WO2018236971A1

WO2018236971A1 - Single molecule compounds providing multi-target inhibition of parp and other proteins and methods of use thereof

Info

Publication number: WO2018236971A1
Application number: PCT/US2018/038456
Authority: WO
Inventors: Guillermo A. Morales; Joseph R. Garlich; Donald L. Durden
Original assignee: Signalrx Pharmaceuticals, Inc.
Priority date: 2017-06-21
Filing date: 2018-06-20
Publication date: 2018-12-27

Abstract

The invention relates to compounds useful for inhibiting PARP and at least one other protein and to methods of treating diseases including cancer by administration of a compound(s) of Formula I-V (or pharmaceutically acceptable salts thereof) as defined herein.

Description

SINGLE MOLECULE COMPOUNDS PROVIDING MULTI-TARGET INHIBITION OF PARP AND OTHER PROTEINS AND METHODS OF USE THEREOF

FIELD OF THE INVENTION

[001] The present invention relates to thienopyranone and furanopyranone compounds and methods of treating diseases in mammals including humans by administering a compound(s) of the invention. In one aspect of the invention, a compound or composition is administered to provide therapeutic benefit by inhibiting Poly (ADP-ribose) polymerase ("PARP") and at least one other kinase such as PI3K, and/or an epigenetic regulator such as bromodomain containing proteins.

BACKGROUND

[002] A number of biochemical pathways and enzymes are important in DNA repair and chemo- radiation sensitivity including phosphoinositide 3-kinase (PI3K) which controls degradation of p53 and DNA repair by regulation of MDM2, and PARP control of several processes including base excision repair, BRCAl/2 controlled homologous recombination, double-stranded DNA break repair, and non-homologous end-joining repair (see Benada and Macurek, Biomolecules, 5, 1912-1937, 2015; N.P. Dantuma et al. EMBO J, 35, 6-23, 2016).

[003] PARP enzymes play a key role in both base excision repair after single strand breaks occur, and in regulating BRCA function (Hu et al. Cancer Discov, 4, 1430-1447, 2014). Cancer cells with BRCA 1/2 loss of function mutations are profoundly sensitive to PARP inhibitors (PARPi), and a number of PARPi's have been tested in the clinic for their selective toxicity to cancer cells with BRCAl/2 loss of function somatic or germline mutations. While PARP inhibitors represent a promising avenue for treating cancers with BRCA 1/2 loss of function mutations, many cancer types possess wild type BRCAl/2 genes, and as such are not sensitive to PARPi's.

[004] Recent research has shown that PI3K inhibition impairs BRCAl/2 expression which effectively mimics the BRCA 1/2 loss of function mutation. As such, PI3K inhibition has the potential to sensitize BRCA-wild type cancers to PARP inhibition (YH Ibrahim et al. Cancer Discov. 2, 1036-1047, 2012; FL Rehman et al. Cancer Discov. 2, 982-984, 2012), and

combination therapies in which PI3K and PARP are simultaneously inhibited offer a promising new avenue for cancer treatment. In addition, in certain cancers such as small cell lung cancer (SCLC) treatment with a PARP inhibitor has been associated with an upregulation of the

PI3K/mTOR pathway and downregulation of proteins such as LKB1 which negatively regulate the PI3K pathway suggesting that sensitivity to PARP inhibition is inversely related to

PI3K/mTOR pathway activity. As such, concomitant inhibition of PI3K and PARP is expected to achieve synergistic inhibitory effects (see e.g., R.J. Cardnell et al. PLOS ONE, DOI: 10.1371, April 7, 2016). Further support for inhibiting both PI3K and PARP comes from the fact that c- MYC abundance can induce resistance to PARP inhibitors (see S. Ganesan, Science Signaling, Volume 4, issue 166, pel5, March 29, 2011) and it is now known that inhibition of PI3K can enhance the degradation of MYC protein (Belkina AC, Denis GV. BET domain co-regulators in obesity, inflammation and cancer. Nat Rev Cancer. 2012; 12(7):465-77. Epub 2012/06/23).

[005] In addition to defects in one or more kinase pathways, a growing list of diseases including cancer can arise by epigenetically-induced changes in gene expression and cellular phenotype by mechanisms other than changes in DNA nucleotide sequence. Epigenetic effects can be controlled by three types of proteins: the writers (i.e., DNA methyltransferase which adds methyl groups to DNA), the erasers (i.e., histone deacetylase, HDAC, which removes acetyl groups from histones), and the readers (i.e., BET bromodomain proteins such as BRD2, BRD3, BRD4 and BRDT). Bromodomain proteins serve as "readers" to recruit regulatory enzymes such as writers and erasers leading to regulation of gene expression. Inhibitors of bromodomain proteins are potentially useful in the treatment of diseases including obesity, inflammation, and cancer (A.C. Belkina et al., Nat. Rev. Cancer 2012, 12, 465-477). The BET bromodomain protein BRD4 is a current target to inhibit in cancer and a number of inhibitors are known and in development (Wadhwa E, Nicolaides T. Bromodomain Inhibitor Review: "Bromodomain and Extra-terminal Family Protein Inhibitors as a Potential New Therapy in Central Nervous System Tumors".

Muacevic A, Adler JR, eds. Cureus. 2016, 8(5), e620. doi: 10.7759/cureus.620).

[006] BET inhibitors act as acetylated lysine mimetics that disrupt the binding interaction of BET proteins with acetylated lysine residues on histones (D.S. Hewings et al., J. Med. Chem. 2012, 55, 9393-9413). This leads to suppression of transcription of some key genes involved in cancer including c-MYC, MYCN, BCL-2, and some NF-kB-dependent genes (J.E. Delmore et al., Cell 2011, 146, 904-917) (A. Puissant et al., Cancer Discov. 2013, 3, 308-323). Most B-cell malignancies are associated with the activation of the c-MYC gene which is partially controlled by the PI3 kinase-AKT-GSK3beta signaling axis (J.E. Delmore et al., Cell 2011, 146, 904-917). MYC (encompassing c-MYC and MYCN) is an oncoprotein that has been difficult to inhibit using small molecule approaches (E.V. Prochownik et al., Genes Cancer 2010, 1, 650-659).

Recently, it has been shown that BET inhibition prevents the transcription of MYCN (A. Puissant et al., Cancer Discov. 2013, 3, 308-323), and blocking PI3K enhances MYC degradation (L. Chesler et al., Cancer Res. 2006, 66, 8139-8146). Therefore, a single molecule that inhibits both PI3K and bromodomain proteins would provide a more effective way to inhibit MYC activity. Additional support for inhibiting both bromodomain proteins such as BRD4 and PARP comes from recent reports of synthetic lethality of cancer cells with such a combination along with BRD4 inhibition reversing PARP inhibitor resistance (see e.g., C. Sun et al., Cancer Cell, volume 33, pp401-416, 2018; S. Karakashev et al., Cell Reports, volume 21, pp3398-3405, 2017; and L. Yang et al., Science Translational Medicine, volume 9, eaall645, 2017) Several reported BET inhibitors contain the 3,5-dimethylisoxazole chemotype as the acetyl -lysine mimetic moiety (D.S. Hewings, J. Med. Chem. 2011, 54, 6761-6770) (D.S. Hewings et al., J. Med. Chem. 2012, 55, 9393-9413) (D.S. Hewings et al., J. Med. Chem. 2013, 56, 3217-3227).

[007] While treatments involving inhibition of PI3K and PARP by administering separate agents hold considerable promise, in practice additive off -target toxicities from the combination of individual inhibitors has revealed significant problems with this strategy. In a recent clinical trial, the PI3K inhibitor BKM120 was co-administered with the PARP inhibitor Olaparib. The combination of these two agents resulted in significant toxicity issues, and the maximum tolerated dose of the PI3K inhibitor was only half the amount of that achievable by administration as a single agent (see Matulonis U. et al., "Phase I of oral BLK120 or BLY719 and olaparib for high- grade serous ovarian cancer or triple-negative breast cancer: final results of the BMK120 plus olaparib cohort". 106th Annual Meeting of the American Association for Cancer Research; April 18-22: AACR; 2015).

[008] Off-target toxicities represent a major hurdle when administering multiple single molecule inhibitors to target multiple proteins. A more nuanced approach involves administering multi- target single molecule inhibitors which are potentially advantageous over combinations of single- target inhibitors for a number of reasons including: a) reduced development costs; b) lower toxicity; c) lower non-target side effects due to non-target drug interactions; d) simultaneous target inhibition to provide greater efficacy (versus combinations of agents suffering from differing ADME dynamics); e) lower financial costs to patients and the healthcare system; f) increased efficacy and longer durations of response; and g) accelerated drug development.

[009] Single-molecule, multi -target inhibition can avoid some of the problems arising from differing ADME properties associated with the administration of separate agents such as dose limiting toxicity resulting from additive off-target toxicities of the individual drugs. In addition, a single molecule, multi-target inhibitor could dramatically simplify taking medications and improve patient compliance. For example, a patient whose treatment includes inhibition of multiple targets would generally be required to take separate medicines to achieve inhibition of each target, whereas a single molecule, multitarget inhibitor could achieve the same objective with just a single medication. Additionally, the desirable combination of more agents for more efficacy is possible using an inhibitor that targets multiple proteins and could serve as three drugs in a four-drug regiment such that the patient would only be administered two drugs one of which is a compound of the invention to achieve such a tolerable four-drug exposure.

[010] There remains a need for single molecule, multi-target inhibitors of kinases including inhibitors of PARP and at least one other protein including but not limited to PI3K and a bromodomain protein such as BRD4 to provide effective treatments for diseases including but not limited to cancer arising from BRCA 1/2 loss of function somatic or germ line mutations, or cancers in which the BRCA genes are wild-type including but not limited to medulloblastoma (MB) and neuroblastoma ( B).

SUMMARY OF THE INVENTION

[Oil] The present invention relates to thienopyranone and furanopyranone compounds that are useful as inhibitors of PARP and at least one other anti-cancer target protein and find utility in the treatment and prevention of diseases including cancer.

[012] In particular, the present invention relates to new thienopyranone and furanopyranone compounds, conjugates, and pharmaceutical compositions thereof containing the compounds, and use of the compounds as therapeutic agents including as anticancer and antitumor agents for the treatment of disorders including but not limited to cancer. Some of the compounds disclosed in this application can be prepared by methods described in U.S. Patent 8,557,807, US9,505,780, and Morales et al., J. Med. Chem. 2013, the entire contents of which are herein incorporated by reference.

[013] The present invention relates in one aspect to methods for treating diseases in mammals including humans by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof:

wherein M is independently oxygen (O) or sulfur (S);

Rl is selected from H, halogen, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted aryl, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, nitroso, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate;

R2 is selected from Rl or morpholine or thiomorpholine or piperazine;

R3 is selected from Rl; and

R4 is selected from Rl .

[014] These and other objects of the invention are evidenced by the summary of the invention, the description of the preferred embodiments and the claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[015] Fig. 1 shows that dual PARP/PI3K inhibitor Compound 1 inhibits PARP activity with an ICso value of 13.19 μΜ.

[016] Fig. 2 shows that a combination of separate inhibitors against PI3K and PARP are more toxic to cells than dual inhibitor molecule Compound 1.

[017] Fig. 3 shows that dual inhibitor Compound 1 induces apoptosis better than a combination of two separate agents.

[018] Fig. 4 shows that dual inhibitor Compound 1 shows a 5-fold increase in the number of cancer cells with dual target impairment versus use of two single inhibitors.

[019] Fig. 5 shows that dual PARP/PI3K inhibitor Compound 1 sensitized BRCA wild type cells to PARP inhibition.

DETAILED DESCRIPTION

A. Definitions.

[020] As used herein, the term "disease" or "condition" refers to various diseases and/or conditions in a mammal including a human as generally understood and as described herein.

[021] "Cancer" refers to cellular-proliferative disease states, including cancers with loss of function somatic or germline mutations in BRCA 1/2, and cancers without loss of function mutations in BRCA 1/2 (i.e., "BRCA wild type" or "BRCA competent") including but not limited to medulloblastoma (MB) and neuroblastoma (NB), and further including the following cancers: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal

adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilms tumor [nephroblastoma], lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis

(seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochondroma

(osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma [serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal

rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; Adrenal Glands: neuroblastoma; and breast cancer.

[022] The term "cancerous cell" as provided herein, includes a cell affected by any one of the cancers identified herein. The term "cancer stem cell" refers to a subpopulation of cells in a solid or non-solid tumor that demonstrate enhanced drug efflux properties, are lacking in cell cycle progression, and are resistant to anoikis.

[023] As used herein, the term "branched" refers to a group containing from 1 to 24 backbone atoms wherein the backbone chain of the group contains one or more subordinate branches from the main chain. Preferred branched groups herein contain from 1 to 12 backbone atoms. Examples of branched groups include, but are not limited to, isobutyl, t-butyl, isopropyl,—

CH₂CH2CH(CH3)CH₂CH3, -CH₂CH(CH₂ CH₃)CH₂ CH₃, -CH₂CH₂C(CH₃)₂CH₃, -- CH₂CH₂C(CH₃)₃ and the like.

[024] The term "unbranched" as used herein refers to a group containing from 1 to 24 backbone atoms wherein the backbone chain of the group extends in a direct line. Preferred unbranched groups herein contain from 1 to 12 backbone atoms.

[025] The term "cyclic" or "cyclo" as used herein alone or in combination refers to a group having one or more closed rings, whether unsaturated or saturated, possessing rings of from 3 to 12 backbone atoms, preferably 3 to 7 backbone atoms.

[026] The term "lower" as used herein refers to a group with 1 to 6 backbone atoms.

[027] The term "saturated" as used herein refers to a group where all available valence bonds of the backbone atoms are attached to other atoms. Representative examples of saturated groups include, but are not limited to, butyl, cyclohexyl, piperidine and the like.

[028] The term "unsaturated" as used herein refers to a group where at least one available valence bond of two adjacent backbone atoms is not attached to other atoms. Representative examples of unsaturated groups include, but are not limited to,— CH₂CH₂CH=CH₂, phenyl, pyrrole and the like.

[029] The term "aliphatic" as used herein refers to an unbranched, branched or cyclic

hydrocarbon group, which may be substituted or unsubstituted, and which may be saturated or unsaturated, but which is not aromatic. The term aliphatic further includes aliphatic groups, which comprise oxygen, nitrogen, sulfur or phosphorous atoms replacing one or more carbons of the hydrocarbon backbone.

[030] The term "aromatic" as used herein refers to an unsaturated cyclic hydrocarbon group which may be substituted or unsubstituted having 4n+2 delocalized π(ρί) electrons. The term aromatic further includes aromatic groups, which comprise a nitrogen atom replacing one or more carbons of the hydrocarbon backbone. Examples of aromatic groups include, but are not limited to, phenyl, naphthyl, thienyl, furanyl, pyridinyl, (is)oxazolyl and the like.

