TOMMANNTILUS009938254B2 UT AT MAN AT THE (12 ) United States Patent ( 10 ) Patent No. : US 9 ,938 ,254 B2 Alexander et al. (45 ) Date of Patent: Apr . 10 , 2018

(54 ) ANTIPROLIFERATIVE COMPOUNDS, AND 5 ,052 ,558 A 10 / 1991 Carter THEIR PHARMACEUTICAL 5 , 059 , 595 A 10 / 1991 Le Grazie 5 , 073 ,543 A 12 / 1991 Marshall et al. COMPOSITIONS AND USES 5 , 120 ,548 A 6 / 1992 McClelland et al . 5 ,229 ,496 A 7 / 1993 Deeley et al. ( 71 ) Applicant: Celgene Corporation , Summit, NJ 5 , 323 , 907 A 6 / 1994 Kalvelage (US ) 5 , 354 , 556 A 10 / 1994 Sparks et al . 5 , 391 ,485 A 2 / 1995 Deeley et al. 5 , 393 , 870 A 2 / 1995 Deeley et al. (72 ) Inventors : Matthew D . Alexander , San Diego , 5 ,528 ,823 A 6 / 1996 Rudy , Jr . et al. CA (US ) ; Matthew D . Correa , San 5 .580 .755 A 12 / 1996 Souza Diego , CA (US ) ; Joshua Hansen , La 5 , 591, 767 A 1 / 1997 Mohr et al. Jolla , CA (US ) ; Raj Kumar Raheja , 5 ,639 ,476 A 6 / 1997 Oshlack et al . Poway, CA (US ) ; John Sapienza , 5 ,639 ,480 A 6 / 1997 Bodmer et al . 5 ,674 , 533 A 10 / 1997 Santus et al . Chula Vista , CA (US ) 5 ,709 ,874 A 1 / 1998 Hanson et al . 5 , 733 ,566 A 3 / 1998 Lewis (73 ) Assignee : Celgene Corporation, Summit, NJ 5 , 739 , 108 A 4 / 1998 Mitchell (US ) 5 , 759 ,542 A 6 / 1998 Gurewich 5 , 811, 097 A 9 / 1998 Allison et al. 5 ,840 ,674 A 11/ 1998 Yatvin et al. ( * ) Notice : Subject to any disclaimer, the term of this 5 ,855 , 887 A 1 / 1999 Allison et al. patent is extended or adjusted under 35 5 , 891 , 474 A 4 / 1999 Busetti et al. U . S . C . 154 ( b ) by 0 days . 5 , 900 , 252 A 5 / 1999 Calanchi et al . 5 ,922 , 356 A 7 / 1999 Koseki et al. ( 21) Appl. No .: 15 /400 , 208 5 , 948 , 893 A 9 / 1999 June et al. 5 , 972 , 366 A 10 / 1999 Haynes et al . 5 ,972 , 891 A 10 / 1999 Kamei et al. ( 22 ) Filed : Jan . 6 , 2017 5 , 980 , 945 A 11/ 1999 Ruiz 5 , 985 , 307 A 11/ 1999 Hanson et al . (65 ) Prior Publication Data 5 ,993 , 855 A 11/ 1999 Yoshimoto et al . 6 ,004 , 534 A 12/ 1999 Langer et al. US 2017 /0197933 A1 Jul. 13 , 2017 6 ,039 ,975 A 3 /2000 Shah et al. Related U .S . Application Data (Continued ) (60 ) Provisional application No . 62 /276 ,763 , filed on Jan . FOREIGN PATENT DOCUMENTS 8 , 2016 . WO WO 2003 /042402 A2 5 /2003 (51 ) Int. Cl. WO WO 2008 / 156712 A1 12 / 2008 CO7D 401 /04 ( 2006 .01 ) CO7F 9 / 59 ( 2006 .01 ) ( Continued ) A61K 31454 ( 2006 . 01 ) OTHER PUBLICATIONS A61K 31 /675 ( 2006 .01 ) U .S . CI. Anguille et al . , “ Leukemia -associated antigens and their relevance (52 ) to the immunotherapy of acute myeloid leukemia ,” Leukemia , CPC ...... C07D 401/ 04 ( 2013 .01 ); A61K 31 /454 26 ( 10 ) :2186 -2196 ( 2012 ) . ( 2013. 01 ) ; A61K 31/ 675 (2013 . 01 ); CO7F Brignone et al. , “ A soluble form of lymphocyte activation gene - 3 9 /591 (2013 .01 ) ( IMP321 ) induces activation of a large range of human effector (58 ) Field of Classification Search cytotoxic cells , " J . Immunol. , 179 (6 ) :4202 - 4211 ( 2007) . CPC . .. . . C07D 401 /04 ; C07F 9 /591 ; A61K 31/ 454 ; Buchwald et al . , “ Long -term , continuous intravenous heparin A61K 31 /675 administration by an implantable infusion pump in ambulatory patients with recurrent venous thrombosis ,” Surgery , 88 : 507 -516 See application file for complete search history. ( 1980 ) . Carstensen , Drug Stability : Principles & Practices , Second Edition , ( 56 ) References Cited Marcel Dekker, New York , NY, pp . 379 - 380 ( 1995 ). Emens et al. , “ : friend of foe to vaccines, " U .S . PATENT DOCUMENTS Curr. Opin . Mol. Ther . , 3 ( 1 ) : 77 - 84 (2001 ) . Folkman et al. , “ Angiogenesis inhibition and tumor regression 3 , 536 ,809 A 10 / 1970 Applezweig caused by heparin or a heparin fragment in the presence of corti 3 , 598 , 123 A 8 / 1971 Zaffaroni sone, ” Science , 221: 719 -725 ( 1983 ) . 3 , 845, 770 A 11/ 1974 Theeuwes et al. Foster , “ Deuterium isotope effects in the metabolism of drugs and 3 , 916 , 899 A 11/ 1975 Theeuwes et al . xenobiotics : implications for drug design , ” Adv. Drug Res ., 14 : 1 -40 4 ,008 ,719 A 2 / 1977 Theeuwes et al. 4 , 044 , 126 A 8 / 1977 Cook et al. ( 1985 ) . 4 , 328 , 245 A 5 / 1982 Yu et al. (Continued ) 4 , 364 , 923 A 12 / 1982 Cook et al . 4 ,409 , 239 A 10 / 1983 Yu et al. Primary Examiner - John M Mauro 4 . 410 . 545 A 10 / 1983 Yu et al . (74 ) Attorney , Agent, or Firm — Jones Day 4 ,414 , 209 A 11/ 1983 Cook et al. 4 , 522 , 811 A 6 / 1985 Eppstein et al . (57 ) ABSTRACT 4 ,810 ,643 A 3 / 1989 Souza Compounds of formula A - I and B - I , compositions compris 4 , 994 ,443 A 2 / 1991 Folkman et al . ing the compounds, methods ofmaking the compounds and 4 , 999 ,291 A 3 / 1991 Souza 5 ,001 , 116 A 3 / 1991 Folkman et al . methods of their uses are disclosed . 5 , 033 , 252 A 7 / 1991 Carter 33 Claims, No Drawings US 9 ,938 , 254 B2 Page 2

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Zello et al. , “ Plasma and urine enrichments following infusion of Fourcade et al. , “ Upregulation of Tim - 3 and PD - 1 expression is L - [ 1 - 13C ]phenylalanine and L - [ ring -2H5 ] phenylalanine in associated with tumor antigen - specific CD8+ T cell dysfunction in humans: evidence for an isotope effect in renal tubular reabsorp melanoma patients , " J . Exp . Med . , 207 ( 10 ) :2175 - 2186 ( 2010 ) . tion , ” Metabolism , 43 ( 4 ) :487 -491 ( 1994 ) . US 9 , 938 , 254 B2 ANTIPROLIFERATIVE COMPOUNDS , AND genic properties . Examples of these cytokines include acidic THEIR PHARMACEUTICAL and basic fibroblastic growth factor ( a , b - FGF ) , angiogenin , COMPOSITIONS AND USES vascular endothelial growth factor ( VEGF ) , and TNF - a . Alternatively , tumor cells can release angiogenic peptides 1 . CROSS REFERENCE TO RELATED 5 through the production of proteases and the subsequent APPLICATIONS breakdown of the extracellular matrix where some cytokines are stored ( e . g . , b - FGF ) . Angiogenesis can also be induced This application claims the benefit of the priority of U . S . indirectly through the recruitment of inflammatory cells Provisional Application No . 62/ 276 , 763 , filed Jan . 8 , 2016 , (particularly macrophages ) and their subsequent release of the disclosure of which is incorporated herein by reference 10 angiogenic cytokines (e .g ., TNF - a , b -FGF ). in its entirety. A variety of other diseases and disorders are also associ ated with , or characterized by , undesired angiogenesis . For 2 . FIELD example , enhanced or unregulated angiogenesis has been implicated in a number of diseases and medical conditions Provided herein are compounds of Formula A - I or B - I or 15 including , but not limited to , ocular neovascular diseases , a stereoisomer or mixture of stereoisomers, tautomer, phar - choroidal neovascular diseases, retina neovascular diseases , maceutically acceptable salt , solvate , hydrate, co -crystal , rubeosis ( neovascularization of the angle ) , viral diseases , clathrate , isotopologue or polymorph thereof for treating , genetic diseases , inflammatory diseases, allergic diseases , preventing or managing cancer. Also provided are pharma and autoimmune diseases . Examples of such diseases and ceutical compositions comprising the compounds and meth - 20 conditions include , but are not limited to , diabetic retinopa ods of use of the compounds and compositions. In certain thy, retinopathy of prematurity , corneal graft rejection , neo embodiments , the methods encompass treating , preventing vascular glaucoma, retrolental fibroplasia , arthritis , and pro or managing cancer, including solid tumors and blood borne liferative vitreoretinopathy . tumors using the compounds provided herein In certain Accordingly , compounds that can control angiogenesis or embodiments , the methods encompass treating , preventing 25 inhibit the production of certain cytokines , including TNFa , or managing cancer , including acute myeloid leukemia and may be useful in the treatment and prevention of various myelodysplastic syndrome, using the compounds provided diseases and conditions . herein . 3 . 2 Methods of Treating Cancer 3 . BACKGROUND OF THE DISCLOSURE 30 Current cancer therapy may involve surgery , chemo 3 . 1 Pathobiology of Cancer and Other Diseases therapy, hormonal therapy and / or radiation treatment to eradicate neoplastic cells in a patient ( see , e . g . , Stockdale , Cancer is characterized primarily by an increase in the 1998 , Medicine , vol . 3 , Rubenstein and Federman , eds. , number of abnormal cells derived from a given normal 35 Chapter 12 , Section IV ). Recently , cancer therapy could also tissue , invasion of adjacent tissues by these abnormal cells , involve biological therapy or immunotherapy . All of these or lymphatic or blood -borne spread of malignant cells to approaches pose significant drawbacks for the patient. Sur regional lymph nodes and to distant sites (metastasis ) . gery, for example , may be contraindicated due to the health Clinical data and molecular biologic studies indicate that of a patient or may be unacceptable to the patient. Addi cancer is a multistep process that begins with minor pre - 40 tionally , surgery may not completely remove neoplastic neoplastic changes, which may under certain conditions tissue. Radiation therapy is only effective when the neoplas progress to neoplasia . The neoplastic lesion may evolve tic tissue exhibits a higher sensitivity to radiation than clonally and develop an increasing capacity for invasion , normal tissue . Radiation therapy can also often elicit serious growth , metastasis , and heterogeneity , especially under con side effects . Hormonal therapy is rarely given as a single ditions in which the neoplastic cells escape the host' s 45 agent . Although hormonal therapy can be effective , it is immune surveillance . Roitt , I ., Brostoff , J and Kale , D . , often used to prevent or delay recurrence of cancer after Immunology , 17 . 1 - 17 . 12 (3rd ed ., Mosby , St. Louis , Mo ., other treatments have removed the majority of cancer cells . 1993 ) . Biological therapies and immunotherapies are limited in There is an enormous variety of which are number and may produce side effects such as rashes or described in detail in the medical literature . Examples 50 swellings , flu - like symptoms, including fever, chills and include cancers of the lung, colon , rectum , prostate , breast, fatigue , digestive tract problems or allergic reactions. brain , and intestine . The incidence of cancer continues to With respect to chemotherapy, there is a variety of che climb as the general population ages , as new cancers motherapeutic agents available for treatment of cancer. A develop , and as susceptible populations ( e. g ., people majority of cancer chemotherapeutics act by inhibiting DNA infected with AIDS or excessively exposed to sunlight) 55 synthesis , either directly or indirectly by inhibiting the grow . However , options for the treatment of cancer are biosynthesis of deoxyribonucleotide triphosphate precur limited . For example , in the case of blood cancers ( e . g ., sors , to prevent DNA replication and concomitant cell multiple myeloma ), few treatment options are available , division . Gilman et al ., Goodman and Gilman ' s : The Phar especially when conventional chemotherapy fails and bone macological Basis of Therapeutics , Tenth Ed . (McGraw marrow transplantation is not an option . A tremendous 60 Hill, New York ) . demand therefore exists for new methods and compositions Despite availability of a variety of chemotherapeutic that can be used to treat patients with cancer. agents , chemotherapy has many drawbacks. Stockdale , Many types of cancers are associated with new blood Medicine , vol. 3 , Rubenstein and Federman , eds. , ch . 12, vessel formation , a process known as angiogenesis . Several sect. 10 , 1998 . Almost all chemotherapeutic agents are toxic , of the mechanisms involved in tumor- induced angiogenesis 65 and chemotherapy causes significant, and often dangerous have been elucidated . The most direct of these mechanisms side effects including severe nausea , bone marrow depres is the secretion by the tumor cells of cytokines with angio sion , and immunosuppression . Additionally , even with US 9 ,938 ,254 B2 administration of combinations of chemotherapeutic agents , R2 and R3 are each halo ; and many tumor cells are resistant or develop resistance to the where the substituents on R ' , when present, are one to chemotherapeutic agents . In fact , those cells resistant to the three groups Q , where each Q is independently alkyl, halo , particular chemotherapeutic agents used in the treatment haloalkyl, hydroxyl , alkoxy, optionally substituted protocol often prove to be resistant to other drugs , even if 5 cycloalkyl; optionally substituted cycloalkylalkyl, option those agents act by different mechanism from those of the ally substituted aryl , — ROR ", - R + SR ” , R + N ( R ) (R ) , drugs used in the specific treatment. This phenomenon is R + OR + N ( R ) ( R ?) or R +OR + C ( J ) N ( R ) ( R ? ) ; referred to as pleiotropic drug or multidrug resistance . J is O or S ; Because of the drug resistance , many cancers prove or each R * is independently alkylene, alkenylene or a direct become refractory to standard chemotherapeutic treatment 10 bond ; protocols . each R $ is independently hydrogen , alkyl, haloalkyl or Other diseases or conditions associated with , or charac - hydroxyalkyl; and terized by, undesired angiogenesis are also difficult to treat. R? and R ' are each independently hydrogen or alkyl, or Rº However, some compounds such as protamine , hepain and and R7 together with the nitrogen atom on which they are steroids have been proposed to be useful in the treatment of 13 substituted form a 5 or 6 -membered heterocyclyl or het certain specific diseases. Taylor et al. , Nature 297 :307 eroaryl ring , optionally substituted with one or two halo , ( 1982 ) ; Folkman et al ., Science 221 :719 ( 1983 ) ; and U . S . alkyl or haloalkyl. Pat . Nos . 5 ,001 , 116 and 4 ,994 ,443 . In other embodiments , provided herein are compounds of Still, there is a significant need for safe and effective Formula B - I : methods of treating, preventing and managing cancer and 2 other diseases and conditions , including for diseases that are refractory to standard treatments , such as surgery , radiation B - I therapy , chemotherapy and hormonal therapy , while reduc ing or avoiding the toxicities and / or side effects associated 0 RR with the conventional therapies. R 4 . SUMMARY ?NIR R2 R3 Provided herein are compounds, pharmaceutical compo sitions containing the compounds and methods of usePO 30 R thereof in treating cancer, including solid tumors and blood borne tumors . In one embodiment, the compounds for use in the compositions and methods provided herein are of For or a stereoisomer or mixture of stereoisomers , tautomer, mulatautomer A - I, pharmaceuticallyor a stereoisomer acceptable or mixture salt ofsolvate stereoisomers . hydrate ., 35 pharmaceutically acceptable salt , solvate , hydrate , co - crys co - crystal, clathrate , isotopologues or polymorph thereof tal, clathrate , isotopologues or polymorph thereof ( Com pound B ) , wherein : ( Compound A ) or of Formula B - I or a stereoisomer or R is H , optionally substituted alkyl, or optionally substi mixture of stereoisomers , tautomer , pharmaceutically salt, tuted cycloalkyl; solvate , hydrate , co - crystal, clathrate , isotopologues or poly - 40 t R ' is H or optionally substituted alkyl; morph thereof ( Compound B ) . R ! is optionally substituted cycloalkyl, optionally substi In certain embodiments, provided herein are compounds tuted aryl, optionally substituted heteroaryl or optionally of Formula A - I : substituted heterocyclyl; R2 and R3 are each halo ; and A 45 where the substituents on R ' , when present, are one to three groups Q , where each Q is independently alkyl, halo , R. haloalkyl, hydroxyl, alkoxy , optionally substituted R. cycloalkyl ; optionally substituted cycloalkylalkyl, option ally substituted aryl, — R -OR , - R +SRS , R4N (R ) (R7 ) , — P = O 50 R +OR + N (R ) (R7 ) or R +OR + C (J )N ( R )( R7 ); Jis O or S ; each R4 is independently alkylene , alkenylene or a direct bond ; each R is independently hydrogen , alkyl, haloalkyl or 55 hydroxyalkyl ; and R? and R ’ are each independently hydrogen or alkyl, or R “ and R7 together with the nitrogen atom on which they are substituted form a 5 or 6 -membered heterocyclyl or het or a stereoisomer or mixture of stereoisomers , tautomer , eroaryl ring , optionally substituted with one or two halo , pharmaceutically acceptable salt, solvate , hydrate , co - crys - 60 alkyl or haloalkyl. tal, clathrate , isotopologues or polymorph thereof ( Com - In one aspect provided herein are pharmaceutical com pound A ), wherein : positionspos containing Compound A or Compound B , and Ris H , optionally substituted alkyl, or optionally substi - methods of use thereof in treating cancer , including solid tuted cycloalkyl; tumors and blood borne tumors . R is optionally substituted cycloalkyl, optionally substi - 65 In one embodiment, the compound provided herein is a tuted aryl , optionally substituted heteroaryl or optionally compound of formula A -I . In one embodiment, the com substituted heterocyclyl; pound provided herein is a tautomer of the compound of US 9 , 938 , 254 B2 formula A - I. In one embodiment, the compound provided ods provided herein encompass methods of preventing vari herein is a pharmaceutically acceptable salt of the compound ous forms of leukemias such as chronic lymphocytic leuke of formula A - I. In one embodiment, the compound provided mia , chronic myeloid leukemia , acute lymphocytic herein is a solvate of the compound of formula A - I . In one leukemia , acute myeloid leukemia and acute myeloblastic embodiment, the compound provided herein is a hydrate of 5 leukemia . In certain embodiments, methods provided herein compound of formula A - I . In one embodiment , the com - encompass methods of managing various forms of leuke pound provided herein is a clathrate of the compound of mias such as chronic lymphocytic leukemia, chronic formula A - I . In one embodiment, the compound provided myeloid leukemia , acute lymphocytic leukemia , acute herein is an isotopologue of the compound of formula A -1 . myeloid leukemia and acute myeloblastic leukemia . The In one embodiment, the compound provided herein is a 10 methods provided herein include treatment of leukemias that compound of formula B -I . In one embodiment, the com - are relapsed , refractory or resistant. The methods provided pound provided herein is a tautomer of the compound of herein include prevention of leukemias that are relapsed , formula B - I. In one embodiment, the compound provided refractory or resistant. The methods provided herein include herein is a pharmaceutically acceptable salt of the compound management of leukemias that are relapsed , refractory or of formula B - I. In one embodiment, the compound provided 15 resistant. In one embodiment, methods provided herein herein is a solvate of the compound of formula B - I . In one encompass methods of treating acute myeloid leukemia . In embodiment , the compound provided herein is a hydrate of one embodiment methods provided herein encompass compound of formula B - I . In one embodiment, the com methods of preventing acute myeloid leukemia . In one pound provided herein is a clathrate of the compound of embodiment methods provided herein encompass methods formula B - I. In one embodiment, the compound provided 20 of managing acute myeloid leukemia . In one embodiment, herein is an isotopologue of the compound of formula B - I . methods provided herein encompass methods of treating a Also provided are pharmaceutical compositions formu myelodysplastic syndrome. In one embodiment, methods lated for administration by an appropriate route and means provided herein encompass methods of preventing a myelo containing effective concentrations of one or more of the dysplastic syndrome. In one embodiment, methods provided compounds provided herein and optionally comprising at 25 herein encompass methods of managing a myelodysplastic least one pharmaceutical carrier. syndrome. In one embodiment the compounds described In one embodiment, the pharmaceutical compositions herein may be used in a method of treating , preventing deliver amounts effective for the treatment of cancer, includ and / or ameliorating any of the diseases described herein . ing solid tumors and blood borne tumors . In one embodi In practicing the methods, effective amounts of the com ment, the pharmaceutical compositions deliver amounts 30 pounds or compositions containing therapeutically effective effective for the prevention of cancer , including solid tumors concentrations of the compounds are administered to an and blood borne tumors. In one embodiment, the pharma- individual exhibiting the symptoms of the disease or disor ceutical compositions deliver amounts effective for the der to be treated . The amounts are effective to ameliorate or amelioration of cancer, including solid tumors and blood eliminate one or more symptoms of the disease or disorder . borne tumors . 35 Further provided is a pharmaceutical pack or kit compris Also provided herein are combination therapies using one ing one or more containers filled with one or more of the or more compounds or compositions provided herein , in ingredients of the pharmaceutical compositions. Optionally combination with a therapy e . g ., another pharmaceutical associated with such container( s ) can be a notice in the form agent with activity against cancer or its symptoms. prescribed by a governmental agency regulating the manu Examples of therapies within the scope of the methods 40 facture, use or sale of pharmaceuticals or biological prod include , but are not limited to , surgery, chemotherapy, ucts , which notice reflects approval by the agency ofmanu radiation therapy , hormonal therapy, biological therapy , facture , use of sale for human administration . The pack or kit immunotherapy, and combinations thereof. can be labeled with information regarding mode of admin The compounds or compositions provided herein may be istration , sequence of drug administration ( e . g ., separately, administered simultaneously with , prior to , or after admin - 45 sequentially or concurrently ) , or the like. istration of one or more of the above therapies . Pharmaceu - These and other aspects of the subject matter described tical compositions containing Compound A or Compound B herein will become evident upon reference to the following provided herein and one or more of the above agents are also detailed description . provided . In certain embodiments , provided herein are methods of 50 5 . DETAILED DESCRIPTION treating , preventing or ameliorating cancer, including solid tumors and blood borne tumors , or one or more symptoms The compounds , methods and compositions are described or causes thereof. In certain embodiments , provided herein in detail in the sections below . are methods of treating cancer, including solid tumors and blood borne tumors , or one or more symptoms or causes 55 5 . 1. Definitions thereof. In certain embodiments , provided herein are meth ods of preventing cancer , including solid tumors and blood Unless defined otherwise , all technical and scientific borne tumors , or one or more symptoms or causes thereof . terms used herein have the same meaning as is commonly In certain embodiments , provided herein are methods of understood by one of ordinary skill in the art . All patents , ameliorating cancer, including solid tumors and blood borne 60 applications , published applications and other publications tumors , or one or more symptoms or causes thereof . In are incorporated by reference in their entirety . In the event certain embodiments , the blood borne tumor is leukemia . In that there are a plurality of definitions for a term herein , certain embodiments , methods provided herein encompass those in this section prevail unless stated otherwise . methods of treating various forms of leukemias such as “ Alkyl” refers to a straight or branched hydrocarbon chain chronic lymphocytic leukemia , chronic myeloid leukemia , 65 group consisting solely of carbon and hydrogen atoms, acute lymphocytic leukemia , acute myeloid leukemia and containing no unsaturation , having from one to ten , one to acute myeloblastic leukemia . In certain embodiments, meth - eight, one to six or one to four carbon atoms, and which is US 9 , 938 , 254 B2 attached to the rest of the molecule by a single bond , e . g ., morpholinyl, piperidinyl, piperazinyl , pyranyl , pyrrolidinyl, methyl, ethyl, n -propyl , 1 -methylethyl ( iso -propyl ) , n -butyl , oxetanyl , azetidinyl, quinuclidinyl , octahydroquinolizinyl, n -pentyl , 1 , 1 -dimethylethyl ( t- butyl) , and the like . decahydroquinolizinyl, azabicyclo [ 3 . 2 . 1 ] octanyl, azabicy “ Alkylene ” and “ alkylene chain ” refer to a straight or clo [ 2 . 2 . 2 ]octanyl , isoindolinyl, indolinyl and others . branched divalent hydrocarbon chain consisting solely of 5 “ Heteroaryl ” refers to a heterocyclyl group as defined carbon and hydrogen , containing no unsaturation and having above which is aromatic . The heteroaryl groups include , but from one to eight carbon atoms, e . g ., methylene , ethylene , propylene , n - butylene and the like . The alkylene chain may are not limited to monocyclyl , bicyclyl and tricyclyl groups, be attached to the rest of the molecule through any two and may be attached to the main structure at any heteroatom carbons within the chain . or carbon atom which results in the creation of a stable “ Alkenylene ” or “ alkenylene chain ” refers to a straight or compound . Examples of such heteroaryl groups include , but branched chain unsaturated divalent radical consisting are not limited to : furanyl, imidazolyl, oxazolyl, isoxazolyl, solely of carbon and hydrogen atoms, having from two to pyrimidinyl, pyridinyl, pyridazinyl, thiazolyl, thienyl, ben eight carbon atoms, wherein the unsaturation is present only zimidazolyl, imidazo [4 ,5 -b ]pyridinyl , imidazo [ 1, 2 -a ]pyridi as double bonds and wherein the double bond can exist 15 nyl, imidazo [ 1 , 2 - b ]pyridazinyl , imidazo [ 1 , 2 - a ) pyrazinyl between any two carbon atoms in the chain , e . g ., ethenylene, and others . prop - 1 - enylene , but- 2 - enylene and the like. The alkenylene “ IC50 ” refers to an amount, concentration or dosage of a chain may be attached to the rest of the molecule through particular test compound that achieves a 50 % inhibition of any two carbons within the chain . a maximal response , such as cell growth or proliferation , “ Alkoxy ” refers to the group having the formula — OR 20 measured via any of the in vitro or cell based assay described wherein R is alkyl or haloalkyl. An “ optionally substituted herein . alkoxy ” refers to the group having the formula OR “ Tautomers ” refers to isomeric forms of a compound that wherein R is an optionally substituted alkyl as defined are in equilibrium with each other. The concentrations of the herein . isomeric forms will depend on the environment the com “ Amino ” refers to a radical having the formula - NR ' R " 25 pound is found in and may be different depending upon , for wherein R ' and R " are each independently hydrogen , alkyl or example , whether the compound is a solid or is in an organic haloalkyl. An " optionally substituted amino ” refers to a cr aqueous solution . For example , in aqueous solution , radical having the formula — NR 'R " wherein one or both of pyrazoles may exhibit the following isomeric forms, which R ' and R " are optionally substituted alkyl as defined herein . are referred to as tautomers of each other: “ Aryl” refers to a group of carbocylic ring system , includ - 30 ing monocyclic , bicyclic , tricyclic , tetracyclic Co - C18 ring systems, wherein at least one of the rings is aromatic . The aryl may be fully aromatic , examples of which are phenyl, naphthyl , anthracenyl , acenaphthylenyl, azulenyl, fluorenyl, HN indenyl and pyrenyl. The aryl may also contain an aromatic 35 ring in combination with a non -aromatic ring , examples of which are acenaphene , indene, and fluorene . As readily understood by one skilled in the art, a wide “ Cycloalkyl” refers to a stable monovalent monocyclic or variety of functional groups and other structures may exhibit bicyclic hydrocarbon group consisting solely of carbon and tautomerism and all tautomers of Compound A or Com hydrogen atoms, having from three to ten carbon atoms 40 pound B are within the scope of the present invention . which is saturated , e . g . , cyclopropyl, cyclobutyl, cyclopen - Pharmaceutically acceptable salts include , but are not tyl, cyclohexyl, decalinyl, norbornane , norbornene , adaman - limited to , amine salts , such as but not limited to N , N tyl, bicyclo [ 2 . 2 . 2 ] octane and the like . dibenzylethylenediamine, chloroprocaine , choline , ammo “ Halo , “ halogen ” or “ halide” refers to F , C1, Br or I . nia , diethanolamine and other hydroxyalkylamines , ethyl " Haloalkyl ” refers to an alkyl group , in certain embodi- 45 enediamine, N -methylglucamine , procaine , ments , C1- alkyl group in which one or more of the hydro - N -benzylphenethylamine , 1 - para -chlorobenzyl - 2 -pyrroli gen atoms are replaced by halogen . Such groups include , but din - 1' - ylmethyl- benzimidazole , diethylamine and other are not limited to , chloromethyl, trifluoromethyl 1 - chloro alkylamines, piperazine and tris( hydroxymethyl ) amin 2 - fluoroethyl, 2 , 2 - difluoroethyl, 2 - fluoropropyl , 2 - fluoro - omethane; alkali metal salts , such as but not limited to propan - 2 - yl, 2 , 2 , 2 - trifluoroethyl, 1 , 1 - difluoroethyl, 1 , 3 - dif - 50 lithium , potassium and sodium ; alkali earth metal salts , such luoro - 2 -methylpropyl , 2 , 2 - difluorocyclopropyl, as but not limited to barium , calcium and magnesium ; ( trifluoromethyl) cyclopropyl , 4 , 4 -difluorocyclohexyl and transition metal salts , such as but not limited to zinc ; and 2 ,2 , 2 - trifluoro - 1, 1- dimethylethyl. other metal salts , such as but not limited to sodium hydrogen “ Heterocycle ” or “ Heterocyclyl” refers to a stable 3 - to phosphate and disodium phosphate ; and also including , but 15 -membered non - aromatic ring radical which consists of 55 not limited to , salts of mineral acids, such as but not limited carbon atoms and from one to five heteroatoms selected to hydrochlorides and sulfates ; and salts of organic acids , from a group consisting of nitrogen , oxygen and sulfur. In such as but not limited to acetates , lactates, malates , tar one embodiment, the heterocyclic ring system radical may trates , citrates , ascorbates , succinates , butyrates , valerates , be a monocyclic , bicyclic or tricyclic ring or tetracyclic ring fumarates and organic sulfonates . system , which may include fused or bridged ring systems; 60 As used herein and unless otherwise indicated , the term and the nitrogen or sulfur atoms in the heterocyclic ring “ hydrate ” means a compound provided herein or a salt system radical may be optionally oxidized ; the nitrogen thereof , that further includes a stoichiometric or non - stoi atom may be optionally quaternized ; and the heterocyclyl chiometeric amount of water bound by non - covalent inter radical may be partially or fully saturated . The heterocyclic molecular forces . ring system may be attached to the main structure at any 65 As used herein and unless otherwise indicated , the term heteroatom or carbon atom which results in the creation of " solvate ” means a solvate formed from the association of a stable compound . Exemplary heterocylic radicals include , one or more solvent molecules to a compound provided US 9 ,938 ,254 B2 10 herein . The term " solvate ” includes hydrates ( e . g ., mono for compounds that undergo epimerization in vivo , to hydrate , dihydrate , trihydrate , tetrahydrate and the like ) . administration of the compound in its ( S ) form . Unless stated otherwise specifically described in the Optically active ( + ) and ( - ), ( R ) - and ( S )- , or ( D ) - and specification , it is understood that the substitution can occur ( L ) -isomers may be prepared using chiral synthons or chiral on any atom of the alkyl, alkenyl, alkynyl, cycloalkyl, 5 reagents , or resolved using conventional techniques, such as heterocyclyl, aryl or heteroaryl group . chromatography on a chiral stationary phase . Where the number of any given substituent is not speci In the description herein , if there is any discrepancy between a chemical name and chemical structure , the struc fied ( e .g ., haloalkyl) , there may be one or more substituents ture controls. present. For example , “ haloalkyl” may include one or more 10 As used herein and unless otherwise indicated , the terms of the same or different halogens . " treat, " " treating ” and “ treatment” refer to alleviating or When the groups described herein , with the exception of reducing the severity of a symptom associated with the alkyl group , are said to be “ substituted ,” they may be disease or condition being treated . substituted with any appropriate substituent or substituents . The term " prevention ” includes the inhibition of a symp Illustrative examples of substituents are those found in the 15 tom of the particular disease or disorder. In some embodi exemplary compounds and embodiments disclosed herein , ments , patients with familial history of cancer, including as well as halogen ( chloro , iodo , bromo, or fluoro ) ; alkyl ; solid tumors and blood borne tumors, are candidates for hydroxyl ; alkoxy ; alkoxyalkyl; amino ; alkylamino ; carboxy ; preventive regimens. Generally , the term " preventing ” refers nitro ; cyano ; thiol; thioether; imine ; imide; amidine ; guani to administration of the drug prior to the onset of symptoms, dine ; enamine ; aminocarbonyl; acylamino ; phosphonate ; 20 particularly to patients at risk of cancer , including solid phosphine ; thiocarbonyl; sulfinyl; sulfone; sulfonamide ; tumors and blood borne tumors . ketone ; aldehyde; ester; urea ; urethane ; oxime; hydroxyl As used herein and unless otherwise indicated , the term amine ; alkoxyamine ; aryloxyamine , aralkoxyamine ; N -ox “ managing " encompasses preventing the recurrence of the ide ; ; hydrazide ; hydrazone ; azide ; isocyanate ; particular disease or disorder in a patient who had suffered isothiocyanate ; cyanate ; thiocyanate ; oxygen ( O ) ; B (OH ) 25 from it, lengthening the time a patient who had suffered from 2 , O (alkyl ) aminocarbonyl; cycloalkyl, which may be mono - the disease or disorder remains in remission , reducing mor cyclic or fused or non - fused polycyclic ( e . g ., cyclopropyl, tality rates of the patients, and /or maintaining a reduction in cyclobutyl, cyclopentyl, or cyclohexyl) , or a heterocyclyl, severity or avoidance of a symptom associated with the which may be monocyclic or fused or non - fused polycyclic disease or condition being managed . ( e . g ., pyrrolidyl , piperidyl , piperazinyl, morpholinyl, or thi- 30 As used herein , “ subject ” is an animal, typically a mam azinyl ); monocyclic or fused or non - fused polycyclic aryl or mal, including a human , such as a human patient . heteroaryl ( e. g . , phenyl , naphthyl , pyrrolyl, indolyl, furanyl, As used herein , the term “ tumor ,” refers to all neoplastic thiophenyl, imidazolyl, oxazolyl , isoxazolyl, thiazolyl , tri - cell growth and proliferation , whether malignant or benign , azolyl , tetrazolyl , pyrazolyl , pyridinyl, quinolinyl, isoquino and all pre -cancerous and cancerous cells and tissues . “ Neo linyl, acridinyl , pyrazinyl, pyridazinyl, pyrimidinyl, benz - 35 plastic ," as used herein , refers to any form of dysregulated imidazolyl, benzothiophenyl, or benzofuranyl) aryloxy ; or unregulated cell growth , whether malignant or benign , aralkyloxy ; heterocyclyloxy ; and heterocyclyl alkoxy. When resulting in abnormal tissue growth . Thus, “ neoplastic cells ” the alkyl groups described herein are said to be “ substi - include malignant and benign cells having dysregulated or tuted ,” they may be substituted with any substituent or unregulated cell growth . substituents as those found in the exemplary compounds and 40 As used herein , " hematologic malignancy ” refers to can embodiments disclosed herein , as well as halogen ( chloro , cer of the body ' s blood - forming and immune system the iodo , bromo , or fluoro ) ; alkyl ; hydroxyl; alkoxy ; alkoxy - bone marrow and lymphatic tissue . Such cancers include alkyl; amino ; alkylamino ; carboxy ; nitro ; cyano ; thiol; thio leukemias , (Non -Hodgkin ' s ) , ether ; imine; imide; amidine; guanidine; enamine ; aminocar Hodgkin ' s disease (also called Hodgkin ' s Lymphoma) and bonyl; acylamino ; phosphonate ; phosphine ; thiocarbonyl ; 45 myeloma . In one embodiment, the myeloma is multiple sulfinyl; sulfone ; sulfonamide ; ketone ; aldehyde ; ester; urea ; myeloma. In some embodiments , the leukemia is , for urethane ; oxime; hydroxyl amine ; alkoxyamine ; ary - example , acute myelogenous leukemia (AML ) , acute lym loxyamine, aralkoxyamine ; N -oxide ; hydrazine ; hydrazide ; phocytic leukemia ( ALL ) , adult T - cell leukemia , chronic hydrazone ; azide ; isocyanate ; isothiocyanate ; cyanate ; thio - lymphocytic leukemia (CLL ) , hairy cell leukemia , myelo cyanate ; B (OH ) , or O ( alkyl) aminocarbonyl. 50 dysplasia , myeloproliferative disorders , chronic myelog Unless specifically stated otherwise , where a compound enous leukemia (CML ), myelodysplastic syndrome (MDS ) , may assume alternative tautomeric , regioisomeric and / or human lymphotropic virus - type 1 (HTLV 1 ) leukemia , mas stereoisomeric forms, all alternative isomers are intended to tocytosis , or B - cell acute lymphoblastic leukemia . In some be encompassed within the scope of the claimed subject embodiments , the lymphoma is, for example , diffuse large matter . For example , where a compound is described as 55 B -cell lymphoma (DLBCL ), B -cell immunoblastic lym having one of two tautomeric forms, it is intended that the phoma, small non -cleaved cell lymphoma, human lympho both tautomers be encompassed herein . tropic virus - type 1 (HTLV - 1 ) leukemia / lymphoma, adult Thus, the compounds provided herein may be T - cell lymphoma, peripheral T - cell lymphoma (PTCL ) , cuta enantiomerically pure , or be stereoisomeric or diastereo - neous T - cell lymphoma ( CTCL ) , mantle cell lymphoma meric mixtures . 60 (MCL ) , Hodgkin lymphoma ( HL ) , non -Hodgkin lymphoma It is to be understood that the compounds provided herein (NHL ), AIDS - related lymphoma, follicular lymphoma, may contain chiral centers . Such chiral centers may be of small lymphocytic lymphoma, T -cell /histiocyte rich large either the ( R ) or ( S ) configuration , or may be a mixture B - cell lymphoma, transformed lymphoma , primary medi thereof. It is to be understood that the chiral centers of the astinal ( thymic ) large B -cell lymphoma , splenic marginal compounds provided herein may undergo epimerization in 65 zone lymphoma, Richter ' s transformation , nodal marginal vivo . As such , one of skill in the art will recognize that zone lymphoma, or ALK - positive large B - cell lymphoma. In administration of a compound in its ( R ) form is equivalent, one embodiment , the hematological cancer is indolent lym US 9 , 938 , 254 B2 11 12 phoma including , for example , DLBCL , follicular lym The term “ the supportive care agent” refers to any sub phoma, or marginal zone lymphoma . stance that treats , prevents or manages an adverse effect The term “ leukemia ” refers to malignant neoplasms of the from treatment with the compound of Formula I. blood - forming tissues . The leukemia includes, but is not The term “ biological therapy ” refers to administration of limited to , chronic lymphocytic leukemia , chronic myelo 5 biological therapeutics such as cord blood , stem cells , cytic leukemia , acute lymphoblastic leukemia , acute growth factors and the like . myeloid leukemia , and acute myeloblastic leukemia . The The term “ about, " as used herein , unless otherwise indi leukemia can be relapsed , refractory or resistant to conven cated , refers to a value that is no more than 10 % above or tional therapy . below the value being modified by the term . For example, The term “ myelodysplastic syndrome” refers to hemato - 10 tothe 11term mo “ about 10 mg/ m “ ” means a range of from 9 mg/ m “ logical conditions characterized by abnormalities in the “ Anti -cancer agents ” refer to anti -metabolites ( e . g . , production of one or more of the cellular components of 5 - fluoro - uracil , , ) , antimicrotubule blood (red cells , white cells ( other than lymphocytes ) and agents ( e . g ., vinca alkaloids such as , ; platelets ( or their progenitor cells , megakaryocytes )) , and such as , ) , alkylating agents includes the following disorders: refractory anemia (RA ) ; 15 (e . g ., , , , nitrosou RA with ringed sideroblasts (RARS ) ; RA with excess of reas such as bischloroethylnitrosurea and hydroxyurea ) , blasts (RAEB ) ; refractory cytopenia with multilineage dys - platinum agents ( e . g . , , , plasia (RCMD ), refractory cytopenia with unilineage dys JM -216 or , CI- 973 ) , ( e . g . , doxo plasia (RCUD ) ; unclassifiable myelodysplastic syndrome rubicin , ) , antitumor antibiotics ( e . g ., mitomy (MDS - U ) , myelodysplastic syndrome associated with an . cin , , adriamycin , daunomycin ) , topoisomerase isolated del( 59 ) chromosome abnormality , therapy -related inhibitors ( e . g ., , ) , anti - angiogen myeloid neoplasms and chronic myelomonocytic leukemia esis agents ( e . g . Sutent® and Bevacizumab ) or any other cytotoxic agents , ( , ), (CMML ) . hormones or hormone agonists , antagonists, partial agonists As used herein , “ promyelocytic leukemia ” or “ acute pro or partial antagonists , kinase inhibitors , checkpoint inhibi myelocytic leukemia ” refers to a malignancy of the bone .25 tors and radiation treatment. marrow in which there is a deficiency ofmature blood cells As used herein , overall survival (OS ) means the time from in the myeloid line of cells and an excess of immature cells randomization in a clinical trial until death from any cause . called promyelocytes . It is usually marked by an exchange As used herein , progression - free survival ( PFS ) means the of regions of chromosomes 15 and 17. time from randomization in a clinical trial until progression As used herein , “ acute lymphocytic leukemia (ALL )” " , 30 or death . As used herein , event - free survival (EFS ) means also known as " acute lymphoblastic leukemia ” refers to a the time from study entry until any treatment failure , includ malignant disease caused by the abnormal growth and ing disease progression , treatment discontinuation for any development of early nongranular white blood cells , or reason , or death . As used herein , overall response rate lymphocytes . (ORR ) means the sum of the percentage of patients who As used herein , “ T - cell leukemia ” refers to a disease in achieve complete and partial responses . As used herein , which certain cells of the lymphoid system called T lym duration of response (DoR ) is the time from achieving a phocytes or T cells are malignant. T cells are white blood response until relapse or disease progression . cells that normally can attack virus- infected cells , foreign Citation or identification of any reference in this applica cells , and cancer cells and produce substances that regulate tion is not to be construed as an admission that the reference the immune response . is prior art to the present application . The term " relapsed ” refers to a situation where patients 40 As used herein , the abbreviations for any protective who have had a remission of leukemia after therapy have a groups , amino acids and other compounds, are , unless return of leukemia cells in the marrow and a decrease in indicated otherwise , in accord with their common usage , normal blood cells . recognized abbreviations, or the IUPAC - IUB Commission The term " refractory or resistant” refers to a circumstance on Biochemical Nomenclature ( see , Biochem . 1972 , 11 : 942 where patients , even after intensive treatment, have residual 4545 944 ). leukemia cells in their marrow . 5 .2 . Compounds As used herein , and unless otherwise specified , the terms " therapeutically effective amount" and " effective amount" of a compound refer to an amount sufficient to provide a In certain embodiments , provided herein are compounds therapeutic benefit in the treatment, prevention and / or man - 50 of Formula A -I : agement of a disease , to delay or minimize one or more AI symptoms associated with the disease or disorder to be treated . The terms “ therapeutically effective amount” and " effective amount " can encompass an amount that improves RÓ overall therapy , reduces or avoids symptoms or causes of 55 disease or disorder , or enhances the therapeutic efficacy of -O P = O another therapeutic agent. The terms “ co - administration ” and “ in combination with ” include the administration of two therapeutic agents ( for example , a compound provided herein and another anti cancer agent ) either simultaneously , concurrently or sequenden. 60 RR tially with no specific time limits. In one embodiment , both RIA agents are present in the cell or in the patient' s body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form . In another 65 or a stereoisomer or mixture of stereoisomers, tautomer, embodiment, the two therapeutic agents are in separate pharmaceutically acceptable salt , solvate , hydrate , co -crys compositions or unit dosage forms. tal, clathrate , isotopologue or polymorph thereof, wherein : US 9 ,938 ,254 B2 13 14 R is H , optionally substituted alkyl, or optionally substi where the substituents on R ' , when present are one to tuted cycloalkyl ; three groups Q , where each Q is independently alkyl, halo , Rl is optionally substituted cycloalkyl, optionally substi haloalkyl, hydroxyl, alkoxy , optionally substituted tuted aryl, optionally substituted heteroaryl or optionally cycloalkyl, optionally substituted cycloalkylalkyl, option substituted heterocyclyl; 5 ally substituted aryl , — R4OR , R4SRS, - R4N ( R ) ( R ) , R2 and R3 are each halo ; and R ORAN ( R )( R7 ) or R4OR4C (J )N (R )( R7 ); where the substituents on R ' , when present , are one to J is O or S ; three groups Q , where each Q is independently alkyl , halo , each R * is independently alkylene, alkenylene or a direct haloalkyl, hydroxyl, alkoxy , optionally substituted bond ; cycloalkyl; optionally substituted cycloalkylalkyl, option - 10 boneach R is independently hydrogen , alkyl, haloalkyl or ally substituted aryl, - R4ORS, - R4SRS. — RºN ( R (R7 ) . hydroxyalkyl; and R +OR + N (R ) ( R ) or R * OR * C ( J) N (R ) (R ) ; R? and R ’ are each independently hydrogen or alkyl or Ró J is O or S ; and R ’ together with the nitrogen atom on which they are each R4 is independently alkylene. alkenylene or a direct substituted form a 5 or 6 -membered heterocyclyl or het bond ; 15 eroaryl ring , optionally substituted with one or two halo , each R is independently hydrogen , alkyl, haloalkyl or alkyl or haloalkyl. hydroxyalkyl; and In one embodiment, the compounds have Formula A - I or Roand R ' are each independently hydrogen or alkyl, or R6 of Formula A - ll , wherein R is H or ( Cy -C6 )alkyl ; R is and R together with the nitrogen atom on which they are optionally substituted aryl, optionally substituted cycloalkyl, substituted form a 5 or 6 -membered heterocyclvl or het- 20 optionally substituted heterocyclyl, or optionally substituted eroaryl ring , optionally substituted with one or two halo heteroaryl , where the substituents on R ', when present, are alkyl or haloalkyl. one to three groups Q , where each Q is independently halo , In one embodiment, provided herein are compounds of alkyl, optionally substituted cycloalkyl, optionally substi tuted aryl , ROR ” , orR + N ( R ) ( R ) ; each R is inde Formula A - II : 25 pendently a direct bond or alkylene ; each R is indepen dently hydrogen , halo , alkyl , alkoxy, haloalkoxy, or haloalkyl ; and R? and R ’ are each independently hydrogen A - II or alkyl, or R™ and R ’ together with the nitrogen atom on which they are substituted form a 5 or 6 -membered hetero 30 cyclyl or heteroaryl ring , optionally substituted with one or O - P = 0 two halo , alkyl or haloalkyl. In one embodiment, the compounds have Formula A - I or Formula A - II , wherein R is H or (C , -C .) alkyl ; R is option ally substituted phenyl, optionally substituted cyclohexyl, RI 35 optionally substituted piperidinyl, or optionally substituted L N N pyridyl, where the substituents on R ' , when present, are one L to three groups Q , where each Q is independently halo , alkyl, — R OR ' or — R * N ( R ) ( R ' ) ; each R * is independently a direct bond or alkylene ; each R is independently hydro 40 gen , halo , alkyl, alkoxy, haloalkoxy or haloalkyl; and Rand or a stereoisomer or mixture of stereoisomers , tautomer , R ’ are each independently hydrogen or alkyl; or ii ) R and pharmaceutically acceptable salt, solvate , hydrate , co - crys - RP together with the nitrogen atom on which they are tal, clathrate, isotopologue or polymorph thereof, wherein : substituted form a 5 or 6 -membered heterocyclyl ring . Ris H , optionally substituted alkyl , or optionally substi - In one embodiment, the compounds have Formula A - I or tuted cycloalkyl; 45 of Formula A - II, R is H or ( C , - C . )alkyl ; wherein Rl is R ! is optionally substituted cycloalkyl , optionally substi - optionally substituted phenyl, optionally substituted cyclo tuted aryl, optionally substituted heteroaryl or optionally hexyl, optionally substituted piperidinyl , or optionally sub substituted heterocyclyl; stituted pyridyl, where the substituents on R ', when present where the substituents on R ' , when present are one to are one to three groups Q , where each Q is independently three groups Q , where each Q is independently alkyl, halo , 50 bromo, fluoro , chloro , methyl, isopropyl, tert butyl tri haloalkyl, hydroxyl, alkoxy , optionally substituted fluromethyl, methoxy, ethoxy , isopropyloxy, methoxy cycloalkyl, optionally substituted cycloalkylalkyl, option - ethoxy, isopropyloxyethoxy, trifluoromethoxy, methyl ally substituted aryl, - R OR , R +SR , - RºN ( R ) ( R ) , amino , dimethylamino or piperidinyl . R4OR4N (R )( R7 ) or R4OR4C (J ) N (R )( R7 ); In one embodiment, the compounds have Formula A - I or J is O or S ; 55 Formula A - II , wherein R is H or (C - C )alkyl ; R ' is option each R * is independently alkylene , alkenylene or a direct ally substituted aryl, where the substituents on R ' , when bond ; present, are one to three groups Q , where each Q is inde each R is independently hydrogen , alkyl, haloalkyl or pendently halo , alkyl , - R OR " , - R + SR or R + OR + C ( O ) N hydroxyalkyl ; and (RC ) (R7 ) ; each R4 is independently a direct bond or alkylene ; Rº and R ' are each independently hydrogen or alkyl or R 60 each R is independently hydrogen , halo , alkyl or haloalkyl; and R7 together with the nitrogen atom on which they are and R? and R ? are each independently hydrogen or alkyl. substituted form a 5 or 6 -membered heterocyclyl or het - In one embodiment, the compounds have Formula A - I or eroaryl ring , optionally substituted with one or two halo , Formula A - II, wherein R is H or ( C , -C .) alkyl ; R ' is option alkyl or haloalkyl. ally substituted aryl, where the substituents on R ' , when In one embodiment, the compounds have Formula A - I or 65 present, are one to three groups Q , where each Q is inde of Formula A - II , wherein R is H or (C1 - C . ) alkyl; pendently fluoro , chloro ,methyl , - R - OR " , - R *N ( R )( R ?) , Rl is optionally substituted aryl, - R SRS or R * OR * C ( O ) N (RC ) ( R ? ) ; each R4 is indepen US 9 ,938 ,254 B2 15 16 dently a direct bond or methylene ; each R is independently hydrogen , methyl, ethyl or trifluoromethyl ; and R? and R ? A - IV are each independently hydrogen or methyl. In one embodiment, the compounds have Formula A - I or ? Formula A - II , wherein R is H or ( C . - C . )alkyl ; R is option 5 O O - P = C ally substituted phenyl, where the substituents on R ' , when ? present, are one to three groups Q , where each Q is inde pendently fluoro , chloro , methyl, tert butyl, — R *OR , - R + N ( R ) ( R ? ) , — R SRS or R *OR * C ( O ) N ( R ) (R ') ; each 10 R4 is independently a direct bond or methylene ; each R is 1 independently hydrogen , methyl, ethyl or trifluoromethyl; and R? and R ’ are each independently hydrogen or methyl. In one embodiment, provided herein are compounds of 15 Formula A - III: or a stereoisomer or mixture of stereoisomers , tautomer , pharmaceutically acceptable salt, solvate , hydrate , co - crys tal, clathrate , or polymorph thereof, wherein : R is H , optionally substituted alkyl, or optionally substi 20 tuted cycloalkyl; A - III Q2 is hydrogen , alkyl, halo , haloalkyl, hydroxyl, alkoxy , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl , optionally substituted aryl, R *OR " , - R4SR " , - R4N ( R " ) (R7 ) , R4ORAN ( R ' ) (R7 ) or R4OR4C ( J ) O - P = 0 25 N (R ) (R ') ; J is O or S ; each R4 is independently alkylene , alkenylene or a direct bond ; HN each RS is independently hydrogen , alkyl , haloalkyl or hydroxyalkyl; and 17 Rº and R ' are each independently hydrogen or alkyl. In one embodiment, the compounds herein are of Formula A - IV , where R is H , optionally substituted alkyl, or option or a stereoisomer or mixture of stereoisomers, tautomer , 35 ally substituted cycloalkyl; Q is hydrogen , halo , alkyl, pharmaceutically acceptable salt , solvate , hydrate , co -crys optionally substituted aryl, — R OR > or R?N ( R )( R ?) ; R4 tal, clathrate, isotopologue or polymorph thereof, wherein : is independently a direct bond or alkylene ; Rºis hydrogen , alkyl or haloalkyl; and R and R7 are each independently R is H , optionally substituted alkyl, or optionally substi hydrogen or alkyl. In some embodiments , R is H , optionally tuted cycloalkyl; 40 substituted alkyl, or optionally substituted cycloalkyl; Q is each Q1 is independently alkyl, halo , haloalkyl, alkoxy - hydrogen , Br, C1, F, methyl, isopropyl, t- butyl , isopropyl, alkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl, OCHz, - C (CH3 ) 2F, OCH ( CH3) 2, O (CH2 ) 2OCHz , optionally substituted cycloalkylalkyl, optionally substituted or p - fluorophenyl. aryl — R OR " , - R * SR " , - RºN ( R ) ( R ) , R OR + N ( R ' ) ( R ) In one embodiment , the compoundsherein are of Formula or R +OR + C ( J) N ( R ) (R7 ) ; 45 A - IV , where R is independently H , optionally substituted alkyl, or optionally substituted cycloalkyl; and Q2 is Br, Cl, J is O or S ; or F . each R4 is independently alkylene , alkenylene or a directect In one embodiment, provided herein are compounds of bond ; Formula A - V : each R is independently hydrogen , alkyl , haloalkyl or 50 hydroxyalkyl ; R? and R ’ are each independently hydrogen or alkyl or Rº A -V and R together with the nitrogen atom on which they are substituted form a 5 or 6 -membered heterocyclyl or het ROO eroaryl ring , optionally substituted with one or two halo , 0 - P = O alkyl or haloalkyl; and

