US 2012007 7820A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0077820 A1 Danter et al. (43) Pub. Date: Mar. 29, 2012

(54) COMPOUNDS AND METHOD FOR Publication Classification TREATMENT OF CANCER (51) Int. Cl. A63/496 (2006.01) (75) Inventors: Wayne R. Danter, London (CA); A6IP35/00 (2006.01) Martyn Brown, Scarborough (CA); A6IP35/02 (2006.01) Franck LePifre, Olivet (FR) C07D 40/4 (2006.01) (52) U.S. Cl...... 514/253.03:544/363; 514/253.06; 544/361 (73) Assignee: CRITICAL OUTCOME TECHNOLOGIES INC., London (57) ABSTRACT (CA) The present invention is directed to methods of use of a compound of Formula I: (21) Appl. No.: 13/310,506 Formula I R (22) Filed: Dec. 2, 2011 1/ R5 R4 S NC Related U.S. Application Data R6 R3 A V (60) Continuation of application No. 13/190.230, filed on R7-Y N-(A), Jul. 25, 2011, which is a division of application No. 12/013,079, filed on Jan. 11, 2008, now Pat. No. 8,034, - (-, 815. R9 R10

and/or a pharmaceutically-acceptable salt, hydrate, Solvate, (60) Provisional application No. 60/884,489, filed on Jan. tautomer, optical isomer, or combination thereof, a composi 11, 2007, provisional application No. 60/884,504, tion comprising the thiosemicarbazone, a method of admin filed on Jan. 11, 2007. istration thereof, and use thereof to treat a cancer. Patent Application Publication Mar. 29, 2012 Sheet 1 of 8 US 2012/007,782.0 A1

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COMPOUNDS AND METHOD FOR SUMMARY OF THE INVENTION TREATMENT OF CANCER 0008. In accordance with an aspect, there is provided a compound of Formula I:

STATEMENT OF RELATED APPLICATIONS Formula I R 1/ 0001. The present application is a continuation of pending RRS R4R S NEC U.S. application Ser. No. 13/190.230 filed on Jul. 25, 2011, ) NR12A VR which is a divisional of U.S. application Ser. No. 12/013,079, filed Jan. 11, 2008, (now U.S. Pat. No. 8,034,815), which R7-Y N-(A) claims the benefit of U.S. provisional application U.S. Ser. R11 No. 60/884,489, filed Jan. 11, 2007, which also claims benefit R&R. Rio of U.S. provisional application U.S. Ser. No. 60/884,504, and/or a pharmaceutically-acceptable salt, hydrate, Solvate, filed Jan. 11, 2007, each of which are incorporated herein by tautomer, optical isomer, or combination thereof, wherein: reference in their entireties. 0009 R and R together form a substituted or unsubsti tuted polycyclic ring comprising at least two ring systems, said at least two ring systems comprising a first ring system FIELD OF THE INVENTION bonded to C1 and a second ring system fused to the first ring system, wherein: 0002 The present invention relates generally to com 0010 the first ring system is a substituted or unsubstituted pounds, compositions and methods for treatment of cancer. aromatic group, the second ring system is a Substituted or unsubstituted aromatic group, a Substituted or unsubstituted heteroaromatic group, a Substituted or unsubstituted carbocy BACKGROUND OF THE INVENTION clic group, or a Substituted or unsubstituted heterocyclic group; or 0003 Cancer, irrespective of its pathogenesis, is charac 0011 the first ring system is a substituted or unsubstituted terized by uncontrolled growth and survival of cells. Com heteroaromatic group, the second ring system is a Substituted monto most forms of cancer is an error in the cellular mecha or unsubstituted aromatic group, a Substituted or unsubsti tuted heteroaromatic group, a Substituted or unsubstituted nism responsible for balancing cell Survival and cell death. carbocyclic group, or a Substituted or unsubstituted hetero 0004. According to the American Cancer Society, lung cyclic group; or cancer is the leading cause of cancer death for both men and 0012 the first ring system is a substituted or unsubstituted women. Small cell lung cancer (SCLC) accounts for approxi saturated carbocyclic group, the second ring system is a Sub mately 20% of all lung cancers. The 5-year survival rate for stituted or unsubstituted aromatic group, a Substituted or unsubstituted unsaturated carbocyclic group, a Substituted or small cell lung cancer is about 15%. unsubstituted heterocyclic group, or a Substituted or unsub 0005 Certainthiosemicarbazones, such as those disclosed stituted ring B: in British Patent No. 1,026,401, International Patent Appli cation No. WO2004/066725, Japanese Patent No. 56-95.161 and U.S. Pat. No. 4,927,843, have been used to treat, for Ring B example, a variety of viruses. Other thiosemicarbazones, however, may be used to treat cancer. French Patent No. 2,879,194 is directed to certain thiosemicarbazones that may be used in the treatment or prevention of cancer, in dermato logical treatment, in the treatment of cardiovascular and wherein X to X are each independently selected from car immune diseases, lipid-metabolism related diseases and bon or a heteroatom; or modulate PPAR's. International Patent Application No. WO 0013 the first ring system is a substituted or unsubstituted 2006/009765 is directed to specific thiosemicarbazones that unsaturated carbocyclic group, the second ring system is a may be used in anti-cancer therapy that mitigates the devel Substituted or unsubstituted aromatic group, a Substituted or unsubstituted carbocyclic group, a Substituted or unsubsti opment of drug resistance. U.S. Pat. No. 4,593,027 is directed tuted heterocyclic group, or a Substituted or unsubstituted to hydrazone derivatives that may be used as a chemothera ring B: peutic. 0006. There is a need, however, for new therapeutic drug treatments to treat cancers more efficiently, and lung cancer in Ring B particular. Current treatment regimes for Small cell lung can cer involve surgery, radiation and chemotherapy. While timely Surgery can be curative, new therapies are necessary when timely Surgery is not an option. 0007 All patents and patent applications referenced wherein X to X are each independently selected from car herein are incorporated by reference herein in their entireties. bon or a heteroatom; or US 2012/0077.820 A1 Mar. 29, 2012

0014 the first ring system is a substituted or unsubstituted 0034. The term “therapeutically effective amount’ as used heterocyclic group, the second ring system is a substituted or herein means that amount of active compound or pharmaceu unsubstituted heteroaromatic group, a Substituted or unsub tical agent that elicits the biological or medicinal response in stituted carbocyclic group, or a Substituted or unsubstituted a tissue, system, animal or human that is being sought by a heterocyclic group; and researcher, Veterinarian, medical doctor or other clinician. 0015 R to R are each independently selected from H, a 0035. The compounds of the present invention may have Substituted or unsubstituted hydrocarbon group, a Substituted or unsubstituted heterogeneous group, a Substituted or unsub asymmetric centers, chiral axes, and chiral planes (as stituted carbocyclic group, a Substituted or unsubstituted het described, for example, in: E. L. Eliel and S. H. Wilen, Stereo erocyclic group, Substituted or unsubstituted aromatic, or a chemistry of Carbon Compounds, John Wiley & Sons, New substituted or unsubstituted heteroaromatic; York, 1994, pages 1119-1190), and occur as racemates, race 0016 R is selected from H or a hydrocarbyl group; mic mixtures, and as individual diastereomers, with all pos 0017. Y is selected from a heteroatom or a carbon atom; sible isomers and mixtures thereof, including optical isomers, 0.018 A is selected from a substituted or unsubstituted being included in the present invention. In addition, the com hydrocarbon group, a Substituted or unsubstituted heteroge pounds disclosed herein may exist as tautomers and both neous group, a Substituted or unsubstituted carbocyclic tautomeric forms are intended to be encompassed by the group, a Substituted or unsubstituted heterocyclic group, Sub Scope of the invention, even though only one tautomeric stituted or unsubstituted aromatic, or a Substituted or unsub structure may be depicted. stituted heteroaromatic; and 0036 Generally, reference to a certain element such as 0019 n is an integer. hydrogen or His meant to, if appropriate, include all isotopes 0020. In a further aspect, there is provided a composition of that element. comprising the compound of Formula I. 0037. Where the term “alkyl group” is used, either alone or 0021. In another aspect, there is provided a method of within other terms such as “haloalkyl group' and “alkylamino administration of the compound of Formula I or composition thereof to treat a cancer. group', it encompasses linear or branched carbon radicals 0022. In yet another aspect, there is provided use of the having, for example, one to about twenty carbon atoms or, in compound of Formula I or composition thereof to treat a specific embodiments, one to about twelve carbon atoms. In CaCC. other embodiments, alkyl groups are “lower alkyl groups 0023. Other features and advantages of the present inven having one to about six carbon atoms. Examples of Such tion will become apparent from the following detailed groups include, but are not limited thereto, methyl, ethyl, description. It should be understood, however, that the n-propyl, isopropyl. n-butyl, isobutyl, sec-butyl, tert-butyl, detailed description and the specific examples while indicat pentyl, iso-amyl, hexyl and the like. In more specific embodi ing embodiments of the invention are given by way of illus ments, lower alkyl groups have one to four carbon atoms. tration only, since various changes and modifications within 0038. The term “alkenyl group' encompasses linear or the spirit and scope of the invention will become apparent to branched carbon radicals having at least one carbon-carbon those skilled in the art from the detailed description. double bond. The term “alkenyl group' can encompass con jugated and non-conjugated carbon-carbon double bonds or BRIEF DESCRIPTION OF THE DRAWINGS combinations thereof. An alkenyl group, for example and 0024. Embodiments of the present invention will now be without being limited thereto, can encompass two to about described, by way of example only, with reference to the twenty carbon atoms or, in a particular embodiment, two to attached Figures. about twelve carbon atoms. In embodiments, alkenyl groups 0025 FIG. 1 shows the volume of SHP77 human SCLC are “lower alkenyl groups having two to about four carbon tumour in nude mice treated with test compounds; atoms. Examples of alkenyl groups include, but are not lim 0026 FIG. 2 shows number of SHP77 human SCLC ited thereto, ethenyl, propenyl, allyl, propenyl, butenyl and tumours in nude mice treated with test compounds; 4-methylbutenyl. The terms “alkenyl group' and “lower alk 0027 FIG. 3 shows the volume of N417 human SCLC enyl group', encompass groups having "cis' and “trans' ori tumour in nude mice treated with COTI-2 and control; entations, or alternatively, “E” and “Z” orientations. 0028 FIG. 4 shows lack of emerging resistance in 0039. The term “alkynyl group' denotes linear or DMS153 cells treated with COTI-2 and COTI-219; branched carbon radicals having at least one carbon-carbon 0029 FIG. 5 lack of emerging resistance in SHP77 cells triple bond. The term “alkynyl group' can encompass conju treated with COTI-2 and COTI-219; gated and non-conjugated carbon-carbon triple bonds or 0030 FIGS. 6A and 6B show volume of U87 human combinations thereof. Alkynyl group, for example and with glioma tumours in nude mice treated with two different con out being limited thereto, can encompass two to about twenty centrations of COTI-2; and carbon atoms or, in a particular embodiment, two to about 0031 FIG. 7 shows Western blot analysis of cellular twelve carbon atoms. In embodiments, alkynyl groups are lysates of SHP77 cells that have been treated with COTI-2. “lower alkynyl groups having two to about ten carbonatoms. DETAILED DESCRIPTION Some examples are lower alkynyl groups having two to about 0032. The present invention is directed to a thiosemicar four carbon atoms. Examples of such groups include propar baZone, a composition comprising the thiosemicarbazone, a gyl, butynyl, and the like. method of administration thereof, and use thereof to treat a 0040. The term “halo' means halogens such as fluorine, chlorine, bromine or iodine atoms. CaCC. 0041. The term “haloalkyl group' encompasses groups Definitions wherein any one or more of the alkyl carbon atoms is Substi 0033. When describing the compounds, compositions, tuted with halo as defined above. Specifically encompassed methods and uses of this invention, the following terms have are monohaloalkyl, dihaloalkyl and polyhaloalkyl groups the following meanings unless otherwise indicated. including perhaloalkyl. A monohaloalkyl group, for one US 2012/0077.820 A1 Mar. 29, 2012