[031] The term "substituted" as used herein refers to a group having one or more hydrogens or other atoms removed from a carbon or suitable heteroatom and replaced with a further group. Preferred substituted groups herein are substituted with one to five, most preferably one to three substituents. An atom with two substituents is denoted with "di" whereas an atom with more than two substituents is denoted by "poly." Representative examples of such substituents include, but are not limited to aliphatic groups, aromatic groups, alkyl, alkenyl, alkynyl, aryl, alkoxy, halo, aryloxy, carbonyl, acryl, cyano, amino, amide, nitro, phosphate-containing groups, sulfur- containing groups, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,

aryloxycarbonyloxy, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,

alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, acylamino, amidino, imino, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, trifluoromethyl, azido, heterocyclyl, alkylaryl, heteroaryl, semicarbazido, thiosemicarbazido, maleimido, oximino, imidate, cycloalkyl, cycloalkylcarbonyl, dialkylamino, arylcycloalkyl, arylcarbonyl, arylalkylcarbonyl,

arylcycloalkylcarbonyl, arylphosphinyl, arylalkylphosphinyl, arylcycloalkylphosphinyl, arylphosphonyl, arylalkylphosphonyl, arylcycloalkylphosphonyl, arylsulfonyl, arylalkylsulfonyl, arylcycloalkylsulfonyl, combinations thereof, and substitutions thereto.

[032] As described herein, compounds of the invention may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[033] The terms "optionally substituted", "optionally substituted alkyl", "optionally substituted alkenyl", "optionally substituted alkynyl", "optionally substituted carbocyclic", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocyclic", and any other optionally substituted group as used herein, refer to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to: -F, -CI, -Br, -I, -OH, protected hydroxy, alkoxy, oxo, thiooxo, -NO2, -CN, -CF₃, -N₃, - H2, protected amino, -NH- alkyl, - H-alkenyl, - H-alkynyl, - H-cycloalkyl, - H-aryl, - H-heteroaryl, - H-heterocyclic, - dialkylamino, - diarylamino, -diheteroarylamino, -O-alkyl, -O-alkenyl, -O-alkynyl, -O-cycloalkyl, - O-aiyl, -O- heteroaryl, -O-heterocyclic, -C(0)-alkyl, -C(0)-alkenyl, -C(0)-alkynyl, -C(O)- cycloalkyl, -C(O)- aryl, -C(0)-heteroaryl, -C(0)-heterocycloalkyl, -CO H2, -CO H-alkyl, - CO H-alkenyl, - CONH-alkynyl, -CONH-cycloalkyl, -CONH-aryl, -CONH-heteroaryl, -CONH- heterocycloalkyl, -OC0₂-alkyl, -OC0₂-alkenyl, -OC0₂-alkynyl, -OC0₂-cycloalkyl, -OC0₂-aryl, - OCO2- heteroaryl, -OC0₂-heterocycloalkyl, -OCONH2, -OCONH-alkyl, -OCONH-alkenyl, - OCONH- alkynyl, -OCONH-cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH- heterocycloalkyl, - NHC(0)-alkyl, -NHC(0)-alkenyl, -NHC(0)-alkynyl, -NHC(0)-cycloalkyl, - NHC(0)-aryl, - NHC(0)-heteroaiyl, -NHC(0)-heterocycloalkyl, -NHC0₂-alkyl, -NHC0₂-alkenyl, -NHCO2- alkynyl, -NHC0₂-cycloalkyl, -NHC0₂-aryl, -NHCO 2 -heteroaryl, -NHCO2- heterocycloalkyl, - NHC(0)NH₂, -NHC(0)NH-alkyl, -NHC(0)NH-alkenyl, -NHC(0)NH-alkenyl, -NHC(0)NH- cycloalkyl, -NHC(0)NH-aryl, -NHC(0)NH-heteroaryl, -NHC(0)NH- heterocycloalkyl, - NHC(S)NH₂, -NHC(S)NH-alkyl, -NHC(S)NH-alkenyl, -NHC(S)NH-alkynyl, - NHC(S)NH- cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, -NHC(S)NH- heterocycloalkyl, - NHC(NH)NH₂, -NHC(NH)NH-alkyl, -NHC(NH)NH-alkenyl, -NHC(NH)NH- alkenyl, - NHC(NH)NH-cycloalkyl, -NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, - NHC(NH)NH- heterocycloalkyl, -NHC(NH)-alkyl, -NHC(NH)-alkenyl, -NHC(NH)-alkenyl, - NHC(NH)- cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, - C(NH)NH- alkyl, -C(NH)NH-alkenyl, -C(NH)NH-alkynyl, -C(NH)NH-cycloalkyl, -C(NH)NH- aryl, - C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, -S(0)-alkyl, -S(0)-alkenyl, -S(O)- alkynyl, - S(0)-cycloalkyl, -S(0)-aryl, -S(0)-heteroaryl, -S(0)-heterocycloalkyl -SO2NH2, - S0₂NH-alkyl, -S0₂NH-alkenyl, -S0₂NH-alkynyl, -S0₂NH-cycloalkyl, -S0₂NH-aryl, -SO2NH- heteroaryl, - S0₂NH-heterocycloalkyl, -NHS0₂-alkyl, -NHSO2 -alkenyl, -NHS0₂-alkynyl, - NHSO2- cycloalkyl, -NHS0₂-aryl, -NHS0₂-heteroaryl, -NHS0₂-heterocycloalkyl, -CH₂NH₂, - CH2S02CH₃, -alkyl, -alkenyl, -alkynyl, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, - heterocycloalkyl, -cycloalkyl, -carbocyclic, -heterocyclic, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, -methoxyethoxy, -SH, -S-alkyl, -S-alkenyl, -S-alkynyl, -S-cycloalkyl, -S-aryl, - S-heteroaryl, -S-heterocycloalkyl, or methylthiom ethyl.

[034] The term "unsubstituted" as used herein refers to a group that does not have any further groups attached thereto or substituted therefore. [035] The term "alkyl" as used herein, alone or in combination, refers to a branched or unbranched, saturated aliphatic group. The alkyl radical may be optionally substituted

independently with one or more substituents described herein. Lower alkyl refers to alkyl groups of from one to six carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, and the like. Higher alkyl refers to alkyl groups containing more than seven carbon atoms. A "Co" alkyl (as in "Co-Co-alkyl") is a covalent bond. Exemplary alkyl groups are those of C20 or below. In this application, alkyl refers to alkanyl, alkenyl, and alkynyl residues (and combinations thereof); it is intended to include vinyl, allyl, isoprenyl, and the like. Thus, when an alkyl residue having a specific number of carbons is named, all geometric isomers having that number of carbons are intended to be encompassed; thus, for example, either "butyl" or "C4 alkyl" is meant to include n-butyl, sec-butyl, isobutyl, t- butyl, isobutenyl and but-2-ynyl groups; and for example, "propyl" or "C3 alkyl" each include n- propyl, propenyl, and isopropyl. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, octyl, decyl, tetradecyl, hexadecyl, eicosyl, tetracosyl and the like. The terms "alkyl" or "alk" as used herein refer to a saturated linear or branched-chain monovalent hydrocarbon radical of one to twelve carbon atoms (C 1-C12), wherein the alkyl radical may be optionally substituted independently with one or more substituents described below. In another embodiment, an alkyl radical is one to eight carbon atoms (Ci-C₈), or one to six carbon atoms (Ci-C₆). Examples of alkyl groups include, but are not limited to, methyl (Me,— CH3), ethyl (Et,— CH2CH3), 1-propyl (n-Pr, n- propyl,— CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, - CH2CH2CH2CH3), 2-methyl- 1-propyl (1-Bu, i-butyl, -CH₂CH(CH₃)2), 2-butyl (s-Bu, s-butyl, - CH(CH3)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH₃)3), 1-pentyl (n-pentyl, - CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH₂CH₂CH3), 3-pentyl (-CH(CH₂CH₃)2), 2- methyl-2-butyl (-C(CH₃)2CH₂CH3), 3 -methyl -2-butyl (-CH(CH3)CH(CH₃)₂), 3 -methyl -1-butyl (-CH₂CH₂CH(CH3)2), 2-methyl- 1-butyl (-CH₂CH(CH3)CH₂CH3), 1-hexyl (- CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH₂CH₂CH3), 3-hexyl (- CH(CH₂CH3)(CH₂CH₂CH3)2), 2-methyl-2-pentyl (-C(CH3)2CH₂CH₂CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH₃)CH₂CH(CH3)2), 3-methyl-3- pentyl (-C(CH₃)(CH₂CH3)2), 2-methyl -3 -pentyl (-CH(CH₂CH3)CH(CH3)₂), 2,3-dimethyl-2- butyl (-C(CH₃)2CH(CH3)₂), 3,3-dimethyl-2-butyl (-CH(CH₃)C(CH₃)3, 1-heptyl, 1-octyl, and the like.

[036] The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloalkyl" refer to a monovalent non-aromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms (C 3 -C 12) as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. The cycloalkyl radical may be optionally substituted independently with one or more substituents described herein. Bicyclic carbocycles having 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, and bicyclic carbocycles having 9 or 10 ring atoms can be arranged as a bicyclo[5,6] or [6,6] system, or as bridged systems such as bicyclo[2.2.1]heptane,

bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[037] The term "alkenyl" as used herein alone or in combination refers to a branched or unbranched, unsaturated aliphatic group containing at least one carbon-carbon double bond which may occur at any stable point along the chain. The alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations, or alternatively, "E" and "Z" orientations. Representative examples of alkenyl groups include, but are not limited to, ethenyl, E- and Z-pentenyl, decenyl and the like.

[038] The term "alkynyl" as used herein alone or in combination refers to a branched or unbranched, unsaturated aliphatic group containing at least one carbon-carbon triple bond which may occur at any stable point along the chain. The alkynyl radical may be optionally substituted independently with one or more substituents described herein. Representative examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl and the like.

[039] The term "aryl" as used herein alone or in combination refers to a substituted or unsubstituted aromatic group, which may be optionally fused to other aromatic or non-aromatic cyclic groups. Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, biphenyl, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like. Aryl groups are optionally substituted independently with one or more substituents described herein.

[040] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 18 ring atoms, preferably 5, 6, 7, 9, or 14 ring atoms; having 6, 10, or 14 (pi) electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" includes but is not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. A heteroaryl may be a single ring, or two or more fused rings. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyndazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyndinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H- quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,

tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like.

[041] The term "alkoxy" as used herein alone or in combination refers to an alkyl, alkenyl or alkynyl group bound through a single terminal ether linkage. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, 3- methylpentoxy, fluorom ethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy,

dichloromethoxy, and trichloromethoxy.

[042] The term "aryloxy" as used herein alone or in combination refers to an aryl group bound through a single terminal ether linkage.

[043] The terms "halogen", "halo" and "hal" as used herein refer to monovalent atoms of fluorine, chlorine, bromine, iodine and astatine.

[044] The term "hetero" or "heteroatom" as used herein combination refers to a group that includes one or more atoms of any element other than carbon or hydrogen. Representative examples of hetero groups include, but are not limited to, those groups that contain heteroatoms including, but not limited to, nitrogen, oxygen, sulfur and phosphorus.

[045] The term "heterocycle" or "heterocyclyl" or "heterocyclic ring" or "heterocyclic" as used herein refers to a cyclic group containing one or more heteroatoms. The heterocyclic radical may be optionally substituted independently with one or more substituents described herein. Representative examples of heterocycles include, but are not limited to, pyridine, piped dine, pyrimidine, pyridazine, piperazine, pyrrole, pyrrolidinone, pyrrolidine, morpholine,

thiomorpholine, indole, isoindole, imidazole, triazole, tetrazole, furan, benzofuran, dibenzofuran, thiophene, thiazole, benzothiazole, benzoxazole, benzothiophene, quinoline, isoquinoline, azapine, naphthopyran, furanobenzopyranone and the like.

[046] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[047] PARP inhibitors were originally based on the observation that the second product of NAD+ cleavage by PARP, nicotinamide, is itself a weak PARP inhibitor. The first generation of PARP inhibitors were simple analogs of nicotinamide with carbon substituting for the nitrogen at position 3, the 3-substituted benzamides, of which 3-aminobenzamide (3AB) was the most commonly used. As used herein, the term 'nicotinamide mimetic" refers to such 3-substituted benzamides. Exemplary nicotinamide mimetics are disclosed in ICOLA J. CURTIN and

THOMAS HELLED AY, CHAPTER 12 - Inhibition of DNA repair as a therapeutic target, In Cancer Drug Design and Discovery, edited by Stephen Neidle, Academic Press, New York, 2008, Pages 284-304, ISBN 9780123694485.

[048] The term "substituent" means any group selected from H, F, CI, Br, I, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, amide, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyl amide, halo, haloalkyl, haloalkoxy, hydroxy, oxo (valency rules permitting), lower alkanyl, lower alkenyl, lower alkynyl, alkoxy, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally' substituted aryl, optionally substituted heteroaryl, alkylaminoalkyl, dialkylaminoalkyl, carboxy, carboxy ester, -C(0) R⁵R" (where R⁵ is hydrogen or alkyl and R" is hydrogen, alkyl, aryl, or heterocyclyl), - R⁵C(0)R" (where R⁵ is hydrogen or alkyl and R" is alkyl, aryl, or heterocyclyl), amino, alkylamino, dialkylamino, and - HS(0)2R (where R is alkyl, aryl, or heteroaryl).

[049] The term "carbonyl" or "carboxy" as used herein alone or in combination refers to a group that contains a carbon-oxygen double bond. Representative examples of groups which contain a carbonyl include, but are not limited to, aldehydes (i.e., formyls), ketones (i.e., acyls), carboxylic acids (i.e., carboxyls), amides (i.e., amidos), imides (i.e., imidos), esters, anhydrides and the like.

[050] The term "carbamate" as used herein alone or in combination refers to an ester group represented by the general structure - H(CO)0-. Carbamate esters may have alkyl or aryl groups substituted on the nitrogen, or the amide function.

[051] The term "cyanate" "isocyanate", "thiocyanate", or "isothiocyanate" as used herein alone or in combination refers to an oxygen- or sulfur-carbon double bond carbon-nitrogen double bond. Representative examples of cyano groups include, but are not limited to, isocyanate, isothiocyanate and the like.

[052] The term "cyano", "cyanide", "isocyanide", "nitrile", or "isonitrile" as used herein alone or in combination refers to a carbon-nitrogen triple bond.

[053] The term "amino" as used herein alone or in combination refers to a group containing a backbone nitrogen atom. Representative examples of amino groups include, but are not limited to, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido and the like.

