Kinase inhibitor compositions and therapeutic uses thereof

Abstract

Aspects of the present disclosure are directed to methods and compositions for treating kinase-mediated diseases or disorders in a subject by administering to the subject a therapeutically effective amount of a compound as disclosed herein. The kinase inhibitors exhibit activity against a broad array of cancer cell lines and can be employed in the treatment of different types of cancers and other kinase-mediated diseases.

Description

KINASE INHIBITOR COMPOSITIONS AND THERAPEUTIC USES THEREOFBACKGROUNDI. Cross Reference to Related Applications

[0001] This application claims the benefit of priority to U. S. Provisional Patent Application Serial No. 63 / 696,346, filed on September 18, 2024, the contents of which are hereby incorporated by reference in their entirety.

[0002] Further applicable details may be found in U.S. Provisional Application Serial No. 63 / 696,341, filed September 18, 2024 entitled “Reversible and Irreversible Kinome Probes and Uses Thereof’ and U.S. Provisional Application Serial No. 63 / 696,271 filed September 18, 2024 entitled “Methods and Compositions for Activity-Dependent Protein Labeling” both of which are incorporated by reference in their entireties herein.II. Field of the Disclosure

[0003] Aspects of this disclosure relate, generally, to at least the fields of biology, molecular biology, and medicine.III. Background

[0004] Kinases, like serine hydrolases, are an extremely large and diverse enzyme class with several hundred members in humans. Several kinases, especially those with genetic ties to cancer, have been the focus of intense drug development programs in the pharmaceutical industry, but in aggregate, these only account for a modest fraction of all human kinases. Academic and biotechnology researchers have begun to fill in the pharmacological gaps in the kinome, often using various strategies to optimize the target selectivity of lead inhibitors.

[0005] The activity-dependent proximity ligation (ADPL) technique employs chemical probes for quantifying proteins of interest in single cells. The chemical probes comprise a reactive group that can covalently bind to an epitope tag of a side chain of an amino acid of a protein of interest and a retrieval tag that can be used to covalently bind the chemical probe to a retrieval tag recognition element.

[0006] In related work, the present inventors have developed APDL probes for the detection of kinases in lysates and live cells. Ongoing research on the kinase probe scaffolds has led to the development of small molecules with kinase-inhibitory activity. Owing to the299713171.1 - 1 -roles of kinases in numerous cellular pathways, including regulation of cell cycle, mediation of toll-like receptor signaling, and control of cell fate, the kinase inhibitors disclosed herein can be employed in a therapeutic applications.SUMMARY

[0007] Aspects of the present disclosure address needs in the art by providing methods for treating a subject with a kinase-mediated disease or disorder in a subject. Accordingly, provided herein, in some aspects, are methods for treating a pan-kinase-mediated disease or disorder. In some aspects, the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease. In some aspects, the hyperproliferative disease or disorder is a cancer. In some aspects, the method comprise administering to the subject an effective amount of a compound as disclosed herein.

[0008] Some aspects of the present disclosure are directed to a compound of formula I:wherein A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom; Ri, R2, R3, and R4 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; Rs, Re, R7, and Rs are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide, wherein one of Rs, Re, R7, and Rs is optionally replaced by X; wherein X comprises, consists of, or consists essentially of a phenyl ring comprising groups R9 (ortho), Rio (meta), R11 (para), R12 (meta), and R13 (ortho), where R9, Rio, R11, R12, and R13 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl,299713171.1 - 2 -ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein X is optionally linked to the indazole phenyl ring through a linker Li; wherein Li comprises, consists of, or consists essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; Ri4 comprises, consists of, or consists essentially of hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or 06-benzylguanine; wherein Ru is optionally linked to the piperazine through a linker L2; and wherein L2 comprises, consists of, or consists essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; or an enantiomer, diastereomer, racemic mixture, or salt thereof. In some aspects, any of the aforementioned functional groups is specifically excluded.

[0009] In some aspects, the compound of formula I is further defined as a compound of formula II:

[0010] In some aspects, the compound of formula I is further defined as a compound of formula III:299713171.1 - 3 -

[0011] In some aspects, the compound of formula I is further defined as a compound of formula IV:(IV).

[0012] In some aspects, the compound of formula I is further defined as a compound of formula V:

[0013] In some aspects, Re is replaced by X and Rn is an aldehyde. In some aspects, R7 is replaced by X and R11 is an aldehyde. R7 is replaced by X, Rn is an aldehyde, and R12 is a hydroxyl. In some aspects, an aldehyde group is protected as an acetal or hemi-acetal. wherein R7 is replaced by X and Rn is the hemi-acetal 1,3 -di oxolane. In some aspects, Rw is H. In some aspects, R14 is ethyl. In some aspects, R14 is propargyl. In some aspects, X comprises, consists of, or consists essentially of a molecule with biological activity. In some aspects, R14 comprises, consists of, or consists essentially of a molecule with biological activity.

[0014] In some aspects, the compound formula is one of:299713171.1 - 4 -299713171.1299713171.1 -6-

[0015] Some aspects of the disclosure include a compound of formula VI:wherein A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom; Ri and R2 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic299713171.1acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; R3, R4, Rs, and Re are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide, wherein one of R3, R4, Rs, and Re is optionally replaced by X; wherein X comprises, consists of, or consists essentially of a phenyl ring comprising groups R7 (ortho), Rs (meta), R9 (para), Rio (meta), and R11 (ortho), where R7 Rs R9 Rio and R11 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein X is optionally linked to the indolin-2-one phenyl ring through a linker Li; wherein Li is a linker selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; R12 comprises, consists of, or consists essentially of hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or 06- benzylguanine; wherein R12 is optionally linked to the piperazine ring through a linker L2; wherein L2 is a linker selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof, wherein L2 optionally comprises a moiety that covalently binds to an amino acid side chain moiety or an epitope tag; and R13 is hydrogen or alkyl; or an enantiomer, diastereomer, racemic mixture, or salt thereof. In some aspects, any of the aforementioned functional groups is specifically excluded. In some aspects, X comprises, consists of, or consists essentially of a299713171.1 - 8 -molecule with biological activity. In some aspects, R12 comprises, consists of, or consists essentially of a molecule with biological activity.

[0016] In some aspects, the compound of formula VI is further defined as a compound of formula VII:(VII).

[0017] In some aspects, the compound of formula VI is further defined as a compound of formula VIII:In some aspects, the compound of formula VI is one of:299713171.1 - 9 -

[0018] Some aspects of the disclosure are directed to a compound of formula IX:wherein A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom; Ri is CH2, O, or NH; R2 and R3 are each independently is CH or N, where each R2 and R3 carbon atom is optionally and independently substituted with halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; R4 and Rs are each independently is CH, CH2, N, or NH, where each R4 and Rs carbon atom and the R4 and Rs NH nitrogen atom is optionally and independently substituted with halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; Re is hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; R7 is X, hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide,299713171.1 - 10 -alkoxyamine, diazirine, tetrazine, or O6-benzylguanine, wherein X is optionally linked to the piperazine ring through a linker Li; Rs is hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or 06-benzylguanine, wherein Rs is optionally linked to the piperazine ring through a linker L2; where X is phenyl or benzyl comprising groups R9 (ortho), Rio (meta), R11 (para), R12 (meta), and R13 (ortho), where R9, Rio, R11, R12, and R13 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; where X is phenyl or benzyl comprising groups R9 (ortho), Rio (meta), R11 (para), R12 (meta), and R13 (ortho), where R9, Rio, R11, R12, and R13 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein linkers Li and L2 are ach independently selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; or an enantiomer, diastereomer, racemic mixture, or salt thereof. In some aspects, any of the aforementioned functional groups is specifically excluded. In some aspects, R7 comprises, consists of, or consists essentially of a molecule with biological activity. In some aspects, Rs comprises, consists of, or consists essentially of a molecule with biological activity. In some aspects, the linker is a triazole linker.

[0019] In some aspects, the compound of formula IX is further defined as a compound of formula X:299713171.1 - 11 -

[0020] In some aspects, the compound of formula IX is one of:299713171.1 - 12 -

[0021] In some aspects, a linker as disclosed herein, e.g., Li and L2, can have a length that is any one of, less than, greater than, or between 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 atoms in length. In some aspects, the molecule with biological activity represented by X and R14 in Formula I, by X and R12 in Formula VI, and by R7 and Rs in Formula IX comprises, consists of, or consists essentially of erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5- fluorouracil, Leucovorin, Rapamycin, Lapatinib, Lonafarnib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU 5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophy cin 1, cryptophy cin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammall, calicheamicin omegall, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone,299713171.1 - 13 -mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, an antibody, or retinoic acid.

[0022] Aspects of the disclosure include methods for treating a kinase-mediated disease or disorder in a subject, wherein the method comprising administering to the subject a therapeutically effective amount of a compound of formula I, a compound of formula VI, and / or a compound of formula IX. In some aspects, the kinase-mediated disease or disorder is a pan-kinase-mediated disease or disorder. In some aspects, the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease. In some aspects, the hyperproliferative disease or disorder is a cancer. In some aspects, the cancer is selected from colorectal cancer, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, cancers of the head and neck, skin cancer, cardiac cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, hematologic, skin cancer, adrenal cancer, oral cavity cancer, hairy cell leukemia, refractory metastatic disease, Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease. In some aspects, the disease or disorder is osteoarthritis, rheumatoid arthritis, angiofibroma, Chron's disease, diabetic retinopathy, retinal vascularisation, macular degeneration, age-related macular degeneration, obesity, multiple sclerosis, allergy, Alzheimer's disease, restenosis, asthma, endometriosis, vein graft stenosis, atherosclerosis, peri-anastomatic prothetic graft stenosis, chronic obstructive pulmonary disease, prostate hyperplasia, psoriasis, scar tissue formation, neurological damage due to tissue repair, infection, inflammatory bowel disease, neoplasm, pulmonary disease, Parkinson's disease, transplant rejection or septic shock.

[0023] Aspects of the disclosure include methods for treating a subject, methods for preventing a disease in a subject, methods for treating a subject having cancer, methods for improving the efficacy of kinase inhibitors, methods for improving therapies used to treat a subject having cancer, and methods for identifying a subject with cancer as a candidate for a treatment with a particular kinase inhibitor. Methods of the disclosure can include 1, 2, 3, 4, 5,299713171.1 - 14 -6, or more of the following steps: determining a subject to have a disease or disorder, administering one or more kinase inhibitors to a subject, administering a compound of formula I, administering a compound of formula VI, administering a compound of formula IX to a subject, providing a second therapeutic composition to a subject, providing two or more types of cancer therapy to a subject, identifying one or more kinase inhibitors as being in need of improved efficacy, identifying a subject as being a candidate for treatment with a particular kinase inhibitor, identifying a subject as being sensitive to a particular kinase inhibitor, identifying a subject as being resistant to a particular kinase inhibitor. Certain aspects of the disclosure may exclude one or more of the preceding elements and / or steps. In certain aspects, the disease or disorder is a disease or disorder disclosed herein. In certain aspects, the disease or disorder is a cancer, including any cancer disclosed herein. In certain aspects, the second therapeutic composition comprises a therapy indicated for the disease or disorder.

[0024] Disclosed herein, in some aspects, is a method for treating a subject for a cancer, the method comprising administering an effective amount of one or more compounds of formula I, formula VI, and formula IX to a subject in need thereof.

[0025] In some aspects, the method comprises administering a compound of formula I to the subject. In some aspects, the method comprises administering a compound of formula VI to the subject. In some aspects, the method comprises administering a compound of formula IX to the subject. In some aspects, the method comprises administering a composition comprising one or more kinase inhibitors, where the one or more kinase inhibitors include a compound of formula I, a compound of formula VI, and / or a compound of formula IX. In some aspects, the subject was previously treated with a therapy, such as cancer therapy. In some aspects, the cancer therapy comprised chemotherapy. In some aspects, the subject was determined to be resistant to the therapy. In some aspects of the methods disclosed herein, the method further comprises administering to the subject an additional therapy. In some aspects, the additional therapy comprises cancer therapy, which may include a chemotherapy, radiotherapy, or immunotherapy. In some aspects, the additional cancer therapy comprises an anaplastic lymphoma kinase (ALK) inhibitor. In some aspects, the ALK inhibitor is brigatinib or AZD3463. In some aspects, the additional cancer therapy comprises a protein kinase C (PKC) inhibitor. In some aspects, the PKC inhibitor is ruboxistaurin, midostaurin, or sotrastaurin.

[0026] Certain aspects of the present invention are characterized through the following enumerated aspects.

[0027] Aspect l is a compound of formula I:299713171.1 - 15 -fl,

[0028] (I) wherein: A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom; Ri, R2, R3, and R4 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; Rs, Re, R7, and Rs are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide, wherein one of Rs, Re, R7, and Rs is optionally replaced by X; wherein X comprises, consists of, or consists essentially of a phenyl ring comprising groups R9 (ortho), Rio (meta), R11 (para), R12 (meta), and R13 (ortho), where R9, Rio, R11, R12, and R13 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein X is optionally linked to the indazole phenyl ring through a linker Li; wherein Li comprises, consists of, or consists essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; R14 comprises, consists of, or consists essentially of hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or O6-benzylguanine; wherein R14 is optionally linked to the299713171.1 - 16 -piperazine through a linker L2; and wherein L2 comprises, consists of, or consists essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; or an enantiomer, diastereomer, racemic mixture, or salt thereof.

[0029] Aspect 2 is the compound of aspect 1, wherein the compound is further defined as a compound of formula II:(II).

[0030] Aspect 3 is the compound of aspect 1, wherein the compound is further defined as a compound of formula III:

[0031] Aspect 4 is the compound of aspect 1, wherein Re is replaced by X and Rn is an aldehyde.

[0032] Aspect 5 is the compound of aspect 1, wherein R? is replaced by X and Rn is an aldehyde.299713171.1 - 17 -

[0033] Aspect 6 is the compound of aspect 1, wherein the compound is further defined asa compound of formula IV : (IV).

[0034] Aspect 7 is the compound of aspect 1, wherein R? is replaced by X, Rn is an aldehyde, and R12 is a hydroxyl.

[0035] Aspect 8 is the compound of aspect 1, wherein an aldehyde group is protected as an acetal or hemi-acetal.

[0036] Aspect 9 is the compound of aspect 8, wherein R7 is replaced by X and R11 is the hemi-acetal 1,3 -di oxolane.

[0037] Aspect 10 is the compound of aspect 1, wherein R14 is H.

[0038] Aspect 11 is the compound of aspect 1, wherein R14 is ethyl.

[0039] Aspect 12 is the compound of aspect 1, wherein R14 is propargyl.

[0040] Aspect 13 is the compound of aspect 1, wherein the compound is further defined asa compound of formula V : (V).

[0041] Aspect 14 is the compound of aspect 1, wherein X comprises, consists of, or consists essentially of a molecule with biological activity.

[0042] Aspect 15 is the compound of aspect 1, wherein R14 comprises, consists of, or consists essentially of a molecule with biological activity.

[0043] Aspect 16 is the compound of aspect 14 or 15, wherein the molecule with biological activity comprises, consists of, or consists essentially of erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, Leucovorin, Rapamycin, Lapatinib, Lonafarnib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU 5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan,299713171.1 - 18 -benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophy cin 1, cryptophy cin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammall, calicheamicin omegall, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, an antibody, or retinoic acid.299713171.1 - 19 -

[0044] Aspect 17 is the compound of aspect 1, wherein the compound is one of:299713171.1 - 20 -299713171.1 -21 -

[0045] Aspect 18 is a method of treating a kinase-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1 to 17.