example, may have either an iodo, bromo, chloro or fluoro ine, indole, benzofuran, benzothiophene, benzimidazole, atom within the group. Dihalo and polyhaloalkyl groups may benzthiazole, quinoline, isoquinoline, quinazoline, quinoxa have two or more of the same halo atoms or a combination of line and the like. different halo groups. "Lower haloalkyl group' encompasses 0047. The term “carbocyclic group” means a saturated or groups having 1-6 carbon atoms. In some embodiments, unsaturated carbocyclic hydrocarbon ring. Carbocyclic lower haloalkyl groups have one to three carbon atoms. groups are not aromatic. Carbocyclic groups are monocyclic Examples of haloalkyl groups include fluoromethyl, difluo or polycyclic. Polycyclic carbocyclic groups can be fused, romethyl, trifluoromethyl, chloromethyl, dichloromethyl, spiro, or bridged ring systems. Monocyclic carbocyclic trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluo groups may contain 4 to 10 carbon atoms, typically 4 to 7 rochloromethyl, dichlorofluoromethyl, difluoroethyl, difluo carbon atoms, and more typically 5 to 6 carbon atoms in the ropropyl, dichloroethyl and dichloropropyl. ring. Bicyclic carbocyclic groups may contain 8 to 12 carbon 0042. The term “hydroxyalkyl group' encompasses linear atoms, typically 9 to 10 carbon atoms in the rings. or branched alkyl groups having, for example and without 0048. The term "heterocyclic group” means a saturated or being limited thereto, one to about ten carbon atoms, any one unsaturated ring structure containing carbon atoms and 1 or of which may be substituted with one or more hydroxyl more heteroatoms in the ring. Heterocyclic groups are not groups. In embodiments, hydroxyalkyl groups are “lower aromatic. Heterocyclic groups are monocyclic or polycyclic. hydroxyalkyl groups having one to six carbonatoms and one Polycyclic heterocyclic groups can be fused, spiro, or bridged or more hydroxyl groups. Examples of Such groups include ring systems. Monocyclic heterocyclic groups may contain 4 hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl to 10 member atoms (i.e., including both carbonatoms and at and hydroxyhexyl. least 1 heteroatom), typically 4 to 7, and more typically 5 to 6 0043. The term “alkoxy group' encompasses linear or in the ring. Bicyclic heterocyclic groups may contain 8 to 18 branched oxy-containing groups each having alkyl portions member atoms, typically 9 or 10 member atoms in the rings. of for example and without being limited thereto, one to Representative heterocyclic groups include, by way of about ten carbon atoms. In embodiments, alkoxy groups are example, pyrrolidine, imidazolidine, pyrazolidine, piperi “lower alkoxy' groups having one to six carbon atoms. dine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, Examples of Such groups include methoxy, ethoxy, propoxy, 3-pyrroline and the like. butoxy and tert-butoxy. In certain embodiments, lower 0049. The term "heterogeneous group” means a saturated alkoxy groups have one to three carbonatoms. The “alkoxy” or unsaturated chain of non-hydrogen member atoms com groups may be further substituted with one or more halo prising carbon atoms and at least one heteroatom. Heteroge atoms, such as fluoro, chloro or bromo, to provide neous groups typically have 1 to 25 member atoms. More “haloalkoxy” groups. In other embodiments, lower typically, the chain contains 1 to 12 member atoms, 1 to 10, haloalkoxy groups have one to three carbonatoms. Examples and most typically 1 to 6. The chain may be linear or of Such groups include fluoromethoxy, chloromethoxy, trif branched. Typical branched heterogeneous groups have one luoromethoxy, trifluoroethoxy, fluoroethoxy, and fluoropro or two branches, more typically one branch. Typically, het pOXy. erogeneous groups are saturated. Unsaturated heterogeneous 0044) The term “aromatic group' or “aryl group” means groups may have one or more double bonds, one or more an aromatic group having one or more rings wherein Such triple bonds, or both. Typical unsaturated heterogeneous rings may be attached togetherina pendent manner or may be groups have one or two double bonds or one triple bond. More fused. In particular embodiments, an aromatic group is one, typically, the unsaturated heterogeneous group has one two or three rings. Monocyclic aromatic groups may contain double bond. 4 to 10 carbonatoms, typically 4 to 7 carbon atoms, and more typically 4 to 6 carbon atoms in the ring. Typical polycyclic 0050. The term “hydrocarbon group” or “hydrocarbyl aromatic groups have two or three rings. Polycyclic aromatic group” means a chain of 1 to 25 carbon atoms, typically 1 to groups having two rings typically have 8 to 12 carbon atoms, 12 carbon atoms, more typically 1 to 10 carbon atoms, and preferably 8 to 10 carbon atoms in the rings. Examples of most typically 1 to 8 carbonatoms. Hydrocarbon groups may aromatic groups include, but are not limited to, phenyl, naph have a linear or branched chain structure. Typical hydrocar thyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, bon groups have one or two branches, typically one branch. anthryl oracenaphthyl. Typically, hydrocarbon groups are saturated. Unsaturated 0045. The term "heteroatom' means an atom other than hydrocarbon groups may have one or more double bonds, one carbon. Typically, heteroatoms are selected from the group or more triple bonds, or combinations thereof. Typical unsat consisting of Sulfur, phosphorous, nitrogen and oxygen urated hydrocarbon groups have one or two double bonds or atoms. Groups containing more than one heteroatom may one triple bond; more typically unsaturated hydrocarbon contain different heteroatoms. groups have one double bond. 0046. The term "heteroaromatic group' or "heteroaryl 0051. When the term “unsaturated” is used in conjunction group” means an aromatic group having one or more rings with any group, the group may be fully unsaturated or par wherein such rings may be attached together in a pendent tially unsaturated. However, when the term “unsaturated' is manner or may be fused, wherein the aromatic group has at used in conjunction with a specific group defined herein, the least one heteroatom. Monocyclic heteroaromatic groups term maintains the limitations of that specific group. For may contain 4 to 10 member atoms, typically 4 to 7 member example, an unsaturated "carbocyclic group', based on the atoms, and more typically 4 to 6 member atoms in the ring. limitations of the “carbocyclic group’ as defined herein, does Typical polycyclic heteroaromatic groups have two or three not encompass an aromatic group. rings. Polycyclic aromatic groups having two rings typically 0.052 The terms “carboxy group' or “carboxyl group', have 8 to 12 member atoms, more typically 8 to 10 member whether used alone or with other terms, such as "carboxy atoms in the rings. Examples of heteroaromatic groups alkyl group', denotes —(C=O)—O—. include, but are not limited thereto, pyrrole, imidazole, thia 0053. The term “carbonyl group', whether used alone or Zole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole, with other terms, such as "aminocarbonyl group', denotes isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triaz —(C=O)—. US 2012/0077.820 A1 Mar. 29, 2012

0054 The terms “alkylcarbonyl group' denotes carbonyl 0063. The term "heteroarylamino denotes amino groups groups which have been Substituted with an alkyl group. In which have been substituted with one or two heteroaryl certain embodiments, “lower alkylcarbonyl group” has lower groups, such as N-thienylamino. The "heteroarylamino” alkyl group as described above attached to a carbonyl group. groups may be further Substituted on the heteroaryl ring por 0055. The term "aminoalkyl group' encompasses linear or tion of the group. branched alkyl groups having one to about ten carbon atoms 0064. The term “aralkylamino group' denotes amino any one of which may be substituted with one or more amino groups which have been substituted with one or two aralkyl groups. In some embodiments, the aminoalkyl groups are groups. In other embodiments, there are phenyl-C-C-alky “lower aminoalkyl groups having one to six carbon atoms lamino groups, such as N-benzylamino. The “aralkylamino” and one or more amino groups. Examples of Such groups groups may be further Substituted on the aryl ring portion of include aminomethyl, aminoethyl, aminopropyl, aminobutyl the group. and aminohexyl. 0065. The term “alkylaminoalkylamino group' denotes 0056. The term “alkylaminoalkyl group' encompasses alkylamino groups which have been substituted with one or aminoalkyl groups having the nitrogen atom independently two alkylamino groups. In embodiments, there are C-C- Substituted with an alkyl group. In certain embodiments, the alkylamino-C-C-alkylamino groups. alkylaminoalkyl groups are “loweralkylaminoalkyl groups 0066. The term “arylthio group' encompasses aryl groups having alkyl groups of one to six carbon atoms. In other of six to ten carbonatoms, attached to a divalent Sulfur atom. embodiments, the lower alkylaminoalkyl groups have alkyl An example of “arylthio’ is phenylthio. The term “aralkylthio groups of one to three carbon atoms. Suitable alkylami group' encompasses aralkyl groups as described above, noalkyl groups may be mono or dialkyl Substituted, such as attached to a divalent Sulfur atom. In certain embodiments N-methylaminomethyl, N,N-dimethyl-aminoethyl, N,N-di there are phenyl-C-C-alkylthio groups. An example of ethylaminomethyl and the like. “aralkylthio’ is benzylthio. 0057 The term “aralkyl group' encompasses aryl-substi 0067. The term “aryloxy group' encompasses optionally tuted alkyl groups. In embodiments, the aralkyl groups are Substituted aryl groups, as defined above, attached to an oxy “lower aralkyl groups having aryl groups attached to alkyl gen atom. Examples of such groups include phenoxy. groups having one to six carbon atoms. In other embodi 0068. The term “aralkoxy group' encompasses oxy-con ments, the lower aralkyl groups phenyl is attached to alkyl taining aralkyl groups attached through an oxygen atom to portions having one to three carbon atoms. Examples of Such other groups. In certain embodiments, aralkoxy groups are groups include benzyl, diphenylmethyl and phenylethyl. The “lower aralkoxy groups having optionally substituted phe aryl in said aralkyl may be additionally substituted with halo, nyl groups attached to lower alkoxy group as described alkyl, alkoxy, haloalkyl and haloalkoxy. above. 0058. The term “arylalkenyl group' encompasses aryl 0069. The term “cycloalkyl group' includes saturated car Substituted alkenyl groups. In embodiments, the arylalkenyl bocyclic groups. In certain embodiments, cycloalkyl groups groups are “lower arylalkenyl groups having aryl groups include C-C rings. In embodiments, there are compounds attached to alkenyl groups having two to six carbon atoms. that include, cyclopentyl, cyclopropyl, and cyclohexyl. Examples of such groups include phenylethenyl. The aryl in 0070 The term “cycloalkenyl group” includes carbocy said arylalkenyl may be additionally substituted with halo, clic groups that have one or more carbon-carbon double alkyl, alkoxy, haloalkyl and haloalkoxy. bonds; conjugated or non-conjugated, or a combination 0059. The term “arylalkynyl group' encompasses aryl thereof. “Cycloalkenyl and “cycloalkyldienyl compounds Substituted alkynyl groups. In embodiments, arylalkynyl are included in the term “cycloalkenyl. In certain embodi groups are “lower arylalkynyl groups having aryl groups ments, cycloalkenyl groups include C-C rings. Examples attached to alkynyl groups having two to six carbon atoms. include cyclopentenyl, cyclopentadienyl, cyclohexenyl and Examples of Such groups include phenylethynyl. The aryl in cycloheptadienyl. The “cycloalkenyl group may have 1 to 3 said aralkyl may be additionally substituted with halo, alkyl, Substituents such as lower alkyl, hydroxyl, halo, haloalkyl, alkoxy, haloalkyl and haloalkoxy. The terms benzyl and phe nitro, cyano, alkoxy, lower alkylamino, and the like. nylmethyl are interchangeable. (0071. The term “suitable substituent”, “substituent’ or “substituted used in conjunction with the groups described 0060. The term “alkylthio group' encompasses groups herein refers to a chemically and pharmaceutically acceptable containing a linear or branched alkyl group, of one to ten group, i.e., a moiety that does not negate the therapeutic carbon atoms, attached to a divalent Sulfur atom. In certain activity of the inventive compounds. It is understood that embodiments, the lower alkylthio groups have one to three Substituents and Substitution patterns on the compounds of carbon atoms. An example of “alkylthio’ is methylthio. the invention may be selected by one of ordinary skill in the (CHS ). art to provide compounds that are chemically stable and that 0061 The term “alkylamino group' denotes amino groups can be readily synthesized by techniques known in the art, as which have been substituted with one alkyl group and with well as those methods set forth below. If a substituent is itself two alkyl groups, including terms "N-alkylamino” and “N.N- Substituted with more than one group, it is understood that dialkylamino'. In embodiments, alkylamino groups are these multiple groups may be on the same carbon/member “lower alkylamino' groups having one or two alkyl groups of atom or on different carbons/member atoms, as long as a one to six carbon atoms, attached to a nitrogenatom. In other stable structure results. Illustrative examples of some suitable embodiments, lower alkylamino groups have one to three Substituents include, cycloalkyl, heterocyclyl, hydroxyalkyl, carbonatoms. Suitable “alkylamino' groups may be mono or benzyl, carbonyl, halo, haloalkyl, perfluoroalkyl, perfluoro dialkylamino such as N-methylamino, N-ethylamino, N.N- alkoxy, alkyl, alkenyl, alkynyl, hydroxy, oxo, mercapto, alky dimethylamino, N,N-diethylamino and the like. lthio, alkoxy, aryl or heteroaryl, aryloxy or heteroaryloxy, 0062. The term “arylamino group' denotes amino groups aralkyl or heteroaralkyl, aralkoxy or heteroaralkoxy, HO which have been substituted with one or two aryl groups, such (C=O)—, amido, amino, alkyl- and dialkylamino, cyano, as N-phenylamino. The “arylamino' groups may be further nitro, carbamoyl, alkylcarbonyl, alkoxycarbonyl, alkylami Substituted on the aryl ring portion of the group. nocarbonyl, dialkylaminocarbonyl, arylcarbonyl, aryloxy US 2012/0077.820 A1 Mar. 29, 2012

carbonyl, alkylsulfonyl, and arylsulfonyl. Typical substitu second ring system is a Substituted or unsubstituted aromatic ents include aromatic groups, Substituted aromatic groups, group, a Substituted or unsubstituted heteroaromatic group, a hydrocarbon groups including alkyl groups such as methyl Substituted or unsubstituted carbocyclic group, a Substituted groups, Substituted hydrocarbon groups such as benzyl, and or unsubstituted heterocyclic group. heterogeneous groups including alkoxy groups such as meth OXy groups. 0080. In a further embodiment, the first ring system is a 0072 The term “fused’ means in which two or more car Substituted or unsubstituted Saturated carbocyclic group and bons/member atoms are common to two adjoining rings, e.g., the second ring system is a Substituted or unsubstituted aro the rings are “fused rings'. matic group, a Substituted or unsubstituted unsaturated car 0073. The pharmaceutically acceptable salts of the com bocyclic group, a Substituted or unsubstituted heterocyclic pounds of this invention include the conventional non-toxic group, or a substituted or unsubstituted ring B: salts of the compounds of this invention as formed, e.g., from non-toxic inorganic or organic acids. For example, such con ventional non-toxic salts include those derived from inor Ring B ganic acids such as hydrochloric, hydrobromic, Sulfuric, Sul famic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, gly colic, Stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, Sulfanilic, 2-acetoxy-benzoic, fumaric, toluene Sulfonic, methanesulfonic, ethane disulfonic, oxalic, wherein X to X are each independently selected from car isethionic, trifluoroacetic and the like. bon or a heteroatom. 0074 The pharmaceutically acceptable salts of the com I0081. In another embodiment, the first ring system is a pounds of this invention can be synthesized from the com Substituted or unsubstituted unsaturated carbocyclic group pounds of this invention which contain a basic or acidic and the second ring system is a Substituted or unsubstituted moiety by conventional chemical methods. Generally, the aromatic group, a Substituted or unsubstituted carbocyclic salts of the basic compounds are prepared either by ion group, a Substituted or unsubstituted heterocyclic group, or a exchange chromatography or by reacting the free base with substituted or unsubstituted ring B: Stoichiometric amounts or with an excess of the desired salt forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly, the salts of the Ring B acidic compounds are formed by reactions with the appropri ate inorganic or organic base. 0075. The present invention includes pharmaceutically acceptable salts, Solvates and prodrugs of the compounds of the invention and mixtures thereof. 0076. The terms “comprising”, “having and “including, and various endings thereof, are meant to be open ended, wherein X to X are each independently selected from car including the indicated component but not excluding other bon or a heteroatom. elements. 0077. The thiosemicarbazone of the invention is repre I0082 In yet another embodiment, the first ring system is a sented by a compound of Formula I: Substituted or unsubstituted heterocyclic group, the second ring system is a Substituted or unsubstituted heteroaromatic group, a Substituted or unsubstituted carbocyclic group, or a Formula I Substituted or unsubstituted heterocyclic group. R 1/ I0083. In another embodiment relating to the above-iden RRS R4R S N=Q tified embodiments, the first ring system is a five- or six membered ring. ) ( )-(, Y, I0084. In embodiments, the R to R groups are each inde R-Y. N-(A) pendently selected from H, a substituted or unsubstituted hydrocarbon group, a Substituted or unsubstituted heteroge R11 Rs Ro Rio neous group, a Substituted or unsubstituted carbocyclic group, a Substituted or unsubstituted heterocyclic group, Sub stituted or unsubstituted aromatic, or a Substituted or unsub wherein: stituted heteroaromatic. The R group is selected from Hor R and R together form a substituted or unsubstituted poly a hydrocarbyl group and Y is selected from a heteroatom or a cyclic ring. The ring has at least two ring systems. The two carbon atom. 'A' is selected from a substituted or unsubsti ring systems have a first ring system that is bonded to C1 and a second ring system that is fused to the first ring system. tuted hydrocarbon group, a Substituted or unsubstituted het 0078. In one embodiment, the first ring system is a substi erogeneous group, a Substituted or unsubstituted carbocyclic tuted or unsubstituted aromatic group and the second ring group, a Substituted or unsubstituted heterocyclic group, Sub system is a Substituted or unsubstituted aromatic group, a stituted or unsubstituted aromatic, or a Substituted or unsub Substituted or unsubstituted heteroaromatic group, a Substi stituted heteroaromatic and “n” is an integer. tuted or unsubstituted carbocyclic group, or a Substituted or 0085. The thiosemicarbazone described herein can be the unsubstituted heterocyclic group. compound of Formula I, a pharmaceutically-acceptable salt 0079. In a second embodiment, the first ring system is a thereof, a hydrate thereof, a solvate thereof, a tautomer Substituted or unsubstituted heteroaromatic group and the thereof, an optical isomer thereof, or a combination thereof. US 2012/0077.820 A1 Mar. 29, 2012