[054] The term "phosphate-containing group" as used herein refers to a group containing at least one phosphorous atom in an oxidized state. Representative examples include, but are not limited to, phosphonic acids, phosphinic acids, phosphate esters, phosphinidenes, phosphinos, phosphinyls, phosphinyli denes, phosphos, phosphonos, phosphoranyls, phosphoranylidenes, phosphorosos and the like.

[055] The term "sulfur-containing group" as used herein refers to a group containing a sulfur atom. Representative examples include, but are not limited to, sulfhydryls, sulfenos, sulfinos, sulfinyls, sulfos, sulfonyls, thios, thioxos and the like.

[056] The term "optional" or "optionally" as used herein means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, the phrase "optionally substituted alkyl" means that the alkyl group may or may not be substituted and that the description includes both unsubstituted alkyl and substituted alkyl. [057] The term "targeting agent" as used herein means any moiety attached to a compound of the invention allowing an increase in concentration of the compound at a site of treatment, for example, a tumor site. Exemplary targeting agents include but are not limited to carbohydrates, peptides, vitamins, and antibodies.

[058] As used herein, the term "multi-target inhibitor" or "multi-target agent" refers to a single molecule having the capacity to interact with PARP and at least one other protein target including but not limited to PI3K and a bromodomain protein including but not limited to BRD4 in vitro or in vivo including the capacity to inhibit the activity or normal function of said targets, e.g., to inhibit binding and/or enzymatic activity of PARP and PI3K.

[059] As used herein, the term "dual inhibitor" refers to the capacity of a single molecule to interact with and/or inhibit the activity or normal function of two different target proteins, for example, PARP and PI3K or PARP and BRD4 in vivo or in vitro.

[060] The term "effective amount" or "effective concentration" when used in reference to a compound, product, or composition as provided herein, means a sufficient amount of the compound, product or composition to provide the desired pharmaceutical or therapeutic result. The exact amount required will vary depending on the particular compound, product or composition used, its mode of administration and the like. Thus, it is not always possible to specify an exact "effective amount." However, an appropriate effective amount may be determined by one of ordinary skill in the art informed by the instant disclosure using only routine experimentation.

[061] The term "hydrolyzable" as used herein refers to whether the group is capable of or prone to hydrolysis (i.e., splitting of the molecule or group into two or more new molecules or groups).

[062] The term "pharmaceutically acceptable salt" of a compound of the instant invention (e.g., Formula I) is one which is the acid addition salt of a basic compound of the invention with an inorganic or organic acid which affords a physiologically acceptable anion or which is the salt formed by an acidic compound of the invention with a base which affords a physiologically acceptable cation.

[063] The term "prodrug" or "procompound" as used in this application refers to a precursor or derivative form of a compound of the invention that may be less cytotoxic to cells compared to the parent compound or drug and is capable of being enzymatically or hydrolytically activated or converted into the more active parent form. See, e.g., Wilman, "Prodrugs in Cancer

Chemotherapy" Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985). The prodrugs of this invention include, but are not limited to, phosphate-containing prodrugs, thiophosphate- containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid- modified prodrugs, glycosylated prodrugs, beta-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs, optionally substituted phenyl acetami de- containing prodrugs, 5-fluorocytosine and other 5-fluorouridine prodrugs which can be converted into the more active cytotoxic free drug. Examples of cytotoxic drugs that can be derivatized into a prodrug form for use in this invention include, but are not limited to, compounds of the invention and chemotherapeutic agents such as described above.

[064] The term "conjugate" as used herein refers to a compound that has been formed by the joining of two or more compounds via either a covalent or non-covalent bond.

[065] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[066] A "metabolite" is a product produced through metabolism in the body of a specified compound or salt thereof. Metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from the oxidation, reduction, hydrolysis, amidation,

deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof.

[067] The phrase "pharmaceutically acceptable salt" as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the invention. Exemplary salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate "mesylate",

ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1 '-methyl ene-bis-(2- hydroxy-3-naphthoate)) salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound.

Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. Instances where multiple charged atoms are part of the pharmaceutically acceptable salt can have multiple counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms and/or one or more counter ion.

[068] If the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[069] If the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[070] As used herein, the terms "treatment", "treat", and "treating" refer to preventing, reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be

administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (i.e., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[071] A "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.

[072] The term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functionality while reacting other functional groups on the compound. For example, an "amino-protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyl oxycarbonyl (CBZ) and 9- fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl) ethyl, 2- (trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2-(p-nitrophenylsulfenyl)ethyl, 2- (diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[073] The terms "compound of this invention," and "compounds of the present invention" include compounds disclosed herein including but not limited to those of Formulas I-V and stereoisomers, geometric isomers, tautomers, solvates, metabolites, and pharmaceutically acceptable salts, prodrugs, and conjugates thereof.

[074] The term "TP scaffold" or "Thienopyranone scaffold" refers to a compound of general Formula I-V where M of the 5-membered ring is S.

[075] The term "Furanopyranone scaffold" refers to a compound of Formula I-V where M of the 5-membered ring is O.

[076] As used herein, the term "PI3K inhibiting" as applied to a compound of the invention means that a compound inhibits the normal or wild-type function of PI3K, i.e., enzymatic activity, in vivo and/or in vitro (e.g., ΡΒΚα, ΡΒΚβ, ΡΒΚγ, ΡΒΚδ) with an IC50 value of less than or equal to 50 μΜ in an appropriate in vitro assay.

[077] As used herein, the term "PARP inhibiting" as applied to a compound of the invention means that a compound inhibits the normal or wild-type function of PARP in vivo and/or in vitro with an IC50 value of less than or equal to 50 μΜ in an appropriate in vitro assay.

[078] As used herein, the term "Bromodomain inhibiting" as applied to a compound of the invention means that a compound inhibits the normal or wild-type function of a Bromodomain protein, in vivo and/or in vitro (e.g., BRD4) with an IC50 value of less than or equal to 50 μΜ in an appropriate in vitro assay.

B. Compounds [079] The present invention relates in part to single molecule, multitargeting compounds of Formula I and their use in therapeutic methods to treat and prevent diseases including cancer by inhibiting PARP and at least one other protein such as but not limited to PI3K and/or BRD4:

wherein M is independently oxygen (O) or sulfur (S);

R2 is selected from Rl or morpholine or thiomorpholine or piperazine;

R3 is selected from Rl; and

R4 is selected from Rl .

Representative compounds of Formula I include the following:

[080] The present invention also provides compounds of Formula II and methods of

administering those compounds to a mammal in need thereof including, but not limited to, compounds that inhibit PARP and at least one other protein such as but not limited to PI3K and/or

BRD4:

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I;

W is null, R1, O, S, CH₂, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate;

X is null or O, N, R1 or S, CH₂, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate;

provided that if W is N, O, or S then X cannot be N, O, or S; and if X is N, O, or S then W cannot be N, O, or S;

Y is null, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, phosphonic acid, phosphinic acid,

phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate; and

Z is a PARP binding group such as but not limited to phthalazinone, indazole, or

quinazolinedione. [081] The present invention also provides compounds of Formula III and methods of

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I;

X is null or O, N, NR1 or S, CH₂, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate;

Y is null, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate; and

Ar is aryl, heteroaryl, or heterocyclic bearing one, two, three or four substituents on the Ar ring independently selected from: H, F, CI, Br, I, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse caboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted aryl, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O-substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, reverse sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, nitroso, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, and substituted carbamate.

Representative examples of compounds of Formula III are shown in Table 1 below.

Table 1. Representative examples of compounds of Formula III.

It should be noted that a variety of different substituents in different positions can be arranged on the aromatic group of the phthalazone to comprise the Ar moiety in Formula III some of which are exemplified in the table above. Additionally, the connection between the 5-membered ring of the thienopyran or furanopyran ring can include a variety of different linkers in various attachment positions (ortho, meta, para for a six membered ring for example) represented by the W-X-Y group in Formula III some of which are exemplified in the table above. These permutations are readily synthetically accessible to one skilled in the art. [082] The present invention also provides compounds of Formula IV and methods of

administering those compounds to a mammal in need thereof including, but not limited to, compounds that inhibit PARP and at least one other protein such as but not limited to PI3K and/or BRD4:

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I;

Representative examples of compounds of Formula IV are shown in Table 2 below.

Table 2. Exemplary structures for Formula IV

It should be noted that a variety of different substituents in different positions can be arranged on the aromatic group of the quinazoline-2,4(lH,3H)-dione to comprise the Ar moiety in Formula IV some of which are exemplified in the table above. Additionally, the connection between the 5- membered ring of the thienopyran or furanopyran ring can be provided by a variety of different linkers in various attachment positions (ortho, meta, para for a six membered ring for example) represented by the W-X-Y group in Formula IV some of which are exemplified in the table above. These permutations are readily synthetically accessible to one skilled in the art.

[083] The present invention also provides compounds of Formula V and methods of

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I;

R5 is one, two or three substituents on the ring independently selected from Rl;

R6 is selected from NHR1, NH₂, OH, or OR1; and

R7 is selected from NHR1, NH₂, OH, or OR1.

Representative examples of compounds of Formula V are shown in Table 3 below. Table 3. Exemplary compounds of Formula V

It should be noted that a variety of different substituents in different positions can be arranged on the aromatic group of the 2H-indazole-7-carboxamide to comprise the Ar moiety in Formula V some of which are exemplified in the table above. Additionally, the connection between the 5- membered ring of the thienopyran or furanopyran ring can be provided by a variety of different linkers in various attachment positions (ortho, meta, para for a six membered ring for example) represented by the W-X-Y group in Formula V some of which are exemplified in the table above. These permutations are readily synthetically accessible to one skilled in the art.

[084] A pharmaceutically acceptable salt of a compound of the invention is one which is the acid addition salt of a basic compound of Formula I-V with an inorganic or organic acid which affords a physiologically acceptable anion, or which is the salt formed by an acidic compound of Formula I-V with a base which affords a physiologically acceptable cation and provides a particular aspect of the invention. Examples of such acids and bases are provided hereinbelow. [085] Another aspect of the invention relates to methods of using a pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of Formula I-V (or a pharmaceutically acceptable salt thereof) as provided in any of the descriptions herein.

[086] In addition, compounds (or salts thereof) of the present invention are useful as an active ingredient in the manufacture of a medicament for use in inhibiting PARP and at least one other protein including but not limited to PI3K and a bromodomain protein for the treatment of diseases including but not limited to cancer.

[087] The present invention also provides a method for treating a disease in a human or other mammal including, but not limited to, cancer by administering a therapeutically effective amount of a compound(s) of the invention including compound(s) or composition(s) of Formula I-V or conjugate or prodrug thereof having any of the definitions herein.

[088] The present invention further provides a method for inhibiting PARP and at least one other protein including but not limited to PI3K and a bromodomain protein in a mammal in need thereof by administering a therapeutically effective amount of a compound of Formula I-V, or conjugate or prodrug thereof having any of the definitions herein.

[089] Further, the present invention provides a method of inhibiting tumor growth comprising administering to a mammal in need of treatment, an effective dose of a compound of Formula I-V, or conjugate or prodrug thereof.

[090] Also, there is provided a compound of Formula I-V (or conjugate, prodrug, or salt thereof) having any of the definitions herein for use as an anticancer agent.

[091] In addition, there is provided use of a compound of Formula I-V having any of the definitions herein for the manufacture of a medicament for the treatment of a disease described herein including, but not limited to, cancer.

[092] As an additional feature of the invention there is provided a pharmaceutical formulation comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a conjugate of a compound of Formula I-V (or of a pharmaceutically acceptable salt thereof) as provided in any of the descriptions herein.

[093] The present invention also includes methods of use of isotopically-labeled compounds, and pharmaceutically acceptable salts thereof, of compounds of Formulas I-V, but where one or more atoms are replaced by a corresponding isotope. Examples of isotopes that can be

incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine. Compounds of the present disclosure, conjugates thereof, and pharmaceutically acceptable salts of said compounds or of said conjugates which contain the aforementioned isotopes and/or other isotopes of other atoms are included within the scope of this disclosure. Certain isotopically-labeled compounds of the present disclosure, for example those into which radioactive isotopes, such as ²H, ¾, ¹⁴C, ¹⁵N, ³²P and ¹³¹I are incorporated, are useful in drug and/or substrate tissue distribution assays for example when imaging tumors. Fluorine-18 (¹⁸F) is particularly preferred for the ease of preparation and detectability it provides. Isotopically labeled compounds of the invention can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[094] It will be appreciated that certain compounds of Formula I-V (or salts, procompounds, conjugates, etc.) may exist in, and be isolated in, isomeric forms, including tautomeric forms, cis- or trans-isomers, as well as optically active, racemic, enantiomeric or diastereomeric forms. It is to be understood that the present invention encompasses a compound of Formula I-V in any of the tautomeric forms or as a mixture thereof; or as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of Formula I-V as a mixture of enantiomers, as well as in the form of an individual enantiomer, any of which mixtures or form desirably possesses inhibitory properties against kinases including but not limited to PI3 kinase, it being well known in the art how to prepare or isolate particular forms and how to determine inhibitory properties against kinases by standard tests including those described herein below.

[095] In addition, a compound of Formula I-V (or salt, procompound, conjugate thereof, etc.) used in the methods of the invention may exhibit polymorphism or may form a solvate with water or an organic solvent. The present invention also encompasses any such polymorphic form, any solvate or any mixture thereof.

[096] The methods of the invention include manufacturing and administering a pharmaceutically acceptable salt of a compound of Formula I-V. A basic compound of the invention possesses one or more functional groups sufficiently basic to react with any of a number of inorganic and organic acids affording a physiologically acceptable counterion to form a pharmaceutically acceptable salt. Acids commonly employed to form pharmaceutically acceptable acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid,

methanesulfonic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts thus are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenyl acetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma-hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1 -sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid, hydrobromic acid and sulfuric acid.

C.l. Synthesis of compounds and conjugates

[097] Compounds of the invention may be prepared according to the examples provided herein as well as by processes known in the chemical arts and described, for example, in US Patent 8,557,807 and references cited therein, as well as in G.A. Morales et al., J. Med. Chem. 2013, 56, 1922-1939, the entire contents of which are herein incorporated by reference. Starting materials and intermediates used to prepare a compound of the invention are either

commercially available or can be readily prepared by one of ordinary skill in the art.

Compounds and conjugates described herein and used in the therapeutic methods of the invention can be made, for example, by the procedures disclosed in US Patents 6,949,537;

7,662,977; 7,396,828; 8,557,807; and 9,505,780; and in US Patent Applications 14/702816, and 15/297293, the entire contents of which are herein incorporated by reference. Compounds of the present invention may also be prepared by methods described in, for example, US20100160340 (LY2835219/Abemaciclib), WO2010020675 (PD-0332991/Palbociclib), WO2010020675 (LEE- 011/Ribociclib), WO200803215 (Palbociclib) and US7781583 (Palbociclib) which are herein incorporated by reference. Thio compounds can be made from oxygen analogs as described in the art, for example by using Lawesson's reagent as described in Morales et al., J. Med. Chem. 2013. Furan analogs of the thiophene-pyranone compounds (termed thienopyranones) can be made, for example, by the general schemes outlined below where the key intermediate "g" is prepared and utilized. Intermediate "g" is then further elaborated to the oxygen analog of "compound 6" as described in Morales et al., J. Med. Chem. 2013 (reference incorporated herein) which is designated below as compound "i". Compound "i" can then be reacted via couplings with boronates to make the final substituted furanopyranones of the invention.