n is 0 - 3 . O In one embodiment, provided herein are compounds of Formula A - III, wherein R is H or (C1 - C™) alkyl and Q ? is ou IZ alkyl or halo . In another embodiment, provided herein are compounds of Formula A - III , wherein R is H and Q ' is halo . In one embodiment, provided herein are compounds of Formula A - III , wherein R is H and Q ' is fluorooro or chlorochloro . 65as or a stereoisomer or mixture of stereoisomers, tautomer , In one embodiment, provided herein are compounds of pharmaceutically acceptable salt , solvate , hydrate , co - crys Formula A - IV : tal, clathrate , or polymorph thereof, wherein : US 9 , 938 , 254 B2 18 R is H , optionally substituted alkyl, or optionally substi R and R7 are selected as follows: tuted cycloalkyl; i ) R and R ’ are each independently hydrogen or alkyl; or ii ) Rº and R7 together with the nitrogen atom on which Q and Q + are each independently hydrogen , alkyl, halo , they are substituted form a 5 or 6 -membered heterocyclyl or haloalkyl, hydroxyl, alkoxy, optionally substituted* 5 heteroaryl ring , optionally substituted with one or two halo , cycloalkyl , optionally substituted cycloalkylalkyl, 5 . alkyl or haloalkyl. - RORS, - R4SRS, R4N (R™ ) ( R ), RAORAN (R ) (R7 ) or In one embodiment, the compounds herein are of Formula R + OR + C ( J) N ( R ) (R7 ) ; A -VI , where R is H , optionally substituted alkyl, or option J is O or S ; ally substituted cycloalkyl; Q4 and are each indepen each R4 is independently alkylene, alkenylene or a direct 10 dently hydrogen , halo , alkyl, alkoxyalkyl, — R + N (Rº ) ( R ) , or — ROR ; R * is a direct bond or alkylene ; Rºis hydrogen , bond ; alkyl or haloalkyl; and Rand R ’ together with the nitrogen each R $ is independently hydrogen , alkyl, haloalkyl, atom on which they are substituted form a 6 -membered hydroxyalkyl, or alkoxyalkyl; and heterocyclyl. In some such embodiments , Q4 and Q are R? and R ’ are each independently hydrogen or alkyl. each independently hydrogen , F , CI, OH , methyl, CF3 , are ofFormula 15 — NHCHZ, - N ( CH3) 2, OCF3, OCH CH3, In one embodiment, the compounds herein are of Formula OCH _ CF3, OCH (CH3 ) 2 , O ( CH2) 2OCH3, A - V , where Ris H , optionally substituted alkyl, or optionally O ( CH2) 2OCH ( CH3) 2 , O ( CH2) 2O (CH2 ) 2OCHz, substituted cycloalkyl; Q4 and Q are each independently O (CH2 ) 2- morpholinyl , piperidyl, morpholinyl, CH2- mor hydrogen , halo , alkyl, alkoxyalkyl, - R OR ” , or - RºN (RO ) pholinyl , or O ( CH2) 2 - 4 ,4 - difluoro - 1 -piperidyl . (R7 ) ; R4 is a direct bond or alkylene ; and R * is hydrogenarogan ,: 202 In one embodiment, provided herein are compounds of alkyl or haloalkyl; and R and R7 are each independently Formula A - VII : hydrogen or alkyl. In some such embodiments , R is H , optionally substituted alkyl, or optionally substituted cycloalkyl; Q4 and Q are each independently hydrogen , F , methyl, CF3 , OH , - OCF3, - OCH2CH3, OCH (CH3 ) 2, 25 A - VII - OCH CF3, or — NHCHZ. R In one embodiment, the compounds herein are of Formula A - V , R is H , optionally substituted alkyl , or optionally - P = O substituted cycloalkyl; where Q4 is hydrogen ; Q is hydro OT gen , halo , alkyl, alkoxyalkyl, - R * N (R )( R7 ), or — R OR "; 30 R4 is a direct bond or alkylene ; R is hydrogen , alkyl or haloalkyl; and R? and R7 are each independently hydrogen L or alkyl. L In one embodiment, provided herein are compounds of Formula A - VI: 35 or a stereoisomer or mixture of stereoisomers , tautomer , A - VI pharmaceutically acceptable salt , solvate, hydrate , co - crys tal, clathrate , or polymorph thereof, wherein : 40 R is H , optionally substituted alkyl, or optionally substi RÓ tuted cycloalkyl; P = 0 Dis hydrogen , alkyl, halo , haloalkyl, hydroxyl, alkoxy , optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, R OR , R -SR , R4N ( R )( R ), o 45 R4ORAN ( R ' ) ( R ) or R4OR4C ( J ) N (RC ) (R7 ) ; = 0 J is O or S ; IT each R4 is independently alkylene, alkenylene or a direct LI bond; OB each R is independently hydrogen , alkyl, haloalkyl , 50 alkoxyalkyl or hydroxyalkyl; and R and R ’ are selected as follows : or a stereoisomer or mixture of stereoisomers , tautomer, i) R™ and R7 are each independently hydrogen or alkyl ; or pharmaceutically acceptable salt, solvate , hydrate , co - crys i i) R and R7 together with the nitrogen atom on which tal, clathrate , or polymorph thereof, they are substituted form a 5 or 6 -membered heterocyclyl or wherein : R is H , optionally substituted alkyl, or optionally 55 heteroaryl ring , optionally substituted with one or two halo , substituted cycloalkyl; alkyl or haloalkyl. Q4 and Q are each independently hydrogen , alkyl, halo , In one embodiment, the compounds herein are of Formula haloalkyl, hydroxyl, alkoxy, optionally substituted A -VII , where R is H , optionally substituted alkyl, or option cycloalkyl, optionally substituted cycloalkylalkyl, ally substituted cycloalkyl; Q is hydrogen , halo , alkyl, - R4ORS , - R4SR " , - R4N ( R ) ( R ? ) , R4ORAN ( R ) ( R ? ) or 60 alkoxyalkyl, — R N ( R ) ( R ) or — R - OR " ; R * is a direct R +OR + C ( J) N (R ) (R7 ) ; bond or alkylene ; and R is hydrogen , alkyl or haloalkyl; and Rºand R together with the nitrogen atom on which they are J is O or S ; substituted form a 6 -membered heterocyclyl. In some such each R * is independently alkylene, alkenylene or a direct embodiments , Q is hydrogen , F , C1, methyl, piperidyl , bond ; 65 morpholinyl, CH2 -morpholinyl , N (CH3 ) 2 , each R is independently hydrogen , alkyl, haloalkyl, O (CH2 ) 2OCHz, O (CH2 ) 2OCH (CH3 ) 2 , O (CH2 ) 20 alkoxyalkyl or hydroxyalkyl; and (CH2 ) 2OCH3 , or O (CH2 ) 2 - 4 ,4 -difluoro - 1- piperidyl . US 9 , 938 ,254 B2 19 20 In one embodiment, provided herein are compounds of each Q1 is independently alkyl, halo , haloalkyl, alkoxy Formula A - VIII : alkyl, hydroxyl, alkoxy, optionally substituted cycloalkyl ; optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, — R OR " , ROR – ROR , R4N ( R ' ) A - VIII 5 ( R ? ) , R SR , R OR N ( R ) ( R ) , R + OR + C ( J ) N ( R ) ( R ), C (JR or R +S (O ), R® ; Jis O or S ; each R4 is independently alkylene, alkenylene or a direct - P = bond ; each R is independently hydrogen , oxo , alkyl, haloalkyl , hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, het

I erocyclyl or heterocyclylalkyl, where alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, het I erocyclyl or heterocyclylalkyl groups in R are each inde pendently optionally substituted with 1 - 3 Q ' groups , each independently selected from alkyl, haloalkyl or halo ; or a stereoisomer or mixture of stereoisomers, tautomer, Ró and R ' are each independently hydrogen or alkyl; pharmaceutically acceptable salt , solvate , hydrate , co -crys R® is alkyl, haloalkyl, or hydroxyalkyl; tal, clathrate , or polymorph thereof, wherein : 20 Rº is alkyl or aryl; Ris H , optionally substituted alkyl, or optionally substi J is O or S ; tuted cycloalkyl; Q and Q are each independently hydrogen , alkyl, halo , t is 1 or 2 ; and haloalkyl, hydroxyl, alkoxy, optionally substituted n is 0 - 3 . cycloalkyl, optionally substituted cycloalkylalkyl, option 25 In one embodiment , the compounds herein are of Formula ally substituted aryl , - R + OR ” , - R SRS, R *N (RO ) ( R ?) , A - IX , where R is H , optionally substituted alkyl, or option R4ORAN ( R™) (R7 ) or R4OR4C ( J ) N ( R ) (R7 ) ; ally substituted cycloalkyl; where each Q ' is independently J is O or S ; hydrogen , halo , alkyl, haloalkyl, alkoxyalkyl or haloalkoxy each R4 is independently alkylene , alkenylene or a direct alkyl. In some embodiments , each Q ' is independently bond ; 30 fluoro, chloro , bromo, methyl , isopropyl , t - butyl, CF3 , each RS is independently hydrogen , alkyl , haloalkyl or O CH2CH3, O CH (CH3 ) 2 , or cyclopropyl . hydroxyalkyl; and In one embodiment, the compound provided herein is Rº and R ' are each independently hydrogen or alkyl, or RC selected from the group consisting of: and R ' together with the nitrogen atom on which they are substituted form a 6 -membered heterocyclyl. In one embodiment, the compounds herein are of Formula OH A - VIII, where R is H , optionally substituted alkyl, or OH, optionally substituted cycloalkyl ; Q and Q are each inde pendently hydrogen , F , Br, Cl, methyl, isopropyl , t -butyl , F F - C ( CH3) 2F , p - fluorophenyl, cyclopropyl, — N (CH3 ) 2 , 40 OCHz, OCH (CH3 ) 2 , O ( CH2) 2OCHz , O (CH2 ) 2OCH ( CH3) 2 , O ( CH2) 2OCHZ , O (CH2 ) 2O (CH2 ) 2OCHZ, - OCF3, O ( CH2) 2 -4 ,4 -difluoro - 1 -piperidyl , SCF3, morpholinyl, piperidyl, or CH2-morpholinyl . ? , ?? In one embodiment, provided herein are compounds of 45 Formula A - IX : F F / H

A - - IX 5050 C OH OCH3, O PE

55 F F floatZ ofofcognitalargements OOH | 60 OCH3,

or a stereoisomer or mixture of stereoisomers , tautomer, F F pharmaceutically acceptable salt, solvate , hydrate , co - crys tal, clathrate, or polymorph thereof, wherein : 65 Ris H , optionally substituted alkyl, or optionally substi - c1 tuted cycloalkyl; ofica US 9 ,938 , 254 B2 21 US9 ,938254 B2 22 - continued2 -continued ? OCH3 OCH3 OCH3, F F F F

F 0 1010) OCH , OCH3 ???? OCH3, F F F F ???? 15 ???? 0H 7 , and OCH2CH3, 20 F F \ / H ??? ?? 25 00H OCH_ CH , F F F F ????= 0 3 ) In one embodiment, the compound provided herein is a 0 OCH2CH : tautomer of the compound of formula A , A -IV , ? OCHOCH2CH3 , CH ,???, 3335 tautomer of the compound of - I, A - II , A - III A - V , AVI, A - VII , A - VIII , or A - IX . In one embodiment, the compound provided herein is a pharmaceutically acceptable ????F F salt of the compound of formulaA - I , A -II , A - III, A - IV , A - V , A - VI, A - VII, A - VIII, or A - IX . In some such embodiments , 40 the salt is a sodium , potassium , magnesium or calcium salt . In one embodiment, the compound provided herein is a ???? ???solvate of the compound of formula A - I , A - II, A - III, A - IV , 0CH2CH3 OCH2CH , A - V , AVI, A - VII , A -VIII , or A - IX . In one embodiment , the compound provided herein is a hydrate of compound of F F 45 formula A - I, A -II , A - III , A - IV , A - V , AVI, A - VII , A - VIII, or A - IX . In one embodiment, the compound provided herein is a clathrate of the compound of formula A - I, A - II, A - III , A - IV , A - V , AVI, A - VII , A - VIII , or A - IX . In one embodi ment, the compound provided herein is an isotopologue of 50 the compound of formula A - I , A - II , A - III, A - IV , A - V , AVI, ????= CH A - VII, A - VIII , or A - IX . In other embodiments , provided herein are compounds of Formula B - I : FF ?? 5555 B - I F 0 R R

