WO2019040467A1

WO2019040467A1 - SELECTIVE α-CYANOACRYLAMIDE AND α-CYANOACRYLATE INHIBTORS OF THE MCL-1 ONCOPROTEIN AND METHODS OF USING THE SAME

Info

Publication number: WO2019040467A1
Application number: PCT/US2018/047278
Authority: WO
Inventors: Steven Fletcher; D. Alexander MACKERELL, Jr.
Original assignee: University Of Maryland, Baltimore
Priority date: 2017-08-22
Filing date: 2018-08-21
Publication date: 2019-02-28

Abstract

α-Cyanoacrylamide and α-cyanoacrylate compounds that allosterically inhibit Myeloid Cell Leukemia-1 (Mcl-1) oncoprotein, and methods of using the same, are provided for treating disease.

Description

SELECTIVE α-CYANOACRYLAMIDE AND a-CYANOACRYLATE INHIBITORS OF THE MCL-1 ONCOPROTEIN AND METHODS OF USING THE SAME

FIELD OF THE INVENTION

[001] The invention relates generally to compounds and methods of using the same for treating conditions characterized by the overexpression or unregulated activity of anti- apoptotic B-Cell Lymphoma (Bcl-2) family proteins and more particularly, but not exclusively, to a-cyanoacrylamide and a-cyanoacrylate compounds that allosterically inhibit the protein Myeloid Cell Leukemia- 1 (Mcl-l).

BACKGROUND OF THE INVENTION

[002] The B-Cell Lymphoma-2 (Bcl-2) family of proteins regulates the intrinsic apoptosis pathway that is responsible for programmed cell death. The pathway involves protein-protein interactions (PPIs) between pro-apoptotic members of the Bcl-2 family, such as Bim, Bak and Bad, and anti-apoptotic members, such as Bcl-xL and myeloid cell leukemia-1 (Mcl-l). Through conserved hydrophobic crevices, the anti-apoptotic Bcl-2 proteins capture the BH3 a-helical domains of their pro-apoptotic counterparts, effectively "neutralizing" their cell killing functions. Evasion of apoptosis is a hallmark of cancer, and is also one culprit for the development of resistance to current chemo- and radiotherapies.

[003] Mcl-l overexpression and/or amplification of the Mcl-l gene immortalizes cells, and has been observed in many human solid tumors, including pancreatic, prostate, cervical, lung and breast cancers, as well as B-cell lymphomas and hematological cancers, including acute myeloid leukemia (AML). While certain BC1-XL/BC1-2 inhibitors perform well in clinical trials, their low affinity for Mcl-l is a contributing factor to the observed resistance of several tumor cell lines. Moreover, the upregulation of Mcl-l has been directly linked to the reduced efficacy of several FDA-approved anti-cancer chemotherapies. Accordingly, the pharmacologic inhibition of Mcl-l is an attractive, complementary, and/or adjuvant strategy towards the execution of cancer cells by re-activating apoptosis.

[004] In a similar vein to the inhibition of Bcl-xL, the development of synthetic agents capable of disrupting the interaction between Mcl-l and the BH3 a-helical "death" domains of pro-apoptotic Bcl-2 proteins could "neutralize" Mcl-l 's cell survival role. Furthermore, small molecules have been developed that inhibit Mcl-l with high affinity and methods for using such compounds to treat diseases characterized by overexpression or unregulated anti- apoptotic B-cell lymphoma-2 (Bcl-2) family proteins. [005] Accordingly, there is a need in the field for small molecules that selectively inhibit Mcl-l for use in the treatment of cancer.

SUMMARY OF THE INVENTION

[006] In order to address the needs in the field, the invention includes a-cyanoacrylamide and a-cyanoacrylate compounds that are selective inhibitors of Mcl-l and methods of using the same in the treatment of cancer.

[007] In an embodiment, the invention includes a compound of formula (I) or formula (II) or formula (III):

wherein X may be a substituent selected from the group consisting of NR³ and O;

R¹ may be a substituent selected from the group consisting of optionally substituted alkyl, aryl, and heteroaryl;

R² may be a substituent selected from the group consisting of halo and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy;

R³ may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and heteroaryl; and the pharmaceutically acceptable salts thereof. [008] In some embodiments, the compound of formula (I) or formula (II) or formula (III) may be an inhibitor of Mcl-l protein. In some embodiments, the compound of formula (I) or formula (II) or formula (III) may be an allosteric inhibitor of Mcl-l protein.

[009] In an embodiment, the invention includes a method of treating a disease by inhibiting Mcl-l protein activity in a patient in need of such treatment, the method may include administering a therapeutically effective amount of a compound of formula (I) or formula (II) or formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[0010] In some embodiments, the disease may be selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small- cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma,

choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.

[0011] In some embodiments, the disease may be selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.

[0012] In an embodiment, the invention includes a pharmaceutical composition for treating a disease alleviated by inhibiting Mcl-l protein activity, the pharmaceutical composition may include one or more compounds according to formula (I) or formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings.

[0014] FIG. 1 shows a western blot of various proteins in several cell lines. Various compounds of the invention were tested at 10 and 100 μΜ against the MV4-11 (AML) and RCH-ACV (ALL) cell lines. Compounds that caused ~ 0.50-fold change (or inhibited growth at ~ 50%) at 10 μΜ were selected for further testing at 1, 5, and 10 μΜ, with positive controls at 1 and 10 μΜ of S63845 (MCL1 inhibitor), ABT199 (BCL2 inhibitor), and Al l 55463 (BCLxL inhibitor).

[0015] FIGS. 2A and 2B show the dose-response curves for compounds NB-1-029 (circle), NB-1-032 (square), and NB-1-036 (triangle), when tested against the MV4-11 AML cell line (FIG. 2A, NB-1-029 ICso = 8.746 μΜ, NB-1-032 ICso = 3.517 μΜ, and NB-1-036 ICso = 12.511 μΜ), and against the RCH-ACV cell line (FIG. 2B, NB-1-029 ICso = 18.703 μΜ, NB- 1-032 ICso = 3.596 μΜ, and NB-1-036 ICso = 4.646 μΜ).

[0016] FIGS. 3A and 3B show the dose-response curves for compounds NB-1-037

(diamond), NB-1-042 (circle), NB-1-056 (triangle), and NB-1-057 (square), when tested against the MV4-11 AML cell line (FIG. 3A, NB-1-037 ICso = 5.521 μΜ, NB-1-042 ICso = 8.212 μΜ, NB-1-056 ICso = 30.312 μΜ, and NB-1-057 ICso = 5.684 μΜ), and against the RCH-ACV cell line (FIG. 3B, NB-1-037 ICso = 6.836 μΜ, NB-1-042 ICso = 4.484 μΜ, and NB-1-057 ICso = 5.318 μΜ).

[0017] FIGS. 4A and 4B show the dose-response curves for compounds SF-6-141 (solid circle), SF-6-142 (x), SF-6-149 (circle), and SF-6-197 (square), when tested against the MV4-11 AML cell line (FIG. 4A, SF-6-141 ICso = 18.433 μΜ, SF-6-142 ICso = 6.275 μΜ, SF-6-149 ICso = 6.275 μΜ, and SF-6-197 ICso = 7.569 μΜ), and against the RCH-ACV cell line (FIG. 4B, SF-6-141 ICso = 7.609 μΜ, SF-6-142 ICso = 6.447 μΜ, SF-6-149 ICso = 5.606 μΜ, and SF-6-197 ICso = 5.739 μΜ).

DETAILED DESCRIPTION OF THE INVENTION

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties. Definitions

[0019] As used herein, the terms "administer," "administration" or "administering" refer to (1) providing, giving, dosing, and/or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and/or (2) putting into, taking or consuming by the mammal, according to the disclosure.

[0020] The terms "co-administration," "co-administering," "administered in combination with," "administering in combination with," "simultaneous," and "concurrent," as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and/or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. Simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.

