyl, substituted or unsubstituted heteroalkyl , substituted or ( TNBC ) , a subtype that lacks clinical expression of estrogen unsubstituted cycloalkyl , substituted or unsubstituted het receptor - alpha, progesterone receptor and HER - 2 overex erocycloalkyl, substituted or unsubstituted aryl , or substi pression or lacks clinical expression of ERa , progesterone 20 tuted or unsubstituted heteroaryl. R is hydrogen or unsub receptor and HER2 receptor or lacks immunohistochemical stituted C . - C , alkyl. R4 is hydrogen , substituted or expression of ERa , progesterone receptor and HER - 2 recep unsubstituted alkyl, substituted or unsubstituted heteroalkyl, tor overexpression . These patients will face limited and substituted or unsubstituted cycloalkyl, substituted or unsub often ineffective therapeutic options . Thus , there is an urgent need to develop new and more effective therapies for this stituted heterocycloalkyl , substituted or unsubstituted aryl , deadly subtype of breast cancer . Triple- negative breast can 25 or substituted or unsubstituted heteroaryl. cer ( TNBC ) cannot be treated with current endocrine or In another aspect , a pharmaceutical composition is pro HER - 2 targeted therapies (11 ) . TNBC occurs in about vided . The composition includes a pharmaceutically accept 15 - 20 % of breast cancers , yet accounts for nearly half of all able excipient and a compound having formula : breast cancer deaths. It is associated with a significantly higher probability of relapse and worse overall survival in 30» the first few years after diagnosis when compared with other (1 ) breast cancer subtypes (12 ) . This is observed despite its high NH NH sesensitivity to chemotherapy . Although initially responsive to some chemotherapies, TNBCs tend to relapse early and Z metastasize , leading to poor patient survival. 35 Ritu Pancreatic carcinoma is a highly lethal disease and the fourth -leading cause for cancer death in men and women in the US ( 1 ) . The overall 5 -year survival rate is approximately 4 % . Conventional treatment approaches (chemotherapy , L ' and L are independently a bond or - NH - C ( NH ) — . R1 radiation , surgery or combinations of these modalities ) have 40 is NRIAR1B . substituted or unsubstituted alkyl, substituted had little impact on the course of this disease . Surgical resection is the only chance at cure, butmost patients present or unsubstituted heteroalkyl, substituted or unsubstituted with advanced , unresectable disease ( 2 , 3 ) . Since effective cycloalkyl, substituted or unsubstituted heterocycloalkyl, therapies are largely lacking , it is clear that new therapeutic substituted or unsubstituted aryl , or substituted or unsubsti approaches to treat pancreatic cancer are urgently needed . 16 tuted heteroaryl, wherein R14 and RB are optionally joined Metformin ( 1 , 1 - dimethyl- biguanide hydrochloride ) is a• 45* together to form a substituted or unsubstituted heterocy widely prescribed antihyperglycemic drug used as first- line cloalkyl. R2 is — NR24R2B , substituted or unsubstituted therapy for diabetes mellitus type 2 , and is now reported to alkyl, substituted or unsubstituted heteroalkyl , substituted or have antitumor efficacy in pancreatic cancer (4 - 7 ) . The unsubstituted cycloalkyl, substituted or unsubstituted het primary systemic effect of metformin is to lower blood s erocycloalkyl, substituted or unsubstituted aryl, or substi glucose , but it also reduces hyperinsulinemia associated tuted or unsubstituted heteroaryl, wherein R24 and R2B are with insulin resistance . Provided herein are solutions to optionally joined together to form a substituted or unsub these and other problems in the art. stituted heterocycloalkyl. R14 , RB, R24 , and R2B are inde pendently hydrogen , — OR , substituted or unsubstituted BRIEF SUMMARY OF THE INVENTION alkyl , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl , substituted or unsubstituted het In a first aspect , a compound is provided having the erocycloalkyl, substituted or unsubstituted aryl, or substi formula : tuted or unsubstituted heteroaryl. R² is hydrogen or unsub stituted C , -C5 alkyl. R4 is hydrogen , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, (1) 60 unsubstituted or unsubstituted cycloalkyl, substituted or unsub ?? ?? stituted heterocycloalkyl, substituted or unsubstituted aryl, RI R2 or substituted or unsubstituted heteroaryl. NL2 In another aspect, a method of treating cancer in a subject 65 in need thereof is provided . The method includes adminis tering a therapeutically effective amount a compound having formula : US 9 , 862 ,693 B2 After 3 days , MTS assay was performed . Survival is expressed as percentage of vehicle treated control. Data ?? ?? represents at least two experiments . R FIG . 5 . Metformin analogue JD003 elicits significantly KN 5 greater inhibition of pancreatic cancer cell proliferation in RW - vitro than parent compound metformin at equivalent doses (P < 0 .01 ) . Cells were counted and plated . At 24 hrs after plating , cells were treated with metformin and JD003 at 0 . 01 mM , 0 .1 mM , and 1 mM concentrations using medium with L ' and L are independently a bond or - NH - C ( NH ) — . R 10 1 % FBS . After 72 hrs , cell proliferation was quantitated is — NRIAR1B , substituted or unsubstituted alkyl, substituted based on cell counts . Experiments were done 3 - times , with or unsubstituted heteroalkyl, substituted or unsubstituted results expressed as percent control (mean : SE ) . cycloalkyl, substituted or unsubstituted heterocycloalkyl, FIGS . 6A -6C . As compared to metformin ( FIG . 6A ) . substituted or unsubstituted aryl, or substituted or unsubsti analogs JD003 (FIG . 6B ) and JD004 ( FIG . 6C ) (Aim 1 ) are tuted heteroaryl, wherein RIA and R are optionally joined 15 more effective in blocking proliferation of MCF - 7 cells but together to form a substituted or unsubstituted heterocy not HMEC . Proliferation was assessed using cell prolifera cloalkyl. R2 is — NR24R2B , substituted or unsubstituted tion ELISA , BrdU colorimetric kit (Roche ) . Cells were alkyl, substituted or unsubstituted heteroalkyl, substituted or counted using a hemocytometer and plated . After 24 hrs , unsubstituted cycloalkyl, substituted or unsubstituted het- cells were treated with metformin and analogs JD003 and erocycloalkyl , substituted or unsubstituted aryl, or substi - 20 JD004 at 0 . 1 mM and 1 mM doses using phenol- red free tuted or unsubstituted heteroaryl, wherein R24 and R2B are medium with 1 % FBS . After 48 hr, BrdU labeling solution optionally joined together to form a substituted or unsub - was added and incubated for 24 h . Proliferation was assessed stituted heterocycloalkyl . R14 , RB, R24 , and R2B are inde - using BrdU incorporation by ELISA during DNA synthesis pendently hydrogen , OR4 , substituted or unsubstituted in proliferating cells . Data shown as % control (mean _ SE ) alkyl, substituted or unsubstituted heteroalkyl, substituted or 25 ( n = 3 experiments ) . unsubstituted cycloalkyl, substituted or unsubstituted het - FIG . 7 . Chemical structures and synthesis of metformin erocycloalkyl, substituted or unsubstituted aryl, or substi aanalogues . tuted or unsubstituted heteroaryl. R3 is hydrogen or unsub - FIG . 8 . Metformin analog 8 (M8 ) stimulates increased stituted C , -C5 alkyl. R4 is hydrogen , substituted or apoptosis of PANC - 1 cells as compared to controls and unsubstituted alkyl, substituted or unsubstituted heteroalkyl. 30 parent compound metformin ( P < 0 .001 ; n = 3 ) . Test com substituted or unsubstituted cycloalkyl, substituted or unsub pounds were administered at 0 . 1 mM doses, with apoptosis stituted heterocycloalkyl, substituted or unsubstituted arvl. assessed after 48 hr by TUNEL assay ( 19 ) . M8. ( 0 .01 mM ) or substituted or unsubstituted heteroaryl. also markedly inhibited tumor cell proliferation as compared to metformin . 35 FIG . 9 . Triple -negative MDA -MB -231 breast cancer cells BRIEF DESCRIPTION OF THE DRAWINGS treated with compounds described herein . FIG . 1. Metformin analogues inhibit growth /survival of DETAILED DESCRIPTION OF THE ER + MCF7 breast cancer cells . MCF7 cells were cultured in INVENTION medium containing different concentrations of metformin 40 and analogues ( 0 . 1 , 1 and 5 mM ) . After 3 days , the percent I. Definitions age of surviving cells relative to controls , defined as 100 % survival , was determined by theMTS assay. Data represents The abbreviations used herein have their conventional three independent experiments . meaning within the chemical and biological arts . The chemi FIGS. 2A -2D . Metformin analogues inhibit growth / surur. 45 cal structures and formulae set forth herein are constructed vival of triple negative breast cancer cells . MDA -MB - 231 according to the standard rules of chemical valency known ( FIG . 2A ), HCC38 (FIG . 2B ), HCC1937 (FIG . 2C ) and in the chemical arts . HCC1806 ( FIG . 2D ) cells were cultured in medium con Where substituent groups are specified by their conven taining 1 % fetal bovine serum and increasing concentrations tional chemical formulae, written from left to right, they of metformin and analogues JD001 - JD009 ( 0 . 1. 1 and 5 50 equally encompass the chemically identical substituents that would result from writing the structure from right to left, mM ) . After 3 days , MTS assay was performed . The per e . g ., CH20 - is equivalent to OCH — . centage of surviving cells relative to controls , defined as The term “ alkyl, ” by itself or as part of another substitu 100 % survival, was determined by the MTS assay . ent, means, unless otherwise stated , a straight (i . e ., FIGS. 3A - 3B . Metformin analogues inhibit survival of 55 unbranched ) or branched carbon chain ( or carbon ), or com non - small cell lung cancer (NSCLC ) (FIG . 3A ) and mela bination thereof , which may be fully saturated , mono - or noma cell lines (FIG . 3B ). A549 (NSCLC ) and MDA -MB polyunsaturated and can include di- and multivalent radi 435 (melanoma ) cells were cultured in medium containing cals , having the number of carbon atoms designated ( i . e . , 1 % fetal bovine serum and increasing concentrations of C1- C10 means one to ten carbons) . Examples of saturated metformin (MET ) and analogues JD001 - JDOOJD007 (( 0 . 11 , 1I and 60 hydrocarbon radicals include, but are not limited to , ogroups 5 mM ). After 3 days , MTS assay was performed . Survival is such as methyl, ethyl, n - propyl , isopropyl, n -butyl , t- butyl , expressed as percentage of control defined at 100 % . isobutyl, sec -butyl , ( cyclohexyl )methyl , homologs and iso FIGS. 4A - 4B . Effects ofmetformin and metformin ana mers of, for example , n -pentyl , n -hexyl , n -heptyl , n -octyl , logues on normal cells . HMEC ( FIG . 4A ) and HUVEC and the like . An unsaturated alkyl group is one having one ( FIG . 4B ) cells were plated in special media . After 24 hours , 65 or more double bonds or triple bonds. Examples of unsatu cells were treated with increasing concentrations of met - rated alkyl groups include , but are not limited to , vinyl, formin and analogues JD001 - JD009 (0 .1 , 1 and 5 mM ). 2 -propenyl , crotyl , 2 - isopentenyl, 2 -( butadienyl ) , 2, 4 -penta US 9 , 862, 693 B2 5 dienyl , 3 - ( 1 , 4 - pentadienyl) , ethynyl, 1 - and 3 - propynyl, hydropyridyl) , 1 - piperidinyl , 2 - piperidinyl, 3 - piperidinyl, 3 -butynyl , and the higher homologs and isomers . An alkoxy 4 -morpholinyl , 3 -morpholinyl , tetrahydrofuran - 2 - yl , tetra is an alkyl attached to the remainder of the molecule via an hydrofuran - 3 -yl , tetrahydrothien - 2 -yl , tetrahydrothien - 3 - yl, oxygen linker ( 0 ) . 1 -piperazinyl , 2 - piperazinyl , and the like. A “ cycloalkylene ” The term “ alkylene ,” by itself or as part of another 5 and a " heterocycloalkylene, ” alone or as part of another substituent, means, unless otherwise stated , a divalent radi- substituent, means a divalent radical derived from a cal derived from an alkyl , as exemplified , but not limited by, cycloalkyl and heterocycloalkyl, respectively . - CH2CH2CH2CH2– Typically , an alkyl (or alkylene ) The terms “ halo ” or “ halogen ,” by themselves or as part group will have from 1 to 24 carbon atoms, with those of another substituent, mean , unless otherwise stated , a groups having 10 or fewer carbon atoms being preferred in 10 fluorine , chlorine, bromine , or iodine atom . Additionally , the present invention . A “ lower alkyl” or “ lower alkylene ” is terms such as “ haloalkyl” are meant to include monoha a shorter chain alkyl or alkylene group , generally having loalkyl and polyhaloalkyl . For example, the term “ halo ( C , eight or fewer carbon atoms. The term “ alkenylene, " by C4) alkyl ” includes, but is not limited to , fluoromethyl , itself or as part of another substituent, means, unless other - difluoromethyl, trifluoromethyl, 2 , 2 , 2 - trifluoroethyl, 4 - chlo wise stated , a divalent radical derived from an alkene . 15 robutyl , 3 -bromopropyl , and the like . The term " heteroalkyl, ” by itself or in combination with The term “ acyl” means, unless otherwise stated , - C ( O ) R another term , means, unless otherwise stated , a stable where R is a substituted or unsubstituted alkyl, substituted or straight or branched chain , or combinations thereof, includ - unsubstituted cycloalkyl, substituted or unsubstituted het ing at least one carbon atom and at least one heteroatom eroalkyl, substituted or unsubstituted heterocycloalkyl, sub selected from the group consisting of O , N , P , Si , and S , and 20 stituted or unsubstituted aryl, or substituted or unsubstituted wherein the nitrogen and sulfur atoms may optionally be heteroaryl . oxidized , and the nitrogen heteroatom may optionally be The term “ aryl” means , unless otherwise stated , a poly quaternized . The heteroatom (s ) O , N , P, S , and Si may be unsaturated , aromatic , hydrocarbon substituent, which can placed at any interior position of the heteroalkyl group or at be a single ring ormultiple rings ( e. g . from 1 to 3 rings ) that the position at which the alkyl group is attached to the 25 are fused together ( i. e ., a fused ring aryl) or linked cova remainder of the molecule . Examples include , but are not lently . A fused ring aryl refers to multiple rings fused limited to : - CH2 - CHO CHZ, - CH2CH2 - NH - together wherein at least one of the fused rings is an aryl CH , CH , CHÚN( CH?) CH?, CH? SCH , — ring. The term " heteroaryl” refers to aryl groups (or rings ) CHz, - CH2- CH , , S ( O ) - CH3, - CH2 - CH2- S ( O ) that contain at least one heteroatom such as N , O , or S , - CHZ, CH = CH – O CHz, — Si( CH3 )3 , CH — 30 wherein the nitrogen and sulfur atoms are optionally oxi CH = N / OCH3, - CH = CH - N (CH3 ) - CH3, O CHz, dized , and the nitrogen atom ( s ) are optionally quaternized . - O CH2 CH3, and CN . Up to two or three heteroa Thus, the term " heteroaryl ” includes fused ring heteroaryl toms may be consecutive , such as , for example , — CH , groups ( i . e ., multiple rings fused together wherein at least NH OCH , and CH , 0 Si( CH ) . one of the fused rings is a heteroaromatic ring ) . A 5 , 6 - fused Similarly , the term “ heteroalkylene ,” by itself or as part of 35 ring heteroarylene refers to two rings fused together , another substituent, means, unless otherwise stated , a diva - wherein one ring has 5 members and the other ring has 6 lent radical derived from heteroalkyl, as exemplified , but not members , and wherein at least one ring is a heteroaryl ring . limited by , CH , CH - S - CH2 - CH2 - and - CH2 — Likewise , a 6 , 6 - fused ring heteroarylene refers to two rings S CH - CH2 - NH CH2 - . For heteroalkylene groups, fused together, wherein one ring has 6 members and the heteroatoms can also occupy either or both of the chain 40 other ring has 6 members , and wherein at least one ring is termini ( e . g ., alkyleneoxy , alkylenedioxy , alkyleneamino , a heteroaryl ring. And a 6 ,5 - fused ring heteroarylene refers alkylenediamino , and the like ) . Still further , for alkylene and to two rings fused together, wherein one ring has 6 members heteroalkylene linking groups, no orientation of the linking and the other ring has 5 members, and wherein at least one group is implied by the direction in which the formula of the ring is a heteroaryl ring. A heteroaryl group can be attached linking group is written . For example , the formula C ( O ) , 45 to the remainder of the molecule through a carbon or R — represents both - C ( O ) R — and R ' C ( 0 ) 2 — . As heteroatom . Non - limiting examples of aryl and heteroaryl described above, heteroalkyl groups , as used herein , include groups include phenyl , 1 - naphthyl, 2 - naphthyl, 4 - biphenyl, those groups that are attached to the remainder of the 1 -pyrrolyl , 2 -pyrroly ), 3 -pyrroly1 , 3 - pyrazolyl, 2 - imidazolyl , molecule through a heteroatom , such as — C ( O ) R ', - C ( O ) 4 - imidazolyl, pyrazinyl, 2 - oxazolyl, 4 -oxazolyl , 2 -phenyl NR ', - NR ' R " , - OR ', SR ', and / or — SO , R '. Where " het - 50 4 -oxazolyl , 5 - oxazolyl, 3 - isoxazolyl, 4 - isoxazolyl, 5 - isox eroalkyl” is recited , followed by recitations of specific azolyl , 2 - thiazolyl, 4 -thiazolyl , 5 - thiazolyl, 2 - furyl, 3 - furyl, heteroalkyl groups , such as — NR' R " or the like, it will be 2 - thienyl, 3 -thienyl , 2 -pyridyl , 3 -pyridyl , 4 - pyridyl, 2 -py understood that the terms heteroalkyl and — NR ' R " are not rimidyl, 4 -pyrimidyl , 5 -benzothiazolyl , purinyl, 2 - benzimi redundant or mutually exclusive. Rather , the specific het dazolyl, 5 - indolyl, 1 - isoquinolyl, 5 - isoquinolyl, 2 - quinox eroalkyl groups are recited to add clarity . Thus, the term 55 alinyl, 5 - quinoxalinyl, 3 - quinolyl , and 6 -quinolyl . " heteroalkyl” should not be interpreted herein as excluding Substituents for each of the above noted aryl and heteroaryl specific heteroalkyl groups , such as — NR' R " or the like . ring systems are selected from the group of acceptable The terms" cycloalkyl” and “ heterocycloalkyl, ” by them substituents described below . An “ arylene ” and a “ het selves or in combination with other terms, mean , unless eroarylene ," alone or as part of another substituent, mean a otherwise stated , cyclic versions of alkyl” and “ het - 60 divalent radical derived from an aryl and heteroaryl, respec eroalkyl, ” respectively . Additionally , for heterocycloalkyl , a tively . heteroatom can occupy the position at which the heterocycle In some embodiments , the heterocycloalkyl may be a is attached to the remainder of the molecule . Examples of fused ring heterocycloalkyl- aryl which is an aryl fused to a cycloalkyl include , but are not limited to , cyclopropyl, heterocycloalkyl. In some embodiments, the heterocy cyclobutyl, cyclopentyl , cyclohexyl, 1 -cyclohexenyl , 3 -cy - 65 cloalkyl may be a fused ring heterocycloalkyl- heteroaryl clohexenyl, cycloheptyl, and the like . Examples of hetero - which is a heteroaryl fused to a heterocycloalkyl. In some cycloalkyl include, but are not limited to , 1 - (1 , 2 , 5 , 6 - tetra embodiments , the heterocycloalkyl may be a fused ring US 9 , 862 ,693 B2 heterocycloalkyl - cycloalkyl which is a heterocycloalkyl heteroalkyl, substituted or unsubstituted cycloalkyl, substi fused to a cycloalkyl. In some embodiments , the heterocy tuted or unsubstituted heterocycloalkyl, substituted or cloalkyl may be a fused ring heterocycloalkyl- heterocy unsubstituted aryl, and substituted or unsubstituted het cloalkyl which is a heterocycloalkyl fused to another het eroaryl. When a compound of the invention includes more erocycloalkyl . Fused ring heterocycloalkyl - aryl , fused ring 5 than one R group , for example , each of the R groups is heterocycloalkyl- heteroaryl , fused ring heterocycloalkyl- cy . independently selected as are each R ', R " , R '" , and R " " cloalkyl, or fused ring heterocycloalkyl- heterocycloalkyl groups when more than one of these groups is present. may each independently be unsubstituted or substituted with A heteroaryl group substituent may be a - - bonded to one or more of the substitutents described herein . a ring heteroatom nitrogen . The term “ oxo ," as used herein , means an oxygen that is 10 Two or more substituents may optionally be joined to double bonded to a carbon atom . form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl The term “ alkylsulfonyl, ” as used herein , means a moiety groups . Such so - called ring - forming substituents are typi having the formula - S (O2 ) — R ' , where R ' is a substituted or cally , though not necessarily , found attached to a cyclic base unsubstituted alkyl group as defined above. R ' may have a structure . In one embodiment, the ring - forming substituents specified number of carbons ( e . g . , " C , - C4 alkylsulfonyl ” ). 15 are attached to adjacent members of the base structure . For Each of the above terms (e . g ., " alkyl, " " heteroalkyl, ” example , two ring - forming substituents attached to adjacent " aryl, ” and “ heteroaryl” ) includes both substituted and members of a cyclic base structure create a fused ring unsubstituted forms of the indicated radical. Preferred sub structure . In another embodiment, the ring - forming substitu stituents for each type of radical are provided below . ents are attached to a single member of the base structure . Substituents for the alkyl and heteroalkyl radicals (includ - 20 For example , two ring - forming substituents attached to a ing those groups often referred to as alkylene , alkenyl, single member of a cyclic base structure create a spirocyclic heteroalkylene , heteroalkenyl, alkynyl, cycloalkyl, hetero - structure . In yet another embodiment, the ring - forming cycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be substituents are attached to non -adjacent members of the one or more of a variety of groups selected from , but not base structure . limited to , - OR ', = 0 , = NR ' , _ N _ OR ', - NR ' R " , - SR ', 25 Two of the substituents on adjacent atoms of the aryl or - halogen , SiR 'R " R "" , OC (O )R ', - C (O ) R ', — CO2R ', heteroaryl ring may optionally form a ring of the formula - CONR ' R " , OC ( O )NR ' R " , — NR " C ( O ) R ', NR - C - T - C ( O ) (CRR ') . — U — , wherein T and U are indepen ( O ) NR " R '" , — NR " C (O ), R ', - NR - C (NR ' R " R " ) = NR " " , dently — NR — , - 0 , CRR - , or a single bond , and q - NR - C (NR ' R " ) = NR ' " , - S ( O ) R ', - S ( O ) R ', - S ( O ) 2 is an integer of from 0 to 3 . Alternatively , two of the NR 'R " , - NRSO , R ', - NRÄNR " R "" , ONR 'R " , - NR 'C = 30 substituents on adjacent atoms of the aryl or heteroaryl ring ( O )NR " NR "" R " " , — CN , — NO ,, in a number ranging from may optionally be replaced with a substituent of the formula zero to ( 2m ' + 1 ) , where m ' is the total number of carbon - A - (CH2 ) . — B — , wherein A and B are independently atoms in such radical. R , R ', R " , R '' , and R " " each preferably CRR - , - - , - NR - - S — , - S ( O ) - , - S ( O ) 2 - , independently refer to hydrogen , substituted or unsubsti - - S ( O ) 2NR — , or a single bond , and ris an integer of from tuted heteroalkyl , substituted or unsubstituted cycloalkyl, 35 1 to 4 . One of the single bonds of the new ring so formed substituted or unsubstituted heterocycloalkyl, substituted or may optionally be replaced with a double bond . Alterna unsubstituted aryl ( e . g ., aryl substituted with 1 - 3 halogens) , tively , two of the substituents on adjacent atoms of the aryl substituted or unsubstituted heteroaryl, substituted or unsub - or heteroaryl ring may optionally be replaced with a sub stituted alkyl, alkoxy , or thioalkoxy groups, or arylalkyl stituent of the formula ( CRR ') . — X ' - ( C " R " R " ) , groups. When a compound of the invention includes more 40 where s and d are independently integers of from 0 to 3 , and than one R group , for example , each of the R groups is X ' is – O , - NR - , - , - S ( O ) - , - S ( O )2 - , or independently selected as are each R ', R " , R ' " , and R " " group - S ( O )2NR ' — . The substituents R , R ', R " , and R '' are when more than one of these groups is present. When R ' and preferably independently selected from hydrogen , substi R " are attached to the same nitrogen atom , they can be tuted or unsubstituted alkyl, substituted or unsubstituted combined with the nitrogen atom to form a 4 - , 5 - , 6 - , or 45 heteroalkyl, substituted or unsubstituted cycloalkyl, substi 7 -membered ring . For example , — NR ' R " includes , but is not tuted or unsubstituted heterocycloalkyl, substituted or limited to , 1 - pyrrolidinyl and 4 -morpholinyl . From the unsubstituted aryl, and substituted or unsubstituted het above discussion of substituents , one of skill in the art will eroaryl. understand that the term “ alkyl” is meant to include groups As used herein , the terms “ heteroatom ” or “ ring heteroa including carbon atoms bound to groups other than hydro - 50 tom ” are meant to include, oxygen (O ), nitrogen (N ), gen groups , such as haloalkyl ( e . g . , — CF and — CH , CF ) sulfur ( S ) , phosphorus ( P ) , and silicon (Si ) . and acyl ( e. g ., - C ( O )CH3 , - C (O )CF3 , - C (O )CH2OCHZ , A " substituent group ,” as used herein , means a group and the like ). selected from the following moieties: Similar to the substituents described for the alkyl radical, ( A ) - OH , - NH2, — SH , CN , CF3, - NO2, oxo , substituents for the aryl and heteroaryl groups are varied and 55 halogen , — COOH , CONH2, SO , C1, SO3H , are selected from , for example : _ OR ', NR 'R " , — SR ', _ SO_ H , SO, NH , NHNHA, ONH , NHC = - halogen , SiR ' R " R " " , - OC ( O ) R ', - C ( O ) R ', - CO R ', ( O )NHNH2 , unsubstituted alkyl, unsubstituted het - CONR 'R " , OC ( O )NR ' R " , — NR " C ( O ) R ', - NR - C eroalkyl, unsubstituted cycloalkyl, unsubstituted het ( O ) NR " R '" , — NR " C ( O ) R ', — NR — C (NR 'R " R " ) = NR " " , erocycloalkyl, unsubstituted aryl, unsubstituted - NR - C (NR ' R " ) = NR" " , - S (O ) R ', - S ( O ) 2R ' , - S ( O ) 2 60 heteroaryl, and NR' R " , - NRSO , R ', - NR 'NR " R "" , - ONR 'R " , - NR ' C = ( B ) alkyl, heteroalkyl , cycloalkyl, heterocycloalkyl , aryl, ( O )NR " NR " R " , CN , _ NO. , LR , LN , CH ( Ph ) , and heteroaryl, substituted with at least one substituent fluoro ( C / - C4 )alkoxy , and fluoro (C1 - C4) alkyl, in a number selected from : ranging from zero to the total number of open valences on ( i ) OH , NH , SH , CN , CF3, - NO2, oxo , the aromatic ring system ; and where R ', R " , R '' , and R " " are 65 halogen , COOH , CONH2, S02C1, SO3H , preferably independently selected from hydrogen , substi — SO4H , SO NH2, NHNH2, ONH2, tuted or unsubstituted alkyl, substituted or unsubstituted - NHC = (O )NHNH ,, unsubstituted alkyl, unsubsti US 9 ,862 , 693 B2 10 tuted heteroalkyl , unsubstituted cycloalkyl, unsub substituted or unsubstituted alkylene is a substituted or stituted heterocycloalkyl, unsubstituted aryl, unsub unsubstituted C -C20 alkylene , each substituted or unsubsti stituted heteroaryl, and tuted heteroalkylene is a substituted or unsubstituted 2 to 20 ( ii ) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, membered heteroalkylene , each substituted or unsubstituted aryl, and heteroaryl, substituted with at least one 5 cycloalkylene is a substituted or unsubstituted C . - C . substituent selected from : cycloalkylene , and /or each substituted or unsubstituted het ( a ) OH , - NH2, — SH , CN , CF3 , - NO2, erocycloalkylene is a substituted or unsubstituted 3 to 8 OXO , halogen , COOH , CONH2, S02C1, — SO , H , SO H , SO ,NH , , - NHNH , , membered heterocycloalkylene . ONH , NHC ( 0 ) NHNH , unsubstituted 10 . In embodiments, each substituted or unsubstituted alkyl is alkyl, unsubstituted heteroalkyl, unsubstituted a substituted or unsubstituted C . - C , alkyl, each substituted cycloalkyl, unsubstituted heterocycloalkyl, unsub or unsubstituted heteroalkyl is a substituted or unsubstituted stituted aryl, unsubstituted heteroaryl , and 2 to 8 membered heteroalkyl, each substituted or unsubsti ( b ) alkyl, heteroalkyl , cycloalkyl, heterocycloalkyl, tuted cycloalkyl is a substituted or unsubstituted C3 - C , arvl, or heteroarvl. substituted with at least one 15 cycloalkyl, and /or each substituted or unsubstituted hetero substituent selected from : OH , NH2, — SH , cycloalkyl is a substituted or unsubstituted 3 to 7 membered - CN , CF . — NO , oxo , halogen , _ COOH . heterocycloalkyl. In embodiments , each substituted or CONH2, SO , C1, SO2H , SO H , unsubstituted alkylene is a substituted or unsubstituted - SO .NH . NHNH , _ ONH , . — NHC = ( 0 ) C - C , alkylene , each substituted or unsubstituted het NHNH , , unsubstituted alkyl, unsubstituted het - 20 eroalkylene is a substituted or unsubstituted 2 to 8 mem eroalkyl, unsubstituted cycloalkyl, unsubstituted bered heteroalkylene , each substituted or unsubstituted heterocycloalkyl, unsubstituted aryl, and unsub - cycloalkylene is a substituted or unsubstituted Cz- C , stituted heteroaryl. cycloalkylene , and / or each substituted or unsubstituted het A " size - limited substituent” or “ size - limited substituent erocycloalkylene is a substituted or unsubstituted 3 to 7 group , " as used herein , means a group selected from all of 25 membered heterocycloalkylene . In embodiments , the com the substituents described above for a “ substituent group , " pound is a chemical species set forth in the Examples section wherein each substituted or unsubstituted alkyl is a substi - below or Table 1 . tuted or unsubstituted C - C20 alkyl , each substituted or The term “ pharmaceutically acceptable salts ” is meant to unsubstituted heteroalkyl is a substituted or unsubstituted 2 include salts of the active compounds that are prepared with to 20 membered heteroalkyl, each substituted or unsubsti - 30 relatively nontoxic acids or bases, depending on the particu tuted cycloalkyl is a substituted or unsubstituted C3 - C , lar substituents found on the compounds described herein . cycloalkyl, and each substituted or unsubstituted heterocy . When compounds of the present invention contain relatively cloalkyl is a substituted or unsubstituted 3 to 8 membered acidic functionalities , base addition salts can be obtained by heterocycloalkyl. contacting the neutral form of such compounds with a A “ lower substituent” or “ lower substituent group , " as 35 sufficient amount of the desired base , either neat or in a used herein , means a group selected from all of the sub - suitable inert solvent. Examples of pharmaceutically accept stituents described above for a " substituent group ,” wherein able base addition salts include sodium , potassium , calcium , each substituted or unsubstituted alkyl is a substituted or ammonium , organic amino , or magnesium salt , or a similar unsubstituted C , - C , alkyl, each substituted or unsubstituted salt . When compounds of the present invention contain heteroalkyl is a substituted or unsubstituted 2 to 8 membered 40 relatively basic functionalities , acid addition salts can be heteroalkyl, each substituted or unsubstituted cycloalkyl is a obtained by contacting the neutral form of such compounds substituted or unsubstituted Cz- C , cycloalkyl, and each with a sufficient amount of the desired acid , either neat or in substituted or unsubstituted heterocycloalkyl is a substituted a suitable inert solvent. Examples of pharmaceutically or unsubstituted 3 to 7 membered heterocycloalkyl20111. acceptable acid addition salts include those derived from In embodiments , each substituted group described in the 45 inorganic acids like hydrochloric , hydrobromic , nitric , car compounds herein is substituted with at least one substituent bonic , monohydrogencarbonic , phosphoric , monohydrogen group . More specifically , in embodiments , each substituted phosphoric , dihydrogenphosphoric , sulfuric , monohydro alkyl, substituted heteroalkyl, substituted cycloalkyl, substi gensulfuric , hydriodic , or phosphorous acids and the like , as tuted heterocycloalkyl , substituted aryl, substituted het well as the salts derived from relatively nontoxic organic eroaryl, substituted alkylene , substituted heteroalkylene , 50 acids like acetic , propionic , isobutyric , maleic , malonic , substituted cycloalkylene , substituted heterocycloalkylene , benzoic , succinic , suberic , fumaric , lactic , mandelic , substituted arylene , and/ or substituted heteroarylene phthalic , benzenesulfonic, p - tolylsulfonic , citric , tartaric , described in the compounds herein are substituted with at oxalic , methanesulfonic , and the like . Also included are salts least one substituent group . In other embodiments , at least of amino acids such as arginate and the like, and salts of one or all of these groups are substituted with at least one 55 organic acids like glucuronic or galactunoric acids and the size - limited substituent group . In other embodiments , at like ( see, for example , Berge et al. , “ Pharmaceutical Salts ” , least one or all of these groups are substituted with at least Journal of Pharmaceutical Science, 1977 , 66 , 1 - 19 ). Certain one lower substituent group . specific compounds of the present invention contain both In other embodiments of the compounds herein , each basic and acidic functionalities that allow the compounds to substituted or unsubstituted alkyl may be a substituted or 60 be converted into either base or acid addition salts . unsubstituted C . - C . , alkyl, each substituted or unsubstituted Thus, the compounds of the present invention may exist heteroalkyl is a substituted or unsubstituted 2 to 20 mem - as salts , such as with pharmaceutically acceptable acids. The bered heteroalkyl , each substituted or unsubstituted present invention includes such salts . Examples of such salts cycloalkyl is a substituted or unsubstituted C3 - C , cycloalkyl, include hydrochlorides, hydrobromides , sulfates , methane and/ or each substituted or unsubstituted heterocycloalkyl is 65 sulfonates , nitrates, maleates , acetates, citrates , fumarates , a substituted or unsubstituted 3 to 8 membered heterocy - tartrates ( e . g . , ( + )- tartrates , ( - ) -tartrates , or mixtures thereof cloalkyl. In embodiments of the compounds herein , each including racemic mixtures) , succinates , benzoates , and salts US 9 , 862 ,693 B2 12 with amino acids such as glutamic acid . These salts may be ture ; i. e ., the R and S configurations for each asymmetric prepared by methods known to those skilled in the art. center. Therefore , single stereochemical isomers as well as The neutral forms of the compounds are preferably regen - enantiomeric and diastereomeric mixtures of the present erated by contacting the salt with a base or acid and isolating compounds are within the scope of the invention . the parent compound in the conventionalmanner . The parent 5 Unless otherwise stated , structures depicted herein are form of the compound may differ from the various salt forms also meant to include compounds which differ only in the in certain physical properties , such as solubility in polar presence of one or more isotopically enriched atoms. For solvents . In addition to salt forms, the present invention provides example , compounds having the present structures except compounds, which are in a prodrug form . Prodrugs of the 10 for the replacement of a hydrogen by a deuterium or tritium , compounds described herein are those compounds that read or the replacement of a carbon by 13C - or 14C - enriched ily undergo chemical changes under physiological condi carbon are within the scope of this invention . tions to provide the compounds of the present invention . The compounds of the present invention may also contain Additionally , prodrugs can be converted to the compounds unnatural proportions of atomic isotopes at one or more of of the present invention by chemical or biochemical meth - 15 the atoms that constitute such compounds. For example , the ods in an ex vivo environment. For example , prodrugs can compounds may be radiolabeled with radioactive isotopes, be slowly converted to the compounds of the present inven - such as for example tritium ( H ) , iodine - 125 ( - 1 ), or tion when placed in a transdermal patch reservoir with a carbon - 14 ( C ). All isotopic variations of the compounds of suitable enzyme or chemical reagent. the present invention , whether radioactive or not , are encom Certain compounds of the present invention can exist in 20 passed within the scope of the present invention . unsolvated forms as well as solvated forms, including The symbol “ w ” denotes the point of attachment of a hydrated forms. In general, the solvated forms are equivalent chemical moiety to the remainder of a molecule or chemical to unsolvated forms and are encompassed within the scope formula . of the present invention . Certain compounds of the present It should be noted that throughout the application that invention may exist in multiple crystalline or amorphous 25 alternatives are written in Markush groups , for example , forms. In general, all physical forms are equivalent for the each amino acid position that contains more than one uses contemplated by the present invention and are intended possible amino acid . It is specifically contemplated that each to be within the scope of the present invention . member of the Markush group should be considered sepa As used herein , the term " salt ” refers to acid or base salts rately , thereby comprising another embodiment, and the of the compounds used in the methods of the present 30 Markush group is not to be read as a single unit . invention . Illustrative examples of acceptable salts are min The terms “ a ” or “ an , ” as used in herein means one or eral acid (hydrochloric acid , hydrobromic acid , phosphoric more . In addition , the phrase " substituted with a [ n ], " as used acid , and the like ) salts , organic acid (acetic acid , propionic herein , means the specified group may be substituted with acid , glutamic acid , citric acid and the like ) salts , quaternary one or more of any or all of the named substituents. For ammonium (methyl iodide , ethyl iodide , and the like) salts . 