? OH ?? R ? 60 2 ??? ? F F ??\ / ???????? US 9 , 938 , 254 B2 23 24 or a stereoisomer or mixture of stereoisomers, tautomer , In one embodiment, the compounds have Formula B - I or pharmaceutically acceptable salt, solvate , hydrate , co -crys of Formula B - II , wherein tal, clathrate, isotopologue or polymorph thereof, wherein : R is H or ( C , - C . ) alkyl ; R is H , optionally substituted alkyl, or optionally substi R ' is H or ( C / - C . )alkyl ; tuted cycloalkyl; 5 R is optionally substituted alkyl or optionally substituted R ' is H or optionally substituted alkyl; aryl, where the substituents on R ', when present are one to R is optionally substituted cycloalkyl, optionally substi three groups Q , where each Q is independently alkyl, halo , tuted aryl , optionally substituted heteroaryl or optionally haloalkyl, hydroxyl, alkoxy , optionally substituted substituted heterocyclyl ; cycloalkyl, optionally substituted cycloalkylalkyl , option R2 and R3 are each halo ; 10 ally substituted aryl, — R OR " , - R + SR , - R + N ( R ) ( R ), where the substituents on R ' , when present are one to R +OR + N (R )( R ) or R +OR C ( J) N ( R ) (R7 ) ; three groups Q , where each Q is independently alkyl, halo , J is O or S ; haloalkyl, hydroxyl, alkoxy , optionally substituted each R * is independently alkylene, alkenylene or a direct cycloalkyl, optionally substituted cycloalkylalkyl, option is bond ; ally substituted aryl, R ORS , R + SRS, R4N ( R )( R7 ), each R is independently hydrogen , alkyl, haloalkyl or R +OR + N (R ) ( R ) or R +OR + C ( J) N (R ) (R7 ) ; hydroxyalkyl ; and J is O or S ; Rand R ' are each independently hydrogen or alkyl or Rº each R4 is independently alkylene , alkenylene or a direct and R ’ together with the nitrogen atom on which they are bond ; 20 substituted form a 5 or 6 -membered heterocyclyl or het each R is independently hydrogen , alkyl, haloalkyl or eroaryl ring , optionally substituted with one or two halo , hydroxyalkyl; and alkyl or haloalkyl. R? andRare each independently hydrogen or alkyl or Rº In one embodiment, the compounds have Formula B - I or and R7 together with the nitrogen atom on which they are of Formula B - II , wherein R is H or ( C - C ) alkyl; R ' is H or substituted form a 5 or 6 -membered heterocyclyl or het 25 ( C . - C . )alkyl ; Rl is optionally substituted aryl, optionally eroaryl ring , optionally substituted with one or two halo , - substituted cycloalkyl, optionally substituted heterocyclyl, alkyl or haloalkyl. or optionally substituted heteroaryl , where the substituents In one embodiment, provided herein are compounds of on R ' , when present are one to three groups Q , where each Formula B - II : R is independently halo , alkyl, optionally substituted 30 cycloalkyl, optionally substituted aryl, R4ORS, or R?N (Rº ) ( R ' ) ; each R * is independently a directbond or alkylene ; B - - II II each R is independently hydrogen , halo , alkyl , alkoxy , 0 RR haloalkoxy , or haloalkyl; and R and R ? are each indepen dently hydrogen or alkyl, or Rº and R together with the LR 35 nitrogen atom on which they are substituted form a 5 or 6 -membered heterocyclyl or heteroaryl ring, optionally sub ??Z stituted with one or two halo , alkyl or haloalkyl. In one embodiment, the compounds have Formula B - I or Formula B - II, wherein R is H or ( C , - C , Jalkyl; R ' is H or 40 (C . - C . )alkyl ; R ' is optionally substituted phenyl, optionally substituted cyclohexyl, optionally substituted piperidinyl, or optionally substituted pyridyl, where the substituents on R ' , or a stereoisomer or mixture of stereoisomers , tautomer , when present, are one to three groups Q , where each Q is pharmaceutically acceptable salt, solvate , hydrate , co - crys independently halo , alkyl, R +OR or — R + N ( R ) ( R ) ; tal, clathrate , isotopologue or polymorph thereof, wherein : 45 each R * is independently a direct bond or alkylene ; each R Ris H , optionally substituted alkyl, or optionally substi - is independently hydrogen , halo , alkyl, alkoxy , haloalkoxy tuted cycloalkyl; or haloalkyl; and R and R7 are each independently hydro R ' is H or optionally substituted alkyl; gen or alkyl ; or ii )Rand R ' together with the nitrogen atom R ! is optionally substituted cycloalkyl, optionally substi - on which they are substituted form a 5 or 6 -membered tuted aryl, optionally substituted heteroaryl or optionally 50 heterocyclyl ring . substituted heterocyclyl; In one embodiment, the compounds have Formula B - I or where the substituents on R ' , when present are one to of Formula B - II , wherein R is H or (C1 - C . )alkyl ; R ' is H or three groups Q , where each Q is independently alkyl, halo , (C , -C . )alkyl ; R is optionally substituted phenyl, optionally haloalkyl, hydroxyl, alkoxy , optionally substituted substituted cyclohexyl, optionally substituted piperidinyl, or cycloalkyl, optionally substituted cycloalkylalkyl, option - 55 optionally substituted pyridyl , where the substituents on R ' , ally substituted aryl , - R - ORS , - R + SRS, - R4N ( R ) ( R ) , when present are one to three groups Q , where each Q is R4ORAN (R )( R ) or R4ORAC (J ) N (R )( R }) ; independently bromo, fluoro , chloro , methyl, isopropyl, tert J is O or S ; butyl, trifluromethyl, methoxy, ethoxy, isopropyloxy, each R * is independently alkylene , alkenylene or a direct methoxyethoxy , isopropyloxyethoxy, trifluoromethoxy , bond ; 60 methylamino , dimethylamino or piperidinyl. each R is independently hydrogen , alkyl , haloalkyl or In one embodiment, the compounds have Formula B -I or hydroxyalkyl; and Formula B - II, wherein R is H or ( C , - C Jalkyl ; R ' is H or RºandRare each independently hydrogen or alkyl or R (C - C )alkyl ; R ' is optionally substituted aryl, where the and R ’ together with the nitrogen atom on which they are substituents on R ' , when present, are one to three groups Q , substituted form a 5 or 6 -membered heterocyclyl or het - 65 where each Q is independently halo , alkyl, — R OR ", eroaryl ring, optionally substituted with one or two halo , - R4SRS or R OR * C ( O ) N ( R )( R ?) ; each R4 is indepen alkyl or haloalkyl. dently a direct bond or alkylene; each R is independently US 9 , 938 , 254 B2 25 26 hydrogen , halo , alkyl or haloalkyl; and R? and R ’ are each pounds of Formula B - III , wherein one of the R is H and the independently hydrogen or alkyl. other is an optionally substituted alkyl; R ' is H ; and Q ? is In one embodiment, the compounds have Formula B - I or fluoro . Formula B - II , wherein R is H or (C2 -C6 )alkyl ; R ' is H or In one embodiment, provided herein are compounds of (C .- C .) alkyl ; R ' is optionally substituted aryl, where the 5 Formula B - IV : substituents on R ', when present, are one to three groups Q , where each is independently fluoro , chloro , methyl, - R + OR , - R4N ( R ) ( R ) , — R SRS or R + OR + C ( O ) N ( R ) B - IV ( R ' ) ; each R * is independently a direct bond or methylene ; each R is independently hydrogen , methyl, ethyl or trifluo 0 RR romethyl; and R? and R ' are each independently hydrogen or methyl. N — R In one embodiment , the compounds have Formula B - I or R ? Formula B - II, wherein R is H or ( C , -C )alkyl ; R ' is H or 15 F ( C . - C .) alkyl; R ' is optionally substituted phenyl, where the substituents on R ' , when present, are one to three groups Q , where each Q is independently fluoro , chloro , methyl, tert butyl, — R OR " , - R4N ( R ) (R ), R + SRS or R +OR + C ( O ) N ( R ) ( R ' ) ; each R4 is independently a direct bond or meth - 20 or a stereoisomer or mixture of stereoisomers , tautomer, ylene; each R is independently hydrogen , methyl, ethyl or pharmaceutically acceptable salt , solvate , hydrate , co - crys trifluoromethyl ; and R? and R ? are each independently tal, clathrate , or polymorph thereof, wherein : talR, is H , optionally substituted alkyl, or optionally substi hydrogen or methyl. tuted cycloalkyl; In one embodiment, provided herein are compounds of 25 theR ' is H or optionally substituted alkyl; Formula B - III : Q2 is hydrogen , alkyl, halo , haloalkyl, hydroxyl, alkoxy , optionally substituted cycloalkyl , optionally substituted cycloalkylalkyl, optionally substituted aryl , R + OR " , B - III - R4SR " , - R4N (R )( R ), R4ORAN (R )( R ) or R4OR4C ( J) O RR 30 N (RO ) ( R ) ; (olin J is O or S ; - RDi each R * is independently alkylene, alkenylene or a direct bond ; ??? each RS is independently hydrogen , alkyl , haloalkyl or 35 hydroxyalkyl; and R and R7 are each independently hydrogen or alkyl. In one embodiment, the compounds herein are of Formula B - IV , where R is H , optionally substituted alkyl, or option ally substituted cycloalkyl; R ' is H or optionally substituted or a stereoisomer or mixture of stereoisomers , tautomer , 40 alkyl ; Q2 is hydrogen , halo , alkyl, optionally substituted pharmaceutically acceptable salt, solvate , hydrate , co - crys aryl, R4ORS or — R N (R ) (R ); R4 is independently a tal, clathrate , isotopologue or polymorph thereof, wherein : direct bond or alkylene ; R is hydrogen , alkyl or haloalkyl; Ris H , optionally substituted alkyl, or optionally substi and R? and R are each independently hydrogen or alkyl. In tuted cycloalkyl; some embodiments , R is H , optionally substituted alkyl, or R ' is H or optionally substituted alkyl; 45 optionally substituted cycloalkyl; R ' is H or optionally each O ' is independently alkyl, halo , haloalkyl, alkoxy - substituted alkyl; Q is hydrogen , Br, C1, F, methyl, isopro alkyl , hydroxyl, alkoxy , optionally substituted cycloalkyl, pyl, t - butyl, isopropyl, OCH3, — SCH3, - C ( CH3) , F , optionally substituted cycloalkylalkyl, optionally substituted OCH ( CH3) 2 , — O (CH2 ) 2OCH3 , or p - fluorophenyl. aryl, R4ORS, - R4SRS, R4N (R )( R7 ), R4ORAN (R ) In one embodiment, the compounds herein are of Formula ( R7) or R + OR C ( I) N ( R ) ( R7) ; 50 B - IV , wherein R is independently H or optionally substituted J is O or S ; alkyl ; R ' is independently H or optionally substituted alkyl ; each R4 is independently alkylene, alkenylene or a direct and Q2 is Br, Cl, or F . bond ; In one embodiment, provided herein are compounds of each R * is independently hydrogen , alkyl, haloalkyl or For hydroxyalkyl; 55 R? and R ' are each independently hydrogen or alkyl or Rº and R7 together with the nitrogen atom on which they are B - V substituted form a 5 or 6 -membered heterocyclyl or het OR R eroaryl ring, optionally substituted with one or two halo , alkyl or haloalkyl; and 60 n is 0 -3 . N — R In one embodiment, provided herein are compounds of Formula B - III , wherein R is H or ( C , - C Jalkyl; R ' is H ; and Q ? is alkyl or halo . In another embodiment, provided herein are compounds of Formula B - III , wherein one of the R is H 65 and the other is an optionally substituted alkyl; R ' is H ; and ficut O ' is halo . In one embodiment, provided herein are com US 9 , 938 , 254 B2 27 28 or a stereoisomer or mixture of stereoisomers, tautomer, R and R7 are selected as follows: pharmaceutically acceptable salt , solvate , hydrate , co -crys i) R™ and R ’ are each independently hydrogen or alkyl; or tal, clathrate , or polymorph thereof, wherein : ii ) R? and R ’ together with the nitrogen atom on which R is H , optionally substituted alkyl, or optionally substi they are substituted form a 5 or 6 -membered heterocyclyl or tuted cycloalkyl; 5 heteroaryl ring , optionally substituted with one or two halo , R ' is H or optionally substituted alkyl; alkyl or haloalkyl. Q3 and Q4 are each independently hydrogen , alkyl, halo , In one embodiment, the compounds herein are of Formula haloalkyl, hydroxyl, alkoxy, optionally substituted B -VI , where R is H , optionally substituted alkyl, or option cycloalkyl, optionally substituted cycloalkylalkyl, ally substituted cycloalkyl; R ' is H or optionally substituted -ROR ", - R4SR , RºN (R % )( R ), R + OR + N (R ') (R ) or 10 alkyl; Q4 and Q are each independently hydrogen, halo , R *OR * C ( J) N (R ) ( R ) ; alkyl, alkoxyalkyl, R4N (R ) (R ?) , or = R * OR *; R * is a J is O or S ; direct bond or alkylene ; R5 is hydrogen , alkyl or haloalkyl ; each R * is independently alkylene, alkenylene or a direct and R? and R together with the nitrogen atom on which they bond ; are substituted form a 6 -membered heterocyclyl. In some each RS is independently hydrogen , alkyl, haloalkyl, 15 such embodiments , Q4 and Q are each independently hydroxyalkyl, or alkoxyalkyl; and hydrogen , F , C1, OH , methyl, CF3 , NHCHZ, Rº and R ' are each independently hydrogen or alkyl. - N (CH3 ) 2 , OCF3, OCH CH3, OCH CF3, OCH In one embodiment, the compounds herein are of Formula ( CH3) 2 , O (CH2 ) 20CHZ, O ( CH2)2OCH ( CH3) 2 , B - V , where R is H , optionally substituted alkyl, or optionally - O ( CH2) 2O (CH2 ) 2OCHz , O (CH2 ) 2 -morpholinyl , piper substituted cycloalkyl ; R ' is H or optionally substituted 20 idyl, morpholinyl, CH2- morpholinyl , or O ( CH2) 2 - 4 , 4 alkyl; Q4 and Q are each independently hydrogen , halo , difluoro - 1 - piperidyl. alkyl, alkoxyalkyl, - R OR " , or — R + N ( R ) ( R ) ; R4 is a In one embodiment , provided herein are compounds of direct bond or alkylene ; and R is hydrogen , alkyl or Formula B - VII : haloalkyl; and R? and R ’ are each independently hydrogen or alkyl. In some such embodiments , R is H , optionally 25 substituted alkyl , or optionally substituted cycloalkyl ; R ' is B - VII H or optionally substituted alkyl ; 04 and 03 are each independently hydrogen , F , methyl, CF3, OH , OCF3, RR - OCH2CH3, OCH (CH3 ) 2 , - OCH CF3, or — NHCHZ. In one embodiment , the compounds herein are of Formula 30 N - R B - V , where R is H , optionally substituted alkyl , or optionally R substituted cycloalkyl; R ' is H or optionally substituted alkyl; Q4 is hydrogen , Qis hydrogen , halo , alkyl , alkoxy alkyl, R4N ( R )( R7) , or - R OR ; R4 is a direct bond or alkylene; R? is hydrogen , alkyl or haloalkyl ; and R and R ? 35 are each independently hydrogen or alkyl. In one embodiment, provided herein are compounds of or a stereoisomer or mixture of stereoisomers , tautomer, Formula B - VI: pharmaceutically acceptable salt , solvate , hydrate , co -crys tal, clathrate , or polymorph thereof, wherein : 40 Ris H , optionally substituted alkyl, or optionally substi B - VI tuted cycloalkyl; R ' is H or optionally substituted alkyl; O . RR Qis hydrogen , alkyl, halo , haloalkyl, hydroxyl, alkoxy , optionally substituted cycloalkyl , optionally substituted N - R 45 cycloalkylalkyl, R4OR , R +SRS , R4N ( R )( R7 ) , R4ORAN (R )( R7) or R4OR4C ( J) N (R ) (R ); N J is O or S ; T each R * is independently alkylene , alkenylene or a direct bond ; 50 each R is independently hydrogen , alkyl, haloalkyl, alkoxyalkyl or hydroxyalkyl; and or a stereoisomer or mixture of stereoisomers , tautomer, RÓ and R ? are selected as follows: pharmaceutically acceptable salt, solvate , hydrate , co - crys i) Rand Rare each independently hydrogen or alkyl; or tal, clathrate, or polymorph thereof, wherein : ii) R™ and R7 together with the nitrogen atom on which Ris H , optionally substituted alkyl, or optionally substi - 55 they are substituted form a 5 or 6 -membered heterocyclyl or tuted cycloalkyl; heteroaryl ring , optionally substituted with one or two halo , R ' is H or optionally substituted alkyl; alkyl or haloalkyl. Q4 and Q are each independently hydrogen , alkyl, halo , In one embodiment, the compounds herein are of Formula haloalkyl, hydroxyl, alkoxy, optionally substituted B - VII , where R is H , optionally substituted alkyl, or option cycloalkyl, optionally substituted cycloalkylalkyl, 60 ally substituted cycloalkyl; R ' is H or optionally substituted - R *ORS , R + SRS, R4N ( R )( R7 ), R ORAN (R )( R ) or alkyl ; Q is hydrogen , halo , alkyl, alkoxyalkyl, R4N (R ) R4ORAC ( J) N (R ) (R ) ; ( R ' ) or — RHOR " ; R * is a direct bond or alkylene ; and R is J is O or S ; hydrogen , alkyl or haloalkyl; and R? and R ’ together with each R * is independently alkylene , alkenylene or a direct the nitrogen atom on which they are substituted form a bond ; 65 6 -membered heterocyclyl. In some such embodiments , R is each RS is independently hydrogen , alkyl, haloalkyl, H , optionally substituted alkyl, or optionally substituted alkoxyalkyl or hydroxyalkyl; and cycloalkyl; Q is hydrogen , F , Cl, methyl, piperidyl, mor US 9, 938 ,254 B2 29 30 pholinyl, - CH2 -morpholinyl , - N (CH3 ) 2 , or a stereoisomer or mixture of stereoisomers , tautomer, - O ( CH2) 2OCH3, O ( CH2) 2OCH ( CH3) 2 O ( CH2) 20 pharmaceutically acceptable salt, solvate , hydrate , co -crys ( CH2) 2OCHz, or O ( CH2) 2- 4 ,4 -difluoro -1 -piperidyl . tal , clathrate , or polymorph thereof, wherein : In one embodiment, provided herein are compounds of Ris H . optionally substituted alkyl, or optionally substi Formula B - VIII: 5 tuted cycloalkyl; R ' is H or optionally substituted alkyl; B - VIII each Q ' is independently alkyl, halo , haloalkyl , alkoxy RR alkyl, hydroxyl , alkoxy, optionally substituted cycloalkyl; 10 optionally substituted cycloalkylalkyl, optionally substituted heterocyclyl, R4ORS, R4OR R OR , — R N (R ) N - R (R7 ) , R - SR5, R4OR N ( R ) (R7 ) , R40R4C ( J) N ( R ) ( R ]) , C (J ) Rº or R +S (O ), R® ; X 15 J is O or S ; each R * is independently alkylene , alkenylene or a direct bond ; each R is independently hydrogen , oxo , alkyl, haloalkyl , or a stereoisomer or mixture of stereoisomers, tautomer, hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, het pharmaceutically acceptable salt, solvate , hydrate , co - crys - 20 erocyclyl or heterocyclylalkyl , where alkyl, haloalkyl, tal, clathrate , or polymorph thereof, wherein : hydroxyalkyl, alkoxyalkyl, cycloalkyl, aryl, heteroaryl, het Ris H , optionally substituted alkyl, or optionally substi erocyclyl or heterocyclylalkyl groups in R are each inde tuted cycloalkyl; pendently optionally substituted with 1 - 3 Q ' groups selected R ' is H or optionally substituted alkyl; from alkyl, haloalkyl or halo ; Q and Q are each independently hydrogen , alkyl, halo , 25 haloalkyl, hydroxyl, alkoxy, optionally substituted R and R ’ are each independently hydrogen or alkyl ; cycloalkyl, optionally substituted cycloalkylalkyl, option R® is alkyl, haloalkyl, or hydroxyalkyl ; ally substituted aryl , - R + ORS , - R4SRS, R4N ( R )( R ?) , Rº is alkyl or aryl; R4ORAN ( R ) ( R ) or R +OR + C ( J) N ( R ) ( R ) ; J is O or S ; 30 J is O or S ; each R * is independently alkylene , alkenylene or a direct t is 1 or 2 ; and bond ; n is 0 -3 . each R is independently hydrogen , alkyl, haloalkyl or In one embodiment , the compounds herein are of Formula hydroxyalkyl; and B - IX , R is H , optionally substituted alkyl, or optionally Rand R ’ are each independently hydrogen or alkyl, or R 35 susubstituted cycloalkyl; R ' is H or optionally substituted and R together with the nitrogen atom on which they are alkyl; where each Q ' is independently hydrogen , halo , alkyl, substituted form a 6 -membered heterocyclyl. haloalkyl, alkoxyalkyl or haloalkoxyalkyl. In some embodi In one embodiment, the compounds herein are of Formula ments , R is H , optionally substituted alkyl, or optionally B -VIII , where R is H , optionally substituted alkyl, or option substituted cycloalkyl; R ' is H or optionally substituted ally substituted cycloalkyl; R ' is H or optionally substituted 40 alkyl, each is independently fluoro , chloro , bromo , methyl. alkyl; Q and Q are each independently hydrogen , halo , isopropyl, t -butyl , CF3, O - CH2CH3, O CH alkyl, alkoxyalkyl, optionally substituted aryl , or - R OR " ; opronyl . R * is a direct bond or alkylene ; and R is hydrogen , alkyl or (CH3 ) 2 , or cyclopropyl. haloalkyl. In some such embodiments , R is H , optionally In one embodiment, the compound provided herein is substituted alkyl, or optionally substituted cycloalkyl: 02 45 selected from the group consisting of: and Q are each independently hydrogen , F , Br, Cl, methyl , isopropyl , t- butyl, C ( CH3) 2F , p - fluorophenyl, cyclopro pyl, — N (CH3 ) 2 , OCHz, - OCH ( CH3 ) 2 , O ( CH2) 2OCH3 , NH , - O (CH2 ) 2OCH (CH3 ) 2, O ( CH2) 2OCHz , O (CH2 ) 20 ( CH2) 2OCHZ, O (CH2 ) 2 -4 ,4 - difluoro - 1 -piperidyl , 50 - SCF3, morpholinyl, piperidyl, or CH2- morpholinyl . In one embodiment, provided herein are compounds of Formula B - IX : F F 55 B - IX F1 O . RR NH2 VerR60

F . F .