I0086. In a specific embodiment, the first ring system of the 0091. In specific embodiments, the compound of Formula compound of Formula I is a substituted or unsubstituted car I can be: bocyclic group and the second ring system is a Substituted or COTI-2 unsubstituted ring B: S l N Ring B r NH1N NN N - N1 N 21 21 COTI-5 wherein X to X are each independently selected from car S bonora heteroatom. In a more specific embodiment, ring B is N N a pyridine ring, typically fused to the first ring at C2 and C3 of n NH1N the pyridine ring. 0087 Although a first and second ring system is described r 21 N herein, the Substituted or unsubstituted polycyclic ring may further comprise other ring systems other than the first and HC1 N 2 second ring systems. For example, a third ring system may COTI-217 also be fused to the first ring system. The third ring system can S be, for instance, a Substituted or unsubstituted aromatic l -N / N group, a Substituted or unsubstituted heteroaromatic group, a N NH1 N Substituted or unsubstituted carbocyclic group, or a Substi N tuted or unsubstituted heterocyclic group. Typically, the third HC1 - Z N N ring system is a Substituted or unsubstituted heteroaromatic group or a substituted or unsubstituted heterocyclic group. S. I0088. With respect to the embodiments described above S COTI-219 with respect to Formula I, typically “n” is 0 or 1. If “n” is 1. N 'A' is typically a substituted or unsubstituted heteroaromatic ls -N / N group, in particular, a pyridinyl group. r NH 0089 Also, with respect to the embodiments of Formula I, N Y is typically a nitrogen atom. The ring: HC1 % \ S.

COTI-220

R5 R4 R7-Y- K.NS R9 R10

Such compounds may be used and/or in the form of a phar can be a variety of rings. The ring can be a Substituted or maceutically-acceptable salt, hydrate, Solvate or any combi unsubstituted thiomorpholinyl group, a Substituted or unsub nation thereof. stituted morpholinyl group, a Substituted or unsubstituted 0092. The compounds of Formula I described herein can piperidinyl group, or a Substituted or unsubstituted piperazi be prepared as follows: nyl group. 0093 a) reacting a compound of Formula II: 0090. In specific embodiments of Formula I, R, is a sub Formula II stituted or unsubstituted alkyl group or a substituted or unsub S stituted heteroaromatic group and R to Re and Rs to R2 are each independently selected from Hora substituted or unsub - stituted hydrocarbon group. More specifically, R, can be the substituted or unsubstituted alkyl group or a substituted or unsubstituted pyridyl group and R to R and Rs to R2 are each H. US 2012/0077.820 A1 Mar. 29, 2012

with a compound of Formula IIA: to forman intermediate of Formula VI, wherein R. R' or R' is substituted or unsubstituted hydrocarbon group, a Substi tuted or unsubstituted heterogeneous group, a Substituted or Formula IIA R5 R4 unsubstituted carbocyclic group, a Substituted or unsubsti R6 R3 tuted heterocyclic group, Substituted or unsubstituted aro matic, or a Substituted or unsubstituted heteroaromatic: R-Y N-(A)-H Formula VI Rs R11 R5 R4 S R9 R10 S “y k" ) V to form an intermediate of Formula III: R7-Y- (-,N-(A)n R Formula III R9 R10 R5 R4 S R6 R3 s N (0098 b) reacting the Intermediate of Formula VI with R-Y N-(A)n \ele N RNHNH2 to form an Intermediate of Formula IV: - K R11 R9 R10 Formula IV R5 R4 S NH2 0094 b) reacting the Intermediate of Formula III with “y k" ) NR12M RNHNH, to form an Intermediate of Formula IV: R7-Y N-(A)n - K R11 Formula IV R9 R10 R5 R4 S NH2 “y k" ) NR12{ (0099 c) reacting the Intermediate of Formula IV with a R 7-Y- N-(A)n ketone: - K R11 R9 R10 O

0095 c) reacting the Intermediate of Formula IV with a R ls R ketone: under condensation conditions, to form the compound of O Formula I. In specific embodiments, the above-identified syn thetic method can be used when “n” is 0 or 1; more typically, when “n” is 1. R R2 0100. The compounds of Formula I described herein can also be prepared as follows: under condensation conditions, to form the compound of 0101 a) esterifying compound of Formula IIA: Formula I. In specific embodiments, the above-identified syn thetic method can be used when “n” is 0 or 1; more typically, when “n” is 0. Formula IIA 0096. The compounds of Formula I described herein can also be prepared as follows: 0097 a) dithioesterifying a halo compound of Formula V:

Formula V Rs R11 R5 R4 R9 R10 R6 R3

R-Y N-(A)-CR'R'-Hal to form an intermediate of Formula VII, wherein R is substi tuted or unsubstituted hydrocarbon group, a Substituted or Rs R11 unsubstituted heterogeneous group, a Substituted or unsub R9 R10 stituted carbocyclic group, a Substituted or unsubstituted het erocyclic group, Substituted or unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic: US 2012/0077.820 A1 Mar. 29, 2012

carcinoma may be selected from Small cell carcinomas, cer Vical carcinomas, glioma, astrocytoma, prostate carcinomas, Formula VII ovarian carcinomas, melanoma, breast carcinomas, or col R5 R4 O orectal carcinomas. Compounds of the present invention may O be even more particularly useful in the treatment of small cell “y k" ) V lung cancer (SCLC) carcinomas. R7-Y. N-(A)n R 0107 Compounds of the present invention can have an ICs for a cancer cell population of less than about 1000 nM. - (-, In specific embodiments, compounds of the present invention R9 R10 show efficacy against SHP77 cells at IC50's of less than about 1000 nM, typically less than about 800 nM, more typically 0102 b) reacting the Intermediate of Formula VII with less than about 500 nM, even more typically less than about RNHNH2 to form an Intermediate of Formula VIII: 200 nM. 0.108 Compounds of the present invention show efficacy against DMS 144 cells at IC50's of less than about 1000 nM, Formula VIII typically less than about 750 nM, more typically less than R5 R4 O NH2 about 500 nM, even more typically less than about 300 nM, NR12 yet more typically less than about 100 nM. “y k" ) A 0109 Compounds of the present invention show efficacy R-Y N-(A)n against U87 cells at IC50's of less than about 2500 nM, typically less than about 1000 nM, more typically less than - (-, about 480 nM, even more typically less than about 200 nM, R9 R10 yet more typically less than about 75 nM. 0110 Compounds of the present invention show efficacy 0103 c) reacting the Intermediate of Formula VIII with a against SNB-19 cells at IC50's of less than about 2150 nM, thiation agent to form an Intermediate of Formula IV: typically less than about 1500 nM, more typically less than about 800 nM, even more typically less than about 100 nM, yet more typically less than about 50 nM, still more typically Formula IV less than about 15 nM. R5 R4 S NH2 0111 Compounds of the present invention are effective in R6 R3 ) NR12A reducing the size of malignant human cancer tumors created from SHP77, DMS114, N417 and/or U87 cell lines. R-Y N-(A)n 0112 Compounds of the present invention can penetrate the blood brain barrier of a mammal, typically, a human. - K R11 0113 Compounds of the present invention may exhibit a R9 R10 reduced tendency to induce cellular resistance to their own anti-cancer effects. Therefore, use of the compounds of the 0104 c) reacting the Intermediate of Formula IV with a present invention to treat a cancer may inhibit development of ketone: a drug resistant form of that cancer. Without wishing to be limited by theory, it is believed that the compounds of the present invention may inhibit development of P-glycoprotein O mediated drug resistance. 0114 Certain compounds of the present invention may exhibit reduced toxicity as compared with conventionally R R administered agents. 0115 The compounds of this invention may be adminis under condensation conditions, to form the compound of tered to mammals, typically humans, either alone or, in com Formula I. Examples of a thiation agent include, but are not bination with pharmaceutically acceptable carriers or dilu limited to, phosphorus pentasulfide or Lawesson's reagent. In ents, optionally with known adjuvants, such as alum, in a specific embodiments, the above-identified synthetic method pharmaceutical composition, according to standard pharma can be used when “n” is 0 or 1; more typically, when “n” is 1. ceutical practice. The compounds can be administered orally 0105. The compounds of the present invention are useful or parenterally, including the intravenous, intramuscular, in the treatment of cancer. High levels of activity for in vitro intraperitoneal, and Subcutaneous routes of administration. and in vivo testing have been observed against cancers and 0116. As noted, compounds of the present invention may cancer models using the compounds of the present invention. be administered orally unlike most current cancer therapies, This may lead to reduced dosages as compared with conven which are administered intravenously. For oral use of a com tional therapeutic dosages of known agents. pound or composition according to this invention, the 0106 The cancer treated may be, for example, lung can selected compound may be administered, for example, in the cer, cervical cancer, ovarian cancer, cancer of CNS, skin form of tablets or capsules, or as an aqueous Solution or cancer, prostate cancer, sarcoma, breast cancer, leukemia, Suspension. In the case of tablets for oral use, carriers which colorectal cancer, head cancer, neck cancer or kidney cancer. are commonly used include lactose and corn starch, and lubri More typically, the cancer may be small cell lung cancer, cating agents, such as magnesium Stearate, are commonly breast cancer, acute leukemia, chronic leukemia, colorectal added. For oral administration in capsule form, useful dilu cancer, or brain cancer. The cancer may be a carcinoma. The ents include lactose and dried corn starch. When aqueous US 2012/0077.820 A1 Mar. 29, 2012