35 example , where a group , such as an alkyl or heteroaryl Certain compounds of the present invention possess group , is “ substituted with an unsubstituted C , -C20 alkyl, or asymmetric carbon atoms (optical or chiral centers ) or unsubstituted 2 to 20 membered heteroalkyl, ” the group may double bonds ; the enantiomers , racemates, diastereomers , contain one or more unsubstituted C -C20 alkyls , and / or one tautomers , geometric isomers , stereoisomeric forms that or more unsubstituted 2 to 20 membered heteroalkyls and may be defined , in terms of absolute stereochemistry , as ( R ) - 40 each such unsubstituted alkylmay be different and each such or ( S ) - or , as ( D ) - or ( L ) - for amino acids , and individual unsubstituted heteroalkylmay be different. Moreover, where isomers are encompassed within the scope of the present a moiety is substituted with an R substituent, the group may invention . The compounds of the present invention do not be referred to as “ R - substituted . ” Where a moiety is R - sub include those which are known in art to be too unstable to stituted , the moiety is substituted with at least one R synthesize and / or isolate . The present invention is meant to 45 substituent and each R substituent is optionally different. include compounds in racemic and optically pure forms. Where a particular R group is present in the description of Optically active (R ) - and ( S ) -, or ( D ) - and (L ) - isomers may a chemical genus ( such as Formula ( I )) , a Roman alphabetic be prepared using chiral synthons or chiral reagents , or symbolmay be used to distinguish each appearance of that resolved using conventional techniques. When the com - particular R group . For example , where multiple R13 sub pounds described herein contain olefinic bonds or other 50 stituents are present, each R13 substituent may be distin centers of geometric asymmetry , and unless specified oth - guished as R134 , R13B , R13C , R13D , etc . , wherein each of erwise , it is intended that the compounds include both E and R134 , R13B , R13C , R13D , etc . is defined within the scope of Z geometric isomers . the definition of R13 and optionally differently . As used herein , the term “ isomers ” refers to compounds Description of compounds of the present invention are having the same number and kind of atoms, and hence the 55 limited by principles of chemical bonding known to those same molecular weight, but differing in respect to the skilled in the art. Accordingly , where a group may be structural arrangement or configuration of the atoms. substituted by one or more of a number of substituents , such The term “ tautomer, " as used herein , refers to one of two substitutions are selected so as to comply with principles of or more structural isomers which exist in equilibrium and chemical bonding and to give compounds which are not which are readily converted from one isomeric form to 60 inherently unstable and / or would be known to one of ordi another . nary skill in the art as likely to be unstable under ambient It will be apparent to one skilled in the art that certain conditions , such as aqueous, neutral , and several known compounds of this invention may exist in tautomeric forms, physiological conditions. For example , a heterocycloalkyl or all such tautomeric forms of the compounds being within the heteroaryl is attached to the remainder of the molecule via scope of the invention . 65 a ring heteroatom in compliance with principles of chemical Unless otherwise stated , structures depicted herein are bonding known to those skilled in the art thereby avoiding also meant to include all stereochemical forms of the struc - inherently unstable compounds . US 9 ,862 , 693 B2 13 14 The terms “ treating ” or “ treatment ” refers to any indicia amount of protein or marker expressed by a non - cancerous of success in the treatment or amelioration of an injury , tissue or cell having the same cellular origin as the cancerous disease , pathology or condition , including any objective or tissue or cell being compared to the control ( e . g . breast, lung , subjective parameter such as abatement; remission ; dimin pancreatic , skin , epidermal, prostate , ovarian , colon , or ishing of symptoms or making the injury , pathology or 5 colorectal) . In embodiments , a control for expression or condition more tolerable to the patient; slowing in the rate of overexpression may be the average amount of expression of degeneration or decline ; making the final point of degen - a protein or marker in the corresponding tissue or cells of a eration less debilitating ; improving a patient ' s physical or person without the disease being treated or monitor or mental well- being . The treatment or amelioration of symp - diagnosed ( e . g . cancer ) . toms can be based on objective or subjective parameters ; 10 " Contacting ” is used in accordance with its plain ordinary including the results of a physical examination , neuropsy - meaning and refers to the process of allowing at least two chiatric exams, and/ or a psychiatric evaluation . For distinct species ( e . g . chemical compounds including biomol example , the certain methods presented herein may success - ecules , proteins , or cells ) to become sufficiently proximal to fully treat cancer by decreasing the incidence of cancer and react, interact or physically touch . It should be appreciated , or causing remission of cancer ( e . g . breast cancer, triple 15 however , the resulting reaction product can be produced negative breast cancer subtype, lung cancer, non -small cell directly from a reaction between the added reagents or from lung cancer, pancreatic cancer , melanoma , colon cancer , an intermediate from one or more of the added reagents prostate cancer, or ovarian cancer ) . The term “ treating , ” and which can be produced in the reaction mixture . conjugations thereof, include prevention of an injury, pathol- The term " contacting ” may include allowing two species ogy , condition , or disease . 20 to react, interact , or physically touch , wherein the two An “ effective amount ” or “ therapeutically effective species may be a compound as described herein and a cancer amount" is an amount sufficient to accomplish a stated cell . In embodiments , the cancer cell may be a breast cancer purpose ( e . g . achieve the effect for which it is administered , cell . In embodiments , the cancer cell may be a triple treat a disease , reduce enzyme activity , reduce one or more negative breast cancer cell . In embodiments , the cancer cell symptoms of a disease or condition ) . An example of an 25 may be a lung cancer cell . In embodiments , the cancer cell " effective amount” is an amount sufficient to contribute to may be a non - small cell lung cancer cell . In embodiments , the treatment, prevention , or reduction of a symptom or the cancer cell may be a pancreatic cancer cell. In embodi symptoms of a disease , which could also be referred to as a ments , the cancer cell may be a melanoma cancer cell. In " therapeutically effective amount. ” A reduction " of a symp - embodiments , the cancer cell may be a colon cancer cell . In tom or symptoms and grammatical equivalents of this 30 embodiments , the cancer cell may be a colorectal cancer phrase ) means decreasing of the severity or frequency of the cell . In embodiments , the cancer cell may be an ovarian symptom ( s ) , or elimination of the symptom ( s ) . A " prophy - cancer cell. In embodiments , the cancer cell may be a lactically effective amount of a drug is an amount of a drug prostate cancer cell . In embodiments contacting includes that, when administered to a subject, will have the intended allowing a compound described herein to interact with a prophylactic effect , e . g . , preventing or delaying the onset ( or 35 protein associated with the cell . reoccurrence ) of an injury, disease , pathology or condition , As defined herein , the term “ inhibition ” , “ inhibit” , “ inhib or reducing the likelihood of the onset ( or reoccurrence ) of iting ” and the like in reference to a protein - inhibitor inter an injury , disease , pathology , or condition , or their symp - action means negatively affecting (e . g . decreasing ) the activ toms. The full prophylactic effect does not necessarily occur i ty or function of the protein (e . g. decreasing the activity of by administration of one dose , and may occur only after 40 a protein ) relative to the activity or function of the protein in administration of a series of doses . Thus , a prophylactically the absence of the inhibitor ( e . g . compound ) . In embodi effective amount may be administered in one or more ments inhibition refers to reduction of a disease or symp administrations . An " activity decreasing amount, " as used toms of disease . In embodiments , inhibition refers to a herein , refers to an amount of antagonist ( e . g . compound ) reduction in the presence of a disease - related protein . Thus , required to decrease the activity of an enzyme relative to the 45 inhibition includes, at least in part, partially or totally absence of the antagonist . A " function disrupting amount, ” blocking stimulation , decreasing , preventing , or delaying as used herein , refers to the amount of antagonist ( e . g . activation , or inactivating, desensitizing , or down - regulating compound ) required to disrupt the function of an enzyme or signal transduction or enzymatic activity or the amount of a protein relative to the absence of the antagonist . The exact protein . Similarly an " inhibitor” is a compound that inhibits amounts will depend on the purpose of the treatment, and 50 cancer cell growth or proliferation , e . g . , by binding, partially will be ascertainable by one skilled in the art using known or totally blocking stimulation of cell growth or prolifera techniques ( see , e . g ., Lieberman , Pharmaceutical Dosage tion , decreasing , preventing, or delaying activation ( e . g . of Forms (vols . 1- 3 , 1992 ); Lloyd , The Art , Science and a protein or enzyme involved in cancer cell growth or Technology of Pharmaceutical Compounding (1999 ); proliferation ), or inactivating , desensitizing, or down - regu Pickar , Dosage Calculations ( 1999 ) ; and Remington : The 55 lating signal transduction or enzymatic activity ( e . g . activity Science and Practice of Pharmacy, 20th Edition , 2003 , responsible for cancer cell growth or proliferation ) . Inhibi Gennaro , Ed ., Lippincott, Williams & Wilkins ). tion may also reduce the amount of a protein by increasing " Control” or “ control experiment” is used in accordance clearance or degradation of the protein . with its plain ordinary meaning and refers to an experiment The term “ modulator ” refers to a composition that in which the subjects or reagents of the experiment are 60 increases or decreases the level of a target molecule or the treated as in a parallel experiment except for omission of a function of a target molecule ( e . g . a target may be a cancer procedure, reagent, or variable of the experiment. In some associated protein or mutant protein and the function may be instances, the control is used as a standard of comparison in increase cell growth or a target may be a cancer cell and the evaluating experimental effects . For example , a control for function may be to replicate and multiply ) . In embodiments , determining expression or overexpression of a protein or 65 a modulator is a compound that reduces the severity of one marker ( e . g . estrogen receptor alpha , progesterone receptor , or more symptoms of a disease ( e . g . tumor growth or or human epidermal growth factor receptor 2 ) may be the metastasis ) . US 9 , 862 ,693 B2 15 “ Patient” or “ subject in need thereof” refers to a living basis of (1 ) the duration and character of the disease -acute organism suffering from or prone to a condition that can be or chronic ; ( 2 ) the type of cell involved ; myeloid (myelog treated by administration of a composition ( e . g . compound ) enous ) , lymphoid (lymphogenous ) , or monocytic ; and ( 3 ) or pharmaceutical composition as provided herein . Non the increase or non - increase in the number abnormal cells in limiting examples include humans , other mammals , bovines , 5 the blood -leukemic or aleukemic ( subleukemic ) . Exemplary rats , mice , dogs , monkeys , goat, sheep , cows, deer , and other leukemias that may be treated with a compound or method non -mammalian animals . In embodiments , a patient is provided herein include , for example , acute nonlymphocytic human . leukemia , chronic lymphocytic leukemia , acute granulocytic “ Disease” or “ condition ” or “ disorder” refers to a state of leukemia , chronic granulocytic leukemia , acute promyelo being or health status of a patient or subject capable of being 10 cytic leukemia , adult T - cell leukemia , aleukemic leukemia , treated with the compounds, drugs , pharmaceutical compo - a leukocythemic leukemia , basophylic leukemia , blast cell sitions , or methods provided herein . In embodiments , the leukemia , bovine leukemia , chronic myelocytic leukemia , disease is a disease related to ( e . g . caused by ) an abnormal leukemia cutis , embryonal leukemia , eosinophilic leukemia , cell growth or abnormal protein activity . Examples of dis - Gross ' leukemia , hairy - cell leukemia , hemoblastic leuke eases, disorders , or conditions include, but are not limited to , 15 mia , hemocytoblastic leukemia , histiocytic leukemia , stem cancer, metastatic cancer, breast cancer, triple -negative cell leukemia , acute monocytic leukemia , leukopenic leu breast cancer subtype, pancreatic cancer, lung cancer, non - kemia , lymphatic leukemia , lymphoblastic leukemia , lym small cell lung cancer , melanoma , prostate cancer, ovarian phocytic leukemia , lymphogenous leukemia , lymphoid leu cancer, colon cancer , colorectal cancer. In some instances , kemia , lymphosarcoma cell leukemia , mast cell leukemia , " disease " or " condition ” refers to cancer . In embodiments , 20 megakaryocytic leukemia, micromyeloblastic leukemia , " disease ” refers to triple negative breast cancer. In embodi- monocytic leukemia , myeloblastic leukemia , myelocytic ments , “ disease ” refers to breast cancer. In embodiments , leukemia , myeloid granulocytic leukemia , myelomonocytic " disease” refers to lung cancer. In embodiments , " disease leukemia , Naegeli leukemia , plasma cell leukemia , multiple refers to non - small cell lung cancer. In embodiments , " dis - myeloma , plasmacytic leukemia , promyelocytic leukemia , ease ” refers to pancreatic cancer. In embodiments , " disease " 25 Rieder cell leukemia, Schilling 's leukemia , stem cell leuke refers to colon cancer. In embodiments , “ disease ” refers to mia , subleukemic leukemia , or undifferentiated cell leuke colorectal cancer. In embodiments , " disease ” refers to pros - mia . tate cancer. In embodiments , " disease ” refers to ovarian The term " sarcoma” generally refers to a tumor which is cancer . In embodiments , " disease ” refers to melanoma . In made up of a substance like the embryonic connective tissue embodiments , “ disease ” refers to pulmonary lymphangio - 30 and is generally composed of closely packed cells embedded leiomyomatosis (LAM ) . In embodiments , “ disease ” refers to in a fibrillar or homogeneous substance . Sarcomas that may renal angiomyolipoma ( AML ). In some further instances, be treated with a compound or method provided herein “ cancer ” refers to human cancers and carcinomas , sarcomas, include a chondrosarcoma, fibrosarcoma , lymphosarcoma, adenocarcinomas, lymphomas, leukemias, etc . , including melanosarcoma, myxosarcoma, osteosarcoma, Abemethy ' s solid and lymphoid cancers , kidney , breast ( e . g . triple nega - 35 sarcoma, adipose sarcoma, liposarcoma, alveolar soft part tive subtype ), lung , bladder , colon , ovarian , prostate , pan - sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma creas , stomach , brain cancer , head and neck , skin , uterine , sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' testicular , glioma, esophagus, and liver cancer, including tumor sarcoma, endometrial sarcoma, stromal sarcoma , hepatocarcinoma, lymphoma, including B -acute lympho Ewing ' s sarcoma, fascial sarcoma, fibroblastic sarcoma , blastic lymphoma, non -Hodgkin ' s lymphomas ( e . g ., 40 giant cell sarcoma, granulocytic sarcoma, Hodgkin ' s sar Burkitt ' s , Small Cell , and Large Cell lymphomas ) , Hodg - coma, idiopathic multiple pigmented hemorrhagic sarcoma, kin ' s lymphoma, leukemia (including AML , ALL , and immunoblastic sarcoma of B cells , lymphoma , immunoblas CML ) , or multiple myeloma . tic sarcoma of T -cells , Jensen ' s sarcoma, Kaposi ' s sarcoma, As used herein , the term “ cancer” refers to all types of Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malig cancer , neoplasm or malignant tumors found in mammals , 45 nant mesenchymoma sarcoma , parosteal sarcoma, reticulo including leukemia , carcinomas and sarcomas . Exemplary cytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial cancers that may be treated with a compound or method sarcoma, or telangiectaltic sarcoma . provided herein include cancer of the brain , breast ( e . g . The term “ melanoma ” is taken to mean a tumor arising triple negative ) , cervix , colon , colorectal, head & neck , liver , from the melanocytic system of the skin and other organs . kidney , lung, non - small cell lung, melanoma , mesothelioma , 50 Melanomas thatmay be treated with a compound or method ovary , sarcoma, stomach , uterus or medulloblastoma. Addi- provided herein include , for example, acral- lentiginous tional examples include , Hodgkin ' s Disease , Non -Hodg - melanoma, amelanotic melanoma, benign juvenile mela kin ' s Lymphoma , multiple myeloma , neuroblastoma, noma , Cloudman ' s melanoma , S91 melanoma, Harding glioma , glioblastoma multiforme, ovarian cancer , rhab Passey melanoma, juvenile melanoma, lentigo maligna domyosarcoma, primary thrombocytosis , primary macro - 55 melanoma, malignant melanoma, nodular melanoma, sub globulinemia , primary brain tumors , cancer , malignant pan - ungal melanoma, or superficial spreading melanoma . creatic insulanoma, malignant carcinoid , urinary bladder The term “ carcinoma” refers to a malignant new growth cancer, premalignant skin lesions, testicular cancer, lympho - made up of epithelial cells tending to infiltrate the surround mas, thyroid cancer, neuroblastoma, esophageal cancer, ing tissues and give rise to metastases . Exemplary carcino genitourinary tract cancer , malignant hypercalcemia , endo - 60 mas that may be treated with a compound or method metrial cancer, adrenal cortical cancer, neoplasms of the provided herein include , for example , acinar carcinoma, endocrine or exocrine pancreas, or prostate cancer. acinous carcinoma , adenocystic carcinoma , adenoid cystic The term " leukemia ” refers broadly to progressive , malig - carcinoma, carcinoma adenomatosum , carcinoma of adrenal nant diseases of the blood - forming organs and is generally cortex , alveolar carcinoma , alveolar cell carcinoma, basal characterized by a distorted proliferation and development 65 cell carcinoma, carcinoma basocellulare , basaloid carci of leukocytes and their precursors in the blood and bone noma, basosquamous cell carcinoma, bronchioalveolar car marrow . Leukemia is generally clinically classified on the cinoma, bronchiolar carcinoma, bronchogenic carcinoma, US 9 , 862 ,693 B2 17 18 cerebriform carcinoma, cholangiocellular carcinoma, chori - pound , drug , antagonist , inhibitor, modulator) having anti onic carcinoma, colloid carcinoma, comedo carcinoma, cor neoplastic properties or the ability to inhibit the growth or pus carcinoma , cribriform carcinoma, carcinoma en cui- proliferation of cells . In embodiments , an anti - cancer agent rasse , carcinoma cutaneum , cylindrical carcinoma is a chemotherapeutic . In embodiments , an anti -cancer agent cylindrical cell carcinoma, duct carcinoma , carcinoma 5 is an agent identified herein having utility in methods of durum , embryonal carcinoma , encephaloid carcinoma , epi- treating cancer . In embodiments , an anti - cancer agent is an ermoid carcinoma, carcinoma epitheliale adenoides , exo - agent identified herein having utility in methods of treating phytic carcinoma, carcinoma ex ulcere , carcinoma fibrosum , breast cancer. In embodiments , an anticancer agent is an gelatiniforni carcinoma , gelatinous carcinoma, giant cell agent identified herein having utility in methods of treating carcinoma, carcinoma gigantocellulare , glandular carci- 10 triple negative breast cancer . In embodiments , an anti - cancer noma , granulosa cell carcinoma, hair -matrix carcinoma, agent is an agent identified herein having utility in methods hematoid carcinoma, hepatocellular carcinoma, Hurthle cell of treating lung cancer . In embodiments , an anti -cancer carcinoma, hyaline carcinoma , hypernephroid carcinoma , agent is an agent identified herein having utility in methods infantile embryonal carcinoma, carcinoma in situ , intraepi - of treating non -small cell lung cancer . In embodiments , an dermal carcinoma , intraepithelial carcinoma , Krompecher ' s 15 anticancer agent is an agent identified herein having utility carcinoma , Kulchitzky -cell carcinoma, large -cell carci- in methods of treating pancreatic cancer . In embodiments , an noma, lenticular carcinoma, carcinoma lenticulare , lipoma - anti - cancer agent is an agent identified herein having utility tous carcinoma, lymphoepithelial carcinoma , carcinoma in methods of treating melanoma . In embodiments , an medullare , medullary carcinoma, melanotic carcinoma , car - anti - cancer agent is an agent identified herein having utility cinoma molle , mucinous carcinoma , carcinoma muciparum , 20 in methods of treating colon cancer. In embodiments , an carcinoma mucocellulare , mucoepidermoid carcinoma, car - anti - cancer agent is an agent identified herein having utility cinoma mucosum , mucous carcinoma , carcinomamyxoma - in methods of treating colorectal cancer . In embodiments , an todes, nasopharyngeal carcinoma , oat cell carcinoma , car - anti - cancer agent is an agent identified herein having utility cinoma ossificans, osteoid carcinoma, papillary carcinoma, in methods of treating prostate cancer. In embodiments , an periportal carcinoma , preinvasive carcinoma, prickle cell 25 anti - cancer agent is an agent identified herein having utility carcinoma , pultaceous carcinoma , renal cell carcinoma of in methods of treating ovarian cancer . In embodiments, an kidney , reserve cell carcinoma , carcinoma sarcomatodes , anti - cancer agent is an agent approved by the FDA or similar schneiderian carcinoma, scirrhous carcinoma, carcinoma regulatory agency of a country other than the USA , for scroti, signet - ring cell carcinoma, carcinoma simplex , small - treating cancer. Examples of anti -cancer agents include , but cell carcinoma, solanoid carcinoma, spheroidal cell carci- 30 are not limited to , alkylating agents ( e . g . , cyclophosph noma, spindle cell carcinoma, carcinoma spongiosum , amide, ifosfamide, chlorambucil, busulfan , melphalan , squamous carcinoma , squamous cell carcinoma, string car - mechlorethamine , uramustine , thiotepa , nitrosoureas , nitro cinoma, carcinoma telangiectaticum , carcinoma telangiec gen mustards ( e. g . , mechloroethamine , cyclophosphamide , todes, transitional cell carcinoma, carcinoma tuberosum , chlorambucil , meiphalan ) , ethylenimine and methyl tuberous carcinoma, verrucous carcinoma, or carcinoma 35 melamines ( e . g . , hexamethlymelamine , thiotepa ), alkyl sul villosum . fonates (e . g. , busulfan ) , nitrosoureas (e . g. , carmustine , “ Pharmaceutically acceptable excipient” and “ pharma- lomusitne, semustine, streptozocin ), triazenes ( decarba ceutically acceptable carrier ” refer to a substance that aids zine ) ) , anti -metabolites ( e . g ., 5 - azathioprine , leucovorin , the administration of an active agent to and absorption by a capecitabine , fludarabine, gemcitabine , pemetrexed , ralti subject and can be included in the compositions of the 40 trexed , folic acid analog ( e . g . , methotrexate ) , pyrimidine present invention without causing a significant adverse analogs ( e . g . , fluorouracil, floxouridine , Cytarabine ), purine toxicological effect on the patient. Non - limiting examples of analogs ( e . g ., mercaptopurine , thioguanine, pentostatin ) , pharmaceutically acceptable excipients include water, NaCl, etc .) , plant alkaloids ( e . g ., vincristine , vinblastine, vinorel normal saline solutions , lactated Ringer’ s , normal sucrose , bine , vindesine , podophyllotoxin , paclitaxel, docetaxel, normal glucose , binders , fillers , disintegrants , lubricants , 45 etc . ), topoisomerase inhibitors ( e . g . , irinotecan , topotecan , coatings , sweeteners , flavors , salt solutions (such as Ring amsacrine, etoposide (VP16 ), etoposide phosphate , tenipo er ' s solution ) , alcohols , oils , gelatins, carbohydrates such as side , etc . ) , antitumor antibiotics ( e . g . , doxorubicin , adriamy lactose , amylose or starch , fatty acid esters , hydroxymethy - cin , daunorubicin , epirubicin , actinomycin , bleomycin , cellulose , polyvinyl pyrrolidine . and colors , and the like . mitomycin , mitoxantrone, plicamycin , etc . ) , platinum -based Such preparations can be sterilized and , if desired , mixed 50 compounds ( e . g . cisplatin , oxaloplatin , carboplatin ) , anthra with auxiliary agents such as lubricants , preservatives , sta - cenedione ( e . g . , mitoxantrone ), substituted urea ( e . g . , bilizers , wetting agents , emulsifiers , salts for influencing hydroxyurea ) , methyl hydrazine derivative ( e . g ., procarba osmotic pressure , buffers , coloring , and / or aromatic sub - zine ) , adrenocortical suppressant ( e . g . , mitotane , aminoglu stances and the like that do not deleteriously react with the tethimide ), epipodophyllotoxins ( e . g ., etoposide ) , antibiotics compounds of the invention . One of skill in the art will 55 ( e . g . , daunorubicin , doxorubicin , bleomycin ) , enzymes ( e . g . , recognize that other pharmaceutical excipients are useful in L -asparaginase ) , inhibitors of mitogen -activated protein the present invention . kinase signaling (e . g . U0126 , PD98059 , PD184352 , The term " preparation ” is intended to include the formu PD0325901 , ARRY - 142886 , SB239063 , SP600125 , BAY lation of the active compound with encapsulating material as 43 - 9006 ) , wortmannin , LY294002 , Syk inhibitors , mTOR a carrier providing a capsule in which the active component 60 inhibitors , antibodies ( e . g . , rituxan ) , gossyphol, genasense , with or without other carriers, is surrounded by a carrier, polyphenol E , Chlorofusin , all trans - retinoic acid ( ATRA ) , which is thus in association with it. Similarly , cachets and bryostatin , tumor necrosis factor- related apoptosis -inducing lozenges are included . Tablets , powders , capsules , pills , ligand ( TRAIL ), 5 - aza -2 ' -deoxycytidine , all trans retinoic cachets , and lozenges can be used as solid dosage forms acid , doxorubicin , vincristine , etoposide , gemcitabine, ima suitable for oral administration . 65 tinib (Gleevec® ) , geldanamycin , 17 - N - Allylamino - 17 “ Anti - cancer agent" is used in accordance with its plain Demethoxygeldanamycin ( 17 -AAG ) , flavopiridol, ordinary meaning and refers to a composition ( e. g. com - LY294002, bortezomib , trastuzumab , BAY 11- 7082 , US 9 ,862 , 693 B2 19 20 PKC412 , PD184352 , 20 -epi - 1 , 25 dihydroxyvitamin D3 , mofarotene , molgramostim , monoclonal antibody, human 5 -ethynyluracil , abiraterone , aclarubicin , acylfulvene , chorionic gonadotrophin , monophosphoryl lipid A +myobac adecypenol, adozelesin , aldesleukin , ALL - TK antagonists , terium cell wall sk , mopidamol , multiple drug resistance altretamine , ambamustine , amidox , ami fostine , aminolevu gene inhibitor , multiple tumor suppressor 1 -based therapy, linic acid , amrubicin , amsacrine , anagrelide , anastrozole , 5 mustard anticancer agent, mycaperoxide B , mycobacterial andrographolide , angiogenesis inhibitors , antagonist D , cell wall extract , myriaporone , N -acetyldinaline , N -substi antagonist G , antarelix , anti - dorsalizing morphogenetic pro - tuted benzamides , nafarelin , nagrestip , naloxone + pentazo tein - 1 , antiandrogen , prostatic carcinoma, antiestrogen , anti cine , napavin , naphterpin , nartograstim , nedaplatin , nemo neoplaston , antisense oligonucleotides , aphidicolin glyci - rubicin , neridronic acid , neutral endopeptidase , nilutamide , nate, apoptosis gene modulators , apoptosis regulators , 10 nisamycin , nitric oxide modulators , nitroxide antioxidant, apurinic acid , ara -CDP -DL -PTBA , arginine deaminase , asu - nitrullyn , 06 -benzylguanine , octreotide , okicenone , oligo lacrine , atamestane, atrimustine , axinastatin 1 , axinastatin 2 , nucleotides, onapristone , ondansetron , ondansetron , oracin , axinastatin 3 , azasetron , azatoxin , azatyrosine , baccatin III oral cytokine inducer, ormaplatin , osaterone , oxaliplatin , derivatives , balanol, batimastat , BCR /ABL antagonists , ben oxaunomycin , palauamine , palmitoylrhizoxin , pamidronic zochlorins, benzoylstaurosporine, beta lactam derivatives, 15 acid , panaxytriol, panomifene, parabactin , pazelliptine, beta - alethine , betaclamycin B , betulinic acid , bFGF inhibi- pegaspargase , peldesine, pentosan polysulfate sodium , pen tor, bicalutamide, bisantrene, bisaziridinylspermine, bisna tostatin , pentrozole , perflubron , perfosfamide, perillyl alco fide, bistratene A , bizelesin , breflate , bropirimine , budoti hol, phenazinomycin , phenylacetate , phosphatase inhibitors, tane , buthionine sulfoximine, calcipotriol, calphostin C , picibanil , pilocarpine hydrochloride , pirarubicin , piritrexim , camptothecin derivatives, canarypox IL -2 , capecitabine , car - 20 placetin A , placetin B , plasminogen activator inhibitor, boxamide - amino - triazole , carboxyamidotriazole , CaRest p latinum complex , platinum compounds, platinum - triamine M3, CARN 700 , cartilage derived inhibitor, carzelesin , complex , porfimer sodium , porfiromycin , prednisone, pro casein kinase inhibitors (ICOS ) , castanospermine, cecropin pyl bis -acridone , prostaglandin J2 , proteasome inhibitors , B , cetrorelix , chlorins , chloroquinoxaline sulfonamide , protein A - based immune modulator, protein kinase C inhibi cicaprost, cis -porphyrin , cladribine , clomifene analogues , 25 tor, protein kinase C inhibitors, microalgal, protein tyrosine clotrimazole , collismycin A , collismycin B , combretastatin phosphatase inhibitors , purine nucleoside phosphorylase A4 , combretastatin analogue , conagenin , crambescidin 816 , inhibitors , purpurins , pyrazoloacridine , pyridoxylated crisnatol, cryptophycin 8 , cryptophycin A derivatives, cura - hemoglobin polyoxyethylerie conjugate , raf antagonists , cin A , cyclopentanthraquinones , cycloplatam , cypemycin , raltitrexed , ramosetron , ras farnesyl protein transferase cytarabine ocfosfate , cytolytic factor, cytostatin , dacliximab , 30 inhibitors , ras inhibitors, ras- GAP inhibitor, retelliptine decitabine , dehydrodidemnin B , deslorelin , dexamethasone , demethylated , rhenium Re 186 etidronate , rhizoxin , dexifosfamide , dexrazoxane , dexverapamil, diaziquone , ribozymes , RII retinamide, rogletimide, rohitukine, didemnin B , didox , diethylnorspermine , dihydro - 5 - azacyti- romurtide , roquinimex , rubiginone B1, ruboxyl, safingol, dine , 9 - dioxamycin , diphenyl spiromustine, docosanol, saintopin , SarCNU , sarcophytol A , sargramostim , Sdi 1 dolasetron , doxifluridine , droloxifene , dronabinol, duocar - 35 mimetics , semustine , senescence derived inhibitor 1 , sense mycin SA , ebselen , ecomustine , edelfosine , edrecolomab , oligonucleotides , signal transduction inhibitors , signal trans eflornithine , elemene, emitefur, epirubicin , epristeride , duction modulators , single chain antigen -binding protein , estramustine analogue , estrogen agonists , estrogen antago - sizofuran , sobuzoxane, sodium borocaptate , sodium pheny nists , etanidazole , etoposide phosphate , exemestane, fadro lacetate , solverol, somatomedin binding protein , sonermin , zole , fazarabine , fenretinide , filgrastim , finasteride , fla - 40 sparfosic acid , spicamycin D , spiromustine , splenopentin , vopiridol, flezelastine, fluasterone , fludarabine , spongistatin 1, squalamine , stem cell inhibitor , stem -cell fluorodaunorunicin hydrochloride, forfenimex , formestane , division inhibitors , stipiamide, stromelysin inhibitors , fostriecin , fotemustine , gadolinium texaphyrin , gallium sulfinosine , superactive vasoactive intestinalpeptide antago nitrate , galocitabine, ganirelix , gelatinase inhibitors , gem nist , suradista , suramin , swainsonine , synthetic gly citabine, glutathione inhibitors, hepsulfam , heregulin , hex - 45 cosaminoglycans , tallimustine, tamoxifen methiodide , tau amethylene bisacetamide, hypericin , ibandronic acid , idaru - romustine, tazarotene , tecogalan sodium , tegafur, bicin , idoxifene, idramantone , ilmofosine , ilomastat, tellurapyrylium , telomerase inhibitors , temoporfin , temozo imidazoacridones , imiquimod , immunostimulant peptides , lomide , teniposide , tetrachlorodecaoxide , tetrazomine , thali insulin - like growth factor - 1 receptor inhibitor, interferon blastine , thiocoraline , thrombopoietin , thrombopoietin agonists , interferons , interleukins , iobenguane , iododoxoru - 50 mimetic , thymalfasin , thymopoietin receptor agonist , thy bicin , ipomeanol, 4 - , iroplact , irsogladine , isobengazole , motrinan , thyroid stimulating hormone , tin ethyl etiopurpu isohomohalicondrin B , itasetron , jasplakinolide , kahalalide rin , tirapazamine, titanocene bichloride, topsentin , tore F , lamellarin - N triacetate , lanreotide, leinamycin , mifene, totipotent stem cell factor, translation inhibitors , lenograstim , lentinan sulfate , leptolstatin , letrozole , leuke tretinoin , triacetyluridine, triciribine, trimetrexate , triptore mia inhibiting factor, leukocyte alpha interferon , leuprolide + 55 lin , tropisetron , turosteride , tyrosine kinase inhibitors , tyr estrogen + progesterone , leuprorelin , levamisole, liarozole , phostins, UBC inhibitors , ubenimex , urogenital sinus - de linear polyamine analogue , lipophilic disaccharide peptide , rived growth inhibitory factor, urokinase receptor lipophilic platinum compounds , lissoclinamide 7 , lobapla antagonists , vapreotide , variolin B , vector system , erythro tin , lombricine , lometrexol, lonidamine , losoxantrone , lov - cyte gene therapy , velaresol, veramine , verdins , verteporfin , astatin , loxoribine, lurtotecan , lutetium texaphyrin , lysofyl- 60 vinorelbine , vinxaltine , vitaxin , vorozole , zanoterone , zeni line , lytic peptides , maitansine, mannostatin A , marimastat , platin , zilascorb , zinostatin stimalamer, Adriamycin , Dac masoprocol , maspin , matrilysin inhibitors , matrix metallo tinomycin , Bleomycin , Vinblastine , Cisplatin , acivicin , acla proteinase inhibitors , menogaril , merbarone, meterelin , rubicin , acodazole hydrochloride , acronine , adozelesin , methioninase ,metoclopramide , MIF inhibitor, mifepristone , aldesleukin , altretamine , ambomycin , ametantrone acetate , miltefosine ,mirimostim , mismatched double stranded RNA , 65 aminoglutethimide, amsacrine , anastrozole , anthramycin , mitoguazone , mitolactol, mitomycin analogues, mitonafide , asparaginase , asperlin , azacitidine , azetepa , azotomycin , mitotoxin fibroblast growth factor - saporin , mitoxantrone, batimastat, benzodepa, bicalutamide, bisantrene hydrochlo US 9 ,862 ,693 B2 21 22 ride, bisnafide dimesylate , bizelesin , bleomycin sulfate , bre pothilone B ( i . e . BMS -310705 ) , 21- hydroxyepothilone D quinar sodium , bropirimine , busulfan , cactinomycin , calus ( i . e . Desoxyepothilone F and dEpoF ) , 26 - fluoroepothilone , terone , caracemide, carbetimer, carboplatin , carmustine , Auristatin PE ( i. e . NSC -654663 ), Soblidotin ( i. e . TZT carubicin hydrochloride , carzelesin , cedefingol, chlorambu - 1027 ), LS - 4559 - P (Pharmacia , i. e . LS -4577 ) , LS - 4578 cil , cirolemycin , cladribine, crisnatol mesylate , cyclophos- 5 (Pharmacia , i. e . LS -477 -P ), LS -4477 (Pharmacia ), LS - 4559 phamide , cytarabine, dacarbazine, daunorubicin hydrochlo ( Pharmacia ) , RPR - 112378 ( Aventis ) , Vincristine sulfate , ride , decitabine, dexormaplatin , dezaguanine, dezaguanine DZ -3358 (Daiichi ) , FR -182877 ( Fujisawa, i. e. WS- 9885B ) , mesylate , diaziquone , doxorubicin , doxorubicin hydrochlo - GS - 164 ( Takeda ), GS - 198 ( Takeda ), KAR - 2 (Hungarian ride, droloxifene , droloxifene citrate , dromostanolone pro - Academy of Sciences ) , BSF - 223651 (BASF , i . e . ILX -651 pionate , duazomycin , edatrexate , eflornithine hydrochloride, 10 and LU - 223651) , SAH -49960 (Lilly /Novartis ), SDZ elsamitrucin , enloplatin , enpromate , epipropidine, epirubi 268970 (Lilly / Novartis ) , AM - 97 (Armad /Kyowa Hakko ) , cin hydrochloride , erbulozole, esorubicin hydrochloride , AM - 132 ( Armad ) , AM - 138 ( Armad /Kyowa Hakko ) , IDN estramustine , estramustine phosphate sodium , etanidazole , 5005 ( Indena ) , Cryptophycin 52 (i .e . LY -355703 ) , AC -7739 etoposide , etoposide phosphate , etoprine , fadrozole hydro ( Ajinomoto , i. e . AVE - 8063A and CS - 39 .HCI ) , AC -7700 chloride , fazarabine , fenretinide, floxuridine , fludarabine 15 (Ajinomoto , i. e . AVE - 8062 , AVE - 8062A , CS - 39 - L - Ser. HC1 , phosphate , fluorouracil, fluorocitabine, fosquidone , fostrie - and RPR -258062A ), Vitilevuamide, Tubulysin A , Canaden cin sodium , gemcitabine, gemcitabine hydrochloride, sol, Centaureidin (i . e . NSC - 106969 ) , T - 138067 ( Tularik , i. e . hydroxyurea , idarubicin hydrochloride, ifosfamide, iimofos- T -67 , TL - 138067 and TI- 138067 ), COBRA - 1 (Parker ine , interleukin II ( including recombinant interleukin II , or Hughes Institute , i . e . DDE - 261 and WHI- 261) , H10 (Kansas rlL .sub . 