62 cmOleaga US 9 ,938 , 254 B2 31 ? 0809as 32 -continued -continued NH 0 . 5

F F

1 (

F F

NH NH 15 ????? = 0. F F 20

NH , NH ???????? 25

? N F F 3 ) F F

F ???NH2. 35

F F 4 { F F

?????NH , 45

F F 50) F ???? 55 F

NH2

?0 , 60

????????F

6 ?????? ? US 9 ,938 ,254 B2 33 34 -continued improve pharmacokinetics (“ PK ” ) , pharmacodynamics (“ PD " ) , and toxicity profiles, has been demonstrated previ ously with some classes of drugs . See , for example , Lijinsky et . al. , Food Cosmet. Toxicol. , 20 : 393 ( 1982 ) ; Lijinsky et . al. , J . Nat. Cancer Inst. , 69 : 1127 ( 1982 ) ; Mangold et. al. , Mutation Res . 308 : 33 (1994 ) ; Gordon et . al. , Drug Metab . Dispos. , 15 : 589 ( 1987 ) ; Zello et. al. , Metabolism , 43 : 487 ( 1994 ); Gately et. al ., J. Nucl . Med ., 27 : 388 (1986 ) ; Wade D , Chem . Biol. Interact. 117 : 191 ( 1999 ) . 10 Without being limited by any particular theory , isotopic enrichment of a drug can be used , for example , to ( 1 ) reduce or eliminate unwanted metabolites , ( 2 ) increase the half - life F of the parent drug , ( 3 ) decrease the number of doses needed to achieve a desired effect, ( 4 ) decrease the amount of a dose 15 necessary to achieve a desired effect , (5 ) increase the for Ofice N mation of active metabolites, if any are formed , and /or (6 ) decrease the production of deleterious metabolites in spe cific tissues and / or create a more effective drug and / or a safer drug for combination therapy, whether the combination 20 therapy is intentional or not. F F Replacement of an atom for one of its isotopes often will result in a change in the reaction rate of a chemical reaction . This phenomenon is known as the Kinetic Isotope Effect (“ KIE ” ) . For example , if a C - H bond is broken during a NH2 25 rate - determining step in a chemical reaction ( i. e . the step Ofiqueswith the highest transition state energy ), substitution of a = O , andand deuterium for that hydrogen will cause a decrease in the reaction rate and the process will slow down . This phenom enon is known as the Deuterium Kinetic Isotope Effect F F 30 (“ DKIE ” ) . (See , e . g , Foster et al ., Adv . Drug Res. , vol. 14 , pp . 1 - 36 ( 1985 ) ; Kushner et al. , Can . J . Physiol. Pharmacol ., vol. 77 , pp . 79- 88 ( 1999 ) ) . The magnitude of the DKIE can be expressed as the ratio F NH , between the rates of a given reaction in which a C - H bond 35 is broken , and the same reaction where deuterium is substi tuted for hydrogen . The DKIE can range from about 1 ( no isotope effect ) to very large numbers , such as 50 or more , meaning that the reaction can be fifty , or more , times slower F when deuterium is substituted for hydrogen . Without being F 40 limited by a particular theory , high DKIE values may be due in part to a phenomenon known as tunneling , which is a consequence of the uncertainty principle . Tunneling is CI ascribed to the small mass of a hydrogen atom , and occurs because transition states involving a proton can sometimes In one embodiment, the compound provided herein is a -45 form in the absence of the required activation energy . tautomer of the compound of formula B - I , B - II , B - IV , B - V , Because deuterium has more mass than hydrogen , it statis ???B - VI, B -VII , B - VIII, B - IX or B - X . In one embodiment, the tically has a much lower probability of undergoing this phenomenon . compound provided herein is a pharmaceutically acceptable Tritium (“ T ” ) is a radioactive isotope ofhydrogen , used in salt of the compound of formula B - 1 , B - 11 , B - 111, B - IV , B - V , 50 research , fusion reactors , neutron generators and radiophar B - VI, B - VII, B -VIII , B - IX or B - X . In some such embodi maceuticals . Tritium is a hydrogen atom that has 2 neutrons ments , the salt is a hydrochloric salt . In one embodiment, the in the nucleus and has an atomic weight close to 3 . It occurs compound provided herein is a solvate of the compound of naturally in the environment in very low concentrations , formula B - I , B - II , B - III , B - IV , B - V , B - VI, B - VII , B - VIII , most commonly found as T , O . Tritium decays slowly (half B - IX or B - X . In one embodiment, the compound provided 55 life = 12 . 3 years) and emits a low energy beta particle that herein is a hydrate of compound of formula B - I , B - II, B - III, cannot penetrate the outer layer of human skin . Internal B - IV , B - V , B - VI, B - VII, B - VIII, B - IX or B - X . In one exposure is the main hazard associated with this isotope , yet embodiment, the compound provided herein is a clathrate of it must be ingested in large amounts to pose a significant the compound of formula B - I , B - II , B - III , B -IV , B - V , B - VI, health risk . As compared with deuterium , a lesser amount of B - VII , B - VIII , B - IX or B - X . In one embodiment, the 60 tritium must be consumed before it reaches a hazardous compound provided herein is an isotopologue of the com - level. Substitution of tritium (“ T ” ) for hydrogen results in pound of formula B - I , B - II, B - III, B - IV , B - V , B - VI, B - VII, yet a stronger bond than deuterium and gives numerically B -VIII , B - IX or B - X . larger isotope effects . Isotopologues of Compounds Similarly , substitution of isotopes for other elements , Also provided herein are isotopically enriched analogs of 65 including, but not limited to , 13C or 14C for carbon , 338 , 34S, the compounds ( “ isotopologues ”) provided herein . Isotopic or 365 for sulfur , 15N for nitrogen , and 170 or 180 for enrichment ( for example , deuteration ) of pharmaceuticals to oxygen , will provide a similar kinetic isotope effects . US 9 , 938 ,254 B2 35 36 5 . 3 . Methods of Treatment In certain embodiments , the cancer is a solid tumor. In certain embodiments , the solid tumor is metastatic . In cer In one embodiment, provided herein is a method of tain embodiments , the solid tumor is drug -resistant . In treating, preventing and managing cancer, which comprises certain embodiments , the solid tumor is hepatocellular car administering to a patient Compound A or Compound B 5 cinoma , prostate cancer , ovarian cancer, or glioblastoma. provided herein . In certain embodiments , the cancer is a blood borne In one embodiment provided herein is a method of tumor. In certain embodiments , the blood borne tumor is treating cancer , which comprises administering to a patient metastatic . In certain embodiments , the blood borne tumor is Compound Apr Compound B provided herein . drug resistant. In certain embodiments , the cancer is leuke In one embodiment provided herein is a method of 10 mia . preventing cancer, which comprises administering to a In one embodiment, methods provided herein encompass patient Compound A or Compound B provided herein . treating, preventing or managing various types of leukemias In another embodiment, provided herein is method of such as chronic lymphocytic leukemia (CLL ) , chronic managing cancer, which comprises administering to a myelocytic leukemia (CML ) , acute lymphoblastic leukemia patient Compound A or Compound B provided herein . 15 ( ALL ) , acute myeloid leukemia (AML ) , and acute myelo Also provided herein are methods of treating patients who blastic leukemia ( AML ) by administering a therapeutically have been previously treated for cancer but are non - respon - effective amount of Compound A or Compound B provided sive to standard therapies , as well as those who have not herein . previously been treated . The invention also encompasses In some embodiments , the methods provided herein methods of treating patients regardless of patient' s age , 20 encompass treating , preventing or managing acute leukemia although some diseases or disorders are more common in in a subject. In some embodiments, the acute leukemia is certain age groups. The invention further encompasses acute myeloid leukemia (AML ) , which includes, but is not methods of treating patients who have undergone surgery in limited to , undifferentiated AML (MO ) , myeloblastic leuke an attempt to treat the disease or condition at issue, as well mia (M1 ) , myeloblastic leukemia (M2 ) , promyelocytic leu as those who have not. Because patients with cancer have 25 kemia (M3 or M3 variant (M3V ) ) , myelomonocytic leuke heterogeneous clinical manifestations and varying clinical mia (M4 or M4 variant with eosinophilia (M4E ) ) , monocytic outcomes, the treatment given to a patientmay vary , depend leukemia (M5 ) , erythroleukemia (M6 ) , and megakaryoblas ing on his /her prognosis . The skilled clinician will be able to tic leukemia (M7 ) . In one embodiment, the acute myeloid readily determine without undue experimentation specific leukemia is undifferentiated AML (MO ) . In one embodi secondary agents , types of surgery , and types of non - drug 30 ment, the acute myeloid leukemia is myeloblastic leukemia based standard therapy that can be effectively used to treat (M1 ) . In one embodiment, the acute myeloid leukemia is an individual patient with cancer. myeloblastic leukemia (M2 ) . In one embodiment, the acute As used herein , the term " cancer” includes , but is not myeloid leukemia is promyelocytic leukemia (M3 or M3 limited to , solid tumors and blood borne tumors . The term variant (M3V ) ) . In one embodiment, the acute myeloid " cancer ” refers to disease of skin tissues , organs , blood , and 35 leukemia is myelomonocytic leukemia (M4 or M4 variant vessels, including, but not limited to , cancers of the bladder , with eosinophilia (M4E ) ) . In one embodiment, the acute bone , blood , brain , breast, cervix , chest , colon , endrome- myeloid leukemia is monocytic leukemia (M5 ) . In one trium , esophagus , eye , head , kidney , liver, lymph nodes, embodiment, the acute myeloid leukemia is erythroleukemia lung, mouth , neck , ovaries , pancreas , prostate , rectum , stom (M6 ) . In one embodiment, the acute myeloid leukemia is ach , testis , throat, and uterus. Specific cancers include, but 40 megakaryoblastic leukemia (M7 ) . are not limited to , advanced malignancy , amyloidosis , neu - In certain embodiments , the methods of treating, prevent roblastoma, meningioma, hemangiopericytoma , multiple ing or managing acute myeloid leukemia in a subject com brain metastase , glioblastoma multiforms, glioblastoma, prise the step of administering to the subject an amount of brain stem glioma, poor prognosis malignant brain tumor, Compound A or Compound B provided herein effective to malignant glioma, recurrent malignant glioma , anaplastic 45 treat, prevent or manage acute myeloid leukemia alone or in astrocytoma, anaplastic oligodendroglioma, neuroendocrine combination . tumor, rectal adenocarcinoma, colorectal cancer, including In one embodiment, provided herein are methods of stage 3 and stage 4 colorectal cancer , unresectable colorectal treating , preventing or managing acute myeloid leukemia by carcinoma , metastatic hepatocellular carcinoma , Kaposi ' s intravenous administration of Compound A or Compound B . sarcoma, karotype acute myeloblastic leukemia , Hodgkin ' s 50 In some embodiments , the methods comprise the step of lymphoma, non -Hodgkin ' s lymphoma, cutaneous T - Cell administering to the subject Compound A or Compound B lymphoma, cutaneous B -Cell lymphoma, diffuse large provided herein , in combination with a second active agent B - Cell lymphoma , low grade follicular lymphoma, malig - in amounts effective to treat, prevent or manage acute nantmelanoma , malignant mesothelioma, malignant pleural myeloid leukemia . effusion mesothelioma syndrome, peritoneal carcinoma, 55 In some embodiments , the methods provided herein papillary serous carcinoma, gynecologic sarcoma, soft tissue encompass treating , preventing or managing acute lympho sarcoma, scleroderma, cutaneous vasculitis , Langerhans cell cytic leukemia (ALL ) in a subject. In some embodiments , histiocytosis , leiomyosarcoma, fibrodysplasia ossificans acute lymphocytic leukemia includes leukemia that origi progressive , hormone refractory prostate cancer, resected nates in the blast cells of the bone marrow ( B - cells ) , thymus high - risk soft tissue sarcoma, unresectable hepatocellular 60 ( T - cells ) , and lymph nodes . The acute lymphocytic leukemia carcinoma, Waldenstrom ' s macroglobulinemia , smoldering can be categorized according to the French - American - Brit myeloma, indolentmyeloma , fallopian tube cancer , andro - ish ( FAB ) Morphological Classification Scheme as gen independent prostate cancer, androgen dependent stage L1 — Mature - appearing lymphoblasts ( T - cells or pre - B IV non -metastatic prostate cancer, hormone - insensitive cells ), L2 — Immature and pleomorphic (variously shaped ) prostate cancer , chemotherapy - insensitive prostate cancer, 65 lymphoblasts ( T - cells or pre - B - cells ) , and L3 — Lympho papillary thyroid carcinoma, follicular thyroid carcinoma, blasts ( B -cells ; Burkitt ' s cells ) . In one embodiment, the medullary thyroid carcinoma, and leiomyoma. acute lymphocytic leukemia originates in the blast cells of US 9 , 938 , 254 B2 37 38 the bone marrow ( B - cells) . In one embodiment, the acute cytopenia with unilineage dysplasia (RCUD ) ; unclassifiable lymphocytic leukemia originates in the thymus ( T - cells ). In myelodysplastic syndrome (MDS - U ) , myelodysplastic syn one embodiment, the acute lymphocytic leukemia originates drome associated with an isolated del (5q ) chromosome in the lymph nodes. In one embodiment , the acute lympho - abnormality , therapy - related myeloid neoplasms and cytic leukemia is L1 type characterized by mature - appearing 5 chronic myelomonocytic leukemia (CMML ) . lymphoblasts ( T - cells or pre - B - cells ) . In one embodiment, In certain embodiments , provided herein are methods of the acute lymphocytic leukemia is L2 type characterized by treating, preventing, and / or managing lymphoma, including immature and pleomorphic ( variously shaped ) lymphoblasts non - Hodgkin ' s lymphoma. In some embodiments , provided ( T - cells or pre - B - cells ) . In one embodiment, the acute lym - herein are methods for the treatment or management of phocytic leukemia is L3 type characterized by lymphoblasts 10 non -Hodgkin ' s lymphoma (NHL ) , including but not limited ( B -cells ; Burkitt ' s cells ) . In certain embodiments , the acute to , diffuse large B - cell lymphoma (DLBCL ), using prognos lymphocytic leukemia is T - cell leukemia . In one embodi- tic factors . ment, the T -cell leukemia is peripheral T - cell leukemia . In In certain embodiments , provided herein are methods of another embodiment , the T - cell leukemia is T -cell lympho - treating, preventing , and/ or managing multiple myeloma, blastic leukemia . In another embodiment, the T- cell leuke - 15 including relapsed /refractory multiple myeloma in patients mia is cutaneous T -cell leukemia . In another embodiment, with impaired renal function or a symptom thereof, com the T -cell leukemia is adult T -cell leukemia . Thus , the prising administering a therapeutically effective amount of methods of treating, preventing or managing acute lympho - Compound A or Compound B provided herein to a patient cytic leukemia in a subject comprise the step of adminis - having relapsed / refractory multiple myeloma with impaired tering to the subject an amount of Compound A or Com - 20 renal function . pound B provided herein , effective to treat, prevent or In some embodiments , provided herein are Compounds A manage acute lymphocytic leukemia alone or in combina - and Compounds B for use in a method of treating , prevent tion with a second active agent. In some embodiments , the ing and / or managing any of the above -mentioned diseases or methods comprise the step of administering to the subject conditions. Compound A or Compound B provided herein in combina - 25 In certain embodiments , a therapeutically or prophylac tion with a second active agent in amounts effective to treat , tically effective amount of Compound A or Compound B prevent or manage acute lymphocytic leukemia . provided herein is from about 0 .005 to about 1 ,000 mg per In some embodiments, the methods provided herein day , from about 0 .01 to about 500 mg per day , from about encompass treating, preventing or managing chronic myel- 0 .01 to about 250 mg per day, from about 0 . 01 to about 100 ogenous leukemia (CML ) in a subject . The methods com - 30 mg per day , from about 0 . 1 to about 100 mg per day , from prise the step of administering to the subject an amount of about 0 . 5 to about 100 mg per day , from about 1 to about 100 Compound A or Compound B provided herein , effective to mg per day , from about 0 .01 to about 50 mg per day, from treat , prevent or manage chronic myelogenous leukemia . In about 0 . 1 to about 50 mg per day , from about 0 . 5 to about some embodiments , the methods comprise the step of 50 mg per day, from about 1 to about 50 mg per day , from administering to the subject Compound A or Compound B 35 about 0 .02 to about 25 mg per day , from about 0 .05 to about provided herein , in combination with a second active agent 10 mg per day, from about 0 .05 to about 5 mg per day , from in amounts effective to treat, prevent or manage chronic about 0 . 1 to about 5 mg per day , or from about 0 . 5 to about myelogenous leukemia . 5 mg per day. In some embodiments , the methods provided herein In certain embodiments , the therapeutically or prophylac encompass treating , preventing or managing chronic lym - 40 tically effective amount is about 0 . 1 , about 0 . 2 , about 0 . 5 , phocytic leukemia (CLL ) in a subject. The methods com - about 1 , about 2 , about 3 , about 4 , about 5 , about 6 , about prise the step of administering to the subject an amount of 7 , about 8 , about 9 , about 10 , about 15 , about 20 , about 25 , Compound A or Compound B provided herein , effective to about 30 , about 40 , about 45 , about 50 , about 60 , about 70 , treat, prevent or manage chronic lymphocytic leukemia . In about 80 , about 90 , about 100 , or about 150 mg per day . In some embodiments , the methods comprise the step of 45 some such embodiments, the therapeutically or prophylac administering to the subject Compound A or CompoundB t ically effective amount is about 2 , about 3 , about 4 , about provided herein , in combination with a second active agent 5 , about 6 or about 7 mg per day . in amounts effective to treat, prevent or manage chronic In one embodiment, the recommended daily dose range of lymphocytic leukemia . Compound A or Compound B provided herein , for the In certain embodiments , provided herein are methods of 50 conditions described herein lie within the range of from treating , preventing , and /or managing disease in patients about 0 . 05 mg to about 50 mg per day , preferably given as with impaired renal function . In certain embodiments , pro - a single once - a - day dose , or in divided doses throughout a vided herein are method of treating , preventing , and / or day . In some embodiments , the dosage ranges from about 1 managing cancer in patients with impaired renal function . In mg to about 50 mg per day . In other embodiments, the certain embodiments , provided herein are methods of pro - 55 dosage ranges from about 0 . 5 to about 5 mg per day . Specific viding appropriate dose adjustments for patients with doses per day include 0 . 1 , 0 . 2 , 0 . 5 , 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , impaired renal function due to , but not limited to , disease , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19, 20 , 21, 22 , 23 , 24 , 25 , aging , or other patient factors. 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33, 34 , 35 , 36 , 37 , 38 , 39, 40 , 41, In one embodiment, provided herein are methods of 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 or 50 mg per day . treating, preventing , and / or managing a myelodysplastic 60 In a specific embodiment , the recommended starting syndrome (MDS ) by administering a therapeutically active dosage may be 0 . 1 , 0 . 5 , 1 , 2 , 3 , 4 , 5 , 10 , 15 , 20 , 25 or 50 mg amount of Compound A or Compound B provided herein . In per day . In another embodiment, the recommended starting one embodiment, the MDS is relapsed , resistant or refrac - dosage may be 0 . 1 , 0 . 5 , 1 , 2 , 3 , 4 , or 5 mg per day . The dose tory MDS . In one embodiment, MDS is selected from may be escalated to 15 , 20 , 25, 30 , 35 , 40 , 45 and 50 mg/ day . refractory anemia (RA ); RA with ringed sideroblasts 65 In a specific embodiment, Compound A or Compound B (RARS ) ; RA with excess of blasts (RAEB ); refractory provided herein can be administered in an amount of about cytopenia with multilineage dysplasia (RCMD ), refractory 25 mg/ day to patients with leukemia , including AML . In a US 9 , 938 , 254 B2 39 40 particular embodiment , Compound A or Compound B pro - nM , about 5 to about 50 nM , about 10 to about 100 nM , vided herein can be administered in an amount of about 10 about 10 to about 50 nM or from about 50 to about 100 nM . mg/ day to patients with leukemia , including AML . In a As used herein , the term “ plasma concentration at steady particular embodiment, Compound A or Compound B pro - state” is the concentration reached after a period of admin vided herein can be administered in an amount of about 5 5 istration of Compound A or Compound B provided herein . mg/ day to patients with leukemia , including AML . In a Once steady state is reached , there are minor peaks and particular embodiment, Compound A or Compound B pro - troughs on the time dependent curve of the plasma concen vided herein can be administered in an amount of about 4 tration of the compound . mg/ day to patients with leukemia , including AML . In a In certain embodiments , the amount of Compound A or particular embodiment, Compound A or Compound B pro - 1 Compound B provided herein administered is sufficient to vided herein can be administered in an amount of about 3 provide a maximum plasma concentration (peak concentra mg /day to patients with leukemia , including AML . tion ) of the compound , ranging from about 0 . 001 to about In a specific embodiment, Compound A or Compound B 500 uM , about 0 .002 to about 200 uM , about 0 .005 to about can be administered in an amount of about 25 mg/ day to 1 100 uM , about 0 .01 to about 50 UM , from about 1 to about patients with MDS. In a particular embodiment, Compound 50 uM , about 0 .02 to about 25 uM , from about 0 .05 to about A or Compound B can be administered in an amount of 20 uM , from about 0 .1 to about 20 uM , from about 0 .5 to about 10 mg/ day to patients with MDS . In a particular about 20 uM , or from about 1 to about 20 uM . embodiment, Compound A or Compound B can be admin - In certain embodiments , the amount of Compound A or istered in an amount of about 5 mg/ day to patients with 20 Compound B provided herein administered is sufficient to MDS . In a particular embodiment, Compound A or Com - provide a minimum plasma concentration ( trough concen pound B can be administered in an amount of about 4 tration ) of the compound, ranging from about 0 . 001 to about mg/ day to patients with MDS. In a particular embodiment, 500 UM , about 0 .002 to about 200 uM , about 0 .005 to about Compound A or Compound B provided herein can be 100 uM , about 0 .01 to about 50 uM , from about 1 to about administered in an amount of about 3 mg/ day to patients 25 50 uM , about 0 .01 to about 25 uM , from about 0 . 01 to about with MDS. In a particular embodiment, Compound A or 20 uM , from about 0 .02 to about 20 uM , from about 0 . 02 to Compound B provided herein can be administered in an about 20 uM , or from about 0 .01 to about 20 uM . amount of about 2 mg/ day to patients with MDS . In a In certain embodiments , the amount of Compound A or particular embodiment, Compound A or Compound B pro - Compound B provided herein administered is sufficient to vided herein can be administered in an amount of about 1 30 provide an area under the curve (AUC ) of the compound , mg / day to patients with MDS . In a particular embodiment, ranging from about 100 to about 100 , 000 ng * hr /mL , from Compound A or Compound B provided herein can be about 1 , 000 to about 50 ,000 ng * hr/ mL , from about 5 ,000 to administered in an amount of about 0 . 5 mg/ day to patients about 25 ,000 ng* hr /mL , or from about 5 ,000 to about with MDS . 10 ,000 ng * hr /mL . In certain embodiments , the therapeutically or prophylac - 35 In certain embodiments , the patient to be treated with one tically effective amount is from about 0 . 001 to about 100 of the methods provided herein has not been treated with mg/ kg /day , from about 0 . 01 to about 50 mg/kg /day , from a nticancer therapy prior to the administration of Compound about 0 .01 to about 25 mg/kg / day , from about 0 .01 to about or Compound B provided herein . In certain embodiments , 10 mg/ kg / day , from about 0 . 01 to about 9 mg/ kg / day , 0 .01 the patient to be treated with one of the methods provided to about 8 mg/ kg / day , from about 0 .01 to about 7 mg/kg / day , 40 herein has been treated with anticancer therapy prior to the from about 0 .01 to about 6 mg/ kg / day, from about 0 . 01 to administration of Compound A or Compound B provided about 5 mg/ kg / day, from about 0 .01 to about 4 mg/ kg / day, herein . In certain embodiments, the patient to be treated with from about 0 .01 to about 3 mg/kg / day , from about 0 .01 to one of the methods provided herein has developed drug about 2 mg/kg /day , from about 0 .01 to about 1 mg/ kg / day , resistance to the anticancer therapy . or from about 0 . 01 to about 0 . 05 mg/kg / day. 45 The methods provided herein encompass treating a patient The administered dose can also be expressed in units regardless of patient' s age , although some diseases or dis other than mg/ kg / day . For example , doses for parenteral orders are more common in certain age groups administration can be expressed as mg / m ^ / day . One of Depending on the disease to be treated and the subject' s ordinary skill in the art would readily know how to convert condition , Compound A or Compound B provided herein doses from mg/ kg /day to mg /m² / day to given either the 50 may be administered by oral , parenteral (e .g . , intramuscular , height or weight of a subject or both ( see , www . fda . gov / intraperitoneal , intravenous, CIV , intracistemal injection or cder/ cancer / animalframe. htm ). For example, a dose of 1 infusion , subcutaneous injection , or implant ), inhalation , mg/ kg / day for a 65 kg human is approximately equal to 38 nasal, vaginal , rectal, sublingual, or topical ( e . g . , transder mg/ m² / day . mal or local) routes of administration . Compound A or In certain embodiments , the amount of Compound A or 55 Compound B provided herein may be formulated , alone or Compound B provided herein administered is sufficient to together , in suitable dosage unit with pharmaceutically provide a plasma concentration of Compound A or Com acceptable excipients, carriers, adjuvants and vehicles , pound B at steady state , ranging from about 0 .001 to about appropriate for each route of administration . 500 uM , about 0 .002 to about 200 uM , about 0 . 005 to about In one embodiment, Compound A or Compound B pro 100 uM , about 0 .01 to about 50 UM , from about 1 to about 60 vided herein is administered orally . 50 uM , about 0 . 02 to about 25 uM , from about 0 .05 to about In another embodiment, Compound A or Compound B 20 UM , from about 0 . 1 to about 20 uM , from about 0 . 5 to provided herein is administered parenterally. In certain about 20 uM , or from about 1 to about 20 uM . embodiments , an aqueous solution containing Compound A In other embodiments , the amount of Compound A or or Compound B provided herein is administered parenter Compound B provided herein administered is sufficient to 65 ally . provide a plasma concentration of Compound A or Com In yet another embodiment, Compound A or Compound B pound B at steady state , ranging from about 5 to about 100 provided herein is administered intravenously . In certain US 9 ,938 ,254 B2 41 42 embodiments , an aqueous solution containing Compound A one week to two weeks . In certain embodiments , Compound or Compound B provided herein is administered intrave A or Compound B provided herein is administered once per nously . day for one week , two weeks, three weeks , or four weeks. In Compound A or Compound B provided herein can be one embodiment, Compound A or Compound B provided delivered as a single dose such as , e . g . , a single bolus 5 herein is administered once per day for 4 days . In one injection , or oral tablets or pills ; or over time, such as , e . g . , embodiment, Compound A or Compound B provided herein continuous infusion over time or divided bolus doses over is administered once per day for 5 days . In one embodiment , time. Compound A or Compound B provided herein can be Compound A or Compound B provided herein , is adminis administered repeatedly if necessary , for example , until the tered once per day for 6 days . In one embodiment, Com patient experiences stable disease or regression , or until the 10 pound A or Compound B provided herein is administered patient experiences disease progression or unacceptable once per day for one week . In another embodiment, Com toxicity . For example , stable disease for solid tumors gen pound A or Compound B provided herein is administered erally means that the perpendicular diameter of measurable once per day for two weeks. In yet another embodiment , lesions has not increased by 25 % or more from the last Compound A or Compound B provided herein is adminis measurement. Response Evaluation Criteria in Solid Tumors 15 tered once per day for three weeks . In still another embodi (RECIST ) Guidelines, Journal of the National Cancer Insti - ment, Compound A or Compound B provided herein is tute 92 ( 3 ) : 205 - 216 (2000 ) . Stable disease or lack thereof is administered once per day for four weeks . determined by methods known in the art such as evaluation 5 . 3 . 1 . Combination Therapy with a Second Active Agent of patient symptoms, physical examination , visualization of Compound Aor Compound B provided herein can also be the tumor that has been imaged using X - ray, CAT, PET, or 20 combined or used in combination with other therapeutic MRI scan and other commonly accepted evaluation modali - agents useful in the treatment and/ or prevention of cancer ties . described herein . Compound A or Compound B provided herein can be In one embodiment, provided herein is a method of administered once daily ( QD ), or divided into multiple daily treating, preventing, or managing cancer , comprising admin doses such as twice daily (BID ), three times daily ( TID ) , and 25 istering to a patient Compound A or Compound B provided four times daily ( QID ) . In addition , the administration can herein in combination with one or more second active be continuous (i . e . , daily for consecutive days or every day ) , agents , and optionally in combination with radiation therapy , intermittent , e . g . , in cycles (i . e ., including days, weeks, or blood transfusions, or surgery . Examples of second active months of rest without drug ) . As used herein , the term agents are disclosed herein ( see , e . g . , section 5 . 4 ) . For " daily ” is intended to mean that a therapeutic compound , 30 example , Compound A or Compound B may be used in such as Compound A or Compound B provided herein , is combination with one or more second active agents in a administered once or more than once each day, for example , method of treating cancer. for a period of time. The term " continuous ” is intended to Compound A or Compound B provided herein can also be mean that a therapeutic compound , such as Compound A or combined or used in combination with other therapeutic Compound B provided herein , is administered daily for an 35 agents useful in the treatment and / or prevention of MDS uninterrupted period of at least 10 days to 52 weeks . The described herein . term “ intermittent” or “ intermittently ” as used herein is in one embodiment, provided herein is a method of intended to mean stopping and starting at either regular or treating , preventing , and /or managing MDS , comprising irregular intervals . For example, intermittent administration administering to a patient Compound A or Compound B of Compound A or Compound B provided herein is admin - 40 provided herein in combination with one or more second istration for one to six days per week , administration in active agents , and optionally in combination with radiation cycles (e . g ., daily administration for two to eight consecu - therapy, blood transfusions , or surgery . Examples of second tive weeks, then a rest period with no administration for up active agents are disclosed herein . to one week ) , or administration on alternate days. The term As used herein , the term “ in combination ” includes the " cycling ” as used herein is intended to mean that a thera - 45 use ofmore than one therapy ( e . g . , one or more prophylactic peutic compound , such as Compound A or Compound B and /or therapeutic agents ) . However, the use of the term " in provided herein is administered daily or continuously but combination " does not restrict the order in which therapies with a rest period . In some such embodiments , administra - ( e . g . , prophylactic and / or therapeutic agents ) are adminis tion is once a day for two to six days , then a rest period with tered to a patient with a disease or disorder. A first therapy no administration for five to seven days . 50 ( e . g . , a prophylactic or therapeutic agent such as a com In some embodiments , the frequency of administration is pound provided herein , e . g. , Compound A or Compound B in the range of about a daily dose to about a monthly dose . can be administered prior to ( e . g ., 5 minutes , 15 minutes , 30 In certain embodiments , administration is once a day , twice minutes, 45 minutes, 1 hour, 2 hours , 4 hours , 6 hours , 12 a day , three times a day, four times a day , once every other hours , 24 hours , 48 hours , 72 hours , 96 hours , 1 week , 2 day , twice a week , once every week , once every two weeks, 55 weeks , 3 weeks, 4 weeks, 5 weeks , 6 weeks , 8 weeks, or 12 once every three weeks , or once every four weeks. In one weeks before ), concomitantly with , or subsequent to ( e . g . , 5 embodiment, Compound A or Compound B provided herein minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 is administered once a day . In another embodiment, Com hours , 4 hours , 6 hours , 12 hours , 24 hours , 48 hours , 72 pound A or Compound B provided herein is administered hours, 96 hours , 1 week , 2 weeks , 3 weeks , 4 weeks , 5 twice a day. In yet another embodiment, Compound A or 60 weeks , 6 weeks, 8 weeks, or 12 weeks after the adminis Compound B provided herein , is administered three times a tration of a second therapy ( e . g ., a prophylactic or thera day. In still another embodiment, Compound A or Com - peutic agent ) to the subject. Triple therapy is also contem pound B provided herein is administered four times a day . plated herein . In certain embodiments, Compound A or Compound B Administration of Compound A or Compound B provided provided herein is administered once per day from one day 65 herein and one or more second active agents to a patient can to six months , from one week to three months, from one occur simultaneously or sequentially by the same or differ week to four weeks , from one week to three weeks, or from ent routes of administration . The suitability of a particular US 9 , 938 , 254 B2 43 44 route of administration employed for a particular active 5 to about 12 mcg/ m2 / day subcutaneously . In certain agent will depend on the active agent itself ( e . g . , whether it embodiments , G - CSF may be administered subcutaneously can be administered orally without decomposing prior to in an amount of about 1 mcg /kg / day initially and can be entering the blood stream ) and the cancer being treated . adjusted depending on rise of total granulocyte counts. The The route of administration of Compound Aor Compound 5 maintenance dose of G -CSF may be administered in an B is independent of the route of administration of a second amount of about 300 ( in smaller patients ) or 480 mcg therapy . In one embodiment, Compound A or Compound B subcutaneously . In certain embodiments , EPO may be is administered orally . In another embodiment, Compound A or Compound B is administered intravenously . Thus , in administered subcutaneously in an amount of 10, 000 Unit 3 accordance with these embodiments , Compound A or Com - 10 times per week . pound B provided herein is administered orally or intrave Particular proteins that can be used in the methods and nously , and the second therapy can be administered orally , compositions include , but are not limited to : filgrastim , parenterally , intraperitoneally, intravenously, intraarterially, which is sold in the United States under the trade name transdermally, sublingually , intramuscularly, rectally , trans Neupogen ( Amgen , Thousand Oaks, Calif . ) ; sargra buccally , intranasally , liposomally , via inhalation , vaginally , is15 mostimmost , which is sold in the United States under the trade intraoccularly , via local delivery by catheter or stent, sub name Leukine® (Immunex , Seattle , Wash . ) ; and recombi cutaneously, intraadiposally , intraarticularly , intrathecally , nant EPO , which is sold in the United States under the trade or in a slow release dosage form . In one embodiment, name Epogen® (Amgen , Thousand Oaks, Calif. ) . Compound A or Compound B provided herein and a second Recombinant and mutated forms of GM - CSF can be therapy are administered by the same mode of administra - 20 prepared as described in U . S . Pat. Nos . 5 , 391 ,485 ; 5 , 393 , tion , orally or by IV . In another embodiment, Compound A 870 ; and 5 , 229 , 496 ; all of which are incorporated herein by or Compound B provided herein is administered by one reference . Recombinant and mutated forms of G -CSF can be mode of administration , e . g ., by IV , whereas the second prepared as described in U . S . Pat. Nos . 4 , 810 ,643 ; 4 , 999 , agent (an anticancer agent) is administered by another mode 291 ; 5 , 528 , 823 ; and 5 ,580 , 755 ; the entireties of which are of administration , e. g ., orally . 25 incorporated herein by reference . In one embodiment, the second active agent is adminis - Also provided for use in combination with Compound A tered intravenously or subcutaneously and once or twice or Compound B provided herein are native , naturally occur daily in an amount of from about 1 to about 1000 mg, from ring , and recombinant proteins. Further encompassed are about 5 to about 500 mg, from about 10 to about 350 mg, or from about 50 to about 200 mg. The specific amount of the 30 mutants and derivatives (e . g. , modified forms) of naturally second active agent will depend on the specific agent used , occurring proteins that exhibit, in vivo , at least some of the the type of disease being treated or managed , the severity pharmacological activity of the proteins upon which they are and stage of disease , and the amount of Compound A or based . Examples ofmutants include, but are not limited to , Compound B provided herein and any optional additional proteins that have one or more amino acid residues that active agents concurrently administered to the patient. 35 differ from the corresponding residues in the naturally One or more second active ingredients or agents can be occurring forms of the proteins . Also encompassed by the used together with Compound A or Compound B in the term “ mutants ” are proteins that lack carbohydrate moieties methods and compositions provided herein . Second active normally present in their naturally occurring forms ( e . g . , agents can be large molecules ( e . g . , proteins ) or small nonglycosylated forms) . Examples of derivatives include , molecules ( e . g . , synthetic inorganic , organometallic , or 40 but are not limited to , pegylated derivatives and fusion organic molecules ) . proteins, such as proteins formed by fusing IgGl or IgG3 to Examples of large molecule active agents include , but are the or active portion of the protein of interest. See , not limited to , hematopoietic growth factors , cytokines, and e. g. , Penichet , M . L . and Morrison , S . L ., J. Immunol. monoclonal and polyclonal antibodies, particularly , thera - Methods 248 : 91- 101 ( 2001) . peutic antibodies to cancer antigens . Typical large molecule 45 Antibodies that can be used in combination with Com active agents are biological molecules , such as naturally pound Aor Compound B include monoclonal and polyclonal occurring or synthetic or recombinant proteins . Proteins that antibodies. Examples of antibodies include , but are not are particularly useful in the methods and compositions limited to , trastuzumab (Herceptin® ) , rituximab provided herein include proteins that stimulate the survival (Rituxan® ) , bevacizumab ( AvastinTM ) , pertuzumab (Omni and / or proliferation of hematopoietic precursor cells and 50 targTM ) , tositumomab (Bexxar® ) , edrecolomab (Panorex® ) , immunologically active poietic cells in vitro or in vivo . and G250 . Compound A or Compound B can also be Other useful proteins stimulate the division and differentia combined with , or used in combination with , anti- TNF- a tion of committed erythroid progenitors in cells in vitro or in antibodies , and /or anti- EGFR antibodies , such as , for vivo . Particular proteins include, but are not limited to : example, Erbitux® or panitumumab . interleukins , such as IL - 2 ( including recombinant IL - II 55 Large molecule active agents may be administered in the (“ rIL 2 ” ) and canarypox IL - 2 ), IL - 10 , IL - 12, and IL - 18 ; form of anti- cancer vaccines . For example , vaccines that interferons, such as interferon alfa - 2a , interferon alfa - 2b , secrete , or cause the secretion of, cytokines such as IL - 2 , interferon alfa -n1 , interferon alfa -n3 , interferon beta - I a, and G -CSF , and GM - CSF can be used in the methods and interferon gamma - I b ; GM -CF and GM -CSF ; and EPO . pharmaceutical compositions provided . See , e . g ., Emens , L . In certain embodiments , GM -CSF , G - CSF , SCF or EPO is 60 A . , et al ., Curr. Opinion Mol. Ther . 