[0021] The terms "active pharmaceutical ingredient" and "drug" include the compounds described herein and, more specifically, the compounds described by formula (I)-(XXI). The terms "active pharmaceutical ingredient" and "drug" may also include those compounds described herein that bind Mcl-1 protein, and thereby modulate Mcl-1 protein activity.

[0022] The term vivo" refers to an event that takes place in a subject's body.

[0023] The term vitro" refers to an event that takes places outside of a subject's body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.

[0024] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A

therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g. , the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g. , the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried. [0025] A "therapeutic effect" as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0026] The terms "QD," "qd," or "q.d." mean quaque die, once a day, or once daily. The terms "BID," "bid," or "b.i.d." mean bis in die, twice a day, or twice daily. The terms "TID," "tid," or "t.i.d." mean ter in die, three times a day, or three times daily. The terms "QID," "qid," or "q.i.d." mean quater in die, four times a day, or four times daily.

[0027] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine,

tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.

[0028] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs disclosed herein, can also be incorporated into the described compositions and methods.

[0029] As used herein, the terms "treat," "treatment," and/or "treating" may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and/or control the disease, disorder, pathological condition or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, "control" may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition).

[0030] As used herein, the terms "modulate" and "modulation" refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g., increased activity, agonism, activation, expression, upregulation, and/or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression,

deactivation, downregulation, and/or decreased expression) for the biological molecule. In some embodiments, the biological molecules modulated by the methods and compounds of the invention to effect treatment may include the Mcl-1 oncoprotein.

[0031] As used herein, the term "allosteric inhibitor" or "allosteric modulator" refers to a compound that inhibits or modulates a protein's biological activity by binding at the protein's allosteric site, which is different from the binding site of the protein's endogenous ligand. In some embodiments, the compounds of the invention are allosteric inhibitors of the Mcl-1 oncoprotein. In some embodiments, a compound's allosteric binding activity for a specific protein, such as Mcl-1, may be determined by way of the Hill equation as described in U.S. Patent No. 6,534,501, the entirety of which is incorporated herein by reference.

[0032] As used herein, the term "prodrug" refers to a derivative of a compound described herein, the pharmacologic action of which results from the conversion by chemical or metabolic processes in vivo to the active compound. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues is covalently joined through an amide or ester bond to a free amino, hydroxyl or carboxylic acid group of formulas I, II, and/or III. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by one or three letter symbols but also include, for example, 4-hydroxyproline, hydroxylysine, desmosine, isodesmosine, 3- methylhistidine, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, ornithine and methionine sulfone. Additional types of prodrugs are also encompassed. For instance, free carboxyl groups can be derivatized as amides or alkyl esters (e.g., methyl esters and acetoxy methyl esters). Prodrug esters as employed herein includes esters and carbonates formed by reacting one or more hydroxyls of compounds of the method of the invention with alkyl, alkoxy, or aryl substituted acylating agents employing procedures known to those skilled in the art to generate acetates, pivalates, methylcarbonates, benzoates and the like. As further examples, free hydroxyl groups may be derivatized using groups including but not limited to hemisuccinates, phosphate esters, dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlined in Advanced Drug Delivery Reviews, 1996, 19, 1 15. Carbamate prodrugs of hydroxyl and amino groups are also included, as are carbonate prodrugs, sulfonate prodrugs, sulfonate esters and sulfate esters of hydroxyl groups. Free amines can also be derivatized to amides, sulfonamides or phosphonamides. All of the stated prodrug moieties may incorporate groups including but not limited to ether, amine and carboxylic acid functionalities. Moreover, any compound that can be converted in vivo to provide the bioactive agent (e.g., a compound of formula I, II, and/or III) is a prodrug within the scope of the invention. Various forms of prodrugs are well known in the art. A comprehensive description of pro drugs and prodrug derivatives are described in: (a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al, (Academic Press, 1996); (b) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985); (c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds., (Harwood

Academic Publishers, 1991). In general, prodrugs may be designed to improve the penetration of a drug across biological membranes in order to obtain improved drug absorption, to prolong duration of action of a drug (slow release of the parent drug from a prodrug, decreased first-pass metabolism of the drug), to target the drug action (e.g. organ or tumor-targeting, lymphocyte targeting), to modify or improve aqueous solubility of a drug (e.g., i.v. preparations and eyedrops), to improve topical drug delivery (e.g. dermal and ocular drug delivery), to improve the chemical/enzymatic stability of a drug, or to decrease off- target drug effects, and more generally in order to improve the therapeutic efficacy of the compounds utilized in the invention. [0033] Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by ¹³C- or ¹⁴C-enriched carbons, are within the scope of this invention.

[0034] When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and

subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from 0% to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that "consist of or "consist essentially of the described features.

[0035] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g. , (Ci-io)alkyl or Ci-io alkyl). Whenever it appears herein, a numerical range such as " 1 to 10" refers to each integer in the given range - e.g. , "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term "alkyl" where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, w-butyl, isobutyl, sec- butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), ^-propyl (Pr), 1 -methylethyl (isopropyl), w-butyl, n- pentyl, 1,1-dimethylethyl (/-butyl) and 3-methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,

trifiuoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, - C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)2 where each R^a is independently hydrogen, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0036] "Alkylaryl" refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0037] "Alkylhetaryl" refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0038] "Alkylheterocycloalkyl" refers to an -(alkyl) heterocyclyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.

[0039] An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

[0040] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i. e., (C2-io)alkenyl or C2-10 alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range - e.g. , "2 to 10 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-1 - enyl (i. e., allyl), but-l-enyl, pent-l -enyl and penta-l,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)2, - C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)2, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. [0041] "Alkenyl-cycloalkyl" refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.

[0042] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i. e. , (C2-io)alkynyl or C2-10 alkynyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range - e.g. , "2 to 10 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, - C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, - N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P03(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0043] "Alkynyl-cycloalkyl" refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.

[0044] "Carboxaldehyde" refers to a -(C=0)H radical.

[0045] "Carboxyl" refers to a -(C=0)OH radical.

[0046] "Cyano" refers to a -CN radical.

[0047] "Cycloalkyl" refers to a monocyclic or poly cyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i. e. (C3-io)cycloalkyl or C3-10 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range - e.g. , "3 to 10 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, - OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂,

N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or

2), -S(0)tN(R^a)₂ (where t is 1 or 2), or P03(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0048] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0049] "Cycloalkyl-heterocycloalkyl" refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.

[0050] "Cycloalkyl-heteroaryl" refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0051] The term "alkoxy" refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. "Lower alkoxy" refers to alkoxy groups containing one to six carbons.

[0052] The term "substituted alkoxy" refers to alkoxy wherein the alkyl substituent is substituted (i.e., -0-(substituted alkyl)). Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0053] The term "alkoxycarbonyl" refers to a group of the formula (alkoxy)(C=0)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (Ci-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. "Lower alkoxycarbonyl" refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.

[0054] The term "substituted alkoxycarbonyl" refers to the group (substituted alkyl)-0- C(O)- wherein the group is attached to the parent structure through the carbonyl functionality. Unless stated otherwise specifically in the specification, the alkyl moiety of an

alkoxycarbonyl group is optionally substituted by one or more substituents which

independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,

trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0055] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. [0056] "Acyloxy" refers to a R(C=0)0- radical wherein R is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are as described herein. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0057] "Amino" or "amine" refers to a -N(R^a)₂ radical group, where each R^a is

independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a -N(R^a)₂ group has two R^a substituents other than hydrogen, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example, -N(R^a)₂ is intended to include, but is not limited to, 1 -pyrrolidinyl and 4- morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0058] The term "substituted amino" also refers to N-oxides of the groups -NHR^a, and NR^aR^a each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0059] "Amide" or "amido" refers to a chemical moiety with formula -C(0)N(R)₂ or -NHC(0)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. The R2 of -N(R)2 of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

[0060] "Aromatic" or "aryl" or "Ar" refers to an aromatic radical with six to ten ring atoms (e.g. , C6-C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g. , phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g. , a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as "6 to 10" refers to each integer in the given range; e.g. , "6 to 10 ring atoms" means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, - OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0061] The term "aryloxy" refers to the group -O-aryl. [0062] The term "substituted aryloxy" refers to aryloxy wherein the aryl substituent is substituted (i.e., -0-(substituted aryl)). Unless stated otherwise specifically in the specification, the aryl moiety of an aryloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0063] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0064] "Ester" refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(O)- R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0065] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group. [0066] "Halo," "halide," or, alternatively, "halogen" is intended to mean fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and

"fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[0067] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g. , oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given - e.g. , C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0068] "Heteroalkylaryl" refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[0069] "Heteroalkylheteroaryl" refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[0070] "Heteroalkylheterocycloalkyl" refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.