2 ) , interferon alfa - 2a , interferon alfa - 2b , interferon 20 State University ) , H16 (Kansas State University ) , Oncocidin alfa - nl , interferon alfa - n3 , interferon beta - la , interferon A1 ( i. e . BTO - 956 and DIME ) , DDE - 313 ( Parker Hughes gamma - 1b , iproplatin , irinotecan hydrochloride , lanreotide Institute ), Fijianolide B , Laulimalide , SPA - 2 ( Parker Hughes acetate , letrozole , leuprolide acetate , liarozole hydrochlo - Institute ), SPA - 1 ( Parker Hughes Institute , i. e . SPIKET- P ) , ride, lometrexol sodium , lomustine , losoxantrone hydro - 3 -IAABU (Cytoskeleton /Mt . Sinai School of Medicine , i . e . chloride , masoprocol, maytansine , mechlorethamine hydro - 25 MF- 569) , Narcosine ( also known as NSC -5366 ) , Nascapine , chloride , megestrol acetate , melengestrol acetate , D - 24851 (Asta Medica ) , A - 105972 ( Abbott ), Hemiasterlin , melphalan , menogaril , mercaptopurine , methotrexate , 3 - BAABU (Cytoskeleton /Mt . Sinai School of Medicine , i. e . methotrexate sodium , metoprine, meturedepa, mitindomide , MF - 191) , TMPN ( Arizona State University ), Vanadocene mitocarcin , mitocromin , mitogillin , mitomalcin , mitomycin , acetylacetonate , T - 138026 ( Tularik ) , Monsatrol, Inanocine mitosper, mitotane, mitoxantrone hydrochloride, mycophe - 30 (i . e . NSC -698666 ), 3 - IAABE (Cytoskeleton /Mt . Sinai nolic acid , nocodazoie , nogalamycin , ormaplatin , oxisuran , School of Medicine ), A - 204197 ( Abbott ) , T - 607 ( Tuiarik , pegaspargase , peliomycin , pentamustine , peplomycin sul- i. e . T- 900607 ), RPR - 115781 (Aventis ), Eleutherobins ( such fate , perfosfamide , pipobroman , piposulfan , piroxantrone as Desmethyleleutherobin , Desaetyleleutherobin , Iso hydrochloride, plicamycin , plomestane , porfimer sodium , eleutherobin A , and Z - Eleutherobin ) , Caribaeoside , Carib porfiromycin , prednimustine , procarbazine hydrochloride, 35 aeolin , Halichondrin B , D -64131 (Asta Medica ) , D -68144 puromycin , puromycin hydrochloride , pyrazofurin , ribo ( Asta Medica ) , Diazonamide A , A -293620 ( Abbott ) , NPI prine , rogletimide , safingol, safingol hydrochloride , semus 2350 (Nereus ), Taccalonolide A , TUB -245 ( Aventis ) , tine , simtrazene, sparfosate sodium , sparsomycin , spiroger - A - 259754 ( Abbott ) , Diozostatin , ( - ) - Phenylahistin (i .e . manium hydrochloride , spiromustine , spiroplatin , NSCL - 96F037 ) , D -68838 ( Asta Medica ) , D -68836 ( Asta streptonigrin , streptozocin , sulofenur, talisomycin , tec - 40 Medica ), Myoseverin B , D -43411 (Zentaris , i . e . D -81862 ) , ogalan sodium , tegafur, teloxantrone hydrochloride, A - 289099 (Abbott ), A -318315 ( Abbott ), HTI- 286 (i .e . SPA temoporfin , teniposide, teroxirone, testolactone , thia - 110 , trifluoroacetate salt) (Wyeth ), D - 82317 (Zentaris ) , miprine , thioguanine , thiotepa, tiazofurin , tirapazamine , D - 82318 (Zentaris ), SC - 12983 (NCI ) , Resverastatin phos toremifene citrate , trestolone acetate , triciribine phosphate , phate sodium , BPR -OY - 007 (National Health Research trimetrexate , trimetrexate glucuronate , triptorelin , tubulo - 45 Institutes ) , or SSR - 250411 (Sanofi ) ) , steroids ( e . g ., dexam zole hydrochloride , uracil mustard , uredepa , vapreotide , ethasone ) , finasteride , aromatase inhibitors , gonadotropin verteporfin , vinblastine sulfate , vincristine sulfate , vin releasing hormone agonists (GnRH ) such as goserelin or desine , vindesine sulfate , vinepidine sulfate , vinglycinate leuprolide , adrenocorticosteroids ( e . g . , prednisone ) , proges sulfate , vinleurosine sulfate , vinorelbine tartrate , vinrosidine tins ( e . g ., hydroxyprogesterone caproate , megestrol acetate , sulfate , vinzolidine sulfate , vorozole , zeniplatin , zinostatin , 50 medroxyprogesterone acetate ), estrogens ( e .g ., diethlystil zorubicin hydrochloride , agents that arrest cells in the G2 - M bestrol, ethinyl estradiol) , antiestrogen ( e . g ., tamoxifen ) , phases and /or modulate the formation or stability of micro - androgens ( e .g ., testosterone propionate , fluoxymesterone) , tubules ( e . g . TaxolTM ( i. e . paclitaxel) , TaxotereTM , com - antiandrogen ( e . g ., flutamide ) , immunostimulants ( e . g . , pounds comprising the taxane skeleton , Erbulozole ( i. e . Bacillus Calmette -Guérin (BCG ), levamisole , interleukin - 2 , R -55104 ) , Dolastatin 10 ( i. e . DLS - 10 and NSC - 376128 ) , 55 alpha - interferon , etc . ) , monoclonal antibodies ( e . g . , anti Mivobulin isethionate ( i . e . as CI - 980 ) , Vincristine , NSC - CD20 , anti -HER2 , anti - CD52, anti -HLA - DR , and anti 639829 , Discodermolide ( i. e . as NVP - XX - A - 296 ) , ABT -751 VEGF monoclonal antibodies ) , immunotoxins ( e . g . , anti ( Abbott , i .e . E -7010 ), Altorhyrtins (e . g . Altorhyrtin A and CD33 monoclonal antibody -calicheamicin conjugate , anti Altorhyrtin C ), Spongistatins (e . g . Spongistatin 1, Spong - CD22 monoclonal antibody -pseudomonas exotoxin istatin 2 , Spongistatin 3 , Spongistatin 4 , Spongistatin 5 , 60 conjugate, etc . ), radioimmunotherapy ( e . g . , anti -CD20 Spongistatin 6 , Spongistatin 7 , Spongistatin 8 , and Spong - monoclonal antibody conjugated to 111In , 90Y , or 1311 , etc . ) , istatin 9 ) , Cemadotin hydrochloride ( i . e . LU - 103793 and or the like . NSC - D - 669356 ) , Epothilones ( e . g . Epothilone A , Epoth “ Chemotherapeutic ” or “ chemotherapeutic agent” is used ilone B , Epothilone C (i . e . desoxyepothilone A or dEpoA ) , in accordance with its plain ordinary meaning and refers to Epothilone D (i . e . KOS - 862, dEpoB , and desoxyepothilone 65 a chemical composition or compound having antineoplastic B ) , Epothilone E , Epothilone F , Epothilone B N -oxide , properties or the ability to inhibit the growth or proliferation Epothilone A N -oxide , 16 - aza -epothilone B , 21 -aminoe of cells . US 9 ,862 , 693 B2 23 24 " Analog ” or “ analogue ” is used in accordance with its human ; cow ; dog ; cat; a rodent, e . g ., guinea pig , rat ,mouse ; plain ordinary meaning within Chemistry and Biology and rabbit ; or a bird ; reptile ; or fish . In embodiments , the sample refers to a chemical compound that is structurally similar to is obtained from a human . another compound ( i. e ., a so -called “ reference” compound ) A “ biopsy ” refers to the process of removing a tissue but differs in composition , e . g . , in the replacement of one 5 sample for diagnostic or prognostic evaluation , and to the atom by an atom of a different element, or in the presence of tissue specimen itself . Any biopsy technique known in the a particular functional group , or the replacement of one art can be applied to the diagnostic and prognostic methods of the present invention . The biopsy technique applied will functional group by another functional group , or the abso depend on the tissue type to be evaluated ( e . g . , breast, lung , lute stereochemistry of one or more chiral centers of the pancreas , skin , etc . ), the size and type of the tumor ( e . g . , reference compound . Accordingly, an analog is a compound 10 solid or suspended , blood or ascites ) , among other factors . that is similar or comparable in function and appearance but Representative biopsy techniques include, but are not lim not in structure or origin to a reference compound . In ited to , excisional biopsy , incisional biopsy, needle biopsy, embodiments , a reference compound is metformin . surgical biopsy , and bone marrow biopsy . An “ excisional As used herein , the term “ disease -related cells ” means biopsy ” refers to the removal of an entire tumor mass with cells that are associated with a disease or condition , which 15 a small margin of normal tissue surrounding it . An “ inci include but are not limited to cells that initiate a disease , sional biopsy ” refers to the removal of a wedge of tissue that cells that propogate a disease, cells that cause a disease, cells includes a cross -sectional diameter of the tumor. A diagnosis that cause one or more symptoms of a disease , cells that are or prognosis made by endoscopy or fluoroscopy can require a hallmark of a disease ; cells that contain a particular protein a “ core - needle biopsy ” of the tumor mass, or a “ fine - needle or mRNA molecule that causes a symptom of the disease . In 20 aspiration biopsy ” which generally obtains a suspension of embodiments , the disease is a cancer ( e . g . breast cancer , cells from within the tumor mass . Biopsy techniques are triple negative breast cancer subtype , lung cancer , non - small discussed , for example, in Harrison ' s Principles of Internal cell lung cancer , pancreatic cancer, melanoma, prostate Medicine, Kasper , et al ., eds. , 16th ed. , 2005 , Chapter 70 , cancer , ovarian cancer , colon cancer , or colorectal cancer ) and throughout Part V . and the disease -related cell is a cancer ( e . g . breast cancer , 25 As used herein , the term " administering” includes paren triple negative breast cancer subtype , lung cancer, non - small teral administration , oral administration , administration as a cell lung cancer , pancreatic cancer , melanoma, prostate suppository , topical contact, intravenous , intraperitoneal, cancer, ovarian cancer, colon cancer, or colorectal cancer ) intramuscular , intralesional, intrathecal, intranasal or subcu cell. In embodiments , the disease is a metastatic cancer and taneous administration , or the implantation of a slow -release the disease -related cell is a metastatic cancer cell . In 30 device , e . g . , a mini- osmotic pump , to a subject . Adminis embodiments , the disease is triple negative breast cancer tration is by any route , including parenteral and transmu subtype ( i. e . TNBC ) and the disease- related cell is a TNBC cosal (e .g ., buccal, sublingual, palatal, gingival , nasal, vagi cell . nal, rectal, or transdermal) . Parenteral administration The term " expression ” refers to a gene that is transcribed includes, e . g . , intravenous, intramuscular, intra -arteriole , or translated at a detectable level . As used herein , expression 35 intradermal, subcutaneous , intraperitoneal, intraventricular, also encompasses “ overexpression , " which refers to a gene and intracranial . Other modes of delivery include , but are that is transcribed or translated at a detectably greater level, not limited to , the use of liposomal formulations, intrave usually in a cancer cell, in comparison to a normal cell. nous infusion , transdermal patches , etc . By “ co -administer " Expression can be detected using conventional techniques it is meant that a composition described herein is adminis for detecting protein ( e . g ., ELISA , Western blotting , flow 40 tered at the same time, just prior to , or just after the cytometry , immunofluorescence , immunohistochemistry , administration of one or more additional therapies , for etc . ) or mRNA ( e . g . , RT- PCR , PCR , hybridization , etc .) . example cancer therapies such as chemotherapy, hormonal “ Therapy resistant" cancers , tumor cells, and tumors refer therapy , radiotherapy, or immunotherapy . The agents ( e . g . to cancers that have become resistant to one or more compounds , drugs , antagonists ) of the invention can be therapies , including one or both of apoptosis -mediated ( e . g . , 45 administered alone or can be coadministered to the patient . through death receptor cell signaling , for example , Fas Coadministration is meant to include simultaneous or ligand receptor , TRAIL receptors , TNF -R1 , chemotherapeu sequential administration of the agents ( e . g . compounds, tic drugs, radiation , etc .) and non -apoptosis mediated ( e . g ., drugs, antagonists ) individually or in combination (more toxic drugs , chemicals , etc .) cancer therapies . In embodi- than one agent ( e . g . compound , drug , antagonist )) . Thus , the ments, the therapy may be a chemotherapy , hormonal 50 preparations can also be combined , when desired , with other therapy, radiotherapy , immunotherapy , or combinations active substances ( e . g . to reduce metabolic degradation ) . thereof. The compositions of the present invention can be delivered As used herein , the term “marker ” refers to any biochemi- by transdermally , by a topical route , formulated as applicator cal marker, serological marker, genetic marker, or other sticks, solutions , suspensions, emulsions , gels , creams, oint clinical or echographic characteristic that can be used to 55 ments , pastes, jellies , paints , powders , and aerosols . In diagnose or provide a prognosis for a cancer . embodiments , the compounds described herein ( including The term “ sample ” includes sections of tissues such as embodiments ) may be co - administered with one ore more biopsy and autopsy samples , and frozen sections taken for anti - cancer agents . histological purposes. Such samples include blood and “ Triple negative breast cancer ” or “ triple negative breast blood fractions or products ( e . g . , serum , plasma, platelets , 60 cancer subtype ” is used in accordance with its plain ordinary red blood cells , and the like ) , sputum , tissue , cultured cells meaning within the areas of medicine and oncology and ( e. g ., primary cultures, explants , and transformed cells ), refer to breast cancer that lacks clinical expression of stool, urine , other biological fluids ( e . g ., prostatic fluid , estrogen receptor -alpha , progesterone receptor and HER - 2 gastric fluid , intestinal fluid , renal fluid , lung fluid , cerebro overexpression or breast cancer that lacks clinical expres spinal fluid , and the like ) , etc . A sample is typically obtained 65 sion of estrogen receptor alpha , progesterone receptor and from a “ subject ” such as a eukaryotic organism , most HER2 receptor. In embodiments , the level of expression or preferably a mammal such as a primate , e .g . , chimpanzee or overexpress is in comparison to non -cancerous breast tissue . US 9 ,862 , 693 B2 25 26 In embodiments , the level of expression or overexpress is in embodiment, where L and L ? are a bond and Rl is a comparison to non -cancerous breast tissue from the same piperidinyl substituted with an unsubstituted C , to C , alkyl patient as the cancerous tissue . In embodiments , the level of (e . g . 4 '- substituted piperidinyl) , R2 is not - NH2. In one expression or overexpress is in comparison to the average embodiment, where L ' and L ? are a bond and Rl is a expression of each marker in non - triple negative breast 5 piperidinyl substituted with an unsubstituted C to Cz alkyl cancer samples (e . g . breast cancer samples ). In embodi ( e .g . substituted piperidinyl ), R² is not NH2. In one ments , the level of expression or overexpression is in embodiment, where L ' and L are a bond and R ' is substi comparison to the expression levels in therapy responsive tuted 3 to 6 membered heterocycloalkyl , R² is not — NH . breast cancers that respond to therapies targeting one or In one embodiment, where L ' and L are a bond and R ! more of estrogen receptor alpha , progesterone receptor, or is unsubstituted C , to C , alkyl ( e . g . - C (CH3 ) (CH3 ) , R² is human epidermal growth factor receptor 2 . In embodiments not - NH2. In one embodiment, where L ' and L are a bond triple negative breast cancer cells do not express ( e . g . and Rl is unsubstituted C , -Cz alkyl, R2 is not — NH , . In one clinically ) classical estrogen receptors ( e . g . ER -alpha ) , do embodiment, where L ' and L2 are a bond and Rl is substi not express ( e . g . clinically ) progesterone receptors , and do 15 tuted or unsubstituted C -Cz alkyl, R2 is not - NH2. In one not express (e . g . clinically ) high levels of HER2 / neu ( epi- embodiment, where L ' and L2 are a bond and Rl is substi dermal growth factor receptor 2 ) compared to a control . In tuted or unsubstituted C , to C , alkyl, R² is not — NH2. embodiments , triple negative breast cancer cells do not In one embodiment, where L ' and L2 are a bond and R express (e .g . clinically ) estrogen receptor alpha, progester - is phenyl, R² is not — NH2. In one embodiment, where L ' one receptor and HER2 receptor. In embodiments triple 20 and L are a bond and R ' is substituted or unsubstituted negative breast cancer subtype refers to breast cancer that phenyl , R2 is not — NH2. In one embodiment, where L ' and lacks clinical expression of estrogen receptor- alpha, proges - L ’ are a bond and R ' is substituted or unsubstituted 6 terone receptor and HER - 2 overexpression . In embodiments membered aryl, R² is not — NH . In one embodiment, where triple negative breast cancer cells lack clinical expression of Land L ? are a bond and Rl is 5 to 8 membered substituted estrogen receptor- alpha , progesterone receptor and HER - 2 25 or unsubstituted aryl, R ' is not — NH2. overexpression . In one embodiment, where L ' and L2 are a bond and R14 and RB are both hydrogen , R2A and R2B are notboth methyl. II . Compounds In one embodiment, where L ' and L are a bond and R14 and RIB are both hydrogen , R24 and R2B are not both unsubsti In a first aspect is a compound having the formula : 30 tuted C -Cz alkyl. In one embodiment, where L ' and L2 are a bond and R14 and RIB are both hydrogen , R24 and R2B are not both substituted or unsubstituted C -Cz alkyl. In one (1 ) embodiment, where L ' and L2 are a bond and R14 and RIB NH NH are both hydrogen , R24 and R2B are not both substituted or 35 ununsubstituted C , -C , alkyl. RI L1 NC In one embodiment, where L ' and L are a bond and R ! is 2 '- or 3 '- pyridinyl , R2 is not NH2. In one embodiment, where L and L are a bond and Rl is unsubstituted or substituted 2 ' - or 3 '- pyridinyl, R2 is not — NH , . In one pl 40 embodiment, where L ' and L2 are a bond and Rl is substi L ' and L are independently a bond or - NH - C ( NH ) — . R tuted or unsubstituted pyridinyl, RP is not — NH , . In one is — NRIAR1B , substituted or unsubstituted alkyl, substituted embodiment, where L ' and L2 are a bond and Rl is substi or unsubstituted heteroalkyl, substituted or unsubstituted tuted or unsubstituted 3 to 7 membered heteroaryl, R² is not cycloalkyl, substituted or unsubstituted heterocycloalkyl, — NH , substituted or unsubstituted aryl, or substituted or unsubsti - 45 In one embodiment, where Ll and L2 are a bond and RIA tuted heteroaryl, wherein R ' A and R ' ” are optionally joined and RIB are both methyl . R2 is not morpholino . In one together to form a substituted or unsubstituted heterocy embodiment , where L ' and L2 are a bond and R14 and RIB cloalkyl. R² is - NR24R2B , substituted or unsubstituted are both methyl, R² is not unsubstituted morpholino . In one alkyl, substituted or unsubstituted heteroalkyl, substituted or embodiment, where L ' and L2 are a bond and R14 and RIB unsubstituted cycloalkyl, substituted or unsubstituted het - 50 are both methyl, R2 is not substituted or unsubstituted erocycloalkyl, substituted or unsubstituted aryl, or substi - morpholino . In one embodiment, where L and L ’ are a bond tuted or unsubstituted heteroaryl, wherein R24 and R2B are and R14 and RB are both methyl, R2 is not 6 unsubstituted optionally joined together to form a substituted or unsub - membered heterocycloalkyl. In one embodiment, where L stituted heterocycloalkyl. R14 ,RB , R24 , and R2B are inde - and L ? are a bond and R14 and RIB are both methyl, R2 is not pendently hydrogen , _ OR , substituted or unsubstituted 55 substituted or unsubstituted 6 membered heterocycloalkyl. alkyl, substituted or unsubstituted heteroalkyl, substituted or L ' may be a bond . L may be bond . L ' and L ? may be a unsubstituted cycloalkyl, substituted or unsubstituted het - bond . When Ll is a bond , L2 may be - NH - C (NH ) . erocycloalkyl, substituted or unsubstituted aryl, or substi When L ' is - NH - C (NH ) — , L may be a bond . L ' and L2 tuted or unsubstituted heteroaryl. R * is hydrogen or unsub - may be — NH - C (NH ) — The compound of formula ( I ) stituted C -C5 alkyl. R4 is hydrogen , substituted or 60 may be a pharmaceutically salt thereof. Where L ' or La are unsubstituted alkyl, substituted or unsubstituted heteroalkyl, - NH - C (NH ) — , the carbon of the - NH - C (NH ) may substituted or unsubstituted cycloalkyl, substituted or unsub - be directly bound to R ' or R2 and the — NH — portion may stituted heterocycloalkyl, substituted or unsubstituted aryl, be directly bound to the remainder of the molecule . or substituted or unsubstituted heteroaryl . R ? may be substituted or unsubstituted alkyl, substituted In one embodiment, where L ' and L are a bond and R 65 or unsubstituted heteroalkyl, substituted or unsubstituted is a piperidinyl substituted with an unsubstituted C , to C cycloalkyl, substituted or unsubstituted heterocycloalkyl, alkyl (e . g . 4' - methyl piperidinyl) , R² is not - NH2. In one substituted or unsubstituted aryl. US 9 ,862 , 693 B2 27 28 R ? may independently be Rli - substituted or unsubstituted 5 to 8 membered aryl. R ? may be substituted or unsubstituted alkyl ( e . g . C , to Cg alkyl) , Rii- substituted or unsubstituted 5 to 8 membered heteroaryl. R ' may be unsubstituted 5 to 8 heteroalkyl ( e .g . 2 to 8 membered heteroalkyl) , Rli - substi - membered heteroaryl. R ? may be substituted 5 to 8 mem tuted or unsubstituted cycloalkyl ( e . g . C3 - C , cycloalkyl) , bered heteroaryl. Rii- substituted or unsubstituted heterocycloalkyl ( e . g . 3 to 6 5 Rimay be — NRIARTB . R14 may be hydrogen , substituted membered heterocycloalkyl) , Rli substituted or unsubsti or unsubstituted alkyl, substituted or unsubstituted het tuted aryl ( e . g. phenyl) , or Rli- substituted or unsubstituted eroalkyl, substituted or unsubstituted cycloalkyl, substituted heteroaryl ( e . g . 5 or 6 membered heteroaryl) . or unsubstituted heterocycloalkyl, substituted or unsubsti Rli is independently hydrogen , halogen , — N3, CF3, tuted aryl, or substituted or unsubstituted heteroaryl. CC13 , CBr3 , C13 , CN , CHO , OH , - NH2, 10 R14 may independently be hydrogen , halogen , N3, - COOH , CONH2, — NO2, SH , SO2, S02C1 , CF3 , CC1z , CBrz , C13 , CN , CHO , OH , - SO2H , SO , H , SO2NH2, - NHNH2, ONH2, - NH2, COOH , CONH2, — NO2, SH , SO2, - NHC ( O )NHNH2 , Rlii - substituted or unsubstituted alkyl SO , C1, SO3H , SOH , SO NH , NHNH2, ( e . g . C , to Cg alkyl) , Rli - substituted or unsubstituted het - ONH2, - NHC ( O )NHNH2 , R14i - substituted or unsubsti eroalkyl ( e . g . 2 to 8 membered heteroalkyl) , Rlii - substituted 15 tuted alkyl ( e . g . C , to C , alkyl ), R1Ai - substituted or unsub or unsubstituted cycloalkyl (e .g . C3 -C , cycloalkyl ), Rlii- stituted heteroalkyl ( e .g . 2 to 8 membered heteroalkyl) , substituted or unsubstituted heterocycloalkyl ( e . g . 3 to 6 R4ii -substituted or unsubstituted cycloalkyl ( e . g . Cz- C , membered heterocycloalkyl) , Rli -substituted or unsubsti cycloalkyl) , R14i- substituted or unsubstituted heterocy tuted aryl ( e . g . phenyl ) , or Rlii - substituted or unsubstituted cloalkyl ( e . g . 3 to 6 membered heterocycloalkyl) , Ridi. heteroaryl ( e . g . 5 or 6 membered heteroaryl) . 20 substituted or unsubstituted aryl ( e . g . phenyl ) , or R14i Rli is independently hydrogen , halogen , — N3, CF3, substituted or unsubstituted heteroaryl ( e . g . 5 or 6 membered CCl4 , CBr , CII , CN , ?CHO , JOH , NH , heteroaryl ). - COOH , CONH2, — NO , , SH , SO2, S02C1 , Ridi is independently hydrogen , halogen , N3, CF3, -SOH , SOH, SO, NH , _ NHNH , JONH , CCl4 , CBry , CI , CN , CHO, OH, NHA, - NHC ( O )NHNH2 , unsubstituted alkyl ( e . g . C , to Cg alkyl) , 25 COOH , CONH2, — NO2, SH , SO2, SO , C1, unsubstituted heteroalkyl ( e . g . 2 to 8 membered het SO3H , SO4H , SO2NH2, — NHNH2, CONH2, eroalkyl) , unsubstituted cycloalkyl ( e . g . Cz- Cg cycloalkyl) , — NHC ( O )NHNH2 , RlAii- substituted or unsubstituted alkyl unsubstituted heterocycloalkyl ( e .g . 3 to 6 membered het (e .g . C , to Cg alkyl) , RlAii- substituted or unsubstituted het erocycloalkyl) , unsubstituted aryl ( e . g . phenyl) , or unsub - eroalkyl ( e . g . 2 to 8 membered heteroalkyl) , RlAii -substi stituted heteroaryl ( e . g . 5 or 6 membered heteroaryl) . 30 tuted or unsubstituted cycloalkyl ( e . g . Cz- C , cycloalkyl) , R ? may be substituted or unsubstituted C , -C20 alkyl. R RlAii- substituted or unsubstituted heterocycloalkyl ( e. g . 3 to may be unsubstituted C - C20 alkyl. R ' may be substituted 6 membered heterocycloalkyl) , R1Aii -substituted or unsub CZ -C20 alkyl. R ? may be substituted or unsubstituted 2 to 20 stituted aryl ( e .g . phenyl) , or RlAii - substituted or unsubsti membered heteroalkyl . Rl may be unsubstituted 2 to 20 membered heteroalkyl . Rl may be substituted 2 to 20 mem - 35 Ridii is independently hydrogen , halogen , N3, CF3, bered heteroalkyl. R ? may be substituted or unsubstituted CCl , CBry, CIA , CN , CHO, OH, NHA, C -Cg alkyl. R ' may be unsubstituted C . - C alkyl. R 'may be COOH , CONH2, — NO ,, SH , SO2, SO , C1, substituted C , - C , alkyl. R may be substituted or unsubsti SO3H , SOUH , SO NH2, — NHNH2, ONH2, tuted 2 to 8 membered heteroalkyl. R1 may be unsubstituted NHC ( O ) NHNH , , unsubstituted alkyl ( e . g . C , to C , alkyl) , 2 to 8 membered heteroalkyl. Rl may be substituted 2 to 8 40 unsubstituted heteroalkyl ( e . g . 2 to 8 membered het membered heteroalkyl . R may be substituted or unsubsti - eroalkyl) , unsubstituted cycloalkyl ( e . g . Cz - C , cycloalkyl) , tuted CZ -C4 alkyl. R ? may be unsubstituted C -C4 alkyl. R1 unsubstituted heterocycloalkyl, unsubstituted aryl ( e . g . phe may be substituted C1 -C4 alkyl. R may be substituted or nyl) , or unsubstituted heteroaryl ( e . g . 5 or 6 membered unsubstituted 2 to 4 membered heteroalkyl. R may be heteroaryl) . unsubstituted 2 to 4 membered heteroalkyl . R ? may be 45 R1B may be hydrogen , substituted or unsubstituted alkyl , substituted 2 to 4 membered heteroalkyl. substituted or unsubstituted heteroalkyl, substituted or R ? may be substituted or unsubstituted 2 to 20 membered unsubstituted cycloalkyl, substituted or unsubstituted het cycloalkyl. R may be unsubstituted 2 to 20 membered erocycloalkyl, substituted or unsubstituted aryl, or substi cycloalkyl. R may be substituted 2 to 20 membered tuted or unsubstituted heteroaryl. cycloalkyl. R ? may be substituted or unsubstituted 2 to 20 50 RB may independently be hydrogen , halogen , N3, membered heterocycloalkyl. R ' may be unsubstituted 2 to CFz, — CC1z , — CBrz, — CI2 , — CN , — CHO , — OH , 20 membered heterocycloalkyl. R ? may be substituted 2 to — NH , COOH , CONH , — NO , SH , SO2, 20 membered heterocycloalkyl. R ? may be substituted or SO , Cl, SO2H , SO4H , SO NH , NHNH2, unsubstituted 2 to 8 membered cycloalkyl. RI may be ONH ,, — NHC ( O )NHNH ,, RIBI -substituted or unsubsti unsubstituted 2 to 8 membered cycloalkyl. RI may be 55 tuted alkyl ( e. g . C , to C alkyl) , RIBI- substituted or unsub substituted 2 to 8 membered cycloalkyl. R ? may be substi stituted heteroalkyl ( e . g . 2 to 8 membered heteroalkyl) , tuted or unsubstituted 2 to 8 membered heterocycloalkyl. R1 RIBI - substituted or unsubstituted cycloalkyl ( e . g . Cz - C may be unsubstituted 2 to 8 membered heterocycloalkyl. R cycloalkyl) , RIBI - substituted or unsubstituted heterocy may be substituted 2 to 8 membered heterocycloalkyl. cloalkyl ( e . g . 3 to 6 membered heterocycloalkyl) , RlBi Rl may be substituted or unsubstituted 5 to 20 membered 60 substituted or unsubstituted aryl (e . g . phenyl) , or RlBi aryl. R ? may be unsubstituted 5 to 20 membered aryl. R substituted or unsubstituted heteroaryl ( e .g . 5 or 6 membered may be substituted 5 to 20 membered aryl. R ? may be heteroaryl ) . substituted or unsubstituted 5 to 20 membered heteroarylR . R IBI is independently hydrogen , halogen , — Nz, — CF3 , may be unsubstituted 5 to 20 membered heteroaryl . R may CC13 , CBrz , C1z , CN , CHO , OH , - NH2, be substituted 5 to 20 membered heteroaryl. R ! may be 65 COOH , CONH2, - NO2, SH , SO2, SO , C1, substituted or unsubstituted 5 to 8 membered aryl . R may be SO3H , SO4H , SO2NH2, — NHNH2, CONH2, unsubstituted 5 to 8 membered aryl. Rl may be substituted — NHC (O )NHNH2 , R1 Bii- substituted or unsubstituted alkyl US 9 ,862 , 693 B2 29 30 (e .g . C , to C , alkyl ), RIBil -substituted or unsubstituted het unsubstituted tetrahydrofuranyl, substituted or unsubstituted eroalkyl ( e. g. 2 to 8 membered heteroalkyl) , RIBil - substi tetrahydrothiophenyl, or substituted or unsubstituted tetra tuted or unsubstituted cycloalkyl ( e . g . Cz -Cg cycloalkyl) , hydropyranyl. R1Bii -substituted or unsubstituted heterocycloalkyl (e .g . 3 to RBmay be substituted or unsubstituted cycloalkyl. RIB 6 membered heterocycloalkyl) , R1 Bii - substituted or unsub - 5 may be substituted or unsubstituted 3 to 8 membered stituted aryl ( e . g . phenyl) , or RlBii -substituted or unsubsti - cycloalkyl . R " may be substituted 3 to 8 membered cycloalkyl. RIB may be substituted 5 or 6 membered tuted heteroaryl ( e . g . 5 or 6 membered heteroarylY ?) ) . cycloalkyl. RIB may be unsubstituted 3 to 8 membered RlBii is independently hydrogen , halogen , N3, CF3 , cycloalkyl. R1B may be unsubstituted 5 or 6 membered _ COOHCCl4 , CBryCONH , LCI . ,_ _ NOCN . , _ SHCHO _, SO OH , _ SociNH , 10 cycloalkyl. R " may be substituted or unsubstituted hetero cycloalkyl. RIB may be substituted or unsubstituted 3 to 8 - SOZH , SO H , SO NH , NHNH , ONH2, membered heterocycloalkyl . RIB may be substituted or - NHC( O )NHNH2 , unsubstituted alkyl (e .g . C , to Cg alkyl) , unsubstituted 3 , 5 , or 6 membered heterocycloalkyl. RIB unsubstituted heteroalkyl ( e . g . 2 to 8 membered het may be, for example , substituted or unsubstituted pyrrolidi eroalkyl) , unsubstituted cycloalkyl ( e . g . C3 - Cg cycloalkyl) , 15 nvl. substituted or unsubstituted imidazolidinyl, substituted unsubstituted heterocycloalkyl ( e . g . 3 to 6 membered het or unsubstituted oxazolidinyl, substituted or unsubstituted erocycloalkyl ) , unsubstituted aryl ( e . g . phenyl) , or unsub - thiazolidinyl, substituted or unsubstituted dioxolanyl, sub stituted heteroaryl ( e . g . 5 or 6 membered heteroaryl) . stituted or unsubstituted dithiolanyl , substituted or unsub In embodiments , R14 may be substituted or unsubstituted stituted piperidinyl, substituted or unsubstituted morpholi heteroalkyl or substituted or unsubstituted alkyl. R ' A may be 20 nyl, substituted or unsubstituted dioxanyl, or substituted or substituted or unsubstituted 2 to 6 membered heteroalkyl. unsubstituted dithianyl, substituted or unsubstituted aziridi R14 may be substituted 2 to 6 membered heteroalkyl. R14 nyl, substituted or unsubstituted azetidinyl, substituted or may be unsubstituted 2 to 6 membered heteroalkyl. R14 may unsubstituted azepinyl, substituted or unsubstituted oxira be O Me. RlA may be substituted or unsubstituted C -C10 nyl, substituted or unsubstituted oxetanyl, substituted or alkyl. RlA may be substituted or unsubstituted C . - C , alkyl. 