3 ( 1 ): 77 - 84 ( 2001 ) . administered subcutaneously during about five days in a four Second active agents that are small molecules can also be or six week cycle in an amount ranging from about 1 to used to alleviate adverse effects associated with the admin about 750 mg/ m² / day, from about 25 to about 500 mg/ m² ) istration of Compound A or Compound B provided herein . day , from about 50 to about 250 mg/ m² / day , or from about However, like some large molecules, many are believed to 50 to about 200 mg/ m² / day. In certain embodiments , GM - 65 be capable of providing a synergistic effect when adminis CSF may be administered in an amount of from about 60 to tered with ( e . g . , before , after or simultaneously ) Compound about 500 mcg/ m² intravenously over 2 hours or from about A or Compound B provided herein . Examples of small US 9 ,938 ,254 B2 45 46 molecule second active agents include , but are not limited ALL - TK antagonists ; ; ambamustine ; amidox ; to , anti - cancer agents , antibiotics , immunosuppressive amifostine ; ; ; ; agents , and steroids . ; anastrozole ; andrographolide; angiogenesis In certain embodiments, the second agent is an HSP inhibitors ; antagonist D ; antagonist G ; antarelix ; anti- dor inhibitor, a , a FLT3 inhibitor or a TOR 5 salizing morphogenetic protein - 1 ; antiandrogen , prostatic kinase inhibitor . carcinoma; antiestrogen ; antineoplaston ; antisense oligo Examples of anti- cancer agents to be used within the nucleotides ; aphidicolin glycinate ; apoptosis gene modula methods or compositions described herein include , but are tors ; apoptosis regulators ; apurinic acid ; ara -CDP - DL not limited to : acivicin ; ; acodazole hydrochlo - PTBA ; arginine deaminase ; asulacrine ; atamestane ; ride ; acronine ; adozelesin ; aldesleukin ; altretamine ; 10 atrimustine; axinastatin 1 ; axinastatin 2 ; axinastatin 3 ; azase ambomycin ; ametantrone acetate ; amsacrine ; anastrozole ; tron ; azatoxin ; azatyrosine; baccatin III derivatives ; balanol; anthramycin ; ; asperlin ; ; azetepa ; batimastat ; BCR / ABL antagonists ; benzochlorins; benzoyl azotomycin ; batimastat ; benzodepa ; bicalutamide ; bisant- staurosporine; beta lactam derivatives ; beta - alethine ; beta rene hydrochloride ; bisnafide dimesylate ; bizelesin ; bleo - clamycin B ; betulinic acid ; bFGF inhibitor ; bicalutamide ; mycin sulfate ; brequinar sodium ; bropirimine ; ; 15 bisantrene ; bisaziridinylspermine; bisnafide ; bistratene A ; cactinomycin ; calusterone ; caracemide ; carbetimer ; carbo - bizelesin ; breflate ; bropirimine ; budotitane; buthionine sul platin ; carmustine ; carubicin hydrochloride ; carzelesin ; foximine ; calcipotriol; calphostin C ; deriva cedefingol; (COX - 2 inhibitor ); ; tives ; ; carboxamide- amino - triazole ; car cirolemycin ; cisplatin ; ; ; boxyamidotriazole ; CaRest M3; CARN 700 ; cartilage mesylate ; cyclophosphamide ; Ara - C ; ; dactino - 20 derived inhibitor; carzelesin ; casein kinase inhibitors mycin ; daunorubicin hydrochloride ; ; dexorma ( ICOS ) ; castanospermine ; cecropin B ; cetrorelix ; chlorins ; platin ; dezaguanine; dezaguanine mesylate; diaziquone ; chloroquinoxaline sulfonamide ; cicaprost ; cis - porphyrin ; docetaxel ; ; doxorubicin hydrochloride; drolox cladribine ; clomifene analogues; clotrimazole ; collismycin ifene ; droloxifene citrate ; dromostanolone propionate ; dua - A ; collismycin B ; combretastatin A4 ; combretastatin ana zomycin ; edatrexate ; eflornithine hydrochloride ; elsamitru - 25 logue ; conagenin , crambescidin 816 ; crisnatol ; cryptophycin cin ; enloplatin ; enpromate ; epipropidine ; 8 ; cryptophycin A derivatives ; curacin A ; cyclopentanthra hydrochloride ; erbulozole ; esorubicin hydrochloride ; estra - quinones ; cycloplatam ; cypemycin ; Ara - C ocfosfate ; mustine ; estramustine phosphate sodium ; etanidazole ; cytolytic factor ; cytostatin ; dacliximab ; decitabine ; dehy etoposide ; etoposide phosphate ; etoprine ; fadrozole hydro - drodidemnin B ; deslorelin ; dexamethasone ; dexifosfamide ; chloride; fazarabine ; fenretinide ; ; fludarabine 30 dexrazoxane ; dexverapamil; diaziquone ; didemnin B ; didox ; phosphate ; ; flurocitabine; fosquidone ; fostriecin diethylnorspermine ; dihydro - 5 - azacytidine ; dihydrotaxol, sodium ; ; gemcitabine hydrochloride ; 9 - ; dioxamycin ; diphenyl spiromustine ; docetaxel ; docosa hydroxyurea ; idarubicin hydrochloride ; ; ilmo - nol; dolasetron ; ; doxorubicin ; droloxifene ; fosine ; iproplatin ; ; irinotecan hydrochloride ; lan dronabinol; duocarmycin SA ; ebselen ; ecomustine ; edelfos reotide acetate ; letrozole ; leuprolide acetate ; liarozole 35 ine; edrecolomab ; eflornithine ; elemene ; emitefur; epirubi hydrochloride; lometrexol sodium ; ; cin ; epristeride; estramustine analogue ; estrogen agonists ; hydrochloride ; ; maytansine ; mechlorethamine estrogen antagonists ; etanidazole ; etoposide phosphate ; hydrochloride ; megestrol acetate ; melengestrol acetate ; mel - exemestane ; fadrozole ; fazarabine ; fenretinide ; filgrastim ; phalan ; menogaril ; ; methotrexate ; metho finasteride ; flavopiridol; flezelastine ; fluasterone ; fludara trexate sodium ; metoprine ; meturedepa ; mitindomide ; mito - 40 bine; fluorodaunorunicin hydrochloride ; forfenimex ; form carcin ; mitocromin ; mitogillin ; mitomalcin ; mitomycin ; estane; fostriecin ; ; gadolinium texaphyrin ; gal mitosper ; ; hydrochloride; mycophe lium nitrate ; galocitabine ; ganirelix ; gelatinase inhibitors ; nolic acid ; ; nogalamycin ; omacetaxine ; orma - gemcitabine ; glutathione inhibitors; hepsulfam ; heregulin ; platin ; oxisuran ; paclitaxel; ; peliomycin ; pen hexamethylene bisacetamide; hypericin ; ibandronic acid ; tamustine ; peplomycin sulfate ; perfosfamide ; ; 45 idarubicin ; idoxifene ; idramantone ; ilmofosine ; ilomastat ; piposulfan ; piroxantrone hydrochloride; ; plom imatinib ( e . g . , Gleevec® ) ; imiquimod ; immunostimulant estane ; ; porfiromycin ; prednimustine ; pro - peptides ; insulin - like growth factor - 1 receptor inhibitor; carbazine hydrochloride; puromycin ; puromycin hydrochlo interferon agonists ; interferons; interleukins; iobenguane ; ride ; pyrazofurin ; riboprine ; safingol; safingol iododoxorubicin ; ipomeanol, 4 - ; iroplact; irsogladine ; hydrochloride ; ; simtrazene ; sorafenib ; sparfosate 50 isobengazole ; isohomohalicondrin B ; itasetron ; jasplakino sodium ; sparsomycin ; spirogermanium hydrochloride ; lide ; kahalalide F ; lamellarin -N triacetate ; lanreotide ; lein spiromustine; spiroplatin ; streptonigrin ; streptozocin ; amycin ; lenograstim ; lentinan sulfate ; leptolstatin ; letrozole ; sulofenur ; talisomycin ; tecogalan sodium ; taxotere; ; leukemia inhibiting factor; leukocyte alpha interferon ; leu teloxantrone hydrochloride ; ; ; terox prolide + estrogen + progesterone; leuprorelin ; levamisole ; irone ; ; thiamiprine ; thioguanine ; ; 55 liarozole ; linear polyamine analogue; lipophilic disaccharide ; tirapazamine ; toremifene citrate; trestolone peptide; lipophilic platinum compounds; lissoclinamide 7 ; acetate ; triciribine phosphate ; trimetrexate ; trimetrexate glu - lobaplatin ; lombricine ; lometrexol; ; losoxan curonate ; triptorelin ; tubulozole hydrochloride ; uracil mus trone ; loxoribine ; ; lutetium texaphyrin ; lysofyl tard ; uredepa ; vapreotide ; ; vinblastine sulfate ; line ; lytic peptides ; maitansine ; mannostatin A ; marimastat; vincristine sulfate ; ; vindesine sulfate ; vinepidine 60 masoprocol; maspin ; matrilysin inhibitors ; matrix metallo sulfate ; vinglycinate sulfate ; vinleurosine sulfate ; vinorel- proteinase inhibitors ; menogaril ; merbarone; meterelin ; bine tartrate ; vinrosidine sulfate ; vinzolidine sulfate ; voro - methioninase; metoclopramide ; MIF inhibitor; mifepris zole ; zeniplatin ; zinostatin ; and hydrochloride . tone ; miltefosine; mirimostim ; ; mitolactol; Other anti- cancer drugs to be included within the methods mitomycin analogues ; mitonafide ; mitotoxin fibroblast or compositions include , but are not limited to : 20 - epi- 1 , 25 65 growth factor - saporin ; mitoxantrone; mofarotene ; molgra dihydroxyvitamin D3; 5 -ethynyluracil ; abiraterone ; aclaru - mostim ; Erbitux , human chorionic gonadotrophin ; mono bicin ; acylfulvene; adecypenol; adozelesin ; aldesleukin ; phosphoryl lipid A +myobacterium cell wall sk ; mopidamol; US 9 , 938 , 254 B2 47 48 mustard anticancer agent; mycaperoxide B ; mycobacterial partially reduce , inhibit , interfere with or modulate one or cell wall extract ; myriaporone ; N - acetyldinaline; N - substi more checkpoint proteins. Without being limited by a par tuted benzamides ; nafarelin ; nagrestip ; naloxone + pentazo - ticular theory , checkpoint proteins regulate T -cell activation cine; napavin ; naphterpin ; nartograstim ; ; nemo - or function . Numerous checkpoint proteins are known , such rubicin ; neridronic acid ; nilutamide; nisamycin ; nitric oxide 5 as CTLA - 4 and its ligands CD80 and CD86 ; and PD - 1 with modulators ; nitroxide antioxidant; nitrullyn ; (Genasense® ); 06 benzylguanine ; octreotide; okicenone ; its ligands PD -L1 and PD -L2 (Pardoll , Nature Reviews oligonucleotides; onapristone ; ondansetron ; ondansetron ; Cancer , 2012, 12, 252 - 264 ) . These proteins appear respon oracin ; oral cytokine inducer , ormaplatin ; osaterone ; oxali sible for co -stimulatory or inhibitory interactions of T -cell platin ; oxaunomycin ; paclitaxel ; paclitaxel analogues; pacli - 10 responses . Immune checkpoint proteins appear to regulate taxel derivatives ; palauamine ; palmitoylrhizoxin ; and maintain self- tolerance and the duration and amplitude pamidronic acid ; panaxytriol; panomifene; parabactin ; of physiological immune responses . Immune checkpoint pazelliptine ; pegaspargase ; peldesine ; pentosan polysulfate inhibitors include antibodies or are derived from antibodies . sodium ; ; pentrozole ; perflubron ; perfosfamide ; In one embodiment , the checkpoint inhibitor is a CTLA - 4 perillyl alcohol; phenazinomycin ; phenylacetate ; phos - 1515 inhibitor . In one embodiment, the CTLA - 4 inhibitor is an phatase inhibitors; picibanil ; pilocarpine hydrochloride ; anti -CTLA -4 antibody . Examples of anti -CTLA - 4 antibod ; piritrexim ; placetin A ; placetin B ; plasminogen i es include , but are not limited to , those described in U .S . activator inhibitor ; platinum complex ; platinum compounds; Pat. Nos. 5 ,811 , 097 ; 5 ,811 , 097 ; 5 , 855 , 887 ; 6 ,051 ,227 ; platinum - triamine complex ; porfimer sodium ; porfiromycin ; 6 , 207, 157 ; 6 ,682 ,736 ; 6 , 984 ,720 ; and 7 ,605 , 238 , all of prednisone ; propyl bis -acridone ; prostaglandin J2 ; protea - 20 which are incorporated herein in their entireties . In one some inhibitors; protein A -based immune modulator ; pro - embodiment, the anti -CTLA - 4 antibody is tremelimumab tein kinase C inhibitor; protein kinase C inhibitors, microal ( also known as ticilimumab or CP -675 ,206 ) . In another gal; protein tyrosine phosphatase inhibitors ; purine embodiment, the anti- CTLA - 4 antibody is ipilimumab ( also nucleoside phosphorylase inhibitors ; purpurins ; pyrazolo known as MDX -010 or MDX - 101) . Ipilimumab is a fully acridine ; pyridoxylated hemoglobin polyoxyethylene con - 25 human monoclonal IgG antibody that binds to CTLA - 4 . jugate ; raf antagonists ; ; ramosetron ; ras farnesyl Ipilimumab is marketed under the trade name YervoyTM protein transferase inhibitors; ras inhibitors ; ras -GAP inhibi In one embodiment, the checkpoint inhibitor is a PD - 1 / tor; retelliptine demethylated ; rhenium Re 186 etidronate ; PD -L1 inhibitor. Examples of PD - 1 / PD - L1 inhibitors rhizoxin ; ribozymes; RII retinamide ; rohitukine; romurtide ; include , but are not limited to , those described in U . S . Pat. roquinimex ; rubiginone B1; ruboxyl; safingol; saintopin ; 30 Nos. 7 ,488 , 802; 7 , 943 , 743 ; 8 , 008, 449 ; 8 , 168 ,757 ; 8 ,217 , SarCNU ; sarcophytol A ; sargramostim ; Sdi 1 mimetics ; 149 , and PCT Patent Application Publication Nos . semustine ; senescence derived inhibitor 1; sense oligonucle WO2003042402 , WO2008156712 , WO2010089411 , otides; signal transduction inhibitors ; sizofiran ; sobuzoxane ; WO2010036959 , WO2011066342 , WO2011159877 , sodium borocaptate ; sodium phenylacetate ; solverol; WO2011082400 , and WO2011161699, all of which are somatomedin binding protein ; sonermin ; sparfosic acid ; 35 incorporated herein in their entireties . spicamycin D ; spiromustine ; splenopentin ; spongistatin 1; In one embodiment, the checkpoint inhibitor is a PD - 1 squalamine ; stipiamide; stromelysin inhibitors ; sulfinosine; inhibitor. In one embodiment , the PD - 1 inhibitor is an superactive vasoactive intestinal peptide antagonist; sura - anti - PD - 1 antibody. In one embodiment, the anti- PD - 1 anti dista ; suramin ; swainsonine; tallimustine; tamoxifen body is nivolumab (also known as ONO - 4538 , BMS methiodide ; tauromustine ; tazarotene ; tecogalan sodium ; 40 936558 , or MDX1106 ) or pembrolizumab ( also known as tegafur; tellurapyrylium ; telomerase inhibitors; temoporfin ; MK - 3475 , SCH 900475 , or lambrolizumab ) . In one embodi teniposide ; tetrachlorodecaoxide ; tetrazomine ; thaliblastine ; ment, the anti- PD - 1 antibody is nivolumab . Nivolumab is a thiocoraline ; thrombopoietin ; thrombopoietin mimetic ; thy - human IgG4 anti - PD - 1 monoclonal antibody, and is mar malfasin ; thymopoietin receptor agonist ; thymotrinan ; thy - keted under the trade name OpdivoTM . In another embodi roid stimulating hormone ; tin ethyl etiopurpurin ; tira - 45 ment , the anti- PD - 1 antibody is pembrolizumab . Pembroli pazamine ; titanocene bichloride ; topsentin ; toremifene ; zumab is a humanized monoclonal IgG4 antibody and is translation inhibitors; ; triacetyluridine ; triciribine ; marketed under the trade name KeytrudaTM . In yet another trimetrexate ; triptorelin ; tropisetron ; turosteride ; tyrosine embodiment, the anti -PD - 1 antibody is CT- 011 , a human kinase inhibitors ; tyrphostins ; UBC inhibitors ; ubenimex ; ized antibody. CT- 011 administered alone has failed to show urogenital sinus - derived growth inhibitory factor ; urokinase 50 response in treating acute myeloid leukemia (AML ) at receptor antagonists ; vapreotide ; variolin B ; velaresol; relapse . In yet another embodiment, the anti -PD - 1 antibody veramine; verdins ; verteporfin ; ; vinxaltine ; is AMP- 224 , a fusion protein . vitaxin ; vorozole ; zanoterone ; zeniplatin ; zilascorb ; and In one embodiment, the checkpoint inhibitor is a PD - L1 zinostatin stimalamer . inhibitor. In one embodiment, the PD -L1 inhibitor is an In certain embodiments , Compound A or Compound B is 55 anti- PD -L1 antibody . In one embodiment, the anti -PD -L1 administered in combination with checkpoint inhibitors . In antibody is MEDI4736 (durvalumab ) . In another embodi one embodiment, one checkpoint inhibitor is used in com - ment, the anti - PD -L1 antibody is BMS - 936559 (also known bination with Compound A or Compound B in connection as MDX - 1105 -01 ) . In yet another embodiment , the PD -L1 with the methods provided herein . In another embodiment, inhibitor is atezolizumab (also known as MPDL3280A , and two checkpoint inhibitors are used in combination with 60 Tecentriq® ) . Compound A or Compound B in connection with the meth - In one embodiment, the checkpoint inhibitor is a PD - L2 ods provided herein . In yet another embodiment, three or inhibitor. In one embodiment, the PD -L2 inhibitor is an morem checkpoint inhibitors are used in combination with anti -PD - L2 antibody. In one embodiment, the anti -PD -L2 Compound A or Compound B in connection with the meth - antibody is rHIgM12B7A . ods provided herein . 65 In one embodiment, the checkpoint inhibitor is a lym As used herein , the term " immune checkpoint inhibitor” phocyte activation gene - 3 (LAG - 3 ) inhibitor. In one or “ checkpoint inhibitor ” refers to molecules that totally or embodiment, the LAG - 3 inhibitor is IMP321 , a soluble Ig US 9 , 938 , 254 B2 49 50 fusion protein (Brignone et al ., J . Immunol . , 2007 , 179 , In certain embodiments , the antigen recognized by the 4202 -4211 ) . In another embodiment, the LAG -3 inhibitor is extracellular domain of a polypeptide described herein is a BMS - 986016 . tumor- associated antigen ( TAA ) or a tumor- specific antigen In one embodiment, the checkpoint inhibitors is a B7 ( TSA ). In various specific embodiments , the tumor -associ inhibitor. In one embodiment, the B7 inhibitor is a B7 -H3 5 ated antigen or tumor- specific antigen is , without limitation , inhibitor or a B7 -H4 inhibitor. In one embodiment, the Her2 . prostate stem cell antigen ( PSCA ) , alpha - fetoprotein B7 -H3 inhibitor is MGA271, an anti- B7 -H3 antibody (Loo ( AFP ) , carcinoembryonic antigen (CEA ), cancer antigen et al. , Clin . Cancer Res. , 2012 , 3834 ). In one embodiment, the checkpoint inhibitors is a TIM3 125 (CA - 125 ) , CA19 - 9 , calretinin , MUC - 1 , B cell matura ( T -cell immunoglobulin domain and mucin domain 3 ) 10 tion antigen (BCMA ), epithelial membrane protein (EMA ) , inhibitor (Fourcade et al. , J . Exp . Med . , 2010 , 207 , 2175 - 86 ; epithelial tumor antigen (ETA ), tyrosinase, melanoma - 24 Sakuishi et al ., J. Exp . Med ., 2010 , 207 , 2187 - 94 ) . associated antigen (MAGE ), CD19 , CD22 , CD27 , CD30 , In one embodiment, the checkpoint inhibitor is an OX40 CD34 , CD45 , CD70 , CD99 , CD117 , EGFRvIII (epidermal ( CD134 ) agonist . In one embodiment, the checkpoint inhibi growth factor variant III ) , mesothelin , PAP (prostatic acid tor is an anti -OX40 antibody. In one embodimentmbodiment, the 15 Phosphatasephosphatase )), prostein ,, TARP ll(T cellcell receptor gamindgamma alleralter anti -OX40 antibody is anti -OX - 40 . In another embodiment nate reading frame protein ) , Trp -p8 , STEAPI ( six - trans the anti -OX40 antibody is MEDI6469 . membrane epithelial antigen of the prostate 1 ) , chromogra In one embodiment, the checkpoint inhibitor is a GITR nin , cytokeratin , desmin , glial fibrillary acidic protein agonist. In one embodiment, the checkpoint inhibitor is an (GFAP ) , gross cystic disease fluid protein (GCDFP - 15 ) , anti -GITR antibody. In one embodiment, the anti -GITR 20 HMB - 45 antigen , protein melan - A (melanoma antigen rec antibody is TRX518 . ognized by T lymphocytes; MART- I) , myo -Di , muscle In one embodiment, the checkpoint inhibitor is a CD137 specific actin (MSA ) , neurofilament , neuron - specific eno agonist. In one embodiment, the checkpoint inhibitor is an lase (NSE ), placental alkaline phosphatase , synaptophysis , anti -CD137 antibody . In one embodiment, the anti -CD137 thyroglobulin , thyroid transcription factor- 1 , the dimeric antibody is urelumab . In another embodiment, the anti- 25 form of the pyruvate kinase isoenzyme type M2 (tumor CD137 antibody is PF -05082566 . M2- PK ) , an abnormal ras protein , or an abnormal p53 In one embodiment, the checkpoint inhibitor is a CD40 protein . In certain other embodiments , the TAA or TSA agonist. In one embodiment, the checkpoint inhibitor is an recognized by the extracellular domain of a CAR is integrin anti -CD40 antibody. In one embodiment, the anti -CD40 avß3 (CD61 ) , galactin , or Ral- B . antibody is CF - 870 , 893 . 30 In certain embodiments , the TAA or TSA recognized by In one embodiment, the checkpoint inhibitor is recombi the extracellular domain of a CAR is a cancer /testis (CT ) nant human interleukin - 15 ( rhIL - 15 ) . antigen , e . g ., BAGE , CAGE, CTAGE , FATE , GAGE, In one embodiment, the checkpoint inhibitor is an IDO HCA661, HOM - TES - 85 , MAGEA , MAGEB , MAGEC , inhibitor. In one embodiment, the IDO inhibitor is NA88 , NY - ES0 - 1 , NY -SAR - 35 , OY - TES - 1 , SPANXBI, INCB024360 . In another embodiment, the IDO inhibitor is 35 SPA17 , SSX , SYCPI, or TPTE . indoximod . In certain other embodiments , the TAA or TSA recognized In certain embodiments , the combination therapies pro - by the extracellular domain of a CAR is a carbohydrate or vided herein include two or more of the checkpoint inhibi- ganglioside, e . g ., fuc -GMI , GM2 (oncofetal antigen - immu tors described herein ( including checkpoint inhibitors of the nogenic - 1 ; OFA - I - 1 ); GD2 (OFA - 1- 2 ) , GM3 , GD3 , and the same or different class ) . Moreover, the combination thera - 40 like . pies described herein can be used in combination with In certain other embodiments , the TAA or TSA recognized second active agents as described herein where appropriate by the extracellular domain of a CAR is alpha - actinin - 4 , for treating diseases described herein and understood in the Bage - 1 , BCR - ABL , Bcr -Abl fusion protein , beta - catenin , art . CA 125 , CA 15 - 3 (CA 27 . 29 \BCAA ) , CA 195 , CA 242 . In certain embodiments, Compound A or Compound B 45 CA -50 , CAM43 , Casp - 8 , cdc27 , cdk4 , cdkn2a , CEA , coa - 1 , can be used in combination with one or more immune cells d ek - can fusion protein , EBNA , EF2, Epstein Barr virus expressing one or more chimeric antigen receptors (CARs ) antigens, ETV6 - AML1 fusion protein , HLA - A2 , HLA -A11 , on their surface (e . g. , a modified immune cell ). Generally , hsp70 - 2 , KIAA0205 , Mart2 , Mum - 1 , 2 , and 3 , neo - PAP , CARs comprise an extracellular domain from a first protein myosin class I, OS - 9 , pm1- RARa fusion protein , PTPRK , e . g . , an antigen - binding protein ) , a transmembrane domain , 50 K -ras , N - ras , triosephosphate isomerase , Gage 3 , 4 , 5 , 6 , 7 , and an intracellular signaling domain . In certain embodi- GnTV , Herv - K -mel , Lage - 1 , NA - 88 , NY - Eso - 1 /Lage - 2 , ments , once the extracellular domain binds to a target SP17 , SSX - 2 , TRP2 - Int2 , gp100 ( Pmel17 ) , tyrosinase, TRP protein such as a tumor- associated antigen ( TAA ) or tumor 1 , TRP - 2 , MAGE - 1 ,MAGE -3 , RAGE , GAGE - 1 , GAGE -2 , specific antigen ( TSA ) , a signal is generated via the intra p15 (58 ), RAGE , SCP - 1 , Hom /Mel - 40 , PRAME , p53 , HRas , cellular signaling domain that activates the immune cell, 55 HER - 2 /neu , E2A - PRL , H4 -RET , IGH -IGK , MYL -RAR , e . g ., to target and kill a cell expressing the target protein . human papillomavirus (HPV ) antigens E6 and E7 , TSP - 180 , Extracellular domains: The extracellular domains of the MAGE - 4 , MAGE- 5 , MAGE - 6 , p185erbB2 , p180erbB - 3 , CARs bind to an antigen of interest . In certain embodiments , c -met , nm - 23H1, PSA , TAG - 72 - 4 , CA 19 - 9 , CA 72 - 4 , CAM the extracellular domain of the CAR comprises a receptor, or 17 . 1 , NuMa, K - ras , 13 - Catenin , Mum - 1 , p16 , TAGE, a portion of a receptor , that binds to said antigen . In certain 60 PSMA , CT7 , telomerase, 43 -9F , 5T4 , 791Tgp72 , 13HCG , embodiments , the extracellular domain comprises , or is , an BCA225 , BTAA , CD68 \KP1 , CO -029 , FGF - 5 , G250 , Ga733 antibody or an antigen -binding portion thereof. In specific (EpCAM ) , HTgp - 175 , M344 , MA -50 , MG7 -Ag , MOV18 , embodiments , the extracellular domain comprises , or is , a NB \ 7OK , NY - C0 - 1 , RCAS1 , SDCCAG16 , TA - 90 , TAAL , single chain Fv ( scFv ) domain . The single - chain Fv domain TAG72 , TLP, or TPS . can comprise , for example , a VL linked to VH by a flexible 65 In various specific embodiments , the tumor- associated linker , wherein said VL and VH are from an antibody that antigen or tumor -specific antigen is an AML - related tumor binds said antigen . antigens , as described in S . Anguille et al, Leukemia ( 2012 ), US 9 , 938 , 254 B2 51 52 26 , 2186 - 2196 . Other tumor- associated and tumor- specific 4 - 1BB ( CD137 ) polypeptide sequence , or a co - stimulatory antigens are known to those in the art . inducible T - cell costimulatory ( ICOS ) polypeptide Receptors , antibodies, and scFvs that bind to TSAs and sequence , or other costimulatory domain or motif, or any TAAs, useful in constructing chimeric antigen receptors, are combination thereof. known in the art, as are nucleotide sequences that encode 5 The CAR may also comprise a T cell survival motif . The them . T cell survival motif can be any polypeptide sequence or In certain specific embodiments , the antigen recognized motif that facilitates the survival of the T lymphocyte after by the extracellular domain of a chimeric antigen receptor is stimulation by an antigen . In certain embodiments , the T cell an antigen not generally considered to be a TSA or a TAA , survival motif is , or is derived from , CD3, CD28 , an but which is nevertheless associated with tumor cells , or 10 intracellular signaling domain of IL - 7 receptor (IL - 7R ) , an damage caused by a tumor. In certain embodiments, for intracellular signaling domain of IL - 12 receptor, an intrac example , the antigen is , e . g . , a growth factor, cytokine or ellular signaling domain of IL - 15 receptor, an intracellular interleukin , e . g . , a growth factor, cytokine , or interleukin signaling domain of IL - 21 receptor, or an intracellular associated with angiogenesis or vasculogenesis . Such signaling domain of transforming growth factor B ( TGFB ) growth factors, cytokines , or interleukins can include , e . g . , 15 receptor. vascular endothelial growth factor (VEGF ) , basic fibroblast The modified immune cells expressing the CARs can be, growth factor (bFGF ), platelet- derived growth factor e . g. , T lymphocytes ( T cells , e. g. , CD4 + T cells or CD8 + T (PDGF ) , hepatocyte growth factor (HGF ) , insulin - like cells ) , cytotoxic lymphocytes (CTLs ) or natural killer (NK ) growth factor ( IGF ) , or interleukin - 8 ( IL - 8 ) . Tumors can cells . T lymphocytes used in the compositions and methods also create a hypoxic environment local to the tumor. As 20 provided herein may be naive T lymphocytes or MHC such , in other specific embodiments , the antigen is a restricted T lymphocytes . In certain embodiments , the T hypoxia -associated factor, e . g . , HIF - la , HIF - 1B , HIF - 2a , lymphocytes are tumor infiltrating lymphocytes ( TILs) . In HIF - 2B , HIF - 3a , or HIF - 3B . Tumors can also cause local- certain embodiments , the T lymphocytes have been isolated ized damage to normal tissue , causing the release of mol- from a tumor biopsy , or have been expanded from T lym ecules known as damage associated molecular pattern mol - 25 phocytes isolated from a tumor biopsy . In certain other ecules (DAMPs ; also known as alarmins ) . In certain other embodiments , the T cells have been isolated from , or are specific embodiments , therefore, the antigen is a DAMP, expanded from T lymphocytes isolated from , peripheral e . g ., a heat shock protein , chromatin -associated protein high blood , cord blood , or lymph . Immune cells to be used to mobility group box 1 (HMGB 1 ) , S100A8 (MRP8 , calgranu - generate modified immune cells expressing a CAR can be lin A ), S100A9 (MRP14 , calgranulin B ) , serum amyloid A 30 isolated using art - accepted , routine methods, e . g . , blood (SAA ), or can be a deoxyribonucleic acid , adenosine collection followed by apheresis and optionally antibody triphosphate , uric acid , or heparin sulfatefoto . mediated cell isolation or sorting . Transmembrane domain : In certain embodiments , the The modified immune cells are preferably autologous to extracellular domain of the CAR is joined to the transmem - an individual to whom the modified immune cells are to be brane domain of the polypeptide by a linker, spacer or hinge 35 administered . In certain other embodiments , the modified polypeptide sequence , e . g ., a sequence from CD28 or a immune cells are allogeneic to an individual to whom the sequence from CTLA4 . The transmembrane domain can be modified immune cells are to be administered . Where allo obtained or derived from the transmembrane domain of any geneic T lymphocytes or NK cells are used to prepare transmembrane protein , and can include all or a portion of modified T lymphocytes , it is preferable to select T lym such transmembrane domain . In specific embodiments, the 40 phocytes or NK cells that will reduce the possibility of transmembrane domain can be obtained or derived from , graft - versus -host disease (GVHD ) in the individual. For e . g ., CD8, CD16 , a cytokine receptor, and interleukin recep - example , in certain embodiments , virus -specific T lympho tor, or a growth factor receptor, or the like . cytes are selected for preparation of modified T lympho Intracellular signaling domains: In certain embodiments , cytes; such lymphocytes will be expected to have a greatly the intracellular domain of a CAR is or comprises an 45 reduced native capacity to bind to , and thus become acti intracellular domain or motif of a protein that is expressed vated by, any recipient antigens. In certain embodiments , on the surface of T cells and triggers activation and / or recipient- mediated rejection of allogeneic T lymphocytes proliferation of said T cells . Such a domain or motif is able can be reduced by co - administration to the host of one or to transmit a primary antigen - binding signal that is neces - more immunosuppressive agents , e . g ., cyclosporine , tacroli sary for the activation of a T lymphocyte in response to the 50 mus , sirolimus , cyclophosphamide , or the like . antigen ' s binding to the CAR ' s extracellular portion . Typi - T lymphocytes, e . g . , unmodified T lymphocytes, or T cally , this domain or motif comprises, or is , an ITAM lymphocytes expressing CD3 and CD28 , or comprising a ( immunoreceptor tyrosine - based activation motif) . ITAM - polypeptide comprising a CD35 signaling domain and a containing polypeptides suitable for CARs include , for CD28 co -stimulatory domain , can be expanded using anti example , the zeta CD3 chain (CD3C ) or ITAM - containing 55 bodies to CD3 and CD28 , e . g . , antibodies attached to beads ; portions thereof. In a specific embodiment, the intracellular see , e . g . , U . S . Pat. Nos . 5 ,948 ,893 ; 6 ,534 , 055 ; 6 , 352 ,694 ; domain is a CD3C intracellular signaling domain . In other 6 ,692 , 964 ; 6 , 887 , 466 ; and 6 , 905 ,681 . specific embodiments , the intracellular domain is from a The modified immune cells, e . g ., modified T lympho lymphocyte receptor chain , a TCR /CD3 complex protein , an cytes, can optionally comprise a “ suicide gene” or “ safety Fe receptor subunit or an IL - 2 receptor subunit . In certain 60 switch ” that enables killing of substantially all of the modi embodiments , the CAR additionally comprises one or more fied immune cells when desired . For example , the modified co -stimulatory domains or motifs , e . g . , as part of the intra - T lymphocytes, in certain embodiments , can comprise an cellular domain of the polypeptide . The one or more co - HSV thymidine kinase gene (HSV - TK ) , which causes death stimulatory domains or motifs can be , or can comprise , one of themodified T lymphocytes upon contact with gancyclo or more of a co - stimulatory CD27 polypeptide sequence , a 65 vir . In another embodiment, the modified T lymphocytes co - stimulatory CD28 polypeptide sequence , a co - stimula - comprise an inducible caspase , e . g . , an inducible caspase 9 tory OX40 ( CD134 ) polypeptide sequence , a co - stimulatory ( icaspase9 ) , e . g ., a fusion protein between caspase 9 and US 9 , 938 , 254 B2 53 54 human FK506 binding protein allowing for dimerization tane, selective estrogen modulators , estrogen receptor using a specific small molecule pharmaceutical. See antagonists , anthracyclines, emtansine , and / or pexidartinib Straathof et al. , Blood 105 ( 11 ): 4247 -4254 ( 2005 ) . to patients with metastatic . Specific second active agents particularly useful in the In certain embodiments , Compound A or Compound B methods or compositions include , but are not limited to , 5 provided herein is administered with , doxo rituximab , oblimersen (Genasense® ) , remicade , docetaxel, rubicin (Adriamycin ), fluorouracil ( Adrucil , 5 - fluorouracil ) , celecoxib , melphalan , dexamethasone (Decadron® ), ste or streptozocin ( Zanosar ) to patients with neuroendocrine roids, gemcitabine, cisplatinum , temozolomide , etoposide , tumors . cyclophosphamide , temodar, carboplatin , , In certain embodiments , Compound A or Compound B gliadel, tamoxifen , , methotrexate , Arisa? , taxol, 10 provided herein is administered with methotrexate , gemcit taxotere , fluorouracil, leucovorin , irinotecan , xeloda , inter - abine , cisplatin , cetuximab , 5 - fluorouracil, , doc feron alpha , pegylated interferon alpha ( e . g . , PEG INTRON etaxel or carboplatin to patients with recurrent or metastatic A ), capecitabine , cisplatin , thiotepa, fludarabine , carbopla - head or neck cancer . tin , liposomal daunorubicin , Ara - C , doxetaxol, pacilitaxel, In certain embodiments , Compound A or Compound B vinblastine , IL - 2, GM CSF , dacarbazine , vinorelbine, zole - 15 provided herein is administered with gemcitabine , abraxane , dronic acid , palmitronate , biaxin , busulphan , prednisone , 5 - fluorouracil , afinitor, irinotecan , , sunitinib or bisphosphonate , , vincristine , doxorubicin tarceva to patients with pancreatic cancer . ( Doxil® ) , paclitaxel , ganciclovir , adriamycin , estramustine In certain embodiments , Compound A or Compound B sodium phosphate (Emcyt® ) , sulindac , and etoposide. provided herein is administered to patients with colon cancer Compound A or Compound B In certain embodiments of 20 in combination with ARISA® , avastatin , oxaliplatin , 5 - fluo the methods provided herein , use of a second active agent in rouracil , irinotecan , capecitabine, cetuximab , ramucirumab , combination with provided herein may be modified or panitumumab , bevacizumab , leucovorin calcium , lonsurf, delayed during or shortly following administration of Com - regorafenib , ziv -aflibercept , taxol, and /or taxotere . pound A or Compound B provided herein as deemed appro - In certain embodiments , Compound A or Compound B priate by the practitioner of skill in the art. In certain 25 provided herein is administered with capecitabine and/ or embodiments , subjects being administered Compound A or vemurafenib to patients with refractory colorectal cancer or Compound B provided herein alone or in combination with patients who fail first line therapy or have poor performance other therapies may receive supportive care including anti- in colon or rectal adenocarcinoma. emetics , myeloid growth factors , and transfusions of plate - In certain embodiments , Compound A or Compound B lets , when appropriate . In some embodiments , subjects 30 provided herein is administered in combination with fluo being administered provided herein may be administered a rouracil, leucovorin , and irinotecan to patients with Dukes C growth factor as a second active agent according to the & D colorectal cancer or to patients who have been previ judgment of the practitioner of skill in the art. In some ously treated for metastatic colorectal cancer. embodiments , provided is administration of Compound Aor I n certain embodiments , Compound A or Compound B Compound B provided herein in combination with erythro - 35 provided herein is administered to patients with refractory poietin or darbepoetin ( Aranesp ) . colorectal cancer in combination with capecitabine , xeloda , In certain embodiments , Compound A or Compound B and /or irinotecan . provided herein is administered with gemcitabine , cisplati - In certain embodiments , Compound A or Compound B num , 5 - fluorouracil, mitomycin , methotrexate , vinblastine , provided herein is administered with capecitabine and iri doxorubicin , carboplatin , thiotepa , paclitaxel or docetaxel to 40 notecan to patients with refractory colorectal cancer or to patients with locally advanced or metastatic transitional cell patients with unresectable or metastatic colorectal carci bladder cancer. noma . In certain embodiments , Compound A or Compound B In certain embodiments , Compound A or Compound B provided herein is administered in combination with a provided herein is administered alone or in combination second active ingredient as follows : temozolomide to pedi- 45 with interferon alpha or capecitabine to patients with unre atric patients with relapsed or progressive brain tumors or sectable or metastatic hepatocellular carcinoma ; or with recurrent neuroblastoma; celecoxib , etoposide and cyclo - cisplatin and thiotepa , or with sorafenib tosylate to patients phosphamide for relapsed or progressive CNS cancer , temo - with primary or metastatic liver cancer. dar to patients with recurrent or progressive meningioma, In certain embodiments , Compound A or Compound B malignant meningioma, hemangiopericytoma, multiple 50 provided herein is administered in combination with doxo brain metastases, relapsed brain tumors, or newly diagnosed rubicin , paclitaxel, vinblastine or pegylated interferon alpha glioblastoma multiforms; irinotecan to patients with recur - to patients with Kaposi ' s sarcoma. rent glioblastoma; carboplatin to pediatric patients with In certain embodiments , Compound A or Compound B brain stem glioma; procarbazine to pediatric patients with provided herein is administered in combination with arsenic progressive malignant gliomas ; cyclophosphamide to 55 trioxide , fludarabine , carboplatin , daunorubicin , cyclophos patients with poor prognosis malignant brain tumors , newly phamide, , doxorubicin , idarubicin , mitoxantrone diagnosed or recurrent glioblastoma multiforms; Gliadel® hydrochloride , thioguanine , vincritine, and / or topotecan to for high grade recurrent malignant gliomas ; temozolomide patients with refractory or relapsed or high - risk acute and tamoxifen for anaplastic astrocytoma; or topotecan for myeloid leukemia . gliomas, glioblastoma, anaplastic astrocytoma or anaplastic 60 In certain embodiments , Compound A or Compound B oligodendroglioma. provided herein is administered in combination with lipo In certain embodiments , Compound A or Compound B somal daunorubicin , topotecan and / or cytarabine to patients provided herein is administered with methotrexate , cyclo with unfavorable karotype acute myeloblastic leukemia . phosphamide , 5 - fluorouracil , , everolimus , abraxane , In certain embodiments , Compound A or Compound B lapatinib , herceptin , pamidronate disodium , mesy - 65 provided herein is administered in combination with metho late , everolimus, gemcitabine , , , kad trexate , mechlorethamine hydrochloride , afatinib dimaleate , cyla , pertuzumab , theotepa , aromatase inhibitors, exemes , bevacizumab , carboplatin , cisplatin , ceritinib , US 9 ,938 ,254 B2 55 56 crizotinib , ramucirumab , pembrolizumab , docetaxel, vinore - types or stages of multiple myeloma in combination with lbine tartrate , gemcitabine , abraxane , erlotinib , geftinib , chimeric antigen receptor (CAR ) T - cells . and / or irinotecan to patients with non -small cell lung cancer. In certain embodiments , Compound A or Compound B In certain embodiments , Compound A or Compound B provided herein is administered to patients with relapsed or provided herein is administered in combination with carbo - 5 refractory multiple myeloma in combination with doxoru platin and irinotecan to patients with non - small cell lung bicin (Doxil® ) , vincristine and / or dexamethasone (Decad cancer . ron® ) . In certain embodiments , Compound A or Compound B In certain embodiments , Compound A or Compound B provided herein is administered to patients with various provided herein is administered with doxetaxol to patientssly 10 types or stages of ovarian cancer such as peritoneal carci with non -small cell lung cancer who have been previously noma, papillary serous carcinoma, refractory ovarian cancer treated with carbo / etoposide and radiotherapy . or recurrent ovarian cancer , in combination with taxol, In certain embodiments , Compound A or Compound B carboplatin , doxorubicin , gemcitabine , cisplatin , xeloda , provided herein is administered in combination with carbo paclitaxel , dexamethasone, avastin , cyclophosphamide, platin and /or taxotere , or in combination with carboplatin , 15 topotecan , , thiotepa , or a combination thereof . pacilitaxel and /or thoracic radiotherapy to patients with In certain embodiments , Compound A or Compound B non - small cell lung cancer. provided herein is administered to patients with various In certain embodiments , Compound A or Compound B types or stages of prostate cancer, in combination with provided herein is administered in combination with taxo xeloda , 5 FU /LV , gemcitabine, irinotecan plus gemcitabine , tere to patients with stage IIIB or IV non - small cell lung 20 cyclophosphamide, vincristine, dexamethasone , GM -CSF , cancer . celecoxib , taxotere, ganciclovir , paclitaxel, adriamycin , doc In certain embodiments , Compound A or Compound B etaxel , estramustine, Emcyt, denderon , zytiga, bicalutamide , provided herein is administered in combination with , degarelix , enzalutamide , zoladex , leuprolide oblimersen (Genasense® ) , methotrexate , mechlorethamine acetate , mitoxantrone hydrochloride , prednisone, sipuleu hydrochloride , etoposide , topotecan or doxorubicin to 25 cel - T , radium 223 dichloride , or a combination thereof. patients with small cell lung cancer. In certain embodiments , Compound A or Compound B In certain embodiments , Compound A or Compound B provided herein is administered to patients with various provided herein is administered in combination with ABT types or stages of renal cell cancer , in combination with 737 ( Abbott Laboratories ) and / or obatoclax (GX15 -070 ) to capecitabine , IFN , tamoxifen , IL - 2 , GM -CSF , Celebrex® , or patients with lymphoma and other blood cancers . 30 a combination thereof. In certain embodiments , Compound A or Compound B In certain embodiments , Compound A or Compound B provided herein is administered alone or in combination provided herein is administered to patients with various with a second active ingredient such as vinblastine , fludara - types or stages of gynecologic , uterus or soft tissue sarcoma bine adcetris , ambochlorin , becenum , bleomycin , brentux cancer in combination with IFN , , doxorubicin , imab vedotin , carmustinem chlorambucil , cyclophosph - 35 imatinib mesylate , pazopanib , hydrochloride , , a amide , dacarbazine, doxorubicin , lomustine , matulane , COX - 2 inhibitor such as Celebrex® , and / or sulindac . mechlorethamine hydrochloride , prednisone, procarbazine In certain embodiments , Compound A or Compound B hydrochloride or vincristine to patients with various types of provided herein is administered to patients with various lymphoma, including , but not limited to , Hodgkin ' s lym types or stages of solid tumors in combination with celebrex , phoma, non - Hodgkin ' s lymphoma, cutaneous T - Cell lym - 40 etoposide, cyclophosphamide, docetaxel , apecitabine, IFN , phoma, cutaneous B - Cell lymphoma, diffuse large B -Cell tamoxifen , IL - 2 , GM - CSF , or a combination thereof. lymphoma or relapsed or refractory low grade follicular In certain embodiments , Compound A or Compound B lymphoma. provided herein is administered to patients with scleroderma In certain embodiments , Compound A or Compound B or cutaneous vasculitis in combination with celebrex , etopo provided herein is administered in combination with taxo - 45 side , cyclophosphamide , docetaxel , apecitabine , IFN , tere , dabrafenib , imlygic , ipilimumab , pembrolizumab , tamoxifen , IL - 2 , GM -CSF , or a combination thereof. nivolumab , trametinib , vemurafenib , talimogene laher In certain embodiments , Compound A or Compound B parepvec, IL - 2 , IFN , GM -CSF , and / or dacarbazine to provided herein is administered to patients with MDS in patients with various types or stages of melanoma. combination with azacitidine , cytarabine , daunorubicin , In certain embodiments , Compound A or Compound B 50 decitabine , idarubicin , lenalidomide or a combination provided herein is administered alone or in combination thereof. with vinorelbine to patients with malignant mesothelioma, Also encompassed herein is a method of increasing the or stage IIIB non - small cell lung cancer with pleural dosage of an anti -cancer drug or agent that can be safely and implants or malignant pleural effusion mesothelioma syn effectively administered to a patient, which comprises drome . 55 administering to the patient ( e . g . , a human ) Compound A or In certain embodiments , Compound A or Compound B Compound B provided herein . Patients that can benefit by provided herein is administered to patients with various this method are those likely to suffer from an adverse effect types or stages of multiple myeloma in combination with associated with anti - cancer drugs for treating a specific dexamethasone , zoledronic acid , palmitronate , GM - CSF , cancer of the skin , subcutaneous tissue , lymph nodes, brain , biaxin , vinblastine, melphalan , busulphan , cyclophosph - 60 lung, liver, bone , intestine , colon , heart , pancreas , adrenal, amide , IFN , prednisone , bisphosphonate , celecoxib , arsenic kidney, prostate , breast, colorectal, or combinations thereof. trioxide , PEG INTRON - A , vincristine , becenum , bort - The administration of Compound A or Compound B pro ezomib , , doxorubicin , , lenalido vided herein alleviates or reduces adverse effects which are mide , pomalidomide, thalidomide, mozobil or a combina - of such severity that it would otherwise limit the amount of tion thereof. 65 anti -cancer drug . In certain embodiments , Compound A or Compound B In one embodiment, Compound A or Compound B pro provided herein is administered to patients with various vided herein is administered daily in an amount ranging US 9 , 938 , 254 B2 57 58 from about 0 . 1 to about 150 mg, from about 1 to about 50 supplementation is administered to deliver about 1000 IU mg, or from about 2 to about 25 mg, prior to , during, or after vitamin D2 or D3 once daily . In certain embodiments , the occurrence of the adverse effect associated with the vitamin D supplementation is administered to deliver about administration of an anti -cancer drug to a patient. In certain 50 ,000 IU vitamin D2 or D3 weekly . embodiments , Compound A or Compound B provided 5 In certain embodiments , Compound A or Compound B herein is administered in combination with specific agents provided herein and doxetaxol are administered to patients such as heparin , aspirin , coumadin , or G -CSF to avoid with non -small cell lung cancer who were previously treated adverse effects that are associated with anti - cancer drugs with carbo /VP 16 and radiotherapy . such as but not limited to neutropenia or thrombocytopenia . 5 . 3 . 