Suspensions are required for oral use, the active ingredient is I0123 “Cytotoxic agents’ refer to compounds which cause combined with emulsifying and Suspending agents. If cell death primarily by interfering directly with the cell's desired, certain Sweetening and/or flavoring agents may be functioning or inhibit or interfere with cell myosis, including added. For intramuscular, intraperitoneal, Subcutaneous and alkylating agents, tumor necrosis factors, intercalators, intravenous use, Sterile Solutions of the active ingredient are microtubulin inhibitors, and topoisomerase inhibitors. usually prepared, and the pH of the solutions should be suit 0.124 Examples of cytotoxic agents include, but are not ably adjusted and buffered. For intravenous use, the total limited thereto, cyclophosphamide ifosfamide, hexameth concentration of solutes should be controlled in order to ren ylmelamine, tirapazimine, sertenef, cachectin, ifosfamide, der the preparation isotonic. tasonermin, lonidamine, carboplatin, mitomycin, altre tamine, prednimustine, dibromodulcitol, ranimustine, fote 0117. At least about 50% of the compound of the present mustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, invention can be orally absorbed by a mammal. In specific estramustine, improSulfan tosilate, trofosfamide, nimustine, embodiments, at least about 60%; about 60% to about 85%; dibrospidium chloride, pumitepa, lobaplatin, satraplatin, pro about 65%; about 70%; about 72%; about 73%, about 75%: firomycin, cisplatin, irofulven, dexifosfamide, cis about 80%; about 82%; or about 85% of the compound of the aminedichloro(2-methyl-pyridine) platinum, benzylguanine, present invention can be orally absorbed by a mammal, more glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane typically, a human. “Oral absorption' is used in the context of 1,6-diamine)-mu-diamine-platinum(II)bis diamine how the compound/composition of the present invention are (chloro)-platinum (II) tetrachloride, diarizidinylspermine, delivered and absorbed into the blood. Typically, the com arsenic trioxide, 1-(11-dodecylamino-10-hydroxyundecyl)- pound/composition is administered orally and crosses a 3,7-dimethylxanthine, Zorubicin, idarubicin, daunorubicin, mucosal membrane of the gastro-intestinal tract, typically in bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, the intestines. However, other methods of contacting the com amrubicin, antineoplaston, 3'-deamino-3'-morpholino-1-13 pounds/compositions of the present invention with the deoxo-10-hydroxycaminomycin, annamycin, galarubicin, mucosal membrane of the gastro-intestinal tract may also be elinafide, MEN10755, and 4-demethoxy-3-deamino-3-aziri used. dinyl-4-methylsulphonyl-daunor-ubicin (see International 0118. The compounds of the present invention may also be Patent Application No. WO 00/50032). combined and/or co-administered with other therapeutic 0.125 Examples of microtubulin inhibitors include pacli agents that are selected for their particular usefulness against taxel (Taxol.R.), vindesine sulfate, 3',4'-didehydro-4'-deoxy the cancer that is being treated. For example, the compounds 8'-norvincaleukoblastine, docetaxel, rhizoxin, dolastatin, of the present invention may be combined and/or co-admin mivobulin isethionate, auristatin, cemadotin, RPR109881, istered with anti-cancer agent(s). BMS184476, Vinflunine, cryptophycin, 2,3,4,5,6-pen 0119 Examples of anti-cancer agents include, without tafluoro-N-(-3-fluoro-4-methoxyphenyl)benzene sulfona being limited thereto, the following: estrogen receptor modu mide, anhydrovinblastine, N,N-dimethyl-L-valyl-L-valyl-N- lators, androgen receptor modulators, retinoid receptor methyl-L-valyl-L-prolyl-L-proline-t-butylamide, TDX258, modulators, cytotoxic agents, antiproliferative agents, and BMS1887.97. tyrosine kinase inhibitors, prenyl-protein transferase inhibi 0.126 Some examples of topoisomerase inhibitors are tors, HMG-CoA reductase inhibitors, HIV protease inhibi topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypro tors, reverse transcriptase inhibitors, other angiogenesis pionyl-3',4'-O-exo-benzylidene-chartreusin, 9-methoxy-N, inhibitors and combinations thereof. The present compounds N-dimethyl-5-nitropyrazolo 3,4,5-klacridine-1-2-(6H)pro may also be useful with other therapies such as when co panamine, 1-amino-9-ethyl-5-fluoro-2,3-dihydro-9- administered with radiation therapy. hydroxy-4-methyl-1-1H, 12H benzodelpyrano.3',4':b.7 0120 “Estrogen receptor modulators’ refers to com indolizino 1.2bquinoline-10,13(9H, 15H) dione, lurtotecan, pounds which interfere or inhibit the binding of estrogen to 7-2-(N-isopropylamino)ethyl-(20S)camptothecin, the receptor, regardless of mechanism. Examples of estrogen BNP1350, BNPI1100, BN80915, BN80942, etoposide phos receptor modulators include, but are not limited thereto, phate, teniposide, Sobuzoxane, 2-dimethylamino-2'-deoxy tamoxifen, raloxifene, idoxifene, LY353381, LY117081, etoposide, GL331, N-2-(dimethylamino)ethyl-9-hydroxy toremifene, fulvestrant, 4-7-(2,2-dimethyl-1-oxopropoxy 5,6-dimethyl-6H-pyrido4.3-bcarbazo-le-1-carboxamide, 4-methyl-2-4-2-(1-piperidinyl)ethoxyphenyl-2H-1-ben asulacrine, (5a.5aB,8aa,9b)-9-2-N-2-(dimethylamino)- Zopyran-3-yl-phenyl-2,2-dimethylpropanoate, 4,4'-dihy ethyl-N-methylaminoethyl-5-4-Hydroxy-3,5-dimethox droxybenzophenone-2,4-dinitrophenyl-hydrazone, and yphenyl-5.5a,6,8.8a.-9-hexohydrofuro(3',4':6.7)naphtho(2. SH646. 3-d)-1,3-dioxol-6-one, 2.3-(methylenedioxy)-5-methyl-7- 0121 “Androgen receptor modulators' refers to com hydroxy-8-methoxybenzoc-phenanthridiniu-m, 6.9-bis(2- pounds which interfere or inhibit the binding of androgens to aminoethyl)aminobenzoglisoquinoline-5,10-dione, 5-(3- the receptor, regardless of mechanism. Examples of androgen aminopropylamino)-7.10-dihydroxy-2-(2- receptor modulators include finasteride and other 5C.-reduc hydroxyethylaminomethyl)-6H-py-razolo 4,5,1-delacridin tase inhibitors, nilutamide, flutamide, bicalutamide, liaro 6-one, N-1-2(diethylamino)ethylamino-7-methoxy-9- Zole, and abiraterone acetate. oxo-9H-thioxanthen-4-ylmethylformamide, N-(2- 0122) “Retinoid receptor modulators' refers to com (dimethylamino)ethyl)acrid-ine-4-carboxamide, 6-2- pounds which interfere or inhibit the binding of retinoids to (dimethylamino)ethylamino-3-hydroxy-7H-indeno.2-, 1 the receptor, regardless of mechanism. Examples of Such cquinolin-7-one, and dimeSna. retinoid receptor modulators include beXarotene, tretinoin, (O127 “Antiproliferative agents” includes BCNU, anti 13-cis-retinoic acid, 9-cis-retinoic acid, C.-difluoromethylo sense RNA and DNA oligonucleotides such as G3139, mithine, ILX23-7553, trans-N-(4-hydroxyphenyl) retina ODN698, RVASKRAS, GEM231, and INX3001, and anti mide and N-4-carboxyphenyl retinamide. metabolites Such as floXuridine, enocitabine, carmofur, US 2012/0077.820 A1 Mar. 29, 2012 tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, 0.133 When a compound according to this invention is capecitabine, galocitabine, cytarabine ocfosfate, fosteabine administered into a human Subject, the daily dosage will Sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, normally be determined by the prescribing physician with the decitabine, nolatrexed, pemetrexed, nelZarabine, 2'-deoxy-2'- dosage generally varying according to the age, weight, and methylidenecytidine, 2'-fluoromethylene-2'-deoxy-cytidine, response of the individual patient, as well as the severity of the N-5-(2,3-dihydro-benzofuryl)sulfonyl-N'-(3,4-dichlo patient's symptoms. rophenyl)urea, N6-4-deoxy-4-N2-2(E),4(E)-tetradecadi I0134. In one exemplary application, a suitable amount of enoylglycylamino-L-glycer-o-B-L-manno-heptopyrano compound is administered to a mammal undergoing treat sylladenine, aplidine, ecteinascidin, troxacitabine, 4-2- ment for cancer. Administration occurs in an amount from amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino.54-b1,4 about 0.01 mg/kg of body weight to greater than about 100 thiazin-6-yl-(S)-ethyl-2,5-thienoyl-L-glutamic acid, mg/kg of body weight per day; from about 0.01 mg/kg of aminopterin, 5-fluorouracil, alanosine, 11-acetyl-8-(carbam body weight to about 500 mg/kg of body weight per day; from oyloxymethyl)-4-formyl-6-methoxy-14-Oxa-1,1-diazatetra about 0.01 mg/kg of body weight to about 250 mg/kg of body cyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, weight per day; or 0.01 mg/kg of body weight to about 100 Swainsonine, lometrexol, dexraZoxane, methioninase, 2'-cy mg/kg of body weight per day. These dosages can be more ano-2'-deoxy-N4-palmitoyl-1-B-D-arabino furanosyl particularly used orally. cytosine, and 3-aminopyridine-2-carboxaldehyde thiosemi 0.135 The compounds of this invention may be prepared carbazone. by employing reactions and standard manipulations that are 012.8 “Antiproliferative agents' also includes monoclonal known in the literature or exemplified herein. antibodies to growth factors, other than those listed under 0.136. When introducing elements disclosed herein, the “angiogenesis inhibitors'. Such as trastuzumab, and tumor articles “a”, “an', “the’, and "said are intended to mean that Suppressor genes, such as p53, which can be delivered via there are one or more of the elements. recombinant virus-mediated gene transfer (see U.S. Pat. No. 0.137 The above disclosure generally describes the 6,069,134, for example). present invention. A more complete understanding can be 0129. Some specific examples of tyrosine kinase inhibi obtained by reference to the following specific Examples. tors include N-(trifluoromethylphenyl)-5-methylisoxazol-4- These Examples are described solely for purposes of illustra carboxamide, 3-(2,4-dimethylpyrrol-5-yl)methylidenyl)in tion and are not intended to limit the scope of the invention. dolin-2-one, 17-(allylamino)-17-demethoxygeldanamycin, Changes in form and Substitution of equivalents are contem 4-(3-chloro-4-fluorophenylamino-)-7-methoxy-6-3-(4- plated as circumstances may suggest or render expedient. morpholinyl)propoxyl-quinazoline, N-(3-ethynylphenyl)-6, Although specific terms have been employed herein, Such 7-bis(2-methoxyethoxy)-4-quinazolinamine, 2.3,9,10,11. terms are intended in a descriptive sense and not for purposes 12-hexahydro-10-(hydroxymethyl)-10-hydroxy-9-methyl-9, of limitation. 12-epoxy-1H-diindolo 1,2,3-fg:3'2", 1'-klpyrrolo3.4-i1, 6 benzodiazocin-1-one, SH1382, genistein, 4-(3- chlorophenylamino)-5,6-dimethyl-7H-pyrrolo2,3-d EXAMPLES pyrimidinemethane Sulfonate, 4-(3-bromo-4- hydroxyphenyl)-amino-6,7-dimethoxyquinazoline, 4-(4- Synthesis of COTI-2 hydroxyphenyl)amino-6,7-dimethoxyquinazoline, N-4- 0.138. The synthesis of COTI-2, as depicted above, was chlorophenyl-4-(4-pyridylmethyl)-1-phthalazinamine, and conducted according to the following synthetic methodology: Tarceva R (erlotinib). 0130. If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described below and the other pharmaceutically active agent(s) within its approved dosage range. Compounds 1. NS of the present invention may alternatively be used sequen tially with known pharmaceutically acceptable agent(s) when a combination formulation is inappropriate. (C) O-() 0131 The term “administration” (e.g., “administering a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the com pound into the system of the animal in need of treatment. | When a compound of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), “administration' and its variants N l N N are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents. 0132) The term “treating cancer or “treatment of cancer' l refers to administration to a mammal afflicted with a cancer ous condition and refers to an effect that alleviates the can cerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis in-Ni. of the cancer. US 2012/0077.820 A1 Mar. 29, 2012 11

-continued -continued S r ls.-N1 N N N

21 2 COTI-2

0141 Finally, COTI-2 was formed as follows. 1-N-(2- pyridyl)-piperazine)-carbothioic acid hydrazide (MW 237. 33, 0.475g, 2.0 mmol. 1 eq) 4 and 6,7-dihydro-5H-quinolin 0.139. Imidazol-1-yl-(4-pyridin-2-yl-piperazin-1-yl)- 8-one (MW 147.18, 0.306 g, 2.0 mmol. 1 eq) 5 was dissolved methanethione (or intermediate 3 above) was formed as fol in 15 ml of ethanol at room temperature. The mixture was lows. N-(2-pyridyl)piperazine (MW 163.22, 0.91 ml, 6.0 then stirred under reflux for 20 hours. A yellow solid precipi mmoles, 1 eq) 2 was added to a solution of 1,1'-thiocarbon tated out of the solution. This solid was filtered off then rinsed yldiimidazole (MW 178.22, 1.069 g, 6.0 mmoles, 1 eq) 1 in with methanol and diethyl ether to yield COTI-2 (MW 366. 50 ml of dichloromethane at room temperature. The reaction 48, 0.60 g, 1.64 mmol. 82% yield) as a yellow solid. TLC mixture was stirred overnight at room temperature. The mix (CHC1/MeOH: 95/5); Rf-0.75, Product UV and Ninhy ture was washed with water, dried over sodium sulfate, fil drine stain active. HPLC analysis showed a mixture of iso tered and concentrated to provide imidazol-1-yl-(4-pyridin mers (approximately in 80/20 ratio), and >98% purity. During 2-yl-piperazin-1-yl)-methanethione (MW 273.36, 1.354 g. the HPLC Method Development, as expected, this product tends to be hydrolyzed in presence of TFA in mobile phase 4.95 mmol, 83% yield) 3, which was used without further solution. MS (ESI+, 0.025% TFA in 50/50 MeOH/HO): purification. TLC (CHC1/MeoH: 95/5): Rf 0.60, Product M+H=367.1, M+Na'-389.1; "H-NMR (400 MHz, UV and Ninhydrin stain active." H-NMR (400 MHz, CDC1), CDC1), 6 ppm (Major isomer): 2.09 (m. 2H), 2.92 (m, 4H), 8 ppm: 3.72 (s, 4H), 4.02 (s, 4H), 6.67 (d. 1H, J–7 Hz), 6.72 3.67 (m, 4H), 4.27 (m, 4H), 6.69 (dd. 1H, J–8 and 5 Hz), 7.25 (dd. 1H, J–7 and 5 Hz), 7.11 (s, 1H), 7.24 (s, 1H), 7.54 (t, 1H, (dd. 1H, J=8 and 5 Hz), 7.55 (d. 2H, J=8 Hz), 8.23 (d. 1H, J=5 J=7 Hz), 7.91 (s, 1H), 8.20 (d. 1H, J=5 Hz). Hz), 8.63 (d. 1H, J=5 Hz), 14.76 (s, 1H). 8 ppm (Minor 0140 Hydrazine hydrate (MW 50.06, 0.26 ml, 5.44 isomer): 2.09 (m, 2H), 3.14 (t, 4H, J=6Hz), 3.80 (m, 4H), 4.27 mmoles, 1.1 eq) was added to a solution of imidazol-1-yl-(4- (m, 4H), 6.66 (m, 1H), 7.31 (dd. 1H, J=8 and 5 Hz), 7.52 (m, pyridin-2-yl-piperazin-1-yl)-methanethione 3 (MW 210.30, 1H), 7.70 (d. 1H, J=8 Hz), 8.23 (d. 1H, J=5 Hz), 8.53 (d. 1H, 1.040 g, 4.95 mmol. 1 eq) in 30 ml of ethanol at room tem J=5 Hz), 15.65 (s, 1H). perature. The reaction mixture was stirred under reflux for 2 Synthesis of COTI-219 hours. A white precipitate formed. This white solid was fil tered off and rinsed with diethyl ether to yield 1-N-(2-py 0142. The synthesis of COTI-219, as depicted above, was ridyl)-piperazine)-carbothioic acid hydrazide (MW 237.33, conducted according to the following synthetic methodology: 0.86 g, 3.62 mmol. 73% yield) 4 as a white solid, and used without further purification. TLC (CH.Cl/MeOH: 95/5): Rf 0.20, Product UV and Ninhydrin stain active. 'H-NMR (400 MHz, DMSO-d), 6 ppm. 3.53 (s, 4H), 3.85 (s, 4H), 6.66 (dd. 1H, J=8 and 5 Hz), 6.82 (d. 1H, J=8 Hz), 7.55 (t, 1H, J=8 Hz), 8.12 (d. 1H, J=5 Hz). C ty -- IO-ch