[0071] "Heteroalkylcycloalkyl" refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively. [0072] "Heteroaryl" or "heteroaromatic" or "HetAr" refers to a 5- to 18-membered aromatic radical (e.g. , C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range - e.g. , "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "- idene" to the name of the corresponding univalent radical - e.g. , a pyridyl group with two points of attachment is a pyridylidene. A N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The

heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[cf]thiazolyl, benzothiadiazolyl, benzo[Z>] [l,4]dioxepinyl,

benzo[Z>] [l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,

benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-cf|pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[cf|pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3- cf|pyrimidinyl, 5,6-dihydrobenzo[/2]quinazolinyl, 5,6-dihydrobenzo[/2]cinnolinyl, 6,7- dihydro-5H-benzo[6,7]cyclohepta[l,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9, 10- hexahydrocycloocta[cf|pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta[cf|pyridazinyl,

5,6,7,8,9, 10-hexahydrocycloocta[cf|pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8- methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9, 10, 10a-octahydrobenzo[ 2]quinazolinyl, 1 - phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2- cf|pyrimidinyl, pyrido[3,4-cf|pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8- tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-cf|pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5- c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3- cf|pyrimidinyl, thieno[3,2-cf]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0073] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-0-) substituents, such as, for example, pyridinyl N-oxides.

[0074] "Heteroarylalkyl" refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.

[0075] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as "3 to 18" refers to each integer in the given range - e.g. , "3 to 18 ring atoms" means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The

heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such

heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1 -oxo-thiomorpholinyl, and l,l-dioxo-thiomo holinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, - SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, - N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or

P03(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0076] "Heterocycloalkyl" also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.

[0077] "Nitro" refers to the -N0₂ radical.

[0078] "Oxa" refers to the -O- radical.

[0079] "Oxo" refers to the =0 radical.

[0080] "Isomers" are different compounds that have the same molecular formula.

"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space - i.e. , having a different stereochemical configuration. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (S). Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (<S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0081] "Enantiomeric purity" as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (5)-isomeric

configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (5)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (5)-isomer and 20% (i?)-isomer, the enantiomeric purity of the compound with respect to the (<S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle's reagents, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0082] In preferred embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et ai, Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).

[0083] The terms "enantiomerically enriched" and "non-racemic," as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g. , greater than 1 : 1 by weight). For example, an enantiomerically enriched preparation of the (<S)-enantiomer, means a preparation of the compound having greater than 50% by weight of the (<S)-enantiomer relative to the (i?)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a "substantially enantiomerically enriched" or a "substantially non- racemic" preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight. The terms "enantiomerically pure" or "substantially enantiomerically pure" refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0084] "Moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0085] "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adj acent double bond. Where tautomerization is possible (e.g. , in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.

[0086] A "leaving group or atom" is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.

[0087] "Protecting group" is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. Η. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).

[0088] "Solvate" refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent. [0089] "Substituted" means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo,

perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[0090] "Sulfanyl" refers to groups that include -S-(optionally substituted alkyl), -S- (optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).

[0091] "Sulfinyl" refers to groups that include -S(0)-H, -S(0)-(optionally substituted alkyl), -S(0)-(optionally substituted amino), -S(0)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(0)-(optionally substituted heterocycloalkyl).

[0092] "Sulfonyl" refers to groups that include -S(02)-H, -S(02)-(optionally substituted alkyl), -S(02)-(optionally substituted amino), -S(02)-(optionally substituted aryl), -S(02)- (optionally substituted heteroaryl), and -S(02)-(optionally substituted heterocycloalkyl).

[0093] "Sulfonamidyl" or "sulfonamido" refers to a -S(=0)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=0)2-NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0094] "Sulfoxyl" refers to a -S(=0)₂OH radical.

[0095] "Sulfonate" refers to a -S(=0)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively. [0096] Compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. "Crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[0097] For the avoidance of doubt, it is intended herein that particular features (for example integers, characteristics, values, uses, diseases, formulae, compounds or groups) described in conjunction with a particular aspect, embodiment or example of the invention are to be understood as applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Thus such features may be used where appropriate in conjunction with any of the definition, claims or embodiments defined herein. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and/or steps are mutually exclusive. The invention is not restricted to any details of any disclosed

embodiments. The invention extends to any novel one, or novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0098] Moreover, as used herein, the term "about" means that dimensions, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, a dimension, size, formulation, parameter, shape or other quantity or characteristic is "about" or "approximate" whether or not expressly stated to be such. It is noted that embodiments of very different sizes, shapes and dimensions may employ the described arrangements.

[0099] Furthermore, the transitional terms "comprising", "consisting essentially of and "consisting of, when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s). The term "comprising" is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material. The term "consisting of excludes any element, step or material other than those specified in the claim and, in the latter instance, impurities ordinary associated with the specified material(s). The term "consisting essentially of limits the scope of a claim to the specified elements, steps or material(s) and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. All embodiments of the invention can, in the alternative, be more specifically defined by any of the transitional terms "comprising," "consisting essentially of," and "consisting of."

Methods of Treating Cancers and Other Diseases

[00100] The compounds and compositions described herein can be used in methods for treating diseases. In some embodiments, the compounds and compositions described herein can be used in methods for treating diseases associated with the upregulation of myeloid cell leukemia-1 (Mcl-1) oncoprotein. In some embodiments, the compounds and compositions described herein can be used for the treatment of hyperproliferative disorders, including those hyperproliferative disorders associated with the upregulation of Mcl-1. The compounds and compositions described herein may also be used in treating other disorders as described herein and in the following paragraphs.

[00101] In some embodiments, the hyperproliferative disorder is cancer. In some embodiments, the cancer is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia,

neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma, and the like. [00102] In some embodiments, the hyperproliferative disorder treated by the compounds and compositions described herein includes cells having Mcl-1 protein and/or Mcl-1 related protein expression. In some embodiments, the disease treated by the compounds and compositions described herein is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.

[00103] In some embodiments, the methods include inhibiting Mcl-1 protein activity, comprising contacting Mcl-1 protein with a therapeutically effective amount of a compound of formula (I)-(XXI), or pharmaceutically acceptable salt thereof.

[00104] In some embodiments, the methods include treating a disease by inhibiting Mcl-1 protein activity in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of formula (I)-(XXI), or a pharmaceutically acceptable salt thereof.

[00105] In some embodiments, the methods include allosterically inhibiting Mcl-1 protein activity, comprising contacting Mcl-1 protein with a therapeutically effective amount of a compound of formula (I)-(XXI), or pharmaceutically acceptable salt thereof.

[00106] In some embodiments, the methods include treating a disease by allosterically inhibiting Mcl-1 protein activity in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of formula (I)- (XXI), or a pharmaceutically acceptable salt thereof.