2 . Use with Transplantation Therapy In one embodiment, Compound A or Compound B pro - 10 Compound A or Compound B provided herein can be vided herein is administered to patients with diseases and used to reduce the risk of Graft Versus Host Disease disorders associated with or characterized by, undesired (GVHD ) . Therefore , encompassed herein is a method of angiogenesis in combination with additional active ingredi- treating, preventing and /or managing cancer, which com ents, including , but not limited to , anti - cancer drugs, anti - prises administering Compound A or Compound B provided inflammatories , antihistamines, antibiotics , and steroids . 15 herein in conjunction with transplantation therapy. In another embodiment, encompassed herein is a method As those of ordinary skill in the art are aware , the of treating , preventing and / or managing cancer, which com - treatment of cancer is often based on the stages and mecha prises administering Compound A or Compound B of pro - nism of the disease. For example , as inevitable leukemic vided herein in conjunction with ( e . g . before , during , or transformation develops in certain stages of cancer, trans after ) conventional therapy including , but not limited to , 20 plantation of peripheral blood stem cells , hematopoietic surgery, immunotherapy , biological therapy, radiation stem cell preparation or bone marrow may be necessary. The therapy, or other non - drug based therapy presently used to combined use of Compound A or Compound B provided treat , prevent or manage cancer. The combined use of the herein and transplantation therapy provides a unique and compound provided herein and conventional therapy may unexpected synergism . In particular, Compound A or Com provide a unique treatment regimen that is unexpectedly 25 pound B provided herein exhibits immunomodulatory activ effective in certain patients. Without being limited by theory , ity that may provide additive or synergistic effects when it is believed that Compound A or Compound B provided given concurrently with transplantation therapy in patients herein may provide additive or synergistic effects when with cancer. given concurrently with conventional therapy . Compound A or Compound B provided herein can work As discussed elsewhere herein , encompassed herein is a 30 in combination with transplantation therapy reducing com method of reducing , treating and /or preventing adverse or plications associated with the invasive procedure of trans undesired effects associated with conventional therapy plantation and risk of GVHD . Encompassed herein is a including, but not limited to , surgery , chemotherapy , radia - method of treating , preventing and /or managing cancer tion therapy, hormonal therapy , biological therapy and which comprises administering to a patient ( e . g ., a human ) immunotherapy . Compound A or Compound B provided 35 Compound A or Compound B provided herein before , herein and other active ingredient can be administered to a during , or after the transplantation of umbilical cord blood , patient prior to , during , or after the occurrence of the adverse placental blood , peripheral blood stem cell, hematopoietic effect associated with conventional therapy. stem cell preparation , or bone marrow . Some examples of In one embodiment, the compound provided herein can be stem cells suitable for use in the methods provided herein are administered in an amount ranging from about 0 . 1 to about 40 disclosed in U . S . Pat . No. 7 ,498 , 171, the disclosure of which 150 mg, from about 1 to about 25 mg, or from about 2 to is incorporated herein by reference in its entirety . about 10 mg orally and daily alone , or in combination with In one embodiment, Compound A or Compound B pro a second active agent disclosed herein (see , e . g ., section vided herein is administered to patients with acute myeloid 5 . 4 ) , prior to , during , or after the use of conventional leukemia ( AML ) before , during , or after transplantation . therapy . 45 In one embodiment, Compound A or Compound B pro In certain embodiments , the methods provided herein vided herein is administered to patients with multiple comprise administration of calcium , calcitriol, and vitamin myeloma before , during , or after the transplantation of D supplementation with Compound A or Compound B . In autologous peripheral blood progenitor cell. certain embodiments , the methods provided herein comprise In one embodiment, Compound A or Compound B pro administration of calcium , calcitriol, and vitamin D supple - 50 vided herein is administered to patients with NHL ( e . g ., mentation prior to the treatment with Compound A or DLBCL ) before , during , or after the transplantation of Compound B . autologous peripheral blood progenitor cell . In certain embodiments , calcium supplementation is 5. 3 .3 . Cycling Therapy administered to deliver at least 1200 mg of elemental In certain embodiments , Compound A or Compound B calcium per day given in divided doses . In certain embodi- 55 provided herein are cyclically administered to a patient. ments, calcium supplementation is administered as calcium Cycling therapy involves the administration of an active carbonate in a dose of 500 mg administered three times a day agent for a period of time, followed by a rest for a period of per orally (PO ). time, and repeating this sequential administration . Cycling In certain embodiments , calcitriol supplementation is therapy can reduce the development of resistance to one or administered to deliver 0 . 25 ug calcitriol ( PO ) once daily . 60 more of the therapies , avoid , or reduce the side effects of one In certain embodiments , vitamin D supplementation is of the therapies , and /or improves the efficacy of the treat administered to deliver about 500 IU to about 5000 IU ment. vitamin D once daily . In certain embodiments , vitamin D Consequently , in certain embodiments , Compound A or supplementation is administered to deliver about 1000 IU Compound B provided herein is administered daily in a vitamin D once daily . In certain embodiments , vitamin D 65 single or divided doses in a four to six week cycle with a rest supplementation is administered to deliver about 50 ,000 IU period of about a week or two weeks . The cycling method vitamin D weekly . In certain embodiments , vitamin D further allows the frequency, number , and length of dosing US 9 ,938 ,254 B2 59 cycles to be increased . Thus, encompassed herein in certain bed bound ; 4 denoting bed bound ; and 5 denoting death . In embodiments is the administration of Compound A or Com some embodiments , the subject has an ECOG performance pound B provided herein for more cycles than are typical status score of 0 or 1 . In some embodiments , the subject has when it is administered alone. In certain embodiments , an ECOG performance status score of 0 . In some embodi Compound A or Compound B provided herein is adminis - 5 ments , the subject has an ECOG performance status score of tered for a greater number of cycles that would typically 1 . In other embodiments , the subject has an ECOG perfor cause dose - limiting toxicity in a patient to whom a second mance status score of 2 . active ingredient is not also being administered . In certain embodiments , the methods provided herein In one embodiment, Compound A or Compound B pro - encompass the treatment of subjects who have not been vided herein is administered daily and continuously for three 10 previously treated for leukemia . In some embodiments , the or four weeks at a dose of from about 0 . 1 to about 150 mg / d subject has not undergone allogeneic bone marrow trans followed by a break of one or two weeks . plantation . In some embodiments , the subject has not under In another embodiment, Compound A or Compound B gone a stem cell transplantation . In some embodiments , the and a second active ingredient are administered orally , with subject has not received hydroxyurea treatment. In some administration of the compound occurring 30 to 60 minutes 15 embodiments , the subject has not been treated with any prior to a second active ingredient, during a cycle of four to investigational products for leukemia . In some embodi six weeks . In certain embodiments , the combination of ments , the subject has not been treated with systemic glu Compound A or Compound B and a second active ingredient cocorticoids . is administered by intravenous infusion over about 90 min - In other embodiments , the methods encompass treating utes every cycle . In certain embodiments , one cycle com - 20 subjects who have been previously treated or are currently prises the administration from about 0 . 1 to about 150 being treated for leukemia . For example , the subject may mg /day of Compound A or Compound B and from about 50 have been previously treated or are currently being treated to about 200 mg/ mº / day of a second active ingredient daily with a standard treatment regimen for leukemia . The subject for three to four weeks and then one or two weeks of rest. may have been treated with any standard leukemia treatment In certain embodiments , the number of cycles during which 25 regimen known to the practitioner of skill in the art . In the combinatorial treatment is administered to a patient is certain embodiments, the subject has been previously treated ranging from about one to about 24 cycles , from about two with at least one induction / reinduction or consolidation to about 16 cycles , or from about four to about three cycles . AML regimen . In some embodiments , the subject has under gone autologous bone marrow transplantation or stem cell 5. 4 . Patient Population 30 transplantation as part of a consolidation regimen . In some embodiments , the bone marrow or stem cell transplantation In certain embodiments of the methods provided herein , occurred at least 3 months prior to treatment according to the the subject is an animal, preferably a mammal , more pref - methods provided herein . In some embodiments , the subject erably a non - human primate . In particular embodiments, the has undergone hydroxyurea treatment. In some embodi subject is a human . The subject can be a male or female 35 ments , the hydroxyurea treatment occurred no later than 24 subject. hours prior to treatment according to the methods provided Particularly useful subjects for the methods provided herein . In some embodiments , the subject has undergone herein include human cancer patients , for example , those prior induction or consolidation therapy with cytarabine who have been diagnosed with leukemia , including acute ( Ara - C ) . In some embodiments , the subject has undergone myeloid leukemia , acute lymphocytic leukemia , chronic 40 treatment with systemic glucocorticosteroids . In some myelogenous leukemia , and chronic myelogenous leukemia . embodiments , the glucocorticosteroid treatment occurred no In certain embodiments , the subject has not been diagnosed later 24 hours prior to treatment according to the methods with acute promyelocytic leukemia . described herein . In other embodiments , the methods In some embodiments , the subject has a higher than encompass treating subjects who have been previously normal blast population . In some embodiments , the subject 45 treated for cancer, but are non - responsive to standard thera has a blast population of at least 10 % . In some embodiments , pies . the subject has a blast population of between 10 and 15 % . Also encompassed are methods of treating subjects hav In some embodiments , the subject has a blast population of ing relapsed or refractory leukemia . In some embodiments , at least 15 % . In some embodiments , the subject has a blast the subject has been diagnosed with a relapsed or refractory population of between 15 and 20 % . In some embodiments , 50 AML subtype, as defined by the World Health Organization the subject has a blast population of at least 20 % . In some (WHO ) . Relapsed or refractory disease may be de novo embodiments , the subject has a blast population of about AML or secondary AML , e . g . , therapy - related AML 10 - 15 % , about 15 - 20 % , or about 20 - 25 % . In other embodi - (T - AML ) . ments , the subject has a blast population of less than 10 % . In some embodiments , the methods provided herein are In the context of the methods described herein , useful 55 used to treat drug resistant leukemias, such as chronic subjects having a blast population of less than 10 % includes myelogenous leukemia (CML ) . Thus, treatment with Com those subjects that , for any reason according to the judgment pound A or Compound B provided herein could provide an of the skilled practitioner in the art, are in need of treatment alternative for patients who do not respond to othermethods with Compound A or Compound B provided herein , alone or of treatment. In some embodiments , such other methods of in combination with a second active agent. 60 treatment encompass treatment with Gleevec® ( imatinib In some embodiments , the subject is treated based on the mesylate ). In some embodiments , provided herein are meth Eastern Cooperative Oncology Group (ECOG ) performance ods of treatment of Philadelphia chromosome positive status score of the subject for leukemia . ECOG performance chronic myelogenous leukemia (Ph + CML ). In some status can be scored on a scale of 0 to 5 , with 0 denoting embodiments , provided herein are methods of treatment of asymptomatic ; 1 denoting symptomatic but completely 65 Gleevec® ( imatinib mesylate ) resistant Philadelphia chro ambulant; 2 denoting symptomatic and < 50 % in bed during mosome positive chronic myelogenous leukemia (Ph + the day ; 3 denoting symptomatic and > 50 % in bed , but not CML ) . US 9 ,938 , 254 B2 62 Also encompassed are methods of treating a subject and procedures well known in the art ( see , e . g ., Ansel regardless of the subject ' s age , although some diseases or Introduction to Pharmaceutical Dosage Forms, Seventh Edi disorders are more common in certain age groups. In some tion 1999 ) . embodiments , the subject is at least 18 years old . In some In the compositions , effective concentrations of one or embodiments , the subject is more than 18 , 25 , 35 , 40 , 45 , 50 , 5 more compounds provided herein is mixed with a suitable 55 , 60 , 65 , or 70 years old . In other embodiments , the subject pharmaceutical carrier or vehicle . In certain embodiments , is less than 65 years old . In some embodiments , the subject the concentrations of Compound A or Compound B pro is less than 18 years old . In some embodiments , the subject vided herein are effective for delivery of an amount, upon is less than 18 , 15 , 12 , 10 , 9 , 8 or 7 years old . administration , that treats , prevents , or ameliorates one or In some embodiments , the methods may find use in 10 more of the symptoms and / or progression of cancer, includ subjects at least 50 years of age , although younger subjects ing solid tumors and blood borne tumors. could benefit from the method as well . In other embodi Typically , the compositions are formulated for single ments , the subjects are at least 55 , at least 60 , at least 65 , and at least 70 years of age . In another embodiment , the subjects dosage administration . To formulate a composition , the have adverse cytogenetics. “ Adverse cytogenetics ” is 15 weight fraction of Compound A or Compound B provided defined as any nondiploid karyotype , or greater than or equal herein is dissolved , suspended , dispersed or otherwise mixed to 3 chromosomal abnormalities . In another embodiment, in a selected vehicle at an effective concentration such that the subjects are at least 60 years of age and have adverse the treated condition is relieved or ameliorated . Pharmaceu cytogenetics . In another embodiment , the subjects are 60 -65 tical carriers or vehicles suitable for administration of Com years of age and have adverse cytogenetics . In another 20 pound A or Compound B provided herein include any such embodiment, the subjects are 65 - 70 years of age and have carriers known to those skilled in the art to be suitable for the adverse cytogenetics . particular mode of administration . In certain embodiments , the subject treated has no history In addition , Compound A or Compound B provided of myocardial infarction within three months of treatment herein may be formulated as the sole pharmaceutically according to the methods provided herein . In some embodi- 25 active ingredient in the composition or may be combined ments , the subject has no history of cerebrovascular accident with other active ingredients . Liposomal suspensions , or transient ischemic attack within three months of treatment including tissue- targeted liposomes, such as tumor - targeted according to the methods provided herein . In some embodi - liposomes . may also be suitable as pharmaceutically accept ments , the subject has no suffered no thromboembelic event, able carriers. These may be prepared according to methods including deep vein thrombosis or pulmonary embolus, 30 known to those skilled in the art. For example , liposome within 28 days of treatment according to the methods provided herein . In other embodiments , the subject has not formulations may be prepared as known in the art . Briefly , experienced or is not experiencing uncontrolled dissemi liposomes such as multilamellar vesicles (MLV ' s ) may be nated intravascular coagulation . formed by drying down egg phosphatidyl choline and brain Because subjects with cancer have heterogeneous clinical 35 phosphatidyl% serine ( 7 : 3 molar ratio ) on the inside of a flask . manifestations and varying clinical outcomes , the treatment A solution of Compound A or Compound B provided herein given to a patient may vary, depending on his /her prognosis . in phosphate buffered saline lacking divalent cations (PBS ) The skilled clinician will be able to readily determine is added and the flask shaken until the lipid film is dispersed . without undue experimentation specific secondary agents , The resulting vesicles are washed to remove unencapsulated types of surgery , and types of non - drug based standard 40 compound , pelleted by centrifugation , and then resuspended therapy that can be effectively used to treat an individual in PBS. subject with cancer . Compound A or Compound B provided herein is included It will be appreciated that every suitable combination of in the pharmaceutically acceptable carrier in an amount the compounds provided herein with one or more of the sufficient to exert a therapeutically useful effect in the aforementioned compounds and optionally one or more 45 absence of undesirable side effects on the patient treated . further pharmacologically active substances is contemplated The therapeutically effective concentration may be deter herein . mined empirically by testing Compound A or Compound B provided herein in in vitro and in vivo systems described 5 . 5 . Formulation of Pharmaceutical Compositions herein and then extrapolated therefrom for dosages for 50 humans. The pharmaceutical compositions provided herein contain The concentration of Compound A or Compound B therapeutically effective amounts of one or more compounds provided herein in the pharmaceutical composition will provided herein and a pharmaceutically acceptable carrier, depend on absorption , tissue distribution , inactivation and diluent or excipient. excretion rates of the compound , the physicochemical char In one embodiment, the pharmaceutical compositions 55 acteristics of the compound , the dosage schedule , and provided herein comprise Compound A or Compound B amount administered as well as other factors known to those provided herein and one or more pharmaceutically accept of skill in the art. For example , the amount that is delivered able excipients or carriers. is sufficient to ameliorate one or more of the symptoms of Compound A or Compound B provided herein can be cancer, including solid tumors and blood borne tumors. formulated into suitable pharmaceutical preparations such as 60 In certain embodiments , a therapeutically effective dosage solutions, suspensions , tablets , dispersible tablets, pills, cap - should produce a serum concentration of active ingredient of sules , powders, sustained release formulations or elixirs , for from about 0 . 1 ng/ mL to about 50 - 100 ug/ mL . In one oral administration or in sterile solutions or suspensions for embodiment , the pharmaceutical compositions provide a ophthalmic or parenteral administration , as well as transder - dosage of from about 0 . 001 mg to about 2000 mg of mal patch preparation and dry powder inhalers. Typically 65 compound per kilogram of body weight per day. Pharma Compound A and /or Compound B described above is for ceutical dosage unit forms are prepared to provide from mulated into pharmaceutical compositions using techniques about 1 mg to about 1000 mg and in certain embodiments , US 9 , 938 , 254 B2 63 64 from about 10 to about 500 mg of the essential active The pharmaceutical compositions are provided for admin ingredient or a combination of essential ingredients per istration to humans and animals in unit dosage forms, such dosage unit form . as tablets , capsules , pills , powders , granules , sterile paren The active ingredient may be administered at once , or teral solutions or suspensions, and oral solutions or suspen may be divided into a number of smaller doses to be 5 sions , and oil water emulsions containing suitable quantities administered at intervals of time. It is understood that the of Compound A or Compound B provided herein . Com precise dosage and duration of treatment is a function of the pound A or Compound B provided herein are formulated and disease being treated and may be determined empirically administered in unit dosage forms or multiple dosage forms. using known testing protocols or by extrapolation from in Unit dose forms as used herein refer to physically discrete vivo or in vitro test data . It is to be noted that concentrations 10 units suitable for human and animal subjects and packaged and dosage values may also vary with the severity of the individually as is known in the art . Each unit dose contains condition to be alleviated . It is to be further understood that a predetermined quantity of Compound A or Compound B for any particular subject, specific dosage regimens should provided herein sufficient to produce the desired therapeutic be adjusted over time according to the individual need and effect, in association with the required pharmaceutical car the professional judgment of the person administering or 15 rier, vehicle or diluent . Examples of unit dose forms include supervising the administration of the compositions, and that ampules and syringes and individually packaged tablets or the concentration ranges set forth herein are exemplary only capsules. Unit dose forms may be administered in fractions and are not intended to limit the scope or practice of the or multiples thereof. A multiple dose form is a plurality of claimed compositions . identical unit dosage forms packaged in a single container to Thus, effective concentrations or amounts of Compound 20 be administered in segregated unit dose form . Examples of A or Compound B provided herein are mixed with a suitable multiple dose forms include vials , bottles of tablets or pharmaceutical carrier or vehicle for systemic , topical or capsules or bottles of pints or gallons . Hence ,multiple dose local administration to form pharmaceutical compositions. form is a multiple of unit doses which are not segregated in Compound A or Compound B provided herein are included packaging . in an amount effective for ameliorating one or more symp- 25 Sustained -release preparations can also be prepared . Suit toms of, or for treating, retarding progression , or preventing able examples of sustained - release preparations include The concentration of Compound Aor Compound B provided semipermeable matrices of solid hydrophobic polymers con herein in the composition will depend on absorption , tissue taining Compound A or Compound B provided herein , distribution , inactivation , excretion rates of the compound , which matrices are in the form of shaped articles , e . g . , films, the dosage schedule , amount administered , particular for - 30 or microcapsule . Examples of sustained - release matrices mulation as well as other factors known to those of skill in include iontophoresis patches , polyesters , hydrogels ( for the art . example , poly ( 2 -hydroxyethyl - methacrylate ), or poly (vinyl The compositions are intended to be administered by a alcohol) ), polylactides , copolymers of L - glutamic acid and suitable route , including but not limited to orally , parenter - ethyl- L - glutamate , non -degradable ethylene- vinyl acetate , ally , rectally, topically and locally . For oral administration , 35 degradable lactic acid - glycolic acid copolymers such as the capsules and tablets can be formulated . The compositions LUPRON DEPOTTM ( injectable microspheres composed of are in liquid , semi- liquid or solid form and are formulated in lactic acid -glycolic acid copolymer and leuprolide acetate) , a manner suitable for each route of administration . and poly - D - ( - ) - 3 -hydroxybutyric acid . While polymers Solutions or suspensions used for parenteral , intradermal, such as ethylene -vinyl acetate and lactic acid - glycolic acid subcutaneous , or topical application can include any of the 40 enable release of molecules for over 100 days , certain following components : a sterile diluent, such as water for hydrogels release proteins for shorter time periods. When injection , saline solution , fixed oil, polyethylene glycol, encapsulated compound remain in the body for a long time, glycerine , propylene glycol, dimethyl acetamide or other they may denature or aggregate as a result of exposure to synthetic solvent ; antimicrobial agents, such as benzyl alco moisture at 37° C . , resulting in a loss of biological activity hol and methyl parabens ; antioxidants , such as ascorbic acid 45 and possible changes in their structure . Rational strategies and sodium bisulfate ; chelating agents , such as ethylenedi- can be devised for stabilization depending on the mechanism aminetetraacetic acid (EDTA ) ; buffers , such as acetates, of action involved . For example , if the aggregation mecha citrates and phosphates , and agents for the adjustment of nism is discovered to be intermolecular S S bond forma tonicity such as sodium chloride or dextrose . Parenteral tion through thio - disulfide interchange, stabilization may be preparations can be enclosed in ampules, pens, disposable 50 achieved by modifying sulfhydryl residues, lyophilizing syringes or single or multiple dose vials made of glass , from acidic solutions, controlling moisture content, using plastic or other suitable material. appropriate additives, and developing specific polymer In instances in which Compound A or Compound B matrix compositions . provided herein exhibit insufficient solubility , methods for Dosage forms or compositions containing Compound A solubilizing compounds may be used . Such methods are 55 or Compound B provided herein in the range of 0 .005 % to known to those of skill in this art , and include, but are not 100 % with the balance made up from non toxic carrier may limited to , using cosolvents , such as dimethylsulfoxide be prepared . For oral administration , a pharmaceutically ( DMSO ), using surfactants , such as TWEEN® , or dissolu acceptable non toxic composition is formed by the incorpo tion in aqueous sodium bicarbonate . ration of any of the normally employed excipients, such as, Upon mixing or addition of the compound ( s ), the result - 60 for example pharmaceutical grades of mannitol, lactose , ing mixture may be a solution , suspension , emulsion or the starch , magnesium stearate , talcum , cellulose derivatives , like. The form of the resulting mixture depends upon a sodium crosscarmellose , glucose , sucrose , magnesium car number of factors , including the intended mode of admin bonate or sodium saccharin . Such compositions include istration and the solubility of the compound in the selected solutions, suspensions, tablets , capsules , powders and sus carrier or vehicle . The effective concentration is sufficient 65 tained release formulations, such as, but not limited to , for ameliorating the symptoms of the disease , disorder or implants and microencapsulated delivery systems, and bio condition treated and may be empirically determined . degradable , biocompatible polymers, such as collagen , eth US 9 ,938 ,254 B2 65 66 ylene vinyl acetate , polyanhydrides , polyglycolic acid , poly provided in non effervescent or effervescent form with the orthoesters , polylactic acid and others . Methods for combination of other ingredients known to those skilled in preparation of these compositions are known to those skilled the art . in the art . The contemplated compositions may contain In certain embodiments , the formulations are solid dosage about 0 .001 % 100 % active ingredient, in certain embodi- 5 forms, such as capsules or tablets. The tablets , pills , cap ments , about 0 . 1 85 % or about 75 - 95 % . sules , troches and the like can contain any of the following Compound A or Compound B provided herein may be ingredients , or compounds of a similar nature: a binder , a prepared with carriers that protect the compound against diluent ; a disintegrating agent; a lubricant ; a glidant; a rapid elimination from the body , such as time release for sweetening agent; and a flavoring agent. mulations or coatings . 10 Examples of binders include microcrystalline cellulose , The compositions may include other active compounds to gum tragacanth , glucose solution , acacia mucilage , gelatin obtain desired combinations of properties. Compound A or solution , sucrose and starch paste . Lubricants include talc , Compound B provided herein may also be advantageously starch , magnesium or calcium stearate , lycopodium and administered for therapeutic or prophylactic purposes stearic acid . Diluents include , for example , lactose , sucrose , together with another pharmacological agent known in the 15 starch , kaolin , salt, mannitol and dicalcium phosphate . Gli general art to be of value in treating one or more of the dants include , but are not limited to , colloidal silicon diox diseases or medical conditions referred to hereinabove , such ide. Disintegrating agents include crosscarmellose sodium , as diseases related to oxidative stress . It is to be understood sodium starch glycolate , alginic acid , corn starch , potato that such combination therapy constitutes a further aspect of starch , bentonite , methylcellulose , agar and carboxymethyl the compositions and methods of treatment provided herein . 20 cellulose . Coloring agents include , for example, any of the Lactose - free compositions provided herein can contain approved certified water soluble FD and C dyes , mixtures excipients that are well known in the art and are listed , for thereof; and water insoluble FD and C dyes suspended on example , in the U . S . Pharmocopia (USP ) SP (XXI ) /NF alumina hydrate . Sweetening agents include sucrose , lac (XVI ) . In general, lactose - free compositions contain an tose , mannitol and artificial sweetening agents such as active ingredient, a binder / filler , and a lubricant in pharma- 25 saccharin , and any number of spray dried flavors . Flavoring ceutically compatible and pharmaceutically acceptable agents include natural flavors extracted from plants such as amounts . Exemplary lactose - free dosage forms contain an fruits and synthetic blends of compounds which produce a active ingredient, microcrystalline cellulose , pre - gelatinized pleasant sensation , such as , but not limited to peppermint starch and magnesium stearate . and methyl salicylate . Wetting agents include propylene Further encompassed are anhydrous pharmaceutical com - 30 glycolmonostearate , sorbitan monooleate , diethylene glycol positions and dosage forms containing Compound A or monolaurate and polyoxyethylene laural ether. Emetic coat Compound B provided herein . For example , the addition of ings include fatty acids , fats , waxes , shellac , ammoniated water ( e . g . , 5 % ) is widely accepted in the pharmaceutical shellac and cellulose acetate phthalates . Film coatings arts as a means of simulating long - term storage in order to include hydroxyethylcellulose , sodium carboxymethylcellu determine characteristics such as shelf - life or the stability of 35 lose , polyethylene glycol 4000 and cellulose acetate phtha formulations over time. See , e . g . , Jens T. Carstensen , Drug late . Stability : Principles & Practice , 2d . Ed ., Marcel Dekker , NY, If oral administration is desired , Compound A or Com N . Y ., 1995 , pp . 379 - 80 . In effect , water and heat accelerate pound B provided herein could be provided in a composition the decomposition of some compounds . Thus, the effect of that protects it from the acidic environment of the stomach . water on a formulation can be of great significance since 40 For example, the composition can be formulated in an moisture and / or humidity are commonly encountered during enteric coating thatmaintains its integrity in the stomach and manufacture , handling , packaging, storage , shipment and releases the active compound in the intestine . The compo use of formulations . sition may also be formulated in combination with an Anhydrous pharmaceutical compositions and dosage antacid or other such ingredient. forms provided herein can be prepared using anhydrous or 45 When the dosage unit form is a capsule , it can contain , in low moisture containing ingredients and low moisture or addition to material of the above type , a liquid carrier such low humidity conditions. Pharmaceutical compositions and as a fatty oil. In addition , dosage unit forms can contain dosage forms that comprise lactose and at least one active various other materials which modify the physical form of ingredient that comprises a primary or secondary amine are the dosage unit , for example , coatings of sugar and other anhydrous if substantial contact with moisture and/ or 50 enteric agents . Compound A or Compound B provided humidity during manufacturing, packaging, and /or storage is herein can also be administered as a component of an elixir, expected . suspension , syrup , wafer , sprinkle , chewing gum or the like . An anhydrous pharmaceutical composition should be A syrup may contain , in addition to the active compounds , prepared and stored such that its anhydrous nature is main - sucrose as a sweetening agent and certain preservatives, tained . Accordingly , anhydrous compositions are packaged 55 dyes and colorings and flavors . using materials known to prevent exposure to water such The active materials can also be mixed with other active that they can be included in suitable formulary kits . materials which do not impair the desired action , or with Examples of suitable packaging include , but are not limited materials that supplement the desired action , such as antac to , hermetically sealed foils , plastics , unit dose containers ids, H2 blockers , and diuretics. The active ingredient is ( e. g ., vials ) , blister packs and strip packs. 60 Compound A or Compound B as described herein . Higher 5 . 5 . 1 . Oral Dosage Forms concentrations , up to about 98 % by weight of the active Oral pharmaceutical dosage forms are either solid , gel or ingredient may be included . liquid . The solid dosage forms are tablets , capsules, gran Pharmaceutically acceptable carriers included in tablets ules , and bulk powders . Types of oral tablets include com - are binders , lubricants, diluents , disintegrating agents , col pressed , chewable lozenges and tablets which may be enteric 65 oring agents , flavoring agents, and wetting agents . Enteric coated , sugar coated or film coated . Capsules may be hard or coated tablets , because of the enteric coating , resist the soft gelatin capsules , while granules and powders may be action of stomach acid and dissolve or disintegrate in the US 9 ,938 ,254 B2 68 neutral or alkaline intestines. Sugar coated tablets are com Alternatively , liquid or semi solid oral formulations may pressed tablets to which different layers of pharmaceutically be prepared by dissolving or dispersing the active compound acceptable substances are applied . Film coated tablets are or salt in vegetable oils , glycols , triglycerides, propylene compressed tablets which have been coated with a polymer glycol esters (e . g. , propylene carbonate ) and other such or other suitable coating . Multiple compressed tablets are 5 carriers , and encapsulating these solutions or suspensions in compressed tablets made by more than one compression hard or soft gelatin capsule shells . Other useful formulations cycle utilizing the pharmaceutically acceptable substances include , but are not limited to , those containing Compound A or Compound B provided herein , a dialkylated mono - or previously mentioned . Coloring agents may also be used in poly - alkylene glycol, including , but not limited to , 1 , 2 the above dosage forms. Flavoring and sweetening agents 10 dimethoxymethane , diglyme, triglyme, tetraglyme, polyeth are used in compressed tablets , sugar coated , multiple com ylene glycol - 350 - dimethyl ether , polyethylene glycol - 550 pressed and chewable tablets. Flavoring and sweetening dimethyl ether , polyethylene glycol- 750 - dimethyl ether agents are especially useful in the formation of chewable wherein 350 , 550 and 750 refer to the approximate average tablets and lozenges . molecular weight of the polyethylene glycol, and one or Liquid oral dosage forms include aqueous Solutionssolutions , 15 more antioxidants , such as butylated hydroxytoluene (BHT ) , emulsions , suspensions, solutions and / or suspensions recon butylated hydroxyanisole ( BHA) , propyl gallate , vitamin E , stituted from non effervescent granules and effervescent hydroquinone , hydroxycoumarins , ethanolamine, lecithin , preparations reconstituted from effervescent granules . Aque cephalin , ascorbic acid , malic acid , sorbitol, phosphoric ous solutions include, for example , elixirs and syrups. Emul acid , thiodipropionic acid and its esters , and dithiocarbam sions are either oil in - water or water in oil. 20 ates . Elixirs are clear, sweetened , hydroalcoholic preparations. Other formulations include, but are not limited to , aque Pharmaceutically acceptable carriers used in elixirs include ous alcoholic solutions including a pharmaceutically accept solvents . Syrups are concentrated aqueous solutions of a able acetal. Alcohols used in these formulations are any sugar, for example , sucrose , and may contain a preservative . pharmaceutically acceptable water -miscible solvents having An emulsion is a two phase system in which one liquid is 25 one or more hydroxyl groups , including , but not limited to , dispersed in the form of small globules throughout another propylene glycol and ethanol . Acetals include , but are not liquid . Pharmaceutically acceptable carriers used in emul- limited to , di (lower alkyl) acetals of lower alkyl aldehydes sions are non aqueous liquids , emulsifying agents and pre - such as acetaldehyde diethyl acetal. servatives . Suspensions use pharmaceutically acceptable In all embodiments , tablets and capsules formulations suspending agents and preservatives . Pharmaceutically 30 may be coated as known by those of skill in the art in order acceptable substances used in non effervescent granules , to to modify or sustain dissolution of the active ingredient. be reconstituted into a liquid oral dosage form , include Thus, for example , they may be coated with a conventional diluents , sweeteners and wetting agents . Pharmaceutically enterically digestible coating, such as phenylsalicylate , acceptable substances used in effervescent granules, to be waxes and cellulose acetate phthalate . reconstituted into a liquid oral dosage form , include organic 35 5 . 5 . 2 . Injectables, Solutions and Emulsions acids and a source of carbon dioxide. Coloring and flavoring Parenteral administration , generally characterized by agents are used in all of the above dosage forms. injection , either subcutaneously , intramuscularly or intrave Solvents include glycerin , sorbitol, ethyl alcohol and nously is also contemplated herein . Injectables can be pre syrup . Examples of preservatives include glycerin , methyl p ared in conventional forms, either as liquid solutions or and propylparaben , benzoic add , sodium benzoate and alco - 40 suspensions , solid forms suitable for solution or suspension hol. Examples of non aqueous liquids utilized in emulsions in liquid prior to injection , or as emulsions. Suitable excipi include mineral oil and cottonseed oil . Examples of emul ents are , for example , water, saline , dextrose , glycerol or sifying agents include gelatin , acacia , tragacanth , bentonite , ethanol. In addition , if desired , the pharmaceutical compo and surfactants such as polyoxyethylene sorbitan sitions to be administered may also contain minor amounts monooleate . Suspending agents include sodium carboxym - 45 of non toxic auxiliary substances such as wetting or emul ethylcellulose , pectin , tragacanth , Veegum and acacia . sifying agents , pH buffering agents , stabilizers , solubility Diluents include lactose and sucrose . Sweetening agents enhancers , and other such agents , such as for example , include sucrose , syrups, glycerin and artificial sweetening sodium acetate , sorbitan monolaurate , triethanolamine agents such as saccharin . Wetting agents include propylene oleate and cyclodextrins . Implantation of a slow release or glycolmonostearate , sorbitan monooleate , diethylene glycol 50 sustained release system , such that a constant level of dosage monolaurate and polyoxyethylene lauryl ether. Organic adds is maintained is also contemplated herein . Briefly, Com include citric and tartaric acid . Sources of carbon dioxide pound A or Compound B provided herein is dispersed in a include sodium bicarbonate and sodium carbonate . Coloring solid inner matrix , e . g . , polymethylmethacrylate , polybutyl agents include any of the approved certified water soluble methacrylate , plasticized or unplasticized polyvinylchloride, FD and C dyes, and mixtures thereof. Flavoring agents 55 plasticized nylon , plasticized polyethyleneterephthalate , include natural flavors extracted from plants such fruits , and natural rubber , polyisoprene, polyisobutylene , polybutadi synthetic blends of compounds which produce a pleasant ene, polyethylene, ethylene -vinylacetate copolymers, sili taste sensation . cone rubbers , polydimethylsiloxanes , silicone carbonate For a solid dosage form , the solution or suspension , in for copolymers , hydrophilic polymers such as hydrogels of example propylene carbonate , vegetable oils or triglycer - 60 esters of acrylic and methacrylic acid , collagen , cross- linked ides, is encapsulated in a gelatin capsule . Such solutions, and polyvinylalcohol and cross- linked partially hydrolyzed the preparation and encapsulation thereof, are disclosed in polyvinyl acetate , that is surrounded by an outer polymeric U . S . Pat. Nos . 4 , 328 , 245 ; 4 ,409 , 239 ; and 4 ,410 ,545 . For a membrane , e . g ., polyethylene , polypropylene , ethylene/ pro liquid dosage form , the solution , e . g ., for example , in a pylene copolymers , ethylene/ ethyl acrylate copolymers , eth polyethylene glycol, may be diluted with a sufficient quan - 65 ylene / vinylacetate copolymers, silicone rubbers , polydim tity of a pharmaceutically acceptable liquid carrier , e . g ., ethyl siloxanes, neoprene rubber, chlorinated polyethylene , water, to be easily measured for administration . polyvinylchloride , vinylchloride copolymers with vinyl US 9 , 938 , 254 B2 69 70 acetate , vinylidene chloride, ethylene and propylene, iono solution or suspension containing an active material injected mer polyethylene terephthalate , butyl rubber epichlorohy - as necessary to produce the desired pharmacological effect . drin rubbers , ethylene /vinyl alcohol copolymer , ethylene/ Injectables are designed for local and systemic adminis vinyl acetate / vinyl alcohol terpolymer, and ethylene t ration . Typically a therapeutically effective dosage is for vinyloxyethanol copolymer, that is insoluble in body fluids. 5 mulated to contain a concentration of at least about 0 . 