S ls NH2 r NH N | N Nu -- 2N

2N O

EtOH Reflux, 20 h US 2012/0077.820 A1 Mar. 29, 2012 12

0144) 1-(N-Methyl piperazine)-carbothioic acid -continued hydrazide (or intermediate 8 above) was formed as follows. Hydrazine hydrate (MW 50.06, 0.26 ml, 5.44 mmol. 1.1 eq) was added to a solution of imidazol-1-yl-(4-methyl-piper azin-1-yl)-methanethione 7 (MW 210.30, 1.040 g, 4.95 mmol. 1 eq) in 30 ml of ethanol at room temperature. The reaction mixture was stirred under reflux for 2 hours. This mixture was concentrated. The solid thus obtained was tritu 0143. Imidazol-1-yl-(4-methyl-piperazin-1-yl)-meth rated with diethyl ether and filtered to yield 1-(N-Methyl anethione (or intermediate 7 above) was formed as follows. piperazine)-carbothioic acid hydrazide (MW 174.27, 0.53 g, N-Methylpiperazine (MW 100.16, 0.67 ml, 6.0 mmol. 1 eq) 3.04 mmol. 61% yield) 8 as a white solid which was used 6 was added to a solution of 1,1'-thiocarbonyldiimidazole (MW 178.22, 1.069 g, 6.0 mmol. 1 eq) 1 in 50 ml of dichlo without further purification. TLC (CHC1/MeoH: 90/10): romethane at room temperature. The reaction mixture was Rf 0.15, Product UV and Ninhydrin stain active. 'H-NMR stirred overnight at room temperature. This mixture was (400 MHz, DMSO-d), 8 ppm: 2.17 (s.3H), 2.28 (t, 4H, J=5 washed with water, dried over sodium sulfate, filtered and Hz), 3.69 (t, 4H, J=5 Hz). concentrated to provide imidazol-1-yl-(4-methyl-piperazin 1-yl)-methanethione (MW 210.30, 1.040 g, 4.95 mmol, 82% (0145 Finally, COTI-219 was made as follows. 1-(N-Me yield) 7 and used without further purification. TLC (CH2Cl2/ thyl piperazine)-carbothioic acid hydrazide (MW 174.27, MeOH: 95/5): Rf 0.35, Product UV and Ninhydrine stain 0.174g, 1.0 mmol. 1 eq) 8 and 1,8-diazafluoren-9-one (MW active. 'H-NMR (400 MHz, CDC1), 6 ppm: 2.37 (s, 3H), 182.18, 0.182 g, 1.0 mmol. 1 eq) 9 was dissolved in 15 ml of 2.56 (s, 4H), 3.94 (s, 4H), 7.11 (s, 1H), 7.21 (s, 1H), 7.88 (s, ethanol at room temperature, in the presence of 1% glacial 1H). acetic acid (MW 60.05, 0.15 ml, 2.6 mmol. 2.6 eq). The mixture was stirred under reflux for 6 hours. After concentra tion, the crude thus obtained was taken up in dichlo romethane, washed with a potassium carbonate aqueous solu tion then with water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude was purified by ISCO CombiFlashTM Companion (RedisepTM cartridge 12g, Normal phase, Gradient DCM/MeOH: 10/0 to 9/1) and pro vided COTI-219 (MW 338.43, 0.330 g, 0.975 mmol, 98% yield) as a rust red solid. >95% purity by H-NMR. MS ESI+, 90/10 MeOH/HO (5 mM NHOAc, 0.2% Acetic acid): M+H=339.1, M+Nat=361.1; "H-NMR (400 MHz, CDC1), 8 ppm: 2.31 (s.3H), 2.56 (t, 4H, J=5 Hz), 4.17 (t, 4H, J=5 Hz), 7.23 (dd. 1H, J=8 and 5Hz), 7.31 (dd. 1H, J=8 and 5 Hz), 7.86 (d. 1H, J=8 Hz), 7.97 (d. 1H, J=8 Hz), 8.47 (d. 1H, J=5 Hz), 8.51 (d. 1H, J=5 Hz), 13.53 (s, 1H). Synthesis of COTI-5 COTI-219 0146 The synthesis of COTI-5, as depicted above, is con ducted according to the following synthetic methodology:

N-CH \ / -e- N N-CH H2O, Reflux o \ / HC 10 11 HN-NH EtOH US 2012/0077.820 A1 Mar. 29, 2012 13

-continued O N

HN-NH) ()-o \ /N-CH 12

0147 Intermediate 11 is formed by reacting compound 10 with potassium, permanganate under reflux conditions. Inter mediate 11 is reacted with hydrazine hydrate in ethanol to form intermediate 12.

O y \ N N-CH H2N-NH o V / 12 S N Lawesson's Reagent N-CH Dioxane H2N-NH 13

0148 Intermediate 12 is reacted with Lawesson's reagent in dioxane to form intermediate 13. -continued S

N N n NH

N r 2 N S N / \ 2 HC1 Nu 2 H2N-NH)-()- o \ /N-CH + O N COTI-5 13 5 0149 Finally, COTI-5 is formed as follows. Intermediate EtOH 13 and 6,7-dihydro-5H-quinolin-8-one 5 is dissolved in etha AcOH cat. nol at room temperature to yield COTI-5. Synthesis of COTI-5 0150. The synthesis of COTI-5, as depicted above, is con ducted according to the following synthetic methodology:

C N Chlorination -- N-CH hy / \ N N-CH \ / o \ / 14 4. Ss, TEA, DMF US 2012/0077.820 A1 Mar. 29, 2012 14

-continued CH3 / S N / \ N N-CH S o \ / 15 HN-NH EtOH

M HN y \ N N-CH S o V / 13

0151. Intermediate 14 is formed by irradiating compound pharmacology principles, statistical modeling and machine 10 in the presence of chlorine (the corresponding bromo learning technologies. At the centre of the CHEMSAS(R) plat compound of intermediate 14 can be formed using N-bromo form is a hybrid machine learning technology that may be Succinimide, benzyl peroxide in benzene). Intermediate 14 is used to: find, profile and optimize new targeted lead com reacted with Ss and methyl iodide in TEA and DMF pounds; find novel uses for known compounds; and, Solve (PhSO,Na, acetonitrile, PrNBr at 80° C. for 24 h or Ss. problems with existing or potential drugs. In using the t-BuOKat R.T., THF then methyl iodide may also be used) to CHEMSAS(R)platform, first a therapeutic target was selected, yield intermediate 15. Intermediate 15 is reacted with hydra in this case cancer and more particularly Small Cell Lung zine hydrate in ethanol to form intermediate 13. Cancer. The second step involved the design of a candidate molecule library containing thousands of potential com pounds through the assembly of privileged molecular frag n ments. Thirdly, the candidate library was profiled and opti S N mized using a combination of validated computational M V 2 models and traditional expert medicinal chemistry. In this ) ()- N-CH3 + N step, the CHEMSAS(R) platform developed 244 molecular HN-NH o \ / O descriptors for each candidate therapeutic compound. For 13 5 example, molecular properties relating to a candidate com EtOH pounds therapeutic efficacy, expected human toxicity, oral AcOH cat. absorption, cumulative cellular resistance and/or kinetics were assessed. In some instances, comparative properties S relating to commercially relevant benchmark compounds N N were also assessed. Potential lead compounds were then selected from the candidate library using a proprietary deci sion making tool designed to identify candidates with the C. NH n optimal physical chemical properties, efficacy, ADME/Tox r 2 N icity profile, etc. according to a pre-determined set of design criteria. The lead compounds selected from the candidate HC1 Nu 2 library were then synthesized for further pre-clinical devel COTI-5 opment. 0154 The properties of certain compounds according to the present invention, specifically COTI-217, COTI-220, 0152 Finally, COTI-5 is formed as follows. Intermediate COTI-219, COTI-2 and COTI-5, that were assessed in-silico 13 and 6,7-dihydro-5H-quinolin-8-one 5 is dissolved in etha using the CHEMSASR computational platform are shown in nol at room temperature to yield COTI-5. Tables 1 to 13. Some of the predicted properties are validated by the experimental data provided herein, while other prop Example 1 erties have been validated elsewhere during the development In-Silico Assessment of Properties of other clinical candidates. The CHEMSAS(R) platform therefore provides a means of determining, predicting and/or 0153. An in-silico assessment of the properties of com testing the properties of a compound, particularly when used pounds according to the present invention was performed to determine the properties of compounds according to the using the CHEMSASR computational platform. CHEM present invention. The CHEMSAS(R) platform is also particu SAS(R) is a robust proprietary computational platform for larly useful in comparing the properties of compounds accelerated drug discovery, optimization and lead selection according to the invention with prior art compounds on a based upon a unique combination of traditional and modern relative basis in silico. US 2012/0077.820 A1 Mar. 29, 2012

Tables 1A and 1B: Physical Chemical Properties O155 Tables 1A and 1B shows that COTI-217, COTI-220, COTI-219, COTI-2 and COTI-5 are “drug-like” with good drug like physical properties.

TABLE 1A

MoIID FORMULA MolWeight MnLogP HBnd Don HBndAcc

COTI217 C17H22N6S 342.469 1.8591.99 1 6 COTI220 C18H2ON6S 352.464 2.078432 1 6 COTI219 C17H18N6S 338.437 17646 1 6 COTI2 C19H22N6S 366.491 3.04.1311 1 6 COTIS C2OH24N6S 380.518 2.22023 1 6

TABLE 1B TABLE 2B MoIID TPSA RotBnds LipinskiAlerts Weber MoID FORMULA Acid pKa 2 Base pKa1 Base pKa 2 COTI217 37.5435 3 O O COTI217 C17H22N6S None 7.65056 None COTI220 53.3605 3 O O COTI220 C18H2ON6S None 7.65056 4.7.1559 COTI219 53.3605 3 O O COTI219 C17H18N6S None 7.65056 3.90 139 COTI2 53.3605 4 O O COTI2 C19H22N6S None 5.653.56 4.882592 COTIS 53.3605 4 O O COTIS C20H24N6S None 7.870707 S. 617688

Legend for Table 1: Legend for Table 2: 0156 MolWeight stands for Molecular Weight measured (0165 MnLogP is an average of MLogP, ALogP98 and in Daltons and is a size descriptor, CLogP, all of which are calculated lipophilicity/solubility (O157 MnLogP is an average of MLogP, ALogP98 and estimates; CLogP, all of which are calculated lipophilicity/solubility 0166 LogD (7.4) is a measure of relative solubility in estimates; octanol vs water at a specific pH, in this case pH-7.4: 0158 HBndDon stands for Hydrogen Bond Donor and refers to the number of atoms able to donate electrons to 0.167 LogS is the logarithm of the calculated solubility in potentially form Hydrogen bonds; pure water usually measured at 25 degrees centigrade; 0159 HBndAcc stands for Hydrogen Bond Acceptor and 0168 pKa is a calculated estimate of the pH at which the refers to the number of atoms able to accept electrons to drug or substructures of the drug is 50% ionized and 50% is potentially form Hydrogen bonds; unionized. (0160 TPSA stands for Topological Polar Surface Area and is a measure of Molecular Surface Charge/Polarity; Table 3: Efficacy (LogGI50) 0161 Rot3nds stands for Rotatable Bonds which is a (0169 Table 3 shows that COTI-217, COTI-220, COTI count of freely rotatable single bonds in the molecule: 219, COTI-2 and COTI-5 are predicted to have sub-micro 0162 Lipinski Alerts If any 2 of (Molecular weight-500 molar in vitro activity vs human SCLC cell lines. Actual Daltons, Hydrogen Bond Donors-5, Hydrogen Bond Accep measurements obtained in vitro confirm the prediction of tors 10, MLogP-4.15) are true, then a molecule is likely to activity at sub-micromolar levels for COTI-2 and COTI-219. have poor bioavailability; (0163 Veber Alerts: If TPSA>140 or number of Rotatable Bonds is >10, then bioavailability is likely to be poor. MoID FORMULA DMS114 SHP-77 Predicted Actual

Tables 2A and 2B: Solubility Properties COTI217 C17H22N6S <-6 <-6 Active ND COTI220 C18H2ON6S <-6 <-6 Active ND (0164. Tables 2A and 2B shows that COTI-217, COTI-220, COTI219 C17H18N6S <-6 <-6 Active Active COTI-219, COTI-2 and COTI-5 are expected to have accept COTI2 C19H22N6S <-6 <-6 Active Active able solubility values for drug-like compounds. COTIS C20H24N6S <-6 <-6 Active ND

TABLE 2A MoIID FORMULA MnLogP LogD (pH 7) LogS Legend for Table 3: COTI217 C17H22N6S 1.8591.99 O.309304 -3.09009 0170 DMS114 is a “classical human small cell lung can COTI220 C18H2ON6S 2.0.78432 O.99.2417 -42O136 cer line that is maintained by the National Cancer Institute in COTI219 C17H18N6S 1.7646 1.067558 -3.784O7 COTI2 C19H22N6S 3.04.1311 2.38O243 -452904 the United States: COTIS C2OH24N6S 2.22023 1.O19701 -449499 0171 SHP-77 is a “variant human small cell lung cancer line that is maintained by the National Cancer Institute in the United States: US 2012/0077.820 A1 Mar. 29, 2012 16

(0172 Predicted is the predicted in vitro Activity of the 0182 ClarkLogBBB is an estimate of a drugs penetration drug. of the blood brain barrier based on the drugs LogP and TPSA; 0173 Actual is the actual outcome of in vitro testing in 0183 SubKitLogBB is another estimate of a drugs pen both of the reference human Small cell lung cancer lines; etration of the blood brain barrier based on the drugs LogP 0.174 Active' refers to drugs with predicted or measured and TPSA: G150<1 umol/L: 0.184 LogBB: if LogBB <=-1 the drug does not pentrate 0175 ND means that the drug has not yet been tested in the BBB: if Log BBD0 there is likely to be good BB penetra vitro. tion; if -1

COTI217 O.918.625 -0.32584 2.280S 28 -0.09599 -0.22923 COTI22O O.26949 -0.24921 O.254967 -0.361.11 -0.20053 COTI219 O.331 -0.39022 O.551314 -0.39876 -0.31048 Legend for Table 5: COTI2 O.710661 -O.O1576 0.416152 -0.19558 -0.0185 0186 Liver Microsomes is the estimated percent remain COTIS O.O898.84 -0.0646 (O.3152O8 -0.37444 -0.05658 ing at 60 minutes after introduction of a dose of the drug into an in vitro/human liver microsomal enzyme system; 0187 Hepatocytes is the estimated percent remaining at Legend for Table 4: 60 minutes after introduction of a dose of the drug into an in (0177 Mn.% OrlAbs is the prediction of the mean percent vitro/human hepatocyte cellular system; oral absorption of the drug from an ensemble of 5-7 different 0188 T1/2 hrs is a calculated estimate of the halflife of the models; drug measured in hours; 95% C1 in Hrs is the calculated 95% 0.178 Min 96 Abs is the minimum value for the Min 96 confidence interval estimate of the half life of the drug mea OrlAbs at the lower 95% Confidence Interval: Sured in hours; (0179 HIA-T2(MD) is the Malanabois distance, which is a (0189 In vitro T1/2(Hrs) is the actual half life in hours measure of the calculated Statistical distance from the centre obtained from 3 in vitro experiments carried out at doses of 1 of a population of drugs with optimal oral absorption; umol, 10umol and 100 umol (in brackets). 0180 ProbBBBPene is an estimate of the probability that Table 6: Probability (CYP450 Isoenzyme Substrate) the drug will penetrate the blood brain barrier and enter the (0190. Table 6 shows that COTI-217, COTI-220, COTI central nervous system (CNS); 219, COTI-2 and COTI-5 are likely to be metabolized by the 0181 BBB-T2(MD) is the Malanabois distance, which is CYP450 enzyme system. COTI-217, COTI-220, COTI-219, a measure of the calculated Statistical distance from the centre COTI-2 and COTI-5 are expected to undergo at least some of a population of drugs with optimal blood brain barrier CYP3A457 metabolism and COTI-2 may also undergo some penetration; CYP2D6 metabolism.