Alternatively, the bromine atom in compound "i" can be converted to a boron derivative and then coupled with aryl or heteroaryl bromides or iodides to make furanopyranones of the invention. [098] A reaction scheme is shown below for preparing furanopyranones of the invention via the key furan intermediate "g" and subsequent conversion to compound "i" which is then further reacted to produce compounds of the invention:

[099] Expanded reaction scheme for introducing substituents at R4 of furan-based compounds of the invention are based on methods described in US20120022059-A1 which are herein incorporated by reference and shown below:

[0100] Scheme for introducing substituents at R4 of TP scaffold core. The selective introduction of substituents at the R4 position of thiophene containing compounds of the invention is based on the synthesis of molecule "m" (R4 is pyrazole) starting from molecule "1" as disclosed in published US Patent Application 2016/0287561, the entire contents of which is herein incorporated by reference.

[0101] An additional scheme to obtain furanopyranones is shown below using NaN₃ to arrive at the key bromo-hydroxy-furan "g" which can then be used to make intermediate "i" and subsequent elaboration to compounds of the invention:

Compounds of the invention with various R2 substituents other than morpholine are made using for example acetylated amines, acetylated alcohols or other methyl ketones in place of the acetyl morpholine. For example, use of acetone in the reaction scheme would give R2 = methyl group. Also, compounds of the invention with various Rl substituents are made using substituted ketones or substituted acetyl morpholine, for example, use of propionylmorpholine would yield Rl= methyl group. [0102] Exemplary schemes for synthesizing compounds of Formula I are shown below:

rs

[0103] A specific example of a dual PARP/PI3K inhibitor of Formula I and III is illustrated by Compound 1 which was synthesized by the method described in Example 1. The use of different phthalic anhydrides in this procedure results in differently substituted analogs of Compound 1 bearing substituents on the aryl group designated in Formula III.

[0104] Compounds of Formula IV can be made by the reaction scheme below showing the synthesis of Compound 6 as representative of Formula rV:

It should be recognized by those skilled in the art that many different amino-aryl-halides or amino-heteroaryl-halides can be substituted in the above scheme to produce analogous compounds where the 5 membered ring thiazole is replaced by a different 5 or 6 membered ring optionally substituted.

[0105] Compounds of Formula V can be made by the reaction scheme below showing the synthesis of Compound 5 as representative of Formula V:

It should be recognized by those skilled in the art that many different amino-aryl-halides or amino-heteroaryl-halides can be substituted in the above scheme to produce analogous compounds where the 5 membered thiazole is replaced by a different 5 or 6 membered ring optionally substituted.

[0106] The compounds used in the methods of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms or quatemized nitrogen atoms in their structure. It will be appreciated that certain compounds of Formula I-V (or salts, conjugates, etc.) may exist in, and be isolated in, isomeric forms, including tautomeric forms, cis- or trans-isomers, as well as optically active, racemic, enantiomeric, or diastereomeric forms. It is to be understood that the present invention encompasses a compound of Formula I-V in any of the tautomeric forms or as a mixture thereof; or as a mixture of diastereomers, as well as in the form of an individual diastereomer, and that the present invention encompasses a compound of Formula I-V as a mixture of enantiomers, as well as in the form of an individual enantiomer, any of which mixtures or form possesses inhibitory properties against kinases, for example PI3 kinases. The compounds of the invention and their pharmaceutically acceptable salts may exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of the compounds used in the methods of the invention. The carbonyl of the chromone is converted to the thione moiety as described above by reaction with Lawesson's reagent, or other ketone to thioketone conversion conditions known to those skilled in the art.

D. Formulations

[0107] As an additional aspect of the invention there is provided a pharmaceutical formulation or composition comprising in association with a pharmaceutically acceptable carrier, diluent or excipient, a compound of the invention, e.g., a compound of Formula I-V (or a pharmaceutically acceptable salt or procompound or conjugate thereof) as provided in any of the descriptions herein for use in a method of the invention. Compositions of the present invention may be in the form of tablets or lozenges formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binding agents, fillers, lubricants, disintegrants and wetting agents. Binding agents include, but are not limited to, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch and

polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, maize starch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycollate. Wetting agents include, but are not limited to, sodium lauryl sulfate. Tablets may be coated according to methods well known in the art.

[0108] Compositions used in the methods of the present invention may also be liquid

formulations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups, and elixirs. The compositions may also be formulated as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain additives including, but not limited to, suspending agents, emulsifying agents, nonaqueous vehicles and preservatives. Suspending agent include, but are not limited to, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxy ethyl cellulose, carboxym ethyl cellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Nonaqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Preservatives include, but are not limited to, methyl or propyl p-hydroxybenzoate and sorbic acid.

[0109] Compositions used in the methods of the present invention may also be formulated as suppositories, which may contain suppository bases including, but not limited to, cocoa butter or glycerides. Compositions of the present invention may also be formulated for inhalation, which may be in a form including, but not limited to, a solution, suspension, or emulsion that may be administered as a dry powder or in the form of an aerosol using a propellant, such as

dichlorodifluoromethane or trichlorofluoromethane. Compositions of the present invention may also be formulated transdermal formulations comprising aqueous or nonaqueous vehicles including, but not limited to, creams, ointments, lotions, pastes, medicated plaster, patch, or membrane.

[0110] Compositions used in the methods of the present invention may also be formulated for parenteral administration including, but not limited to, by injection or continuous infusion.

Formulations for injection may be in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulation agents including, but not limited to, suspending, stabilizing, and dispersing agents. The composition may also be provided in a powder form for reconstitution with a suitable vehicle including, but not limited to, sterile, pyrogen-free water.

[0111] Compositions used in the methods of the present invention may also be formulated as a depot preparation, which may be administered by implantation or by intramuscular injection. The compositions may be formulated with suitable polymeric or hydrophobic materials (as an emulsion in an acceptable oil, for example), ion exchange resins, or as sparingly soluble derivatives (as a sparingly soluble salt, for example).

[0112] Compositions used in the methods of the present invention may also be formulated as a liposome preparation. The liposome preparation can comprise liposomes which penetrate the cells of interest or the stratum corneum, and fuse with the cell membrane, resulting in delivery of the contents of the liposome into the cell. For example, liposomes such as those described in U.S. Pat. No. 5,077,211 of Yarosh et al., U.S. Pat. No. 4,621,023 of Redziniak et al., or U.S. Pat. No.

4,508,703 of Redziniak et al., can be used. Other suitable formulations can employ niosomes. Niosomes are lipid vesicles similar to liposomes, with membranes consisting largely of non-ionic lipids, some forms of which are effective for transporting compounds across the stratum corneum.

[0113] The following formulation examples are illustrative only and are not intended to limit the scope of the compounds used in the methods of the invention in any way. The phrase "active ingredient" refers herein to a compound according to Formula I-V or a pharmaceutically acceptable salt, procompound, conjugate, or solvate thereof.

Formulation 1 : Tablet containing the following components:

Formulation 2: Capsules containing the following components:

[0114] Parenteral dosage forms for administration to patients by various routes including, but not limited to, subcutaneous, intravenous (including bolus injection), intramuscular, and intra-arterial are also contemplated by the present invention. Parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a patient. Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable vehicle for injection, suspensions ready for injection, and emulsions. Suitable vehicles that can be used to provide parenteral dosage forms of the invention are well known to those skilled in the art. Examples include, but are not limited to: Water for Injection USP; aqueous vehicles such as, but not limited to, Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, and Lactated Ringer's Injection; water-miscible vehicles such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

[0115] An example parenteral composition used in the method of the invention would be intended for dilution with aqueous solution(s) comprising for example 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, prior to administration to a patient, and is an aqueous solution that comprises irinotecan, sorbitol F powder, and lactic acid, USP, and has a pH of from about 3.0 to about 3.8.

E. Therapeutic Use [0116] In one embodiment of the present invention, a compound or composition of the invention is administered to a mammal in need thereof including a human to treat or prevent a disease including, but not limited to, cancer by administering a therapeutically effective dose of a compound of Formula I-V. In one aspect, a compound of the invention provides therapeutic benefit by inhibiting PARP and at least one other protein including but not limited to PI3K and bromodomain protein. Without intending to be bound by theory, it is believed that the therapeutic effectiveness of a compound of the invention involves simultaneous inhibition, for example, of PARP and PI3K, or PARP and a bromodomain protein such as BRD4 with a single molecule. Inhibiting PARP and PI3K or a bromodomain protein with a single drug provides a sophisticated combination therapy for patients resulting in more effective and durable clinical benefits.

[0117] In one aspect, the invention relates to a method for inhibiting PARP in a mammal by administering a compound of the invention.

[0118] In another aspect, the invention relates to a method for inhibiting PI3K in a mammal by administering a compound of the invention.

[0119] In another aspect, the invention relates to a method for inhibiting a bromodomain protein in a mammal by administering a compound of the invention.

[0120] In another aspect, the invention relates to a method for inhibiting PARP and PI3K or PARP and a bromodomain protein in one cell at the same time in a mammal by administering a compound of the invention.

[0121] In another aspect, the invention relates to a method for inhibiting PARP and at least one of PI3K and a bromodomain protein with a single compound in each cell at the same time wherein the inhibition achieved is superior in a greater percentage of cells than that achieved by a combination of inhibitors of those same targets.

[0122] In another aspect, the present invention provides a method for enhancing the

chemosensitivity of tumor cells comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-V.

[0123] In another aspect, the present invention provides a method for enhancing the

radiosensitivity of tumor cells comprising administering to a patient in need thereof a

therapeutically effective amount of a compound of Formula I-V.

[0124] In another aspect, the present invention provides a method for inhibiting or reducing tumor growth comprising administering to a patient in need thereof a therapeutically effective amount of a compound of a compound of Formula I-V. [0125] In another aspect, the present invention provides a method for inducing oxidative stress in tumor cells comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-V.

[0126] In another aspect, the present invention provides a method for inhibiting or reducing tumor growth by inhibiting cancer stem cell growth and/or proliferation comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-V.

[0127] In another aspect, the present invention provides a method for inhibiting tumor induced angiogenesis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-V.

[0128] Further, the present invention provides a method for inhibiting angiogenesis associated with cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-V.

[0129] In yet another aspect, the present invention provides a therapeutic method for increasing apoptosis in cancer cells and cancerous tumors comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-V.

[0130] The present invention also provides a method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I-V.

[0131] In another aspect, a compound of the invention provides dual inhibitory activity against PARP and PI3K, or PARP and a bromodomain protein such as BRD4 to treat lymphoid malignancy in particular B cell driven lymphoma and leukemias.

[0132] The PARP, PI3K, and/or bromodomain inhibitory activity of a compound of the invention can be determined by methods known to the skilled artisan, or by procuring relevant analysis by a commercial vendor offering such services. For example, in vitro kinase inhibition (e.g., PI3K inhibition) can be determined by a standard kinase inhibition assay using labeled ATP to determine if a test compound inhibits the transfer of phosphate from ATP to the kinase substrate. In vivo, PI3K inhibition can be determined from target tissue biopsies by standard tissue processing in which cells are disrupted and Western Blot analysis performed to determine the presence or absence of pAKT (substrate of PI3K) relative to a control sample. The activity of a compound of the invention as an inhibitor of a bromodomain-containing protein, such as a BET protein, such as BRD2, BRD3, BRD4, and/or BRDT, or an isoform or mutant thereof, may be determined in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of bromodomain-containing proteins. Alternatively, inhibitor binding may be determined by running a competition experiment where a provided compound is incubated with a bromodomain-containing protein, such as a BET protein bound to known ligands, labeled or unlabeled. For example, bromodomain inhibition can be determined in vitro using Alpha Screen Technology (Perkin Elmer Life and Analytical Sciences, Shelton, CT). In vivo bromodomain inhibition can be determined indirectly by evaluating the amount of a protein whose gene transcription is influenced or controlled by the bromodomain protein, for example, the MYCN protein transcription is controlled by BRD4 (J.E. Delmore et al., Cell 2011, 146, 904-917; A. Puissant, Cancer Discov. 2013, 3, 308-323). PARP inhibition can be determined using an activity assay (PARP Assay Kit) to measure the incorporation of biotinylated poly(ADP-ribose) onto histone proteins. Trevigen's HT Universal 96-well PARP Assay Kits (Trevigen Inc., Gaithersburg, MD) which measures the incorporation of biotinylated poly(ADP-ribose) onto histone proteins in a 96-well strip well format was used to measure PARP activity. Further details are available at the supplier's website (https://trevigen.com/docs/protocol/protocol 4676-096-K.pdf).

Additionally, PARP inhibition was performed as a service provided by a vendor such as BPS Bioscience (6042 Cornerstone Court West, Suite B San Diego, CA 92121).

[0133] In certain embodiments, the invention provides a method for treating a disorder (as described above) in a mammal, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of the invention. The identification of those patients who are in need of treatment for the disorders described herein is within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients who are at risk of developing the above disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the subject patient.

[0134] Assessing the efficacy of a treatment in a patient may include determining the pre- treatment extent of a disorder by methods known in the art (i.e., determining tumor size or screening for tumor markers where the cell proliferative disorder is cancer), then administering a therapeutically effective amount of a compound of the invention, to the patient. After an appropriate period of time after administration (e.g., 1 day, 1 week, 2 weeks, one month, six months), the extent of the disorder is again determined. Modulation (e.g., decrease) of the extent or invasiveness of the disorder (i.e., reduced tumor size) would indicate efficacy of the treatment. The extent or invasiveness of the disorder may be determined periodically throughout treatment. For example, the extent or invasiveness of the disorder may be assessed every few hours, days or weeks to assess the further efficacy of the treatment. A decrease in extent or invasiveness of the disorder indicates that the treatment is efficacious. The methods described may be used to screen or select patients that may benefit from treatment with a compound of the invention. [0135] A variety of cancers may be treated according to the methods of the present invention. The cancer progression may involve cells with BRCA 1/2 loss of function somatic or germline mutations, or may involve BRCA wild type cancers. Exemplary cancers that can be treated according to the present invention include, but are not limited to: carcinoma of the bladder (including accelerated and metastatic bladder cancer), breast, colon (including colorectal cancer), kidney, liver, lung (including small and non-small cell lung cancer and lung adenocarcinoma), ovary, prostate, testes, genitourinary tract, lymphatic system, rectum, larynx, pancreas (including exocrine pancreatic carcinoma), esophagus, stomach, gall bladder, cervix, thyroid, and skin (including squamous cell carcinoma); hematopoietic tumors of lymphoid lineage including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma, histiocytic lymphoma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage including acute and chronic myelogenous leukemias, myelodysplastic syndrome, myeloid leukemia, and promyelocytic leukemia; tumors of the central and peripheral nervous system including astrocytoma, medulloblastoma, neuroblastoma, glioma, and schwannomas; tumors of

mesenchymal origin including fibrosarcoma, rhabdomyosarcoma, and osteosarcoma; and other tumors including melanoma, xeroderma pigmentosum, keratoacanthoma, seminoma, thyroid follicular cancer, and teratocarcinoma. The methods of the invention may also be used to treat accelerated or metastatic cancers of the bladder, pancreatic cancer, prostate cancer, non-small cell lung cancer, colorectal cancer, and breast cancer.