[0046] Aspect 19 is the method of aspect 18, wherein the kinase-mediated disease or disorder is a pan-kinase-mediated disease or disorder.

[0047] Aspect 20 is the method of aspect 18 or 19, wherein the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease.

[0048] Aspect 21 is the method of any one of aspects 18 to 20, wherein the hyperproliferative disease or disorder is a cancer.

[0049] Aspect 22 is the method of aspect 21, wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, cancers of the head and neck, skin cancer, cardiac cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, hematologic cancer, skin cancer, adrenal cancer, oral cavity cancer, hairy cell leukemia, refractory metastatic disease, Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

[0050] Aspect 23 is the method of any one of aspects 18 to 20, wherein the disease or disorder is osteoarthritis, rheumatoid arthritis, angiofibroma, Crohn's disease, diabetic retinopathy, retinal vascularisation, macular degeneration, age-related macular degeneration,299713171.1 - 22 -obesity, multiple sclerosis, allergy, Alzheimer's disease, restenosis, asthma, endometriosis, vein graft stenosis, atherosclerosis, peri-anastomatic prosthetic graft stenosis, chronic obstructive pulmonary disease, prostate hyperplasia, psoriasis, scar tissue formation, neurological damage due to tissue repair, infection, inflammatory bowel disease, neoplasm, pulmonary disease, Parkinson's disease, transplant rejection or septic shock.

[0051] Aspect 24 is the method of any one of aspects 18 to 23, wherein the subject is a human patient.

[0052] Aspect 25 is the method of any one of aspects 18 to 24, wherein the subject is diagnosed with having, has symptoms of, or is suspected of having the disease or disorder.

[0053] Aspect 26 is the method of any one of aspects 18 to 25, further comprising administering a second therapeutic composition to the subject.

[0054] Aspect 27 is the method of aspect 26, wherein the second therapeutic composition comprises a therapy indicated for the disease or disorder.

[0055] Aspect 28 is a compound of formula VI:wherein A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom; Ri and R2 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; R3, R4, Rs, and Re are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide, wherein one of R3, R4, Rs, and Re is optionally replaced by X; wherein X comprises, consists of, or consists essentially of a phenyl ring comprising groups R7 (ortho), Rs (meta), R9 (para), Rio (meta), and R11 (ortho), where R7 Rs R9 Rio and R11 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester,299713171.1 - 23 -ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein X is optionally linked to the indolin-2-one phenyl ring through a linker Li; wherein Li is a linker selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; R12 comprises, consists of, or consists essentially of hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or O6-benzylguanine; wherein R12 is optionally linked to the piperazine ring through a linker L2; wherein L2 is a linker selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof, wherein L2 optionally comprises a moiety that covalently binds to an amino acid side chain moiety or an epitope tag; and R13 is hydrogen or alkyl; or an enantiomer, diastereomer, racemic mixture, or salt thereof.

[0056] Aspect 29 is the compound of aspect 28, wherein the compound of formula VI is further defined as a compound of formula VII:(VII).299713171.1 - 24 -

[0057] Aspect 30 is the compound of aspect 20, wherein the compound of formula VI is further defined as a compound of formula VIII:(VIII).

[0058] Aspect 31 is the compound of aspect 28, wherein the compound is one of:

[0059] Aspect 32 is the compound of aspect 28, wherein X comprises, consists of, or consists essentially of a molecule with biological activity.

[0060] Aspect 33 is the compound of aspect 28, wherein R12 comprises, consists of, or consists essentially of a molecule with biological activity.

[0061] Aspect 34 is the compound of aspect 32 or 33, wherein the molecule with biological activity comprises, consists of, or consists essentially of erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil,299713171.1 - 25 -Leucovorin, Rapamycin, Lapatinib, Lonafarnib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU 5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophy cin 1, cryptophy cin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammall, calicheamicin omegall, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, an antibody, or retinoic acid.299713171.1 - 26 -

[0062] Aspect 35 is a method of treating a kinase-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any of aspects 28 to 34.

[0063] Aspect 36 is the method of aspect 35, wherein the kinase-mediated disease or disorder is a pan-kinase-mediated disease or disorder.

[0064] Aspect 37 is the method of aspect 35 or 36, wherein the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease.

[0065] Aspect 38 is the method of any one of aspects 35 to 37, wherein the hyperproliferative disease or disorder is a cancer.

[0066] Aspect 39 is the method of aspect 38, wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, cancers of the head and neck, skin cancer, cardiac cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, hematologic cancer, skin cancer, adrenal cancer, oral cavity cancer, hairy cell leukemia, refractory metastatic disease, Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

[0067] Aspect 40 is the method of any one of aspects 35 to 39, wherein the disease or disorder is osteoarthritis, rheumatoid arthritis, angiofibroma, Crohn's disease, diabetic retinopathy, retinal vascularization, macular degeneration, age-related macular degeneration, obesity, multiple sclerosis, allergy, Alzheimer's disease, restenosis, asthma, endometriosis, vein graft stenosis, atherosclerosis, peri-anastomotic prosthetic graft stenosis, chronic obstructive pulmonary disease, prostate hyperplasia, psoriasis, scar tissue formation, neurological damage due to tissue repair, infection, inflammatory bowel disease, neoplasm, pulmonary disease, Parkinson's disease, transplant rejection, or septic shock.

[0068] Aspect 41 is the method of any one of aspects 35 to 40, wherein the subject is a human patient.

[0069] Aspect 42 is the method of any one of aspects 35 to 41, wherein the subject is diagnosed with having, has symptoms of, or is suspected of having the disease or disorder.

[0070] Aspect 43 is the method of any one of aspects 35 to 42, further comprising administering a second therapeutic composition to the subject.

[0071] Aspect 44 is the method of aspect 43, wherein the second therapeutic composition comprises a therapy indicated for the disease or disorder.299713171.1 - 27 -

[0072] Aspect 45 is a compound of formula IX:(IX) wherein:A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom; Ri is CH2, O, or NH; R2 and R3 are each independently is CH or N, where each R2 and R3 carbon atom is optionally and independently substituted with halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; R4 and Rs are each independently is CH, CH2, N, or NH, where each R4 and Rs carbon atom and the R4 and Rs NH nitrogen atom is optionally and independently substituted with halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; Re is hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; R7 is X, hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or O6-benzylguanine, wherein X is optionally linked to the piperazine ring through a linker Li; Rs is hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or O6-benzylguanine, wherein Rs is optionally linked to the piperazine ring through a linker L2; where X is phenyl or benzyl comprising groups R9 (ortho), Rio (meta), R11 (para), R12 (meta), and R13 (ortho), where R9, Rio, R11, R12, and R13 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl,299713171.1 - 28 -ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein linkers Li and L2 are ach independently selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; or an enantiomer, diastereomer, racemic mixture, or salt thereof.

[0073] Aspect 46 is the method of aspect 45, wherein the compound of formula IX isfurther defined as a compound of formula X:

[0074] Aspect 47 is the method of aspect 45, wherein the linker is a triazole linker.

[0075] Aspect 48 is the method of aspect 45, wherein the compound of formula IX is one of:299713171.1 - 29 -

[0076] Aspect 49 is the compound of aspect 45, wherein R? comprises, consists of, or consists essentially of a molecule with biological activity.

[0077] Aspect 50 is the compound of aspect 45, wherein Rs comprises, consists of, or consists essentially of a molecule with biological activity.

[0078] Aspect 51 is the compound of aspect 49 or 50, wherein the molecule with biological activity comprises, consists of, or consists essentially of erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, Leucovorin, Rapamycin, Lapatinib, Lonafarnib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU 5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophy cin 1, cryptophy cin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammall, calicheamicin omegall, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore,299713171.1 - 30 -aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6- diazo-5-oxo-L-norieucine, doxorubicin, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2,2',2"-trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, an antibody, or retinoic acid.

[0079] Aspect 52 is a method of treating a kinase-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 45 to 51.

[0080] Aspect 53 is the method of aspect 52, wherein the kinase-mediated disease or disorder is a pan-kinase-mediated disease or disorder.

[0081] Aspect 54 is the method of aspect 52 or 53, wherein the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease.

[0082] Aspect 55 is the method of aspect 54, wherein the hyperproliferative disease or disorder is a cancer.299713171.1 - 31 -

[0083] Aspect 56 is the method of aspect 55, wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, cancers of the head and neck, skin cancer, cardiac cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, hematologic cancer, adrenal cancer, oral cavity cancer, hairy cell leukemia, refractory metastatic disease, Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

[0084] Aspect 57 is the method of any of aspects 52 to 54, wherein the disease or disorder is osteoarthritis, rheumatoid arthritis, angiofibroma, Crohn’s disease, diabetic retinopathy, retinal vascularisation, macular degeneration, age-related macular degeneration, obesity, multiple sclerosis, allergy, Alzheimer's disease, restenosis, asthma, endometriosis, vein graft stenosis, atherosclerosis, peri-anastomatic prosthetic graft stenosis, chronic obstructive pulmonary disease, prostate hyperplasia, psoriasis, scar tissue formation, neurological damage due to tissue repair, infection, inflammatory bowel disease, neoplasm, pulmonary disease, Parkinson's disease, transplant rejection, or septic shock.

[0085] Aspect 58 is the method of any one of aspects 52 to 57, wherein the subject is a human patient.

[0086] Aspect 59 is the method of any one of aspects 52 to 58, wherein the subject is diagnosed with having, has symptoms of, or is suspected of having the disease or disorder.

[0087] Aspect 60 is the method of any one of aspects 52 to 59, further comprising administering a second therapeutic composition to the subject.

[0088] Aspect 65 is the method of aspect 60, wherein the second therapeutic composition comprises a therapy indicated for the disease or disorder.

[0089] “Individual, “subject,” and “patient” are used interchangeably and can refer to a human or non-human. In certain aspects, the subject is a human patient having, diagnosed with having, suspected of having, or having symptoms of a disease or disorder, including any disease or disorder listed herein.

[0090] As used herein, “treat,” “treating,” or “treatment” or equivalent terminology refer to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) an undesired physiological change or disorder, such as the growth, development, or spread of cancer. For purposes of this disclosure, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (ie., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as299713171.1 - 32 -compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented. The results of treatment can be determined by methods known in the art, such as determination of reduction of pain as measured by reduction of requirement for administration of opiates or other pain medication, determination of reduction of tumor burden, determination of restoration of function, or other methods known in the art.

[0091] Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the measurement or quantitation method.

[0092] The use of the word “a” or “an” when used in conjunction with the term “comprising” may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.”

[0093] The phrase “and / or” means “and” or “or”. To illustrate, A, B, and / or C includes: A alone, B alone, C alone, a combination of A and B, a combination of A and C, a combination of B and C, or a combination of A, B, and C. In other words, “and / or” operates as an inclusive or.

[0094] The words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0095] The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of’ any of the ingredients or steps disclosed throughout the specification. Compositions and methods “consisting essentially of’ any of the ingredients or steps disclosed limits the scope of the claim to the specified materials or steps which do not materially affect the basic and novel characteristics of the disclosure.

[0096] Any method in the context of a therapeutic, diagnostic, or physiologic purpose or effect may also be described in “use” claim language such as “use of’ any compound, composition, or agent discussed herein for achieving or implementing a described therapeutic, diagnostic, or physiologic purpose or effect.

[0097] It is contemplated that any aspect discussed in this specification can be implemented with respect to any method or composition of the disclosure, and vice versa. Furthermore, compositions of the disclosure can be used to achieve methods of the disclosure.299713171.1 - 33 -

[0098] Other objects, features and advantages of the present disclosure will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific aspects of the disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.BRIEF DESCRIPTION OF THE DRAWINGS

[0099] The following drawings form part of the present specification and are included to further demonstrate certain aspects of the present disclosure. The disclosure may be better understood by reference to one or more of these drawings in combination with the detailed description of specific aspects presented herein.

[0100] Fig. 1: Exemplary procedure for a compound (KW50P) as disclosed herein.

[0101] Fig. 2: 1H NMR of compound KW50P.

[0102] Fig. 3: LC / MS traces of synthesis of compound KW50P, M+l = 687 g / mol.

[0103] Fig. 4: Chemical structures of probe compounds XO44-4, XO44-8, and XO44-12.

[0104] Fig. 5 : Chemical structures of compounds S50P and S52P.

[0105] Fig. 6: Exemplary procedure for synthesis of a compound (S50P) as disclosed herein.

[0106] Fig. 7: Exemplary procedure for synthesis of a compound (S52P) as disclosed herein.

[0107] Fig. 8: 1H NMR of compound S52P.

[0108] Figs. 9A-9B: Kinome probes show differential effect on growth inhibition for various cancer cell lines.

[0109] Fig. 10: Kinome probes show highly potent and selective growth inhibition of AML cell lines.

[0110] Fig. 11: Chemical structures of exemplary compounds.

[0111] Fig. 12: Chemical structures of exemplary compounds.

[0112] Fig. 13: Chemical structures of exemplary compounds.DETAILED DESCRIPTION

[0113] The present disclosure is based, at least in part, on the discovery of compounds useful for treating kinase-mediated diseases and disorders. The kinase inhibitors exhibit299713171.1 - 34 -activity against a broad array of cancer cell lines and can be employed in the treatment of different types of cancers and other kinase-mediated diseases.I. Therapeutic Methods

[0114] Aspects of the disclosure are directed to compositions comprising therapeutically effective amounts of one or more therapies, including one or more of the compounds disclosed herein, and administration of such compositions to a subject or patient in need thereof. In some aspects, the one or more therapies comprise one or more kinase inhibitors. The therapies can be used to treat a number of kinase-mediated diseases or disorders. In some aspects, the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease.

[0115] The compositions of the disclosure may be used for in vivo, in vitro, or ex vivo administration. The route of administration of the composition may be, for example, intratumoral, intravenous, intramuscular, intraperitoneal, subcutaneous, intraarticular, intrasynovial, intrathecal, oral, topical, through inhalation, or through a combination of two or more routes of administration. The cancer therapies may be administered via the same or different routes of administration.

[0116] The term “cancer,” as used herein, may be used to describe a solid tumor, metastatic cancer, or non-metastatic cancer. In certain aspects, the cancer may originate in the blood, bladder, bone, bone marrow, brain, breast, colon, esophagus, duodenum, small intestine, large intestine, colon, rectum, anus, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, pancreas, prostate, skin, stomach, testis, tongue, or uterus.