1 % The compound diffuses through the outer polymeric mem - w / w up to about 90 % w / w or more , such as more than 1 % brane in a release rate controlling step . The percentage of w / w of Compound A or Compound B provided herein to the active compound contained in such parenteral compositions treated tissue( s ) . The active ingredient may be administered is highly dependent on the specific nature thereof, as well as at once , or may be divided into a number of smaller doses the activity of the compound and the needs of the subject . 10 to be administered at intervals of time. It is understood that Parenteral administration of the compositions includes the precise dosage and duration of treatment is a function of intravenous , subcutaneous and intramuscular administra - the tissue being treated and may be determined empirically tions . Preparations for parenteral administration include using known testing protocols or by extrapolation from in sterile solutions ready for injection , sterile dry soluble vivo or in vitro test data . It is to be noted that concentrations products, such as lyophilized powders , ready to be combined 15 and dosage values may also vary with the age of the with a solvent just prior to use , including hypodermic individual treated . It is to be further understood that for any tablets , sterile suspensions ready for injection , sterile dry particular subject, specific dosage regimens should be insoluble products ready to be combined with a vehicle just adjusted over time according to the individual need and the prior to use and sterile emulsions . The solutions may be professional judgment of the person administering or super either aqueous or nonaqueous . 20 vising the administration of the formulations , and that the If administered intravenously , suitable carriers include concentration ranges set forth herein are exemplary only and physiological saline or phosphate buffered saline (PBS ) , and are not intended to limit the scope or practice of the claimed solutions containing thickening and solubilizing agents , formulations. such as glucose , polyethylene glycol, and polypropylene Compound A or Compound B provided herein may be glycol and mixtures thereof . 25 suspended in micronized or other suitable form or may be Pharmaceutically acceptable carriers used in parenteral derivatized to produce a more soluble active product or to preparations include aqueous vehicles, nonaqueous vehicles , produce a prodrug . The form of the resulting mixture antimicrobial agents , isotonic agents , buffers , antioxidants , depends upon a number of factors, including the intended local anesthetics , suspending and dispersing agents, emul mode of administration and the solubility of the compound sifying agents , sequestering or chelating agents and other 30 in the selected carrier or vehicle . The effective concentration pharmaceutically acceptable substances. is sufficient for ameliorating the symptoms of the condition Examples of aqueous vehicles include Sodium Chloride and may be empirically determined . Injection , Ringers Injection , Isotonic Dextrose Injection , 5 . 5 . 3 . Lyophilized Powders Sterile Water Injection , Dextrose and Lactated Ringers Of interest herein are also lyophilized powders , which can Injection . Nonaqueous parenteral vehicles include fixed oils 35 be reconstituted for administration as solutions , emulsions of vegetable origin , cottonseed oil , corn oil , sesame oil and and other mixtures . They may also be reconstituted and peanut oil . Antimicrobial agents in bacteriostatic or fungi- formulated as solids or gels . static concentrations must be added to parenteral prepara - The sterile , lyophilized powder is prepared by dissolving tions packaged in multiple dose containers which include Compound A or Compound B provided herein in a suitable phenols or cresols , mercurials , benzyl alcohol, chlorobuta - 40 solvent. The solvent may contain an excipient which nol, methyl and propyl p hydroxybenzoic acid esters , thime- improves the stability or other pharmacological component rosal, benzalkonium chloride and benzethonium chloride . of the powder or reconstituted solution , prepared from the Isotonic agents include sodium chloride and dextrose . Buf- powder . Excipients that may be used include, but are not fers include phosphate and citrate . Antioxidants include limited to , dextrose , sorbital, fructose , corn syrup , xylitol, sodium bisulfate . Local anesthetics include procaine hydro - 45 glycerin , glucose , sucrose or other suitable agent. The sol chloride . Suspending and dispersing agents include sodium vent may also contain a buffer , such as citrate , sodium or carboxymethylcelluose, hydroxypropylmethylcellulose and potassium phosphate or other such buffer known to those of polyvinylpyrrolidone . Emulsifying agents include Polysor- skill in the art at, in one embodiment, about neutral pH . bate 80 ( TWEEN® 80 ) . A sequestering or chelating agent of Subsequent sterile filtration of the solution followed by metal ions include EDTA . Pharmaceutical carriers also 50 lyophilization under standard conditions known to those of include ethyl alcohol, polyethylene glycol and propylene skill in the art provides the desired formulation . Generally , glycol for water miscible vehicles and sodium hydroxide , the resulting solution will be apportioned into vials for hydrochloric acid , citric acid or lactic acid for pH adjust - lyophilization . Each vial will contain a single dosage ( in ment. cluding but not limited to 10 - 1000 mg or 100 - 500 mg ) or The concentration of the pharmaceutically active com - 55 multiple dosages of the compound . The lyophilized powder pound is adjusted so that an injection provides an effective can be stored under appropriate conditions , such as at about amount to produce the desired pharmacological effect . The 4° C . to room temperature . exact dose depends on the age , weight and condition of the Reconstitution of this lyophilized powder with water for patient or animal as is known in the art. injection provides a formulation for use in parenteral admin The unit dose parenteral preparations are packaged in an 60 istration . For reconstitution , about 1 - 50 mg, about 5 - 35 mg, ampule, a vial or a syringe with a needle . All preparations for or about 9 - 30 mg of lyophilized powder, is added per mL of parenteral administration must be sterile , as is known and sterile water or other suitable carrier. The precise amount practiced in the art . depends upon the selected compound provided herein . Such Illustratively , intravenous or intraarterial infusion of a amount can be empirically determined . sterile aqueous solution containing Compound A or Com - 65 5 . 5 . 4 . Topical Administration pound B provided herein is an effective mode of adminis - Topical mixtures are prepared as described for the local tration . Another embodiment is a sterile aqueous or oily and systemic administration . The resulting mixture may be US 9 ,938 ,254 B2 71 72 a solution , suspension , emulsion or the like and are formu - dosage forms can be used to provide slow or controlled lated as creams, gels , ointments , emulsions , solutions, elix release of one or more active ingredients using, for example , irs , lotions, suspensions, tinctures, pastes, foams, aerosols , hydropropylmethyl cellulose , other polymer matrices, gels , irrigations, sprays, suppositories , bandages , dermal patches permeable membranes, osmotic systems, multilayer coat or any other formulations suitable for topical administration . 5 ings, microparticles, liposomes , microspheres, or a combi Compound A or Compound B provided herein may be nation thereof to provide the desired release profile in formulated as aerosols for topical application , such as by varying proportions. Suitable controlled -release formula inhalation (see , e .g . , U .S . Pat. Nos. 4 ,044 , 126 , 4 ,414 , 209, tions known to those of ordinary skill in the art , including and 4 , 364 , 923 , which describe aerosols for delivery of a those described herein , can be readily selected for use with steroid useful for treatment of inflammatory diseases , par - 10 the active ingredients provided herein . ticularly asthma ) . These formulations for administration to All controlled -release pharmaceutical products have a the respiratory tract can be in the form of an aerosol or common goal of improving drug therapy over that achieved solution for a nebulizer, or as a microtine powder for by their non - controlled counterparts . In one embodiment , insufflation , alone or in combination with an inert carrier the use of an optimally designed controlled - release prepa such as lactose . In such a case , the particles of the formu - 15 ration in medical treatment is characterized by a minimum lation will have diameters of less than 50 microns or less of drug substance being employed to cure or control the than 10 microns . condition in a minimum amount of time. In certain embodi Compound A or Compound B provided herein may be ments , advantages of controlled -release formulations formulated for local or topical application , such as for include extended activity of the drug , reduced dosage fre topical application to the skin and mucous membranes , such 20 quency , and increased patient compliance . In addition , con as in the eye , in the form of gels , creams, and lotions and for trolled -release formulations can be used to affect the time of application to the eye or for intracisternal or intraspinal onset of action or other characteristics, such as blood levels application . Topical administration is contemplated for of the drug , and can thus affect the occurrence of side ( e . g . , transdermal delivery and also for administration to the eyes adverse ) effects . or mucosa , or for inhalation therapies . Nasal solutions of the 25 Most controlled -release formulations are designed to ini compound alone or in combination with other pharmaceu - tially release an amount of drug (active ingredient) that tically acceptable excipients can also be administered . promptly produces the desired therapeutic effect , and gradu These solutions , particularly those intended for ophthal- ally and continually release of other amounts of drug to mic use , may be formulated as 0 .01 % - 10 % isotonic solu - maintain this level of therapeutic or prophylactic effect over tions , pH about 5 - 7 , with appropriate salts . 30 an extended period of time. In order to maintain this constant 5 . 5 . 5 . Compositions for Other Routes of Administration level of drug in the body , the drug must be released from the Other routes of administration , such as topical applica dosage form at a rate that will replace the amount of drug tion , transdermal patches, and rectal administration are also being metabolized and excreted from the body . Controlled contemplated herein . release of an active ingredient can be stimulated by various For example , pharmaceutical dosage forms for rectal 35 conditions including, but not limited to , pH , temperature , administration are rectal suppositories , capsules and tablets enzymes , water , or other physiological conditions . for systemic effect . Rectal suppositories are used herein In certain embodiments , the agent may be administered mean solid bodies for insertion into the rectum which melt using intravenous infusion , an implantable osmotic pump, a or soften at body temperature releasing one or more phar- transdermal patch , liposomes, or other modes of adminis macologically or therapeutically active ingredients. Pharma- 40 tration . In one embodiment, a pump may be used ( see , ceutically acceptable substances utilized in rectal supposi - Sefton , CRC Crit . Ref. Biomed . Eng. 14 : 201 ( 1987 ) ; Buch tories are bases or vehicles and agents to raise the melting wald et al . , Surgery 88 : 507 ( 1980 ) ; Saudek et al ., N . Engl. point. Examples of bases include cocoa butter ( theobroma J . Med . 321: 574 ( 1989 ) . In another embodiment , polymeric oil) , glycerin gelatin , carbowax (polyoxyethylene glycol) materials can be used . In yet another embodiment, a con and appropriate mixtures of mono , di and triglycerides of 45 trolled release system can be placed in proximity of the fatty acids. Combinations of the various bases may be used . therapeutic target , i. e . , thus requiring only a fraction of the Agents to raise the melting point of suppositories include systemic dose (see , e . g ., Goodson , Medical Applications of spermaceti and wax . Rectal suppositories may be prepared Controlled Release , vol. 2 , pp . 115 - 138 ( 1984 ). either by the compressed method or by molding. An exem - In some embodiments , a controlled release device is plary weight of a rectal suppository is about 2 to 3 grams. 50 introduced into a subject in proximity of the site of inap Tablets and capsules for rectal administration are manu - propriate immune activation or a tumor. Other controlled factured using the same pharmaceutically acceptable sub release systems are discussed in the review by Langer stance and by the samemethods as for formulations for oral (Science 249: 1527 - 1533 ( 1990 ) . The active ingredient can administration . be dispersed in a solid inner matrix , e . g. , polymethylmeth 5 . 5 . 6 . Sustained Release Compositions 55 acrylate , polybutylmethacrylate , plasticized or unplasticized Active ingredients provided herein can be administered polyvinylchloride, plasticized nylon , plasticized polyethyl by controlled release means or by delivery devices that are eneterephthalate , natural rubber, polyisoprene , polyisobuty well known to those of ordinary skill in the art. Examples lene , polybutadiene , polyethylene , ethylene - vinylacetate include, but are not limited to , those described in U . S . Pat. copolymers , silicone rubbers , polydimethylsiloxanes , sili Nos. 3 ,845 ,770 ; 3 ,916 ,899 ; 3, 536 , 809 ; 3, 598 , 123 ; and U . S . 60 cone carbonate copolymers , hydrophilic polymers such as Pat. Nos . 4 ,008 ,719 , 5 ,674 ,533 , 5 ,059 , 595 , 5 ,591 , 767, hydrogels of esters of acrylic and methacrylic acid , collagen , 5 , 120 ,548 , 5 ,073 ,543 , 5 ,639 , 476 , 5 , 354 ,556 , 5 ,639 ,480 , cross - linked polyvinylalcohol and cross - linked partially 5 ,733 ,566 , 5 ,739 , 108 , 5 , 891, 474 , 5 , 922 ,356 , 5 , 972 , 891 , hydrolyzed polyvinyl acetate, that is surrounded by an outer 5 , 980 , 945 , 5 , 993 , 855 , 6 ,045 ,830 , 6 , 087 , 324 , 6 , 113, 943 , polymeric membrane , e . g . , polyethylene, polypropylene , 6 , 197 , 350 , 6 ,248 , 363, 6 , 264, 970 , 6 , 267 , 981, 6 ,376 , 461 , 65 ethylene /propylene copolymers , ethylene / ethyl acrylate 6 ,419 , 961, 6 , 589 , 548 , 6 ,613 ,358 , 6 ,699 , 500 and 6 , 740 ,634 , copolymers , ethylene/ vinylacetate copolymers , silicone rub each of which is incorporated herein by reference. Such bers , polydimethyl siloxanes , neoprene rubber , chlorinated US 9 ,938 , 254 B2 73 74 polyethylene , polyvinylchloride, vinylchloride copolymers well as a variety of cell based assays , including KG - 1 cell with vinyl acetate , vinylidene chloride, ethylene and pro - proliferation assay described in the Example section . pylene , ionomer polyethylene terephthalate , butyl rubber epichlorohydrin rubbers , ethylene /vinyl alcohol copolymer, 5 .7 . Preparation of Compounds ethylene / vinyl acetate / vinyl alcohol terpolymer , and ethyl- 5 ene/ vinyloxyethanol copolymer , that is insoluble in body Compound A or Compound B provided herein can be fluids. The active ingredient then diffuses through the outer prepared by methods known to one of skill in the art and polymeric membrane in a release rate controlling step . The following procedures similar to those described in the percentage of active ingredient contained in such parenteral Examples section herein and routine modifications thereof. compositions is highly dependent on the specific nature thereof, as well as the needs of the subject. 6 . EXAMPLES 5 . 5 . 7 . Targeted Formulations Compound A or Compound B provided herein may also The following Examples are presented by way of illus be formulated to be targeted to a particular tissue , receptor. „ tration , not limitation . The following abbreviations are used or other area of the body of the subject to be treated .Many b in descriptions and examples . such targeting methods are well known to those of skill in the art. All such targeting methods are contemplated herein Example 1 for use in the instant compositions. For non - limiting examples of targeting methods, see , e. g ., U . S . Pat. Nos . 20 Preparation of ( 3 - ( 5 - ( 2 , 2 -difluoro - 2 - ( 4 - fluorophe 6 ,316 ,652 , 6 ,274 ,552 , 6 , 271 , 359 , 6 , 253 ,872 , 6 , 139 , 865, nyl) acetamido )methyl ) - 1 -oxoisoindolin - 2 -yl ) - 2 , 6 6 ,131 , 570 , 6 , 120 ,751 , 6 , 071, 495 , 6 , 060 , 082 , 6 ,048 ,736 , dioxopiperidin - 1 - yl) methyl Dihydrogen Phosphate 6 ,039 , 975 , 6 , 004, 534 , 5 , 985 , 307, 5 , 972, 366 , 5 , 900 ,252 , 5 , 840 ,674 , 5 , 759, 542 and 5 ,709 ,874 . In one embodiment, liposomal suspensions, including 25 O= tissue- targeted liposomes, such as tumor- targeted liposomes, D - OH may also be suitable as pharmaceutically acceptable carriers . o OH These may be prepared according to methods known to those skilled in the art . For example , liposome formulations FF F may be prepared as described in U . S . Pat. No . 4 , 522 ,811 . 30 Briefly , liposomes such as multilamellar vesicles (MLV ' s ) may be formed by drying down egg phosphatidyl choline and brain phosphatidyl serine ( 7: 3 molar ratio ) on the inside of a flask . A solution of Compound A or Compound B 35 provided herein in phosphate buffered saline lacking diva lent cations (PBS ) is added and the flask shaken until the A . Methyl 4 - bromo - 2 -methylbenzoate lipid film is dispersed . The resulting vesicles are washed to remove unencapsulated compound , pelleted by centrifuga 4 -Bromo - 2 -methylbenzoic acid ( 100 g , 465 . 02 mmol ), tion , and then resuspended in PBS . 40 concentrated sulfuric acid (52 mL ) in methanol ( 1 L ) were 5 . 5 . 8 . Articles of Manufacture combined and heated to 65° C . for 18 hours . The reaction Compound A or Compound B provided herein which is was concentrated and the residue diluted with ethyl acetate used for treatment , prevention or amelioration of one or ( 500 mL ) , washed with saturated sodium bicarbonate solu more symptoms or progression of cancer , including solid tion (150 mL ) , water ( 200 mL ) , and brine ( 250 mL ) and tumors and blood borne tumors , and a label that indicates 45 drieddrie over sodium sulfate . The organic phase was concen that the compound is used for treatment, prevention or trated under reduced pressure and further dried under high amelioration of one or more symptoms or progression of vacuum to give methyl 4 - bromo - 2 -methylbenzoate ( 102 g , cancer , including solid tumors and blood borne tumors . 445 .27 mmol , 95 % yield ) as a red liquid . 1H NMR ( 400 The articles of manufacture provided herein contain pack MHz, Chloroform - d1 ) 8 7 . 78 (d , J = 8 . 3 Hz, 1H ) , 7 .45 - 7 . 30 aging materials . Packaging materials for use in packaging 50 ( m , 2H ) , 3 .88 ( s , 3H ) , 2 .57 ( s , 3H ) . pharmaceutical products are well known to those of skill in the art . See, e . g ., U . S . Pat. Nos. 5 , 323 , 907 , 5 ,052 , 558 and B . Methyl- 4 - bromo - 2 - (bromomethyl ) benzoate 5 , 033 ,252 . Examples of pharmaceutical packaging materials include , but are not limited to , blister packs , bottles, tubes , Methyl 4 -bromo - 2 -methylbenzoate ( 102 g , 445 . 27 inhalers, pumps, bags, vials , containers, syringes , pens, 55 mmol) , NBS ( 79 . 2 g , 445 . 27 mmol) , Azo - isobutyronitrile bottles , and any packaging material suitable for a selected ( 2 . 58 g , 16 mmol) in acetonitrile (600 mL ) were combined formulation and intended mode of administration and treat - and refluxed at 85° C . for 18 hours . The mixture was ment. A wide array of formulations of the compounds and concentrated , and to the residue was added dichloromethane compositions provided herein are contemplated . ( 150 mL ) . The resultant solid was removed by filtration . The 60 filtrate was concentrated and purified by flash column chro 5 .6 . Evaluation of Activity matography ( 0 - 4 % EtoAc in Hexanes ) . Fractions containing product was concentrated under reduced pressure and fur Standard physiological, pharmacological and biochemical ther dried under high vacuum to give Methyl- 4 -bromo - 2 procedures are available for testing the compounds to iden - (bromomethyl ) benzoate ( 100 g , 324 .70 mmol, 72 . 9 % yield ) tify those that possess the desired anti- proliferative activity . 65 as an off -white solid . 1H NMR (300 MHz, Dimethylsulfox Such assays include, for example , biochemical assays ide - do) d 7 . 88 (d , J = 2 . 2 Hz, 1H ) , 7 .82 ( dd , J = 8 . 4 , 2 . 1 Hz , such as binding assays, radioactivity incorporation assays, as 1H ) , 7 . 72 - 7 .64 ( m , 1H ), 5 .00 ( s , 2H ), 3 . 88 ( s , 3H ) . US 9 , 938 , 254 B2 75 76 C . 3 -( 5 -Bromo - 1 - oxoisoindolin - 2 -yl ) piperidine - 2 ,6 ppm 10 . 98 (br . s ., 1H ) 9 .66 ( t, J = 5 . 99 Hz, 1H ) 7 .58 - 7 .73 (m , dione 3H ) 7 . 29 - 7 . 47 ( m , 4H ) 5 . 11 ( dd , J = 13 . 40 , 5 .20 Hz , 1H ) 4 .38 -4 .53 ( m , 3H ) 4 . 24 - 4 . 36 (m , 1H ) 2 . 81 -3 . 00 ( m , 1H ) Methyl - 4 -bromo - 2 - (bromomethyl ) benzoate ( 100 g 2 .56 - 2 .67 ( m , 1H ) 2 .40 ( qd , J= 13 .19 , 4 .57 Hz, 1H ) 1. 91 -2 .07 324 . 70 mmol) , 3 - Aminopiperidine- 2 ,6 - dione .hydrochloride 5 (m , 1H ) . (53 . 2 g , 324. 70 mmol) , triethylamine (113 . 29 mL , 811. 75 mmol) , and dry dimethylformamide (400 mL ) were com G . Di- tert - butyl (( 3 - ( 5 - ( ( 2 , 2 - difluoro - 2 - ( 4 - fluoro bined and stirred at room temperature under inert atmo phenyl) acetamido )methyl ) - 1 -oxoisoindolin - 2 -yl ) - 2, sphere for 18 hours . The reaction was cooled to 5º C . and 6 -dioxopiperidin -1 - yl )methyl ) phosphate diluted with water ( 400 mL ) , acetic acid ( 115 mL ) , diethy - 10 lether (300 mL ) with continued stirring at room temperature A mixture of N - (( 2 -( 2 ,6 -dioxopiperidin - 3 -yl ) - 1 -oxoisoin for 2 hours . The resultant solid was filtered , washed with dolin - 5 -yl ) methyl ) - 2 , 2 -difluoro - 2 - ( 4 - fluorophenyl) acet ether ( 100 mL ) and further dried under high vacuum to give amide ( 1 . 0 g , 2 . 245 mmol) , cesium carbonate ( 2 . 195 g , 6 . 74 3 - ( 5 - Bromo - 1 -oxoisoindolin - 2 - yl) piperidine - 2 , 6 - dione (46 mmol) , and potassium iodide ( 0 . 745 g , 4 .49 mmol ) in NMP g , 142. 35 mmol, 43 . 8 % yield ) as a light blue solid . MS ( ESI ) 15 (4 ml) was stirred at room temperature and di- tert- butyl m / z 325 . 0 ( M + 1 ] + . ( chloromethyl) phosphate ( 4 .65 g , 17 . 96 mmol) was added . The mixture was stirred at 30° C . for 2 hours , at which point D . 2 - ( 2 ,6 -Dioxopiperidin - 3 - yl) - 1 - oxoisoindoline - 5 the starting material was barely detectable by LCMS . The carbonitrile reaction was stirred at ambient temperature overnight. After 20 14 hours , the reaction was diluted with DMSO and purified 3 - ( 5 -Bromo - 1 - oxoisoindolin - 2 - yl) piperidine - 2 ,6 - dione by preparatory HPLC (Gemini -NX C18 column ; 40 - 85 % (46 g , 142 . 35 mmol) , 1 , 1 ' - Bis( diphenylphosphino ) ferrocene acetonitrile in 10 mM ammonium carbonate in water ) to ( 788 mg, 1. 423 mmol) , zinc cyanide ( 25 g. 213 .52 mmol) . give 1 . 12 g white solid that was 86 % pure desired product zinc acetate ( 7 .83 g , 42 .7 mmol) and drydry dimethylformadimethylforma (64 . 4 % yield ) by LCMS . This material was carried on to the mide (360 mL ) were combined and degassed before addition 25 next step without further purification . “HNMR ( 500 MHz, of tris (dibenzylideneacetone ) dipalladium ( 0 ) ( 0 . 364 g , 0 .398 DMSO -do ) 8 ppm 9 .55 - 9. 79 (m , 1H ) , 7 .60 -7 .77 (m , 3H ), mmol) . The mixture was evacuated and replaced with argon 7 . 32 - 7 .50 ( m , 4H ) , 5 . 35 - 5 . 48 ( m , 2H ) , 5 . 24 - 5 .32 ( m , 1H ) , 3 times, then stirred at 120° C . for 20 hours . The mixture was 5 . 10 -5 .21 ( m , 2H ), 4 .41 - 4 .52 (m , 3H ) , 4 . 23 - 4 .33 ( m , 1H ) , cooled to room temperature , filtered and purified by silica 3 .07 - 3 . 15 ( m , 1H ) , 2 .81 - 2 .89 ( m , 1H ) , 2 .35 - 2 .43 ( m , 1H ) , column chromatography (0 - 5 % methanol in dichlorometh - on 2 .04 - 2 . 10 ( m , 1H ) , 1 .43 - 1 .45 ( m , 4H ) , 1 .42 ( s , 12H ) , 1 .40 ( s , ane ). Fractions containing product were combined and sol- 2H ) , 1 . 37 - 1 . 39 ( m , 1H ) , 1 . 34 ( s , 6H ) , 1 . 34 ( s , 3H ) . vent removed under reduced pressure and then further dried under high vacuum to give 2 - ( 2 ,6 - dioxopiperidin - 3 - yl) - 1 H . (3 -( 3 -( ( 2 ,2 - Difluoro -2 -( 4 - fluorophenyl )acet amido )methyl ) - 1 -oxoisoindolin - 2 -yl ) - 2 , 6 -dioxopip oxoisoindoline - 5 - carbonitrile (22 g , 81 .78 mmol, 57 . 2 % eridin - 1 -yl )methyl dihydrogen phosphate yield ) as a brown solid . MS ( ESI) m / z 268 . 0 [ M - H + ]. 35 E . 3 -( 5 -( Aminomethyl) - 1- oxoisoindolin -2 -yl ) piperi To a stirred solution of di- tert - butyl ( ( 3 - ( 5 - ( ( 2 , 2 -difluoro dine - 2 , 6 - dione 2 - ( 4 - fluorophenyl) acetamido )methyl ) - 1 -oxoisoindolin - 2 yl) - 2 ,6 - dioxopiperidin - 1 -yl ) methyl ) phosphate ( 1 . 12 g , 2 - ( 2 , 6 -Dioxopiperidin - 3 - yl) - 1 -oxoisoindoline - 5 - carboni 1 .648 mmol) in DCM (20 mL ) , was added trifluoroacetic trile ( 10 g . 37 . 13 mmol) , methanesulfonic acid ( 2 .6 mL , 40 acid ( 20 mL , 260 mmol) and the reaction stirred at ambient 40 . 85 mmol ), 10 % dry Palladium on carbon ( 4 g ) and temperature . After 15 minutes , LCMS indicated complete dimethylacetamide ( 320 mL ) were combined and shaken in conversion to the desired product . The reaction was con a hydrogenation vessel and kept under 50 Psi at 40° C . for centrated by rotary evaporation and purified by prep -HPLC 20 hours . The hydrogen atmosphere was evacuated and the (Polar Luna column ; 5 -65 % acetonitrile in water with 0 . 1 % mixture was filtered through a celite pad , washed with water 45 formic acid ) . The product containing fractions were frozen ( 100 mL ) , and concentrated . To the resulting residue was and lyophilized to give a fluffy white powder (410 mg , 0 . 738 added 1 % methanol -dichloromethane which upon filtration mmol, 44 . 8 % yield ) that was determined to be 99 . 9 % pure and drying under high vacuum to provide 3 -( 5 -( aminom desired product by LCMS and HNMR . ' H NMR ( 500 MHz , ethyl) - 1 -oxoisoindolin - 2 - yl )piperidine - 2 ,6 -dione ( 5 .6 g , DMSO - d6 ) d 9 .67 ( t , J = 5 . 99 Hz, 1H ) , 7 .53 - 7 . 80 ( m , 3H ) , 15 . 17 mmol, 40 % yield ) as an off -white solid . MS ( ESI) m / z s 7 . 24 - 7 .50 ( m , 4H ) , 5 .42 ( d , J = 7 . 25 Hz, 2H ) , 5 . 24 ( dd , 272 .0 [M – 1 ]. J = 5 .04 , 13 .24 Hz, 1H ), 4 . 38 -4 .53 ( m , 3H ) , 4 .27 -4 . 34 (m , 1H ) , 4 .00 - 4 . 13 ( m , 2H ) , 3 . 00 - 3 . 12 ( m , 1H ) , 2 .78 - 2 .87 ( m , F . N - ( ( 2 - ( 2 , 6 -dioxopiperidin - 3 - yl) - 1 -oxoisoindolin 1H ) , 2 . 33 - 2 .44 ( m , 1H ) , 2 . 00 - 2 . 10 ( m , 1H ) . 5 - yl) methyl ) - 2 ,2 - difluoro - 2 -( 4 - fluorophenyl) acet Alternatively , ( 3 -( 5 -( ( 2 , 2 -difluoro - 2 -( 4 - fluorophenyl) ac etamido )methyl ) - 1 - oxoisoindolin - 2 - yl ) - 2 , 6 - dioxopiperidin amide 55 1 - yl) methyl dihydrogen phosphate may be prepared accord To 3 -( 5 -( aminomethyl) - 1 -oxoisoindolin - 2 - yl )piperidine ing to the following steps . 2 . 6 - dione methanesulfonate ( 0 .200 g . 0 . 541 mmol ) in DMF Steps A - F are the same as in the above method , and Step ( 3 mL ) was added HATU ( 0 .226 g , 0 .596 mmol) . 2 . 2 - G and Step H are as follows: difluoro - 2 -( 4 - fluorophenyl) acetic acid (0 .103 g , 0 .541 mmol) followed by N - ethyl- N - isopropylpropan - 2 - amine 60 G . Di- tert -butyl ( ( 3 - ( 5 - ( ( 2 , 2 -difluoro - 2 - ( 4 - fluoro ( 0 .262 ml, 1. 624 mmol) . The mixture was stirred at 25° C . phenyl )acetamido )methyl ) - 1 -oxoisoindolin - 2 -yl ) - 2 , for 16 hours. Thirty ( 30 ) mL of water was added , and the 6 - dioxopiperidin - 1 -yl ) methyl ) phosphate resulting mixture was filtered . Filtrate was rinsed with EtoAc, dried under vacuum to afford N - ( ( 2 - ( 2 , 6 - dioxopip - A suspension of N - ( ( 2 - ( 2 , 6 - dioxopiperidin - 3 - yl) - 1 -ox eridin - 3 -yl ) -1 -oxoisoindolin - 5 -yl ) methyl ) -2 ,2 -difluoro - 2- 65 oisoindolin - 5 -yl ) methyl ) -2 ,2 -difluoro - 2- (4 - fluorophenyl) ( 4 - fluorophenyl) acetamide ( 0 . 100 g , 0 .225 mmol, 41. 5 % acetamide ( 2 . 0 g , 4 .49 mmol ) in DMA ( 45 mL ) was heated yield ) as a white solid . ' H NMR (500 MHz, DMSO -do ) d at 40° C . until a clear solution was obtained ( ~ 30 sec ). Solid US 9 ,938 ,254 B2 77 78 potassium iodide ( 1 . 491 g , 8 . 98 mmol) and di - tert -butyl A . Methyl 4 - bromo- 2 -methylbenzoate ( chloromethyl) phosphate ( 9 . 29 g , 35 . 9 mmol) were added . The mixture was stirred at 40° C . for 5 min before sodium 4 - Bromo - 2 -methylbenzoic acid ( 100 g , 465 . 02 mmol) , hydride (0 . 198 g , 4 . 94 mmol) was added in one portion . After 45 min , analysis by LCMS indicated a clean reaction 5 concentrated sulfuric acid (52 mL ) in methanol ( 1 L ) were with ~ 7 % starting material remaining. After 2 h , the reactionin 5 combined and heated to 65° C . for 18 hours. The reaction was diluted with 300 mL EtoAc and washed with water was concentrated and the residue diluted with ethyl acetate ( 2x300 mL ) . The organic layer was diluted with hexanes (500 mL ) , washed with saturated sodium bicarbonate solu ( 100 mL ) and washed with brine (2x300 mL ) , dried tion (150 mL ), water ( 200 mL ), brine (250 mL ) and dried (Na SO4) , filtered , and concentrated to give 11 . 3 g yellow over sodium sulfate . The organic phase was concentrated oil that still contained 6 % starting material by LCMS. " under reduced pressure and further dried under high vacuum HNMR and FNMR spectra of this material were consistent to give methyl 4 -bromo - 2 -methylbenzoate ( 102 g , 445 . 27 with the desired product along with a tiny bit of starting mmol, 95 % yield ) as a red liquid . 1H NMR (400 MHz, material, a large amount of phosphate reagent, and some Chloroform -di ) 87. 78 ( d , J = 8 . 3 Hz, 1H ) , 7 . 45 - 7 . 30 ( m , 2H ) . EtOAc . The crude product was carried on as is in the next 15 3 . 88 ( s , 3H ) , 2 .57 ( s , 3H ) . reaction . H . ( 3 - ( 5 - ( ( 2 , 2 -Difluoro - 2 - ( 4 - fluorophenyl) acet B . Methyl- 4 -bromo -2 - (bromomethyl ) benzoate amido )methyl ) - 1 - oxoisoindolin - 2 - yl) - 2 , 6 - dioxopip eridin - 1 - yl) methyl dihydrogen phosphate Methyl 4 -bromo - 2 -methylbenzoate (102 g , 445 .27 To a stirred solution of crude di - tert- butyl ( ( 3 - ( 5 - ( ( 2 , 2 - 420 mmol) , NBS ( 79 . 2 g , 445 . 27 mmol) , Azo - isobutyronitrile difluoro - 2 - ( 4 - fluorophenyl) acetamido )methyl ) - 1 -oxoisoin ( 2 .58 g , 16 mmol) in acetonitrile (600 mL ) were combined dolin - 2 - yl) - 2 ,6 -dioxopiperidin - 1- yl) methyl ) phosphate and refluxed at 85° C . for 18 hours . The mixture was ( 3 . 00 g , 4 .49 mmol) in DCM (20 mL ) at 0° C . was added concentrated , and to the residue was added dichloromethane trifluoroacetic acid ( 20 mL , 260 mmol) and the reaction was ( 150 mL ). The resultant solid was removed by filtration . The stirred for 5 min at 0° C . and for 90 min at ambient 25 filtrate was concentrated and purified by flash column chro temperature . LCMS analysis indicated 82 % desired product matography ( 0 - 4 % EtoAc in Hexanes ) . Fractions containing and 6 . 7 % N - ( ( 2 - ( 2, 6 - dioxopiperidin - 3 -yl ) - 1 -oxoisoindolin product was concentrated under reduced pressure and fur 5 - yl) methyl ) - 2 , 2 - difluoro - 2 - ( 4 - fluorophenyl) acetamide ther dried under high vacuum to give Methyl- 4 -bromo - 2 ( starting material from the previous reaction ) along with (bromomethyl ) benzoate ( 100 g , 324 .70 mmol, 72. 9 % yield ) some minor impurities . The reaction was concentrated by 30 as an off -white solid . 1H NMR ( 300 MHz, Dimethylsulfox rotary evaporation and placed under high vacuum for 1 h . The resulting thick orange oil (8 . 48 g ) was dissolved in ide -do ) 8 7 .88 (d , J = 2 . 2 Hz, 1H ), 7 .82 (dd , J = 8 . 4 , 2. 1 Hz, EtoAc ( 200 mL ) with sonication and allowed to stand at 1H ), 7 .72 - 7 .64 ( m , 1H ), 5 .00 (s , 2H ), 3. 88 (s , 3H ). ambient temperature . After 90 min , a large volume of white solid precipitated . The solid was collected by vacuum fil C . 3 -( 5 -Bromo -1 -oxoisoindolin -2 -yl ) piperidine -2 ,6 tration and washed with Et O to give 1. 738 g (67 . 8 % yield 35 dione for 2 steps ) fine white powder. LCMS analysis indicated 97. 3 % purity . The HNMR spectra was clean and consistent Methyl - 4 - bromo- 2 -( bromomethyl ) benzoate ( 100 g , with the desired product and there was no detectable TFA by 324 . 70 mmol) , 3 - Aminopiperidine - 2 , 6 - dione .hydrochloride FNMR . ' H NMR (500 MHz, DMSO - do ) 8 9 .67 ( t, J = 5 .99 4 ( 53 . 2 g , 324 . 70 mmol ) , triethylamine (113 . 29 mL , 811. 75 Hz, 1H ) , 7 .63 - 7 . 73 ( m , 3H ) , 7 . 34 - 7 . 46 ( m , 4H ) , 5 .44 ( d , tu mmol) , and dry dimethylformamide ( 400 mL ) were com J = 1 . 25 Hz, 2H ) , 5 .25 ( dd , F= 5 . 20 , 13 .40 Hz, 1H ), 4 . 42 - 4 .49 bined and stirred at room temperature under inert atmo ( m , 3H ) , 4 . 28 - 4 . 34 ( m , 1H ) , 3 .58 - 3 . 89 ( m , 2H ), 3 .08 ( ddd , J = 5 . 36 , 13 . 48 , 17 .73 Hz, 1H ) , 2 . 80 - 2 . 87 ( m , J = 2 . 21 , 4 . 10 sphere for 18 hours. The reaction was cooled to 5º C . and Hz, 1H ) , 2 . 35 ( br. s ., 1H ), 2 . 03 - 2 . 10 ( m , 1H ) ; 19F NMR (471 diluted with water (400 mL ) , acetic acid ( 115 mL ) , diethy MHz , DMSO -do ) 8 - 100 .62 ( s, 2F ), - 109. 54 (s , 1F ); MS 45 letherleth ( 300 mL ) with continued stirring at room temperature ( ESI) m / z 458 .2 ( 100 % ) [ M - PO4H2] * , 556 . 1 (90 % ) [ M + 1 ] ", for 2 hours . The resultant solid was filtered , washed with ether ( 100 mL ) and further dried under high vacuum to give 578 . 1 ( 15 % ) [ M + Na ]* . 3 - ( 5 - Bromo - 1 -oxoisoindolin - 2 - yl ) piperidine - 2 , 6 - dione ( 46 Example 2 g , 142. 35 mmol, 43. 8 % yield ) as a light blue solid . MS (ESI ) Preparation of ( 3 - ( 5 - ( ( 2 , 2 - difluoro - 2 - ( 4 - fluorophe 50 m / z 325 . 0 ( M + 11+ . nyl) acetamido )methyl ) - 1 -oxoisoindolin -2 -yl ) -2 ,6 D . 2 - ( 2 ,6 -Dioxopiperidin -3 -yl ) - 1 -oxoisoindoline - 5 dioxopiperidin - 1 - yl) methyl L - valinate carbonitrile 55 3 - ( 5 - Bromo - 1 - oxoisoindolin - 2 -yl ) piperidine - 2 , 6 -dione ( 46 g , 142 . 35 mmol ), 1 , 1 '- Bis ( diphenylphosphino ) ferrocene NHNH2 (788 mg , 1 .423 mmol) , zinc cyanide (25 g , 213 .52 mmol) , . . . zinc acetate ( 7 .83 g , 42 . 7 mmol) and dry dimethylforma FO mide ( 360 mL ) were combined and degassed before addition 60 of tris (dibenzylideneacetone ) dipalladium (0 ) (0 .364 g , 0 .398 mmol) . The mixtures was evacuated and replaced with argon F F 3 times, then stirred at 120° C . for 20 hours . The mixture was N cooled to room temperature , filtered and purified by silica column chromatography (0 - 5 % methanol in dichlorometh F 65 ane ) . Fractions containing product were combined and sol otu vent removed under reduced pressure and then further dried under high vacuum to give 2 -( 2 ,6 -dioxopiperidin - 3 -yl ) - 1 US 9 ,938 ,254 B2 79 80 oxoisoindoline - 5 -carbonitrile (22 g , 81 . 78 mmol, 57 . 2 % 44 .9 mmol: Split into twenty 1 gram batches ) was dissolved yield ) as a brown solid . MS ( ESI) m / z 268 . 0 [ M - H + ]. in hot N , N - Dimethylformamide (90 mL ) . To the homoge neous room temperature solution was added dropwise (S ) E . 3 -( 5 - ( Aminomethyl) -1 -oxoisoindolin - 2 -yl ) piperi chloromethyl 2 - ( ( tert -butoxycarbonyl ) amino ) - 3 -methylbu dine - 2 , 6 -dione 5 tanoate ( 13 . 13 g , 49 . 4 mmol) followed immediately by cesium carbonate ( 16 .09 g , 49 . 4 mmol) and the mixture 2 - ( 2 , 6 -Dioxopiperidin - 3 - yl) - 1 - oxoisoindoline - 5 - carboni stirred at ambient temperature . After 2 hours , all of the trile ( 10 g , 37 . 13 mmol) , methanesulfonic acid ( 2 . 6 mL, reaction vials were combined and partitioned between 10 % 40 .85 mmol) , 10 % dry Palladium on carbon ( 4 g ) and methanol in dichloromethane ( 1 L ) and water (750 mL ). The dimethylacetamide ( 320 mL ) were combined and shaken in 10 aqueous was partitioned additionally with dichloromethane a hydrogenation vessel and kept under 50 Psi at 40° C . for (2x500 mL ) . The organics were dried over magnesium 20 hours . The hydrogen atmosphere was evacuated and the sulfate , filtered and solvent removed under reduced pressure mixture was filtered through a celite pad , washed with water to afford a viscous yellow liquid . The viscous liquid was ( 100 mL ) , and concentrated . To the resulting residue, was diluted with 75 % ethyl acetate in hexanes ( 1 L ) and washed added 1 % methanol- dichloromethane which upon filtration with water (2x500 mL ) to remove dimethylformamide . The and drying under high vacuum to provide 3 - (5 - (aminom - 15 organics were dried over magnesium sulfate , filtered and ethyl) - 1- oxoisoindolin -2 -yl ) piperidine - 2 ,6 -dione (5 .6 g , solvent removed under reduced pressure to afford a yellow 15 . 17 mmol, 40 % yield ) as an off -white solid . MS (ESI ) m / z foam ( 25 .05 g ) . The yellow foam was purified using biotage 272 . 0 [ M – 1 ]. chromatography ( ( 340 g column ( 100 mL /min ), 0 - 70 % ethyl acetate in hexanes ( 1 . 3 L ) , then 70 % ethyl acetate in hexanes F . N - (( 2 - ( 2 , 6 -Dioxopiperidin - 3 - yl ) - 1 -oxoisoindolin 20 (3 .0 L )) . Pertinent fractions were combined to afford the title 5 -yl )methyl ) - 2 ,2 -difluoro - 2 -( 4 - fluorophenyl )acet compound as a white foam solid ( 6 . 34 g , 9 .40 mmol, 21 % amide yield ). MS ( ESI ) m / z 575 [ M - Boc ] * To 3 - (5 - (Aminomethyl ) - 1 -oxoisoindolin - 2 -yl ) piperidine I. ( 3 - (5 - ( 2 , 2 -Difluoro -2 - ( 4 - fluorophenyl) acetamido ) 2 , 6 -dione methanesulfonate ( 0 . 200 g , 0 .541 mmol) in DMF 25 methyl ) - 1 - oxoisoindolin - 2 - yl) - 2 ,6 - dioxopiperidin - 1 ( 3 mL ) was added HATU ( 0 . 226 g , 0 .596 mmol ) , 2 ,2 yl) methyl L -valinate difluoro - 2 - ( 4 - fluorophenyl) acetic acid ( 0 . 103 g , 0 .541 mmol) followed by N -ethyl - N -isopropylpropan - 2 - amine ( 2S ) -( 3 - ( 5 - ( ( 2 , 2 - Difluoro - 2 -( 4 - fluorophenyl) acetamido ) (0 . 262 ml, 1 .624 mmol ). The mixture was stirred at 25° C . methyl) - 1 - oxoisoindolin - 2 - yl) - 2 , 6 - dioxopiperidin - 1 - yl) for 16 hours . Water ( 30 mL ) was added , and the resulting 30 methyl 2 - ( ( tert - butoxycarbonyl) amino ) - 3 -methylbutanoate mixture filtered . Filtrate was rinsed with EtoAc, dried under (6 .34 g . 9. 40 mmol) was dissolved in 4 .0M hydrochloric vacuum to afford N - ( (2 - (2 ,6 - dioxopiperidin - 3 -yl ) - 1 -ox acid ( 117 mL , 468 mmol) in dioxanes at 0° C . The mixture oisoindolin - 5 -yl ) methyl ) - 2 , 2 -difluoro - 2 - ( 4 - fluorophenyl ) was allowed to stir at 0° C . (homogeneous ) . After 45 minutes acetamide ( 0 . 100 g , 0 . 225 mmol, 41 . 5 % yield ) as a white at 0° C . , the mixture was filtered through a paper filter and solid . ' H NMR ( 500 MHz, DMSO - d ) 8 ppm 10 . 98 (br . S ., - washed additionally with dioxanes . The solution was con 1H ) 9 .66 ( t , J = 5 . 99 Hz, 1H ) 7 .58 - 7 .73 ( m , 3H ) 7 .29 - 7 .47 ( m , densed under reduced pressure at 38° C . water bath tem 4H ) 5 . 11 (dd , J = 13 .40 , 5 . 20 Hz, 1H ) 4 . 38 - 4 .53 ( m , 3H ) perature to afford a white solid . The solid was triturated with 4 .24 -4 . 36 ( m , 1H ) 2 .81 - 3. 00 (m , 1H ) 2 . 56 -2 .67 (m , 1H ) 2 .40 anhydrous ethyl acetate (200 mL ). The solution was then ( qd , J = 13 . 19 , 4 .57 Hz, 1H ) 1 .91 - 2 .07 ( m , 1H ) . condensed under reduced pressure to afford a glassy solid ( 5 . 40 g , 8 . 84 mmol , 94 % yield ) . The solid was the dissolved G . Chloromethyl ( tert -butoxycarbonyl ) - L - valinate 40 in pH 3 water (100 mL ) and then condensed under reduced pressure . The solid was again subjected to pH 3 water ( 100 ( S ) - 2 - ( ( Tert- butoxycarbonyl ) amino ) - 3 -methylbutanoic mL ) and condensed under reduced pressure to afford the title acid (20 g, 92 mmol) , sodium bicarbonate (30 . 9 g , 368 compound (4 .95 g , 8. 10 mmol, 86 % yield ). ' H NMR (500 mmol) , and tetrabutylammonium hydrogen sulfate ( 3 . 13 g , MHz, DMSO - d ) 8 ppm 9 .70 ( t , J = 5 .83 Hz, 1H ) , 8 . 43 (br . s . , 9 .21 mmol) were combined in dichloromethane (150 mL ) 45 2H ), 7 .57 - 7 .77 ( m , 3H ) , 7 . 30 - 7 . 51 ( m , 4H ) , 5 .83 ( dd , J = 9 .62 , and water ( 150 mL ) . The mixture was stirred at ambient 5 .52 Hz, 1H ) , 5 .70 - 5 . 78 ( m , 1H ) , 5 .24 - 5 . 33 ( m , 1H ) , 4 .42 temperature for 5 minutes . The mixture was cooled to 0° C . 4 . 53 ( m , 3H ) , 4 . 28 (t , J = 17 .50 Hz, 1H ) , 3 . 94 (br . s ., 1H ) , and chloromethyl sulfochloridate (11 . 17 mL , 110 mmol) 3 .64 - 3 .76 ( m , 1H ) , 3 .49 ( dd , J = 15 . 13 , 4 . 73 Hz, 1H ) , 3 . 05 was then added dropwise and the mixture allowed to stir at 3. 19 (m , 1H ) , 2 .82 - 2 . 93 (m , 1H ), 2. 34 - 2. 48 ( m , 2H ), 2. 03 ambient temperature . After 2 hours , the solution was added 50 2 . 22 (m , 2H ), 0 .89 - 1 .01 ( m , 6H ) ; MS( ESI ) m / z 575 [ M ] * . to a separatory funnel and the aqueous was partitioned with dichloromethane (3x150 mL ) . The organics were combined Example 3 : KG - 1 Cell Proliferation Assay and washed additionally with water (2x150 mL ) and the organics dried over magnesium sulfate , filtered and solvent The following is an example of an assay that can be used removed under reduced pressure to afford a colorless oil to determine the anti - proliferative activity of Compound A ( 28 . 0 g ) . The oil was purified via normal phase chromatog - and Compound B in KG - 1 cell line ( American Type Culture raphy ( 5 % ethyl acetate in hexanes ) to afford a colorless oil Collection ( ATCC ) : catalogue number ATCC® CCL - 246TM ) as the title compound ( 24 . 3 g , 91 mmol, 99 % yield ) . ' H at 72 hours post - treatment. The seeding density for KG - 1 NMR (500 MHz, DMSO - d ) 8 6 . 94 - 7 .44 ( m , 1H ) , 5 .79 - 6 . 02 can be optimized to ensure assay linearity in 384 -well plates . ( m , 2H ) , 3 .72 - 3 .98 ( m , 1H ) , 2 .00 ( s , 1H ) , 1 .40 ( s , 9H ) , 0 . 91 Increasing concentrations of test compounds ( 0 . 5 nM to ( dd , J = 2 . 36 , 6 . 78 Hz, 6H ) . 60 10 uM ) was spotted in a 10 - point serial dilution fashion ( 3 - fold dilution ) in duplicate via an acoustic dispenser ( EDC H . ( 3 -( 5 - ( ( 2 , 2 - Difluoro - 2 - ( 4 - fluorophenyl ) acet ATS - 100 ) into an empty 384 -well plate . The dimethyl sul amido )methyl ) - 1 -oxoisoindolin - 2 - yl) - 2 , 6 -dioxopip foxide (DMSO ) concentration was kept constant for a final eridin - 1 - yl) methyl ( tert -butoxycarbonyl ) - L -valinate assay concentration of 0 . 1 % DMSO . Prior to testing, KG - 1 65 cells were grown in RPMI- 1640 (Roswell Park Memorial N - ( ( 2 - ( 2 , 6 - Dioxopiperidin - 3 -yl ) - 1 - oxoisoindolin - 5 - yl) Institute - 1640 ) medium with 10 % FBS ( fetal bovine serum : methyl) - 2 ,2 -difluoro -2 -( 4 - fluorophenyl )acetamide (20 g , HyClone ) and expanded in culture flasks to provide suffi US 9 , 938 , 254 B2 cient amounts of starting material. Cells were then diluted to While the disclosure has been described with respect to 5000 cells per well , in a 50 uL volume and added directly to the compound- spotted 384 -well plates . Cells were allowed the particular embodiments , it will be apparent to those to grow for 72 hours in 5 % CO , at 37° C . At the time when skilled in the art that various changes and modifications may exposure of cells to compound began ( to ) , initial viable cell 5 be made without departing from the spirit and scope of the number was assessed via Cell Titer- Gb® Luminescent Cell Viability Assay at a 1 vol: 2 vol ratio according to manufac disclosure as defined in the claims. Such modifications are turer ' s instructions (Promega Corporation , Madison , Wis .) also intended to fall within the scope of the appended claims. by quantifying the level of luminescence generated by adenosine - 5 ' - triphosphate ( ATP ) present in viable cells . All of the patents , patent applications and publications After 72 hours , cell viability of the treated cells is assessed referred to herein are incorporated herein in their entireties . via Cell Titer- Glo® and read for luminescence . IC50 values Citation or identification of any reference in this application for exemplary compounds are provided in Table 1 . Activity of representative compounds is shown in Table 1 , is not an admission that such reference is available as prior with IC50 values as provided below : art to this disclosure . The full scope of the disclosure is A : 0 .01 to 0 . 1 uM and B : >0 . 1 uM to 0 . 7 UM . better understood with reference to the appended claims. TABLE 1 FCA Prolif Cell TiterGlo KG - 1 72 h Compound ( IC50 )