[0136] Additional cancers treatable using an effective amount of a compound of Formula I-V include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive K-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt' s lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, Leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangiosarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non- small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, Merkle cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom macroglobulinemia, Warthin's tumor, and Wilms' tumor.

[0137] A method of the invention may be performed simultaneously or metronomically with other anti-cancer treatments such as chemotherapy and radiation therapy. The term

"simultaneous" or "simultaneously" as used herein, means that the other anti -cancer treatment and the compound of the present invention are administered within 48 hours, preferably 24 hours, more preferably 12 hours, yet more preferably 6 hours, and most preferably 3 hours or less, of each other. The term "metronomically" as used herein means the administration of the compounds at times different from the chemotherapy and at a certain frequency relative to repeat

administration and/or the chemotherapy regimen.

[0138] Chemotherapy treatment may comprise administration of a cytotoxic agent or cytostatic agent, or combination thereof. Cytotoxic agents prevent cancer cells from multiplying by: (1) interfering with the cell's ability to replicate DNA, and (2) inducing cell death and/or apoptosis in the cancer cells. Cytostatic agents act via modulating, interfering or inhibiting the processes of cellular signal transduction which regulate cell proliferation and sometimes at low continuous levels.

[0139] Classes of compounds that may be used as cytotoxic agents include but are not limited to the following: alkylating agents (including, without limitation, nitrogen mustards, ethyl enimine derivatives, alkyl sulfonates, nitrosoureas and triazenes): uracil mustard, chlormethine, cyclophosphamide (Cytoxan®), ifosfamide, melphalan, chlorambucil, pipobroman, triethylene- melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide; antimetabolites (including, without limitation, folic acid antagonists, pyrimidine analogs, purine analogs and adenosine deaminase inhibitors):

methotrexate, 5-fluorouracil, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine; natural products and their derivatives (for example, vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and

epipodophyllotoxins): vinblastine, vincristine, vindesine, bleomycin, dactinomycin,

daunorubicin, doxorubicin, epirubicin, idarubicin, ara-c, paclitaxel (paclitaxel is commercially available as Taxol®), mithramycin, deoxyco-formycin, mitomycin-c, 1 -asparaginase, interferons (preferably IFN-. alpha.), etoposide, and teniposide. Other proliferative cytotoxic agents are navelbene, CPT-11, anastrozole, letrozole, capecitabine, raloxifene, cyclophosphamide, ifosamide, and droloxifene. [0140] Microtubule affecting agents interfere with cellular mitosis and are well known in the art for their cytotoxic activity. Microtubule affecting agents useful in the invention include, but are not limited to, allocolchicine (NSC 406042), halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolastatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®, NSC 125973), Taxol® derivatives (e.g., derivatives NSC 608832), thiocolchicine NSC 361792), trityl cysteine (NSC 83265), vinblastine sulfate (NSC 49842), vincristine sulfate (NSC 67574), natural and synthetic epothilones including but not limited to epothilone A, epothilone B, and discodermolide (see R. F. Service, Science 1996, 274, 2009) estramustine, nocodazole, MAP4, and the like. Examples of such agents are also described in J.C. Bulinski et al., J. Cell Sci. 1997, 110, 3055-3064; D. Panda et al., Proc. Natl. Acad. Sci. USA 1997, 94, 10560-10564; P.F. Muhlradt et al., Cancer Res. 1997, 57, 3344-3346; K.C. Nicolaou et al., Nature 1997, 387, 268-272; R.J. Vasquez et al., Mol. Biol. Cell. 1997, 8, 973-985; and D. Panda et al., J. Biol. Chem. 1996, 271, 29807-29812.

[0141] Other suitable cytotoxic agents include but are not limited to epipodophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor; procarbazine; mitoxantrone; platinum coordination complexes such as cis-platin and carboplatin; biological response modifiers;

growth inhibitors; antihormonal therapeutic agents; leucovorin; tegafur; and haematopoietic growth factors.

[0142] Cytostatic agents that may be used according to the methods of the invention include, but are not limited to, hormones and steroids (including synthetic analogs): 17 alpha-ethinylestradiol, diethylstilbestrol, testosterone, prednisone, fluoxymesterone, dromostanolone propionate, testolactone, megestrol acetate, methylprednisolone, methyl -testosterone, prednisolone, triamcinolone, chlorotrianisene, hydroxyprogesterone, aminoglutethimide, estramustine, medroxyprogesterone acetate, leuprolide, flutamide, toremifene, zoladex. Other cytostatic agents are antiangiogenics such as matrix metalloproteinase inhibitors, and other VEGF inhibitors, such as anti-VEGF antibodies and small molecules such as ZD6474 and SU6668 are also included. Anti-Her2 antibodies from Genentech may also be utilized. A suitable EGFR inhibitor is EKB- 569 (an irreversible inhibitor). Also included are ImClone antibody C225 immunospecific for the EGFR, and Src inhibitors. Also suitable for use as a cytostatic agent is Casodex® (bicalutamide, AstraZeneca) which renders androgen-dependent carcinomas non-proliferative. Yet another example of a cytostatic agent is the antiestrogen Tamoxifen® which inhibits the proliferation or growth of estrogen dependent breast cancer. Inhibitors of the transduction of cellular proliferative signals are cytostatic agents. Representative examples include but are not limited to epidermal growth factor inhibitors, Her-2 inhibitors, MEK-1 kinase inhibitors, MAPK kinase inhibitors, PI3K inhibitors, Src kinase inhibitors, and PDGF inhibitors.

[0143] Methods of the invention also include treating a subject with a MYC-dependent cancer, comprising administration of a compound of Formula I-V. Subjects with MYC-dependent cancer can be determined by several methods including but not limited to determining MYC mRNA expression levels in the tumor and/or MYC protein expression in the tumor. Preferred subjects for treatment with the methods of the invention can be identified by historical experience or known prevalence of MYC activation in certain cancers such as multiple myeloma (J.E. Delmore, Cell 2011, 146, 904-917), CLL (J.R. Brown et al., Clin. Cancer Res. 2012, 18, 3791-3802), leukemia (M.A. Dawson et al., Nature 2013, 478, 529-533), neuroblastoma (A. Puissant et al., Cancer Discov. 2013, 3, 308-323), or medulloblastoma (Y.J. Cho et al., J. Clin. Oncol. 2010, 29, 1424-1430).

[0144] Other diseases and conditions treatable according to the methods of this invention include, but are not limited to, other proliferative disorders, sepsis, autoimmune disease, infections including but not limited to viral infections. Diseases such as atherosclerosis and type 2 diabetes (V.A. DeWaskin et al., Nature Rev. Drug Disc. 2013, 12, 661-662) and obesity and inflammation (A.C. Belkina et al., Nature Rev. Cancer 2012, 12, 465-474) are also treatable according to the methods of the invention.

[0145] The methods of this invention further include administering one or more compounds of Formula I-V for treating benign proliferative disorders such as, but are not limited to,

meningioma, cerebri, seborrheic keratoses, stomach polyps, thyroid nodules, cystic neoplasms of the pancreas, hemangiomas, multiple endocrine neoplasia, nasal polyps, pituitary tumors, juvenile polyposis syndrome, prolactinoma, pseudotumor benign soft tissue tumors, bone tumors, brain and spinal tumors, eyelid and orbital tumors, granuloma, lipoma, vocal cord nodules, polyps, and cysts, chronic pilonidal disease, dermatofibroma, pilar cyst, pyogenic granuloma, and Castleman disease.

F. Administration and Dosage

[0146] Compounds of Formula I-V for use in a therapeutic method of the present invention can be administered in any manner including but not limited to orally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, pulmonarily, nasally, or bucally. Parenteral administration includes but is not limited to intravenous, intraarterial, intraperitoneal,

subcutaneous, intramuscular, intrathecal, and intraarticular. Compounds or compositions of the invention may also be administered via slow controlled i.v. infusion or by release from an implant device. [0147] A therapeutically effective amount of a compound of Formula I-V for use in a method of the invention varies with the nature of the condition being treated, the length of treatment time desired, the age and the condition of the patient, and is ultimately determined by the attending physician. In general, however, doses employed for adult human treatment typically are in arange of about 0.001 mg/kg to about 200 mg/kg per day, or about 1 µg/kg to about 100 µg/kg per day. The desired dose may be conveniently administered in a single dose, or as multiple doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. Multiple doses over a 24-hour period may be desired or required.

[0148] A number of factors may lead to the compounds of Formula I-V being administered according to the methods of the invention over a wide range of dosages. When given in combination with other therapeutic agents, compounds of the present invention may be provided at relatively lower dosages. In addition, the use of targeting agents on a conjugate is expected to lower the effective dosage required for treatment. As a result, the daily dosage of a targeted compound administered according to the methods of the present invention may be from about 1 ng/kg to about 100 mg/kg. The dosage of a compound of Formula I-V according to the methods of the present invention may be at any dosage including, but not limited to, about 1 µg/kg, 25 µg/kg, 50 µg/kg, 75 µg/kg, 100 µg/kg, 125 µg/kg, 150 µg/kg, 175 µg/kg, 200 µg/kg, 225 µg/kg, 250 µg/kg, 275 µg/kg, 300 µg/kg, 325 µg/kg, 350 µg/kg, 375 µg/kg, 400 µg/kg, 425 µg/kg, 450 µg/kg, 475 µg/kg, 500 µg/kg, 525 µg/kg, 550 µg/kg, 575 µg/kg, 600 µg/kg, 625 µg/kg, 650 µg/kg, 675 µg/kg, 700 µg/kg, 725 µg/kg, 750 µg/kg, 775 µg/kg, 800 µg/kg, 825 µg/kg, 850 µg/kg, 875 µg/kg, 900 µg/kg, 925 µg/kg, 950 µg/kg, 975 µg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, or 100 mg/kg.

[0149] The present invention has multiple aspects, illustrated by the following non-limiting examples. The examples are merely illustrative and do not limit the scope of the invention in any way. EXAMPLES

[0150] HPLC traces for example compounds synthesized were recorded using a HPLC consisting of Shimadzu or Agilent HPLC pumps, degasser and UV detector, equipped with an Agilent 1100 series auto-sampler. The UV detection provided a measure of purity by percent peak area. A MS detector (APCI) PE Sciex API 150 EX was incorporated for purposes of recording mass spectral data providing compound identification. HPLC/mass traces were obtained using one of three chromatographic methods. If a method is not specifically listed in the example then method A was utilized. The three methods are listed below:

Method A: Column SunFire™ (Waters) CI 8, size 2.1 mm X 50 mm;

Solvent A: 0.05 % TFA in water, Solvent B: 0.05 % TFA in acetonitrile;

Flow rate - 0.8 mL/min; Gradient: 10 % B to 90 % B in 2.4 min, hold at 90 % B for 1.25 min and 90 % B to 10 % B in 0.25 min, hold at 10 % B for 1.5 min.; UV detector - channel 1 = 220 nm, channel 2 = 254 nm.

Method B: Column Aquasil™ (Thermo) C18, size 2.1 mm X 150 mm; particle size 5 μ. Solvent A: 0.05 % TFA in water, Solvent B: 0.05 % TFA in acetonitrile;

Flow rate - 0.3 mL/min; Gradient: 10 % B to 95 % B in 2.4 min, hold at 95 % B for 6.25 min and 95 % B to 10 % B in 0.2 min, hold at 10 % B for 1.5 min.; UV detector - channel 1 = 220 nm, channel 2 = 254 nm.

Method C: Column Phenomenex CI 8, size 2 mm X 50 mm; particle size 5 μ. Solvent A: 0.05 % TFA in water, Solvent B: 0.05 % TFA in acetonitrile; Flow rate - 0.8 mL/min; Gradient: 10 % B to 90 % B in 2.4 min, hold at 90 % B for 1.25 min and 90 % B to 10 % B in 0.25 min, hold at 10 % B for 1.5 min.; UV detector - channel 1 = 220 nm, channel 2 = 254 nm.

[0151] EXAMPLE 1. PREPARATION OF DUAL PARP PI3K INHIBITOR COMPOUND

1: (Note that preparation of the key starting material 3-bromo-5-mo holino-4-oxa-l-thia-7- indenone is described in the references in the specification for example Morales et al., J. Med. Chem. 2013).

Step 1: o-[f5-Morpholino-7-oxo-4-oxa-l-thia-3-indenyl)carbonyl1benzoic acid: A stirring solution of 3-bromo-5-mo holino-4-oxa-l-thia-7-indenone (825 mg, 2.60 mmol) in THF (16 mL), under an inert atmosphere of N₂, was cooled to -78 °C (dry ice/acetone bath) and the treated with dropwise addition of n-butyl lithium (1.20 mL of a 2.5M solution in hexanes, 2.99 mmol). The resulting reddish reaction mixture was kept for 1 hour at -78 °C and then treated with a solution of phthalic anhydride (770 mg, 5.20 mmol). After keeping the mixture at -78 °C, the dry ice/acetone bath was removed and the reaction allowed to warm to room temperature with stirring over 1 hour. The reaction mixture was quenched by addition of saturated NH CI aqueous solution and the product was extracted with ethyl acetate in a separatory funnel. The organics were washed brine, dried over anhydrous MgS0₄, filtered and concentrated to yield the crude product. This was purified by automated reverse phase chromatography (CI 8), eluting with a CH₃CN:H20 20% to 70% CH₃CN with 0.1% TFA gradient. The fractions containing the title product were concentrated to yield 196 mg (-50% purity by LCMS, 0.25 mmol, 10 %) as light-yellow oil used directly in the next reaction.

LC/MS - HPLC (254 nm) - Rt 2.30 min. MS (ESI) m/z 386.4 [M⁺ + H⁺].