[0117] The cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acidophil carcinoma; oxyphilic adenocarcinoma; basophil carcinoma; clear cell adenocarcinoma; granular cell carcinoma; follicular adenocarcinoma;299713171.1 - 35 -papillary and follicular adenocarcinoma; nonencapsulating sclerosing carcinoma; adrenal cortical carcinoma; endometroid carcinoma; skin appendage carcinoma; apocrine adenocarcinoma; sebaceous adenocarcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma; papillary cystadenocarcinoma; papillary serous cystadenocarcinoma; mucinous cystadenocarcinoma; mucinous adenocarcinoma; signet ring cell carcinoma; infiltrating duct carcinoma; medullary carcinoma; lobular carcinoma; inflammatory carcinoma; paget’s disease, mammary; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w / squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granulosa cell tumor, malignant; androblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipid cell tumor, malignant; paraganglioma, malignant; extra-mammary paraganglioma, malignant; pheochromocytoma; glomangiosarcoma; malignant melanoma; amelanotic melanoma; superficial spreading melanoma; malignant melanoma in giant pigmented nevus; epithelioid cell melanoma; blue nevus, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; mullerian mixed tumor; nephroblastoma; hepatoblastoma; carcinosarcoma; mesenchymoma, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma; mesothelioma, malignant; dysgerminoma; embryonal carcinoma; teratoma, malignant; struma ovarii, malignant; choriocarcinoma; mesonephroma, malignant; hemangiosarcoma; hemangioendothelioma, malignant; kaposi’s sarcoma; hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxtacortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone; ewing’s sarcoma; odontogenic tumor, malignant; ameloblastic odontosarcoma; ameloblastoma, malignant; ameloblastic fibrosarcoma; pinealoma, malignant; chordoma; glioma, malignant; ependymoma; astrocytoma; protoplasmic astrocytoma; fibrillary astrocytoma; astroblastoma; glioblastoma; oligodendroglioma; oligodendroblastoma; primitive neuroectodermal; cerebellar sarcoma; ganglioneuroblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; neurilemmoma, malignant; granular cell tumor, malignant; malignant lymphoma; hodgkin’s disease; hodgkin’s; paragranuloma; malignant lymphoma, small lymphocytic; malignant lymphoma, large cell, diffuse; malignant lymphoma, follicular; mycosis fungoides; other specified non-hodgkin’s lymphomas; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative small intestinal disease; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia;299713171.1 - 36 -lymphosarcoma cell leukemia; myeloid leukemia; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryoblastic leukemia; myeloid sarcoma; and hairy cell leukemia.A. Kinase Inhibitors

[0118] In some aspects, the one or more cancer therapies comprise one or more kinase inhibitors. In some aspects, the disclosed methods comprise administration of one or more kinase inhibitors to a subject or patient in need thereof. As used herein, kinase inhibitors describe pharmaceutical compounds that inhibit kinases. Examples of kinases which may be inhibited by kinase inhibitors of the disclosure include pan-kinase, epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and protein kinase C (PKC). Kinases are a part of many cell functions, including cell signaling, growth, and division. Specifically, tyrosine kinases are responsible for the activation of many proteins by signal transduction cascades resulting from phosphorylation of the proteins by tyrosine kinases. Kinase inhibitors inhibit the phosphorylation and subsequent activation of proteins by tyrosine kinases.

[0119] Kinase inhibitors may operate by competing with adenosine triphosphate, the phosphorylating entity, the substrate, or both, or acting in an allosteric fashion, namely binding to a site outside the active site, affecting its activity by a conformational change. The amount of the one or more kinase inhibitors delivered to the patient may be variable. In one suitable aspect, the kinase inhibitors may be administered in an amount effective to cause arrest or regression of the cancer in a host. In other aspects, the kinase inhibitors may be administered in an amount that is anywhere between 2 to 10,000 fold less than the chemotherapeutic effective dose of the kinase inhibitors. For example, the kinase inhibitors may be administered in an amount that is about 20 fold less, about 500 fold less or even about 5000 fold less than the chemotherapeutic effective dose of the kinase inhibitors.

[0120] The kinase inhibitors of the disclosure can be tested in vivo for the desired therapeutic activity alone or in combination with another cancer therapy, as well as for determination of effective dosages. For example, such compounds can be tested in suitable animal model systems prior to testing in humans, including, but not limited to, rats, mice, chicken, cows, monkeys, rabbits, etc. In vitro testing may also be used to determine suitable combinations and dosages, as described in the examples.

[0121] The compositions of the one or more kinase inhibitor compositions may or may not be tailored to address any kinase inhibitor sensitivity or resistance of a cancer as determined299713171.1 - 37 -based on analysis of the genome of a subject having cancer for one or more mutations in the EGFR gene of the subject. The compositions may be given to a subject without having prior analysis of their genome. The kinase inhibitor compositions may comprise any one or more kinase inhibitors associated with an efficacious therapy for treating cancer.

[0122] The subject may be given one or more kinase inhibitor compositions, including compositions that comprise one or more kinase inhibitors that overcome any sensitivity or resistance of a cancer as determined based on analysis of the genome of a subject having cancer for one or more mutations in the EGFR gene of the subject. The kinase inhibitors may be given to treat cancer and / or enhance therapy to treat cancer.

[0123] The kinase inhibitor composition can be administered alone or in combination with one or more additional therapeutic agents disclosed herein. Administration “in combination with” one or more additional therapeutic agents includes both simultaneous (at the same time) and consecutive administration in any order. The kinase inhibitor composition and one or more additional therapeutic agents can be administered in one composition, or simultaneously as two separate compositions, or sequentially. Administration can be chronic or intermittent, as deemed appropriate by the supervising practitioner, including in view of any change in any undesirable side effects.

[0124] In some aspects, the kinase inhibitor of the present disclosure is a pan-kinase inhibitor. Aspects of the disclosure comprise administration of at least 1, 2, 3, 4, 5, or 6 pan- kinase inhibitors to a subject having cancer.

[0125] In some aspects, the methods disclosed herein further comprise administering to the subject an additional cancer therapy. In some aspects, the additional cancer therapy comprises chemotherapy, radiotherapy, or immunotherapy.B. Radiotherapy

[0126] In some aspects, a radiotherapy, such as ionizing radiation, is administered to a subject as a therapeutic agent. As used herein, “ionizing radiation” means radiation comprising particles or photons that have sufficient energy or can produce sufficient energy via nuclear interactions to produce ionization (gain or loss of electrons). A preferred non-limiting example of ionizing radiation is an x-radiation. Means for delivering x-radiation to a target tissue or cell are well known in the art.

[0127] In some aspects, the radiotherapy can comprise external radiotherapy, internal radiotherapy, radioimmunotherapy, or intraoperative radiation therapy (IORT). In some299713171.1 - 38 -aspects, the external radiotherapy comprises three-dimensional conformal radiation therapy (3D-CRT), intensity modulated radiation therapy (IMRT), proton beam therapy, image-guided radiation therapy (IGRT), or stereotactic radiation therapy. In some aspects, the internal radiotherapy comprises interstitial brachytherapy, intracavitary brachytherapy, or intraluminal radiation therapy. In some aspects, the radiotherapy is administered to a primary tumor.

[0128] In some aspects, the amount of ionizing radiation is greater than 20 Gy and is administered in one dose. In some aspects, the amount of ionizing radiation is 18 Gy and is administered in three doses. In some aspects, the amount of ionizing radiation is at least, at most, or exactly 0.5, 1, 2, 4, 6, 8, 10, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 18, 19, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 Gy (or any derivable range therein). In some aspects, the ionizing radiation is administered in at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 does (or any derivable range therein). When more than one dose is administered, the does may be about 1, 4, 8, 12, or 24 hours or 1, 2, 3, 4, 5, 6, 7, or 8 days or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, or 16 weeks apart, or any derivable range therein.

[0129] In some aspects, the amount of radiotherapy administered to a subject may be presented as a total dose of radiotherapy, which is then administered in fractionated doses. For example, in some aspects, the total dose is 50 Gy administered in 10 fractionated doses of 5 Gy each. In some aspects, the total dose is 50-90 Gy, administered in 20-60 fractionated doses of 2-3 Gy each. In some aspects, the total dose of radiation is at least, at most, or about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103,104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 125, 130, 135, 140, or 150 Gy (or any derivable range therein). In some aspects, the total dose is administered in fractionated doses of at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 20, 25, 30, 35, 40, 45, or 50 Gy (or any derivable range therein). In some aspects, at least, at most, or exactly 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100 fractionated doses are administered (or any derivable range therein). In some aspects, at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 (or any derivable range299713171.1 - 39 -therein) fractionated doses are administered per day. In some aspects, at least, at most, or exactly 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 (or any derivable range therein) fractionated doses are administered per week.C. Cancer Immunotherapy

[0130] In some aspects, the methods comprise administration of a cancer immunotherapy as a therapeutic agent. In some aspects, a cancer immunotherapeutic agent can be linked to a compound as disclosed herein through a linker. Cancer immunotherapy (sometimes called immuno-oncology, abbreviated IO) is the use of the immune system to treat cancer. Immunotherapies can be categorized as active, passive or hybrid (active and passive). These approaches exploit the fact that cancer cells often have molecules on their surface that can be detected by the immune system, known as tumor-associated antigens (TAAs); they are often proteins or other macromolecules (e.g. carbohydrates). Active immunotherapy directs the immune system to attack tumor cells by targeting TAAs. Passive immunotherapies enhance existing anti-tumor responses and include the use of monoclonal antibodies, lymphocytes and cytokines. Various immunotherapies are known in the art, and examples are described below.1. Checkpoint Inhibitors and Combination Treatment

[0131] Aspects of the disclosure may include administration of immune checkpoint inhibitors, examples of which are further described below. As disclosed herein, “checkpoint inhibitor therapy” (also “immune checkpoint blockade therapy”, “immune checkpoint therapy”, “ICT,” “checkpoint blockade immunotherapy,” or “CBI”), refers to cancer therapy comprising providing one or more immune checkpoint inhibitors to a subject suffering from or suspected of having cancer.

[0132] PD -1 can act in the tumor microenvironment where T cells encounter an infection or tumor. Activated T cells upregulate PD-1 and continue to express it in the peripheral tissues. Cytokines such as IFN-gamma induce the expression of PDL1 on epithelial cells and tumor cells. PDL2 is expressed on macrophages and dendritic cells. The main role of PD-1 is to limit the activity of effector T cells in the periphery and prevent excessive damage to the tissues during an immune response. Inhibitors of the disclosure may block one or more functions of PD-1 and / or PDL1 activity.

[0133] Alternative names for “PD-1” include CD279 and SLEB2. Alternative names for “PDL1” include B7-H1, B7-4, CD274, and B7-H. Alternative names for “PDL2” include B7-299713171.1 - 40 -DC, Btdc, and CD273. In some aspects, PD-1, PDL1, and PDL2 are human PD-1, PDL1 and PDL2.

[0134] In some aspects, the PD-1 inhibitor is a molecule that inhibits the binding of PD-1 to its ligand binding partners. In a specific aspect, the PD-1 ligand binding partners are PDL1 and / or PDL2. In another aspect, a PDL1 inhibitor is a molecule that inhibits the binding of PDL1 to its binding partners. In a specific aspect, PDL1 binding partners are PD-1 and / or B7- 1. In another aspect, the PDL2 inhibitor is a molecule that inhibits the binding of PDL2 to its binding partners. In a specific aspect, a PDL2 binding partner is PD-1. The inhibitor may be an antibody, an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide. Exemplary antibodies are described in U.S. Patent Nos. 8,735,553, 8,354,509, and 8,008,449, all incorporated herein by reference. Other PD-1 inhibitors for use in the methods and compositions provided herein are known in the art such as described in U.S. Patent Application Nos. US2014 / 0294898, US2014 / 022021, and US2011 / 0008369, all incorporated herein by reference.

[0135] In some aspects, the PD-1 inhibitor is an anti-PD-1 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody). In some aspects, the anti-PD-1 antibody is selected from the group consisting of nivolumab, pembrolizumab, and pidilizumab. In some aspects, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PDL1 or PDL2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some aspects, the PDL1 inhibitor comprises AMP- 224. Nivolumab, also known as MDX-1106-04, MDX-1106, ONO-4538, BMS- 936558, and OPDIVO®, is an anti-PD-1 antibody described in W02006 / 121168. Pembrolizumab, also known as MK-3475, Merck 3475, lambrolizumab, KEYTRUDA®, and SCH-900475, is an anti-PD-1 antibody described in W02009 / 114335. Pidilizumab, also known as CT-011, hBAT, or hBAT-1, is an anti-PD-1 antibody described in W02009 / 101611. AMP-224, also known as B7-DCIg, is a PDL2-Fc fusion soluble receptor described in W02010 / 027827 and WO2011 / 066342. Additional PD-1 inhibitors include MEDI0680, also known as AMP-514, and REGN2810.

[0136] In some aspects, the immune checkpoint inhibitor is a PDL1 inhibitor such as Durvalumab, also known as MEDI4736, atezolizumab, also known as MPDL3280A, avelumab, also known as MSB00010118C, MDX-1105, BMS-936559, or combinations thereof. In certain aspects, the immune checkpoint inhibitor is a PDL2 inhibitor such as rHIgM12B7.299713171.1 - 41 -

[0137] In some aspects, the inhibitor comprises the heavy and light chain CDRs or VRs of nivolumab, pembrolizumab, or pidilizumab. Accordingly, in one aspect, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of nivolumab, pembrolizumab, or pidilizumab, and the CDR1, CDR2 and CDR3 domains of the VL region of nivolumab, pembrolizumab, or pidilizumab. In another aspect, the antibody competes for binding with and / or binds to the same epitope on PD-1, PDL1, or PDL2 as the above- mentioned antibodies. In another aspect, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.

[0138] Another immune checkpoint that can be targeted in the methods provided herein is the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152. The complete cDNA sequence of human CTLA-4 has the Genbank accession number LI 5006. CTLA-4 is found on the surface of T cells and acts as an “off’ switch when bound to B7-1 (CD80) or B7-2 (CD86) on the surface of antigen-presenting cells. CTLA4 is a member of the immunoglobulin superfamily that is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. CTLA4 is similar to the T-cell co-stimulatory protein, CD28, and both molecules bind to B7-1 and B7-2 on antigen-presenting cells. CTLA-4 transmits an inhibitory signal to T cells, whereas CD28 transmits a stimulatory signal. Intracellular CTLA- 4 is also found in regulatory T cells and may be important to their function. T cell activation through the T cell receptor and CD28 leads to increased expression of CTLA-4, an inhibitory receptor for B7 molecules. Inhibitors of the disclosure may block one or more functions of CTLA-4, B7-1, and / or B7-2 activity. In some aspects, the inhibitor blocks the CTLA-4 and B7-1 interaction. In some aspects, the inhibitor blocks the CTLA-4 and B7-2 interaction.

[0139] In some aspects, the immune checkpoint inhibitor is an anti-CTLA-4 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.

[0140] Anti-human-CTLA-4 antibodies (or VH and / or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art. Alternatively, art recognized anti-CTLA-4 antibodies can be used. For example, the anti- CTLA-4 antibodies disclosed in: US 8,119,129, WO 01 / 14424, WO 98 / 42752; WO 00 / 37504 (CP675,206, also known as tremelimumab; formerly ticilimumab), U.S. Patent No. 6,207,156; Hurwitz et al., 1998; can be used in the methods disclosed herein. The teachings of each of the aforementioned publications are hereby incorporated by reference. Antibodies that compete with any of these art-recognized antibodies for binding to CTLA-4 also can be used. For299713171.1 - 42 -example, a humanized CTLA-4 antibody is described in International Patent Application No. W02001 / 014424, W02000 / 037504, and U.S. Patent No. 8,017,114; all incorporated herein by reference.

[0141] A further anti-CTLA-4 antibody useful as a checkpoint inhibitor in the methods and compositions of the disclosure is ipilimumab (also known as 10D1, MDX- 010, MDX- 101, and Yervoy®) or antigen binding fragments and variants thereof (see, e.g., WO 01 / 14424).