25 unsubstituted tetrahydrofuranyl, substituted or unsubstituted R14 may be substituted or unsubstituted C , -Cz alkyl. R14 tetrahydrothiophenyl, or substituted or unsubstituted tetra maybe be substituted C - C5 alkyl. RIA may be unsubstituted hydropyranyl. C . - C , alkyl. R14 may be methyl, ethyl, or propyl. R14 may be substituted or unsubstituted aryl. R1A may be In embodiments , RIP may be substituted or unsubstituted substituted or unsubstituted 5 to 8 membered aryl . R1A may heteroalkyl or substituted or unsubstituted alkyl. RIB may be 30 be substituted 5 to 8 membered aryl. R14 may be substituted substituted or unsubstituted 2 to 6 membered heteroalkyl. 5 or 6 membered aryl. R14 may be unsubstituted 5 to 8 RB may be substituted 2 to 6 membered heteroalkyl. RB membered aryl. R ' A may be unsubstituted 5 or 6 membered may be unsubstituted 2 to 6 membered heteroalkyl . RIB may aryl. R14 may be substituted or unsubstituted heteroaryl. R14 be OMe. RIB may be substituted or unsubstituted C -C10 may be substituted or unsubstituted 5 to 8 membered het alkyl. R1B may be substituted or unsubstituted C . - C alkyl. 35 eroaryl. R14 may be substituted 5 to 8 membered heteroaryl. RIB may be substituted or unsubstituted C . - Cz alkyl. RIB R14 may be substituted 5 or 6 membered aryl. R14 may be maybe be substituted C . - C5 alkyl . R1B may be unsubstituted unsubstituted 5 to 8 membered heteroaryl. R14 may be C -C5 alkyl . R1B may be methyl , ethyl, or propyl. When R1B unsubstituted 5 or 6 membered heteroaryl. is unsubstituted C . - C alkyl, R14 may be substituted or RlB may be substituted or unsubstituted aryl. R1B may be unsubstituted heteroalkyl or substituted or unsubstituted 40 substituted or unsubstituted 5 to 8 membered aryl. R1B may alkyl. When RB is unsubstituted alkyl, R14 may be substi - be substituted 5 to 8 membered aryl . R1B may be substituted tuted or unsubstituted heteroalkyl. R14 may be substituted or 5 or 6 membered aryl. RIB may be unsubstituted 5 to 8 unsubstituted 3 to 6 membered heteroalkyl. R14 may be membered aryl. R1B may be unsubstituted 5 or 6 membered unsubstituted 3 to 6 membered heteroalkyl. When RB is aryl. RIP may be substituted or unsubstituted heteroaryl. R1B unsubstituted alkyl , RlA may be substituted or unsubstituted 45 may be substituted or unsubstituted 5 to 8 membered het alkyl. R14 may be unsubstituted C1- C5 alkyl. eroaryl. RB may be substituted 5 to 8 membered heteroaryl. R14 may be substituted or unsubstituted cycloalkyl. R14 R1B may be substituted 5 or 6 membered aryl. R1B may be may be substituted or unsubstituted 3 to 8 membered unsubstituted 5 to 8 membered heteroaryl. R1B may be cycloalkyl. R14 may be substituted 3 to 8 membered unsubstituted 5 or 6 membered heteroaryl. cycloalkyl. R14 may be substituted 5 or 6 membered 50 R14 and RB may optionally be joined to form substituted cycloalkyl. R1A may be unsubstituted 3 to 8 membered or unsubstituted 3 to 8 membered heterocycloalkyl. R14 and cycloalkyl. R1A may be unsubstituted 5 or 6 membered RIB may optionally be joined to form substituted or unsub cycloalkyl. R14 may be substituted or unsubstituted hetero - stituted 5 or 6 membered heterocycloalkyl. cycloalkyl. R14 may be substituted or unsubstituted 3 to 8 The ring formed by joining R14 and RB may be R - sub membered heterocycloalkyl. RlA may be substituted or 55 stituted or unsubstituted heterocycloalkyl. Rºmay indepen unsubstituted 3 , 5 , or 6 membered heterocycloalkyl. R14 dently be hydrogen , halogen , N3, CF3, CC13 , may be, for example , substituted or unsubstituted pyrrolidi- CBrz , — C13, CN , CHO , OH , - NH2, COOH , nyl, substituted or unsubstituted imidazolidinyl, substituted CONH2, — NO2, SH , SO2, S02C1, SO2H , or unsubstituted oxazolidinyl, substituted or unsubstituted SO _ H , SO NH , NHNH ,, ONH2, — NHC ( O ) thiazolidinyl , substituted or unsubstituted dioxolanyl, sub - 60 NHNH , , R3a -substituted or unsubstituted alkyl (e . g . C , to stituted or unsubstituted dithiolanyl, substituted or unsub - Cg alkyl) , R $ a - substituted or unsubstituted heteroalkyl (e . g . stituted piperidinyl, substituted or unsubstituted morpholi - 2 to 8 membered heteroalkyl) , R3a - substituted or unsubsti nyl, substituted or unsubstituted dioxanyl, or substituted or tuted cycloalkyl ( e . g . C3- C , cycloalkyl) , R $ a - substituted or unsubstituted dithianyl, substituted or unsubstituted aziridi- unsubstituted heterocycloalkyl ( e . g . 3 to 6 membered het nyl, substituted or unsubstituted azetidinyl, substituted or 65 erocycloalkyl) , R $ a - substituted or unsubstituted aryl ( e . g . unsubstituted azepinyl, substituted or unsubstituted oxira - phenyl) , or R $ a -substituted or unsubstituted heteroaryl ( e . g . nyl, substituted or unsubstituted oxetanyl, substituted or 5 or 6 membered heteroaryl) . US 9 , 862 ,693 B2 31 32 RSa is independently hydrogen , halogen , N3, CF3, substituted or unsubstituted aryl ( e . g . phenyl) , or R2i- sub - CC13 , CBrz , - C1z , CN , CHO , OH , - NH2, stituted or unsubstituted heteroaryl ( e . g . 5 or 6 membered - COOH , CONH2, - NO2, SH , SO2, S02C1, heteroaryl) . - SO2H , SO _ H , SO2NH2, NHNH2, ONH2, R2i is independently hydrogen , halogen , N3, CF3 , - NHC ( O )NHNH2 , R5b - substituted or unsubstituted alkyl 5 CC1z , CBrz , C13 , CN , CHO , OH , - NH2, ( e . g . C , to C , alkyl ), R5b -substituted or unsubstituted het COOH , CONH2, — NO2, SH , SO2, SO C1, eroalkyl ( e . g . 2 to 8 membered heteroalkyl) , R56 - substituted SOzH , SO4H , SO2NH2, — NHNH2, ONH2, or unsubstituted cycloalkyl ( e . g . Cz- Cg cycloalkyl) , R56 NHC (O )NHNH ,, R2i -substituted or unsubstituted alkyl substituted or unsubstituted heterocycloalkyl (e . g . 3 to 6 (e . g . C , to C , alkyl) , R211 - substituted or unsubstituted het membered heterocycloalkyl) , R5b - substituted or unsubsti - 10 eroalkyl ( e . g . 2 to 8 membered heteroalkyl ), R2ii - substituted tuted aryl ( e . g . phenyl) , or R5b- substituted or unsubstituted or unsubstituted cycloalkyl ( e . g . Cz -Cg cycloalkyl) , R2ii heteroaryl (e . g. 5 or 6 membered heteroaryl) . substituted or unsubstituted heterocycloalkyl ( e . g . 3 to 6 RB is independently hydrogen , halogen , — N3, CF3, membered heterocycloalkyl) , R2ii- substituted or unsubsti - CC13 , CBrz , - C1z , CN , CHO , OH , - NH2, 15 tuted aryl ( e . g . phenyl ) , or R2ii- substituted or unsubstituted - COOH , CONH2, — NO2, SH , SO2, S02C1, heteroaryl ( e. g . 5 or 6 membered heteroaryl) . - SO3H , SO4H , SO NH , NHNH2, CONH2, Rail is independently hydrogen , halogen , N3 , CF3, - NHC ( O )NHNH , , unsubstituted alkyl, unsubstituted het CCl4 , CB , CI , CN , CHO, OH, NHA, eroalkyl, unsubstituted cycloalkyl, unsubstituted heterocy - COOH , CONH2, — NO2, SH , SO2, S02C1, cloalkyl, unsubstituted aryl, or unsubstituted heteroaryl . 20 SO2H , SO _ H , SO NH , NHNH2, ONH2, R14 and RB may optionally be joined to form , for — NHC ( O )NHNH2 , unsubstituted alkyl ( e . g . C , to Cg alkyl) , example , substituted or unsubstituted pyrrolidinyl, substi - unsubstituted heteroalkyl ( e . g . 2 to 8 membered het tuted or unsubstituted imidazolidinyl , substituted or unsub eroalkyl) , unsubstituted cycloalkyl (e . g. C3 -C , cycloalkyl) , stituted oxazolidinyl, substituted or unsubstituted thiazolidi- unsubstituted heterocycloalkyl ( e . g . 3 to 6 membered het nyl, substituted or unsubstituted dioxolanyl, substituted or 25 erocycloalkyl) , unsubstituted ar aryl (e . g. phenyl) yl , or unsubstituted dithiolanyl, substituted or unsubstituted pip - unsubstituted heteroaryl ( e . g . 5 or 6 membered heteroaryl) . eridinyl, substituted or unsubstituted morpholinyl, substi - R ? may be substituted or unsubstituted C , -C20 alkyl. R ? tuted or unsubstituted dioxanyl, or substituted or unsubsti may be unsubstituted C , -C20 alkyl . R ? may be substituted tuted dithianyl, substituted or unsubstituted aziridinyl, C . -C2 alkyl. R ? may be substituted or unsubstituted 2 to 20 substituted or unsubstituted azetidinyl, substituted or unsub - 30 membered heteroalkyl. R may be unsubstituted 2 to 20 stituted azepinyl, substituted or unsubstituted oxiranyl, sub membered heteroalkyl. R ? may be substituted 2 to 20 mem stituted or unsubstituted oxetanyl, substituted or unsubsti - bered heteroalkyl. R ? may be substituted or unsubstituted tuted tetrahydrofuranyl, substituted or unsubstituted C . - C alkyl . R ? may be unsubstituted C , - C , alkyl. R ? may be tetrahydrothiophenyl, or substituted or unsubstituted tetra substituted C - C , alkyl. R ? may be substituted or unsubsti hydropyranyl. 35 tuted 2 to 8 membered heteroalkyl. R2 may be unsubstituted R14 and RIB may optionally be joined to form , R -sub - 2 to 8 membered heteroalkyl. R2 may be substituted 2 to 8 stituted or unsubstituted pyrrolidinyl, R - substituted or membered heteroalkyl. R2 may be substituted or unsubsti unsubstituted imidazolidinyl, Rº- substituted or unsubsti tuted C , -C4 alkyl. R ? may be unsubstituted C . - C4 alkyl. R ? tuted oxazolidinyl, Rº - substituted or unsubstituted thiazo may be substituted C . - C4 alkyl. R ? may be substituted or lidinyl, R - substituted or unsubstituted dioxolanyl, R - sub - 40 unsubstituted 2 to 4 membered heteroalkyl. R2 may be stituted or unsubstituted dithiolanyl, Rº - substituted or unsubstituted 2 to 4 membered heteroalkyl. R2 may be unsubstituted piperidinyl, RS -substituted or unsubstituted substituted 2 to 4 membered heteroalkyl. morpholinyl, R » - substituted or unsubstituted dioxanyl, R ? may be substituted or unsubstituted 2 to 20 membered Rº- substituted or unsubstituted dithianyl, R ' - substituted or cycloalkyl . R ? may be unsubstituted 2 to 20 membered unsubstituted aziridinyl, R - substituted or unsubstituted aze - 45 cycloalkyl. R2 may be substituted 2 to 20 membered tidinyl , RP- substituted or unsubstituted azepinyl, Rº - substi - cycloalkyl. R ? may be substituted or unsubstituted 2 to 20 tuted or unsubstituted oxiranyl, R -substituted or unsubsti - membered heterocycloalkyl . R may be unsubstituted 2 to tuted oxetanyl , R -substituted or unsubstituted 20 membered heterocycloalkyl. R ? may be substituted 2 to tetrahydrofuranyl , R - substituted or unsubstituted tetrahy 20 membered heterocycloalkyl. R ? may be substituted or dropyranyl, or RS - substituted or unsubstituted tetrahydroth - 50 unsubstituted 2 to 8 membered cycloalkyl . R ? may be iophenyl. R is as described herein , including embodiments unsubstituted 2 to 8 membered cycloalkyl. R ? may be thereof. substituted 2 to 8 membered cycloalkyl. R2 may be substi R ? may be hydrogen , substituted or unsubstituted alkyl, tuted or unsubstituted 2 to 8 membered heterocycloalkyl. R2 substituted or unsubstituted heteroalkyl, substituted or may be unsubstituted 2 to 8 membered heterocycloalkyl. R2 unsubstituted cycloalkyl, substituted or unsubstituted het- 55 may be substituted 2 to 8 membered heterocycloalkyl. erocycloalkyl, substituted or unsubstituted aryl , or substi R ? may be substituted or unsubstituted 5 to 20 membered tuted or unsubstituted heteroaryl . aryl. R2 may be unsubstituted 5 to 20 membered aryl. R2 R ? may independently be hydrogen , halogen , N3, may be substituted 5 to 20 membered aryl. R may be - CF , - CC1z , - CBrz , - CI, , - CN , — CHO , OH , substituted or unsubstituted 5 to 20 membered heteroaryl. R2 - NH , – COOH , CONH , — NO , , SH , SO , , 60 may be unsubstituted 5 to 20 membered heteroaryl. R² may - SO , C1, SO2H , SO H , SO NH , NHNH , , be substituted 5 to 20 membered heteroaryl. R ? may be - ONH2, - NHC (O )NHNH2 , R2i- substituted or unsubsti - substituted or unsubstituted 5 to 8 membered aryl. R ? may be tuted alkyl ( e. g . C , to C , alkyl) , R2i - substituted or unsub - unsubstituted 5 to 8 membered aryl. R ? may be substituted stituted heteroalkyl ( e . g . 2 to 8 membered heteroalkyl) , 5 to 8 membered aryl. R ? may be substituted or unsubstituted R2 -substituted or unsubstituted cycloalkyl (e . g. Cz- C , 65 5 to 8 membered heteroaryl. R ? may be unsubstituted 5 to 8 cycloalkyl) , R2i- substituted or unsubstituted heterocy - membered heteroaryl. R ? may be substituted 5 to 8 mem cloalkyl ( e . g . 3 to 6 membered heterocycloalkyl) , R21 bered heteroaryl. US 9 ,862 , 693 B2 33 34 R ? may be — NR24R2B . R24 may be hydrogen , substituted 6 membered heterocycloalkyl) , R2Bii - substituted or unsub or unsubstituted alkyl, substituted or unsubstituted het stituted aryl ( e . g . phenyl ) , or R2Bii -substituted or unsubsti eroalkyl, substituted or unsubstituted cycloalkyl, substituted tuted heteroaryl ( e .g . 5 or 6 membered heteroaryl) . or unsubstituted heterocycloalkyl, substituted or unsubsti - R2Bil is independently hydrogen , halogen , — N3, CF3, tuted aryl, or substituted or unsubstituted heteroaryl. 5 - CCI. . _ - CBr. . CI . . CN . _ CHO . OH . — NH . . R24 may independently be hydrogen , halogen , N3 , COOH , CONH2, - NO2, SH , SO2, SO , C1, CF , CC1 , CBr , CIF , CN , CHO, JOH, SOH, JSOH, JSO, NH – NHNH , LONH , - NH2, COOH , CONH2, NO2, SH , SO2, NHC ( O )NHNH ,, unsubstituted alkyl ( e . g . C , to Cg alkyl) , - SOCI, SO, H , SOH, JSO, NH , NHNHA- 2 , - ONH , NHC (O )NHNH2 , R24i- substituted or unsubsti - 10 unsubstituted heteroalkyl ( e . g . 2 to 8 membered het tuted alkyl ( e . g . C , to Cg alkyl) , R241 - substituted or unsub eroalkyl) , unsubstituted cycloalkyl ( e . g . C3 - C , cycloalkyl ) , stituted heteroalkyl (e . g. 2 to 8 membered heteroalkyl) , unsubstituted heterocycloalkyl ( e . g . 3 to 6 membered het R241 -substituted or unsubstituted cycloalkyl (e .g . Cz- Cg erocycloalkyl) , unsubstituted aryl ( e . g . phenyl) , or unsub cycloalkyl) , R24i- substituted or unsubstituted heterocy stituted heteroaryl ( e . g . 5 or 6 membered heteroaryl) . cloalkyl ( e . g . 3 to 6 membered heterocycloalkyl) . R2Ai _ 15 In embodiments , R ^ may be substituted or unsubstituted substituted or unsubstituted aryl ( e . g . phenyl) , or R241 . substituted or unsubstituted heteroaryl ( e . g . 5 or 6 membered substituted or unsubstituted 2 to 6 membered heteroalkyl. heteroaryl) . R24 may be substituted 2 to 6 membered heteroalkyl. R24 R241 is independently hydrogen , halogen , N3, CF3, may be unsubstituted 2 to 6 membered heteroalkyl. R24 may - CC13 , CBrz, — C13 , CN , CHO , — OH , - NH2, 20 be - OCHZ . R24 may be substituted or unsubstituted C , -C10 - COOH , CONH2, - NO2, SH , SO2, SO , C1, alkyl. R24 may be substituted or unsubstituted C . - C , alkyl. - SO2H , SO _ H , SO2NH2, NHNH2, ONH2, R24 may be substituted or unsubstituted C . - Cz alkyl. R24 - NHC ( O )NHNH2 , R24ii- substituted or unsubstituted alkyl maybe be substituted C , - C alkyl. R24 may be unsubstituted ( e . g . C , to Cg alkyl) , R24ii- substituted or unsubstituted het - C -C5 alkyl . R24 may be methyl, ethyl, or propyl. eroalkyl ( e . g . 2 to 8 membered heteroalkyl) , R24ii- substi - 25 In embodiments , R2B may be substituted or unsubstituted tuted or unsubstituted cycloalkyl ( e . g . Cz- Cg cycloalkyl) , heteroalkyl or substituted or unsubstituted alkyl. R2B may be R24ii -substituted or unsubstituted heterocycloalkyl ( e . g . 3 to substituted or unsubstituted 2 to 6 membered heteroalkyl. 6 membered heterocycloalkyl) , R24ii -substituted or unsub R2B may be substituted 2 to 6 membered heteroalkyl. R2B stituted aryl ( e .g . phenyl) , or R2411 - substituted or unsubsti may be unsubstituted 2 to 6 membered heteroalkyl. R2B may tuted heteroaryl ( e . g . 5 or 6 membered heteroaryl ) . 30 be ?Me. R2B may be substituted or unsubstituted C -C10 R24il is independently hydrogen , halogen , — N3, CF3, alkyl. R2B may be substituted or unsubstituted C , -C5 alkyl. - CC13 , CBrz , — C1z , CN , CHO , — OH , — NH2, R2B may be substituted or unsubstituted C - Cz alkyl. R2B - COOH , CONH ,, - NO2, SH , SO2, SO ,C1 , maybe be substituted C , -Cz alkyl. R2B may be unsubstituted - SO3H , SO4H , SO NH , NHNH2, ONH2, C - C , alkyl. R2B may be methyl (also referred to herein as - NHC ( O )NHNH ,, unsubstituted alkyl ( e . g . C , to Cg alkyl) , 35 “ Me” ), ethyl, or propyl . When R2B is unsubstituted C , - C5 unsubstituted heteroalkyl ( e . g . 2 to 8 membered het alkyl, R24 may be substituted or unsubstituted heteroalkyl or eroalkyl) , unsubstituted cycloalkyl ( e. g . C3 - C , cycloalkyl) , substituted or unsubstituted alkyl. When R2B is unsubstituted unsubstituted heterocycloalkyl (e . g. 3 to 6 membered het - alkyl, R24 may be substituted or unsubstituted heteroalkyl. erocycloalkyl) , unsubstituted aryl ( e. g . phenyl) , or unsub R24 may be substituted or unsubstituted 3 to 6 membered stituted heteroaryl ( e . g . 5 or 6 membered heteroaryl ) . 40 heteroalkyl . R24 may be unsubstituted 3 to 6 membered R ? may be hydrogen , substituted or unsubstituted alkyl, heteroalkyl. When R2B is unsubstituted alkyl, R24 may be substituted or unsubstituted heteroalkyl, substituted or substituted or unsubstituted alkyl. R24 may be unsubstituted unsubstituted cycloalkyl, substituted or unsubstituted het- C2 -C alkyl. erocycloalkyl, substituted or unsubstituted aryl, or substi - R24 may be substituted or unsubstituted cycloalkyl . R24 tuted or unsubstituted heteroaryl. 45 may be substituted or unsubstituted 3 to 8 membered R2B may independently be hydrogen , halogen , N3 , cycloalkyl. R24 may be substituted 3 to 8 membered - CF , — CC1Z, — CBrz, — CI , — CN , — CHO , — OH , cycloalkyl . R24 may be substituted 5 or 6 membered - NH2, COOH , CONH2, NO2, SH , SO2, cycloalkyl. R24 may be unsubstituted 3 to 8 membered — SO , C1, SO , H , SOH , SO NH , NHNH , , cycloalkyl. R24 may be unsubstituted 5 or 6 membered - ONH2, - NHC (O )NHNH2 , R2BI- substituted or unsubsti - 50 cycloalkyl. R24 may be substituted or unsubstituted hetero tuted alkyl ( e . g . C , to Cg alkyl) , R2Bi - substituted or unsub cycloalkyl. R24 may be substituted or unsubstituted 3 to 8 stituted heteroalkyl ( e . g . 2 to 8 membered heteroalkyl ) , membered heterocycloalkyl. R24 may be, for example , sub R2Bi -substituted or unsubstituted cycloalkyl (e .g . Cz- Cg stituted or unsubstituted 3 , 5 , or 6 membered heterocy cycloalkyl) , R2BI -substituted or unsubstituted heterocy - cloalkyl. R24 may be substituted or unsubstituted pyrrolidi cloalkyl ( e . g . 3 to 6 membered heterocycloalkyl) , R2Bi- 55 nyl, substituted or unsubstituted imidazolidinyl, substituted substituted or unsubstituted aryl ( e . g . phenyl) , or R2Bi or unsubstituted oxazolidinyl, substituted or unsubstituted substituted or unsubstituted heteroaryl ( e . g . 5 or 6 membered thiazolidinyl, substituted or unsubstituted dioxolanyl, sub heteroaryl) . stituted or unsubstituted dithiolanyl, substituted or unsub R2Bi is independently hydrogen , halogen , N2, CF , stituted piperidinyl, substituted or unsubstituted morpholi - CC12 , CBrz , — C1z , CN , — CHO , — OH , — NH , , 60 nyl , substituted or unsubstituted dioxanyl, or substituted or - COOH , CONH2, — NO , , SH , SO2, SO ,C1 , unsubstituted dithianyl , substituted or unsubstituted aziridi - SO , H , SO H , SO NH , NHNH ,, ONH , nyl, substituted or unsubstituted azetidinyl, substituted or NHC ( O )NHNH2 , R2Bii- substituted or unsubstituted alkyl unsubstituted azepinyl, substituted or unsubstituted oxira ( e . g . C , to C , alkyl ), R2Bil -substituted or unsubstituted het nyl , substituted or unsubstituted oxetanyl, substituted or eroalkyl ( e . g . 2 to 8 membered heteroalkyl) , R2Bii- substi - 65 unsubstituted tetrahydrofuranyl, substituted or unsubstituted tuted or unsubstituted cycloalkyl ( e . g . C3 -Cg cycloalkyl) , tetrahydrothiophenyl, or substituted or unsubstituted tetra R2Bil - substituted or unsubstituted heterocycloalkyl ( e . g. 3 to hydropyranyl. US 9 , 862 ,693 B2 35 36 R2B may be substituted or unsubstituted cycloalkyl. R2B SO3H , SO4H , SO NH2, — NHNH2, ONH2, may be substituted or unsubstituted 3 to 8 membered - NHC ( O )NHNH ,, R6b -substituted or unsubstituted alkyl cycloalkyl. R2B may be substituted 3 to 8 membered ( e . g . C , to C , alkyl ) , Rob - substituted or unsubstituted het cycloalkyl. R2B may be substituted 5 or 6 membered eroalkyl ( e . g . 2 to 8 membered heteroalkyl) , Rb- substituted cycloalkyl. R2B may be unsubstituted 3 to 8 membered 5 or unsubstituted cycloalkyl ( e . g . C . - C . cycloalkyl ). R6b _ cycloalkyl. R2B may be unsubstituted 5 or 6 membered substituted or unsubstituted heterocycloalkyl ( e . g . 3 to 6 cycloalkyl. R + may be substituted or unsubstituted hetero - membered heterocycloalkyl) , R6b -substituted or unsubsti cycloalkyl . R “ may be substituted or unsubstituted 3 to 8 tuted aryl ( e . g . phenyl) , or R6b - substituted or unsubstituted membered heterocycloalkyl. R may be substituted or heteroaryl ( e . g . 5 or 6 membered heteroaryl) . unsubstituted 3 , 5 , or 6 membered heterocycloalkyl. RS 10 R6b is independently hydrogen , halogen , N ,, _ CF , may be , for example , substituted or unsubstituted pyrrolidi- CC1 , - CBr? , - CI, , - CN , CHO , OH , NH , , nyl, substituted or unsubstituted imidazolidinyl, substituted COOH , CONH2, — NO2, SH , SO2, S02C1, or unsubstituted oxazolidinyl, substituted or unsubstituted - SO . H . - SOH. - SO NH , , - NHNH . ONH . thiazolidinyl, substituted or unsubstituted dioxolanyl, sub - NHC (O )NHNH2 , unsubstituted alkyl ( e. g. C , to Cg alkyl) , stituted or unsubstituted dithiolanyl, substituted or unsub - 15 unsubstituted heteroalkyl ( e . g . 2 to 8 membered het stituted piperidinyl, substituted or unsubstituted morpholi - eroalkyl) , unsubstituted cycloalkyl ( e . g . C . - C . cycloalkyl) . nyl, substituted or unsubstituted dioxanyl, or substituted or unsubstituted heterocycloalkyl ( e . g . 3 to 6 membered het unsubstituted dithianyl, substituted or unsubstituted aziridi erocycloalkyl) , unsubstituted aryl (e . g. phenyl) , or unsub nyl, substituted or unsubstituted azetidinyl, substituted or stituted heteroaryl ( e . g . 5 or 6 membered heteroaryl) . unsubstituted azepinyl, substituted or unsubstituted oxira - 20 R24 and R2B may optionally be joined to form , for nyl, substituted or unsubstituted oxetanyl, substituted or example , substituted or unsubstituted pyrrolidinyl, substi unsubstituted tetrahydrofuranyl, substituted or unsubstituted tuted or unsubstituted imidazolidinyl, substituted or unsub tetrahydrothiophenyl, or substituted or unsubstituted tetra stituted oxazolidinyl, substituted or unsubstituted thiazolidi hydropyranyl. nyl , substituted or unsubstituted dioxolanyl, substituted or R24 may be substituted or unsubstituted aryl. R24 may be 25 unsubstituted dithiolanyl. substituted or unsubstituted pip substituted or unsubstituted 5 to 8 membered aryl . R ' A may e ridinyl, substituted or unsubstituted morpholinyl, substi be substituted 5 to 8 membered aryl. R * may be substituted tuted or unsubstituted dioxanyl, or substituted or unsubsti 5 or 6 membered aryl. R24 may be unsubstituted 5 to 8 tuted dithianyl, substituted or unsubstituted aziridinyl, membered aryl. R24 may be unsubstituted 5 or 6 membered substituted or unsubstituted azetidinyl, substituted or unsub aryl. R24 may be substituted or unsubstituted heteroaryl. R24 30 stituted azepinyl, substituted or unsubstituted oxiranyl, sub may be substituted or unsubstituted 5 to 8 membered het - stituted or unsubstituted oxetanyl, substituted or unsubsti eroaryl. R24 may be substituted 5 to 8 membered heteroaryl. tuted tetrahydrofuranyl, substituted or unsubstituted R ' A may be substituted 5 or 6 membered aryl. R + A may be tetrahydrothiophenyl, or substituted or unsubstituted tetra unsubstituted 5 to 8 membered heteroaryl. R44 may be hydropyranyl. unsubstituted 5 or 6 membered heteroaryl. 35 R24 and R2B may optionally be joined to form , Rº -sub RP may be substituted or unsubstituted aryl. R ' may be stituted or unsubstituted pyrrolidinyl, R6- substituted or substituted or unsubstituted 5 to 8 membered aryl. R may unsubstituted imidazolidinyl, Rº- substituted or unsubsti be substituted 5 to 8 membered aryl. R “ may be substituted tuted oxazolidinyl, RÓ - substituted or unsubstituted thiazo 5 or 6 membered aryl. R may be unsubstituted 5 to 8 lidinyl, Ro -substituted or unsubstituted dioxolanyl, Rº- sub membered aryl. R ? may be unsubstituted 5 or 6 membered 40 stituted or unsubstituted dithiolanyl. R6 - substituted or aryl. R2B may be substituted or unsubstituted heteroaryl. R2B unsubstituted piperidinyl, Rº- substituted or unsubstituted may be substituted or unsubstituted 5 to 8 membered het - morpholinyl, RÓ - substituted or unsubstituted dioxanyl . eroaryl . R2B may be substituted 5 to 8 membered heteroaryl. Ré- substituted or unsubstituted dithianyl, Ré- substituted or RPmay be substituted 5 or 6 membered aryl . R may be unsubstituted aziridinyl , RÓ - substituted or unsubstituted aze unsubstituted 5 to 8 membered heteroaryl. RB may be 45 tidinyl, R6- substituted or unsubstituted azepinyl, RO - substi ununsubstituted 5 or 6 membered heteroaryl. tuted or unsubstituted oxiranyl, Rº -substituted or unsubsti R24 and R2B may optionally be joined to form substituted tuted Oxetanyl , RÓ - substituted or unsubstituted or unsubstituted 3 to 8 membered heterocycloalkyl. R24 and tetrahydrofuranyl, or Rº - substituted or unsubstituted tetra R - P may optionally be joined to form substituted or unsub - hydropyranyl or R6- substituted or unsubstituted tetrahydro stituted 5 or 6 membered heterocycloalkyl. 50 thiophenyl . R is as described herein , including embodi The ring formed by joining R24 and R2 may be Rø- sub - ments thereof . stituted or unsubstituted cycloalkyl. Rº may independently In embodiments, R ' is NR14R1B and R2 is - NR24R2B . be hydrogen , halogen , N3, CF3, — CC3, CBrz, R14 may be substituted or unsubstituted heteroalkyl or CI, CN , CHO, OH, – NH2, COOH, substituted or unsubstituted alkyl and RB may be substi - CONH2, — NO2, — SH , SO2, S02C1, SO3H , 55 tuted or unsubstituted alkyl. R24 and R2B may be hydrogen SOH, JSO , NH , NHNH , JONH , NHC( O ) or substituted or unsubstituted alkyl. R24 and R2B may be NHNH2, R6a -substituted or unsubstituted alkyl ( e .g . C , to hydrogen . In embodiments , the compound of formula ( I) has Cg alkyl ) , Røa - substituted or unsubstituted heteroalkyl (e . g . formula : 2 to 8 membered heteroalkyl) , Røa - substituted or unsubsti tuted cycloalkyl (e . g. C3 -Cg cycloalkyl) , Røa -substituted or 60 unsubstituted heterocycloalkyl ( e . g . 3 to 6 membered het (001 ) erocycloalkyl) , Røa - substituted or unsubstituted aryl ( e . g . | NH NH phenyl) , or Róa -substituted or unsubstituted heteroaryl ( e. g . 5 or 6 membered heteroaryl) . Róa is independently hydrogen , halogen , — N3, CF3 , 65 N NH2 or CCl4 , CBry , JCI?, CN, CHO , OH, NHA, R3 - COOH , CONH2, NO2, SH , SO2, S02C1, US 9 , 862 ,693 B2 37 38 - continued The compound of formula ( II ) may have formula : (008 ) NH NH ( IIa ) N Z CNH , i NH NH Ra or CN CN CN R3 R56 10 (IIb ) and pharmaceutically acceptable salts thereof. NH NH When R ' is — NR14R1B , R ? may be substituted or unsub = stituted heteroalkyl. R ? may be substituted 5 to 8 membered heteroalkyl. R ? may be unsubstituted 5 to 8 membered VRS heteroalkyl. ( R ) R 50 In embodiments , R ' is - NR4R1B and R14 and R1B are wolle joined together to form a substituted or unsubstituted 3 to 8 membered heterocycloalkyl and R2 is - NR24R2B . R14 and and pharmaceutically acceptable salts thereof. RIB may be joined together to form a substituted or unsub - 20 The compound of formula ( Ila ) may have formula : stituted 5 or 6 membered heterocycloalkyl . R14 and RB may be joined to form , for example , a substituted or unsubstituted (015 ) pyrrolidinyl, substituted or unsubstituted imidazolidinyl, NH NH substituted or unsubstituted oxazolidinyl , substituted or 25 Or unsubstituted thiazolidinyl, substituted or unsubstituted Z 'N dioxolanyl, substituted or unsubstituted dithiolanyl, substi R3 tuted or unsubstituted tetrahydrofuranyl, or substituted or unsubstituted tetrahydrothiophenyl, substituted or unsubsti- 30 otherNH NH (018 ) tuted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted dioxanyl, substituted or unsub CN CNH , stituted tetrahydropyranyl, or substituted or unsubstituted dithianyl . R24 and R2B may be hydrogen or substituted or 35 R3 unsubstituted alkyl. R24 and R2B may be hydrogen or ter methyl. The compound of formula (1 ) may have formula : and pharmaceutically acceptable salts thereof. The compound of formula ( IIa ) may have formula : 40 NH NH (ID) (015a ) IL T NH NH (Rºzi R2 NRZQ or ??Z R25 45 N N and pharmaceutically acceptable salts thereof . (018 ) Ring A is substituted or unsubstituted 3 to 8 membered oblemNH NH heterocycloalkyl. The symbol zl is an integer from 2 to 7 . 50 A person having ordinary skill in the art will understand that the value of zl will depend upon the size of Ring A ( e . g . N NH2 where ring Ais a 5 membered heterocycloalkyl, zl will have a maximum value of 4 ). R? is hydrogen , halogen , N3, — NO , , — CF2, CC123 ,) — CBrz, - CI2 , CN , OH , bore - NH2, COOH , CONH ,, - NO2, SH , SO2Cl, and pharmaceutically acceptable salts thereof. - SO2H , SO H , SO2NH2, — NHNH2, CONH2, - NHC = ( O ) NHNH2; substituted or unsubstituted alkyl, The compound of formula (IIb ) may have formula: substituted or unsubstituted heteroalkyl , substituted or 60 unsubstituted cycloalkyl, substituted or unsubstituted het (019 ) erocycloalkyl, substituted or unsubstituted aryl , or substi NH NH tuted or unsubstituted heteroaryl, or are optionally bonded together to form a substituted or unsubstituted cycloalkyl, a N NH2 or substituted or unsubstituted heterocycloalkyl, a substituted 65 or unsubstituted aryl, or a substituted or unsubstituted het eroaryl. US 9 , 862 ,693 B2 39 40 -continued tuted or unsubstituted heteroaryl, or are optionally bonded (019a ) together to form a substituted or unsubstituted cycloalkyl, a NH NH substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted het CN CNH ). 5 eroaryl. Ring A and Ring B may be identical . Ring A may be different than Ring B . Ring A may be a 5 membered In embodiments, R ' is NR14R1B and R14 and RIB are heterocycloalkyl and ring B may be a 6 membered hetero joined together to form a substituted or unsubstituted 3 to 8 10 cycloalkyl. Ring A may , for example, substituted or unsub membered heterocycloalkyl and R2 is — NR24R2B and R24 and R2B are joined together to form a substituted or unsub stituted pyrrolidinyl , substituted or unsubstituted imidazo stituted 3 to 8 membered heterocycloalkyl. RA and RB may lidinyl, substituted or unsubstituted oxazolidinyl, substituted be joined together to form a substituted or unsubstituted 5 or or unsubstituted thiazolidinyl, substituted or unsubstituted 6 membered heterocycloalkyl. R44 and RP may be joined 15 dioxolanyl, substituted or unsubstituted dithiolanyl, substi together to form a substituted or unsubstituted 5 or 6 membered heterocycloalkyl. RIA and RB may be joined to tuted or unsubstituted tetrahydrofuranyl, or substituted or form , for example , a substituted or unsubstituted pyrrolidi- unsubstituted tetrahydrothiophenyl and ring B may be , for nyl, substituted or unsubstituted imidazolidinyl, substituted example , substituted or unsubstituted piperidinyl, substi or unsubstituted oxazolidinyl, substituted or unsubstituted 20 tuted or unsubstituted morpholinyl, substituted or unsubsti thiazolidinyl, substituted or unsubstituted dioxolanyl, sub stituted or unsubstituted dithiolanyl, substituted or unsub tuted dioxanyl, substituted or unsubstituted tetrahydropyra stituted tetrahydrofuranyl, or substituted or unsubstituted nyl, or substituted or unsubstituted dithianyl. Ring A may be tetrahydrothiophenyl , substituted or unsubstituted piperidi - a 6 membered heterocycloalkyl and ring B may be a 5 nyl, substituted or unsubstituted morpholinyl, substituted or 25 membered heterocycloalkyl. Ring A may be, for example , unsubstituted dioxanyl, substituted or unsubstituted tetrahy dropyranyl, or substituted or unsubstituted dithianyl. R24 substituted or unsubstituted piperidinyl, substituted or and R2B may be joined to form a joined to form a substituted unsubstituted morpholinyl, substituted or unsubstituted or unsubstituted pyrrolidinyl, substituted or unsubstituted dioxanyl, substituted or unsubstituted tetrahydropyranyl, or imidazolidinyl, substituted or unsubstituted oxazolidinyl, 30 substituted or unsubstituted dithianyl and Ring B may be , for substituted or unsubstituted thiazolidinyl, substituted or unsubstituted dioxolanyl, substituted or unsubstituted dithi - example , substituted or unsubstituted pyrrolidinyl , substi olanyl. substituted or unsubstituted tetrahydrofuranyl. or tuted or unsubstituted imidazolidinyl, substituted or unsub substituted or unsubstituted tetrahydrothiophenyl, substi stituted oxazolidinyl, substituted or unsubstituted thiazolidi tuted or unsubstituted piperidinyl, substituted or unsubsti - 35 nyl , substituted or unsubstituted dioxolanyl, substituted or tuted morpholinyl, substituted or unsubstituted dioxanyl, substituted or unsubstituted tetrahydropyranyl, or substi unsubstituted dithiolanyl, substituted or unsubstituted tetra tuted or unsubstituted dithianyl. The compound of formula hydrofuranyl, or substituted or unsubstituted tetrahydroth ( 1 ) may have formula : iophenyl. Ring A and Ring B may be substituted as 40 described herein , including embodiments thereof. The compound of formula (III ) may be have formula : NH NH (III ) ( IIIa ) ?? ?? ( R ) 2 , CN CN CN ( R5) , 45 A IlB Nya and pharmaceutically acceptable salts thereof. Ring A and Ring B are independently substituted or unsub - 50 (R3 ) 21 ( R ) 2, stituted 3 to 8 membered heterocycloalkyl. The symbolzl is an integer from 2 to 7 . The symbol z2 is an integer from 2 and pharmaceutically acceptable salts thereof. to 7 . A person having ordinary skill in the art will understand X is - CH2- , - 0 - , or — NH — . Y is CH - 0 — , or that the value of zl will depend upon the size of Ring A ( e . g . — NH — . The symbol nl is an integer from 1 to 4 . The where ring A is a 5 membered heterocycloalkyl, zl will have 55 symbol n2 is an integer from 1 to 4 . A person having a maximum value of 4 ) . Likewise , a person having ordinary ordinary skill in the art will immediately understand that Rº skill in the art will understand that the value of z2 will and Rº may be attached to X and Y ( e . g . wherein if X and depend upon the size of Ring B ( e . g . where ring B is a 5 Y are — NH — , or CH2 - , respectively, the hydrogen for membered heterocycloalkyl, z2 will have a maximum value — NH — may be replaced with R or Rº; or one or both of of 4 ). R and R? are independently hydrogen , halogen , N3, 60 the hydrogens in CH , — may be replaced with R or R ') . - NO2, CF3, CC1z , — CBrz, C1z , CN , OH , The symbols nl may be equal to n2 . The symbols nl and - NH2, COOH , CONH2, — NO2, SH , S02C1, n2 may be 1 . The symbols nl and n2 may be 2 . The symbols - SO2H , SO _ H , SO NH2, — NHNH2, ONH2, nl and n2 may be 3 . The symbols nl and n2 may be 4 . The — NHC = ( O )NHNHz ; substituted or unsubstituted alkyl, symbol n2 may not equal n2 . The symbol nl may be 1 and substituted or unsubstituted heteroalkyl, substituted or 65 n2 may be 2 . The symbols nlmay be 1 and n2 may be 3 . The unsubstituted cycloalkyl , substituted or unsubstituted het symbols nl may be 2 and n2 may be 1 . The symbols nl may erocycloalkyl, substituted or unsubstituted aryl, or substi - be 2 and n2 may be 3 . US 9 ,862 , 693 B2 The compound of formula ( IIIa ) may have formula : The compound of formula ( IIIc ) may have formula :