[00107] Efficacy of the methods, compounds, and combinations of compounds described herein in treating, preventing and/or managing the indicated diseases or disorders can be tested using various animal models known in the art. For example, methods for determining efficacy of treatments for pancreatic cancer are described in Herreros-Villanueva, et al. , World J. Gastroenterol. 2012, 18, 1286-1294. Models for determining efficacy of treatments for breast cancer are described, e.g. , in Fantozzi, Breast Cancer Res. 2006, 8, 212. Models for determining efficacy of treatments for ovarian cancer are described, e.g. , in Mullany, et al. , Endocrinology 2012, 153, 1585-92; and Fong, et al , J. Ovarian Res. 2009, 2, 12. Models for determining efficacy of treatments for melanoma are described, e.g. , in Damsky, et al , Pigment Cell & Melanoma Res. 2010, 23, 853-859. Models for determining efficacy of treatments for lung cancer are described, e.g. , in Meuwissen, et al. , Genes & Development, 2005, 19, 643-664. Models for determining efficacy of treatments for lung cancer are described, e.g. , in Kim, Clin. Exp. Otorhinolaryngol. 2009, 2, 55-60; and Sano, Head Neck Oncol. 2009, 1, 32. Models for determining efficacy of treatments for colorectal cancer, including the CT26 model, are described in Castle, et al. , BMC Genomics, 2013, 15, 190; Endo, et al, Cancer Gene Therapy, 2002, 9, 142-148; Roth et at , Adv. Immunol. 1994, 57, 281-351; Fearon, et al, Cancer Res. 1988, 48, 2975-2980.

g-Cvanoacrylamide and a-Cvanoacrylate Mcl-l Inhibitors

[00108] In an embodiment, the invention includes compounds of formula (I)-(XXI), which may be allosteric inhibitors of Mcl-l. In some embodiments, the compounds described herein may be selective, allosteric inhibitors of Mcl-l protein activity as compared to BC1-XL.

[00109] In some embodiments, the compounds described herein may selectively decrease the activity of Mcl-l protein as compared to BC1-XL protein in a ratio of at least about 1.5 to about 1, or at least about 2 to about 1, or at least about 3 to about 1, or at least about 4 to about 1, or at least about 5 to about 1, or at least about 10 to about 1, or at least about 15 to about 1, or at least about 20 to about 1, or at least about 25 to about 1, or at least about 30 to about 1, or at least about 35 to about 1, or at least about 40 to about 1, or at least about 45 to about 1, or at least about 50 to about 1, or at least about 100 to about 1, or at least about 200 to about 1, or at least about 300 to about 1, or at least about 400 to about 1, or at least about 500 to about 1, or at least about 600 to about 1, or at least about 700 to about 1, or least about 800 to about 1, or at least about 900 to about 1, or at least about 1000 to about 1, or at least about 10000 to about 1, or at least about 100000 to about 1, respectively.

[00110] In an embodiment, the invention includes a compound of formula (I) or formula (II) or formula (III):

R³ may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and heteroaryl; and the pharmaceutically acceptable salts thereof.

[00111] In some embodiments, the invention includes a compound of formula (IV) or formula (V) or formula (VI):

wherein X may be a substituent selected from the group consisting of NR³ and O; R¹ may be a substituent selected from the group consisting of optionally substituted alkyl, aryl, and heteroaryl;

R³ may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and heteroaryl;

R⁴ may be one or more substituents selected from the group consisting of hydrogen, alkyl, aryl, halo, hydroxyl, methoxy, alkyloxy, aryloxy, and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy; and the pharmaceutically acceptable salts thereof.

[00112] In an embodiment, the invention includes a compound of formula (VII) or formula (VIII) or formula (IX):

R³ may be a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and heteroaryl; R⁴ may be a substituent selected from the group consisting of hydrogen, alkyl, aryl, halo, hydroxyl, methoxy, alkyloxy, aryloxy, and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy; and

R⁵ may be a substituent selected from the group consisting of hydrogen, alkyl, aryl, halo, hydroxyl, methoxy, alkyloxy, aryloxy, and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy; and the pharmaceutically acceptable salts thereof.

[00113] In some embodiments, the invention includes a compound of formula (X) or formula (XI) or formula (XII):

wherein R⁴ may be one or more substituents selected from the group consisting of hydrogen, alkyl, aryl, halo, hydroxyl, methoxy, alkyloxy, aryloxy, and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy; and

R⁵ may be one or more substituents selected from the group consisting of hydrogen, alkyl, aryl, halo, hydroxyl, methoxy, alkyloxy, aryloxy, and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy; and the pharmaceutically acceptable salts thereof. [00114] In some embodiments, the invention includes a compound of formula (XIII) or formula (XIV) or formula (XV):

wherein R⁴ may be one or more substituents selected from the group consisting of hydrogen, alkyl, aryl, halo, hydroxyl, methoxy, alkyloxy, aryloxy, and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy; and the pharmaceutically acceptable salts thereof.

[00115] In some embodiments, the invention includes a compound of formula (XVI) or formula (XVII) or formula (XVIII):

(xvi),

wherein R⁵ may be one or more substituents selected from the group consisting of hydrogen, alkyl, aryl, halo, hydroxyl, methoxy, alkyloxy, aryloxy, and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy; and the pharmaceutically acceptable salts thereof.

[00116] In an embodiment, the invention includes a compound of formula (XIX) or formula (XX) or formula (XXI):

R¹ may be a substituent selected from the group consisting of optionally substituted alkyl, cycloalkyl, aryl, and heteroaryl; and

[00117] In some embodiments, the one or more R⁴ and the one or more R⁵ are independently selected from -H, -OH, -OMe, -Me, -CI, -OPh, substituted -OPh, -0(3,5-dimethyl-4-Cl)Ph, -

[00118] In an embodiment, the invention includes the compounds included in Table 1.

Table 1

[00119] In some embodiments, the Mcl-1 inhibitors described herein may be delivered as listed or as a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, tautomer, or prodrug thereof.

[00120] Regarding the compounds of the invention as a whole, and without being limited to any one theory of the invention, the compounds of formula (I)-(XXI) reversibly react with Cys286 on the opposite face of the canonical BH3 binding groove of the Mcl-1 oncoprotein, which allows for allosteric inhibition of Mcl-1. In some embodiments, the compounds of formula (I), formula (II), and formula (III) are selective, reversible covalent inhibitors of Mcl- 1.

Pharmaceutical Compositions

[00121] In an embodiment, the invention provides a pharmaceutical composition for use in the treatment of the diseases and conditions described herein.

[00122] The pharmaceutical compositions are typically formulated to provide a

therapeutically effective amount of a compound of formula (I)-(XXI), as described herein, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, as the active ingredient.

Typically, the pharmaceutical compositions also comprise one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[00123] The pharmaceutical compositions described above are preferably for use in the treatment of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, or retinoblastoma.

[00124] In some embodiments, the concentration of a compound of formula (I)-(XXI) provided in the pharmaceutical compositions of the invention is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01 %, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001 %, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v or v/v of the pharmaceutical composition.

[00125] In some embodiments, the concentration of a compound of formula (I)-(XXI) provided in the pharmaceutical compositions of the invention is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 1 1.50%, 11.25% 11 %, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w/w, w/v, or v/v of the pharmaceutical composition.

[00126] In some embodiments, the concentration of a compound of formula (I)-(XXI) provided in the pharmaceutical compositions of the invention is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w/w, w/v or v/v of the pharmaceutical composition.

[00127] In some embodiments, the concentration of a compound of formula (I)-(XXI) provided in the pharmaceutical compositions of the invention is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w/w, w/v or v/v of the pharmaceutical composition.

[00128] In some embodiments, the amount of a compound of formula (I)-(XXI) provided in the pharmaceutical compositions of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[00129] In some embodiments, the amount of a compound of formula (I)-(XXI) provided in the pharmaceutical compositions of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

[00130] Each of the compounds provided according to the invention is effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently ranging from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subj ect to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[00131] Described below are non-limiting pharmaceutical compositions and methods for preparing the same.