[0142] In some aspects, the inhibitor comprises the heavy and light chain CDRs or VRs of tremelimumab or ipilimumab. Accordingly, in one aspect, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of tremelimumab or ipilimumab, and the CDR1, CDR2 and CDR3 domains of the VL region of tremelimumab or ipilimumab. In another aspect, the antibody competes for binding with and / or binds to the same epitope on PD-1, B7-1, or B7- 2 as the above- mentioned antibodies. In another aspect, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.

[0143] Another immune checkpoint that can be targeted in the methods provided herein is the lymphocyte-activation gene 3 (LAG3), also known as CD223 and lymphocyte activating 3. The complete mRNA sequence of human LAG3 has the Genbank accession number NM 002286. LAG3 is a member of the immunoglobulin superfamily that is found on the surface of activated T cells, natural killer cells, B cells, and plasmacytoid dendritic cells. LAG3’s main ligand is MHC class II, and it negatively regulates cellular proliferation, activation, and homeostasis of T cells, in a similar fashion to CTLA-4 and PD-1, and has been reported to play a role in Treg suppressive function. LAG3 also helps maintain CD8+ T cells in a tolerogenic state and, working with PD-1, helps maintain CD8 exhaustion during chronic viral infection. LAG3 is also known to be involved in the maturation and activation of dendritic cells. Inhibitors of the disclosure may block one or more functions of LAG3 activity.

[0144] In some aspects, the immune checkpoint inhibitor is an anti-LAG3 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.

[0145] Anti-human-LAG3 antibodies (or VH and / or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art. Alternatively, art recognized anti-LAG3 antibodies can be used. For example, the anti-LAG3 antibodies can include: GSK2837781, IMP321, FS-118, Sym022, TSR-033, MGD013, BI754111, AVA-017, or GSK2831781. The anti-LAG3 antibodies disclosed in: US 9,505,839 (BMS-986016, also known as relatlimab); US 10,711,060 (IMP-701, also known as LAG525);299713171.1 - 43 -US 9,244,059 (IMP731, also known as H5L7BW); US 10,344,089 (25F7, also known as LAG3.1); WO 2016 / 028672 (MK-4280, also known as 28G-10); WO 2017 / 019894 (BAP050); Burova E., et al., J. ImmunoTherapy Cancer, 2016; 4(Supp. 1):P195 (REGN3767); Yu, X., et al., mAbs, 2019; 11 :6 (LBL-007) can be used in the methods disclosed herein. These and other anti-LAG-3 antibodies useful in the claimed disclosure can be found in, for example: WO 2016 / 028672, WO 2017 / 106129, WO 2017062888, WO 2009 / 044273, WO 2018 / 069500, WO 2016 / 126858, WO 2014 / 179664, WO 2016 / 200782, WO 2015 / 200119, WO 2017 / 019846, WO 2017 / 198741, WO 2017 / 220555, WO 2017 / 220569, WO 2018 / 071500, WO2017 / 015560; WO 2017 / 025498, WO 2017 / 087589 , WO 2017 / 087901, WO 2018 / 083087, WO 2017 / 149143, WO 2017 / 219995, US 2017 / 0260271, WO 2017 / 086367, WO2017 / 086419, WO 2018 / 034227, and WO 2014 / 140180. The teachings of each of the aforementioned publications are hereby incorporated by reference. Antibodies that compete with any of these art-recognized antibodies for binding to LAG3 also can be used.

[0146] In some aspects, the inhibitor comprises the heavy and light chain CDRs or VRs of an anti-LAG3 antibody. Accordingly, in one aspect, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of an anti-LAG3 antibody, and the CDR1, CDR2 and CDR3 domains of the VL region of an anti-LAG3 antibody. In another aspect, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.

[0147] Another immune checkpoint that can be targeted in the methods provided herein is the T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), also known as hepatitis A virus cellular receptor 2 (HAVCR2) and CD366. The complete mRNA sequence of human TIM-3 has the Genbank accession number NM_032782. TIM-3 is found on the surface IFNy- producing CD4+ Thl and CD8+ Tel cells. The extracellular region of TIM-3 consists of a membrane distal single variable immunoglobulin domain (IgV) and a glycosylated mucin domain of variable length located closer to the membrane. TIM-3 is an immune checkpoint and, together with other inhibitory receptors including PD-1 and LAG3, it mediates the T-cell exhaustion. TIM-3 has also been shown as a CD4+ Thl-specific cell surface protein that regulates macrophage activation. Inhibitors of the disclosure may block one or more functions of TIM-3 activity.

[0148] In some aspects, the immune checkpoint inhibitor is an anti-TIM-3 antibody (e.g., a human antibody, a humanized antibody, or a chimeric antibody), an antigen binding fragment thereof, an immunoadhesin, a fusion protein, or oligopeptide.299713171.1 - 44 -

[0149] Anti-human-TIM-3 antibodies (or VH and / or VL domains derived therefrom) suitable for use in the present methods can be generated using methods well known in the art. Alternatively, art recognized anti-TIM-3 antibodies can be used. For example, anti-TIM-3 antibodies including: MBG453, TSR-022 (also known as Cobolimab), and LY3321367 can be used in the methods disclosed herein. These and other anti-TIM-3 antibodies useful in the claimed disclosure can be found in, for example: US 9,605,070, US 8,841,418, US2015 / 0218274, and US 2016 / 0200815. The teachings of each of the aforementioned publications are hereby incorporated by reference. Antibodies that compete with any of these art-recognized antibodies for binding to LAG3 also can be used.

[0150] In some aspects, the inhibitor comprises the heavy and light chain CDRs or VRs of an anti-TIM-3 antibody. Accordingly, in one aspect, the inhibitor comprises the CDR1, CDR2, and CDR3 domains of the VH region of an anti-TIM-3 antibody, and the CDR1, CDR2 and CDR3 domains of the VL region of an anti-TIM-3 antibody. In another aspect, the antibody has at least about 70, 75, 80, 85, 90, 95, 97, or 99% (or any derivable range therein) variable region amino acid sequence identity with the above-mentioned antibodies.2. Inhibition of co-stimulatory molecules

[0151] In some aspects, the immunotherapy comprises an inhibitor of a co-stimulatory molecule. In some aspects, the inhibitor comprises an inhibitor of B7-1 (CD80), B7-2 (CD86), CD28, ICOS, 0X40 (TNFRSF4), 4-1BB (CD137; TNFRSF9), CD40L (CD40LG), GITR (TNFRSF18), and combinations thereof. Inhibitors include inhibitory antibodies, polypeptides, compounds, and nucleic acids.3. Dendritic cell therapy

[0152] Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present the antigen. Dendritic cells are antigen presenting cells (APCs) in the mammalian immune system. In cancer treatment they aid cancer antigen targeting. One example of cellular cancer therapy based on dendritic cells is sipuleucel-T.

[0153] One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of protein that correspond to the protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other299713171.1 - 45 -adjuvants include proteins or other chemicals that attract and / or activate dendritic cells, such as granulocyte macrophage colony-stimulating factor (GM-CSF).

[0154] Dendritic cells can also be activated in vivo by making tumor cells express GM- CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF.

[0155] Another strategy is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide / protein or a tumor cell lysate (a solution of broken down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response.

[0156] Dendritic cell therapies include the use of antibodies that bind to receptors on the surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3, TLR7, TLR8 or CD40 have been used as antibody targets.4. CAR-T cell therapy

[0157] Chimeric antigen receptors (CARs, also known as chimeric immunoreceptors, chimeric T cell receptors or artificial T cell receptors) are engineered receptors that combine a new specificity with an immune cell to target cancer cells. Typically, these receptors graft the specificity of a monoclonal antibody onto a T cell. The receptors are called chimeric because they are fused of parts from different sources. CAR-T cell therapy refers to a treatment that uses such transformed cells for cancer therapy.

[0158] The basic principle of CAR-T cell design involves recombinant receptors that combine antigen-binding and T-cell activating functions. The general premise of CAR-T cells is to artificially generate T-cells targeted to markers found on cancer cells. Scientists can remove T-cells from a person, genetically alter them, and put them back into the patient for them to attack the cancer cells. Once the T cell has been engineered to become a CAR-T cell, it acts as a “living drug”. CAR-T cells create a link between an extracellular ligand recognition domain and an intracellular signaling molecule which in turn activates T cells. The extracellular ligand recognition domain is usually a single-chain variable fragment (scFv). An important aspect of the safety of CAR-T cell therapy is how to ensure that only cancerous tumor cells are targeted, and not normal cells. The specificity of CAR-T cells is determined by the choice of molecule that is targeted.299713171.1 - 46 -

[0159] Example CAR-T therapies include Tisagenlecleucel (Kymriah) and Axicabtagene ciloleucel (Yescarta).5. Cytokine therapy

[0160] Cytokines are proteins produced by many types of cells present within a tumor. They can modulate immune responses. The tumor often employs them to allow it to grow and reduce the immune response. These immune-modulating effects allow them to be used as drugs to provoke an immune response. Two commonly used cytokines are interferons and interleukins.

[0161] Interferons are produced by the immune system. They are usually involved in antiviral response, but also have use for cancer. They fall in three groups: type I (IFNa and IFNP), type II (IFNy) and type III (IF NX).

[0162] Interleukins have an array of immune system effects. IL-2 is an example interleukin cytokine therapy.6. Adoptive T-cell therapy

[0163] Adoptive T cell therapy is a form of passive immunization by the transfusion of T- cells (adoptive cell transfer). They are found in blood and tissue and usually activate when they find foreign pathogens. Specifically they activate when the T-cell’s surface receptors encounter cells that display parts of foreign proteins on their surface antigens. These can be either infected cells, or antigen presenting cells (APCs). They are found in normal tissue and in tumor tissue, where they are known as tumor infiltrating lymphocytes (TILs). They are activated by the presence of APCs such as dendritic cells that present tumor antigens. Although these cells can attack the tumor, the environment within the tumor is highly immunosuppressive, preventing immune-mediated tumor death.

[0164] Multiple ways of producing and obtaining tumor targeted T-cells have been developed. T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. Subsequent activation and culturing is performed ex vivo, with the results reinfused. Activation can take place through gene therapy, or by exposing the T cells to tumor antigens.

[0165] It is contemplated that a cancer treatment may exclude any of the cancer treatments described herein. Furthermore, aspects of the disclosure include patients that have been previously treated for a therapy described herein, are currently being treated for a therapy299713171.1 - 47 -described herein, or have not been treated for a therapy described herein. In some aspects, the patient is one that has been determined to be resistant to a therapy described herein. In some aspects, the patient is one that has been determined to be sensitive to a therapy described herein. For example, the patient may be one that has been determined to be sensitive to an immune checkpoint inhibitor therapy based on a determination that the patient has or previously had pancreatitis.D. Oncolytic virus

[0166] In some aspects, the additional therapy comprises an oncolytic virus as a therapeutic agent. An oncolytic virus is a virus that preferentially infects and kills cancer cells. As the infected cancer cells are destroyed by oncolysis, they release new infectious virus particles or virions to help destroy the remaining tumor. Oncolytic viruses are thought not only to cause direct destruction of the tumor cells, but also to stimulate host anti-tumor immune responses for long-term immunotherapyE. Polysaccharides

[0167] In some aspects, the additional therapy comprises polysaccharides as a therapeutic agent. Certain compounds found in mushrooms, primarily polysaccharides, can up-regulate the immune system and may have anti-cancer properties. For example, beta-glucans such as lentinan have been shown in laboratory studies to stimulate macrophage, NK cells, T cells and immune system cytokines and have been investigated in clinical trials as immunologic adjuvants.F. Neoantigens

[0168] In some aspects, the additional therapy comprises neoantigen administration as a therapeutic agent. Many tumors express mutations. These mutations potentially create new targetable antigens (neoantigens) for use in T cell immunotherapy. The presence of CD8+ T cells in cancer lesions, as identified using RNA sequencing data, is higher in tumors with a high mutational burden. The level of transcripts associated with cytolytic activity of natural killer cells and T cells positively correlates with mutational load in many human tumors.G. Chemotherapies299713171.1 - 48 -

[0169] In some aspects, the additional therapy comprises a chemotherapy as a therapeutic agent. Suitable classes of chemotherapeutic agents include (a) Alkylating Agents, such as nitrogen mustards (e.g., mechlorethamine, cylophosphamide, ifosfamide, melphalan, chlorambucil), ethylenimines and methylmelamines (e.g., hexamethylmelamine, thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g., carmustine, lomustine, chlorozoticin, streptozocin) and triazines (e.g., dicarbazine), (b) Antimetabolites, such as folic acid analogs (e.g., methotrexate), pyrimidine analogs (e.g., 5-fluorouracil, floxuridine, cytarabine, azauridine) and purine analogs and related materials (e.g., 6-mercaptopurine, 6-thioguanine, pentostatin), (c) Natural Products, such as vinca alkaloids (e.g., vinblastine, vincristine), epipodophylotoxins (e.g., etoposide, teniposide), antibiotics (e.g., dactinomycin, daunorubicin, doxorubicin, bleomycin, plicamycin and mitoxanthrone), enzymes (e.g., L-asparaginase), and biological response modifiers (e.g., Interferon-a), and (d) Miscellaneous Agents, such as platinum coordination complexes (e.g., cisplatin, carboplatin), substituted ureas (e.g., hydroxyurea), methylhy diazine derivatives (e.g., procarbazine), and adreocortical suppressants (e.g., taxol and mitotane). In some aspects, cisplatin is a particularly suitable chemotherapeutic agent.

[0170] Cisplatin has been widely used to treat cancers such as, for example, metastatic testicular or ovarian carcinoma, advanced bladder cancer, head or neck cancer, cervical cancer, lung cancer or other tumors. Cisplatin is not absorbed orally and must therefore be delivered via other routes such as, for example, intravenous, subcutaneous, intratumoral or intraperitoneal injection. Cisplatin can be used alone or in combination with other agents, with efficacious doses used in clinical applications including about 15 mg / m2to about 20 mg / m2for 5 days every three weeks for a total of three courses being contemplated in certain aspects. In some aspects, the amount of cisplatin delivered to the cell and / or subject in conjunction with the construct comprising an Egr-1 promoter operatively linked to a polynucleotide encoding the therapeutic polypeptide is less than the amount that would be delivered when using cisplatin alone.

[0171] Other suitable chemotherapeutic agents include antimicrotubule agents, e.g., Paclitaxel (“Taxol”) and doxorubicin hydrochloride (“doxorubicin”). The combination of an Egr-1 promoter / TNFa construct delivered via an adenoviral vector and doxorubicin was determined to be effective in overcoming resistance to chemotherapy and / or TNF-a, which suggests that combination treatment with the construct and doxorubicin overcomes resistance to both doxorubicin and TNF-a.299713171.1 - 49 -

[0172] Doxorubicin is absorbed poorly and is preferably administered intravenously. In certain aspects, appropriate intravenous doses for an adult include about 60 mg / m2 to about 75 mg / m2 at about 21-day intervals or about 25 mg / m2 to about 30 mg / m2 on each of 2 or 3 successive days repeated at about 3 week to about 4 week intervals or about 20 mg / m2 once a week. The lowest dose should be used in elderly patients, when there is prior bone-marrow depression caused by prior chemotherapy or neoplastic marrow invasion, or when the drug is combined with other myelopoietic suppressant drugs.