( IIId ) NH NH ( IIIb ) NH NH

- CN CN N N - ( R ”) = 1 ole 22 , 10 olla and pharmaceutically acceptable salts thereof. and pharmaceutically acceptable salts thereof. The compound of formula ( IIIb ) may have formula : The compound of formula (IIIc ) may have formula : 15

(006 ) ( 002 ) NH NH NH NH ' N N N 20 N R3 (003 ) og i ollaNH NH and pharmaceutically acceptable salts thereof. 25 N N The compound of formula (006 ) may have formula : -

(004 ) seNH NH mohla(006 ) 30 NH NH 23

- NH or 35 , or ( 006b ) (016 ) otty?? ?? cottaNH NH ZN N colo 740 otto and pharmaceutically acceptable salts thereof. and pharmaceutically acceptable salts thereof. The compound of formula ( IIIa ) may have formula : 45 The compound of formula ( IIIc ) may have formula :

(002a ) NH NH (IIIC ) NH NH (R )A (RRO ^) /22 2 , 50 N

(003a ) Bel 55 otro?? NH and pharmaceutically acceptable salts thereof. In certain embodiments X and Y are independently hydro NH gen , O - , - NH - , or - CH2- . In certain embodiments X and Y are both hydrogen , O - , - NH — , or - CH2 - . 60 (004a ) A person having ordinary skill in the art will immediately ?? ?? understand that Rs and R may be attached to X and Y , respectively , where X and Y are — NH — , or CH — , N NN respectively ( i. e . the hydrogen for — NH — may be replaced 65 with R $ or Rº; or one or both of the hydrogens in CH , — , or may be replaced with R or Rº) . Colla . US 9 , 862 ,693 B2 43 44 -continued The compound of formula (IV? ) may have formula : NH NH (016a ) (017 ) more phonecome NH NH r NCN CN o R3 and pharmaceutically acceptable salts thereof. 10 The compound of formula ( IIIc ) may have formula : and pharmaceutically acceptable salts thereof. The compound of formula (017 ) may have formula : NH NH (002b ) 15 (017a ) ?? ??

20 (003b ) N or OltaNH NH molty (017b ) NH ANH 25

(004b ) NH NHI

NNN 30 and pharmaceutically acceptable salts thereof. , or (016b ) The compound of formula (IVb ) may have formula : ohlaNH NH 35 NANON (005 ) NH NH

NANON 40 and pharmaceutically acceptable salts thereof. The compoundotto of formula ( IIIa ) may have formula : : oa 45 and pharmaceutically acceptable salts thereof . ( IVA ) The compound of formula (005 ) may have formula : NH NH ( 005 ) - N - CN ( R ^) NH NH NIR or 50 N Or NH NH ( VID ) (Rº ) p RZ22( 55 N (005b ) ???-z NH NH

' N and pharmaceutically acceptable salts thereof. A person 60 having ordinary skill in the art will immediately understand that Rs and R? may be attached to X and Y ( e . g wherein if X and Y are - NH — , or — CH , — , respectively , the hydro - and pharmaceuticallyolla acceptable salts thereof . gen for — NH — may be replaced with Rs or R " ; or one or 65 R may be substituted or unsubstituted aryl or substituted both of the hydrogens in - CH2 - may be replaced with RS or unsubstituted heteroaryl and R2 may be — NR24R2B . The or R ) . compound of formula (I ) may have : US 9 ,862 , 693 B2 45 46 45 -continued NH NH NH NH (022 ) ( R ) 1 12 N NR24N N NH2, or R2B (023a ) and pharmaceutically acceptable salts thereof. NH NH Ring C is substituted or unsubstituted 5 to 8 membered 10 aryl or substituted or unsubstituted 5 to 8 membered het N CNH , eroaryl. Z is 6 - - 0 , or - S — .R24 , R2B, R3, RS, and zl are as described herein , including embodiments thereof. oth R24 and R2B may independently be hydrogen , substituted or unsubstituted alkyl or substituted or unsubstituted alkyl, as described herein , including embodiments thereof. R24 and and pharmaceutically acceptable salts thereof. R2B may optionally be joined together to form a heterocy The compound of formula ( V ) may have formula : cloalkyl as described herein , including embodiments thereof. 20 The compound of formula ( V ) may have formula : NH NH ( 020b )

N CNH , (020 ) NH NH 25 (0216 ) N Z CNH , NH NH

- CN CNH , (021 ) 30 NH NH - RS121 (022b ) CN CNH , NH NH enher -35 N NH2, or NH NH (022 ) ( 023b ) Z NH2, or NH NH - 40 Che (R )zi ? CN CNH ) , NH NH (023 )

45 N Z CNH2 and pharmaceutically acceptable salts thereof. In embodiments , L ' of the compound of formula (I ) is a bond and L2 of the compound of formula ( I) is — NH?C 50 (NH ) — . L ' and L ? of the compound of formula (I ) may both and pharmaceutically acceptable salts thereof. be - NH - C (NH ) — . R ', R2, R14, R1B , R24 and R2B are as The compound of formula ( V ) may have formula : described herein , including embodiments thereof. When L is a bond and L2 is - NH - C (NH ) — , R and R2 may independently be substituted or unsubstituted aryl, substi NH NH (020a ) tuted or unsubstituted heteroaryl, or substituted or unsub stituted alkyl. When L is a bond and L2 is — NH?C (NH ) — , R and R may independently be substituted or NH2, unsubstituted aryl. R may be substituted or unsubstituted 5 NH to 8 membered aryl. R may be substituted 5 to 8 membered 60 aryl. R may be unsubstituted 5 to 8 membered aryl. R may (021a ) be substituted or unsubstituted phenyl. R ? may be substi NH NH tuted phenyl. R may be unsubstituted phenyl. R ? may be substituted or unsubstituted 5 to 8 membered aryl. R ? may be NH2, substituted 5 to 8 membered aryl. R ? may be unsubstituted 65 5 to 8 membered aryl. R ? may be substituted or unsubstituted phenyl. R ? may be substituted phenyl. R ? may be unsubsti dir tuted phenyl. US 9 , 862 ,693 B2 47 48 When L ’ is a bond and L ’ is - NH - C (NH ) — , R1 and R2 The compound of formula (VI ) may have formula : may independently be substituted or unsubstituted het eroaryl. R ! may be substituted or unsubstituted 5 to 8 membered heteroaryl. R ' may be substituted 5 to 8 mem (010 ) bered heteroaryl. R ' may be unsubstituted 5 to 8 membered 5 NH NH NH heteroaryl. R ' may be substituted or unsubstituted 4 , 5 , or 6 membered heteroaryl. R ' may be , for example , substituted IZ or unsubstituted pyridinyl, substituted or unsubstituted pyr rolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thiophenyl, substituted or unsubstituted imi- 10 dazlyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted thiaz and pharmaceutically acceptable salts thereof . olyl, substituted or unsubstituted pyranyl, substituted or The compound of formula (010 )may have formula : unsubstituted thiopyranyl, substituted or unsubstituted 1516 pyrazinyl, substituted or unsubstituted pyrimindyl, substi (010a ) tuted or unsubstituted pyridazinyl, substituted or unsubsti ?? ?? ?? tuted oxazinyl, substituted or unsubstituted thiazinyl, sub stituted or unsubstituteddoxinyl , substituted or or unsubstituted dithiinyl , substituted or unsubstituted azetyl, 20 NH substituted or unsubstituted oxetyl, substituted or unsubsti tuted thietyl, substituted or unsubstituted azirinyl, substi ( 010b ) tuted or unsubstituted oxirenyl or substituted or unsubsti ?? ?? ?? tuted thirenyl. R ? may be substituted or unsubstituted 5 to 8 membered - - IZ heteroaryl . R2 may be substituted 5 to 8 membered het eroaryl. R may be unsubstituted 5 to 8 membered het eroaryl. R ’ may be substituted or unsubstituted 4 , 5 , or 6 membered heteroaryl. R2 may be, for example , substituted 30 and pharmaceutically acceptable salts thereof. or unsubstituted pyridinyl, substituted or unsubstituted pyr When L ' is a bond and L ’ is - NH - C (NH ) — , R ' may be rolyl, substituted or unsubstituted furanyl, substituted or — NRAR " , substituted or unsubstituted alkyl or substituted unsubstituted thiophenyl. substituted or unsubstituted imi- or unsubstituted aryl or unsubstituted heteroaryl and R´may 35 be substituted or unsubstituted alkyl or - NR24R2B . R ' may dazlyl, substituted or unsubstituted pyrazolyl, substituted or be a substituted or unsubstituted aryl or substituted or unsubstituted oxazolyl, substituted or unsubstituted thiaz unsubstituted heteroaryl as described herein , including olyl , substituted or unsubstituted pyranyl, substituted or embodiments thereof. R2 may be substituted or unsubsti unsubstituted thiopyranyl, substituted or unsubstituted tuted C . - C , alkyl. R2 may be methyl , ethyl, or propyl . R2 pyrazinyl, substituted or unsubstituted pyrimindyl, substi - 40 may be methyl. When Rºis — NR 4R , R24 and RÞ may tuted or unsubstituted pyridazinyl, substituted or unsubsti be hydrogen . The compound of formula (1 ) may have tuted oxazinyl, substituted or unsubstituted thiazinyl , sub formula : stituted or unsubstituted doxinyl, substituted or unsubstituted dithiinyl , substituted or unsubstituted azetyl, NH NH NH ( VII) substituted or unsubstituted oxetyl , substituted or unsubsti Rz1 tuted thietyl, substituted or unsubstituted azirinyl, substi tuted or unsubstituted oxirenyl or substituted or unsubsti -Z EZ tuted thirenyl. 50 R3 The compound of formula ( 1) may have formula : and pharmaceutically acceptable salts thereof. Ring C , Z , zl, R ?, R }, and R are as described herein including embodi (VI ) 55 ments thereof. ?? ?? ?? The compound of formula (VII ) may have formula : R1( z Z (011 ) 60 NH NH NH (R )z1 and pharmaceutically acceptable salts thereof. 2 N Ring D is substituted or unsubstituted 5 to 8 membered aryl or substituted or unsubstituted 5 to 8 membered heteroaryl. 65 Za is — C — , - 0 — , or - S — . R , RS, R " , zl and z2 are as described herein , including embodiments thereof. and pharmaceutically acceptable salts thereof. US 9 , 862 ,693 B2 49 50 The compound of formula (011 ) may have formula : In embodiments , the compound of Formula ( I) is met formin . In embodiments , the compound of Formula (I ) is NH NH NH (011a ) CH? NH NH or NH2 10 À À (011b ) CH3 ?? ?? ?? In embodiments , the compound of Formula ( I) is 15 NH NH and pharmaceutically acceptable salts thereof. When L ' is a bond and L² is - NH - C (NH ) , R1 and R2 20 NH may independently be substituted or unsubstituted alkyl. R ! may be C7 -C10 substituted or unsubstituted alkyl. R ? may be substituted or unsubstituted C -C5 alkyl. R ' may be methyl. In embodiments, the compound of Formula ( 1) is R ! may be substituted or unsubstituted alkyl as described 25 herein , including embodiments thereof. R ? may be C1- C10 substituted or unsubstituted alkyl. R ? may be substituted or unsubstituted C - C5 alkyl. R ? may be methyl. R ? may be ?? ?? substituted or unsubstituted alkyl as described herein , 30 1 [ including embodiments thereof. R may be - NRAR B and R ? may be substituted or unsubstituted alkyl as described herein , including embodiments thereof. R may be - NR4R1B and R ? may be - NR24R2B. R14 ,R1B , R24 , and 35 R2B may be hydrogen . ad In embodiments , the compound of Formula ( I) is The compound of formula ( 1) may have formula :

40 ?? ?? (VIII ) NH NH NH NH R19 Z NH 45 ????In embodiments , the compound of Formula (I ) is and pharmaceutically acceptable salts thereof. R1, R², and R3 are as described herein , including embodiments thereof. 50 The compound of formula ( VIII ) may have formula : NH NH

?? ?? ?? (012a ) 55 In embodiments , the compound?? of Formula ( I ) is NH NH (012b ) 60 NH NINH NH NH NH NH Qui 65 ofly and pharmaceutically acceptable salts thereof. US 9 ,862 , 693 B2 51 52 In embodiments , the compound of Formula ( I ) is In embodiments , the compound of Formula (I ) is

NH NH NH NH N NH ..