MoIID FORMULA CYP1A2

COTI217 C17H22N6S 0.57 COTI220 C18H2ON6S O.O7 COTI219 C17H18N6S O.34 COTI2 C19H22N6S O.OS US 2012/0077.820 A1 Mar. 29, 2012 17

Legend for Table 6: 0191 Table 6 represents the estimated probabilities that the drug in question will undergo at least 20% of its phase 1 MoIID FORMULA ProbHepTox1 ProbHepTox2 metabolism by one or more of the 7 major isoenzyme forms of Cytochrome P450 (CYP450). The isoenzyme forms of CYP450 in Table 6 are: 1A2, 2B6, 2C8 or 9, 2C19, 2D6, 2E1 and 3A4, 5 or 7; these 7 isoenzyme forms account for >80% of phase 1 metabolism of all drugs that are orally adminis COTIS C2OH24N6S O.O99 O.252 tered to humans. The majority of all orally administered drugs are metabolized by the CYP3A family of isoenzymes. Table 7: Probability (CYP450 Iso Enzyme Inhibitor) Legend for Table 9: (0192 Table 7 shows that COTI-217, COTI-220, COTI (0197) ProbHepTox1 is the average calculated probability 219, COTI-2 and COTI-5 are not expected to significantly from an ensemble of models that the drug in question will inhibit any CYP450 isoenzyme. cause liver toxicity;

MoIID FORMULA CYP1A2 CYP2B6 CYP2C8/9 CYP2C19 CYP2D6 CYP2E1 CYP3A457

COTI220 C18H2ON6S O.09 O.O6 O.33 O.12 O.16 O.O6 O.12

COTIS C20H24N6S O.11 O.O6 O.23 O16 O.31 O.O7 0.37

Legend for Table 7: 0198 ProbHepTox2 is the average calculated probability from a second, different ensemble of models that the drug in (0193 Table 7 represents the estimated probabilities that question will cause liver toxicity. the drug in question will inhibit a given CYP isoenzyme activity by at least 20%; the isoenzyme forms of CYP450 in Table 10: Probability of P-glycoprotein Interaction table 7 are: 1A2, 2B6, 2C8 or 9, 2C19, 2D6, 2E1 and 3A4, 5 (0199 Table 10 shows that COTI-217, COTI-220, COTI or 7; these 7 isoenzyme forms account for >80% of phase 1 219, COTI-2 and COTI-5 are expected to inhibit P-glycopro metabolism of all drugs that are orally administered to tein (P-gp) enzyme activity. COTI-2 and COTI-5 may also be humans. substrates for P-gp, whereas COTI-219 is relatively unlikely to be a Substrate for P-gp. P-gp is a protein expressed by many Table 8: Probability (CYP450 Iso Enzyme Inducer) cancer cells and is felt to contribute to cellular resistance to many cancer drugs. Ideally, an effective cancer drug would 0194 Table 8 shows that COTI-217, COTI-220, COTI either not be a substrate for P-gp or would inhibit P-gp activ 219, COTI-2 and COTI-5 are not expected to induce any of ity, thereby reducing the likelihood of P-gp related drug resis the CYP450 isoenzymes. tance.

MoIID FORMULA CYP1A2 CYP2B6 CYP2C8/9 CYP2C19 CYP2D6 CYP2E1 CYP3A457

COTI217 C17H22N6S O.O6 O.OS O.OS O.OS O.OS O.OS O.OS COTI220 C18H2ON6S O.23 O.OS O.OS O.OS O.OS O.OS O.OS COTI219 C17H18N6S O.O6 O.OS O.OS O.OS O.OS O.OS O.O7 COTI2 C19H22N6S O.O7 O.OS O.OS O.OS O.OS O.OS O.09 COTIS C20H24N6S O.O7 O.OS O.OS O.OS O.OS O.OS O.O7

Legend for Table 8: (0195 Table 8 represents the estimated probabilities that the drug in question will induce a given CYP isoenzyme activity by at least 20%. The isoenzyme forms of CYP450 in MoIID FORMULA Substrate Inhibitor table 8 are: 1A2, 2B6, 2C8 or 9, 2C19, 2D6, 2E1 and 3A4, 5 or 7; these 7 isoenzyme forms account for >80% of phase 1 COTI217 C17H22N6S 0.57 O.81 metabolism of all drugs that are orally administered to humans. COTI220 C18H2ON6S O.62 O.87 COTI219 C17H18N6S O.19 0.75 Table 9: Probability of any Hepatic Toxicity COTI2 C19H22N6S 0.79 O.9 0196) Table 9 shows that COTI-217, COTI-220, COTI COTIS C2OH24N6S O.82 O.9 219, COTI-2 and COTI-5 are not expected to cause Hepatic Toxicity. US 2012/0077.820 A1 Mar. 29, 2012

Legend for Table 10: 0210 ProblC50>1 umol is the calculated probability that the IC50 for the drug with regards to the hERG potassium 0200 Table 10 represents the calculated probabilities channel is greater than 1 Jumol/L. from an ensemble of models that the drug in question will 0211 ProblC50>10umol is the calculated probability that interact with P-glycoprotein (P-gp) as a substrate or inhibitor. the IC50 for the drug with regards to the hERG potassium Table 11: Animal and Human Toxicity Predictions channel is greater than 10 umol/L.; 0201 Table 11 shows that COTI-217, COTI-220, COTI Table 13: Predicted Genotoxicity 219, COTI-2 and COTI-5 are expected to have low to mod erate acute toxicity as measured by LD50 when given by the 0212 Table 13 shows that COTI-2 and 219 are expected to oral and intraperitoneal route. have a negative AMES test and that COTI-217, COTI-220,

Lower Lower ORL- IPR- IPR MRTD MRTD MolID FORMULA ORL-LD50 LD50 LD50 LD50 mg/kg/day mg day COTI217 C17H22N6S 609.7 1928 139.6 44.2 2 12O.S COTI220 C18H2ON6S 76.1.1 240.7 175.5 55.5 1.3 79.9 COTI219 C17H18N6S 1022 323.2 227.8 72 1.2 704 COTI2 C19H22N6S 842.8 266.S 1953 61.8 1.6 99 COTIS C20H24N6S 773.9 244.7 151.S. 47.9 1.1 67

Legend for Table 11: COTI-219, COTI-2 and COTI-5 are not expected to cause 0202) ORL-LD50 is the calculated point estimate of the Polyploidicity in the Guinea Pig cell model. dose of the drug in mg/kg that would cause death in 50% of healthy test lab rats when the drug is given orally; 0203 LowerORL-LD50 is the calculated lower 95% con fidence interval point estimate of the dose of the drug in MoIID FORMULA ProbAMES- PolyPldy mg/kg that would cause death in 50% of healthy test lab rats COTI217 C17H22N6S O.94 O.15 when the drug is given orally; COTI220 C18H2ON6S O.O6 O16 0204 IPR-LD50 is the calculated point estimate of the COTI219 C17H18N6S O.O6 O.15 dose of the drug in mg/kg that would cause death in 50% of COTI2 C19H22N6S O.O6 O16 healthy test lab mice when the drug is given intraperitoneally; COTIS C2OH24N6S O.O6 O.23 0205 LowerORL-LD50 is the calculated lower 95% con fidence interval point estimate of the dose of the drug in mg/kg that would cause death in 50% of healthy test lab mice when the drug is given intraperitoneally; Legend for Table 13: 0206 MRTDmg/kg/day is the calculated maximum rec ommended therapeutic daily dose of the drug in milligrams 0213 ProbAMES+ is the probability that the drug will per kg per day for the average 60 Kg human adult; induce a recognized gene mutation in a standard strain of 0207 MRTDmg/day is the calculated maximum recom cultured bacteria; mended therapeutic daily dose of the drug in milligrams per 0214 PolyPldy is the probability that the drug will induce day for the average 60 Kg human adult. polyploidicity (i.e. an increased/abnormal number of chro Table 12: Predicted hERG Interaction mosomes) in cultured guinea pig cells. 0208 Table 12 shows that COTI-217, COTI-220, COTI 219, COTI-2 and COTI-5 are expected to have hERG IC50 Example 2 values of 1 Limol/l in keeping with a decreased risk of cardiac toxicity. In general, a hERG IC50 of <1 umol/L would be In Vitro Efficacy Against Various Cancer Cell Lines associated with an increased probability of potential drug induced cardiac toxicity. 0215. To assess the efficacy of compounds according to the present invention in the treatment of cancer, in vitro activ ity expressed as IC50 (represents the concentration of an inhibitor that is required for 50% inhibition of its target, in IC50 nmol) was measured for several cancer cell lines using stan MoIID FORMULA (Imol) ProblC50 > 1 Imol ProblC50 > 10 dard methods for such tests known to persons skilled in the COTI217 C17H22N6S 2.6 O.88 O.O6 art. Briefly, cells were plated in plastic tissue culture plates COTI220 C18H2ON6S 1.8 O.9 O.O3 and grown under standard conditions for each cell line, in COTI219 C17H18N6S 2.2 O.92 O.04 carbon dioxide/oxygen atmosphere in plastic tissue culture COTI2 C19H22N6S 1.6 O.92 O.O2 plates, in the presence of COTI-2 or COTI-219 compounds at COTIS C2OH24N6S O6 0.79 O.04 35° C. for 3 days. Control cultures were treated with vehicle minus compound. Cells were counted after 3 days in culture and at a cell density of no more than 80%. The following cell Legend for Table 12: lines, obtained from the National Cancer Institute, were 0209 IC50 (umol) is the calculated concentration of the tested: human SCLC cell lines DMS 153, DMS114, SHP77: drug that inhibits 50% of the activity of the hERG potassium human NSCLC cell lines H226, A460, A560; human breast channel and is an estimate of potential cardiac toxicity; cancer cell lines T47D, MCF7; human colon cancer cell line US 2012/0077.820 A1 Mar. 29, 2012

HT29; and, human Leukemia cell lines K562, HL60. The mm and those treated with TaxotereR, which produced results of these assays are presented in Table 14. tumors having mean volume 183 mm. Animals treated with Tarceva R died before study conclusion at 31 days. TABLE 1.4 0219 Referring to FIG. 2, compounds according to the invention showed a marked decrease in number of tumors as in vitro IC50 against cancer cell lines compared with both the control and conventional agents. COTI-219 ICSO Control animals produced an average of 0.9 tumors per injec Cell Line Tumor Type COTI-2 IC50 (nM) (nM) tion site, whereas those treated with COTI-2 produced 0.28. SHP77 SCLC 156 +/- 8 787+f- 61 those treated with COTI-219 produced 0.38, those treated DMS153 SCLC 73+f-9 233 +f-39 with CisplatinR produced 0.48 and those treated with Taxo DMS114 SCLC 51 +f-9 267 +/- 40 tere?R) produced 0.48. Animals treated with Tarceva(R) died H226 NSCLC 15000+f-1129 Not tested A460 NSCLC 7900 +f- 620 Not tested before study conclusion at 31 days. A549 NSCLC 6300+f- 671 Not tested 0220. The above data show the efficacy of compounds T47D Breast Cancer 221 +/- 12 367 +/- 44 according to the invention in Vivo against SCLC cell lines. MCF7 Breast Cancer 101 +/- 8 421 +f- 31 Furthermore, compounds according to the invention show HT29 Colorectal Cancer 121 +f-11 403 +f-32 KS 62 Leukemia 176 +/- 22 222 +/- 28 better efficacy compared to conventionally administered HL60 Leukemia 236 +/- 9 374 +/- 46 therapeutic agents.

0216 Table 14 shows that both COTI-2 and COTI-219 Example 4 possess potent activity in the low nanomolar range against SCLC tumor cell types, as well as several other tumor cell In Vivo Effect of COTI-2 in SCLC Treatment on types such as breast cancer, colorectal cancer and Leukemia. N417 Tumor xenografts Both drugs had an IC50 of less than 850 nM for the SHP77 cell line, which is known to be resistant to several conven 0221 Malignant N417 human SCLC cells in MatrigeITM tional therapeutic agents. COTI-2 did not possess nanomolar were injected Subcutaneously into hind legs of nude mice and level activity against NSCLC cell types and COTI-219 was xenograft tumors were allowed to grow to about 100 mm. not tested against those cell types. At least COTI-2 therefore Mice were then administered daily intraperitoneal injections exhibits selectivity in lung cancer treatment towards SCLC with indicated concentrations of COTI-2 (in isotonic saline, cell types. The in vitro data also confirms the in-silico pre as a cloudy liquid, total volume of 1 ml per injection) for one dictions of efficacy, which estimated that less than 1 uM week. Tumor Volumes were estimated by caliper measure (1000 nM) would be required for efficacy in the SHP 77 and ment. The results are shown in FIG. 3. DMS 114 cell lines. 0222 Referring to FIG.3, tumor volumes were graphed as meansistandard error (SE). Example 3 0223) A significant difference in tumor growth was observed at all dosage levels. The decrease in efficacy seen at In Vivo Efficacy in SCLC Treatment the 8 mg/kg level relative to other treatment levels is attrib uted to an error in solubilizing the compound, since a small 0217. The nude mouse model of human SCLC was used to amount ofundissolved material was observed at the bottom of evaluate the in vivo efficacy of compounds of the present the treatment vial. Percentage values reported on FIG. 3 are invention in comparison with several known chemotherapeu for efficacy of the compound expressed in terms of inhibition tic agents. Nude mice were obtained form the National Can of tumor growth according to the following formula: cer Institute and the SHP-77 human SCLC cell line was chosen for metastatic tumor Xenografts. The control group consisted of 10 animals, each of which were administered wherein Tf is the final tumor volume, Ti is the initial tumor bilateral thigh injections of a prescribed volume of tumor Volume at the onset of treatment, Cfis the final control tumor cells. There were 6 treatment groups, each containing 5 ani Volume and Ci is the initial control tumor volume at the onset mals: COTI-2, COTI-4, COTI-219, TaxotereR (docetaxel), Cisplatin R. (cis-diamminedichloroplatinum) and Tarceva(R) of treatment. Even when the 8 mg/kg dose is included, tumor (erlotinib) The therapeutic agent was administered by intra growth inhibition of 30% or more was observed across all peritoneal (IP) injection on alternate days beginning on Day 3 dosage levels. It is noted that the N417 cell line is generally post tumor cell injection. Each animal in a treatment group regarded as the hardest SCLC cell line to treat. The com was administered bilateral thigh injections with the same pounds according to the invention therefore exhibit in vivo prescribed Volume of tumor cells as the control animals. efficacy against a number of different SCLC cell lines. Treatment continued for 31 days, following which the ani mals were euthanized and tissues were collected for subse Example 5 quent analysis. The final tumor size in mm is reported in FIG. 1 and the number of tumors is reported in FIG. 2. Resistance Testing 0218. Referring to FIG. 1, compounds according to the invention showed a marked decrease in tumor growth as 0224. In order to evaluate the induction of resistance in compared with both the control and conventional agents. vitro, compounds according to the invention were tested in Control animals produced tumors having a mean Volume of head to head comparisons against conventional therapeutic 260+/-33 mm. Animals treated with COTI-2 produced agents CisplatinRand TaxotereR). The compound designated tumors of mean volume 9.9 mm, while those treated with COTI-4 (which is the subject of Applicant’s co-pending U.S. COTI-219 produced tumors having mean volume 53+/-28 provisional patent application entitled “Composition and mm. This compared well with those treated with Cisplatin R, Method for Treatment” filed Dec. 26, 2007) was also tested. which produced tumors having means Volume 132+/-26 The structure for COTI-4 is: US 2012/0077.820 A1 Mar. 29, 2012 20