[0173] Nitrogen mustards are another suitable chemotherapeutic agent useful in the methods of the disclosure. A nitrogen mustard may include, but is not limited to, mechlorethamine (HN2), cyclophosphamide and / or ifosfamide, melphalan (L-sarcolysin), and chlorambucil. Cyclophosphamide (CYTOXAN®) is available from Mead Johnson and NEOSTAR® is available from Adria), is another suitable chemotherapeutic agent. Suitable oral doses for adults include, for example, about 1 mg / kg / day to about 5 mg / kg / day, intravenous doses include, for example, initially about 40 mg / kg to about 50 mg / kg in divided doses over a period of about 2 days to about 5 days or about 10 mg / kg to about 15 mg / kg about every 7 days to about 10 days or about 3 mg / kg to about 5 mg / kg twice a week or about 1.5 mg / kg / day to about 3 mg / kg / day. Because of adverse gastrointestinal effects, the intravenous route is preferred. The drug also sometimes is administered intramuscularly, by infiltration or into body cavities.

[0174] Additional suitable chemotherapeutic agents include pyrimidine analogs, such as cytarabine (cytosine arabinoside), 5 -fluorouracil (fluouracil; 5-FU) and floxuridine (fluorodeoxyuridine; FudR). 5-FU may be administered to a subject in a dosage of anywhere between about 7.5 to about 1000 mg / m2. Further, 5-FU dosing schedules may be for a variety of time periods, for example up to six weeks, or as determined by one of ordinary skill in the art to which this disclosure pertains.

[0175] Gemcitabine diphosphate (GEMZAR®, Eli Lilly & Co., “gemcitabine”), another suitable chemotherapeutic agent, is recommended for treatment of advanced and metastatic pancreatic cancer, and will therefore be useful in the present disclosure for these cancers as well.

[0176] The amount of the chemotherapeutic agent delivered to the patient may be variable. In one suitable aspect, the chemotherapeutic agent may be administered in an amount effective to cause arrest or regression of the cancer in a host, when the chemotherapy is administered with the construct. In other aspects, the chemotherapeutic agent may be administered in an amount that is anywhere between 2 to 10,000 fold less than the chemotherapeutic effective299713171.1 - 50 -dose of the chemotherapeutic agent. For example, the chemotherapeutic agent may be administered in an amount that is about 20 fold less, about 500 fold less or even about 5000 fold less than the chemotherapeutic effective dose of the chemotherapeutic agent. The chemotherapeutics of the disclosure can be tested in vivo for the desired therapeutic activity in combination with the construct, as well as for determination of effective dosages. For example, such compounds can be tested in suitable animal model systems prior to testing in humans, including, but not limited to, rats, mice, chicken, cows, monkeys, rabbits, etc. In vitro testing may also be used to determine suitable combinations and dosages, as described in the examples.H. Surgery

[0177] In some aspects, the additional therapy comprises surgery as a therapeutic agent. Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative, and palliative surgery. Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and / or destroyed and may be used in conjunction with other therapies, such as the treatment of the present aspects, chemotherapy, radiotherapy, hormonal therapy, gene therapy, immunotherapy, and / or alternative therapies. Tumor resection refers to physical removal of at least part of a tumor. In addition to tumor resection, treatment by surgery includes laser surgery, cryosurgery, electrosurgery, and microscopically-controlled surgery (Mohs’ surgery).

[0178] Upon excision of part or all of cancerous cells, tissue, or tumor, a cavity may be formed in the body. Treatment may be accomplished by perfusion, direct injection, or local application of the area with an additional anti-cancer therapy. Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months. These treatments may be of varying dosages as well.I. Anti-Kinase Antibodies and Antibody-Drug Conjugates

[0179] In certain aspects, one or more anti-kinase antibodies or antibody-like molecules (including, for example, antibody-drug conjugates) are contemplated for use in combination with one or more kinase inhibitors of the disclosure. For example, therapeutic methods of the disclosure may include treatment of a patient with one or more kinase inhibitors as disclosed herein in combination with one or more anti-kinase antibodies (or antibody-drug conjugates thereof).J. Other Agents299713171.1 - 51 -

[0180] It is contemplated that other therapeutic agents may be used in combination with certain aspects of the present aspects to improve the therapeutic efficacy of treatment. These additional agents include agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers, or other biological agents. Increases in intercellular signaling by elevating the number of GAP junctions would increase the anti-hyperproliferative effects on the neighboring hyperproliferative cell population. In other aspects, cytostatic or differentiation agents can be used in combination with certain aspects of the present aspects to improve the anti-hyperproliferative efficacy of the treatments. Inhibitors of cell adhesion are contemplated to improve the efficacy of the present aspects. Examples of cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with certain aspects of the present aspects to improve the treatment efficacy.II. Cancer Treatment

[0181] Aspects of the present disclosure are directed to methods comprising treatment of a subject suffering from, or suspected of having, cancer. In some aspects, the disclosed methods comprise treating a subject suffering from cancer (e.g., lung cancer) by administering a therapeutically effective amount of a composition comprising one or more kinase inhibitors as disclosed herein. As used herein, the term “therapeutically effective amount” is synonymous with “effective amount,” “therapeutically effective dose,” and / or “effective dose,” and refers to an amount of an agent sufficient to produce a desired result or exert a desired influence on the particular condition being treated. In some aspects, a therapeutically effective amount is an amount sufficient to ameliorate at least one symptom, behavior or event, associated with a pathological, abnormal or otherwise undesirable condition, or an amount sufficient to prevent or lessen the probability that such a condition will occur or re-occur, or an amount sufficient to delay worsening of such a condition. For instance, in some aspects, the effective amount refers to the amount of a composition comprising one or more kinase inhibitors that can treat or prevent cancer in a subject. The effective amount may vary depending on the organism or individual treated. The appropriate effective amount to be administered for a particular application of the disclosed methods can be determined by those skilled in the art, using the guidance provided herein. As used herein, the terms “treatment,” “treat,” or “treating” refers to299713171.1 - 52 -intervention in an attempt to alter the natural course of the subject being treated, and may be performed either for prophylaxis or during the course of pathology of a disease or condition. Treatment may serve to accomplish one or more of various desired outcomes, including, for example, preventing occurrence or recurrence of disease, alleviation or reduction in severity of symptoms, and diminishment of any direct or indirect pathological consequences of the disease, preventing disease spread, lowering the rate of disease progression, amelioration or palliation of the disease state, and remission or improved prognosis.III. Administration of Therapeutic Compositions

[0182] In certain aspects, the therapy provided herein comprises administration of a combination of therapeutic agents, including at least one or more kinase inhibitors as disclosed herein are administered. In some aspects, the therapy comprises a cocktail of compounds, which can include one or more of the kinases disclosed herein and / or one or more additional therapies. Aspects of the disclosure relate to compositions and methods comprising therapeutic compositions. In some aspects, the different therapies are administered sequentially (at different times) or concurrently (at the same time). The different therapies may be administered in one composition or in more than one composition, such as 2 compositions, 3 compositions, or 4 compositions. In some aspects, the therapies are administered in a separate composition. In some aspects, the therapies are in the same composition. In some aspects of the methods disclosed herein, a single dose of the cancer therapies are administered. In some aspects of the methods disclosed herein, multiple doses of the cancer therapies are administered. Various combinations of the agents may be employed. For example, a kinase inhibitor of formula I is “A” and a kinase inhibitor of formula VI is “B”:

[0183] A / B / A B / A / B B / B / A A / A / B A / B / B B / A / A A / B / B / B B / A / B / B

[0184] B / B / B / A B / B / A / B A / A / B / B A / B / A / B A / B / B / A B / B / A / A

[0185] B / A / B / A B / A / A / B A / A / A / B B / A / A / A A / B / A / A A / A / B / A

[0186] Compositions according to the present disclosure can be prepared according to standard techniques and may comprise water, buffered water, saline, glycine, dextrose, iso- osmotic sucrose solutions and the like, including glycoproteins for enhanced stability, such as albumin, lipoprotein, globulin, and the like. These compositions may be sterilized by conventional, well-known sterilization techniques. The resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration. The299713171.1 - 53 -compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, and the like. The preparation of compositions that contains the cancer therapies will be known to those of skill in the art in light of the present disclosure, as exemplified by Remington: The Science and Practice of Pharmacy, 21st Ed. Lippincott Williams and Wilkins, 2005, incorporated herein by reference. Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety, and purity standards as required by FDA Office of Biological Standards.

[0187] The compositions will be pharmaceutically acceptable or pharmacologically acceptable. The phrases “pharmaceutically acceptable” or “pharmacologically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic, or other untoward reaction when administered to an animal, or human. As used herein, “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredients, its use in therapeutic compositions is contemplated.

[0188] The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of undesirable microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0189] The cancer therapies or therapeutic agents of the disclosure may be administered by the same route of administration or by different routes of administration. In some aspects, the cancer therapy is administered intraarterially, intravenously, intraperitoneally, subcutaneously, intramuscularly, intratumorally, topically, orally, transdermally, intraorbitally, by299713171.1 - 54 -implantation, by inhalation, intrathecally, intraventricularly, or intranasally. The appropriate dosage may be determined based on the type of disease to be treated, severity and course of the disease, the clinical condition of the subject, the subject’s clinical history and response to the treatment, and the discretion of the attending physician.

[0190] The treatments may include various “unit doses.” Unit dose is defined as containing a predetermined-quantity of the therapeutic composition calculated to produce the desired responses discussed above in association with its administration, z.e., the appropriate route and regimen. The quantity to be administered, and the particular route and formulation, is within the skill of determination of those in the clinical arts and depends on the result and / or protection desired. A unit dose need not be administered as a single injection but may comprise continuous infusion over a set period of time. In some aspects, a unit dose comprises a single administrable dose.

[0191] Typically, compositions are administered in a manner compatible with the dosage formulation, and in such amount as will be therapeutically or prophylactically effective for the subject being treated. Precise amounts of the therapeutic composition also depend on the judgment of the practitioner and are peculiar to each individual. Suitable regimes for initial administration and boosters are also variable, but are typified by an initial administration followed by subsequent administrations. Factors affecting dose include physical and clinical state of the patient, the route of administration, the intended goal of treatment (alleviation of symptoms versus cure) and the potency, stability and toxicity of the particular therapeutic substance or other therapies a subject may be undergoing.

[0192] The quantity to be administered, both according to number of treatments and unit dose, depends on the treatment effect desired. An effective dose is understood to refer to an amount necessary to achieve a particular effect. In the practice in certain aspects, it is contemplated that doses in the range from 10 pg / kg to 200 mg / kg can affect the protective capability of these agents. Thus, it is contemplated that doses include doses of about 0.1, 0.5, 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, and 200, 300, 400, 500, 1000 pg / kg, mg / kg, pg / day, or mg / day or any range derivable therein. Furthermore, such doses can be administered at multiple times during a day, and / or on multiple days, weeks, or months.

[0193] In certain aspects, the effective dose of the pharmaceutical composition is one which can provide a blood level of about 1 pM to 150 pM. In another aspect, the effective dose provides a blood level of about 4 pM to 100 pM.; or about 1 pM to 100 pM; or about 1299713171.1 - 55 -pM to 50 pM; or about 1 pM to 40 pM; or about 1 pM to 30 pM; or about 1 pM to 20 pM; or about 1 pM to 10 pM; or about 10 pM to 150 pM; or about 10 pM to 100 pM; or about 10 pM to 50 pM; or about 25 pM to 150 pM; or about 25 pM to 100 pM; or about 25 pM to 50 pM; or about 50 pM to 150 pM; or about 50 pM to 100 pM (or any range derivable therein). In other aspects, the dose can provide the following blood level of the agent that results from a therapeutic agent being administered to a subject: about, at least about, or at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 pM or any range derivable therein. In certain aspects, the therapeutic agent that is administered to a subject is metabolized in the body to a metabolized therapeutic agent, in which case the blood levels may refer to the amount of that agent. Alternatively, to the extent the therapeutic agent is not metabolized by a subject, the blood levels discussed herein may refer to the unmetabolized therapeutic agent.

[0194] It will be understood by those skilled in the art and made aware that dosage units of pg / kg or mg / kg of body weight can be converted and expressed in comparable concentration units of pg / ml or mM (blood levels). It is also understood that uptake is species and organ / tissue dependent. The applicable conversion factors and physiological assumptions to be made concerning uptake and concentration measurement are well-known and would permit those of skill in the art to convert one concentration measurement to another and make reasonable comparisons and conclusions regarding the doses, efficacies and results described herein.IV. Kits

[0195] Certain aspects of the present disclosure also concern kits containing compositions of the disclosure or compositions to implement methods of the disclosure.

[0196] Kits may comprise components, which may be individually packaged or placed in a container, such as a tube, bottle, vial, syringe, or other suitable container means.

[0197] Individual components may also be provided in a kit in concentrated amounts; in some aspects, a component is provided individually in the same concentration as it would be in a solution with other components. Concentrations of components may be provided as lx, 2x, 5x, lOx, or 20x or more.299713171.1 - 56 -

[0198] Kits for using probes, synthetic nucleic acids, nonsynthetic nucleic acids, and / or inhibitors of the disclosure for prognostic or diagnostic applications are included as part of the disclosure. Specifically contemplated are any such molecules corresponding to any biomarker identified herein, which includes nucleic acid primers / primer sets and probes that are identical to or complementary to all or part of a biomarker, which may include noncoding sequences of the biomarker, as well as coding sequences of the biomarker.

[0199] In certain aspects, negative and / or positive control nucleic acids, probes, and inhibitors are included in some kit aspects. In addition, a kit may include a sample that is a negative or positive control for one or more biomarkers

[0200] Any aspect of the disclosure involving specific biomarker by name is contemplated also to cover aspects involving biomarkers whose sequences are at least 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99% identical to the mature sequence of the specified nucleic acid.

[0201] Aspects of the disclosure include kits for analysis of a pathological sample by assessing biomarker profile for a sample comprising, in suitable container means, two or more biomarker probes, wherein the biomarker probes detect one or more of the biomarkers identified herein. The kit can further comprise reagents for labeling nucleic acids in the sample. The kit may also include labeling reagents, including at least one of amine-modified nucleotide, poly(A) polymerase, and poly(A) polymerase buffer. Labeling reagents can include an aminereactive dye.

[0202] It is contemplated that any method or composition described herein can be implemented with respect to any other method or composition described herein and that different aspects may be combined. The claims originally filed are contemplated to cover claims that are multiply dependent on any filed claim or combination of filed claims.V. Chemical Definitions

[0203] As used herein, the term “nitro” means -NO2; the term “amino” means — NH2; the term “halo” or “halogen” designates -F, -Cl, -Br or -I; the term “mercapto” means -SH; the terms “cyano” and “nitrile” mean -CN; the term “azido” means -N3; the term “silyl” means - SiHs, and the term “hydroxy” means -OH.

[0204] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a linear (i.e., unbranched) or branched carbon chain of 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons, which may be fully saturated, monounsaturated, or polyunsaturated. An unsaturated299713171.1 - 57 -alkyl group includes those having one or more carbon-carbon double bonds (alkenyl) and those having one or more carbon-carbon triple bonds (alkynyl). The groups, -CH3 (Me, methyl), - CH2CH3 (Et, ethyl), -CH2CH2CH3 (n-Pr, n-propyl), propenyl, -CH(CH3)2 (iso-Pr, iso-propyl), - CH2CH2CH2CH3 (n-Bu, n-butyl), butenyl, -CH(CH3)CH2CH3 (sec-butyl), -CH2CH(CH3)2 (isobutyl), -C(CH3)3 (tert-butyl), -CH2C(CH3)3 (neo-pentyl), propargyl, are all non-limiting examples of alkyl groups. Specifically included within the definition of “alkyl” are those alkyl groups that are optionally substituted.