Step 2: 5-Morpholino-3-(4-oxo-3H-phthalazin-l-yl)-4-oxa-l-thia-7-indenone (Compound 1):

A suspension of o-[(5-mo holino-7-oxo-4-oxa-l-thia-3-indenyl)carbonyl]benzoic acid (196 mg, ~ 50% purity, 0.25 mmol) in absolute ethanol (2.5 mL) under magnetic stirring, was treated with hydrazine (24 μΐ_^, 0.75 mmol) and the resulting mixture was heated to reflux. After 1 hour, LCMS indicated partial conversion to product. Another portion of hydrazine (25 μΐ_^, 0.76 mmol) was added and reflux continued for another hour, after which time the reaction was deemed complete by LCMS. After cooling, the reaction was evaporated under vacuum. The crude product was purified by preparative silica-gel chromatography (20 X 20 cm plates, 1 μΜ thickness) eluting with a 95:5 v/v mixture of CL Ch/MeOH mixture. Compound 1 was obtained as a yellow solid. Yield = 21 mg (0.055 mmol, 22%).

LC/MS - HPLC (254 nm) - Rt 2.21 min. MS (ESI) m/z 382.1 [M⁺ + H⁺].

Substituting aromatic 1,2-dicarboxylic acids, esters, or their anhydrides other than plain phthalic acid anhydride as used in step 1 with subsequent cyclization reaction conditions such as those described in step 2 will generate analogs of Compound 1.

[0152] EXAMPLE 2. Molecular design and docking scores of dual PARP-PBK(gamma) inhibitors.

Dual PARP-PI3K inhibitors were devised according to the following procedure. To construct a virtual library of potential dual PARP-PI3K inhibitors moieties believed to exhibit PARP affinity were selected as PARP-recognition building blocks (42PARP building blocks, See Table 4). For PI3K recognition, 82 TP -based building blocks were used where the aromatic units linked to the thiophene group of the TP core included with 5-membered and 6-membered rings (benzene and heterocyclic rings, See Table 5). Each of these 82 TP -based building blocks is further diversified by changing oxygen for sulfur in the thiophene to give a furan ring

(benzofuran) yielding a total of 164 TP -based building blocks. These 164 TP -building blocks were then doubled by also inputting the oxygen of the pyran ring as a sulfur thus making a total of 328 TP -building blocks. These PI3K recognition units contained a single attachment point (permutated on the benzene or heterocycle) for the linkage with the PARP recognition fragment. The 82 TP -based blocks (only oxygen version shown) are shown on subsequent pages after the 42 PARP -recognition unit building blocks.

The PARP and PI3K recognition structures were combined combinatorially to create a virtual library of 13,776 compounds (42 x 328) as shown in the scheme below:

It should be noted that the I, Br, and CI groups in the scheme above are not chemically reacting but are placeholders for points of attachment in silico to combinatorially create a virtual library. The actual synthesis of these compounds can be achieved using the methods described elsewhere in this specification and in the examples some of which may involve chloro, bromo, and/or iodo aromatic coupling reactions.

All hydrogen atoms were added to the compounds. Since these compounds are expected to ultimately be in the blood stream if/when administered to a living organism or animal (i.e., primates, non-primates), the ionized species of the compounds in such environment will be calculated for our in silico studies. Thus, the compounds were ionized based on their calculated ionization state at physiological pH 7.4, and their structures minimized to output a virtual library of 13,776 compounds each with a 3-dimensional structure and 3-dimensional coordinates, herein referred to as 3D virtual library.

To determine what compounds from the 3D virtual library could have high inhibitory affinity against PARP and PI3K, in silico models based on these biological targets were built using the 3-dimensional coordinates of the targets. For this procedure, the crystal structures of human-derived PARP-1 and PI3K-gamma were obtained from the Protein Data Bank (PDB codes 4PJT and 4XZ4, respectively). The crystal structures of these targets contain a co-crystallized small-molecule inhibitor placed at the catalytic domain site of PARP-1 and PI3K.

To construct in silico models for PARP-1 and PI3K-gamma, the atomic coordinates of the co-crystallized small molecules, water molecules, salts and co-crystallization factors were removed from the 3D coordinates of the biological targets, charges were calculated and applied to atoms and ionizable amino acid residues (e.g., lysine, arginine), and the 3-dimensional coordinates of each target was saved for in silico docking studies.

For the identification of potential dual PARP-1 and PI3K-gamma inhibitors, the compounds in the 3D virtual library were docked first against PARP-1 at its catalytic site. For a compound to be considered a viable potential inhibitor, such compound must fit in the catalytic domain (binding site) and interact with key PARP-1 amino acid residues (e.g., GLY863,

SER904). All the compounds were docked at least 100 times in the binding site. The binding affinity for a compound was determined by calculating the free docking energy (also known as and referred to as affinity energy expressed as AG in kcal/mol) where the more negative the AG value the more potency/affinity a compound has for the biological target, in this case PARP-1. The top-best docking pose for each compound was selected based on the best calculated binding affinity. From the docking results, the top 200 compounds predicted to bind with the tightest affinity to PARP-1 were selected to be docked against PI3K-gamma.

PI3K has 4 isoforms, namely alpha, beta, delta and gamma, and their ATP kinase recognition site is highly homologous. PI3K inhibitors are known for making a key hydrogen- bond interaction with a valine residue, in the case of PI3K-gamma it is VAL882. To identify compounds with higher selectivity towards the PI3K-gamma isoform, we identified 2 unique amino acid residues in the PI3K-gamma ATP catalytic pocket: LYS802 and LYS890. For a small compound to be considered a PI3K kinase inhibitor such compound must fit in the ATP kinase catalytic pocket (also referred to as recognition site) and engage in a hydrogen-bond interaction with VAL882. Additional interactions with LYS802 and LYS890 are expected to increase selectivity towards PI3K-gamma.

The top 200 PARP inhibitors were docked against PI3K-gamma at the ATP kinase recognition site. As performed for PARP, each compound was docked at least 100 times and the predicted binding affinity calculated. This process was also performed for PI3K-alpha and PI3K- delta using PDB code 4JPS and PDB code 5DXU, respectively.

The top 200 PARP inhibitors along with their PI3K alpha, delta, and gamma scores are shown in Table 6 below (200 entries) ordered by best PARP-1 scores first.

Table 4. 42 PARP-BUILDING BLOCKS:

Table 5. 82 TP-BASED BUILDING BLOCKS (M is independently O, or S)

Table 6. Top 200 PARP and PI3K Inhibitors Identified by In-Silico Modelling.

[0153] EXAMPLE 3. Compiled compound ICso data for PARP, BRD4, and PI3K (values in iiM)

The compounds of the invention were characterized by their ability to inhibit the target proteins using third party vendors offering such services. PI3K alpha, gamma, and delta inhibition activity was determined by Thermo Fisher Scientific-Biosciences Life Sciences Solutions, Madison, WI. The bromodomain protein inhibition (binding domain 1 and 2 of BRD4) was determined at Reaction Biology Corp., Malvern, PA. PARP inhibition was performed by BPS Bioscience (6042 Cornerstone Court West, Suite B San Diego, C A 92121).

Additional information on each of the above testing procedures and services is available at each company's website on the internet. The data is shown below where the IC50 is calculated from a 10-point curve and is expressed in nanomolar concentration (nM) rounded off to the nearest whole number. NI = no inhibition detected up to 50 micromolar or IC50 was not reached at 50 micromolar. ND = not done.

[0154] EXAMPLE 4. Dual PARP and PI3K inhibition demonstrated by Compound 1.

To demonstrate the inhibitory activities of the prototype dual inhibitor Compound 1, we performed a PARP activity assay using a PARP Assay Kit to measure the incorporation of biotinylated poly(ADP-ribose) onto histone proteins. Trevigen's HT Universal 96-well PARP Assay Kits (Trevigen Inc., Gaithersburg, MD) which measures the incorporation of biotinylated poly(ADP-ribose) onto histone proteins in a 96-well strip well format was used to measure PARP activity. Further technical details are available at the supplier's website (https://trevigen.com/docs/protocol/protocol_4676-096-K.pdf). As a negative control, another dual inhibitor, Compound 0 (shown below), which is built on the same scaffold as Compound 1 but lacks a PARP inhibition moitety, was tested.

Using this assay it was determined that Compound 1 inhibits PARP as a function of concentration with a calculated IC50 of 13.19 μΜ. By comparison, Compound 0, did not present any inhibitory activity over PARP (See Figure 1).

The inhibitory activity of Compound 1 on PI3K isoforms (as described above in Example 3) was determined to have an IC50 of 2.6 μΜ, 1.4 μΜ and 28.5 μΜ on PI3K alpha, delta and gamma respectively.

To further demonstrate PI3K inhibitory activity in cancer cells (CHLA-255 & SMS-KNCR), the phosphorylation of the PI3K substrate Akt in threonine 473 after stimulation of neuroblastoma cells with Insulin growth factor (IGF), a potent PI3K activator, was measured using Western Blots. The results (not shown) showed a marked decrease in phosho-AKT levels when cells were previously treated with 25 μΜ of Compound 1.

[0155] EXAMPLE 5. Combination of inhibitors more toxic on normal cells than dual PARP PI3K inhibitor Compound 1.

The viability of normal epithelial cells (RRP-018 cells) was measured after treatment for 48h with Compound 1, the known PI3K inhibitor LY294002, the PARP inhibitor 3-AB (3-aminobenzoic acid) or a combination of these two single inhibitors. Results (Figure 2) show a lower toxicity of Compound 1 over any other treatment in these cells, demonstrating the suitability of dual inhibitors targeting these pathways over single ones. The IC50 values on normal tonsil cells were calculated from the titration curves shown in Figure 2 to be: LY294002 34.4 μΜ; 3-AB 43.3 μΜ; combined LY294002/3-AB 26.1 μΜ; Compound 1 > 50 μΜ. The normal epithelial tonsil RRP-018 cells were obtained from the Rady Children Hospital Biorepository (UCSD) and grown on DMEM + 10%FBS. All inhibitors were dissolved in DMSO (ATCC) as a 10 mM stock solution and diluted in culture media just before use. AlamarBlue reagent (Therm oFisher) was used to measure cell viability in triplicate on cytotoxicity assays.

[0156] EXAMPLE 6. Dual inhibitor Compound 1 induces caspase-3 mechanism of apoptosis superior to single inhibitory agents.

To ascertain whether the decrease in cell survival after radiation and treatment with compound 1 was due to an increase in apoptosis caused by inhibition of survival signals, levels of caspase-3 cleavage, an early signal of apoptosis activation, was measured in neuroblastoma cells 8h after radiation (5Gy), and treatment with Compound 1 (25 μΜ), or after treatment with individual inhibitors of PARP (Pi) and PI3K (LY). As shown in Figure 3, Compound 1 showed an increase in caspase-3 activation compared with radiation alone, or a combination of single inhibitors.

IR stands for radiation (5 Gy), LY stands for the PI3K only inhibitor LY294002, and Pi stands for PARP inhibitor 3-aminobenzamide (3-AB). Caspase-3 activation was determined using the Caspase-3 Activity Assay from Roche (Indianapolis, FN). Cells were treated with the corresponding inhibitor for 24h before DNA-damage by ionizing radiation exposition. Eight hours after DNA-damage, cells were lysed and caspase 3 activity measured according to manufacturer specifications.

In conclusion, Compound 1 caused an increase in caspase-3 activation compared with radiation alone or a combination of single inhibitors (PI3K + PARP).

[0157] EXAMPLE 7. Compound 1 plus ionizing radiation (IR) shows blockage of DNA repair and inhibition of PI3K survival pathway and cellular pharmacodynamic

improvement.

Immunofluorescence and DNA-damage foci analysis procedures: For DNA-damage analysis by immunofluorescence, neuroblastoma cells (CHLA255) were seeded on glass coverslips pre- coated with PolyD-Lysine (10 μg/mL) for 1 h at 37 °C. Adhered cells were treated with the corresponding inhibitors for 24 h prior to DNA-damage or immediately after. Cells were irradiated with 5-10Gy of ionizing radiation. Cells were fixed with 4%PFA at 30 min, 4 h or 24 h after DNA-damage. Cells were then permeabilized with 0.2% Triton X-100 in PBS and blocked with 1%BSA before incubation with the corresponding antibodies. The following antibodies were used: anti Phospho γΗ2ΑΧ antibody conjugated with FITC (Millipore), Rad51 (Santa Cruz), PhosphoSer483-Akt (Cell Signaling Technology, Inc.). Coverslips were mounted with

ProlongGold +DAPI (ThermoFisher). Images were acquired using a Nikon TiE Eclipse Confocal or a Keyence epifluorescence microscope. Cells on images were classified according to the presence of Ρ-γΗ2ΑΧ and P-Akt foci, with high denoting the presence of 2 or more strongly stained foci. Alternatively, an automatic quantification and classification of foci staining per cell was performed with the help of the Cell Profiler software, with similar results.

Using the maintenance of Phospho-yH2AX foci and the inhibition of P-Akt signal as readouts for PARP and PI3K inhibition respectively, an increase in the number of cells presenting with both phenotypes when Compound 1 is used compared to the single combination of inhibitors with similar or greater potency (Figure 4).

As shown in Figure 4, DNA-damage foci repair and P-Akt inhibition by dual versus combination inhibitors. yFLZAX-labelled DNA-damage foci and P-Akt after 4h irradiation with 5Gy are shown on CHLA255 cells previously treated with compound 1 (25 μΜ) or a combination of PI3K inhibitor LY294002 (5 μΜ) and PARPi 3-aminobenzamide (3-AB) (10 μΜ). Nuclei were stained with DAPI. The bar graph in Figure 4 shows quantification of cells with persistent γΗ2ΑΧ foci and low P-Akt in CHLA255 NB cells after 5Gy irradiation and treated with the indicated inhibitors. Dual inhibitor compound 1 shows significantly more cells with foci persistence AND phosph-Akt loss than does a combination of single inhibitors. This support the concept of improved cellular pharmacodynamics inhibition of multiple targets in each cell is best achieved using a dual inhibitor molecule versus two separate inhibitors.

[0158] EXAMPLE 8. Simultaneous inhibition of PI3K and PARP with Compound 1 extends inhibitor action to BRCA competent cells.

DLD1 colon cancer cell line containing the heterozygous knockin of BRCA2 inactivating point potation and knockout of wild type allele, together with the DLD1 BRCA2 wildtype counterpart, were obtained from ThermoFisher (HGT1000061) and grown on RPMI media supplemented with 10% FBS and IX antibiotics.

PARP inhibitors have been proven to be effective on BRCA-mutated colon cancer. As a proof of concept, it was desired to demonstrate this effect by directly comparing BRCA wild type and BRCA mutant cells from the same background. Using a syngenic BRCA2 wild type (wt)/BRCA2 mutant colon cancer cell line pair obtained by gene editing, it has been previously demonstrated that indeed the known PARP inhibitor NU1025 induces cytotoxicity in BRCA mutant but not BRCA wt cells (Hucl, T., Rago, C, Gallmeier, E., Brody, J.R., Gorospe, M., and Kern, S.E. (2008). A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res 68, 5023-5030). The dual PI3K/PARP inhibitor Compound 1 was used on the same pair of cell lines and checked for cytotoxicity (Figure 5). Effectively previous results were replicated indicating that PARP inhibitors significantly affect cytotoxicity of BRCA mutant colon cancer cells. Importantly, the dual inhibitor Compound 1 killed both BRCA wt and BRCA mutant cells under the same conditions, with mutant cells being more sensitive to the drug. This result demonstrates the sensitization of BRCA wt cells to PARP inhibition when combined with PI3K inhibition in a single molecule.