1 ( In embodiments , the compound of Formula ( I ) is In embodiments , the compound of Formula ( I ) is ?

? NH NH NH NH NHNH2 . ?

????In embodiments , the compound of Formula ( I ) is In embodiments , the compound of Formula ( I ) is 25

NH NH

NH NH 3 )

NH .

?? .35 ??? In embodiments, the compound of Formula ( I) is In embodiments , the compound of Formula (I ) is ?

NHNH NH NH NH NH 4 { LZ

45 In embodiments????? , the compound of Formula (I ) is In embodiments , the compound of Formula ( I) is . In embodiments , the compound of Formula (I ) is

50) NH NH NH NH NH M

55 ??? In embodiments?? , the compound of Formula ( I ) is In embodiments, the compound of Formula ( I ) is NH NH NHNH NH NHNH CN CN CNH . ??IZ ?? US 9 ,862 ,693 B2 53 54 In embodiments, the compound of Formula ( I ) is In embodiments , the compound of Formula ( I) is not metformin . NH NH In embodiments , the compound of Formula (I ) is not CN CNH) . NH NH In embodiments , the compound of Formula (I ) is 10 NH ' N NH NH

Y N NH2NH . 15 In embodiments , the compound of Formula (I ) is not

In embodiments , the compound of Formula (I ) is NH NH 20 ?? ??

NH2. N 25 oll In embodiments the compound of Formula ( I ) is not

In embodiments , the compound of Formula ( I) is NH 30 NH condiments de compensaNH NH kansi on N m NH . N CNH . 35 In embodiments the compound of formula ( I ) is not

In embodiments , the compound of Formula ( I ) is ?? ?? case 40 NH NH NH2. - CNH ,. olla .45 Olle In embodiments the compound of formula (I ) is not In embodiments , the compound of Formula (I ) is 50 NH?? NH?? NH NH NH NH2 olla .55 Ole In embodiments the compound of formula (I ) is not In embodiments , the compound of Formula (I ) is ?? ?? NH NH NH2 elCNHNH , . . Die US 9 ,862 , 693 B2 55 56 In embodiments , the compound of Formula ( 1 ) , or a phar - continued maceutically acceptable salt thereof, is not a compound , or (001 ) a pharmaceutically acceptable salt thereof, described in NH NH James , J. W ., Baker, J. A ., and Wiggins L . F . The Synthesis of Some Heterocyclic Derivatives of Biguanide with Anti- 5 CN CNH , bacterial Activity . J . Med . Chem . 1968 September ; 11 ( 5 ) : - 942 - 5 . (002 ) NHNH NH III . Pharmaceutical Compositions 10 N N In another aspect , a pharmaceutical composition is pro vided . The composition includes a pharmaceutically accept able excipient and a compound having formula : (003 ) 15 NHNH NH ( 1 ) ?? ?? ez N L 20 (004 ) NHNH R3Rz NH L ' and L2 are independently a bond or - NH - C ( NH ) — . R 25 is — NRAR1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, ?? ?? (005 ) substituted or unsubstituted aryl, or substituted or unsubsti tuted heteroaryl, wherein R14 and RB are optionally joined 30 olla together to form a substituted or unsubstituted heterocy cloalkyl. R² is — NR24R2B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted het (006 ) erocycloalkyl, substituted or unsubstituted aryl, or substi - 35 obloNH NH tuted or unsubstituted heteroaryl , wherein R24 and R2B are optionally joined together to form a substituted or unsub N N stituted heterocycloalkyl. R14 , RIB , R24 , and R2B are inde pendently hydrogen , — OR , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or 40 (007 ) unsubstituted cycloalkyl, substituted or unsubstituted het ollesNH NH erocycloalkyl , substituted or unsubstituted aryl, or substi tuted or unsubstituted heteroaryl. R² is hydrogen or unsub stituted C , -C5 alkyl . R * is hydrogen , substituted or z unsubstituted alkyl, substituted or unsubstituted heteroalkyl, 45 substituted or unsubstituted cycloalkyl, substituted or unsub (008 ) stituted heterocycloalkyl, substituted or unsubstituted aryl, ?? ?? or substituted or unsubstituted heteroaryl. L ' , L2 , R ' , R², R14 , RIB , R24, R2B , and R3 are as CN CNH , described herein , including embodiments thereof. The phar - 50 NH2 maceutical composition may include a pharmaceutically R3 acceptable excipient and a compound of formula (I ) , ( II ) , ( III) , ( IV ) , ( V ) , (VI ) , (VII ) , or (VIII ) , including embodi ments thereof . The composition may include one or more of (009 ) the compounds described herein , including embodiments 55 NH NH thereof. The pharmaceutical composition may include a com CN CNHNH2 , pound having formula : 60 (010 ) (0000 ) NH NH NH NH NH ort N ANH , -Z IZ R3 US 9 , 862 ,693 B2 57 58 - continued -continued (011 ) (021 ) NH HN NH NH NH

i CN CNH , HN

(012 ) NH NH NH 10 (022 ) ?? ??

Z- CN CNH , (013 ) 15 R3 NH NH NH NH (023 ) Z NH2, N ANHNH2 ,, 20 NH NH (014 ) Helmond (024 ) NH NH N ANH , Z 25 R3 CN CNH , (015 ) NH NH (025 ) NH 30 HN - CN CN e2 CN CNH ,

NH NH (016 ) 35 wherein , R² is hydrogen or methyl. R3 may be hydrogen . R3 N may be methyl. N The pharmaceutical composition may include a com pound having formula : (017 ) NH NH ( 005a ) Otto Z ?? ?? N N 45

(018 ) NH =2NH (002a ) otta allaNH NH 50 CN CNHINH2.,

(019 ) 55 ) P600( oreNH NH OttoNH NH CN CNH , NH2, or

(020 ) 60 (011a ) NH NH ?? NH NH

CN CNHNH2 ,, OG IZ US 9 , 862 ,693 B2 59 60 The pharmaceutical composition may include a pharma - carbohydrates ; sugars including , but not limited to , lactose , ceutically acceptable salt of a compound , as described herein sucrose , mannitol, or sorbitol, starch from corn , wheat , rice , ( including embodiments ). The pharmaceutical composition potato , or other plants ; cellulose such as methyl cellulose , may include an anti - cancer agent. In embodiments , the hydroxypropylmethyl -cellulose , or sodium carboxymethyl pharmaceutical composition includes a compound as 5 cellulose ; and gums including arabic and tragacanth ; as well described herein and an anti - cancer agent. The pharmaceu as proteins including , but not limited to , gelatin and colla tical composition may be useful in the treatment of cancer gen . If desired , disintegrating or solubilizing agents may be ( e . g . colon cancer , colorectal cancer , ovarian cancer, prostate added , such as the cross - linked polyvinyl pyrrolidone , agar, cancer , lung cancer, breast cancer , pancreatic cancer , mela - alginic acid , or a salt thereof, such as sodium alginate . noma , triple negative breast cancer subtype , or non - small 10 Dragee cores are provided with suitable coatings such as cell lung cancer ). In embodiments, the anti -cancer agent is concentrated sugar solutions , which may also contain gum one that is approved (e .g . by a governmental regulatory arabic , talc , polyvinylpyrrolidone , carbopol gel , polyethyl agency such as the FDA ) for use in a treatment of the cancer ene glycol, and/ or titanium dioxide , lacquer solutions , and for which the pharmaceutical composition is useful. suitable organic solvents or solvent mixtures . Dyestuffs or The pharmaceutical compositions include optical iso - 15 pigments may be added to the tablets or dragee coatings for mers , diastereomers , or pharmaceutically acceptable salts of product identification or to characterize the quantity of the compounds described herein ( including embodiments ) active compound ( i. e ., dosage ) . Pharmaceutical preparations ( e . g . agents , modulators , inhibitors , antagonists ) . The com - of the invention can also be used orally using , for example , pound included in the pharmaceutical composition may be push - fit capsules made of gelatin , as well as soft, sealed covalently attached to a carrier moiety , as described above . 20 capsules made of gelatin and a coating such as glycerol or Alternatively , the compound included in the pharmaceutical sorbitol. composition is not covalently linked to a carrier moiety . For preparing suppositories, a low melting wax , such as a The compounds of the invention can be administered mixture of fatty acid glycerides or cocoa butter , is first alone or can be coadministered to the patient. Coadminis - melted and the active component is dispersed homoge tration is meant to include simultaneous or sequential 25 neously therein , as by stirring . The molten homogeneous administration of the compounds individually or in combi - mixture is then poured into convenient sized molds , allowed nation (more than one compound ) . Thus , the preparations to cool, and thereby to solidify . can also be combined , when desired , with other active Liquid form preparations include solutions, suspensions , substances ( e . g . to reduce metabolic degradation ). In and emulsions, for example , water or water /propylene glycol embodiments , the compounds may be coadministered with 30 solutions . For parenteral injection , liquid preparations can be an anti - cancer agent. formulated in solution in aqueous polyethylene glycol solu The compounds of the present invention can be prepared tion . and administered in a wide variety of oral, parenteral and When parenteral application is needed or desired , particu topical dosage forms. Oral preparations include tablets , pills , larly suitable admixtures for the compounds of the invention powder, dragees, capsules , liquids , lozenges, cachets, gels , 35 are injectable , sterile solutions , preferably oily or aqueous syrups, slurries , suspensions , etc . , suitable for ingestion by solutions, as well as suspensions , emulsions, or implants , the patient. The compounds of the present invention can also including suppositories . In particular, carriers for parenteral be administered by injection , that is , intravenously, intra - administration include aqueous solutions of dextrose , saline , muscularly, intracutaneously , subcutaneously , intraduode pure water, ethanol , glycerol, propylene glycol, peanut oil , nally , or intraperitoneally . Also , the compounds described 40 sesame oil , polyoxyethylene -block polymers , and the like . herein can be administered by inhalation , for example , Ampules are convenient unit dosages . The compounds of the intranasally . Additionally , the compounds of the present invention can also be incorporated into liposomes or admin invention can be administered transdermally. It is also istered via transdermal pumps or patches. Pharmaceutical envisioned thatmultiple routes of administration ( e . g ., intra admixtures suitable for use in the present invention are muscular, oral, transdermal) can be used to administer the 45 well -known to those of skill in the art and are described , for compounds of the invention . Accordingly , the present inven - example , in Pharmaceutical Sciences ( 17th Ed ., Mack Pub . tion also provides pharmaceutical compositions comprising Co ., Easton , Pa .) and WO 96 / 05309, the teachings of both of a pharmaceutically acceptable excipient and one or more which are hereby incorporated by reference . compounds of the invention . Aqueous solutions suitable for oral use can be prepared by For preparing pharmaceutical compositions from the 50 dissolving the active component in water and adding suit compounds of the present invention , pharmaceutically able colorants , flavors , stabilizers, and thickening agents as acceptable carriers can be either solid or liquid . Solid form desired . Aqueous suspensions suitable for oral use can be preparations include powders, tablets, pills , capsules, made by dispersing the finely divided active component in cachets , suppositories , and dispersible granules. A solid water with viscous material, such as natural or synthetic carrier can be one or more substance , that may also act as 55 gums, resins , methylcellulose , sodium carboxymethylcellu diluents , flavoring agents , binders , preservatives , tablet dis - lose , hydroxypropylmethylcellulose , sodium alginate , poly integrating agents , or an encapsulating material. vinylpyrrolidone, gum tragacanth and gum acacia , and dis In powders , the carrier is a finely divided solid in a persing or wetting agents such as a naturally occurring mixture with the finely divided active component (e .g . a phosphatide (e . g. , lecithin ), a condensation product of an compound provided herein . In tablets , the active component 60 alkylene oxide with a fatty acid ( e . g ., polyoxyethylene is mixed with the carrier having the necessary binding stearate ) , a condensation product of ethylene oxide with a properties in suitable proportions and compacted in the long chain aliphatic alcohol ( e . g ., heptadecaethylene oxyc shape and size desired . The powders and tablets preferably etanol) , a condensation product of ethylene oxide with a contain from 5 % to 70 % of the active compound . partial ester derived from a fatty acid and a hexitol ( e . g . , Suitable solid excipients include, but are not limited to , 65 polyoxyethylene sorbitol mono - oleate ) , or a condensation magnesium carbonate ; magnesium stearate ; talc ; pectin ; product of ethylene oxide with a partial ester derived from dextrin ; starch ; tragacanth ; a low melting wax ; cocoa butter; fatty acid and a hexitol anhydride ( e . g ., polyoxyethylene US 9 ,862 , 693 B2 61 62 sorbitan mono -oleate ). The aqueous suspension can also Such agents are typically employed at a level between about contain one or more preservatives such as ethyl or n - propyl 0 .01 % and about 2 % by weight. Determination of acceptable p -hydroxybenzoate , one or more coloring agents , one or amounts of any of the above adjuvants is readily ascertained more flavoring agents and one or more sweetening agents , such as sucrose , aspartame or saccharin . Formulations can 5 by Tone skilled in the art . be adjusted for osmolarity . an 5 The compositions of the present invention may addition Also included are solid form preparations that are ally include components to provide sustained release and /or intended to be converted , shortly before use , to liquid form comfort . Such components include high molecular weight, preparations for oral administration . Such liquid forms anionic mucomimetic polymers , gelling polysaccharides include solutions , suspensions, and emulsions. These prepa - , and finely - divided drug carrier substrates . These compo rations may contain , in addition to the active component, nents are discussed in greater detail in U . S . Pat . Nos. colorants, flavors, stabilizers , buffers , artificial and natural 4 , 911 , 920 ; 5 ,403 , 841 ; 5 ,212 , 162 ; and 4 , 861, 760 . The entire sweeteners , dispersants , thickeners , solubilizing agents , and contents of these patents are incorporated herein by refer the like . ence in their entirety for all purposes. Oil suspensions can contain a thickening agent, such as beeswax , hard paraffin or cetyl alcohol. Sweetening agents 15 Pharmaceutical compositions provided by the present can be added to provide a palatable oral preparation , such as invention include compositions wherein the active ingredi glycerol, sorbitol or sucrose. These formulations can be ent is contained in a therapeutically effective amount, i . e . , in preserved by the addition of an antioxidant such as ascorbic an amount effective to achieve its intended purpose. The acid . As an example of an injectable oil vehicle , see Minto , actual amount effective for a particular application will J . Pharmacol. Exp . Ther. 281: 93 -102 , 1997 . The pharma - 20 depend , inter alia , on the condition being treated . When ceutical formulations of the invention can also be in the form administered in methods to treat a disease , such composi of oil -in -water emulsions. The oily phase can be a vegetable tions will contain an amount of active ingredient effective to oil or a mineral oil , described above , or a mixture of these . achieve the desired result , e . g ., modulating the activity of a Suitable emulsifying agents include naturally occurring target molecule and / or reducing , eliminating , or slowing the gums, such as gum acacia and gum tragacanth , naturally 25 progression of disease symptoms ( e . g . growth , proliferation , occurring phosphatides , such as soybean lecithin , esters or or spread of cancer, breast cancer, triple negative breast partial esters derived from fatty acids and hexitol anhy - cancer subtype , lung cancer , non -small cell lung cancer, drides , such as sorbitan mono -oleate , and condensation pancreatic cancer ,melanoma , metastasis , colon cancer, pros products of these partial esters with ethylene oxide , such as tate cancer, or ovarian cancer ) . Determination of a thera polyoxyethylene sorbitan mono - oleate . The emulsion can 30 peutically effective amount of a compound of the invention also contain sweetening agents and flavoring agents , as in is well within the capabilities of those skilled in the art , the formulation of syrups and elixirs. Such formulations can especially in light of the detailed disclosure herein . also contain a demulcent, a preservative , or a coloring agent. The dosage and frequency (single or multiple doses ) The pharmaceutical preparation is preferably in unit dos - administered to a mammal can vary depending upon a age form . In such form the preparation is subdivided into 35 variety of factors , for example , whether themammal suffers unit doses containing appropriate quantities of the active from another disease , and its route of administration ; size , component. The unit dosage form can be a packaged prepa - age, sex , health , body weight, body mass index , and diet of ration , the package containing discrete quantities of prepa - the recipient; nature and extent of symptoms of the disease ration , such as packeted tablets , capsules, and powders in being treated ( e . g . cancer, metastatic cancer , breast cancer , vials or ampoules . Also , the unit dosage form can be a 40 triple negative breast cancer subtype, lung cancer , non - small capsule , tablet , cachet , or lozenge itself, or it can be the cell lung cancer , pancreatic cancer, melanoma , colon cancer, appropriate number of any of these in packaged form . prostate cancer, or ovarian cancer ) , kind of concurrent The quantity of active component in a unit dose prepa - treatment, complications from the disease being treated or ration may be varied or adjusted from 0 . 1 mg to 10000 mg, other health - related problems. Other therapeutic regimens or more typically 1 . 0 mg to 1000 mg, most typically 10 mg to 45 agents can be used in conjunction with the methods and 500 mg, according to the particular application and the compounds described herein ( including embodiments) . potency of the active component. The composition can , if Adjustment and manipulation of established dosages ( e . g ., desired , also contain other compatible therapeutic agents . frequency and duration ) are well within the ability of those Some compounds may have limited solubility in water skilled in the art. and therefore may require a surfactant or other appropriate 50 For any compound described herein , the therapeutically co - solvent in the composition . Such co - solvents include : effective amount can be initially determined from cell cul Polysorbate 20 , 60 and 80 ; Pluronic F -68 , F - 84 and P - 103 ; ture assays . Target concentrations will be those concentra cyclodextrin ; polyoxyl 35 castor oil , or other agents known tions of active compound ( s ) that are capable of achieving the to those skilled in the art . Such co - solvents are typically methods described herein , as measured using the methods employed at a level between about 0 .01 % and about 2 % by 55 described herein or known in the art . weight. As is well known in the art , therapeutically effective Viscosity greater than that of simple aqueous solutions amounts for use in humans can also be determined from may be desirable to decrease variability in dispensing the animal models . For example , a dose for humans can be formulations, to decrease physical separation of components formulated to achieve a concentration that has been found to of a suspension or emulsion of formulation and /or otherwise 60 be effective in animals . The dosage in humans can be to improve the formulation . Such viscosity building agents adjusted by monitoring compounds effectiveness and adjust include , for example , polyvinyl alcohol, polyvinyl pyrroli - ing the dosage upwards or downwards , as described above . done , methyl cellulose , hydroxy propyl methylcellulose , Adjusting the dose to achieve maximal efficacy in humans hydroxyethyl cellulose , carboxymethyl cellulose , hydroxy based on the methods described above and other methods is propyl cellulose, chondroitin sulfate and salts thereof, 65 well within the capabilities of the ordinarily skilled artisan . hyaluronic acid and salts thereof, combinations of the fore - Dosages may be varied depending upon the requirements going , and other agents known to those skilled in the art of the patient and the compound being employed . The dose US 9 , 862, 693 B2 64 administered to a patient, in the context of the present corresponding free base forms. In other cases, the prepara invention should be sufficient to effect a beneficial thera tion may be a lyophilized powder in 1 mM - 50 mM histidine , peutic response in the patient over time. The size of the dose 0 .1 % -2 % sucrose , 2 % -7 % mannitol at a pH range of 4 .5 to also will be determined by the existence, nature, and extent 5 . 5 , that is combined with buffer prior to use . of any adverse side - effects . Determination of the proper 5 In another embodiment, the compositions of the present dosage for a particular situation is within the skill of the invention are useful for parenteral administration , such as practitioner. Generally , treatment is initiated with smaller intravenous (IV ) administration or administration into a dosages which are less than the optimum dose of the body cavity or lumen of an organ . The formulations for compound . Thereafter, the dosage is increased by small administration will commonly comprise a solution of the increments until the optimum effect under circumstances is 10 compositions of the present invention dissolved in a phar reached . In one embodiment, the dosage range is 0 . 001 % to maceutically acceptable carrier. Among the acceptable 10 % w / v . In another embodiment, the dosage range is 0 . 1 % vehicles and solvents that can be employed are water and to 5 % w / v . Ringer 's solution , an isotonic sodium chloride . In addition , Dosage amounts and intervals can be adjusted individu - sterile fixed oils can conventionally be employed as a ally to provide levels of the administered compound effec - 15 solvent or suspending medium . For this purpose any bland tive for the particular clinical indication being treated . This fixed oil can be employed including synthetic mono - or will provide a therapeutic regimen that is commensurate diglycerides . In addition , fatty acids such as oleic acid can with the severity of the individual 's disease state . likewise be used in the preparation of injectables. These Utilizing the teachings provided herein , an effective pro - solutions are sterile and generally free of undesirable matter . phylactic or therapeutic treatment regimen can be planned 20 These formulations may be sterilized by conventional, well that does not cause substantial toxicity and yet is effective to known sterilization techniques . The formulations may con treat the clinical symptoms demonstrated by the particular tain pharmaceutically acceptable auxiliary substances as patient. This planning should involve the careful choice of required to approximate physiological conditions such as pH active compound by considering factors such as compound adjusting and buffering agents , toxicity adjusting agents , potency , relative bioavailability , patient body weight , pres - 25 e . g . , sodium acetate , sodium chloride , potassium chloride , ence and severity of adverse side effects , preferred mode of calcium chloride , sodium lactate and the like . The concen administration and the toxicity profile of the selected agent. tration of the compositions of the present invention in these The ratio between toxicity and therapeutic effect for a formulations can vary widely , and will be selected primarily particular compound is its therapeutic index and can be based on fluid volumes, viscosities, body weight, and the expressed as the ratio between LD50 (the amount of com - 30 like , in accordance with the particular mode of administra pound lethal in 50 % of the population ) and ED50 (the tion selected and the patient' s needs. For IV administration , amount of compound effective in 50 % of the population ) . the formulation can be a sterile injectable preparation , such Compounds that exhibit high therapeutic indices are pre - as a sterile injectable aqueous or oleaginous suspension . ferred . Therapeutic index data obtained from cell culture This suspension can be formulated according to the known assays and / or animal studies can be used in formulating a 35 art using those suitable dispersing or wetting agents and range of dosages for use in humans . The dosage of such suspending agents. The sterile injectable preparation can compounds preferably lies within a range of plasma con - also be a sterile injectable solution or suspension in a centrations that include the ED50 with little or no toxicity . nontoxic parenterally - acceptable diluent or solvent, such as The dosage may vary within this range depending upon the a solution of 1 , 3 - butanediol. dosage form employed and the route of administration 40 In another embodiment, the formulations of the compo utilized . See , e . g . Fingl et al . , In : THE PHARMACOLOGICAL Basis sitions of the present invention can be delivered by the use OF THERAPEUTICS , Ch . 1 , p . 1 , 1975 . The exact formulation , of liposomes which fuse with the cellular membrane or are route of administration and dosage can be chosen by the endocytosed , i . e . , by employing ligands attached to the individual physician in view of the patient' s condition and liposome, or attached directly to the oligonucleotide , that the particular method in which the compound is used . 45 bind to surface membrane protein receptors of the cell 1 . Administration resulting in endocytosis . By using liposomes , particularly The compositions described herein ( including embodi where the liposome surface carries ligands specific for target ments ) can be delivered transdermally , by a topical route, cells , or are otherwise preferentially directed to a specific formulated as applicator sticks , solutions , suspensions, organ , one can focus the delivery of the compositions of the emulsions, gels , creams, ointments , pastes, jellies, paints , 50 present invention into the target cells in vivo . (See , e . g . , powders , and aerosols . Al- Muhammed , J. Microencapsul. 13 : 293 -306 , 1996 ; The compositions of the present invention can also be Chonn , Curr. Opin . Biotechnol. 6 :698 - 708 , 1995 ; Ostro , Am . delivered as microspheres for slow release in the body . For J . Hosp . Pharm . 46 : 1576 - 1587 , 1989 ) . example , microspheres can be administered via intradermal The pharmaceutical preparation is preferably in unit dos injection of drug -containing microspheres, which slowly 55 age form . In such form the preparation is subdivided into release subcutaneously ( see Rao , J . Biomater Sci. Polym . unit doses containing appropriate quantities of the active Ed . 7 :623 -645 , 1995 ; as biodegradable and injectable gel component. The unit dosage form can be a packaged prepa formulations ( see , e . g . ,Gao Pharm . Res. 12 :857 - 863 , 1995 ) ; ration , the package containing discrete quantities of prepa or, as microspheres for oral administration (see , e . g ., Eyles , ration , such as packeted tablets , capsules , and powders in J . Pharm . Pharmacol . 49 :669 -674 , 1997 ) . Both transdermal 60 vials or ampoules . Also , the unit dosage form can be a and intradermal routes afford constant delivery for weeks or capsule , tablet, cachet , or lozenge itself , or it can be the months. appropriate number of any of these in packaged form . The pharmaceutical compositions of the present invention The compounds described herein can be used in combi can be provided as a salt and can be formed with many acids, nation with one another, with other active agents known to including but not limited to hydrochloric , sulfuric , acetic , 65 be useful in treating cancer ( e . g . breast cancer, triple nega lactic , tartaric , malic , succinic , etc . Salts tend to be more tive breast cancer subtype , lung cancer, non - small cell lung soluble in aqueous or other protonic solvents that are the cancer, pancreatic cancer, melanoma, metastatic cancer, US 9 , 862 ,693 B2 65 66 colon cancer , prostate cancer, or ovarian cancer ), or with ceutical compositions prepared according to the methods adjunctive agents that may not be effective alone , but may described herein , including embodiments thereof. contribute to the efficacy of the active agent. The method may include a compound having formula : In embodiments , co - administration includes administer ing one active agent within 0 . 5 , 1 , 2 , 4 , 6 , 8 , 10 , 12 , 16 , 20 , 5 or 24 hours of a second active agent. Co - administration ( 000b ) includes administering two active agents simultaneously , ?? ?? approximately simultaneously ( e . g ., within about 1 , 5 , 10 , 15 , 20 , or 30 minutes of each other ), or sequentially in any CN CNH , order. In embodiments , co - administration can be accom plished by co - formulation , i. e ., preparing a single pharma ceutical composition including both active agents. In other embodiments , the active agents can be formulated sepa rately . In another embodiment , the active and / or adjunctive 15 (001 ) agents may be linked or conjugated to one another. NH NH In embodiments , a pharmaceutical composition as CN CNH , described herein includes a compound selected from the - NH, compounds described in Table 1. | 20 (002 ) IV . Methods of Treating NH NH In another aspect , a method of treating cancer in a patient ( e . g . subject ) in need of such treatment is provided . The N ' N method includes administering a therapeutically effective 25 amount of a compound described herein . The compound has the formula : oble?? ?? (003 ) N N NH NH (I ) 30 R2. Rih N (004 ) - ?? NH Rz 35 N L ' and L ? are independently a bond or — NHC (NH ) ; R ! N is — NRIAR1B , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, 40 (005 ) substituted or unsubstituted aryl, or substituted or unsubsti NH NH tuted heteroaryl, wherein R1A and RIB are optionally joined together to form a substituted or unsubstituted heterocy cloalkyl. R2 is - NR24R2B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or 45 unsubstituted cycloalkyl, substituted or unsubstituted het erocycloalkyl , substituted or unsubstituted aryl, or substi NH NH (006 ) tuted or unsubstituted heteroaryl , wherein R24 and R2B are otto optionally joined together to form a substituted or unsub stituted heterocycloalkyl. R14 , RIB , R24 , and R2B are inde - 50 N N pendently hydrogen , _ OR , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or (007 ) unsubstituted cycloalkyl, substituted or unsubstituted het ofNH NHthe erocycloalkyl, substituted or unsubstituted aryl, or substi tuted or unsubstituted heteroaryl. R is hydrogen or unsub - 55 stituted C , - C alkyl. R4 is hydrogen , substituted or - N unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsub ya stituted heterocycloalkyl , substituted or unsubstituted aryl, (008 ) or substituted or unsubstituted heteroaryl. NH NH L ' , L², R1, R², R14 ,RB , R24 , R2B , and R3 are as described herein , including embodiments thereof . The administered - CN CNH , compounds may include compounds of formula (I ) , ( II ), ( III ), (IV ), ( V ) , (VI ) , (VII ) , or (VIII ) , including embodi ments thereof. The administration may include one or more 65 of the compounds described herein , including embodiments thereof. The administered compounds may include pharma US 9, 862 ,693 B2 67 68 -continued -continued (009 ) (019 ) NHNH NH NH NH

N z CNH) , | CN CNH ,

(020 ) (010 ) NH NH NH NH NH 10 CN CNHNH2 ,, NH (021 ) (011 ) 15 ?? ?? NHNH NHNH NHNH NH2, HN R3 20 (022 ) HN NH NH NH NH (012 ) | CN CNHNH2 , NH 25 (023 ) NH NH NH ANH (013 ) 30 . HNN ?“ CN CNH , z yeniR3 (024 ) (014 ) NH NH NH NH "35 N CN CNHNH2 , ??Z CNH , (015 ) 40 ( 025 ) OseNH NH NH NH N N Z NH2, 45 R3 (016 ) De oble?? ?? wherein , R2 is hydrogen ormethyl . R3 may be hydrogen . R3 may be methyl. 50 The pharmaceutical composition may include a com pound having formula : (017 ) NH NH NH NH 55 3 (005a ) olio ?? ?? N N HN R3 (018 ) 60 ollaNH NH ottaNH NH (002a ) N CNH , N N oleh orang- US 9 , 862 ,693 B2 69 70 - continued HER - 2 overexpression . In embodiments , triple -negative (009a ) breast cancer cells lack clinical expression of estrogen NH NH receptor- alpha , progesterone receptor and HER - 2 overex pression . N NH , 5 The cancer may be lung, pancreatic , melanoma, colon , colorectal, ovarian , or prostate cancer. The cancer may be lung cancer or pancreatic cancer. In embodiments , the (011a ) NH NH NH cancer is lung cancer. In embodiments , the cancer is non 27 small cell lung cancer. In embodiments, the cancer is pan creatic cancer. In embodiments , the cancer is melanoma . In Z embodiments , the cancer is colon cancer . In embodiments , the cancer is colorectal cancer. In embodiments , the cancer is ovarian cancer. In embodiments , the cancer is prostate ( 0000 ) NH NH cancer. In embodiments of the method of treating cancer, the method includes administering an anti - cancer agent. In embodiments of the method of treating cancer, the method NH , or includes co -administering a compound as described herein ( including embodiments ) and an anti - cancer agent . (0000 ) 20 NH NH V . Embodiments - CN CNH . 1 . A compound having the formula :