concentrations ranging from those that had no effect on pro liferation to those that inhibited proliferation by 90% or more. COTI-4 A viability stain (alamar Blue) was added to cells after 4-7 days of drug exposure (approximately 4 doublings of control cells; maximum cell density in wells approximately 80%), and assayed for total cellular metabolic activity (a function of population density of live cells) by absorbance. Concentra tions of the agent required to inhibit proliferation by 50% (IC50 value) were derived by interpolation of plotted data (mean values derived from 3 independent experiments itstan dard error). Results are reported in Table 15. TABLE 1.5 0225 IC50 values were obtained using methods known to persons skilled in the art with two different human SCLC cell IC50 values for Human Glioma/Astrocytoma cell Lines lines (DMS153 and SHP77) obtained from the National Can cer Institute. The surviving 50% of cells from the initial IC50 COTI-2 COTI-219 Cisplatin BCNU tested were harvested and cultured for 5 days, after which Cell Line (nM) (nM) (nM) (nM) time this new generation of cells was re-treated with the same U87 48 +f-9 2370 +f- 490 +f- 9 1520 + - 130 agent and a new IC50 value was established. The procedure SNB-19 8 +/- 3 1990 +f- 870+f- 40 2250+- 700 was repeated for a total of 5 generations. Emerging resistance SF-268 66 +/- 8 1170 +f- Not tested Not tested was identified by increasing IC50 values in Successive gen SF-295 184 +/- 23 2390 +f- Not tested Not tested erations. The results are shown in FIGS. 4 and 5 (DMS153 and SHP77 cell lines, respectively), where the ordinate axis is provided in terms of the ratio of the IC50 value to the IC50 0229. At least the COTI-2 compounds were shown to have value of the parental generation. better efficacy against glioma/astrocytoma cell lines as com 0226 Referring to FIGS. 4 and 5, both COTI-2 and 219 pared with the conventional agents CisplatinR and BCNU. exhibited little to no emerging resistance over 5 generations. COTI-2 showed an order of magnitude greater efficacy than This was in marked contrast to the conventional therapies Cisplatin R against U87 and two orders of magnitude greater CisplatinR and TaxotereR (labeled Paclitaxel in the figures), efficacy against SNB-19. These results show that at least which showed significant increases in IC50 for both cell lines. COTI-2 compounds have efficacy against glioma?astrocy The SHP77 cell line in particular is known to be resistant to toma cell lines. conventional agents; however, neither COTI 2 nor 219 showed any tendency towards resistance in this cell line. In Example 7 fact, COTI-2 demonstrated a statistically significant tendency to decrease resistance (IC50's less than 1 for successive gen In Vivo Effect of COTI-2 on Cancerous Brain erations) in both cell lines. COTI-2 therefore exhibits a col Tumours lateral sensitivity whereby the resistance of cells is decreased over Successive generations and the drug might actually 0230 Malignant U87 human glioma (brain tumour) cells become more effective overtime against these cell lines. This in MatrigelTM were injected sub-cutaneously into hind legs of corroborates the in-silico predictions for COTI-2 and 219; nude mice, allowed to grow to 200-300 mm, then treated 3 COTI-2 was predicted to be a strong P-glycoprotein inhibitor, times per week (Mon, Wed, Fri) with indicated concentra which is consistent with decreasing the tendency towards tions of COTI-2 (in isotonic saline, as a cloudy liquid, total drug resistance, whereas COTI-219 was predicted to be both volume of 1 ml per injection). Tumour volumes were esti a P-glycoprotein inhibitor and/or a weak substrate for P-gly mated by caliper measurement. The results are shown in coprotein, also consistent with minimal accumulation in FIGS. 6A and 6B. resistance over Successive generations. The in-silico predic 0231. In FIG. 6A, tumour volumes were graphed as tions for resistance profile of compounds according to the meansistandard error (SE) (n=11-14 for each data point). invention are therefore confirmed by these assays. The asterisk indicates a significant difference (p<0.05) Example 6 between the 8 mg/kg treatment group and both the Saline control and 4 mg/kg treatment groups. There was no signifi In Vitro Efficacy in Brain Cancer cant difference between the 4 mg/kg group and the saline 0227. In order to determine the efficacy of the present control group. invention against human Glioma and Astrocytoma cell lines, 0232. In FIG. 6B, tumour volumes were graphed as frac IC50 values were determined by in vitro assay of four malig tional increase in Volume, to correct for differences in starting nant human brain cancer cell lines (U87MG, grade III glio volume, +SE. The asterisk indicates a significant difference blastoma/astrocytoma; SNB-19, glioma?astrocytoma Grade (p<0.05) between the 8 mg/kg treatment group and both the IV, glioblastoma multiforme; SF-268, glioma; SF-295, saline control and 4 mg/kg treatment groups. There was no glioma). Human brain cancers are notoriously difficult to significant difference between the 4 mg/kg group and the treat. 0228 Cell lines were obtained from the Human Tissue saline control group. The flag (P) indicates a significant Culture Collection (ATCC), grown and maintained under difference between the 8 mg/kg group and the saline group, ATCC-specified conditions, and tested to ensure viability and but not between the 8 mg/kg group and the 4 mg/kg group. lack of contaminating mycoplasma and common viruses. 0233 FIGS. 6A and 6B show that compounds of the Healthy cells were plated in 96-well culture plates in medium present invention are effective in the treatment of established plus fetal bovine serum and allowed to adhere for 16 h, human brain tumors. The compounds delayed tumor growth followed by addition of COTI-2, COTI-219, Cisplatin R, or by about 25% at a dosage of 8 mg/kg given just three times per BCNU (1,3-Bis(2-chloroethyl)-1-nitrosourea) at multiple week. Although no significant effect was observed at a dosage US 2012/0077.820 A1 Mar. 29, 2012 of 4 mg/kg, more frequent administration may have produced The following observations were obtained using gene expres a significant effect at this dosage. sion profiling techniques and targeted in vitro testing. Mol ecules of the present invention are believed to function as Example 8 kinase inhibitors. Molecules of the present invention are also believed to function as promoters of apoptosis. Promotion of Toxicity Testing apoptosis is achieved by decreasing phosphorylation of 0234. An escalating dose acute toxicity study was con Caspase 9; this has the effect of increasing active Caspase 9 ducted with COTI-2, COTI-4 and COTI-219. Standard lab and inducing apoptosis via Caspase 3. mice were divided into four treatment groups (control. 4, 8, 16 0238. To confirm this mechanism SHP77 cells were mg/kg) with four animals per group. It should be noted that treated with 250 nM of COTI-2 and incubated for 3 and 6 the highest dose was approximately 10 times the estimated hours. Western blots of the cellular lysates are presented in effective dose. Mice were given alternate day IP injections for FIG. 7. Phospho-Akt expression was decreased as compared 28 days. Weight loss/gain of the mice was measured and the to control at both 3 and 6 hours, with corresponding increases mice were observed for adverse effects such as vomiting, in Akt levels. There was no change in phospho-STAT3 diarrhea, seizures, etc. Blood and tissue samples were har expression, although a slight decrease in total STAT3 (-30%) Vested for histopathology. None of the drugs produced any was observed at 6 hrs. There was no observed reactivation of weight loss at any of the administered doses over the entire 28 Caspase 8; its level of expression remained constant intreated day period. No evidence of acute toxicity was obtained and no and control cells. However, the most dramatic change was a adverse effects were observed. The compounds according to profound suppression of phospho-Caspase 9 at both 3 and 6 the present invention are therefore believed to be safe and hrs of incubation. These results confirm the proposed mecha non-toxic. nism of action. Example 9 Example 11 In Vitro Metabolic Stability in Human Liver In-Silico Comparative Data Microsomes 0239. The in-silico model was used to test properties of compounds described in PCT Publication No. WO2006/ 0235. To evaluate the stability of these compounds in 009765: NSC716768, NSC73306, NSC73303, NSC668496, terms of clearance by the liver, human liver microsomes and NSC693323. Compounds JBC271A, JBC271B (Journal (HLM) at a concentration of 0.5 mg/ml were incubated with of Biological Chemistry 271, 13515-13522 (1996)) and 0.823 mM NADPH, 5 mM UDPGA, 1 mM MgCl, and JICS75 (Journal of the Indian Chemical Society, 75,392-394 COTI-2 or 219 at concentrations of 1, 10 and 100 uM. Sam (1998) and Journal of the Indian Chemical Society, 72, 403 pling was conducted at 1, 20, 40, 60, 120, 180 and 240 minutes and the remaining concentration of each compound 405 (1995)) are as follows: was evaluated. A half life (T2) was calculated at each con JBC271A centration, along with the rate of clearance by the liver (C). The results are provided in Table 16 for each compound. The S ?\, C, values compare favorably with published values for other marketed therapeutic agents under identical conditions. The Y-N- halflife of compounds according to the invention is therefore N-NH likely to be long enough to permit convenient dosing, while not being so long as to lead to accumulation in patients with potential long term toxicity effects. TABLE 16 K"O Half-life and Liver Clearance Rate by HLM at 0.5 mg/mL. JBC271B Compound Concentration (IM) T12 (min) C1 (LL/min/mg) S ?\, COTI-2 1 102.1 12 10 285.7 4 Y-N- 1OO 683.1 2 COTI-219 1 301.2 4.2 N-NH 10 420.7 3 1OO 508.5 2.5 S - 0236. The average halflife for COTI-2 was 6 hours and for K o COTI-219 was 6.8 hours. The in-silico prediction for CL in O the 95% confidence interval was from 3.1-14.3 for COTI-2 JICST5 and from 1.4-6.6 for COTI-219; this compares well with the S data presented in Table 3. Example 10 ---, Mechanism of Action Cro 0237 Without wishing to be limited by theory, it is 0240 Results of in-silico testing are shown in Tables 17 to believed that molecules according to the present invention, 20. The legends for these tables correspond to those of particularly COTI-2, act in the treatment of cancer in a man Example 1, except where indicated, and the methodology ner consistent with the following mechanistic observations. used to create the Tables was identical. US 2012/0077.820 A1 Mar. 29, 2012 22

Tables 17A and 17B: Physical Chemical Properties 0241 Table 17 shows that all tested compounds are drug like with no alerts for poor absorption or bioavailability.

TABLE 17A MoIID FORMULA MolWeight MnLogP HBnd Don HBnd Acc NSCA16768 C17H2ON6O4S 404449 2.082O79 2 10 NSCA3306 C16H12C2N4O2S 395.268 3.155598 3 6 NSCA33O3 C15H12N4OS 296.352 2S64086 3 5 NSC668496 C15H18N4OS 3O2.4 2.541123 2 5 NSC693323 C14H24N6S2 340.516 2.398.91 2 6 JBC271A C8H12N4O2S2 260.338 0.257966 2 6 JBC271B C9H14N4O2S2 274.365 0.542592 1 6 JICST5 C11H19N3OS 241.357 1.600519 1 4

TABLE 17B

MoIID FORMULA TPSA RotRnds Lipinski Alerts Weber

NSCA16768 C17H2ON6O4S 112.7027 7 O O NSCA3306 C16H12C2N4O2S 75.9848 5 O O NSCA33O3 C15H12N4OS 67.0547 4 O O NSC668496 C15H18N4OS 57.597 3 O O NSC693323 C14H24N6S2 54.972 7 O O JBC271A C8H12N4O2S2 66.5271 3 O O JBC271B C9H14N4O2S2 57.0694 3 O O JICST5 C11H19N3OS 36.4161 3 O O

Table 18: Solubility Properties 0242 Table 18 shows that all tested compounds have acceptable and comparable solubility with the COTI com Mean Over pounds except for NSC73306 which would be expected to NCI have very poor water solubility. DTP 60 cell DMS SHP- line MoIID FORMULA MnLogP LogS MoID FORMULA 114 77 Predicted panel

NSCA16768 C17H2ON6O4S 2.08.2079 -3.46551 NSCA16768 C17H2ON6O4S <-6 <-6 Inactive -4.7 NSC73306 C16H12C2N4O2S 3.155598 -5.76993 NSCA3306 C16H12C2N4O2S <-6 <-6 Inactive -4.9 NSC73303 C15H12N4OS 2.564086 -3.7869 NSCA33O3 C15H12N4OS <-6 <-6 Inactive ND NSC668496 C15H18N4OS 2.541123 -387371 NSC668496 C15H18N4OS <-6 <-6 Inactive -6.1 NSC693323 C14H24N6S2 <-6 <-6 Active -6.3 NSC693323 C14H24N6S2 2.398.91 -3.27041 JBC271A C8H12N4O2S2 <-6 <-6 Inactive ND JBC271A C8H12N4O2S2 O.257966 -1.76143 JBC271B C9H14N4O2S2 <-6 <-6 Inactive ND JBC271B C9H14N4O2S2 O.S42592 -1.83773 JICST5 C11H19N3OS <-6 <-6 Inactive ND JICST5 C11H19N3OS 1.600519 -2.45438

Legend for Table 19: Table 19: Efficacy (LogGI50) 0244. Mean Over NC1/DTP 60 cell line panel is the mean 0243 Table 19 shows that all tested compounds except for of the G150's for all 60 cell lines NOT including DMS114 and NSC693323 are predicted to be inactive against human SCLC SHP-77; cell lines DMS114 and SHP-77 in vitro. Therefore, there is no 0245 ND means not done/not available. rationale for use of any of the tested compounds except for NSC693323 as therapeutic agents in the treatment of SCLC. Table 20: Oral Absorption and BBB Penetration NSC693323 has an average G150 of -6.3. By comparison, 0246 Table 20 shows that all tested compounds are pre COTI-2 has LOG (G150) for DMS114 determined in vitro of dicted to have good oral absorption with variable to poor CNS –7.2 to -7.4, representing -10 times better in vitro efficacy penetration. The only potentially active drug, NSC693323, than the predictions for NSC693323 likely penetrates into the CNS poorly. US 2012/0077.820 A1 Mar. 29, 2012

the first ring system is a substituted or unsubstituted het TABLE 20A eroaromatic group, the second ring system is a Substi