Summary/conclusion: A syngeneic BRCA2 wt/BRCA2 mutant colon cancer cell line pair was obtained by gene editing. Previous work showed that PARP inhibitor NU1025 induces cytotoxicity in BRCA mutant (DLDl-BRCA2null) but not BRCA wt cells (DLDl). These paired cell lines were exposed to NU1025 or the dual PI3K/PARP inhibitor Compound 1 at increasing concentrations and surviving cells were determined. Compound 1 dual inhibitor killed both BRCA wt and BRCA mutant cells under the same conditions, with mutant cells being more sensitive to the drug. This demonstrates the sensitization of BRCA wt cells to PARP inhibition when combined with PI3K inhibition in a single molecule such as Compound 1.

[0159] EXAMPLE 9. Synthesis of Compound 2

5-Morpholino-3-(tributylstannyl)-7H-thieno [3,2-b] pyran-7-one (B)

3-Bromo-5-mo holino-7H-thieno[3,2-b]pyran-7-one (Compound A) (0.508 g, 1.61 mmol) was dissolved in THF (25 mL) and cooled to -78 °C under argon. A solution of n-BuLi in hexanes (1.60 M, 2.10 mL, 3.4 mmol) was added to the above mixture, and the reaction mixture was stirred at the same temperature for 0.5 h. Then, tributyltin chloride (0.95 mL, 3.42 mmol) was added to the reaction mixture at -78 °C and the resulting mixture warmed to room temperature. After 12 h, the solvent was evaporated and the crude product was purified by flash column chromatography using silica gel. The fractions containing the product (EtOAc/hexanes, 30:70) were concentrated to afford Compound B (0.072 g, 0.114 mmol). Physical state: brown colored thick liquid, R/ = 0.4 (mobile phase: MeOH/EtOAc, 5:95).

2-Bromo-N-((5-bromothiazol-2-yl)carbamoyl)benzamide (C)

To a solution of 2-bromobenzamide (506 mg, 2.53 mmol) in ethylene dichloride (10 mL) was added oxalyl chloride (0.65 mL, 7.59 mmol) at 0 °C. Then, the reaction mixture was heated to reflux for 2.0 h. The solvent along with excess oxalyl chloride were evaporated under reduced pressure to get the corresponding isocyanate intermediate. The crude isocyanate was dissolved in ethylene chloride (10 mL), added to 5-bromothiazol-2-amine (456 mg, 2.54 mmol) at ambient temperature, and stirred for 3.0 h. The reaction was quenched with water and extracted with dichloromethane. The organic extracts were dried over Na₂S04, filtered and evaporated under reduced pressure. The crude urea product was purified by flash column chromatography on silica gel and eluted with EtOAc/hexanes (15:85). The fractions containing the product were concentrated to yield Compound C (49%) (503 mg, 1.24 mmol) as a pale-yellow solid. 1HNMR (CDCh, 400 MHz): δ 11.6 (brs, 1H), 9.8 (s, 1H), 7.73-7.68 (m, 1H), 7.65-7.6 (m, 1H), 7.55-7.40 (m, 2H) and 7.38 (s, 1H). MS (ES +): m/z 405.90; [M + 1]⁺ calcd for CnHvNsC SB^ 405.90. Physical state: pale-yellow solid; R = 0.6 (mobile phase: EtOAc/hexanes, 30:70). r

l-(5-Bromothiazol-2-yl)quinazoline-2,4(lH,3H)-dione (D)

To a solution of Compound C (306 mg, 0.755 mmol) in DMF was added KF (91 mg, 1.56 mmol) and 18-crown-6 (11 mg, 0.0416 mmol) at ambient temperature, and the resulting mixture was heated to reflux for 3 h. The reaction mixture was cooled to ambient temperature and diluted with diethyl ether. The organic solution was washed with water, dried over Na₂S04, filtered, and evaporated under reduced pressure to afford crude Compound D. This crude material was purified by flash column chromatography on silica gel and the product was eluted with EtOAc/hexanes (20:80). The fractions containing the product were concentrated to yield 46% of Compound D (113 mg, 0.348 mmol) as an off-white solid. 1HNMR (DMSO-D⁶, 400 MHz): δ 11.96 (s, 1H), 8.1 (s, 1H), 8.05-8.0 (m, 1H), 7.68-7.60 (m, 1H), 7.38-7.30 (m, 1H) and 6.77 (d, J=8.4 Hz, 1H). MS (ES -): m/z 321.91/323.82; [M - 1]^" calcd for CnH₆N₃0₂SBr 321.9/323.9. Physical state: Off- white solid, R = 0.6 (mobile phase: EtOAc/hexanes, 30:70).

l-(5-(5-Morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-yl)thiazol-2-yl)quinazoline-2,4(lH,3H)- dione (2)

A solution of Compound B (56.0 mg, 0.106 mmol) and Compound D (51 mg, 0.155 mmol) in toluene (3.0 mL) was degassed with argon for 15 min in a sealed tube. Pd(PPh₃)₄ (58 mg, 0.047 mmol) was added to the above mixture in one portion. The reaction mixture was then heated at 100-105 °C and carefully monitored by TLC. After 12 h of heating, the reaction was cooled to ambient temperature, diluted with EtOAc, and dried over sodium sulfate. The solvents were evaporated under reduced pressure and the crude product was purified by flash column

chromatography on silica gel. The fractions containing the product (EtOAc/MeOH, 99: 1) were concentrated to afford Compound 2 (9 mg, 0.018 mmol) as a pale-yellow solid. ¾ NMR (DMSO- D⁶, 400 MHz): δ 12.0 (s, 1H), 8.4 (s, 1H), 8.0 (d, J = 7.7 Hz, 1H), 7.8 (s, 1 H), 7.6 (t, J= 7.4 Hz, 1H), 7.3 (t, J= 7.7 Hz 1H), 6.8 (d, J = 8.3 Hz, 1H), 5.5 (s, 1H), 3.7 (m, 4H) and 3.5 (m, 4H). MS (ES +): m/z 481.21; [M + 1]⁺ calcd for C22H16N4O5S2 481.06. Physical state: pale-yellow solid, R/ = 0.4 (mobile phase: MeOH/EtOAc, 5:95).

[0160] EXAMPLE 10. SYNTHESIS OF COMPOUNDS 3 AND 4

Methyl 3-methyl-2-nitrobenzoate (E)

To a solution of 3-methyl-2-nitrobenzoic acid (5.07 g, 27.9 mmol) in methanol (70 mL) was added acetyl chloride (12.0 mL, 167 mmol) at 0 °C. After the addition, the reaction mixture was heated to reflux for 20 h. The reaction was cooled to ambient temperature and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed several times with aqueous NaHC0₃ solution, and dried over Na₂S04. Evaporation of solvent provided Compound E (5.2 g, 26.6 mmol) in 95% yield. Compound E was taken for the next reaction without further purification. ¾ NMR (400 MHz, CDCh, 300 K) δ 7.86 (d, J = 7.5 Hz, 1H), 7.53-7.42 (m, 2H), 3.89 (s, 3H), 2.36 (s, 3H). MS (ES+) m/z: C9H9NO4 requires 195; found 218 (M + Na). Physical state: white solid; R = 0.7 (mobile phase: EtOAc/hexanes, 1 : 1).

Methyl 3-(bromomethyl)-2-nitrobenzoate (F)

A mixture of Compound E (5.13 g, 26.3 mmol), benzoyl peroxide (511 mg, 2.11 mmol), and N- bromosuccinamide (14.1 g, 78.8 mmol) in CCU (120 mL) was heated under a nitrogen atmosphere for 20 h. The mixture was cooled to ambient temperature, diluted with dichloromethane and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 10% EtOAc/hexanes (10:90) to yield Compound F (2.14 g, 7.80 mmol) in 30% yield as an off-white solid. ¾ NMR (400 MHz, CDCh) δ 7.93 (d, J= 7.7 Hz, 1H), 7.72 (d, J= 7.7 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 4.43 (s, 2H), 3.88 (s, 3H). MS (ES+) m/z: C₉H₈BrN0₄ requires 273/275, found 242/244 (M - MeO) 227/229 (M - N02). Physical state: Off-white solid; R/= 0.7 (mobile phase: EtOAc/hexanes, 20:80).

Methyl 3-formyl-2-nitrobenzoate (G)

To a mixture of Compound F (1.97 g, 7.18 mmol) in MeCN (20 mL) was added N- methylmorpholine N-oxide (2.15 g, 17.9 mmol) at ambient temperature, and the reaction mixture was stirred for 12 h. The reaction mixture was diluted with EtOAc, washed with water, 1 M HCl and brine. The organic extracts were dried over Na₂S0₄, filtered and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel using 5% EtO Ac/petroleum ether to provide Compound G (824 mg, 3.93 mmol) in 54% yield. ¾ MR (400 MHz, CDCb) δ 9.96 (s, 1H), 8.26 (d, J= 7.9 Hz, 1H), 8.18 (d, J = 7.9 Hz, 1H), 7.77 (t, J= 7.9 Hz, 1H), 3.93 (s, 3H). MS (ES -) m/z: C9H7NO5 requires 209, found 208 (M - H)^". Physical state: Off- white solid; R = 0.6 (mobile phase: EtOAc/hexanes, 1 :9).

4-Bromo-N-(diphenylmethylene)thiophen-3-amine (H)

A mixture of 3,4-dibromothiophene (6.05 g, 25.01 mmol), benzophenone imine (5.0 mL, 27.5 mmol), 2,2'-bis(diphenylphosphino)-l, l '-binaphthalene (774 mg, 1.24 mmol), and cesium carbonate (15.6 g, 47.8 mmol) in toluene (60 mL) was degassed with nitrogen for 10 min.

Pd(OAc)₂ (175 mg, 0.788 mmol) was added to the above mixture, then, the reaction mixture was heated to 116 °C. The reaction mixture was cooled to ambient temperature, filtered through a celite bed, washed with EtOAc, and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel using 5% EtO Ac/petroleum ether to provide Compound H (6.1 g, 17.8 mmol) in 71% yield. ¾ MR (400 MHz, CDCb) δ 7.85-7.82 (m, 3H), 7.64 (m, 2H), 7.53-7.49 (m, 3H), 7.45-7.42 (m, 1H), 7.39-7.36 (m, 2H), 7.23-7.18 (m, 1H); MS (ES +) m/z: CivHi₂BrNS requires 341/343, found 342/344 (M + H)⁺. Physical state: Greenish yellow solid; R = 0.6 (mobile phase: EtOAc/hexanes, 5:95).

4-Bromothiophen-3-amine hydrochloride (I)

To a solution of Compound H (6.1 g, 17.8 mmol) in dichloromethane (60 mL) was added 2 N HC1 in ethanol (30 mL) at 0 °C. The reaction slowly warmed to ambient temperature for 2.5 h. The solvent was evaporated under reduced pressure. The crude reside was triturated with dichloromethane followed by hexanes to provide desired Compound I (3.25 g, 15.1 mmol) in 85% yield as off-white solid. ¾ NMR (400 MHz, CDCb) δ 7.15 (d, J= 3.6 Hz, 1H), 6.25 (d, J = 3.6 Hz, 1H); MS (ES+) m/z: C₄H₄BrNS requires 177/179, found 178/180 (M + H)⁺. Physical state: Off-white solid.

Methyl 3-((4-bromothiophen-3-ylimino)methyl)-2-nitrobenzoate (J)

Compound G (0.500 g, 2.39 mmol) and Compound I (0.460 g, 2.15 mmol) were taken in toluene (7.5 mL). Acetic acid (0.46 mL, 8 mmol) and N,N-diisopropylethylamine (5 mL, 28.7 mmol) were added to the above mixture under stirring. The reaction mixture was refluxed for 8.0 h. The reaction was monitored by TLC. The solvent was stripped off, and the crude product Compound J (1.4 g) was used for the next step. Physical state: brown colored thick liquid; R = 0.3 (mobile phase: EtOAc/hexanes, 1 :9).

Methyl 2-(4-bromothiophen-3-yl)-2H-indazole-7-carboxylate (K)

To a solution of Compound J (150 mg, 2.39 mmol) in DMF was added sodium azide (83 mg, 2.5 mmol), and stirred in a sealed tube. The reaction mixture was then subjected to microwave irradiation for 3 min (300 Watts, 180 °C), cooled to room temperature, and partitioned between EtOAC and water. The aqueous layer was further extracted with EtOAc. The combined organic layers were dried over Na₂S04, filtered and evaporated to dryness under reduced pressure. The crude reaction mixture was purified by column chromatography and eluted with EtOAc/hexanes (20:80). Compound K was obtained as off-white solid (21 mg, 20.0 %). 1H NMR (CDC13, 400 MHz) δ 8.6 (s, 1H), 8.17 (d, J = 0.8 Hz, 1H), 7.9 (d, J = 0.8 Hz, 1H), 7.8 (d, J = 4.0 Hz, 1H), 7.4 (d, J = 4.0 Hz, 1H), 7.2 (t, J = 7.6 Hz, 1H), 4.0 (s, 3H). MS (ES +) m/z: Ci₃H₉BrN₂0₂S requires 335.95; found 337.1 [M + 1]⁺. Physical state: Off-white solid.