25 In embodiments of the method of treating cancer, the NH NH cancer is selected from colon cancer, colorectal cancer, ovarian cancer , prostate cancer , lung cancer, breast cancer , pancreatic cancer , and melanoma. In embodiments of the 30 Z method of treating cancer, the cancer is selected from lung cancer , breast cancer , pancreatic cancer, and melanoma. In embodiments , the cancer is triple negative breast cancer wherein ; subtype . In embodiments , the breast cancer cells do not L ' and L are independently a bond or - NH - C express estrogen receptor alpha . In embodiments , the breast 35 ( NH) ; cancer cells do not express progesterone receptor. In R is — NRIARIB, substituted or unsubstituted alkyl , embodiments , the breast cancer cells do not express human substituted or unsubstituted heteroalkyl, substituted epidermal growth factor receptor 2 (HER2 ) . In embodi or unsubstituted cycloalkyl, substituted or unsubsti ments , the breast cancer cells do not overexpress estrogen tuted heterocycloalkyl, substituted or unsubstituted receptor alpha relative to control cells ( e . g . non - cancerous 40 aryl, or substituted or unsubstituted heteroaryl, breast cells , non - cancerous breast cells of the same cell wherein R14 and RB are optionally joined together original, non - cancerous breast cells from the same subject as to form a substituted or unsubstituted heterocy the breast cancer cells , cells having expression levels of cloalkyl; protein or having transcription levels ofmRNA not associ R is - NR24R2B , substituted or unsubstituted alkyl, ated with cancer ) . In embodiments , the breast cancer cells do 45 substituted or unsubstituted heteroalkyl , substituted not overexpress progesterone receptor relative to control or unsubstituted cycloalkyl, substituted or unsubsti cells . In embodiments , the breast cancer cells do not over tuted heterocycloalkyl, substituted or unsubstituted express human epidermal growth factor receptor 2 (HER2 ) aryl, or substituted or unsubstituted heteroaryl, relative to control cells . wherein R24 and R2B are optionally joined together In embodiments , triple negative breast cancer subtype 50 to form a substituted or unsubstituted heterocy cells do not express estrogen receptor alpha , progesterone cloalkyl; receptor , and HER2 . In embodiments , triple negative breast R14 , RB, R24 , and R2B are independently hydrogen , cancer subtype cells do not overexpress estrogen receptor - OR “ , substituted or unsubstituted alkyl , substi alpha, progesterone receptor, and HER2. In embodiments , tuted or unsubstituted heteroalkyl , substituted or triple negative breast cancer subtype cells do not express 55 unsubstituted cycloalkyl , substituted or unsubsti estrogen receptor alpha and progesterone receptor and do tuted heterocycloalkyl, substituted or unsubstituted not overexpress HER2. In embodiments , triple negative aryl, or substituted or unsubstituted heteroaryl; breast cancer subtype cells do not clinically express estrogen Rºis hydrogen or unsubstituted C . - C , alkyl; and receptor alpha , progesterone receptor, and HER2. In R4 is hydrogen , substituted or unsubstituted alkyl, sub embodiments , triple negative breast cancer subtype cells do 60 stituted or unsubstituted heteroalkyl, substituted or not clinically express estrogen receptor alpha and proges unsubstituted cycloalkyl, substituted or unsubsti terone receptor, and do not overexpress HER2. In embodi tuted heterocycloalkyl, substituted or unsubstituted ments , triple negative breast cancer subtype cells do not aryl, or substituted or unsubstituted heteroaryl; clinically express estrogen receptor alpha and do not over wherein if L ' and L are a bond and R ! is 4 ' -Me express progesterone receptor and HER2. In embodiments, 65 piperidine , R is not — NH2; triple -negative breast cancers lack clinical expression of wherein if L ' and L2 are a bond and Rl is - C (CH3 ) estrogen receptor- alpha and progesterone receptor and ( CH3) , R2 is not - NH2; US 9 ,862 , 693 B2 71 72 wherein if L ' and L2 are a bond and R ' is phenyl, R2 is substituted or unsubstituted morpholinyl, substituted or not — NH , ; unsubstituted dioxanyl, or substituted or unsubstituted wherein if L ' and L2 are a bond and R14 and RIB are dithianyl, substituted or unsubstituted aziridinyl, sub both hydrogen , then R24 and R2B are not both stituted or unsubstituted azetidinyl, substituted or methyl; 5 unsubstituted azepinyl, substituted or unsubstituted wherein if L ' and L are a bond and R ' is 2 - or oxiranyl, substituted or unsubstituted oxetanyl , substi 3 '- pyridinyl, R² is not NHz; and tuted or unsubstituted tetrahydrofuranyl , or substituted wherein L ' and L are a bond and R14 and RB are both or unsubstituted tetrahydropyranyl . methyl, R² is not morpholino . 15 . The compound of any one of embodiments 12 to 14 , 2 . The compound of embodiment 1 having formula ( I) , 10 wherein R2 is — NR24R2B , and wherein R24 and R2B wherein L ' is a bond . are joined to form a substituted or unsubstituted 5 to 8 3 . The compound of embodiments 1 or 2 , wherein L2 is a membered heterocycloalkyl. bond . 16 . The compound of embodiment 15 , wherein R24 and 4 . The compound of any one of embodiments 1 to 3 , R2B are joined to form a substituted or unsubstituted wherein 15 pyrrolidine , substituted or unsubstituted imidazolidine , Rl is - NRlaRlb ; and substituted or unsubstituted oxazolidine , substituted or R2 is - NR24R26 or substituted or unsubstituted het unsubstituted thiazolidine , substituted or unsubstituted erocycloalkyl dioxolane , or substituted or unsubstituted dithiolane , 5 . The compound of embodiment 4 , wherein Rla is substituted or unsubstituted piperidine , substituted or substituted or unsubstituted heteroalkyl or substituted 20 unsubstituted morpholine, substituted or unsubstituted or unsubstituted alkyl. dioxane , or substituted or unsubstituted dithiane , sub 6 . The compound of any one of embodiments 4 to 5 , stituted or unsubstituted aziridinyl, substituted or wherein RIB is substituted or unsubstituted alkyl. unsubstituted azetidinyl, substituted or unsubstituted 7 . The compound of any one of embodiments 4 to 6 , azepinyl , substituted or unsubstituted oxiranyl , substi wherein R² is — NR24R2B . tuted or unsubstituted oxetanyl, substituted or unsub 8 . The compound of claim 7, wherein R24 and R2B are stituted tetrahydrofuranyl, or substituted or unsubsti independently hydrogen or substituted or unsubstituted tuted tetrahydropyranyl. alkyl. 17 . The compound of any one of embodiments 1 to 3 , or 9. The compound of embodiment 7 , wherein R24 and R2B 11 to 16 , said compound having formula : are hydrogen . 30 10 . The compound of any one of embodiments 4 to 9 , (III ) having formula : NH NH (R ) (001 ) 35 ( R ) z1st N ' NH NH AN R3

z N NH or wherein , R3 40 Ring A and Ring B are independently substituted or (008 ) unsubstituted 3 to 8 membered heterocycloalkyl; NH NH zl is an integer from 2 to 7 ; z2 is an integer from 2 to 7 ; NH2 R $ and R? are independently hydrogen , halogen , 45 - N3, ??2 NO2, CF3, CC13, CBr3 , C13 , CN , OH , - NH2, COOH , CONH2, - NO2, SH , - SO , C1, SO2H , SO _ H SO2NH2, — NHNH , LONH , NHC =( O ) NHNH2; substi 11 . The compound of any one of embodiments 4 to 6 , 50 tuted or unsubstituted alkyl, substituted or unsubsti wherein R² is substituted or unsubstituted heterocy tuted heteroalkyl, substituted or unsubstituted cloalkyl. cycloalkyl, substituted or unsubstituted heterocy 12 . The compound of any one of embodiments 1 to 3 , cloalkyl, substituted or unsubstituted aryl, or substi wherein Rl is — NRIARIB or substituted or unsubsti tuted or unsubstituted heteroaryl, or are optionally tuted heterocycloalkyl and R2 is NR24R2B or substi - 55 bonded together to form a substituted or unsubsti tuted or unsubstituted heterocycloalkyl. tuted cycloalkyl, a substituted or unsubstituted het 13 . The compound of embodiment 12 , wherein Rl is erocycloalkyl, a substituted or unsubstituted aryl, or - NRARIB , and wherein R14 and RIB are joined a substituted or unsubstituted heteroaryl. together to form a substituted or unsubstituted 3 to 8 18 . The compound of embodiment 17 , wherein ring A is membered heterocycloalkyl. 60 different from ring B . 14 . The compound of embodiment 13 , wherein R14 and 19 . The compound of embodiment 18 , wherein ring A is RIB are joined to form a substituted or unsubstituted a 5 membered heterocycloalkyl and ring B is a 6 pyrrolidinyl, substituted or unsubstituted imidazolidi membered heterocycloalkyl. nyl, substituted or unsubstituted oxazolidinyl, substi 20 . The compound of embodiment 19 , wherein ring A is tuted or unsubstituted thiazolidinyl, substituted or 65 substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted dioxolanyl, substituted or unsubstituted unsubstituted imidazolidinyl, substituted or unsubsti dithiolanyl, substituted or unsubstituted piperidinyl, tuted oxazolidinyl, substituted or unsubstituted thiazo US 9 ,862 , 693 B2 73 74 lidinyl, substituted or unsubstituted dioxolanyl, or sub 30 . The compound of embodiment 23 having formula : stituted or unsubstituted dithiolanyl and ring B is substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted dioxanyl, or substituted or unsubstituted dithianyl . 5 NH NH (017 ) 21 . The compound of embodiment 18 , wherein ring A is a 6 membered substituted or unsubstituted heterocy N N cloalkyl, and ring B is a 5 membered substituted or unsubstituted heterocycloalkyl . 22 . The compound of embodiment 21 , wherein ring A is 10 substituted or unsubstituted piperidinyl , substituted or otty unsubstituted morpholinyl, substituted or unsubstituted 31 . 1The compound of embodiment 23 having formula : dioxanyl, or substituted or unsubstituted dithianyl and ring B is substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted 15 ( IVD ) or unsubstituted oxazolidinyl, substituted or unsubsti NH NH tuted thiazolidinyl, substituted or unsubstituted dioxo ( R ? ) (R° ) - 2 . lanyl, or substituted or unsubstituted dithiolanyl. N ' N 23. The compound of any one of embodiments 1 to 3 , or 2 -Z 17 to 22 having formula ;

NH NH (IIIa ) 32 . The compound of embodiment 31 having formula : 2525 X LlytheZ (005 ) R3 NH NH (RS ) 1 LRO- (R )322 2 30 Z

- wherein , X is - CH2 - , - O - , or - NH ; Y is CH20 - , or - NH — ; 35 33 . The compound of embodiment 12 , wherein R14 and nl is an integer from 1 to 4 ; and RIB are joined together to form a substituted or unsub n2 is an integer from 1 to 4 stituted heterocycloalkyl and R24 and R2B are hydrogen 24 . The compound of embodiment 23 , wherein nl is not or substituted or unsubstituted alkyl. equal to n2 . 25 . The compound of embodiment 23 , having formula : 40 34 . The compound of claim 33 having formula :

(015 ) NH NH (006 ) NH NH

N N N CN CN - R3 . o NH NH (018 ) 26 . The compound of embodiment 23 having formula : z NH2 NH NH ( IIId ) Or N N NH NH (019 )

60 Z - NH2 27 . The compound of embodiment 26 , wherein X and Y are O 28 . The compound of embodiment 26 , wherein X and Y 35 . The compound of any one of embodiments 1 to 3 , are — NMe. 65 wherein Rl is substituted or unsubstituted aryl or sub 29 . The compound of embodiment 26 , wherein X and Y stituted or unsubstituted heteroaryl and R2 is are CH2 - NR24R2B . US 9 ,862 , 693 B2 75 76 . 36 . The compound of embodiment 35 having formula : 47. The compound of embodiment 46 , wherein R1 and R2 are independently substituted or unsubstituted C - C , alkyl. 48. The compound of embodiment 47, wherein R and R2 ?? ?? 5 are methyl. (R ) 49. The compound of embodiment 42 , wherein Rl is N NR24 substituted or unsubstituted aryl and R² is substituted or orR3 R2BR2B unsubstituted alkyl . 10 50 . The compound of embodiment 49, wherein Riis wherein , substituted or unsubstituted phenyl. Ring C is substituted or unsubstituted 5 to 8 membered 51. The compound of embodiment 50 , wherein Rl is aryl or substituted or unsubstituted 5 to 8 membered unsubstituted phenyl. heteroaryl; and 52 . The compound of embodiment 49, wherein R2 is Z is C - - 0 , or — S — . 15 C , - C , substituted or unsubstituted alkyl. 37 . The compound of embodiment 36 , wherein R24 and 53 . The compound of embodiment 52 , wherein R2 is R2B are hydrogen . methyl . 38. The compound of embodiment 36 , wherein R24 and 54 . The compound of any one of embodiments 1 to 53 , R2B are joined together to form a 3 to 8 membered 20 wherein Rº is hydrogen . heterocycloalkyl. 55 . The compound of any one of embodiments 1 to 53 , 39 . The compound of embodiment 36 having formula : wherein Rº is methyl. 56 . A pharmaceutical composition comprising a pharma ceutically acceptable excipient and a compound having NH NH (020 ) 25 formula : N CNH , NH NH 30 (021 ) NL cheNH NH -z AR | CN CNH , 35 wherein ; (022 ) L and L2 are independently a bond or - NH C ?? ?? ( NH) ; R ' is - NR4R1B , substituted or unsubstituted alkyl , 40 substituted or unsubstituted heteroalkyl, substituted NH2, or or unsubstituted cycloalkyl, substituted or unsubsti tuted heterocycloalkyl, substituted or unsubstituted (023 ) aryl, or substituted or unsubstituted heteroaryl, NH NH wherein R14 and RB are optionally joined together 45 to form a substituted or unsubstituted heterocy CN CNH , cloalkyl; R2 is - NR24R2B, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti 50 tuted heterocycloalkyl, substituted or unsubstituted wherein R * is hydrogen or methyl . aryl, or substituted or unsubstituted heteroaryl, 40 . The compound of any one of claims 1 to 3 , wherein wherein R24 and R2B are optionally joined together R ! is substituted or unsubstituted alkyl and R² is to form a substituted or unsubstituted heterocy - NR24R2B cloalkyl ; 41. The compound of embodiments 1 or 2 , wherein L ’ is 55 NH C( NH) … . R14 , RB, R24 , and R2B are independently hydrogen , 42 . The compound of embodiment 41, wherein R and R2 OR , substituted or unsubstituted alkyl, substi are independently substituted or unsubstituted aryl or tuted or unsubstituted heteroalkyl, substituted or substituted or unsubstituted alkyl. unsubstituted cycloalkyl, substituted or unsubsti 43 . The compound of embodiment 42 , wherein R and R² 60 tuted heterocycloalkyl, substituted or unsubstituted are independently substituted or unsubstituted aryl. aryl, or substituted or unsubstituted heteroaryl; 44 . The compound of embodiment 43 , wherein Rl and R2 R3 is hydrogen or unsubstituted C , -C , alkyl; and are independently substituted or unsubstituted phenyl. R4 is hydrogen , substituted or unsubstituted alkyl , sub 45 . The compound of embodiment 44 , wherein R1 and R ? stituted or unsubstituted heteroalkyl, substituted or are unsubstituted phenyl . 65 unsubstituted cycloalkyl, substituted or unsubsti 46 . The compound of embodiment 42 , wherein R1 and R2 tuted heterocycloalkyl, substituted or unsubstituted are independently substituted or unsubstituted alkyl . aryl, or substituted or unsubstituted heteroaryl. US 9 ,862 , 693 B2 LL 84 57 . The pharmaceutical composition of embodiment 56 , -continued wherein said compound has the formula : HN HN ) 600( ) 9000( S NH NH N7 CN CNHNH2 ,, -

, N N HN “ ?? ?? ?? (010 )

) 100 ( Z- ?? ??

(011 ) N HNN ?? ?? ?? ZEN ?? ?? (002 ) HN HN HN (012 ) NN Z N (003 ) HN HN (013 ) NH NH

-z N HNN Oyna - (004 ) NH HN (014 ) za NH HN ' N N FZHNN

(005 ) 40 NH HN (015 ) z HN HN N N

- ) 900( NH NH ) 910( ?? ?? NN NN R3 HN HN (007 ) (017 ) ?? ?? NN N

R3 ?? ?? )800 ( ) 810( ?? ?? ze NH2, I HNN yoxR3 US 9 , 862 ,693 B2 79 80 -continued wherein ; (019 ) L and L2 are independently a bond or — NH?C ?? ?? ( NH) = ; Riis - NRARIB, substituted or unsubstituted alkyl , CN CNH , substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti tuted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein R14 and RIB are optionally joined together NH NH (020 ) 10 to form a substituted or unsubstituted heterocy cloalkyl; CN CNHNH2 ,, R2 is NR24R2B , substituted or unsubstituted alkyl, -Z substituted or unsubstituted heteroalkyl , substituted or unsubstituted cycloalkyl , substituted or unsubsti 1515 tuted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, (021 ) wherein R24 and R2B are optionally joined together NH NH to form a substituted or unsubstituted heterocy 20 cloalkyl , N NHA, R14 , RIB , R24 , and R2B are independently hydrogen , - OR4 , substituted or unsubstituted alkyl, substi tuted or unsubstituted heteroalkyl, substituted or (022 ) unsubstituted cycloalkyl, substituted or unsubsti NH NH 25 tuted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

Z R3 is hydrogen or unsubstituted CZ - C alkyl; and N ANH , R is hydrogen , substituted or unsubstituted alkyl, sub R3 stituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubsti NH NH (023 ) 30 tuted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 61. The method of embodiment 60 , wherein said com | CN CNHNH2 ,, pound has formula : 35 (024 ) NH NH NH NH (000 )

NANH , CN CN CNHNH ) ,

-2 R3 (001 ) NH NH (025 ) EZ NH

Z NH2 NANH , - Z NH ,

NH NH ( 002 ) wherein R3 is hydrogen or methyl 58 . The pharmaceutical composition of embodiment 57, :N N wherein R * is hydrogen . 59 . The pharmaceutical composition of embodiment 57 , wherein R3 is methyl. ( 003 ) 60 . A method of treating cancer in a subject in need 55 NH NH thereof, said method comprising administering a thera peutically effective amount a compound having for N mula :

NH NH ( 004 ) ?? ?? R NN N L? Colla US 9 , 862 ,693 B2 18 82 -continued -continued ?? ?? ) 500( ?? ?? ) SIC(

NN a|N

| (006 ) ) 910( ?? ?? ?? ??HN 10 NN- R3 (007 ) 15 ?? ?? ?? ?? )10 (

NN NN

20 R3 (008 ) (018 ) ?? ?? NH NH

, HNNTHN “ Z 25 HNNNIR ) 610( ) 600( ?? ?? HN HN 30 HNN HNN - (020 ) 35 ?? ?? ) 010( ?? ?? ?? HNN??? «

40 ?? ?? (021 ) Byto (011 ) ?? ?? ?? . CHN“ HN 45 (022 ) (012 ) HN HN HN NH NH 50 HNN N R3R3 (023 ) ?? HN HN HN (013 ) 55 NH2 Z CHN“ Z -