MI9lo HIA tuted or unsubstituted aromatic group, a Substituted or MoIID FORMULA OrlAbs Min 96 Abs T2 (MD) unsubstituted heteroaromatic group, a Substituted or unsubstituted carbocyclic group, or a Substituted or NSCA16768 C17H2ON6O4S 86.33807 71.33807 3.556507 bstituted h li NSCA3306 C16H12C2N4O2S 73.43S12 58.43S12 2.075257 unsubstituted heterocyclic group; or NSCA33O3 C15H12N4OS 88.14632 73.14632 0.078544 the first ring system is a Substituted or unsubstituted Satu NSC668496 C15H18N4OS 87.81207 72.81207 0.055115 d carb li h d ri NSC693323 C14H24N6S2 84.59.752 69.597 S2 O.O97439 rated carbocyclic group, the second ring system 1s a JBC271A C8H12N4O2S2 80.28443 65.28443 2.273772 Substituted or unsubstituted aromatic group, a Substi JBC271B C9H14N4O2S2 84.O4259 69.04259 2.2672S3 tuted or unsubstituted unsaturated carbocyclic group, a JICST5 C11H19N3OS 91.74OO3 76.74003 2.0236OS Substituted or unsubstituted heterocyclic group, or a Sub stituted or unsubstituted ring B:

TABLE 20B

MoIID FORMULA ProbBBBPene LogBBB BBB-T2 (MD)

NSCA16768 C17H2ON6O4S O.OO9519 <<-1.OO 9.68.1481 NSC73306 C16H12C2N4O2S O.OS1291 -0.1554 4.7S8413 NSC73303 C15H12N4OS O.359669 -0.4.1974 1.216003 NSC668496 C15H18N4OS O.306419 -O.26927 O426904 NSC693323 C14H24N6S2 O.26SS43 -0.24742 O.294411 JBC271A C8H12N4O2S2 O.81813S -1.12483 3.8882O7 JBC271B C9H14N4O2S2 O.806343 -0.911SS 3.439832 JICST5 C11H19N3OS O.84O636 -O.25614 1981566

What is claimed is: 1. A compound of Formula I or IA for use as a pharmaceu tical: Ring B

Formula I R 1/ R5 R4 S NEC R6 R3 A V NR1 R wherein X to X are each independently selected from carbon or a heteroatom; or R7-Y. N-(A) the first ring system is a Substituted or unsubstituted unsat - K R11 urated carbocyclic group, the second ring system is a R9 R10 Substituted or unsubstituted aromatic group, a Substi Formula IA tuted or unsubstituted carbocyclic group, a Substituted or R unsubstituted heterocyclic group, or a Substituted or 1 / S NE unsubstituted ring B: A V NR12 R Ring-(A), Ring B

a pharmaceutically-acceptable salt, hydrate, Solvate, tau tomer, optical isomer, and/or combination thereof; wherein: R and R together form a substituted or unsubstituted wherein X to X are each independently selected from polycyclic ring comprising at least two ring systems, carbon or a heteroatom; or said at least two ring systems comprising a first ring the first ring system is a substituted or unsubstituted het system bonded to C1 and a second ring system fused to erocyclic group, the second ring system is a Substituted the first ring system, wherein: or unsubstituted heteroaromatic group, a Substituted or the first ring system is a Substituted or unsubstituted aro unsubstituted carbocyclic group, or a Substituted or matic group, the second ring system is a Substituted or unsubstituted heterocyclic group; and unsubstituted aromatic group, a Substituted or unsubsti R to R are each independently selected from H, a Sub tuted heteroaromatic group, a Substituted or unsubsti stituted or unsubstituted hydrocarbon group, a Substi tuted carbocyclic group, or a Substituted or unsubstituted tuted or unsubstituted heterogeneous group, a Substi heterocyclic group; or tuted or unsubstituted carbocyclic group, a Substituted or US 2012/0077.820 A1 Mar. 29, 2012 24

unsubstituted heterocyclic group, Substituted or unsub wherein X to X are each independently selected from stituted aromatic, or a substituted or unsubstituted het carbon or a heteroatom. eroaromatic; 5. The compound according to claim3, whereinX is Nand R is selected from H or a hydrocarbyl group; X to X is carbon. Y is a heteroatom; 6. The compound according to claim 4, wherein X is Nand Ring is selected from a substituted or unsubstituted thio X to X is carbon. morpholinyl group, a Substituted or unsubstituted mor 7. The compound according to claim 5, wherein the ring B pholinyl group, or a Substituted or unsubstituted pip is fused to the first ring system at X and X. eridinyl group, wherein the nitrogen in the Ring is bonded to A; 8. The compound according to claim 6, wherein the ring B A is selected from a substituted or unsubstituted hydrocar is fused to the first ring system at X and X. bon group, a Substituted or unsubstituted heterogeneous 9. The compound according to claim 1, wherein the first group, a Substituted or unsubstituted carbocyclic group, ring is a five-membered ring. a Substituted or unsubstituted heterocyclic group, Sub 10. The compound according to claim 1, wherein the first stituted or unsubstituted aromatic, or a substituted or ring is a six-membered ring. unsubstituted heteroaromatic; and 11. The compound according to claim 1, wherein the Sub n is 0 or 1, stituted or unsubstituted polycyclic ring further comprises a when n is 1 and the Ring is selected from a substituted or third ring system fused to the first ring system. unsubstituted morpholinyl group, or a Substituted or 12. The compound according to claim 11, wherein the third unsubstituted piperidinyl group, A is selected from a ring system is a Substituted or unsubstituted aromatic group, Substituted or unsubstituted hydrocarbon group, a Sub a Substituted or unsubstituted heteroaromatic group, a Substi stituted or unsubstituted carbocyclic group, a Substituted tuted or unsubstituted carbocyclic group, or a Substituted or or unsubstituted heterocyclic group, Substituted or unsubstituted heterocyclic group. unsubstituted aromatic, or a substituted or unsubstituted heteroaromatic. 13. The compound according to claim 12, wherein the third 2. The compound according to claim 1, wherein the first ring system is a Substituted or unsubstituted heteroaromatic ring system is a substituted or unsubstituted heterocyclic group or a substituted or unsubstituted heterocyclic group. group, the second ring system is a Substituted or unsubstituted 14. The compound according to claim 1, wherein n is 0. heteroaromatic group, a Substituted or unsubstituted carbocy 15. The compound according to claim 1, wherein n is 1 and clic group, or a Substituted or unsubstituted heterocyclic A is a Substituted or unsubstituted heteroaromatic group. group. 16. The compound according to claim 15, wherein A is a 3. The compound according to claim 1, wherein the first pyridinyl group. ring system is a Substituted or unsubstituted unsaturated car 17. The compound according to claim 1, wherein Y is a bocyclic group, the second ring system is a Substituted or nitrogen atom. unsubstituted aromatic group, a Substituted or unsubstituted 18. The compound according to claim 17, wherein R, is a carbocyclic group, a Substituted or unsubstituted heterocyclic substituted or unsubstituted alkyl group or a substituted or group; or a Substituted or unsubstituted ring B: unsubstituted heteroaromatic group and R to R and Rs to Rare each independently selected from Hora substituted or unsubstituted hydrocarbon group. Ring B 19. The compound according to claim 17, wherein R, is the substituted or unsubstituted alkyl group or a substituted or unsubstituted pyridyl group and R to R and Rs to R2 are each H. 20. A compound according to claim 1, wherein the com wherein X to X are each independently selected from pound is selected from: carbon or a heteroatom. 4. The compound according to claim 1, wherein the first ring system is a Substituted or unsubstituted carbocyclic group and the second ring system is a Substituted or unsub stituted ring B:

Ring B x1 X"Sx, X52X3 US 2012/0077.820 A1 Mar. 29, 2012 25

22. The compound according to claim 20, wherein the -continued compound is:

a pharmaceutically-acceptable salt, hydrate, Solvate, and/ or combination thereof. S N 23. The compound according to claim 1, wherein the com ls -N pound penetrates the blood brain barrier of a mammal. O NH1 N erala 24. The compound according to claim 1, wherein at least about 50% of the compound is orally absorbed by a mammal. HC N 2 \ 25. The compound according to claim 1, wherein the com pound has an ICso for a cancer cell population of less than S. about 1000 nM. 26. The compound according to claim 1 for treatment of a CaCC. S 27. The compound according to claim 26, wherein the ls N cancer is selected from lung cancer, cervical cancer, ovarian r N NH1N cancer, cancer of CNS, skin cancer, prostate cancer, sarcoma, breast cancer, leukemia, colorectal cancer, head cancer, neck N N cancer or kidney cancer. 28. The compound according to claim 26, wherein the 21 2 cancer is selected from Small cell lung cancer, breast cancer, acute leukemia, chronic leukemia, colorectal cancer, or brain CaCC. 29. The compound according to claim 26, wherein the cancer is a carcinoma. -N. 30. The compound according to claim 29, wherein the NH n carcinoma is selected from Small cell carcinomas, cervical carcinomas, glioma, astrocytoma, prostate carcinomas, ova N s rian carcinomas, melanoma, breast carcinomas, or colorectal carcinomas. O 21 31. The compound according to claim 29, wherein the carcinoma is Small cell lung carcinoma. 32. A pharmaceutical composition comprising the com a pharmaceutically-acceptable salt, hydrate, Solvate, and/ pound according to claim 1 and at least one pharmaceutically or combination thereof. acceptable carrier and/or diluent. 33. A pharmaceutical composition comprising an anti-can 21. Th e compoundd accord1ngding to claim 20,ZU, wherein uneth cer agent and the compound according to claim 1. compound is: 34. A method for treating a cancer in a mammal, compris ing administering to the mammal atherapeutically effective S amount of a compound of Formula I or IA:

era. Formula I HC1 Nu Z \ R5 R4 S NEC J. R6 R3 A V S. NR12 R2 R7-Y N-(A)

a pharmaceutically-acceptable salt, hydrate, Solvate and/or - R9 R10K R11 combination thereof. US 2012/0077.820 A1 Mar. 29, 2012 26

or unsubstituted heteroaromatic group, a Substituted or -continued unsubstituted carbocyclic group, or a Substituted or Formula IA unsubstituted heterocyclic group; and R 1/ R to R are each independently selected from H, a Sub S NEC stituted or unsubstituted hydrocarbon group, a Substi M V tuted or unsubstituted heterogeneous group, a Substi NR12 R tuted or unsubstituted carbocyclic group, a Substituted or Ring-(A), unsubstituted heterocyclic group, Substituted or unsub stituted aromatic, or a substituted or unsubstituted het a pharmaceutically-acceptable salt, hydrate, Solvate, tau eroaromatic; tomer, optical isomer, and/or combination thereof; R is selected from H or a hydrocarbyl group: wherein: Y is a heteroatom; R and R together form a substituted or unsubstituted Ring is selected from a substituted or unsubstituted thio polycyclic ring comprising at least two ring systems, morpholinyl group, a Substituted or unsubstituted mor said at least two ring systems comprising a first ring pholinyl group, or a Substituted or unsubstituted pip system bonded to C1 and a second ring system fused to eridinyl group, wherein the nitrogen in the Ring is the first ring system, wherein: bonded to A; the first ring system is a Substituted or unsubstituted aro A is selected from a substituted or unsubstituted hydrocar matic group, the second ring system is a Substituted or bon group, a Substituted or unsubstituted heterogeneous unsubstituted aromatic group, a Substituted or unsubsti group, a Substituted or unsubstituted carbocyclic group, tuted heteroaromatic group, a Substituted or unsubsti a Substituted or unsubstituted heterocyclic group, Sub tuted carbocyclic group, or a Substituted or unsubstituted stituted or unsubstituted aromatic, or a substituted or heterocyclic group; or unsubstituted heteroaromatic; and the first ring system is a substituted or unsubstituted het n is 0 or 1, eroaromatic group, the second ring system is a Substi when n is 1 and the Ring is selected from a substituted or tuted or unsubstituted aromatic group, a Substituted or unsubstituted morpholinyl group, or a Substituted or unsubstituted heteroaromatic group, a Substituted or unsubstituted piperidinyl group, A is selected from a unsubstituted carbocyclic group, or a Substituted or Substituted or unsubstituted hydrocarbon group, a Sub unsubstituted heterocyclic group; or stituted or unsubstituted carbocyclic group, a substituted the first ring system is a Substituted or unsubstituted Satu or unsubstituted heterocyclic group, Substituted or rated carbocyclic group, the second ring system is a unsubstituted aromatic, or a substituted or unsubstituted Substituted or unsubstituted aromatic group, a Substi heteroaromatic. tuted or unsubstituted unsaturated carbocyclic group, a 35. The method according to claim 34, wherein the com Substituted or unsubstituted heterocyclic group, or a Sub pound is co-administered with radiation therapy. stituted or unsubstituted ring B: 36. A method for treating a cancer in a mammal, compris ing administering to the mammal atherapeutically effective amount of the composition according to claim 32. Ring B 37. A method for treating a cancer in a mammal, compris ing administering to the mammal atherapeutically effective amount of the composition according to claim 33. 38. The method according to claim 36, wherein the com position is co-administered with radiation therapy. 39. The method according to claim 34, wherein the mam wherein X to X are each independently selected from mal is a human. carbon or a heteroatom; or 40. The method according to claim 34, wherein the com the first ring system is a Substituted or unsubstituted unsat pound inhibits development of a drug resistant form of the urated carbocyclic group, the second ring system is a CaCC. Substituted or unsubstituted aromatic group, a Substi 41. The method according to claim 34, wherein the cancer tuted or unsubstituted carbocyclic group, a Substituted or is selected from lung cancer, cervical cancer, ovarian cancer, unsubstituted heterocyclic group, or a Substituted or cancer of CNS, skin cancer, prostate cancer, sarcoma, breast unsubstituted ring B: cancer, leukemia, colorectal cancer, head cancer, neck cancer or kidney cancer. 42. The method according to claim 34, wherein the cancer Ring B is selected from Small cell lung cancer, breast cancer, acute leukemia, chronic leukemia, colorectal cancer, or brain can C. 43. The method according to claim 34, wherein the cancer is a carcinoma. 44. The method according to claim 43, wherein the carci wherein X to X are each independently selected from noma is selected from Small cell carcinomas, cervical carci carbon or a heteroatom; or nomas, glioma, astrocytoma, prostate carcinomas, ovarian the first ring system is a substituted or unsubstituted het carcinomas, melanoma, breast carcinomas, or colorectal car erocyclic group, the second ring system is a Substituted cinomas. US 2012/0077.820 A1 Mar. 29, 2012 27

45. The method according to claim 44, wherein the carci b) reacting the Intermediate of Formula III with noma is Small cell lung carcinoma. RNHNH2 to form an Intermediate of Formula IV: 46. The method according to claim 34, wherein the com pound is administered orally and/or parenterally. 47. A method for preparing the compound of claim 1, the method comprising: Formula IV a) reacting a compound of Formula II: R5 R4 S NH2 R6 R3 A NR12 S R5 R4 R7-Y. N-(A) ls * k" - K R11 ( y R7-Y. N-(A)-H R9 R10 - S. R3 R11 Formula II with: R9 R10 c) reacting the Intermediate of Formula IV with a ketone: to form an intermediate of Formula III:

Formula III R5 R4 S R6 R3 S N R-Y N-(A) \e N under condensation conditions, to form the compound of Formula I. R3 R11 48. The method according to claim 47, wherein n is 0.

c c c c c