Pharmaceutical Compositions for Oral Administration

[00132] In preferred embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of formula (I)-(XXI) described herein, and a pharmaceutical excipient suitable for administration.

[00133] In preferred embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of formula (I)-(XXI), and (ii) a pharmaceutical excipient suitable for administration. In some embodiments, the composition further contains (iii) an effective amount of an additional active pharmaceutical ingredient. For example, additional active pharmaceutical ingredients, as used herein, may include one or more compounds that induce cell cycle arrest and/or apoptosis in cells containing functional Mcl-l proteins. Such additional active pharmaceutical ingredients may also include those compounds used for sensitizing cells to additional agent(s), such as inducers of apoptosis and/or cell cycle arrest, and chemoprotection of normal cells through the induction of cell cycle arrest prior to treatment with

chemotherapeutic agents.

[00134] In some embodiments, the pharmaceutical composition may be a liquid

pharmaceutical composition suitable for oral consumption.

[00135] Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, a water-in-oil liquid emulsion, powders for reconstitution, powders for oral consumptions, bottles (including powders or liquids in a bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00136] The invention further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, water may be added (e.g. , 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.

Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[00137] Active pharmaceutical ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[00138] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g. , ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[00139] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g. , granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[00140] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for

disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[00141] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g. , peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof. A lubricant can optionally be added in an amount of less than about 0.5% or less than about 1 % (by weight) of the pharmaceutical composition.

[00142] When aqueous suspensions and/or elixirs are desired for oral administration, the active pharmaceutical ingredient(s) may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[00143] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[00144] Surfactants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[00145] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and

hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e. , hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[00146] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di- glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof.

[00147] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[00148] Ionic surfactants may be the ionized forms of lecithin, lysolecithin,

phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine,

lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[00149] Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols;

polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[00150] Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 com oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, poly glyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-lOoleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[00151] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di -glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[00152] In an embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use - e.g. , compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[00153] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2- pyrrolidone, 2-piperidone, £-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, δ- valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[00154] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol. [00155] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or

evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

[00156] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[00157] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine,

ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para- bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[00158] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thiogly colic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

[00159] In preferred embodiments, the invention provides a pharmaceutical composition for injection containing a compound of formula (I)-(XXI) described herein, and a pharmaceutical excipient suitable for injection. Components and amounts of compounds in the compositions are as described herein.

[00160] The forms in which the compositions of the invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[00161] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[00162] Sterile injectable solutions are prepared by incorporating a compound of formula (I)-(XXI) described herein in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization.

Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Pharmaceutical Compositions for Topical Delivery

[00163] In preferred embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of formula (I)-(XXI) described herein, and a pharmaceutical excipient suitable for transdermal delivery.

[00164] Compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble j ellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)- based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[00165] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g. , urea), glycols (e.g. , propylene glycol), alcohols (e.g. , ethanol), fatty acids (e.g. , oleic acid), surfactants (e.g. , isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g. , menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[00166] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of formula (I)-(XXI) described herein in controlled amounts, either with or without another active pharmaceutical ingredient.

[00167] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U. S. Patent Nos. 5,023,252; 4,992,445 and

5,001 , 139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Pharmaceutical Compositions for Inhalation

[00168] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Dry powder inhalers may also be used to provide inhaled delivery of the compositions.

Other Pharmaceutical Compositions

[00169] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, et al , eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990, each of which is incorporated by reference herein in its entirety.

[00170] Administration of a compound of formula (I)-(XXI) described herein or a pharmaceutical composition of these compounds can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. , transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compound of formula (I)-(XXI) described herein can also be administered intraadiposally or intrathecally.

[00171] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide,

polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g. , PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as

polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. A compound of formula (I)-(XXI) described herein may be applied to the surface of the stent by various methods such as dip/spin coating, spray coating, dip-coating, and/or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. A compound of formula (I)-(XXI) described herein may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of a compound of formula (I)-(XXI) described herein via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.

[00172] Exemplary parenteral administration forms include solutions or suspensions of a compound of formula (I)-(XXI) in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[00173] The invention also provides kits. The kits include a compound of formula (I)-(XXI) described herein in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another active pharmaceutical ingredient. In some embodiments, the compound of formula (I)-(XXI) described herein and another active pharmaceutical ingredient are provided as separate compositions in separate containers within the kit. In some embodiments, the compound of formula (I)-(XXI) and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g. , measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.

[00174] The kits described above are preferably for use in the treatment of the diseases and conditions described herein. In a preferred embodiment, the kits are for use in the treatment of cancer or hyperproliferative disorders.

[00175] In a particular embodiment, the kits described herein are for use in the treatment of cancer. In some embodiments, the kits described herein are for use in the treatment of a cancer selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma. Dosages and Dosing Regimens

[00176] The amounts of a compound of formula (I)-(XXI) described herein administered will be dependent on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage of each is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g. , by dividing such larger doses into several small doses for administration throughout the day. The dosage of a compound of formula (I) or formula (II) described herein may be provided in units of mg/kg of body mass or in mg/m² of body surface area.

[00177] In some embodiments, a compound of formula (I)-(XXI) described herein is administered in multiple doses. In a preferred embodiment, a compound of formula (I)-(XXI) described herein is administered in multiple doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, a compound of formula (I)-(XXI) described herein is administered about once per day to about 6 times per day. In some embodiments, a compound of formula (I)-(XXI) described herein is administered once daily, while in other embodiments, a compound of formula (I)-(XXI) described herein is administered twice daily, and in other embodiments a compound of formula (I)-(XXI) described herein is administered three times daily.

[00178] Administration a compound of formula (I)-(XXI) described herein may continue as long as necessary. In some embodiments, a compound of formula (I)-(XXI) described herein is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of formula (I)-(XXI) described herein is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of formula (I)-(XXI) described herein is administered chronically on an ongoing basis - e.g. , for the treatment of chronic effects. In another embodiment, the administration of a compound of formula (I)-(XXI) described herein continues for less than about 7 days. In yet another embodiment, the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary. [00179] In some embodiments, an effective dosage of a compound of formula (I)-(XXI) described herein is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg.

[00180] In some embodiments, an effective dosage of a compound of formula (I)-(XXI) described herein is in the range of about 0.01 mg/kg to about 4.3 mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg to about 2.85 mg/kg, about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg to about 1.7 mg/kg, about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg to about 1.15 mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg to about 0.85 mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg mg to about 1.6 mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg to about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kg to about 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg.

[00181] In some instances, dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g. , by dividing such larger doses into several small doses for administration throughout the day.

[00182] An effective amount of a compound of formula (I)-(XXI) described herein may be administered in either single or multiple doses by any of the accepted modes of

administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. [00183] The following examples describe the invention in further detail. These examples are provided for illustrative purposes only, and should in no way be considered as limiting the invention.

EXAMPLES

[00184] Example 1 : Chemical Synthesis

[00185] Compounds described herein, for example in Table 1, were prepared according to the following schemes and procedures.

Scheme 1

[00186] (4-(4-Chloro-3,5-dimethylphenoxy)benzonitrile) [2, NB-1 -017]. 4-Chloro-3,5- dimethyl phenol (2 g, 12.8 mmol, 1 eq.) was added to a solution of 4-fluoro benzonitrile (1 ; 1.55 g, 12.8 mmol, 1 eq.) in anhydrous DMF (30 mL). K₂C0₃ (1.76 g, 12.8 mmol, 1 eq.) was added. The reaction was stirred at 100 °C for 16 h. The reaction mixture was then allowed to cool, and poured over ice-water (300 mL). The organic material was extracted into diethyl ether (3 x 150 mL). The combined organic layers were washed with 3 M NaOH (3 x 150 ml), water (3 x 150 mL), brine (150 mL), dried Na2S04), filtered and concentrated to yield a pale brown solid that was used without further purification (100%): ¾ NMR (400 MHz, CDCh) δ = 7.60 (d, J = 8.8 Hz, 2H), 6.99 (d, J = 9.6 Hz, 2H), 6.80 (s, 2H), 2.38 (s, 6H).