(014 ) (024 ) HÑHN HÑHN ?? ?? .NIR N CHN“ HNN US 9 , 862 ,693 B2 83 84 -continued 74 . The compound of any one of embodiments 70 to 73 , (025 ) wherein , NH NH R1, R2, R3, and R4 are independently hydrogen , unsub stituted alkyl , or unsubstituted heteroalkyl; CN CNHNH2 ., 75 . A method of treating cancer in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound of any one of embodiment 70 to 73 . 76 . The method of embodiment 75 , wherein the cancer is wherein Rº is hydrogen or methyl. 10 lung cancer , pancreatic cancer, or breast cancer . 62 . The method of embodiment61 , wherein R3 is hydro 77 . The method of embodiment 75 , wherein the cancer is gen . breast cancer. 63 . The method of embodiment 61 , wherein R3 is methyl. 78 . The method of embodiment 77 , wherein the breast 64 . The method of embodiment 60 , wherein said cancer is cancer is triple negative breast cancer subtype. breast cancer, lung cancer, or pancreatic cancer . 15 79 . The method of embodiment 76 , wherein the cancer is 65 . The method of embodiment 64 , wherein said cancer is lung cancer. breast cancer . 80 . The method of embodiment 79 , wherein the lung 66 . The method of embodiment 65 , wherein said breast cancer is non - small cell lung cancer. cancer is triple negative breast cancer. 81 . A method of treating pulmonary lymphangioleiomyo 67. The method of embodiment 64 , wherein said cancer is 20 matosis (LAM ) or renal angiomyolipoma (AML ) in a lung cancer. patient in need of such treatment , said method com 68 . The method of embodiment 67, wherein said lung prising administering a therapeutically effective cancer is non -small cell lung cancer . amount of a compound of any one of embodiments 70 69. The method of embodiment 64 ,wherein said cancer is to 74 . pancreatic cancer. 25 82 . A pharmaceutical composition comprising a pharma 70 . A compound , or a pharmaceutically acceptable salt ceutically acceptable excipient and a compound of any thereof, having the formula : one of embodiments 70 to 74 . VI. Examples 30 NH NH Overview Metformin , the most commonly prescribed drug to treat N N - R3 Z- -7 type 2 diabetes mellitus in the clinic , has recently emerged NH as a potential anticancer agent. Evidence from epidemio R4 35 logic and preclinical studies suggest that metformin exerts previously unsuspected anti - cancer and chemopreventive wherein , R ', R2, R3, and R4 are each independently activity in breast and other type of malignancies ( 1 - 5 ). hydrogen , substituted or unsubstituted alkyl, or sub - Diabetic patients treated with metformin , but not with other stituted or unsubstituted heteroalkyl; antidiabetic drugs, have a reduced incidence and better R and R2 may optionally be joined to form a substi - 40 survival from breast cancer .Moreover , triple -negative breast tuted or unsubstituted heterocycloalkyl or substituted cancer cells ( a deadly subtype of breast cancer ) are reported or unsubstituted heteroaryl ; to be uniquely sensitive to metformin with profound and R3 and R4 may optionally be joined to form a molecular effects likely to have translational relevance ( 1 , 6 , substituted or unsubstituted heterocycloalkyl or sub - 7 ) . In the clinic , metformin has modest anticancer activity stituted or unsubstituted heteroaryl. 45 but higher doses of the drug appear to exhibit better antitu 71. The compound of embodiment 70 , wherein , mor potency . Described herein is the design and synthesis of R1, R² , R " , and R4 are independently hydrogen , sub - a group of derivatives ofmetformin that show significantly stituted or unsubstituted alkyl, or substituted or more potent anticancer activity than metformin and induce unsubstituted heteroalkyl , or cancer cell death . Rl and R2 may optionally be joined to form a substi - 50 Biguanides, including metformin , phenformin and tuted or unsubstituted heterocycloalkyl; and buformin , are derived from the herb Galega officinalis and R3 and R4 may optionally be joined to form a substi were originally developed for treatment of hyperglicemia tuted or unsubstituted heterocycloalkyl. (high blood glucose levels ) and type 2 diabetes. While 72 . The compound of one of embodiments 70 or 71 , phenformin and buformin were withdrawn from the market wherein , due to undesirable side - effects , metformin has remained one if R and R2 are joined to form an unsubstituted of the most commonly prescribed and safe drugs, with morpholinyl; nearly 120 million prescriptions filled annually worldwide then R3 and R4 are not both unsubstituted methyl; and ( 8 ). Use of metformin in patients with diabetes has been if R3 and R4 are both hydrogen ; associated with reduced cancer incidence and mortality, with then R and Rº are not joined to form a 4 -methyl 60 speculation that insulin - and insulin like growth factor piperidinyl. lowering effects of metformin may be at least in part related 73 . The compound of any one of embodiments 70 to 72 , to its anti -cancer activity ( 1 , 8 ) . wherein , The new compounds synthesized are analogues of the R and R2 are joined to form a substituted or unsubsti- parent metformin drug but designed to exhibit more potent tuted heterocycloalkyl; and 65 anticancer activity ( e . g . anti -breast cancer, anti - TNBC , anti R3 and R4 are joined to form a substituted or unsubsti - lung cancer , anti -non - small cell lung cancer ( anti- NSCLC ) , tuted heterocycloalkyl . anti - pancreatic cancer , anti- melanoma , anti - prostate cancer , US 9 ,862 , 693 B2 85 86 anti- colon cancer , anti -colorectal cancer , or anti - ovarian N - ( Imino (morpholino )methyl ) morpholine - 4 - carboximid cancer ) and safety as compared to metformin . amide hydrochloride , JD003 . The title compound , JD003 , Chemical Syntheses was obtained by following general procedure B using mor All the solvents or reagents were purified according to pholine hydrochloride in 72 % yield after crystallization literature procedures. High Resolution Mass Spectrometry 5 from methanol. ' H NMR ( 300 MHz, DMSO - d . ): 8 7 .06 was obtained on a Waters LCT Premier XE Time of Flight (1H , s ) , 3 .57 (8H , t , J = 4 . 5 Hz) , 3 . 36 (8H , t , J = 4 . 5 Hz ) . 13C LC -MS . H NMR , 13C NMR spectra were obtained on NMR (75 MHz, DMSO - d . ) : 8 157 . 9 , 65 . 5 , 45 . 0 . AV -300 , ARX -400 , ARX -500 or Avance -500 spectrometers. N - ( Imino ( 4 -methylpiperazin - 1 - yl) methyl ) - 4 -methylpip The chemical shifts are reported in parts per million (ppm , erazine - 1 - carboximidamide hydro -chloride , JD004 . The title d ). The coupling constants are reported in Hertz (Hz ) and the 10 compound , JD004 , was obtained by following general pro resonance patterns are reported with the following notations : cedure B using 1 -methyl - piperazine hydrochloride in 63 % br (broad ) , s (singlet ) , d (double ) , t ( triplet) , q (quartet ) and yield after crystallization from methanol. H NMR ( 300 m (multiplet ). Thin - layer chromatography (TLC ) was car - MHz, DMSO - d .) : 7 .01 (1H , s ), 3 . 36 (8H , t, J = 3 .9 Hz ), ried out using precoated silica gel sheets (Merck 60 F254 ) . 2 .34 (8H , t , J = 3 . 9 Hz ) , 2 . 15 (6H , s ) . 13C NMR (75 MHz , Visual detection was performed with ultraviolet light ( short 15 DMSO - do) : 8 158. 4 , 54 .2 , 45 .8 , 44. 9 . wave and long wave ), p - anisaldehyde stain , and potassium N - ( Imino (pyrrolidin - 1 -yl ) methyl ) piperidine - 1 -carboxi permanganate stain . midamide hydrochloride, JD005 . The title compound , General Procedure A : For Compounds JD001, JD008, JD005 , was obtained by following general procedure C JD009 . Dicyandiamide ( cyanoguanidine ) 1 . 26 g , 0 .015 mol) using first pyrrolidine hydrochloride and then piperidine and various secondary amine hydrochloride ( 0 .015 mol) 20 hydrochloride in 35 % yield after crystallization from metha were dissolved in xylenes (40 mL ) , and the mixture was nol. ' H NMR (300 MHz , DMSO - do) : 8 6 .88 ( 1H , s) , 3 .40 stirred under argon at 150° C . for 24 hours . After cooling to (4H , br s ) , 3 .29 ( 4H , br s ) , 1 . 83 (4H , br s ) , 1 . 54 ( 2H , br s ), room temperature , the reaction mixture was evaporated to 1 .48 ( 4H , br s ) . 13C NMR ( 75 MHz, DMSO -do ) : 8 156 . 4 , dryness under reduced pressure . The residue was dissolved 156 . 1 , 46 . 9 , 45 . 6 , 25 . 1 , 24 . 8 , 23 . 7 . in methanol and filtered . The filtrate was concentrated 25 N - (Imino (pyrrolidin - 1 -yl ) methyl ) pyrrolidine- 1 - carboxi followed by crystallization two or three times to obtain the midamide hydrochloride , JD006 . The title compound , desired product . JD006 , was obtained by following general procedure B General Procedure B : For representative symmetrical using pyrrolidine hydrochloride in 42 % yield after crystal metformin analogues ( e . g . JD002 , JD003 , JD004 , JD006 ) . A lization from methanol. ' H NMR ( 300 MHz, DMSO - do ) : 8 mixture of sodium dicyanamide ( 1 . 335 g , 0 .015 mol) and the 30 6 . 97 ( 1H , s ), 3 . 30 ( 8H , br s ) , 1 . 83 ( 8H , br s ). 13C NMR ( 75 appropriate secondary amine hydrochloride ( 0 .030 mol) in MHz , DMSO -do ) : 8 155. 5 , 46 .9 , 24 .8 . xylenes ( 40 mL ) was refluxed for 48 hours . After cooling to N - ( N , N -Dimethylcarbamimidoyl ) morpholine - 4 - car room temperature , the reaction mixture was evaporated to boximidamide hydrochloride , JD007 . The title compound , dryness under reduced pressure . The residue was dissolved JD007 , was obtained by following general procedure C in hot methanol and filtered . The filtrate was concentrated 35 using first dimethylamine hydrochloride and then morpho followed by crystallization two or three times to obtain the line hydrochloride in 47 % yield after crystallization from desired product. methanol. 1H NMR ( 300 MHz , DMSO - 06 ) : 8 7 . 15 ( 1H , s ) , General Procedure C : For representative unsymmetrical 3 .59 ( 4H , br s ), 3 .42 (4H , br s ), 2. 91 (6H , s) . 13C NMR (75 analogues ( e. g . JD005 , JD007) : A mixture of sodium dicy - MHz, DMSO -d6 ) : 8 157 . 9, 65 .5 , 45 .0 , 37 .5 . anamide ( 1 .335 g , 0 . 015 mol) and pyrrolidine hydrochloride 40 N -Methyl - N -propylbiguanide hydrochloride, JD008 . The or dimethylamine hydrochloride ( 0 .015 mol) in xylenes (40 title compound , JD008 , was obtained by following general mL ) was refluxed for 12 h . After it was cooled to room procedure A using N -methylpropylamine hydrochloride in temperature , the reaction mixture was evaporated to dryness 83 % yield after crystallization from methanol. 1H NMR under reduced pressure. The residue was crystallized from (300 MHz, D20 ) : 83. 23 ( 2H , t , J = 7 . 2 Hz ), 2 . 90 (3H , s ), 1 . 48 methanol to obtain the pure N -cyanopyrrolidine - 1 -carboxi - 45 (2H , m ), 0 .75 ( 3H , t, J = 7 . 2 Hz ) . 13C NMR (75 MHz, D20 ): midamide and 3 - cyano - 1 , 1 -dimethylguanidine products . 8 159 .6 , 158 . 1 , 51. 8 , 35 . 4 , 20 . 0 , 10 . 1 . Then these cyanoguanidines (0 .015 mol) were dissolved N - Carbamimidoyl- 4 -methylpiperidine - 1 -carboximid separately in xylenes ( 40 mL ) and piperidine hydrochloride amide , hydrochloride , JD009. The title compound , JD009 , or morpholine hydrochloride ( 0 .015 mol) was added . The was obtained by following general procedure A using mixture was refluxed for 48 h , the solvent was removed 50 4 -methylpiperidine hydrochloride in 34 % yield after crys under vacuum and the residue was recrystallized twice from tallization from methanol. 1H NMR (500 MHz, DMSO - d6 ) : methanol to obtain the two unsymmetrical analogues, JD005 d 6 .04 ( 2H , s ), 4 . 13 ( 4H , m ), 2 .61 (2H , m ) , 1 . 54 (3H , m ) , and JD007, respectively . 0 .85 (3H , d , J = 6 .0 Hz ). 13C NMR (125 MHz, DMSO - 06 ): N -Methoxyl - N -methylbiguanide hydrochloride , JD001 . 8 167 . 3 , 165 .2 , 42 . 9 , 34 . 0 , 31. 1 , 22 .1 . The title compound , JD001, was obtained by following 55 In Vitro and In Vivo Characterization of Compounds general procedure A using N , O - dimethylhydroxylamine The new compounds described herein ( including embodi hydrochloride in 78 % yield after crystallization from metha - ments ) ( e .g . metformin analogues) have been tested using nol . ' H NMR (300 MHz, DMSO - do) : 8 7 .59 (2H , s) , 3 .63 preclinical in vitro models where they are shown to be active (3H , S ), 3 .10 (3H , s ) . 13C NMR ( 75 MHz, DMSO - d . ) : 8 at inducing cell death in different types of malignant cell 160 . 3 , 158 . 6 , 61. 1 , 35 . 2 . 60 types , including triple - negative breast cancer, ER - positive N - ( Imino (piperidin - 1 -yl )methyl ) piperidine - 1 -carboximi breast cancer, non - small cell lung cancer , pancreatic cancer damide hydrochloride, JD002 . The title compound , JD002 , and melanoma cells . The compounds ( e . g . metformin ana was obtained by following general procedure B using pip logues ) are particularly active in inducing the death of eridine hydrochloride in 38 % yield after crystallization from triple -negative breast cancer cells ( TNBC ) . methanol. ' H NMR ( 300 MHz , DMSO - do ): 8 7 . 10 ( 1H , s ) , 65 The effects of compounds described herein ( including 3 .38 (8H , t, J = 15 Hz) , 1. 48 ( 12H , m ) . 13C NMR ( 75 MHz , embodiments ) ( e . g. metformin analogues ) were determined DMSO - do ): 8 157 . 1 , 45 .6 , 25 . 0 , 23. 7 . on two types of normal nonmalignant human cells , human US 9 , 862 ,693 B2 88 umbilical vein endothelial cells (HUVEC ) and human mam deadly subtype of breast cancer , and anticancer activity was mary epithelial cells (HMEC ) . There were no significant also shown for NSCLC and pancreatic cancer cells biologic effects noted on exposure to the metformin ana The anticancer activity of some different metformin ana logues . logues differs in TNBC as compared to NSCLC , suggesting Compounds described herein (including embodiments ) 5 that specific compounds described herein ( including ( e . g . metformin analogues ) are being tested in human tumor embodiments ) may be more potent against different cancer xenografts grown in immunosuppressed mice . types or subtypes of major groups of cancers and different Compounds described herein ( e .g . metformin derivatives compounds may be useful for treating different cancer and / or analogues ) were tested in human MCF - 7 breast subtypes . cancer cells , a standard ERalpha - positive model of breast 10 Study of the activity of these metformin analogues in malignancy ( FIG . 1 ) , and in four different cell lines classi - suppressing melanoma and pancreatic cancer are ongoing . fied as TNBC , including MDA -MB - 231, HCC1937 , HCC38 Compounds ( e . g . novel metformin derivatives or ana and HCC1806 ( FIGS . 2A - 2D ) . All of the compounds ( e . g . logues ) are being tested for their ability to treat triple metformin analogues and/ or derivatives ) tested were more negative breast cancer ( TNBC ) using a panel of different cell effective than metformin at inhibiting cell growth . Experi- 15 line models . Experiments on anticancer activity in other ments were also performed in : 1 ) a non -small cell lung breast, lung and pancreatic cancer cells and melanoma are cancer cell line that is known to be resistant to standard ongoing . Experiments are continuing to determine effects of chemotherapy ( A549 ) ; and 2 ) a melanoma- like cell model compounds described herein ( including embodiments ) on (MDA -MB - 435 ). See FIGS . 3A - 3B . To find if analogues normal cells , including blood vessel cells ( e . g . human have effects on normal cells compounds were tested in two 20 umbilical vein endothelial cells ) , nonmalignant breast epi different types of cells , human umbilical vein endothelial thelial cells and normal lung cells ( e . g . human bronchial cells (HUVEC ) and human mammary epithelial cells epithelial cells ) . ( HMEC ) . The effects of metformin (MET ) were compared Ongoing experiments are determining mechanisms of with compounds JD001- JD009. See FIGS . 4A -4B . action of selected compounds , with investigation of cellular Anti -Cancer Activity of Compounds 25 and molecular pathways in the induction of tumor cell death . Described herein is the synthesis ofmetformin derivatives Activation of AMP kinase or inhibition of mTOR ( and /or ( e . g . analogues ). These novel compounds are shown to be mTORC1 ), MAPK and AKT kinases and nuclear factor more effective than metformin in killing selected cancer kappa B pathways are being investigated . Reduction of cells . Further, several of these novel metformin derivatives insulin and insulin - like growth factors (that play a role in ( e . g . analogues ) do not display significant side - effects in 30 tumor progression ) and inhibition of the activation of insu normal , nonmalignant cells . lin - like growth factor and insulin receptors and their down Development of novel therapies for the treatment of stream signaling are being characterized . In embodiments , triple - negative breast cancer ( TNBC ) are urgently needed as the compounds described herein ( including embodiments ) there are currently no targeted therapies for this deadly modulate ( e . g . inhibit , decrease , or increase ) the activity or subtype of breast cancer. Identification of a new targeted and 35 expression levels or function of mTOR , mTORC1, MAPK , safe therapeutic for TNBC , as well as for other types of and /or AKT kinases . In embodiments , the compounds cancer ( e . g . lung , pancreas , prostate , colon , melanoma, described herein ( including embodiments ) modulate (e . g . ovary ) , would be very significant ( 1 ) . inhibit , decrease , or increase ) the activity or expression level Preclinical investigations on the anticancer activity of or function of AMP kinase . In embodiments , the compounds these novel compounds show high potency in both triple - 40 described herein ( including embodiments ) modulate ( e . g negative breast cancers ( about 15 - 20 % of all breast cancers inhibit , decrease , or increase ) the activity or expression but accounting for almost half of all breast cancer deaths ) as levels or function of insulin , insulin -like growth factor 1 well as in estrogen receptor- alpha - positive breast cancers (IGF1 ) , insulin - like growth factor 2 ( IGF2 ) , IGF1 receptor, ( about 70 % of all breast cancers ) . The compounds described or IGF2 receptor. herein ( including embodiments ) ( e . g . metformin analogues ) 45 Experiments are ongoing to characterize compound have anticancer effects in melanoma, lung and pancreatic described herein ( including embodiments ) in human tumor cancer cells . In contrast, several of the new compounds xenograft models and in orthotopic models for prevention described herein ( including embodiments ) ( e . g . metformin and treatment of lung and breast cancers , particularly analogues ) do not exhibit significant toxicity toward normal TNBC . Compounds are being tested alone or in combination nonmalignant human cells used as controls . 50 with standard chemotherapy treatments currently used in the Metformin has antitumor activity against triple -negative clinic ( e . g . taxanes , docetaxel) . breast cancer cell lines only at high millimolar concentra At a cellular level, metformin stimulates AMP -activated tions ( 2 ,3 ), while several of the compounds described herein protein kinase (AMPK ) activation . Metformin - induced acti have significantly better specific anticancer activity at lower vation of AMPK inhibits downstream mTORC1 which concentrations (e .g . micromolar) than metformin . Some of 55 integrates signals from a diverse array of signaling pathways the compounds described herein , including embodiments , to regulate pancreatic cancer cell survival, growth and exhibit anticancer activity when used to treat non -small cell metastasis . It is postulated that metformin inhibits pancreatic lung cancer . Of note , the antitumor activity of several cancer growth in part via AMPK -mediated inhibition of analogues of metformin appear to differ among different mTORC1 activation . Independent data show that metformin cancers , such as triple -negative breast cancer as compared to 60 also disrupts critical crosstalk between insulin / IGF - 1 and non - small cell lung cancer. GPCR signaling pathways and possibly ERK and Rag The compounds described herein ( including embodi - GTPase signaling . Further laboratory studies show that ments ) demonstrate potent anticancer activity toward triple - metformin markedly inhibits growth of human pancreatic negative breast cancer ( TNBC ) and non - small cell lung cancer cells xenografted in nude mice . This preclinical work cancer (NSCLC ) . The compounds described herein ( includ - 65 is supported by clinical cohort studies showing that met ing embodiments ) ( e . g . metformin analogues ) were shown formin users have a reduced risk of pancreatic cancer; and to be especially active in suppressing TNBC cells , the most that metformin use correlates with a survival benefit in US 9 ,862 , 693 B2 89 90 patients with diabetes and pancreatic cancer . In the latter dates will then be selected and used to probe potential signal study, themedian survival is only prolonged by 4 months in transduction pathways that may underlie antitumor effects in cancer patients who are metformin users compared to non - pancreatic cancer cells . users. It is notable that anticancer effects of metformin Cell Lines and Culture . increase with increasing doses and /or with IV as compared 5 Human pancreatic cancer cells PANC - 1 , MIAPaCa - 2 , to oral administration . Thus , discovery of more potent B xPC - 3 , and AsPC - 1 were from ATCC (Manassas , Va . ) . anticancer analogs of metformin may be required to boost PANC - 1 and MIAPaCa - 2 cells were grown in DMEM with clinical benefit and patient survival. We design , synthesize 2 mm glutamine , 1 mM sodium pyruvate , 100 units /mL and test antitumor activity of new metformin analogs using penicillin , 100 ug /mL streptomycin and 10 % FBS at 37 C in pancreatic cancer models . 10 a humidified atmosphere with 10 % CO2 ( 5 ) . BxPC - 3 cells We hypothesize that metformin analogs can be prepared and AsPC - 1 cells were grown in RPMI 1640 containing 100 with enhanced anticancer activity and minimal non - target units /mL penicillin , 100 ug/ mL streptomycin and 10 % FBS toxicity . Since metformin shows good although modest at 37 C in a humidified atmosphere with 5 % CO2 ( 5 ) . As activity — in pancreatic cancer, we designed two new ana - controls , human breast cancer MCF - 7 cells were obtained logues of metformin and tested them in early studies for 15 from the ATCC and nonmalignant Human Mammary Epi potentially more potent antitumor activity in vitro . Human thelial Cells (HMEC ) obtained from Invitrogen . MCF - 7 pancreatic cancer cells PANC - 1 , were grown in DMEM with cells were routinely maintained in D -MEM /F12 (MCF - 7 ) 2 mM glutamine , 1 mM sodium pyruvate , 100 units /mL with 10 % FBS ( Invitrogen /Life Technologies ) and 1 % anti penicillin , 100 ug /mL streptomycin and 10 % FBS at 37 C in biotic - antimycotic solution 100x , (Mediatech ) . HMEC were a humidified atmosphere with 10 % CO2. Then , effects of 20 maintained in medium 171 supplemented with Mammary treatment with metformin or analog JD003 on cell prolif - Epithelial Growth Supplement ( Invitrogen ) . Breast cells eration in vitro were tested . These initial findings suggest were cultured in 37° C . humidified atmosphere / 5 % CO2. that analog JDOO3 shows promise as a congener with more Cell Proliferation Assays . potent antitumor activity . To find if analogs may have Cell proliferation screening assays were done using cell deleterious effects on normal human cells , we compared the 25 proliferation ELISA , BrdU colorimetric kit (Roche ) . Cells cellular activity of metformin with that of analogs JD003 were counted using a hemocytometer and plated in 96 - well and JD004 using a pair of human breast epithelial cells . plates. At 24 hr after plating , cells were treated with met These included human mammary epithelial cells (HMEC ) formin and analogs ( see Aim 1 ) at 0 . 01mM , 0 . 1 mm , 1 mM and MCF - 7 tumor cells (MCF - 7 ) . Results of this work and 5 mM concentrations using medium with 1 % FBS . After indicate metformin analogs JD003 and JD004 have 30 48 hr, BrdU labeling solution was added and incubated for enhanced antiproliferative activity in breast cancer cells as 24 hr . Cell proliferation were quantitated based on measures compared to metformin at equivalent doses ( P < 0 .01 ) . In of BrDU incorporation ( by ELISA ) during DNA synthesis in contrast, minimal antiproliferative effects are detected in proliferating cells . Experiments were performed at least nonmalignant human epithelial cells. 3 - times ( n > 4 / experiment) . Results were expressed as Compounds described herein ( including embodiments ) 35 mean + SE . Effects of media with or without 10 ng/ ml insulin may be active in suppressing noncancerous pulmonary and with or without GPCR agonists such as neurotensin lymphangioleiomyomatosis (LAM ) and angiomyolipoma were included in these studies . As an alternate measure of ( AML ) cells that afflict an estimated 300 , 000 patients world - proliferation , independent experiments were done to confirm wide . Use of the compound described herein , including changes in actual cell numbers. embodiments , ( e . g . metformin analogues , metformin deriva - 40 Anchorage - Independent Cell Proliferation . tives ) for noncancerous diseases with dysregulated signaling Metformin analogs showing significant antitumor activity pathways , such as lymphangioleiomyomatosis (LAM ) or in screening assays above were tested further using anchor angiomyolipoma ( AML ) , is a novel indication ( e . g . method age - independent assays . Pancreatic cancer cells were plated of treatment, use ) . The frequency of these relatively rare on 12 -well plates coated with polyhydroxyethylmethacry diseases is elevated among patients with tuberous sclerosis 45 late Ipoly - (HEMA ) . Under these conditions, cells do not complex ( TSC ) , an inherited disorder resulting from muta - attach to the substratum . Cultures of PANC - 1 cells , for tions in either the TSC1 or TSC2 genes , but the diseases may example , at 3 - 5 days after passage, were washed and sus also occur in sporadic cases . pended in DMEM . Cells were then disaggregated by two Since metformin has shown good but modest activity passes through a 19 - gauge needle into single - cell suspen against pancreatic cancer in earlier reports , we prepared 50 sion . Cell numbers were determined by Coulter counter, and novel analogs of metformin and test them for potentially 2x104 cells were seeded in DMEM containing 1 % FBS on more potent antitumor activity . In particular , we prepared poly - (HEMA ) - coated dishes. After 24 hr incubation at 37 C , some alkylated analogues ( e . g . , compounds with secondary cells were treated in the absence or presence of metformin amines on both ends ) since those are largely unknown and and selected analogs at 0 . 1 and 1. 0 mM in media with or therefore could be developed as improved anticancer agents . 55 without 10 ng /ml insulin and with or without GPCR agonists Compounds in which there is still a free amino group ( e . g ., such as neurotensin ( 5 ) . Cultures were then incubated at 37 phenformin and buformin ) are known anticancer agents , but C for 7 - 9 days, and total cell counts determined from a no fully alkylated analogues have been made and tested to minimum of 4 wells / condition using a Coulter counter , after date . cell clumps were disaggregated by passing cell suspensions A number of metformin analogs have been be prepared . 60 10 times through a 19 - gauge , and then a 21 - gauge needle . These compounds will be tested and screened using pancre - Cell Migration / Invasion Assays. atic tumor cell proliferation , apoptosis and migration /inva - Since metformin modulates tumor cell invasion ( 20 ), sion as indices for anticancer activity . Nonmalignanthuman migration / invasion of pancreatic tumor cells in Transwell cells will be tested in parallel to assess effects on normal cell culture chambers was assess . For invasion assay , the cells . Modifications in the chemical structure ofmetformin 65 lower surface of filters were coated with 1 ug of fibronectin , analogs will be introduced as dictated by the in vitro with the upper surface coated with 5 ug of Matrigel . Cells screening assays for anticancer activity . Lead drug candi ( 1x105 ) were seeded in the upper compartment and incu US 9 ,862 , 693 B2 91 92 bated with selected agents or combinations in serum - free m ents to assess optimal antitumor efficacy and target speci medium containing 0 . 1 % BSA at 37° C . for 4 h for migration ficity. For a tumor xenograft model , nude mice (Harlan and 8 h for invasion . Filters were stained with crystal violet, Sprague - Dawley ) were injected subcutaneously with , for and cells in five 200x - fields will be counted . Such actions example , 5x106 PANC - 1 cells using established methods. allow metastasis in vivo , and blockade of this process is 5 After implanted tumor cells achieve an average size of critical to stop tumor spread . Signal Transduction Assays. 50 - 100 cm3, mice were randomized into the following Signal transduction pathways altered by metformin in groups ( n = 10 mice / group ) : ( a ) vehicle control) , ( b ) met malignant cells are complex . Crosstalk between insulin and formin control, c ) analog 1 , d ) analog 2 and e ) analog 3 , with GPCR signaling pathways has been identified in pancreatic 10 all agents given by oral gavage once daily. cancer cells ( 2 , 4 , 5 ) . Insulin enhances GPCR signaling Tumors were measured in two dimensions every 2 - 3 days, through a rapamycin - sensitive mTOR -dependent pathway. with area calculated by multiplying length by width . Metformin is noted to activate AMP kinase ( AMPK ) which Therapy was given until tumors reach limiting sizes or until negatively regulates mTORC1. In liver tissue , metformin day 28 in the analog - treated group . At the end of studies , similarly activates AMPK and inhibits mTOR . In lung 15 mice were anesthetized using isoflurane, and blood was tissue, metformin appears to exert greater inhibition on collected by cardiac puncture using BD vacutainer vials phosphorylation of insulin - like growth factor- I receptor/ containing EDTA . Animals were then euthanized with CO2 insulin receptor ( IGF - 1R /IR ) , with downstream effects on by established guidelines . Tumors and liver tissues were ERK and mTORC1. This suggests that metformin inhibits harvested to assess weights and processed for study of mTORC1 in lung tissue in part by decreasing activation of 20 potential biomarkers. Final tumor weights and sizes were IGF - 1R / IR upstream of mTORC1 ( 9 ) . Here , presented are compared among the several treatment groups . studies to find if metformin and its analogs elicit activation of AMPK and inhibition of mTORC1 . Confluent cultures of Immunohistochemistry ( IHC ) . pancreatic cancer cells were grown on 6 - cm dishes , washed For biomarker analyses , formalin - fixed pancreatic tumor twice with PBS and then incubated with serumfree medium 25 tissue were paraffin - embedded , sectioned and placed on for 3 h . Metformin or analogs were added at 0 . 01, 0 . 1 , 1 mM , slides. We have experience in IHC studies and assessed all and cultures were incubated at 37 C for selected times (0 - 24 antibodies for specificity and use appropriate controls . IHC h ) . To detect AMPK activation , cultures were washed in cold analysis of phosphorylation of AMPK , S6 , IGF - 1R / IR , AKT PBS and directly lysed in 2xSDS - PAGE sample buffer [ 200 and ERK 1/ 2 ; and for Ki- 67 was performed . Antigen mM Tris -HCl ( pH 6 . 8 ) , 2 mM EDTA , 0 . 1 mM Na3V04, 6 % 30 retrieval was done using target retrieval solution (pH 6 . 0 ) SDS, 10 % glycerol , 4 % 2 -mercaptoethanol ). Lysates were and a decloaking chamber (Dako ) . Tissues were incubated , subjected to SDS -PAGE on 10 % gels and separated proteins were transferred to Immobilon - P membranes (Millipore ). for example , in phospho - AMPK ( 1 : 50 ) , phospho -S6 ( 1 : 100 ) Western blots were then done on membranes incubated (22 -24 ), Ki- 67 (1 :2 ,000 ) antibodies per manufacturer' s rec overnight with phosphorylated AMPKa ( Thr172 ) or phos - 35 ommendations. Assessment of phosphorylation of IGF - 1R / phorylated ERK1/ 2 ( Thr202 and Tyr204 ) monoclonal anti IR , AKT and ERK 1 / 2 (dilutions to be determined ) was also bodies at a dilution of 1: 1 ,000 in PBS containing 5 % nonfat performed . To verify staining specificity , tissues were incu dried milk and 0 . 1 % Tween 20 . Immunoreactive bands were bated in the absence of primary antibody ( 24 ) . Detection was detected with enhanced chemiluminescence reagents . Mem done using VECTASTAIN Elite ABC kits ( Vector Labora branes were subsequently stripped and probed similarly with 40 tories ). IHC analysis for biomarkers was quantified and anti - AMPKa polyclonal antibody or anti - ERK at a dilution scored using methods as before . Ki- 67 staining was quan of 1 :2 ,000 in PBS containing 5 % nonfat dried milk and 0 . 1 % tified by counting the number of Ki- 67 + cells per tumor, and Tween 20 . Study of the phosphorylation of IGF - 1R /IR using these values were averaged for tumors in mice from each specific antibodies ( Cell Signaling) were done . treatment group . The investigator performing these analyses A decrease in translation caused by metformin in some 45 was blinded to identities of the samples . As an alternative tumors is associated with mTORC1 inhibition , and a approach , samples of pancreatic cancer xenograft and liver decrease in phosphorylation of S6 kinase and ribosomal tissuetissues at harvest were flash - frozen in liquid nitrogen . Fro protein S6 . Such effects of metformin on translation appear zen tissues were then be pulverized on dry ice and lysates to be mediated in part by AMPK , as treatment of cells with prepared using RIPA buffer supplemented with protease and the AMPK inhibitor compound C prevents inhibition of 50 phosphatase inhibitors . Immunoblotting analysis of tissue translation . To test if antitumor effects ofmetformin analogs lysates was done as described previously . Densitometry was are mediated by limiting mTORC1 signaling, we assessed done using NIH Image software at our institution . the relative efficacy ofmetformin congeners and rapamycin Exploratory Pharmacokinetic Analysis of Drug Plasma Lev ( control) to block phosphorylation of downstream mTORC1 els . mediators , S6K and S6 , and mTORC1. 55 Statistical Analysis . 3 Sample preparation and analysis were done. In brief , Triplicates of experiments were done to verify results . plasma was isolated by centrifugation of blood samples Data are presented as mean + SE and analyzed with student' s collected from mice at the end of xenograft studies and sent t - test or other appropriate nonparametric tests . ANOVA , or to a UCLA or commercial analytical laboratory ( Laboratory the Kruskal Wallis test if outcomes are non - normally dis - 60 of Proteomics & Analytical Technologies , Frederick , Md. ) tributed , are used as appropriate to compare multiple inter for pharmacokinetic analysis of metformin and analogs. vention groups . Analyses were evaluated using bar/ scatter Plasma IGF - I and Insulin Analysis . graphs with means, SD and SE . Plasma levels of IGF- I and insulin were measured using Administration of metformin is reported to significantly the Mouse /Rat IGF- I ELISA ( Diagnostic Systems Labora decrease growth of MIAPaCa - 2 and PANC - 1 cells xeno - 65 tories ) and the Rat /Mouse Insulin ELISA kit (Millipore ) , grafted in nude mice . Thus, a potent metformin analogue for respectively . Analyses were done on plasma obtained from in vivo studies was selected on the basis of in vitro experi - mice at the end of the xenograft studies . US 9 ,862 , 693 B2 93 94 Disease Prevention Using Compounds Described Herein drome, tobacco smoking or evidence of premalignant lung ( e . g . Metformin Analogues) or other tissue lesions) . In embodiments , the compounds There is a potential for use of the compounds described described herein ( including embodiments ) are administered herein ( including embodiments ) in cancer prevention among by oral administration . individuals at high risk for cancer ( for example , those with 5 a significant history of diabetes , obesity , metabolic syn - Treatment of Non - Cancer Diseases TABLE 1 Metformin analogues /derivatives

Biodata TNBC ER + Biodata extra

MDA BC Biodata Normal MDA

Code Structure MB- 231 HCC1937 HCC38 HCC1806 MCF7 HUVEC HMEC A549 MB -435

Met NH NH 110 . 3 92 . 9 92 .5 90 . 2 104 . 8 839 . 9 9 . 8 72 . 2 77. 7 for min (000 ) ?NHNH2

JD001 NH NH 92 68. 9 102. 5 80 .1 82. 3 84 .4 101 62. 6 102. 1

JD002 NHNH NHINH 48. 5 17. 1 44. 7 36 .4 46. 2 70 62. 6 4. 6 39. 8 IZ

JDO03 NH NH 93 . 2 37 . 8 61. 3 86 .7 106 .6 98 50 . 4

mobilaJD004 NH NH 89 . 2 64 84 . 4 89 . 1 112 . 8 74 . 3 59 . 6 N

contaJD005 ?? ?? 46. 6 15. 7 43. 4 55 .8 58 .2 54 .6 67. 6 32. 4 42. 2 callyN JD006 ?? ?? - - - - 5959. . 77 112112. . 8 9696 . 6 59 . 7 - US 9 , 862 ,693 B2 95 96 1 TABLE 1 -continued Metformin analogues/ derivatives ? Biodata TNBC ER + Biodata extra MDA BC Biodata Normal MDA Code structureStructure MB- 231 HCC1937 HCC38 HCC1806 MCF7 HUVEC HMEC A549 MB- 435 JD007 NH NH 64 . 3 - 83 . 6 6565 . 7 6565 . 8 112112 . 1 105 . 3 8282. . 3 - NH

JD008 NH NH 38 . 6 - 55 .. 6 5252 . 7 5252. 2 37 . 7 7070 . 9 - - NH NH ,

JD009 NH NH 0. 3 - 0 7. 3 52 .7 39. 5 48. 8 - - NH NH2

Additional data noted in FIG . 9 . Cells were incubated in the presence of vehicle , metformin 4 . Taubes G . Cancer research . Unraveling the obesity - cancer or metformin analogues for 72 hours in their respective connection . Science . 2012 Jan . 6 ; 335 (6064 ) : 28 , 30 - 2 . media . After treatment cell numbers were determined with of 5 . Currie C J , Poole C D , Jenkins- Jones S , Gale E A , Johnson the MTS method using the CellTiter 96 Aqueous Non - JA , Morgan C L . Mortality after incident cancer in people Radioactive Cell Proliferation Assay ( Promega ). Numbers with and without type 2 diabetes: impact of metformin on express percentage of vehicle treated controls at 1 mM survival. Diabetes Care . 2012 ; 35 ( 2 ) : 299 - 304 . concentration metformin or metformin analogues (JD001 - 6 . Jiralerspong S , Gonzalez - Angulo A M , Hung M C . JD009 ) . TNBC : Triple Negative Breast Cancer Cells , 40 Expanding the arsenal : metformin for the treatment of ER + BC : Estrogen receptor positive breast cancer. triple -negative breast cancer ? Cell Cycle. 2009 Sep . 1 ; Since metformin has shown good but modest activity 8 ( 17 ): 2681. against pancreatic cancer in earlier reports , we prepared 7 . Jiralerspong S , Palla S L ,Giordano SH , Meric - Bernstam novel analogs of metformin and test them for potentially F , Liedtke C , Barnett C M , Hsu L , HungMC , Hortobagyi more potent antitumor activity . In particular , we prepared 45 G N , Gonzalez -Angulo A M . Metformin and pathologic alkylated analogues (e . g. , compounds with secondary complete responses to neoadjuvant chemotherapy in dia amines on both ends ) since those are largely unknown and betic patients with breast cancer . J Clin Oncol. 2009 Jul. therefore could be developed as improved anticancer agents . 10 ; 27 ( 20 ) : 3297 - 302 . Epub 2009 Jun . 1 . Compounds in which there is still a free amino group ( e . g ., 8 . Ben Sahra I , Le Marchand - Brustel Y , Tanti J F , Bost F . phenformin and buformin ) are known anticancer agents , but 50 Metformin in cancer therapy : a new perspective for an old no fully alkylated analogues have been made and tested to antidiabetic drug ? Mol Cancer Ther. 2010 May; 9 ( 5 ) : date . 1092 - 9 . Review . VII . References 9 . Dilman V M , Berstein L M , Ostroumova M N , Fedorov 55 S N , Poroshina T E , Tsyrlina E V , Buslaeva V P , Semi 1. Evans J M , Donnelly L A , Emslie - Smith A M , Alessi D glazov V F , Seleznev I K , Bobrov Yu F , Vasilyeva I A , R , Morris A D . Metformin and reduced risk of cancer in Kondratjev V B , Nemirovsky V S , Nikiforov Y F . Meta diabetic patients . BMJ. 2005 , 4 ; 330 (7503 ): 1304 - 5 . bolic immunodepression and metabolic immunotherapy : 2 . Jiralerspong S , Palla SL , Giordano SH , Meric - Bernstam an attempt of improvement in immunologic response in E . Liedtke C . Barnett C M . Hsu L . Hung MC. Hortobagyi 60 breast cancer patients by correction of metabolic distur G N , Gonzalez -Angulo A M . Metformin and pathologic bances. Oncology . 1982 ; 39 ( 1 ) : 13 - 9 . complete responses to neoadjuvant chemotherapy in dia - 10 . Berstein L M . Modern approach to metabolic rehabili betic patients with breast cancer. J Clin Oncol. 2009, tation of cancer patients : biguanides (phenformin and 27 ( 20 ): 3297 - 302 . metformin ) and beyond . Future Oncol. 2010 August ; 3 . Dowling RJ, Goodwin P J, Stambolic V . Understanding 65 6 ( 8 ) :1313 -23 . Review . the benefit of metformin use in cancer treatment . 2011, 11 . Foulkes W D , Smith I E , Reis - Filho JS . Triple -negative BMC Med , 9 : 33 . breast cancer . N Engl J Med . 2010 , 363 (20 ): 1938 -48 . US 9 ,862 , 693 B2 97 98 12 . Carey LA , Perou C M , Livasy CA , Dressler LG , Cowan 4 . The compound of claim 1 , wherein said compound has D , Conway K , Karaca G , Troester M A , Tse C K , the formula : Edmiston S , Deming SL , Geradts J , Cheang MC , Nielsen TO ,Moorman PG , Earp H S , Millikan R C . Race , breast cancer subtypes , and survival in the Carolina Breast 5 (005 ) Cancer Study. JAMA. 2006 Jun . 7 ; 295 (21 ) :2492 -502 . NH NH 13 . Liu B , Fan Z , Edgerton S M , Deng X S , Alimova I N , ?N ' N Lind S E , Thor AD . Metformin induces unique biological or and molecular responses in triple negative breast cancer 10 cells . Cell Cycle . 2009 Jul . 1 ; 8 ( 13 ) : 2031 -40 . (006 ) 14 . Alimova IN , Liu B , Fan Z , Edgerton SM , Dillon T, Lind ?? ?? olla? . SE, Thor A D . Metformin inhibits breast cancer cell growth , colony formation and induces cell cycle arrest in | CN CN: vitro . Cell Cycle . 2009 Mar. 15 ; 8 (6 ) : 909- 15 . 15 15 . James , John W .; Baker , James A . ; Wiggins, Leslie F. Journal of Medicinal Chemistry (1968 ), 11 (5 ) , 942 - 5 . 16 . Kihara , Yoshito ; Kabashima, Shigeru ; Yamasaki , Tetsuo ; 5 . The compound of claim 4 , wherein R3 is hydrogen . Ohkawara , Tadashi; Furukawa, Mitsuru Journal of Het 6 . A pharmaceutical composition comprising a pharma erocyclic Chemistry ( 1990 ) , 27 ( 5 ) , 1913 - 16 . 20 ceutically acceptable excipient and a compound having 17 . Kelarev , V . I. ; Karakhanov , R . A .; Polivin , Yu . N .; formula : Kuatbekov , A . M . ; Remizov , A . S .; Mikaya , A . I. , Khimiya Geterotsiklicheskikh Soedinenii ( 1993 ) , (9 ) , 1271 - 6 . NH NH 18 . Kelarev , V . I. ; Karakhanov , R . A .; Kokosova , A . S .; 25 Gankin , G . D . Khimiya Geterotsiklicheskikh Soedinenii L ' N ( 1992 ), (9 ) , 1250 -6 . - 1R 19 . Kelarev , V . I. ; Karakhanov , R . A .; Bellul, M . ; Ushakova , R . L . ; Mikaya , A . I . Khimiya Geterotsiklicheskikh Soedi nenii ( 1988 ) , ( 5 ) , 674 - 80 . 30 wherein ; 20 . Nagasaka , Hideki; Ichikawa, Eiichi; Odo , Keijiro Yuki L ' and L ? are independently a bond or — NH - C ( NH ) — ; Gosei Kagaku Kyokaishi ( 1967) , 25 (9 ), 802 - 7 . R ' is - NRAR1B , wherein R14 and RB are independently substituted or unsubstituted alkyl and are joined What is claimed is : together to form a substituted or unsubstituted pyrro 1 . A compound having the formula : 35 lidinyl, or an unsubstituted piperidinyl; R² is - NR24R2B , wherein R24 and R2B are independently substituted or unsubstituted alkyl and are joined NH NH together to form a substituted or unsubstituted pyrro lidinyl; and R2 40 R3 is hydrogen or unsubstituted C . - C , alkyl. RIM zN 7 . The pharmaceutical composition of claim 4 , wherein said compound has the formula :

wherein ; (005 ) L ' and L2 are independently a bond or - NH - C ( NH ) ; 45 NH NH Rl is - NR4R1B , wherein R14 and RB are independently substituted or unsubstituted alkyl and are joined N together to form a substituted or unsubstituted pyrro or lidinyl, or an unsubstituted piperidinylnyl:; 50 R² is - NR24R2B , wherein R24 and R2B are independently chlo (006 ) substituted or unsubstituted alkyl and are joined NH NH together to form a substituted or unsubstituted pyrro lidinyl ; and R2 is hydrogen or unsubstituted C , - C alkyl. sig Ž 2 . The compound of claim 1 , wherein L ' and L are bonds and Rº is hydrogen . onda 3 . The compound of claim 2 , wherein R14 and RlB are joined together to form an unsubstituted piperidinyl. * * * *