LOH OH F F ????

NH

F F

F B

LOH ??

F F ??????N US 9 , 938 , 254 B2 84 What is claimed is: each R is independently H , optionally substituted alkyl, or optionally substituted cycloalkyl; 1 . A compound of formula A - I : R ! is optionally substituted cycloalkyl, optionally substi tuted aryl, optionally substituted heteroaryl or option A - I 5 ally substituted heterocyclyl; where the substituents on R ' , when present are one to three groups Q , where each Q is independently alkyl, halo , haloalkyl, hydroxyl, alkoxy , optionally substi RO tuted cycloalkyl, optionally substituted cycloalkylal 0 - P = O kyl, optionally substituted aryl , R + OR , - R SRS, 10 - RAN ( R ) ( R ) , ROR N ( R ) ( R ) or R OR * C ( J ) N ( R ) ( R ) ; R3 J is O or S ; R each R * is independently alkylene, alkenylene or a direct N bond ; 15 each R is independently hydrogen , alkyl, haloalkyl or hydroxyalkyl; and Rand R ’ are each independently hydrogen or alkyl or R “ and R together with the nitrogen atom on which they or a stereoisomer or mixture of stereoisomers, tautomer , are substituted form a 5 or 6 -membered heterocyclyl or pharmaceutically acceptable salt , solvate , hydrate , co -crys - 20 heteroaryl ring, optionally substituted with one or two tal, clathrate , isotopologue or polymorph thereof, wherein : halo , alkyl or haloalkyl. 3 . The compound of claim 1 , wherein each R is indepen each R is independently H , optionally substituted alkyl, or dently H or (C , - C . )alkyl ; Rl is optionally substituted aryl , optionally substituted cycloalkyl; where the substituents on R1, when present, are one to three Rl is optionally substituted cycloalkyl , optionally substi 25 groups Q , where each Q is independently halo , alkyl, tuted aryl, optionally substituted heteroaryl or option - R OR , - R + SRS or R * OR * C ( O ) N ( R ) (R7 ) ; each R * is ally substituted heterocyclyl; independently a direct bond or alkylene; each R is inde pendently hydrogen , halo , alkyl or haloalkyl; and R? and R ? R2 and R are each halo ; are each independently hydrogen or alkyl. where the substituents on R ', when present are one to 4 . The compound of claim 1, wherein each R is indepen three groups Q , where each Q is independently alkyl, 30 dently is H or (C ,- C )alkyl ; and R is optionally substituted halo , haloalkyl, hydroxyl, alkoxy, optionally substi aryl, where the substituents on R ' , when present, are one to tuted cycloalkyl, optionally substituted cycloalkylal three groups Q , where each is independently fluoro , kyl, optionally substituted aryl , R OR , - RASR , chloro , methyl , — ROR " , — R4N ( R ) ( R ) , — R SRS or - R4N (R ) (R ?) , R OR + N (R )( R ) or R4OR4C (J )N (R ) R + OR + C ( O ) N (R )( R7) ; each R4 is independently a direct (R7 ) ; 35 bond or methylene; each R is independently hydrogen , J is O or S ; methyl , ethyl or trifluoromethyl ; and R and R ? are each each R * is independently alkylene , alkenylene or a direct independently hydrogen or methyl. bond; 5 . The compound of claim 1 , wherein each R is indepen each RS is independently hydrogen , alkyl , haloalkyl or dently H or (C1 - C . ) alkyl and R is optionally substituted hydroxyalkyl; and 40 phenyl, where the substituents on R ' , when present, are one to three groups Q , where each Q is independently fluoro , R? and R ' are each independently hydrogen or alkyl or R chloro , methyl, tert butyl, — R -OR " , — R + N ( R ) ( R ) , and R ' together with the nitrogen atom on which they - R + SRS or R + OR + C ( O ) N ( R ) (R7 ) ; each R4 is indepen are substituted form a 5 or 6 -membered heterocyclyl or dently a direct bond ormethylene ; each R is independently heteroaryl ring, optionally substituted with one or two 45 hydrogen , methyl, ethyl or trifluoromethyl; and R and R ? halo , alkyl or haloalkyl. are each independently hydrogen or methyl. 2 . The compound of claim 1 , wherein the compound is of 6 . The compound of claim 1 . wherein the compound is of Formula A - II : Formula A - III: So50 4A. - II Op A - III - P = 0 55 (Qlya O — P = 0

0 0 Ö

Ö 1que or a stereoisomer or mixture of stereoisomers , tautomer, 65 or a stereoisomer or mixture of stereoisomers, tautomer, pharmaceutically acceptable salt, solvate , hydrate , co - crys - pharmaceutically acceptable salt , solvate , hydrate , co - crys tal, clathrate , isotopologue or polymorph thereof, wherein : tal , clathrate , isotopologue or polymorph thereof, wherein : US 9 , 938 , 254 B2 85 86 each R is independently H , optionally substituted alkyl, or optionally substituted cycloalkyl; -continued each Q is independently alkyl, halo , haloalkyl, alkoxy 00H alkyl, hydroxyl, alkoxy, optionally substituted 0 OCH2CH , cycloalkyl, optionally substituted cycloalkylakyl, 5 optionally substituted aryl R4OR , R4SR5, - RN F F ( R )( R ) , ROR * N ( R )( R ) or R +OR + C (J )N (R )( R ' ); J is 0 or S ; each R4 is independently alkylene, alkenylene or a direct bond ; each R is independently hydrogen , alkyl , haloalkyl7 oror 10 00H hydroxyalkyl; -???? (?? OCH2CH ,, R and R ’ are each independently hydrogen or alkyl or R “ and R together with the nitrogen atom on which they F F are substituted form a 5 or 6 -membered heterocyclyl or heteroaryl ring, optionally substituted with one or two 15 halo , alkyl or haloalkyl; and n is 0 - 3 . 7 . The compound of claim 1 , wherein the compound is 0CH2CH , selected from the group consisting of: OCH2CH , 20 -. OR ???" F F OH ,

F F 25 F 0 0CH2CH ? OCH2CH3, F ???? OH F F p=80 OH , 30 F F ???? 35 0H ??? ? F F OCH3, H

F F 40 ? 0= o= OH F 0 OH ???? ???? p- 0C113 OCH :, 45 F F

?? 5 ( ) OCHs ? OCH : OCH3, - N ???? ??F / F ?H F F 55

F OCH ???? POCH3OCH3 60 F F / ?? F F 6° ?????????C US 9, 938 ,254 B2 87 88 - continued B - II 7 , and o 0 RR - N F F

Ri F F 10 F ofrost O N F F . ???? or a stereoisomer or mixture of stereoisomers , tautomer, 15 pharmaceutically acceptable salt , solvate , hydrate , co -crys tal, clathrate , isotopologue or polymorph thereof, wherein : each R is independently H , optionally substituted alkyl, or 8 . A compound of Formula B - I: optionally substituted cycloalkyl; ???? 20 each R ' is independently is H or optionally substituted alkyl; B - I R ! is optionally substituted cycloalkyl , optionally substi OR R tuted aryl, optionally substituted heteroaryl or option R ' 25 ally substituted heterocyclyl; where the substituents on R ', when present are one to three groups Q , where each Q is independently alkyl, R2 23 halo , haloalkyl, hydroxyl, alkoxy , optionally substi tuted cycloalkyl, optionally substituted cycloalkylal 30 kyl, optionally substituted aryl, R4ORS, R SRS, - R + N (R )( R ), R + OR +N (RO ) ( R7 ) or R +OR + C ( J) N ( R ) Sub (R7 ) ; or a stereoisomer or mixture of stereoisomers, tautomer, J is O or S ; pharmaceutically acceptable salt, solvate , hydrate , co - crys- 35 each R4 is independently alkylene , alkenylene or a direct tal, clathrate , isotopologue or polymorph thereof, wherein : bond ; each R ' is independently H or optionally substituted alkyl; each RS is independently hydrogen , alkyl, haloalkyl or or optionally substituted cycloalkyl; hydroxyalkyl; and R ' is H or optionally substituted alkyl ; 40 R and Rare each independently hydrogen or alkyl or Rº R is optionally substituted cycloalkyl, optionally substi and R7 together with the nitrogen atom on which they tuted aryl , optionally substituted heteroaryl or option are substituted form a 5 or 6 -membered heterocyclyl or ally substituted heterocyclyl; heteroaryl ring , optionally substituted with one or two R2 and R3 are each halo ; halo , alkyl or haloalkyl. 45 101 . The compound of claim 8 , wherein each R is inde where the substituents on R ' , when present are one to pendently H or ( C , - C )alkyl ; each R ' is independently is H three groups Q , where each Q is independently alkyl, or ( C1 - C6 ) alkyl; R is optionally substituted aryl, where the halo , haloalkyl , hydroxyl , alkoxy, optionally substi substituents on R ', when present, are one to three groups Q , tuted cycloalkyl , optionally substituted cycloalkylal where each is independently halo , alkyl, RHOR ” , kyl, optionally substituted aryl, — R - OR ", R SR " , " R4SRS or R OR + C (O )N (R ) (R7 ) ; each R4 is indepen RºN (R )( R ) , R +OR +N (R %) ( R7 ) or R OR C ( J) N (RO ) dently a direct bond or alkylene; each R is independently ( R ' ) ; hydrogen , halo , alkyl or haloalkyl; and R and R ’ are each J is O or S ; independently hydrogen or alkyl. + 55 11 . The compound of claim 8 , wherein each R is inde each R4 is independently alkylene , alkenylene or a direct pendently H or ( C . - C . ) alkyl ; each R ' is independently H or bond ; ( C1 - C6 ) alkyl; R ' is optionally substituted phenyl, where the each R $ is independently hydrogen , alkyl, haloalkyl or substituents on R ' , when present, are one to three groups Q , hydroxyalkyl; and where each Q is independently fluoro , chloro , methyl , tert R? and R7 are each independently hydrogen or alkyl or R 60 butyl, — R OR , - R + N ( R ) (R ), - R4SR or R + OR + C ( 0 ) and R ’ together with the nitrogen atom on which they N (R ) ( R ) ; each R * is independently a direct bond or meth are substituted form a 5 or 6 -membered heterocyclyl or ylene ; each R is independently hydrogen , methyl , ethyl or heteroaryl ring, optionally substituted with one or two trifluoromethyl; and R and R7 are each independently halo , alkyl or haloalkyl. 65 hydrogen or methyl. 9 . The compound of claim 8 , wherein the compound is of 12 . The compound of claim 8 , wherein the compound is Formula B - II: of Formula B - III: US 9 ,938 , 254 B2 89 90 -continued B - III NH 0 R R 177 ? - R ?

F F ??? ? ??? 1 ( ??? ??? NH or a stereoisomer or mixture of stereoisomers , tautomer , pharmaceutically acceptable salt, solvate , hydrate , co - crys tal , clathrate , isotopologue or polymorph thereof, wherein : each R is independently H , optionally substituted alkyl, or optionally substituted cycloalkyl ; F F each R ' is independently is H or optionally substituted 20 alkyl ; each Q is independently alkyl, halo , haloalkyl, alkoxy CI alkyl , hydroxyl , alkoxy, optionally substituted NH , cycloalkyl, optionally substituted cycloalkylakyl, 25 optionally substituted aryl, ROR5, R4SR5, R * N ( R )( RZ) , R4ORN ( R )( RZ) or R + OR + C (JN ( R )( R7 ) ; J is 0 or S ; each R * is independently alkylene , alkenylene or a direct F F bond ; 30) each R is independently hydrogen , alkyl , haloalkyl or hydroxyalkyl; ??? R? and R7 are each independently hydrogen or alkyl or R “ ?? NH2 and R together with the nitrogen atom on which they 33 are substituted form a 5 or 6 -membered heterocyclyl or heteroaryl ring , optionally substituted with one or two halo , alkyl or haloalkyl; and F F n is 0 - 3 . 40) 13. The compound of claim 8 , wherein the compound is selected from the group consisting of:

NHL 45 NA , ? 0 ,

N F F 50) ?? F F 55 F

NH2 NH3

0, 60

E F F

???????? 6 ?? ?????? US 9, 938 ,254 B2 91 espara 92 d -continued - continued FO, 5

F F F F 10

F NH Oficeret??? 15 ??? F F 20 F F

NHNH , 25 NH2 FO, and

a F 30 F

F NH 35 ????NH ??? OficoF F .40 Ofronta 45 14 . A pharmaceutical composition comprising a com pound of claim 1 and a pharmaceutically acceptable carrier , diluent or excipient. 15 . The pharmaceutical composition of claim 14 , wherein 50 the composition is formulated for parenteral, or intravenous administration . F F 16 . The pharmaceutical composition of claim 14 , wherein Ofeque the compositionofrecent is formulated as a single unit dosage form . 17 . A pharmaceutical composition comprising a com 55 pound of claim 8 and a pharmaceutically acceptable carrier , diluent or excipient. 18 . The pharmaceutical composition of claim 17 , wherein the composition is formulated for parenteral, or intravenous CO, administration . 19 . The pharmaceutical composition of claim 17, wherein the composition is formulated as a single unit dosage form . F 20 . A method of treating cancer comprising administering to a mammal having cancer a therapeutically effective 65 amount of the compound of claim 1 . 21. The method of claim 20, wherein the cancer is leukemia . US 9 ,938 ,254 B2 93 94 22 . The method of claim 21 , wherein the leukemia is 28 . The method of claim 27 , wherein the cancer is chronic lymphocytic leukemia , chronic myelocytic leuke - leukemia . mia , acute lymphoblastic leukemia or acute myeloid leuke 29 . The method of claim 28 , wherein the leukemia is mia . chronic lymphocytic leukemia , chronic myelocytic leuke 23 . The method of claim 21, wherein the leukemia is an 5 mia , acute lymphoblastic leukemia or acute myeloid leuke acute myeloid leukemia . mia . 24 . The method of claim 21, wherein the leukemia is 30 . The method of claim 28 , wherein the leukemia is an relapsed , refractory or resistant to surgery , radiation therapy, acute myeloid leukemia . chemotherapy or hormonal therapy. 31 . The method of claim 28 , wherein the leukemia is 25 . The method of claim 20 further comprisingo adminisadminis -. 1010 relapsed , refractory or resistant to surgery , radiation therapy, tering a therapeutically effective amount of a second active chemotherapy or hormonal therapy . agent or a support care therapy . 32 . The method of claim 27 further comprising adminis tering a therapeutically effective amount of a second active agent26 . isThe a therapeuticmethod of claimantibody 25 , thatwherein specifically the second binds active to a agentter or a support care therapy. cancer antigen , hematopoietic growth factor , cytokine , anti 15 33 . The method of claim 32 , wherein the second active cancer agent, antibiotic , cox -2 inhibitor, immunomodulatory agent is a therapeutic antibody that specifically binds to a agent, immunosuppressive agent, corticosteroid or a phar cancer antigen , hematopoietic growth factor, cytokine , anti macologically active mutant thereof. cancer agent, antibiotic , cox - 2 inhibitor, immunomodulatory 27 . A method of treating cancer comprising administering agent, immunosuppressive agent, corticosteroid or a phar to a mammal havinghaving cancer aa therapeutically effectiveeffective 2020 macologically active mutant thereof . amount of the compound of claim 8 . * * * *