[00187] (4-(4-Chloro-3,5-dimethylphenoxy)phenyl)methanamine) [3, NB- 1-020] .

Compound 2 was dissolved in anhydrous ether (33 mL), and cooled to 0 °C. L1AIH4 was added carefully, then the reaction was allowed to stir for 2 h, gradually warming to RT. After completion of the reduction, the reaction mixture was quenched by the careful addition of brine (1 mL). The reaction mixture was poured into a separately funnel, and rinsed with further ether (ca. 100 mL) and 1 M NaOH (ca. 100 mL). The organic layer was collected, then the aqueous layer was extracted with further diethyl ether (ca. 100 mL). The organic layers were combined, washed with 1 M NaOH (100 mL), brine (100 mL), dried Na2S04) filtered and concentrated to yield the title compound (100%): ¾ NMR (400 MHz, CDCh) δ = 7.28 (d, obsc, 2H), 6.96 (d, J = 8.8 Hz, 2H), 6.73 (s, 2H), 3.86 (s, 2H), 2.34 (s, 6H), 1.46 (s, 2H).

[00188] (N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyanoacetamide) [4, NB-1-022] . To a solution of compound 3 (500 mg, 2.04 mmol, 1.05 eq.) in EtOH (1 mL) was added ethyl cyanoacetate (207 μί, 1.94 mmol, 1 eq.). The reaction mixture was stirred at RT for 16 h, then poured into a separatory funnel with ethyl acetate (80 mL). The organic phase was washed with 1 M HC1 (25 mL), 1 M NaOH (25 mL), water (25 mL), brine (25 mL), dried Na2S04), filtered and concentrated. The crude residue was dry-loaded onto silica gel and purified by flash column chromatography (Isolera, gradient of EtOAc in Hexanes) to deliver the title compound as a white solid (92%): ¾ NMR (400 MHz, CDCh) δ = 7.25 (d, obsc, 2H), 6.96 (d, J = 7.2 Hz, 2H), 6.75 (s, 2H), 6.33 (s, 1H), 4.60 (d, J = 5.6 Hz, 2H), 3.43 (s, 2H), 2.35 (s, 6H).

[00189] General Knoevenagel Condensation Procedure to Afford 5a-5j : To a solution of 4 (1 eq) and the appropriate aldehyde (1 eq) in EtOH (0.1 M) was added piperidine (10 mol%). The reaction mixture was heated at 70 °C for 16 h. After cooling the reaction mixtures, products were collected by vacuum filtration, washed with cold EtOH, or by flash column chromatography (eluent: CH2Cl2/MeOH/NH40H, 92:7: 1), to deliver the target molecules as white or pale brown solids.

[00190] (E)-N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(3-hydroxy-4- methoxyphenyl)acrylamide [5a, NB-1-027] : ¾ NMR (400 MHz, CDCh) δ = 8.26 (s, 1H), 7.62 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H), 7.29 (obsc, 2H), 6.97 (d, obsc, 2H), 6.76 (s, 2H), 6.60 (t, 1H), 5.69 (s, 1H), 4.57 (d, J = 5.6 Hz, 2H), 3.99 (s, 3H), 2.35 (s, 6H); ¹³C NMR (400 MHz, DMSO) δ = 161.94, 155.87, 155.20, 152.28, 151.12, 147.16, 137.78, 134.73, 129.67, 128.35, 125.24, 125.00, 119.05, 1 17.38, 1 15.92, 102.35, 56.18, 43.00, 20.80.

[00191] N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(2,4- dihydroxyphenyl)acrylamide [5b, NB-1 -029] : ¾ NMR (400 MHz, DMSO) Inseparable mixture of E and Z isomers.

[00192] (E)-N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(2,3,4- trimethoxyphenyl)acrylamide [5c, NB-1 -030] : ¾ NMR (400 MHz, DMSO) δ = 8.97 (t, J = 6.0 Hz, 1H), 8.33 (s, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.34 (d, J = 7.6 Hz, 2H), 7.07 (d, J = 9.2 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.87 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.89 (s, 3H), 2.31 (s, 6H); ¹³C NMR (400 MHz, DMSO) δ = 161.61, 157.88, 155.18, 154.02, 145.42, 141.89, 137.78, 134.73, 129.67, 128.36, 124.14, 119.06, 118.97, 117.29, 108.88, 104.09, 62.29, 60.96, 56.69, 43.04, 20.793.

[00193] N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(2,3- dihydroxyphenyl)acrylamide [5d, NB-1-032] : ¾ NMR (400 MHz, DMSO) Inseparable mixture.

[00194] N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(2-hydroxy-4- methoxyphenyl)acrylamide [5e, NB-1-033]: ¾ NMR (400 MHz, DMSO) Inseparable mixture.

[00195] N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(2,3,4- trihydroxyphenyl)acrylamide [5f, NB-1-036] : ¾ NMR (400 MHz, DMSO) Inseparable mixture.

[00196] 3-(4-Chloro-2-hydroxyphenyl)-N-(4-(4-chloro-3,5-dimethylphenoxy)benzyl)-2- cyanoacrylamide [5g, NB-1-037] : ¾ NMR (400 MHz, DMSO) Inseparable mixture.

[00197] (E)-N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(3- hydroxyphenyl)acrylamide [5h, NB-1-041] : ¾ NMR (400 MHz, DMSO) δ = 9.96 (s, 1H), 9.03 (t, J = 6.0 Hz, 1H), 8.12 (s, 1H), 7.36 (m, 5H), 7.00 (d, J = 8.8 Hz, 2H), 6.87 (s, 2H), 4.41 (d, J = 5.6 Hz, 2H), 2.30 (s, 6H). ¹³C NMR (400 MHz, DMSO) δ = 161.52, 158.17, 155.93, 155.17, 151.33, 137.80, 134.53, 133.47, 130.75, 129.72, 128.28, 121.96, 120.15, 199.08, 118.97, 116.74, 116.30, 106.23, 43.04, 20.79.

[00198] (E)-N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(3,4,5- trihydroxyphenyl)acrylamide [5i, NB-1-042] : ¾ NMR (400 MHz, DMSO) δ = 8.79 (s, 1H), 7.87 (s, 1H), 7.33 (d, J = 8.4 Hz, 2H), 7.00 (m, 4H), 6.86 (s, 2H), 4.38 (d, J = 5.6 Hz, 2H), 2.30 (s, 6H). ¹³C NMR (400 MHz, DMSO) δ = 162.21, 155.84, 155.21, 151.58, 146.43, 139.47, 137.78, 134.84, 129.64, 122.50, 119.05, 118.97, 117.59, 110.64, 100.95, 42.95, 20.80.

[00199] (E)-N-(4-(4-Chloro-3,5-dimethylphenoxy)benzyl)-2-cyano-3-(3-hydroxy-4- methoxyphenyl)acrylamide [5j, NB-1-044] : ¾ NMR (400 MHz, CDC13) δ = 8.27 (s, 1H), 7.30 (d, J = 7.6 Hz, 2H), 7.24 (s, 2H), 6.97 (d, J = 8.4 Hz, 2H), 6.75 (s, 2H), 6.64 (m, 1H), 4.59 (d, J = 5.6 Hz, 2H), 3.93 (m, 9H), 2.35 (s, 6H); ¹³C NMR (400 MHz, CDC13) δ = 160.36, 157.00, 154.58, 153.28, 137.74, 131.90, 129.50, 126.85, 118.95, 117.43, 108.10, 102.00, 61.11, 56.23, 43.98, 20.88. Scheme 2

9 10

[00200] 4-(4-Chloro-3,5-dimethylphenoxy)benzaldehyde [7, NB-1-043]. To a solution of 4- chloro-3,5-dimethylphenol (4 g, 25.5 mmol, 1 eq) in anhydrous DMF (30 mL) was added 4- fluorobenzaldehyde (6; 3.17 g, 25.5 mmol, 1 eq) and K2CO3 (3.53 g, 25.5 mmol, 1 eq). The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was then allowed to cool, and poured over ice-water (300 mL). The organic material was extracted into diethyl ether (3 x 150 mL). The combined organic layers were washed with 3M NaOH (3 x 150 ml), water (3 x 150 mL), brine (150 mL), dried Na2S04), filtered and concentrated to yield a pale brown solid that was used without further purification (100%): ¾ NMR (400 MHz, CDCh) δ = 9.93 (s, 1H), 7.85 (d, J= 8.4 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 6.83 (s, 2H), 2.38 (s, 6H).