[0205] The term “heteroalkyl,” by itself or in combination with another term, means, unless otherwise stated, a linear or branched chain having at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, S, P, and Si. The heteroatom(s) may be placed at any interior position of the heteroalkyl group or at the position at which the heteroalkyl group is attached to the remainder of the molecule. Up to two heteroatoms may be consecutive. The following groups are all non-limiting examples of heteroalkyl groups: trifluoromethyl, -CH2F, -CH2CI, -CH2Br, -CH2OH, -CH2OCH3, -CH2OCH2CF3, - CH2OC(O)CH3, -CH2NH2,-CH2NHCH3, -CH2N(CH3)2, -CH2CH2CI, -CH2SCH3, -CH2CH2OH, -CH2CH2OC(O)CH3, -CH2CH2NHCO2C(CH3)3, and -CH2Si(CH3)3. Specifically included within the definition of “heteroalkyl” are those heteroalkyl groups that are optionally substituted.

[0206] The terms “cycloalkyl” and “heterocyclyl,” by themselves or in combination with other terms, means cyclic versions of “alkyl” and “heteroalkyl”, respectively. Additionally, for heterocyclyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. A cycloalkyl group and a heteroalkyl group can include one or more carbon-carbon double bonds, and / or one or more carbon-carbon triple bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cycloheptyl groups. Examples of heterocyclic groups include indole, azetidinyl, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2- oxoazepinyl, azepinyl, hexahydrodiazepinyl, 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, tetrahydro- 1,1- di oxothienyl, and the like. Specifically included within the definition of “cycloalkyl” are those299713171.1 - 58 -cycloalkyl groups that are optionally substituted. Specifically included within the definition of “heterocyclyl” are those heterocycle groups that are optionally substituted.

[0207] The term “aryl” includes aromatic groups, and is not limited to phenyl, a-naphthyl, P-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenaphthenyl. In certain aspects an aryl group is a phenyl group. Specifically included within the definition of “aryl” are those aromatic groups that are optionally substituted. For example, in some aspects of the present invention, the “aryl” groups are optionally substituted with from 1 to 5 substituents selected from the group consisting of hydrogen, hydroxy, aryl, acyl, Ci-Ce alkyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, amino substituted by one or two Ci-Ce alkyl groups, cyano, halogen, nitro, and trihalomethyl. In some aspects of the present invention, for example, in some aspects wherein the aryl group is phenyl, the aryl groups are optionally substituted with from 1 to 5 substituents selected from the group consisting of hydrogen, hydroxy, aryl, acyl, Ci-Ce alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, amino, amino substituted by one or two Ci-Ce alkyl groups, cyano, halogen, nitro, and trihalomethyl.

[0208] The term “heteroaryl” refers to an aryl group that contains one to four heteroatoms selected from N, O, and S. Specifically included within the definition of “heteroaryl” are those heteroaryl groups that are optionally substituted. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 4-azaindole, 5-azaindole, 6-azaindole, 7-azaindole, 1- naphthyl, 2-naphthyl, 4-biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3 -pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3- isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2- thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5 -benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1 -isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3 -quinolyl, and 6-quinolyl.

[0209] The term “alkoxy” means a group having the structure -OR', where R' is an optionally substituted alkyl or cycloalkyl group. The term “heteroalkoxy” similarly means a group having the structure -OR, where R is a heteroalkyl or heterocyclyl. Specifically included within the definition of “alkoxy” are those alkoxy groups that are optionally substituted.

[0210] Various groups, including alkyl, heteroalky, cycloalkyl, heterocyclyl, aryl, heteroaryl, and alkoxy, are described herein as substituted or unsubstituted (z.e., optionally substituted). Optionally substituted groups may include one or more substituents299713171.1 - 59 -independently selected from: -CF3, -OCF3, halogen, nitro, cyano, hydroxy, amino, amido, mercapto, formyl, carboxy, oxo, acyl, carbamoyl, silyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, alkoxy, alkenyloxy, alkynloxy, aryloxy, acyloxy, alkylthio, alkylamino, alkenylamino, alkynlamino, arylamino, (alkyl)2amino, alkylthio, alkenylthio, alkynylthio, arylthio, alkylsulfinyl, sulfonyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,, arylsulfonyl, acylthio, alkylsilyl, phosphate, phosphonate, phosphinate, cycloalkyl, heterocyclyl, aryl, and heteroaryl. In certain aspects the substituents may be further substituted with one or more substituents.

[0211] The term “amino” means a group having the structure -NR'R", where R' and R" are independently hydrogen or an optionally substituted acyl, alkyl, heteroalkyl, cycloalkyl, or heterocyclyl group. The term “amino” includes primary, secondary, and tertiary amines.

[0212] The term “acyl” includes straight-chain acyl, branched-chain acyl, cycloacyl, cyclic acyl, heteroatom -unsubstituted acyl, heteroatom-substituted acyl, alkylcarbonyl, alkoxycarbonyl and aminocarbonyl groups. The groups, -CHO, -C(O)CH3, -C(O)CH2CH3, - C(O)CH2CH2CH3, -C(O)CH(CH3)2, -C(O)CH(CH2)2, -C(O)C6H5, -C(O)C6H4CH3, - C(O)CeH4CH2CH3, and -COCeH3(CH3)2, are non-limiting examples of heteroatom- unsubstituted acyl groups. The term “heteroatom-substituted acyl” refers to a radical, having a single carbon atom as the point of attachment, the carbon atom being part of a carbonyl group, further having a linear or branched, cyclic or acyclic structure, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The groups, -C(O)CH2CF3, -CO2H, -CO2, -CO2CH3, -CO2CH2CH3, -CO2CH2CH2CH3, - CO2CH(CH3)2, -CO2CH(CH2)2, -C(O)NH2(carbamoyl), -C(O)NHCH3, -C(O)NHCH2CH3, - CONHCH(CH3)2,-CONHCH(CH2)2, -CON(CH3)2, and -CONHCH2CF3, are non-limiting examples of heteroatom-substituted acyl groups.

[0213] The term “alkoxy” includes straight-chain alkoxy, branched-chain alkoxy, cycloalkoxy, cyclic alkoxy, heteroatom -unsubstituted alkoxy, heteroatom-substituted alkoxy, heteroatom -unsubstituted alkoxy, and heteroatom-substituted alkoxy. The term “heteroatom- unsubstituted alkoxy” refers to a group, having the structure -OR, in which R is a heteroatom- unsubstituted alkyl. Heteroatom -unsubstituted alkoxy groups include: -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, and -OCH(CH2)2. The term “heteroatom-substituted alkoxy” refers to a group, having the structure -OR, in which R is a heteroatom-substituted alkyl. For example, -OCH2CF3 is a heteroatom-substituted alkoxy group.

[0214] The term “alkenyloxy” includes straight-chain alkenyloxy, branched-chain alkenyloxy, cycloalkenyloxy, cyclic alkenyloxy, heteroatom-unsubstituted alkenyloxy, and299713171.1 - 60 -heteroatom-substituted alkenyloxy. The term “heteroatom -unsubstituted alkenyloxy” refers to a group, having the structure — OR, in which R is a heteroatom -unsubstituted alkenyl. The term “heteroatom-substituted alkenyloxy” refers to a group, having the structure -OR, in which R is a heteroatom-substituted alkenyl.

[0215] The term “alkynyloxy” includes straight-chain alkynyloxy, branched-chain alkynyloxy, cycloalkynyloxy, cyclic alkynyloxy, heteroatom -unsubstituted alkynyloxy, and heteroatom-substituted alkynyloxy. The term “heteroatom -unsubstituted alkynyloxy” refers to a group, having the structure -OR, in which R is a heteroatom -unsubstituted alkynyl. The term “heteroatom-substituted alkynyloxy” refers to a group, having the structure -OR, in which R is a heteroatom-substituted alkynyl.

[0216] The term “aryloxy” includes heteroatom -unsubstituted aryloxy, heteroatom- substituted aryloxy, heteroaryloxy, and heterocyclic aryloxy groups. The term “heteroatom- unsubstituted aryloxy” refers to a group, having the structure -OAr, in which Ar is a heteroatom -unsubstituted aryl. A non-limiting example of a heteroatom -unsubstituted aryloxy group is -OCeHs. The term “heteroatom-substituted aryloxy” refers to a group, having the structure -OAr, in which Ar is a heteroatom-substituted aryl.

[0217] The term “acyloxy” includes straight-chain acyloxy, branched-chain acyloxy, cycloacyloxy, cyclic acyloxy, heteroatom -unsubstituted acyloxy, heteroatom-substituted acyloxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, and carboxylate groups. The term “heteroatom-unsubstituted acyloxy” refers to a group, having the structure -OAc, in which Ac is a heteroatom -unsubstituted acyl. For example, -OC(O)CH3 is a non-limiting example of a heteroatom -unsubstituted acyloxy group. The term “heteroatom- substituted acyloxy” refers to a group, having the structure -OAc, in which Ac is a heteroatom- substituted acyl. For example, -OC(O)OCH3 and -OC(O)NHCH3 are non-limiting examples of heteroatom -unsubstituted acyloxy groups.

[0218] The term “alkylamino” includes straight-chain alkylamino, branched-chain alkylamino, cycloalkylamino, cyclic alkylamino, heteroatom -unsubstituted alkylamino, and heteroatom-substituted alkylamino. The term “heteroatom -unsubstituted alkylamino” refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, 4 or more hydrogen atoms, a total of 1 nitrogen atom, and no additional heteroatoms. The term “heteroatom -unsubstituted alkylamino” includes groups, having the structure -NHR, in which R is a heteroatom -unsubstituted alkyl. A heteroatom -unsubstituted alkylamino group would include -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2,299713171.1 - 61 --NHCH(CH2)2, -NHCH2CH2CH2CH3, -NHCH(CH3)CH2CH3, -NHCH2CH(CH3)2, - NHC(CH3)3,-N(CH3)2, -N(CH3)CH2CH3, -N(CH2CH3)2, N-pyrrolidinyl, and N-piperidinyl. The term “heteroatom-substituted alkylamino” refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two saturated carbon atoms attached to the nitrogen atom, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The term “heteroatom-substituted alkylamino” includes groups, having the structure -NHR, in which R is a heteroatom-substituted alkyl.

[0219] The term “alkenylamino” includes straight-chain alkenylamino, branched-chain alkenylamino, cycloalkenylamino, cyclic alkenylamino, heteroatom -unsubstituted alkenylamino, heteroatom-substituted alkenylamino, dialkenylamino, and alkyl(alkenyl)amino groups. The term “heteroatom-unsubstituted alkenylamino” refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing at least one nonaromatic carbon-carbon double bond, 4 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms. The term “heteroatom -unsubstituted alkenylamino” includes groups, having the structure -NHR, in which R is a heteroatom- unsubstituted alkenyl. The term “heteroatom-substituted alkenylamino” refers to a radical, having a single nitrogen atom as the point of attachment and at least one nonaromatic carboncarbon double bond, but no carbon-carbon triple bonds, further having one or two carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The term “heteroatom-substituted alkenylamino” includes groups, having the structure -NHR, in which R is a heteroatom-substituted alkenyl.

[0220] The term “alkynylamino” includes straight-chain alkynylamino, branched-chain alkynylamino, cycloalkynylamino, cyclic alkynylamino, heteroatom -unsubstituted alkynylamino, heteroatom-substituted alkynylamino, dialkynylamino, alkyl(alkynyl)amino, and alkenyl(alkynyl)amino groups. The term “heteroatom -unsubstituted alkynylamino” refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two299713171.1 - 62 -carbon atoms attached to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, containing at least one carbon-carbon triple bond, at least one hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms. The term “heteroatom- unsubstituted alkynylamino” includes groups, having the structure -NHR, in which R is a heteroatom -unsubstituted alkynyl. The term “heteroatom-substituted alkynylamino” refers to a radical, having a single nitrogen atom as the point of attachment, further having one or two carbon atoms attached to the nitrogen atom, further having at least one nonaromatic carboncarbon triple bond, further having a linear or branched, cyclic or acyclic structure, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the nitrogen atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The term “heteroatom- substituted alkynylamino” includes groups, having the structure NHR, in which R is a heteroatom-substituted alkynyl.

[0221] The term “arylamino” includes heteroatom -unsubstituted arylamino, heteroatom- substituted arylamino, heteroarylamino, heterocyclic arylamino, and alkyl(aryl)amino groups. The term “heteroatom -unsubstituted arylamino” refers to a radical, having a single nitrogen atom as the point of attachment, further having at least one aromatic ring structure attached to the nitrogen atom, wherein the aromatic ring structure contains only carbon atoms, 6 or more hydrogen atoms, a total of one nitrogen atom, and no additional heteroatoms. The term “heteroatom -unsubstituted arylamino” includes groups, having the structure -NHR, in which R is a heteroatom-unsubstituted aryl. The term “heteroatom-substituted arylamino” refers to a radical, having a single nitrogen atom as the point of attachment, at least one hydrogen atom, at least one additional heteroatoms, that is, in addition to the nitrogen atom at the point of attachment, wherein at least one of the carbon atoms is incorporated into one or more aromatic ring structures, further wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The term “heteroatom-substituted arylamino” includes groups, having the structure -NHR, in which R is a heteroatom-substituted aryl.

[0222] The term “amido” includes straight-chain amido, branched-chain amido, cycloamido, cyclic amido, heteroatom -unsubstituted amido, heteroatom-substituted amido, alkylcarbonylamino, arylcarbonylamino, alkoxycarbonylamino, aryloxycarbonylamino, acylamino, alkylaminocarbonylamino, arylaminocarbonylamino, and ureido groups. The term “heteroatom -unsubstituted amido” refers to a radical, having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen299713171.1 - 63 -atom, further having a linear or branched, cyclic or acyclic structure, 1 or more hydrogen atoms, a total of one oxygen atom, a total of one nitrogen atom, and no additional heteroatoms. The term “heteroatom -unsubstituted amido” includes groups, having the structure -NHR, in which R is a heteroatom -unsubstituted acyl. The group, -NHC(0)CH3, is a non-limiting example of a heteroatom -unsubstituted amido group. The term “heteroatom-substituted amido” refers to a radical, having a single nitrogen atom as the point of attachment, further having a carbonyl group attached via its carbon atom to the nitrogen atom, further having a linear or branched, cyclic or acyclic structure, 0, 1, or more than one hydrogen atom, at least one additional heteroatom in addition to the oxygen of the carbonyl group, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S. The term “heteroatom-substituted amido” includes groups, having the structure -NHR, in which R is a heteroatom -unsubstituted acyl. The group, -NHCO2CH3, is a non-limiting example of a heteroatom-substituted amido group.

[0223] The term “alkylthio” includes straight-chain alkylthio, branched-chain alkylthio, cycloalkylthio, cyclic alkylthio, heteroatom -unsubstituted alkylthio, and heteroatom- substituted alkylthio. The term “heteroatom -unsubstituted alkylthio” refers to a group, having the structure-SR, in which R is a heteroatom -unsubstituted alkyl. The group, -SCH3, is an example of a heteroatom -unsubstituted alkylthio group. The term “heteroatom-substituted alkylthio” refers to a group, having the structure -SR, in which R is a heteroatom- substituted alkyl.