Methyl 2-(4-(5-morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-yl)thiophen-3-yl)-2H-indazole-7- carboxylate (4)

A solution of Compound B (110.0 mg, 0.2091 mmol) and Compound K (88 mg, 0.2611 mmol) in toluene (5.5 mL) was transferred into a sealed tube. Pd(PPh₃)₄ (121 mg, 0.1047 mmol) was added to the above mixture. The reaction mixture was next heated at 100-105 °C for 12 h, cooled to ambient temperature and extracted with EtOAc. The solvent was evaporated under reduced pressure and the crude product was initially purified by column chromatography on silica gel (DCM/MeOH, 98:2). Product Compound 4 (15 mg, 0.03 mmol) was isolated as an off-white solid. ¾ NMR (CDCh, 400 MHz): δ 8.17 (d, J= 6.7 Hz, 1H), 8.10 (s, 1H), 7.9 (d, J= 8.4 Hz, 1H), 7.7 (d, J= 3.5 Hz, 1H), 7.6 (d, J = 3.5 Hz, 1H), 7.2 (m, 1H), 6.6 (s, 1H), 5.4 (s, 1H), 4.0 (s, 3H), 3.7 (m, 4H) and 3.3 (m, 4H). MS (ES+): m/z 494.1; [M + 1]⁺ Calcd for C24H19N3O5S2 494.08. Physical state: Off- white solid; R/ = 0.25 (mobile phase: MeOH/DCM, 5:95)

2-(4-(5-Morpholino-7-oxo-7H-thieno[3,2-b]pyran-3-yl)thiophen-3-yl)-2H-indazole-7- carboxamide (3)

Compound 4 (8.0 mg, 0.0162 mmol) was dissolved in methanol (15 mL). To this solution was bubbled a gentle stream of ammonia at ambient temperature until disappearance of the starting material by TLC. Next, the solvent was evaporated under reduced pressure and the product was dried under vacuum. Compound 3 (7.0 mg) was obtained in more than 90% yield as a pale-yellow solid that did not require any further purification. ¾ NMR (CDCb, 400 MHz): δ 8.90 (s, 1H), 8.25 (brs, 3H,), 8.10 - 7.98 (m, 2H), 7.7 (brs, 1H), 7.3 (m, 1H), 7.2 (s, 1H), 5.4 (s, 1H), 3.6 (m, 4H), and 3.3 (m, 4H). MS (ES+): m/z 479.1; [M + 1]⁺ Calcd for C23H18N4O4S2 479.08. Physical state: pale-yellow solid; R/ = 0.15 (mobile phase: MeOH/DCM, 5:95).

Claims

What is claimed is:

1. A compound of Formula I or a pharmaceutically acceptable salt thereof,

wherein M is independently oxygen (O) or sulfur (S);

R2 is selected from Rl or morpholine or thiomorpholine or piperazine;

R3 is selected from Rl; and

R4 is selected from Rl .

2. A compound of Formula II or a pharmaceutically acceptable salt thereof,

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I; W is null, R1, O, S, CH₂, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate;

phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate;

and

quinazolinedione.

3. A compound of Formula III or a pharmaceutically acceptable salt thereof,

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I;

X is null or O, N, NRl or S, CH₂, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic or substituted heterocyclic, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse carboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O- substituted hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, N-substituted sulfonamide, N,N-di substituted sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, substituted carbamate;

Ar is aryl, heteroaryl, or heterocyclic bearing one, two, three or four substituents on the Ar ring independently selected from: H, F, CI, Br, I, alkyl, alkenyl, alkynyl, carbocycle, aryl, heterocycle, heteroaryl, formyl, nitro, cyano, amino, carboxylic acid, carboxylic ester, carboxyl amide, reverse caboxyamide, substituted alkyl, substituted alkenyl, substituted alkynyl, substituted carbocycle, substituted aryl, substituted heterocycle, substituted heteroaryl, phosphonic acid, phosphinic acid, phosphoramidate, phosphonic ester, phosphinic ester, ketone, substituted ketone, hydroxamic acid, N-substituted hydroxamic acid, O-substituted hydroxamate, N- and O-substituted

hydroxamate, sulfoxide, substituted sulfoxide, sulfone, substituted sulfone, sulfonic acid, sulfonic ester, sulfonamide, reverse sulfonamide, N-substituted sulfonamide, N,N-di substituted

sulfonamide, boronic acid, boronic ester, azo, substituted azo, azido, nitroso, imino, substituted imino, oxime, substituted oxime, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, thioether, substituted thioether, carbamate, and substituted carbamate.

4. A compound of Formula IV or a pharmaceutically acceptable salt thereof,

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I;

5. A compound of Formula V or a pharmaceutically acceptable salt thereof,

wherein M is independently O or S;

Rl and R2 and R4 are as described for Formula I;

R6 is selected from NHR1, NH2, OH, or OR1; and

R7 is selected from NHR1, NH2, OH, or OR1.

6. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6.

7. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of compd III- 1 , compd III-2, compd III-3, compd III-4, compd III-5, compd III-6, compd III-7, compd III-8, compd III-9, compd III-10, compd III-l l, compd 111-12, compd III- 13 , compd 111-14, compd III- 15 , compd III- 16, compd 111-17, compd 111-18, compd 111-19, compd 111-20, compd III-

21, compd 111-22, compd 111-23, compd 111-24, compd 111-25, compd 111-26, compd 111-27, compd

111-28, compd 111-29, compd 111-30, compd 111-31, compd 111-32, compd 111-33, compd 111-34, compd 111-35, compd 111-36, compd 111-37, compd 111-38, compd 111-39, compd 111-40, compd III-

41, compd 111-42, compd 111-43, compd 111-44, compd 111-45, compd 111-46, compd 111-47, compd

111-48, compd 111-49, compd 111-50, compd 111-51, compd 111-52, compd 111-53, compd 111-54, compd 111-55, compd 111-56, compd 111-57, compd 111-58, compd 111-59, compd 111-60, compd III- 61, compd 111-62, compd 111-63, compd 111-64, compd 111-65, compd 111-66, compd 111-67, compd 111-68, compd 111-69, compd 111-70, compd 111-71, compd 111-72, compd 111-73, compd 111-74, compd 111-75, compd 111-76, compd 111-77, compd 111-78, compd 111-79, compd 111-80, compd III- 81, compd 111-82, compd 111-83, compd 111-84, compd 111-85, compd 111-86, compd 111-87, compd

III- 88, compd 111-89, compd 111-90, compd 111-91, compd 111-92, compd 111-93, and compd 111-94.

8. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of compd IV-1, compd IV-2, compd IV-3, compd IV-4, compd IV-5, compd IV-6, compd IV-7, compd IV-8, compd IV-9, compd IV-10, compd IV-11, compd IV-12, compd IV-13, compd IV- 14, compd IV-15, compd IV-16, compd IV-17, compd IV-18, compd IV-19, compd IV-20, compd

IV- 21, compd IV-22, compd IV-23, compd IV-24, compd IV-25, compd IV-26, and compd IV- 27.

9. A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of compd V-1, compd V-2, compd V-3, compd V-4, compd V-5, compd V-6, compd V-7, compd V- 8, compd V-9, compd V-10, compd V-l l, compd V-12, compd V-13, compd V-14, compd V-15, compd V-16, compd V-17, compd V-18, compd V-19, compd V-20, compd V-21, compd V-22, compd V-23, compd V-24, compd V-25, compd V-26, and compd V-27.

10. A compound or a pharmaceutically acceptable salt thereof selected from Table 2 and consisting of the group all inclusive of compd 2-1, compd 2-2, compd 2-3, compd 2-4 . . . through compd 2-200.

11. A pharmaceutical formulation comprising a compound of claims 1-5 in association with a pharmaceutically acceptable carrier, diluent, or excipient.

12. A pharmaceutical formulation comprising a compound of claims 6-10 in association with a pharmaceutically acceptable carrier, diluent, or excipient.

13. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula I.

14. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula II.

15. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula III.

16. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula IV.

17. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound of Formula V.

18. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound selected from the group consisting of Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, and Compound 6.

19. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound selected from the group consisting of compd III- 1, compd III-2, compd III-3, compd III-4, compd III-5, compd III-6, compd III-7, compd III-8, compd III-9, compd III- 10, compd III- 11 , compd III- 12, compd III- 13, compd III- 14, compd III- 15, compd 111-16, compd 111-17, compd 111-18, compd 111-19, compd 111-20, compd 111-21, compd 111-22, compd 111-23, compd 111-24, compd 111-25, compd 111-26, compd 111-27, compd 111-28, compd 111-29, compd 111-30, compd 111-31, compd 111-32, compd 111-33, compd 111-34, compd III- 35, compd 111-36, compd 111-37, compd 111-38, compd 111-39, compd 111-40, compd 111-41, compd 111-42, compd 111-43, compd 111-44, compd 111-45, compd 111-46, compd 111-47, compd 111-48, compd 111-49, compd 111-50, compd 111-51, compd 111-52, compd 111-53, compd 111-54, compd III- 55, compd 111-56, compd 111-57, compd 111-58, compd 111-59, compd 111-60, compd 111-61, compd 111-62, compd 111-63, compd 111-64, compd 111-65, compd 111-66, compd 111-67, compd 111-68, compd 111-69, compd 111-70, compd 111-71, compd 111-72, compd 111-73, compd 111-74, compd III- 75, compd 111-76, compd 111-77, compd 111-78, compd 111-79, compd 111-80, compd 111-81, compd 111-82, compd 111-83, compd 111-84, compd 111-85, compd 111-86, compd 111-87, compd 111-88, compd 111-89, compd 111-90, compd 111-91, compd 111-92, compd 111-93, and compd 111-94.

20. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound selected from the group consisting of compd IV- 1, compd IV-2, compd IV-3, compd IV-4, compd IV-5, compd IV-6, compd IV-7, compd IV-8, compd IV-9, compd IV- 10, compd IV-11, compd IV- 12, compd IV-13, compd IV- 14, compd IV-

15, compd IV- 16, compd IV- 17, compd IV- 18, compd IV- 19, compd IV-20, compd IV-21, compd IV-22, compd IV-23, compd IV-24, compd IV-25, compd IV-26, and compd IV-27.

21. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound selected from the group consisting of compd V-1, compd V-2, compd V-3, compd V-4, compd V-5, compd V-6, compd V-7, compd V-8, compd V- 9, compd V-10, compd V-l l, compd V-12, compd V-13, compd V-14, compd V-15, compd V-

16, compd V-17, compd V-18, compd V-19, compd V-20, compd V-21, compd V-22, compd V- 23, compd V-24, compd V-25, compd V-26, and compd V-27.

22. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound selected from Table 2 consisting of compd 2-1, compd 2-2, compd 2-3 . . . through compd 2-200.

23. A method for treating cancer in a mammal in need thereof comprising administering a therapeutically effective amount of a compound selected from the group consisting of

24. A method of any one of claims 13-23 wherein said cancer is selected from adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute

megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive K-cell leukemia, AIDS-related lymphoma, alveolar

rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell lymphoma, anaplastic thyroid cancer, angioimmunoblastic T-cell lymphoma, angiomyolipoma, angiosarcoma, astrocytoma, atypical teratoid rhabdoid tumor, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, basal cell carcinoma, biliary tract cancer, bladder cancer, blastoma, bone cancer, Brenner tumor, Brown tumor, Burkitt's lymphoma, breast cancer, brain cancer, carcinoma, carcinoma in situ, carcinosarcoma, cartilage tumor, cementoma, myeloid sarcoma, chondroma, chordoma, choriocarcinoma, choroid plexus papilloma, clear-cell sarcoma of the kidney, craniopharyngioma, cutaneous T-cell lymphoma, cervical cancer, colorectal cancer, Degos disease, desmoplastic small round cell tumor, diffuse large B-cell lymphoma, dysembryoplastic neuroepithelial tumor, dysgerminoma, embryonal carcinoma, endocrine gland neoplasm, endodermal sinus tumor, enteropathy-associated T-cell lymphoma, esophageal cancer, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid cancer, ganglioneuroma, gastrointestinal cancer, germ cell tumor, gestational choriocarcinoma, giant cell fibroblastoma, giant cell tumor of the bone, glial tumor, glioblastoma multiforme, glioma, gliomatosis cerebri, glucagonoma, gonadoblastoma, granulosa cell tumor, gynandroblastoma, gallbladder cancer, gastric cancer, hairy cell leukemia, hemangioblastoma, head and neck cancer, hemangiopericytoma, hematological malignancy, hepatoblastoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, invasive lobular carcinoma, intestinal cancer, kidney cancer, laryngeal cancer, lentigo maligna, lethal midline carcinoma, leukemia, leydig cell tumor, liposarcoma, lung cancer, lymphangioma, lymphangio sarcoma, lymphoepithelioma, lymphoma, acute lymphocytic leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, liver cancer, small cell lung cancer, non- small cell lung cancer, MALT lymphoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, malignant triton tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, mediastinal germ cell tumor, medullary carcinoma of the breast, medullary thyroid cancer, medulloblastoma, melanoma, meningioma, merkel cell cancer, mesothelioma, metastatic urothelial carcinoma, mixed Mullerian tumor, mucinous tumor, multiple myeloma, muscle tissue neoplasm, mycosis fungoides, myxoid liposarcoma, myxoma, myxosarcoma, nasopharyngeal carcinoma, neurinoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, ocular cancer, oligoastrocytoma, oligodendroglioma, oncocytoma, optic nerve sheath meningioma, optic nerve tumor, oral cancer, osteosarcoma, ovarian cancer, Pancoast tumor, papillary thyroid cancer, paraganglioma, pinealoblastoma, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmacytoma, polyembryoma, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, primary peritoneal cancer, prostate cancer, pancreatic cancer, pharyngeal cancer, pseudomyxoma peritonei, renal cell carcinoma, renal medullary carcinoma, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter's transformation, rectal cancer, sarcoma, Schwannomatosis, seminoma, Sertoli cell tumor, sex cord-gonadal stromal tumor, signet ring cell carcinoma, skin cancer, small blue round cell tumors, small cell carcinoma, soft tissue sarcoma, somatostatinoma, soot wart, spinal tumor, splenic marginal zone lymphoma, squamous cell carcinoma, synovial sarcoma, Sezary's disease, small intestine cancer, squamous carcinoma, stomach cancer, T-cell lymphoma, testicular cancer, thecoma, thyroid cancer, transitional cell carcinoma, throat cancer, urachal cancer, urogenital cancer, urothelial carcinoma, uveal melanoma, uterine cancer, verrucous carcinoma, visual pathway glioma, vulvar cancer, vaginal cancer, Waldenstrom macroglobulinemia, Warthin's tumor, and Wilms' tumor.

25. A method of claim 24 wherein said cancer relates to a loss of function somatic or germline mutation in BRCA 1/2.

26. A method of claim 24 wherein said cancer does not include a loss of function somatic or germline mutation in BRCA 1/2.

27. A method of claim 26 wherein said cancer is medulloblastoma or neuroblastoma.

28. A method of claim 24 wherein said cancer is a Myc-dependent cancer.

29. A method of claim 28 wherein said Myc-dependent cancer is selected from CLL, multiple myeloma, neuroblastoma, pancreatic, breast, prostate cancer, lymphoid malignancy, myeloid malignancy, medulloblastoma or any other Myc-dependant cancer.

30. A method of claim 24 wherein the administration of a compound of Formula I-V is in combination with one or more additional anticancer agents.

31. A method of claim 30 wherein the additional anticancer agent is an immune-oncology anticancer agent and/or checkpoint inhibitor.

32. A method of claim 24 wherein the compound inhibits PARP and at least one of PI3K and BRD4.

33. A method of claim 24 wherein the disease is cancer associated with cancer stem cell activity.

34. A method of claim 24 wherein the disease is a lymphoid malignancy including B cell driven lymphoma and leukemia.

35. A method of claim 24 wherein the disease is treated in combination with ionizing radiation.