[00201] ter -Butyl-3-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-2-cyanoacrylate [8, NB-1- 052]. To a solution of 7 (500 mg, 1.92 mmol, 1 eq) and fert-butyl cyanoacetate (594 μί, 3.84 mmol, 2 eq) in EtOH (10 mL) was added piperidine (9.5 μί, 5 mol%) at 0 °C. The reaction mixture was then stirred overnight at RT. Upon completion (by TLC), the reaction mixture was partitioned between EtOAc (150 mL) and 0.1 M HC1 (50 mL). The organic layer was collected, washed with brine (50 mL), dried Na2S04), filtered and concentrated. The crude material was adsorbed onto silica gel, then purified by flash column chromatography (Isolera, gradient of EtOAc in Hex) to furnish the title compound as a white solid (89%): ¾ NMR (400 MHz, CDCh) δ = 8.10 (s, 1H), 7.96 (d, J= 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.83 (s, 2H), 2.38 (s, 6H), 1.58 (s, 9H).

[00202] (3-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-2-cyanoacrylic acid) [9, NB-1-053]. To a solution of 8 (230 mg, 0.6 mmol, 1 eq) in anhydrous CH2CI2 (3 mL) was added TFA (3 mL). The reaction mixture was stirred at RT for 2 h, then concentrated to dryness to deliver the title compound as a white solid (100%): ¾ NMR (400 MHz, DMSO) δ = 8.31 (s, 1H), 8.10 (d, J = 8.8, 2H), 7.15 (d, J = 8.8, 2H), 7.05 (s, 2H), 2.35 (s, 6H).

[00203] General Procedure for Amide Bond Formation to Afford lOa-lOj: To a solution of compound 9 (1 eq) in anhydrous DMF (0.1 M) was added the appropriate amine (1.1 eq), followed by HATU (1.2 eq) and then DIPEA (1.3 eq). The reaction mixture was stirred for 16 h at RT, then partitioned between EtOAc and saturated NH4CI. The organic layer was collected, and then the aqueous layer was extracted with further EtOAc. The combined EtOAc extractions were washed with saturated NH4CI, water (x2), brine, dried Na2S04), filtered and concentrated. The residue was adsorbed onto silica gel, then purified by flash column chromatography (Isolera, gradient of EtOAc in Hex).

[00204] (£)-3-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-2-cyano-N-(4- hydroxybenzyl)acrylamide [10a, ΝΒ-1-054] : ¾ NMR (400 MHz, DMSO) δ = 9.33 (s, 1H), 8.86 (t, J = 5.4 Hz, 1H), 8.17 (s, 1H), 7.00 (d, J = 8.8 Hz, 2H), 7.15-7. 13 (m, 4H), 7.05 (s, 2H), 6.72 (d, J = 8.0 Hz, 2H), 4.30 (d, J = 5.2 Hz, 2H), 2.35 (s, 6H); ¹³C NMR (400 MHz, DMSO) δ = 161.42, 160.84, 156.83, 153.21, 150.14, 138.25, 133.02, 129.50, 129.34, 127.02, 120.61, 118.32, 117.09, 1 15.44, 104.73, 43.16, 20.76.

[00205] (£)-3-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-2-cyano-N-(2,6-dioxopiperidin-3- yl)acrylamide [10b, ΝΒ-1-055] : ¾ NMR (400 MHz, DMSO) δ = 10.92 (s, 1H), 8.71 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.03 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 7.06 (s, 2H), 4.73 (m, 1H), 2.80 (m, 1H), 2.36 (s, 6H), 2.32 (m, 1H), 2. 15 (m, 1H), 2.01 (m, 1H); ¹³C NMR (400 MHz, DMSO) δ = 173.39, 172.17, 161.48, 161. 10, 153. 10, 151.00, 138.28, 133.22, 126.82, 120.70, 118.28, 1 16.93, 103. 97, 50.44, 31.32, 24.20, 20.77.

[00206] fert-Butyl (£)-4-((3-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-2- cyanoacrylamido)methyl)piperidine-l -carboxylate [10c, NB-1 -056] : ¾ NMR (400 MHz, CDCh) δ = 8.25 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 6.81 (s, 2H), 6.47 (m, 1H), 4.11 (m, 2H), 3.32 (m, 2H), 2.69 (m, 2H), 2.36 (s, 6H), 1.72 (m, 3H), 1.45 (s, 9H), 1.19 (m, 2H); ¹³C NMR (400 MHz, DMSO) δ = 161.71, 160.81, 154.30, 153.20, 149.95, 138.25, 132.97, 129.92, 127.03, 120.62, 118.31, 1 17.10, 104.83, 78.88, 45.38, 35.98, 28.52, 20.77.

[00207] (£)-3-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-2-cyano-N-(piperidin-4- ylmethyl)acrylamide [lOd, ΝΒ-1-057] : ¾ NMR (400 MHz, DMSO) δ = 8.59 (t, J = 5.8, 1H), 8.15 (s, 1H), 8.00 (d, J = 8.8, 2H), 7.14 (d, J = 8.4, 2H), 7.04 (s, 2H), 3.26 (m, 2H), 3.13 (m, 2H), 2.83 (m, 2H), 2.35 (s, 6H), 1.79 (m, 3H), 1.35 (m, 2H); ¹³C NMR (400 MHz, DMSO) δ = 161.86, 160.84, 153.19, 150.05, 138.25, 133.00, 129.93, 127.016, 120.06, 118.32, 117.09, 104.71, 44.74, 43.15, 33.87, 26.57, 20.77.

[00208] (i¾-N-Benzyl-3-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-2-cyanoacrylamide [lOe, ΝΒ-1-058] : ¾ NMR (400 MHz, CDCh) δ = 8.32 (s, 1H), 7.93 (d, J= 8.8 Hz, 2H), 7.37-7.26 (m, obsc, 3H), 7.03 (d, J= 8.4 Hz, 2H), 6.83 (s, 2H), 6.66 (m, 1H), 4.61 (d, J= 6.8 Hz, 2H), 2.38 (s, 6H); ¹³C NMR (400 MHz, CDCh) δ = 161.81, 160.52, 152.60, 152.35, 138.23, 137.14, 133.00, 130.69, 128.90, 127.91, 126.16, 120.18, 117.77, 117.37, 101.43, 44.56, 20.91.

[00209] (£)-3-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-2-cyano-N-(3,4- dichlorobenzyl)acrylamide [lOf, ΝΒ-1-059]: ¾ NMR (400 MHz, CDCh) δ = 8.30 (s, 1H), 7.93 (d, J = 8.8 Hz, 2H), 7.42 (d, J= 8.0 Hz, 2H), 7.18 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 8.4 Hz, 2H), 6.83 (s, 2H), 6.78 (m, 1H), 5.30 (s, 1H), 4.55 (d, J = 6.4 Hz, 2H), 2.38 (s, 6H); ¹³C NMR (400 MHz, CDCh) δ = 162.02, 160.78, 152.75, 152.51, 138.25, 137.58, 133.12, 132.87, 131.93, 130.76, 129.77, 125.99, 120.22, 120.15, 117.76, 117.33, 100.93, 43.32, 20.91.