[0224] The term “alkenylthio” includes straight-chain alkenylthio, branched-chain alkenylthio, cycloalkenylthio, cyclic alkenylthio, heteroatom -unsubstituted alkenylthio, and heteroatom-substituted alkenylthio. The term “heteroatom -unsubstituted alkenylthio” refers to a group, having the structure -SR, in which R is a heteroatom -unsubstituted alkenyl. The term “heteroatom-substituted alkenylthio” refers to a group, having the structure -SR, in which R is a heteroatom-substituted alkenyl.

[0225] The term “alkynylthio” includes straight-chain alkynylthio, branched-chain alkynylthio, cycloalkynylthio, cyclic alkynylthio, heteroatom -unsubstituted alkynylthio, and heteroatom-substituted alkynylthio. The term “heteroatom -unsubstituted alkynylthio” refers to a group, having the structure -SR, in which R is a heteroatom -unsubstituted alkynyl. The term “heteroatom-substituted alkynylthio” refers to a group, having the structure -SR, in which R is a heteroatom-substituted alkynyl.

[0226] The term “arylthio” includes heteroatom -unsubstituted arylthio, heteroatom- substituted arylthio, heteroarylthio, and heterocyclic arylthio groups. The term “heteroatom-299713171.1 - 64 -unsubstituted arylthio” refers to a group, having the structure -SAr, in which Ar is a heteroatom -unsubstituted aryl. The group, -SCeHs, is an example of a heteroatom -unsubstituted arylthio group. The term “heteroatom-substituted arylthio” refers to a group, having the structure -SAr, in which Ar is a heteroatom-substituted aryl.

[0227] The term “acylthio” includes straight-chain acylthio, branched-chain acylthio, cycloacylthio, cyclic acylthio, heteroatom -unsubstituted acylthio, heteroatom-substituted acylthio, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, and carboxylate groups. The term “heteroatom-unsubstituted acylthio” refers to a group, having the structure -SAc, in which Ac is a heteroatom-unsubstituted acyl. The group, -SCOCH3, is an example of a heteroatom -unsubstituted acylthio group. The term “heteroatom-substituted acylthio” refers to a group, having the structure -SAc, in which Ac is a heteroatom-substituted acyl.

[0228] The term “alkylsilyl” includes straight-chain alkylsilyl, branched-chain alkylsilyl, cycloalkylsilyl, cyclic alkylsilyl, heteroatom -unsubstituted alkylsilyl, and heteroatom- substituted alkylsilyl. The term “heteroatom -unsubstituted alkylsilyl” refers to a radical, having a single silicon atom as the point of attachment, further having one, two, or three saturated carbon atoms attached to the silicon atom, further having a linear or branched, cyclic or acyclic structure, 5 or more hydrogen atoms, a total of 1 silicon atom, and no additional heteroatoms. An alkylsilyl group includes dialkylamino groups. The groups, -Si(CH3)3 and - Si(CH3)2C(CH3)3, are non-limiting examples of heteroatom -unsubstituted alkylsilyl groups. The term “heteroatom-substituted alkylsilyl” refers to a radical, having a single silicon atom as the point of attachment, further having at least one, two, or three saturated carbon atoms attached to the silicon atom, no carbon-carbon double or triple bonds, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, all of which are nonaromatic, 0, 1, or more than one hydrogen atom, and at least one additional heteroatom, that is, in addition to the silicon atom at the point of attachment, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.

[0229] The term “phosphonate” includes straight-chain phosphonate, branched-chain phosphonate, cyclophosphonate, cyclic phosphonate, heteroatom -unsubstituted phosphonate, and heteroatom-substituted phosphonate. The term “heteroatom-unsubstituted phosphonate” refers to a radical, having a single phosphorous atom as the point of attachment, further having a linear or branched, cyclic or acyclic structure, 2 or more hydrogen atoms, a total of three oxygen atom, and no additional heteroatoms. The three oxygen atoms are directly attached to299713171.1 - 65 -the phosphorous atom, with one of these oxygen atoms doubly bonded to the phosphorous atom. The groups, -P(O)(OH)2, -P(O)(OH)OCH3,-P(O)(OH)OCH2CH3, -P(O)(OCH3)2, and - P(O)(OH)(OC6HS) are non-limiting examples of heteroatom -unsubstituted phosphonate groups. The term “heteroatom-substituted phosphonate” refers to a radical, having a single phosphorous atom as the point of attachment, further having a linear or branched, cyclic or acyclic structure, 2 or more hydrogen atoms, three or more oxygen atoms, three of which are directly attached to the phosphorous atom, with one of these three oxygen atoms doubly bonded to the phosphorous atom, and further having at least one additional heteroatom in addition to the three oxygen atoms, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.

[0230] The term “phosphinate” includes straight-chain phosphinate, branched-chain phosphinate, cyclophosphinate, cyclic phosphinate, heteroatom -unsubstituted phosphinate, and heteroatom-substituted phosphinate. The term “heteroatom -unsubstituted phosphinate” refers to a radical, having a single phosphorous atom as the point of attachment, further having a linear or branched, cyclic or acyclic structure, 2 or more hydrogen atoms, a total of two oxygen atom, and no additional heteroatoms. The two oxygen atoms are directly attached to the phosphorous atom, with one of these oxygen atoms doubly bonded to the phosphorous atom. The groups,-P(O)(OH)H, -P(O)(OH)CH3, -P(O)(OH)CH2CH3, -P(O)(OCH3)CH3, and -P(O)(OC6H5)H are non-limiting examples of heteroatom -unsubstituted phosphinate groups. The term “heteroatom-substituted phosphinate” refers to a radical, having a single phosphorous atom as the point of attachment, further having a linear or branched, cyclic or acyclic structure, further having a total of n carbon atoms, 2 or more hydrogen atoms, two or more oxygen atoms, two of which are directly attached to the phosphorous atom, with one of these two oxygen atoms doubly bonded to the phosphorous atom, and further having at least one additional heteroatom in addition to the two oxygen atoms, wherein each additional heteroatom is independently selected from the group consisting of N, O, F, Cl, Br, I, Si, P, and S.

[0231] Any apparently unfulfilled valency is to be understood to be properly filled by hydrogen atom(s). For example, a compound with a substituent of -O or -N is to be understood to be -OH or -NH2, respectively.

[0232] The term “geminal” refers to a carbon atom to which two atoms or functional groups are attached. A geminal diol, for example, is a compound in which two hydroxyl groups are attached to the same carbon atom.299713171.1 - 66 -

[0233] Any genus, subgenus, or specific compound discussed herein is specifically contemplated as being excluded from any aspect described herein.

[0234] Compounds described herein may be prepared synthetically using conventional organic chemistry methods known to those of skill in the art and / or are commercially available (e.g., ChemBridge Co., San Diego, Calif.; MCule, Palo Alto, CA; etc.).

[0235] The claimed invention is also intended to encompass salts of any of the compounds of the present invention. The term “salt(s)” as used herein, is understood as being acidic and / or basic salts formed with inorganic and / or organic acids and bases. Zwitterions (internal or inner salts) are understood as being included within the term “salt(s)” as used herein, as are quaternary ammonium salts such as alkylammonium salts. Nontoxic, pharmaceutically acceptable salts are preferred, although other salts may be useful, as for example in isolation or purification steps during synthesis. Salts include, but are not limited to, sodium, lithium, potassium, amines, tartrates, citrates, hydrohalides, phosphates and the like. A salt may be a pharmaceutically acceptable salt, for example. Thus, pharmaceutically acceptable salts of compounds of the present invention are contemplated.

[0236] The term “pharmaceutically acceptable salts,” as used herein, refers to salts of compounds of this invention that are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of a compound of this invention with an inorganic or organic acid, or an organic base, depending on the substituents present on the compounds of the invention.

[0237] Non-limiting examples of inorganic acids which may be used to prepare pharmaceutically acceptable salts include: hydrochloric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid and the like. Examples of organic acids which may be used to prepare pharmaceutically acceptable salts include: aliphatic mono- and dicarboxylic acids, such as oxalic acid, carbonic acid, citric acid, succinic acid, phenyl- heteroatom-substituted alkanoic acids, aliphatic and aromatic sulfuric acids and the like. Pharmaceutically acceptable salts prepared from inorganic or organic acids thus include hydrochloride, hydrobromide, nitrate, sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, hydroiodide, hydrofluoride, acetate, propionate, formate, oxalate, citrate, lactate, p- toluenesulfonate, methanesulfonate, maleate, and the like.

[0238] Suitable pharmaceutically acceptable salts may also be formed by reacting the agents of the invention with an organic base such as methylamine, ethylamine, ethanolamine, lysine, ornithine and the like.299713171.1 - 67 -

[0239] Pharmaceutically acceptable salts include the salts formed between carboxylate or sulfonate groups found on some of the compounds of this invention and inorganic cations, such as sodium, potassium, ammonium, or calcium, or such organic cations as isopropylammonium, trimethylammonium, tetramethylammonium, and imidazolium.

[0240] Derivatives of compounds of the present invention are also contemplated. In certain aspects, “derivative” refers to a chemically modified compound that still retains the desired effects of the compound prior to the chemical modification. Such derivatives may have the addition, removal, or substitution of one or more chemical moieties on the parent molecule. Non-limiting examples of the types modifications that can be made to the compounds and structures disclosed herein include the addition or removal of lower alkanes such as methyl, ethyl, propyl, or substituted lower alkanes such as hydroxymethyl or aminomethyl groups; carboxyl groups and carbonyl groups; hydroxyls; nitro, amino, amide, and azo groups; sulfate, sulfonate, sulfono, sulfhydryl, sulfonyl, sulfoxido, phosphate, phosphono, phosphoryl groups, and halide substituents. Additional modifications can include an addition or a deletion of one or more atoms of the atomic framework, for example, substitution of an ethyl by a propyl; substitution of a phenyl by a larger or smaller aromatic group. Alternatively, in a cyclic or bicyclic structure, heteroatoms such as N, S, or O can be substituted into the structure instead of a carbon atom.

[0241] Compounds of the present invention may contain one or more asymmetrically- substituted carbon or nitrogen atoms, and may be isolated in optically active or racemic form. Thus, all chiral, diastereomeric, racemic form, epimeric form, and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. Compounds may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. In some aspects, a single diastereomer is obtained. The chiral centers of the compounds of the present invention can have the S- or the R-configuration, as defined by the IUPAC 1974 Recommendations. Compounds may be of the D- or L-form, for example. It is well known in the art how to prepare and isolate such optically active forms. For example, mixtures of stereoisomers may be separated by standard techniques including, but not limited to, resolution of racemic form, normal, reverse-phase, and chiral chromatography, preferential salt formation, recrystallization, and the like, or by chiral synthesis either from chiral starting materials or by deliberate synthesis of target chiral centers. Compounds of the present invention may occur as a hydrate, a compound containing an equivalent of water in the form of an H2O molecule, or polyhydrate, a compound containing more than one equivalent of water in the form of H2O molecules.299713171.1 - 68 -

[0242] In addition, atoms making up the compounds of the present invention are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include13C and14C.

[0243] As noted above, compounds of the present invention may exist in prodrug form. As used herein, “prodrug” is intended to include any covalently bonded carriers which release the active parent drug or compounds that are metabolized in vivo to an active drug or other compounds employed in the methods of the invention in vivo when such prodrug is administered to a subject. Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc.), the compounds employed in some methods of the invention may, if desired, be delivered in prodrug form. Thus, the invention contemplates prodrugs of compounds of the present invention as well as methods of delivering prodrugs. Prodrugs of the compounds employed in the invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.

[0244] Accordingly, prodrugs include, for example, compounds described herein in which a hydroxy, amino, or carboxy group is bonded to any group that, when the prodrug is administered to a subject, cleaves to form a free hydroxyl, free amino, or carboxylic acid, respectively. Other examples include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups; and alkyl, carbocyclic, aryl, and alkylaryl esters such as methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, phenyl, benzyl, and phenethyl esters, and the like.

[0245] It should be recognized that the particular anion or cation forming a part of any salt of this invention is not critical, so long as the salt, as a whole, is pharmacologically acceptable. Additional examples of pharmaceutically acceptable salts and their methods of preparation and use are presented in Handbook of Pharmaceutical Salts: Properties, Selection and Use (2002), which is incorporated herein by reference.Examples

[0246] The following examples are included to demonstrate aspects of the disclosure. It should be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function well in the practice of the disclosure. However, those of skill in the art should, in light of the present disclosure,299713171.1 - 69 -appreciate that many changes can be made in the specific aspects which are disclosed and still obtain a like or similar result without departing from the spirit and scope of the disclosure.

[0247] Referring to the schematic in Figure 1, two probe core structures are depicted, an exemplary procedure for the synthesis of compound KW50P is outlined. The initial ethyl 4- (bromomethyl)benzoate can include different substituents on the phenyl ring. In the exemplary procedure depicted in Figure 2, hydrogen atoms are included as aryl ring substituents. Reaction of ethyl 4-(bromomethyl)benzoate with triphenyl phosphine yields the triphenyl phosphine ylide salt. Wittig reaction with the indazole carbaldehyde yields the trans olefin intermediate ester. BOC protection of the -NH- amine followed by demethylation of the ester yields the corresponding acid. Conversion of the carboxylic acid to the NHS ester is then performed, and the resulting activated ester is reacted with piperazine dethiobiotin. In the final step, Suzuki coupling with aryl fluorosulfonyl boronic acid yields the final irreversible probe product KW50P. Figure 2 includes a 7H NMR spectra of probe KW50P. LC / MS was used to corroborate the mass of probe KW50P. As seen in Figure 3, the M+l peak of KW50P is 687 g / mol.

[0248] Figure 4 includes chemical structures of compounds XO44-4, XO44-8, and XO44- 12. These compounds differ by the length of the linker that links the biotin moiety to the triazole linkr. Figure 5 includes chemical structures of the two compounds, S50P and S52P. An exemplary procedure for the synthesis of irreversible probe compound S50P is depicted in Figure 6. Bromination of indolin-2-one is accomplished using N-bromosuccinimide. Pd(dppf)C12 is used to convert the brominated indolin-2-one intermediate into the corresponding boronate ester. Suzuki coupling between the boronate ester and para-bromo benzenesulfonylfluoride yields an intermediate indolin-2-one benzenesulfonylfluoride. Coupling of mono-BOC-protected piperazine with 5-formyl-2,4-dimethyl-lH-pyrrole-3- carboxylic acid to yield the pyrrole piperazine amide intermediate. This intermediate is reacted with TMS propargyl methylenebromide to yield the TMS-protected propargyl intermediate. Coupling of the TMS-protected propargyl intermediate and the indolin-2-one benzenesulfonylfluoride yields a TMS protected intermediate which is then deprotected to provide irreversible probe compound S50P.

[0249] An exemplary procedure for the synthesis of irreversible probe compound S52P is depicted in Figure 7. Coupling of mono-BOC-protected piperazine with propargyl methylenebromide yields BOC-protected ethylpropargyl piperazine. After removal of the BOC group, the deprotected ethylpropargyl piperazine is coupled with 5-formyl-2,4-dimethyl-lH-299713171.1 - 70 -pyrrole-3 -carboxylic acid. The resulting product is reacted with 5-hydroxyindolin-2-one, and the resulting product is reacted with 4-(bromomethyl)benzenesulfonyl fluoride to yield irreversible probe compound S52P. Figure 8 includes a H NMR spectra of probe S52P.* * *

[0250] All of the methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this disclosure have been described in terms of preferred aspects, it will be apparent to those of skill in the art that variations may be applied to the methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the disclosure. More specifically, it will be apparent that certain agents which are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the disclosure as defined by the appended claims.299713171.1 - 71 -

Claims

WHAT IS CLAIMED:

1. A compound of formula I:wherein:A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom;Ri, R2, R3, and R4 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;Rs, Re, R7, and Rs are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide, wherein one of Rs, Re, R7, and Rs is optionally replaced by X; wherein X comprises, consists of, or consists essentially of a phenyl ring comprising groups R9 (ortho), Rio (meta), R11 (para), R12 (meta), and R13 (ortho), where R9, Rio, R11, R12, and R13 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;299713171.1 - 72 -wherein X is optionally linked to the indazole phenyl ring through a linker Li; wherein Li comprises, consists of, or consists essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof;Ri4 comprises, consists of, or consists essentially of hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or 06-benzylguanine; wherein Rw is optionally linked to the piperazine through a linker L2; and wherein L2 comprises, consists of, or consists essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof; or an enantiomer, diastereomer, racemic mixture, or salt thereof.

2. The compound of claim 1, wherein the compound is further defined as a compound of formula IE3. The compound of claim 1, wherein the compound is further defined as a compound of formula III:299713171.1 - 73 -4. The compound of claim 1, wherein Re is replaced by X and R11 is an aldehyde.

5. The compound of claim 1, wherein R7 is replaced by X and R11 is an aldehyde.

6. The compound of claim 1, wherein the compound is further defined as a compound of formula IV :

7. The compound of claim 1, wherein R? is replaced by X, Rn is an aldehyde, and R12 is a hydroxyl.

8. The compound of claim 1, wherein an aldehyde group is protected as an acetal or hemiacetal.

9. The compound of claim 8, wherein R7 is replaced by X and R11 is the hemi-acetal 1,3- di oxolane.

10. The compound of claim 1, wherein R14 is H.

11. The compound of claim 1, wherein R14 is ethyl.

12. The compound of claim 1, wherein R14 is propargyl.299713171.1 - 74 -13. The compound of claim 1, wherein the compound is further defined as a compound of formula V:

14. The compound of claim 1, wherein X comprises, consists of, or consists essentially of a molecule with biological activity.

15. The compound of claim 1, wherein Ru comprises, consists of, or consists essentially of a molecule with biological activity.

16. The compound of claim 14 or 15, wherein the molecule with biological activity comprises, consists of, or consists essentially of erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, Leucovorin, Rapamycin, Lapatinib, Lonafamib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU 5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, tri ethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammall, calicheamicin omegall, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5- oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholino-299713171.1 - 75 -doxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2, 2', 2"- trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, an antibody, or retinoic acid.

17. The compound of claim 1, wherein the compound is one of:299713171.1 - 76 -299713171.1 -77-299713171.1 -78 -18. A method of treating a kinase-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 17.

19. The method of claim 18, wherein the kinase-mediated disease or disorder is a pan-kinase- mediated disease or disorder.

20. The method of claim 18 or 19, wherein the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease.

21. The method of any one of claims 18 to 20, wherein the hyperproliferative disease or disorder is a cancer.

22. The method of claim 21, wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, cancers of the head and neck, skin cancer, cardiac cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, hematologic, skin cancer, adrenal cancer, oral cavity299713171.1 - 79 -cancer, hairy cell leukemia, refractory metastatic disease, Kaposi's sarcoma, Bannayan- Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

23. The method of any one of claims 18 to 20, wherein the disease or disorder is osteoarthritis, rheumatoid arthritis, angiofibroma, Chron's disease, diabetic retinopathy, retinal vascularisation, macular degeneration, age-related macular degeneration, obesity, multiple sclerosis, allergy, Alzheimer's disease, restenosis, asthma, endometriosis, vein graft stenosis, atherosclerosis, peri-anastomatic prothetic graft stenosis, chronic obstructive pulmonary disease, prostate hyperplasia, psoriasis, scar tissue formation, neurological damage due to tissue repair, infection, inflammatory bowel disease, neoplasm, pulmonary disease, Parkinson's disease, transplant rejection or septic shock.

24. The method of any one of claims 18 to 23, wherein the subject is a human patient.

25. The method of any one of claims 18 to 24, wherein the subject is diagnosed with having, has symptoms of, or is suspected of having the disease or disorder.

26. The method of any one of claims 18 to 25, further comprising administering a second therapeutic composition to the subject.

27. The method of claim 26, wherein the second therapeutic composition comprises a therapy indicated for the disease or disorder.

28. A compound of formula VI:whereinA is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom;299713171.1 - 80 -Ri and R2 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;R3, R4, Rs, and Re are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide, wherein one of R3, R4, Rs, and Re is optionally replaced by X; wherein X comprises, consists of, or consists essentially of a phenyl ring comprising groups R7 (ortho), Rs (meta), R9 (para), Rio (meta), and R11 (ortho), where R7 Rs R9 Rio and R11 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein X is optionally linked to the indolin-2-one phenyl ring through a linker Li; wherein Li is a linker selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof;R12 comprises, consists of, or consists essentially of hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or O6-benzylguanine;299713171.1 - 81 -wherein R12 is optionally linked to the piperazine ring through a linker L2; wherein L2 is a linker selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof, wherein L2 optionally comprises a moiety that covalently binds to an amino acid side chain moiety or an epitope tag; andR13 is hydrogen or alkyl; or an enantiomer, diastereomer, racemic mixture, or salt thereof.

29. The compound of claim 28, wherein the compound of formula VI is further defined as a compound of formula VII:

30. The compound of claim 20, wherein the compound of formula VI is further defined as a compound of formula VIII:299713171.1 - 82 -31. The compound of claim 28, wherein the compound is one of:

32. The compound of claim 28, wherein X comprises, consists of, or consists essentially of a molecule with biological activity.

33. The compound of claim 28, wherein R12 comprises, consists of, or consists essentially of a molecule with biological activity.299713171.1 - 83 -34. The compound of claim 32 or 33, wherein the molecule with biological activity comprises, consists of, or consists essentially of erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, Leucovorin, Rapamycin, Lapatinib, Lonafamib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU 5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, tri ethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammall, calicheamicin omegall, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5- oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2, 2', 2"- trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan,299713171.1 - 84 -vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, an antibody, or retinoic acid.

35. A method of treating a kinase-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any of claims 28 to 34.

36. The method of claim 35, wherein the kinase-mediated disease or disorder is a pan-kinase- mediated disease or disorder.

37. The method of claim 35 or 36, wherein the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease.38 The method of any of claims 35 to 37, wherein the hyperproliferative disease or disorder is a cancer.

39. The method of claim 34, wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, cancers of the head and neck, skin cancer, cardiac cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, hematologic, skin cancer, adrenal cancer, oral cavity cancer, hairy cell leukemia, refractory metastatic disease, Kaposi's sarcoma, Bannayan- Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

40. The method of any of claims 35 to 39, wherein the disease or disorder is osteoarthritis, rheumatoid arthritis, angiofibroma, Chron's disease, diabetic retinopathy, retinal vascularisation, macular degeneration, age-related macular degeneration, obesity, multiple sclerosis, allergy, Alzheimer's disease, restenosis, asthma, endometriosis, vein graft stenosis, atherosclerosis, peri-anastomatic prothetic graft stenosis, chronic obstructive pulmonary disease, prostate hyperplasia, psoriasis, scar tissue formation, neurological damage due to tissue repair, infection, inflammatory bowel disease, neoplasm, pulmonary disease, Parkinson's disease, transplant rejection or septic shock.299713171.1 - 85 -41. The method of any one of claims 35 to 40, wherein the subject is a human patient.

42. The method of any one of claims 35 to 41, wherein the subject is diagnosed with having, has symptoms of, or is suspected of having the disease or disorder.

43. The method of any one of claims 35 to 42, further comprising administering a second therapeutic composition to the subject.

44. The method of claim 43, wherein the second therapeutic composition comprises a therapy indicated for the disease or disorder.

45. A compound of formula IX:wherein:A is oxygen or two hydrogen atoms, wherein each hydrogen atom is covalently bound to the benzylic carbon atom;Ri is CH2, O, or NH;R2and R.3 are each independently is CH or N, where each R2and R3 carbon atom is optionally and independently substituted with halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;R4 and Rs are each independently is CH, CH2, N, or NH, where each R4 and Rs carbon atom and the R4 and Rs NH nitrogen atom is optionally and independently substituted with halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester,299713171.1 - 86 -sulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;Re is hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide;R7 is X, hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or 06-benzylguanine, wherein X is optionally linked to the piperazine ring through a linker Li;Rs is hydrogen, alkyl, alkenyl, alkynyl, propargyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, biotin, desthiobiotin, imidazoline-2-one, N-hydroxysuccinimide (NHS), maleimide, alkyne, azide, imidiester, haloacetyl, pyridyl sulfide, hydrazide, alkoxyamine, diazirine, tetrazine, or 06-benzylguanine, wherein Rs is optionally linked to the piperazine ring through a linker L2; where X is phenyl or benzyl comprising groups R9 (ortho), Rio (meta), R11 (para), R12 (meta), and R13 (ortho), where R9, Rio, R11, R12, and R13 are each independently hydrogen, halogen, hydroxyl, alkoxy, thiol, thioalkyl, ester, ether, epoxide, amine, amide, alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, amine, alkylamine, sulfoxide, sulfone, sulfinic acid, sulfonic acid, sulfonate ester, sulfonyl, fluorosulfonyl, phosphine, phosphate, phosphate ester, aldehyde, carboxylic acid, nitrate, nitrite, nitrile, isocyanate, or azide; wherein linkers Li and L2 are ach independently selected from the group comprising, consisting of, or consisting essentially of a triazole linker, a glycol linker, a polyethylene glycol (PEG) linker, an alkyl linker, an aryl linker, a heteroalkyl linker, a heteroatom linker, an alkylene linker, an amide linker, an ester linker, a thioester linker, an ether linker, a thioether linker, a phosphoester linker, a phosphoramide linker, an anhydride linker, a disulfide linker, or a combination thereof;299713171.1 - 87 -or an enantiomer, diastereomer, racemic mixture, or salt thereof.

46. The method of claim 45, wherein the compound of formula IX is further defined as a compound of formula X:(X).

47. The method of claim 45, wherein the linker is a triazole linker.

48. The method of claim 45, wherein the compound of formula IX is one of:299713171.1 - 88 -49. The compound of claim 45, wherein R7 comprises, consists of, or consists essentially of a molecule with biological activity.

50. The compound of claim 45, wherein Rs comprises, consists of, or consists essentially of a molecule with biological activity.

51. The compound of claim 49 or 50, wherein the molecule with biological activity comprises, consists of, or consists essentially of erlotinib, bortezomib, fulvestrant, sutent, letrozole, imatinib mesylate, PTK787 / ZK 222584, oxaliplatin, 5-fluorouracil, Leucovorin, Rapamycin, Lapatinib, Lonafamib, Sorafenib, Irinotecan, Gefitinib, AG1478, AG1571, SU 5271, thiotepa, cyclosphosphamide, busulfan, improsulfan, piposulfan, benzodopa, carboquone, meturedopa, uredopa, altretamine, triethylenemelamine, triethylenephosphoramide, tri ethylenethiophosphoramide, trimethylomelamine, bullatacin, bullatacinone, topotecan, bryostatin, callystatin, CC-1065, cryptophycin 1, cryptophycin 8, dolastatin, duocarmycin, KW-2189, CB1-TM1, eleutherobin, pancrati statin, spongistatin, chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard, carmustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimnustine, calicheamicin, calicheamicin gammall, calicheamicin omegall, dynemicin, dynemicin A, clodronate, neocarzinostatin chromophore, aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycinis, dactinomycin, daunorubicin, detorubicin, 6-diazo-5- oxo-L-norleucine, doxorubicin, morpholino-doxorubicin, cyanomorpholinodoxorubicin, 2-pyrrolino-doxorubicin, deoxydoxorubicin, epirubicin, esorubicin,299713171.1 - 89 -idarubicin, marcellomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin, methotrexate, denopterin, pteropterin, trimetrexate, fludarabine, 6-mercaptopurine, thiamiprine, thioguanine, ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine, calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone, aminoglutethimide, mitotane, trilostane, frolinic acid, aceglatone, aldophosphamide glycoside, aminolevulinic acid, eniluracil, amsacrine, bestrabucil, bisantrene, edatraxate, defofamine, demecolcine, diaziquone, elformithine, elliptinium acetate, epothilone, etoglucid, gallium nitrate, hydroxyurea, lentinan, lonidainine, maytansine, ansamitocins, mitoguazone, mitoxantrone, mopidanmol, nitraerine, pentostatin, phenamet, pirarubicin, losoxantrone, podophyllinic acid, 2-ethylhydrazide, procarbazine, razoxane, rhizoxin, sizofuran, spirogermanium, tenuazonic acid, triaziquone, 2, 2', 2"- trichlorotriethylamine, T-2 toxin, verracurin A, roridin A, anguidine, urethan, vindesine, dacarbazine, mannomustine, mitobronitol, mitolactol, pipobroman, gacytosine, arabinoside, cyclophosphamide, thiotepa, paclitaxel, docetaxel, chloranmbucil, gemcitabine, 6-thioguanine, mercaptopurine, cisplatin, carboplatin, vinblastine, etoposide, ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, capecitabine, ibandronate, CPT-11, RFS 2000, difluoromethylornithine, an antibody, or retinoic acid.

52. A method of treating a kinase-mediated disease or disorder in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 45 to 51.

53. The method of claim 52, wherein the kinase-mediated disease or disorder is a pan-kinase- mediated disease or disorder.

54. The method of claim 52 or 53, wherein the disease or disorder is a hyperproliferative, inflammatory, cardiovascular, neurodegenerative, gynecological, or dermatological disease.

55. The method of claim 54, wherein the hyperproliferative disease or disorder is a cancer.299713171.1 - 90 -56. The method of claim 55, wherein the cancer is selected from colorectal cancer, breast cancer, gastric cancer, ovarian cancer, non-small cell lung cancer, cancers of the head and neck, skin cancer, cardiac cancer, genitourinary tract cancer, liver cancer, bone cancer, nervous system cancer, hematologic, skin cancer, adrenal cancer, oral cavity cancer, hairy cell leukemia, refractory metastatic disease, Kaposi's sarcoma, Bannayan- Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

57. The method of any of claims 52 to 54, wherein the disease or disorder is osteoarthritis, rheumatoid arthritis, angiofibroma, Chron's disease, diabetic retinopathy, retinal vascularisation, macular degeneration, age-related macular degeneration, obesity, multiple sclerosis, allergy, Alzheimer's disease, restenosis, asthma, endometriosis, vein graft stenosis, atherosclerosis, peri-anastomatic prothetic graft stenosis, chronic obstructive pulmonary disease, prostate hyperplasia, psoriasis, scar tissue formation, neurological damage due to tissue repair, infection, inflammatory bowel disease, neoplasm, pulmonary disease, Parkinson's disease, transplant rejection or septic shock.

58. The method of any one of claims 52 to 57, wherein the subject is a human patient.

59. The method of any one of claims 52 to 58, wherein the subject is diagnosed with having, has symptoms of, or is suspected of having the disease or disorder.

60. The method of any one of claims 52 to 59, further comprising administering a second therapeutic composition to the subject.

61. The method of claim 60, wherein the second therapeutic composition comprises a therapy indicated for the disease or disorder.299713171.1 - 91 -

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