[00210] (£)-3-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-2-cyano-N-(4- (dimethylamino)benzyl)acrylamide [lOg, ΝΒ-1-060] : ¾ NMR (400 MHz, CDCh) δ = 8.37 (s, 1H), 9.98-7.96 (m, 3H), 7.57 (d, J = 8.4 Hz, 2H), 7.33 (d, J= 8.0 Hz, 2H), 7.04 (d, J = 9.6 Hz, 2H), 6.84 (s, 2H), 3.42 (s, 2H), 2.39 (s, 6H), 2.25 (s, 6H); ¹³C NMR (400 MHz, CDCh) δ = 162.05, 158.41, 152.82, 152.53, 138.26, 135.87, 133.18, 130.76, 129.89, 126.10, 120.30, 120.21, 117.80, 117.43, 101.67, 63.70, 45.25, 20.92.

[00211] (£)-N-(Benzo[cf][l,3]dioxol-4-ylmethyl)-3-(4-(4-chloro-3,5- dimethylphenoxy)phenyl)-2-cyanoacrylamide [lOh, NB-1-061] : ¾ NMR (400 MHz, CDCh) δ = 8.30 (s, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 6.82-6.78 (m, 5H), 6.624 (m, 1H), 5.95 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 2.37 (s, 6H); ¹³C NMR (400 MHz, DMSO) δ = 161.53, 160.88, 153.20, 150.32, 147.63, 146.62, 138.25, 133.19, 133.06, 129.93, 127.01, 121.26, 120.61, 118.31, 117.08, 108.64, 108.46, 104.58, 101.28, 43.42, 20.78.

[00212] (£)-3-(4-(4-Chloro-3,5-dimethylphenoxy)phenyl)-2-(4-isopropylpiperazine-l- carbonyl)acrylonitrile [lOi, NB-1-063] : ¾ NMR (400 MHz, CDCh) δ = 7.88 (d, J = 8.8 Hz, 2H), 7.70 (s, 1H), 7.10 (d, J= 8.8 Hz, 2H), 6.81 (s, 2H), 3.69 (m, 4H), 2.75 (m, 1H), 2.59 (m, 4H), 2.37 (s, 6H), 1.06 (d, J= 7.2 Hz, 6H); ¹³C NMR (400 MHz, DMSO) δ = 162.56, 160.42, 153.47, 149.64, 138.19, 132.45, 129.73, 127.50, 120.36, 118.49, 116.95, 104.28, 54.14, 20.77, 18.46. [00213] (£)-3-(4-(4-chloro-3,5-dimethylphenoxy)phenyl)-2-cyano-N-(2- (dimethylamino)ethyl)acrylamide [lOj, ΝΒ-1-064] : ¾ NMR (400 MHz, CDCh) δ = 8.25 (s, 1H), 7.92 (d, J= 8.8 Hz, 2H), 7.00 (m, 3H), 6.82 (s, 2H), 3.48 (m, 2H), 2.50 (m, 2H), 2.37 (s, 6H), 2.27 (s, 6H).

[00214] Example 2: Biology - In Vitro Cell Growth Inhibition of MV4-11 (acute myeloid leukemia) and RCH-ACV (acute lymphocytic leukemia)

[00215] Cell growth inhibition with MV4-11 (acute myeloid leukemia) and RCH-ACV (acute lymphocytic leukemia) cells have been conducted. Unless indicated otherwise, the data represents %growth inhibition, wherein 1 represents zero growth inhibition, and 0 represents complete growth inhibition. FIG. 1 shows a western blot of various proteins in several cell lines. Various compounds of the invention were tested at 1 μΜ and 10 μΜ against the MV4- 11 (AML) and RCH-ACV (ALL) cell lines. Compounds that caused ~ 0.50-fold change (or inhibited growth at ~ 50%) at 10 μΜ were selected for further testing at 1, 5, and 10 μΜ, with positive controls at 1 and 10 μΜ of S63845 (MCL1 inhibitor), ABT199 (BCL2 inhibitor), and Al l 55463 (BCLxL inhibitor); see Tables 2, 3, and 4.

Table 2: Growth Inhibition Compared to No Treatment (DMSO)

NB-1-

055 437.88 1.312538412 0.09617041 1.266763518 0.282250088

NB-1-

056 524.06 0.34845961 1 0.074587339 0.793069945 0.087414878

NB-1-

057 423.94 0.091894937 0.075180258 0.101801826 0.090991717

NB-1-

058 416.91 1.30264634 0. 145540021 1.230978246 0.421850514

NB-1-

059 485.79 1.254728776 0.482749795 1.201582082 0.643460159

NB-1-

060 459.97 1.042199455 0.089636197 0.824147199 0.07963652

NB-1-

061 460.91 1.377386446 0.638225753 1.29392868 0.741727957

NB-1-

063 437.97 1.37938301 1 0.085300222 1.181365586 0.094966518

NB-1-

064 397.9 1.251017988 0.080544767 0.948605754 0.100634469

NB-1-

066 228.35 1.499945296 0.986890567 1.211642092 0.766408869

SF-6- 141 313.36 0.626825164 0.200467747 0.270393217 0.100089381

SF-6- 142 319.41 0.162837536 0.094595342 0.100504227 0.10962601

SF-6- 149 277.33 0.1 19096625 0. 124836246 0.1 11550701 0.11 1362573

SF-6- 175 517.79 1.330477248 0.538018349 1.207305506 0.458725961

SF-6-

196 432.9 1.446423232 0.09678148 1.204741663 0.109900966

SF-6- 197 448.9 0.562993732 0.009717962 0.257632087 0.877150553

Table 3: Raw Data, MV4-1 1

Table 4: Raw Data RCH-ACV

[00216] FIGS. 2Α and 2Β show the dose-response curves for compounds NB-1-029 (circle), NB-1-032 (square), and NB-1-036 (triangle), when tested against the MV4-11 AML cell line (FIG. 2A, NB-1-029 IC50 = 8.746 μΜ, NB-1-032 IC50 = 3.517 μΜ, and NB-1-036 IC50 = 12.511 μΜ), and against the RCH-ACV cell line (FIG. 2B, NB-1-029 IC50 = 18.703 μΜ, NB-1-032 IC50 = 3.596 μΜ, and NB-1-036 IC50 = 4.646 μΜ). FIGS. 3A and 3B show the dose-response curves for compounds NB-1-037 (diamond), NB-1-042 (circle), NB-1-056 (triangle), and NB-1-057 (square), when tested against the MV4-11 AML cell line (FIG. 3A, NB-1-037 IC50 = 5.521 μΜ, NB-1-042 IC50 = 8.212 μΜ, NB-1-056 IC50 = 30.312 μΜ, and NB-1-057 IC50 = 5.684 μΜ), and against the RCH-ACV cell line (FIG. 3B, NB-1-037 IC50 = 6.836 μΜ, NB-1-042 IC50 = 4.484 μΜ, and NB-1-057 IC50 = 5.318 μΜ). FIGS. 4A and 4B show the dose-response curves for compounds SF-6-141 (solid circle), SF-6-142 (x), SF- 6-149 (circle), and SF-6-197 (square), when tested against the MV4-11 AML cell line (FIG. 4A, SF-6-141 IC50 = 18.433 μΜ, SF-6-142 IC50 = 6.275 μΜ, SF-6-149 IC50 = 6.275 μΜ, and SF-6-197 IC50 = 7.569 μΜ), and against the RCH-ACV cell line (FIG. 4B, SF-6-141 IC50 = 7.609 μΜ, SF-6-142 IC50 = 6.447 μΜ, SF-6-149 IC50 = 5.606 μΜ, and SF-6-197 IC50 = 5.739 μΜ).

[00217] A number of patent and non-patent publications are cited herein in order to describe the state of the art to which this invention pertains. The entire disclosure of each of these publications is incorporated by reference herein. [00218] While certain embodiments of the present invention have been described and/or exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present invention is, therefore, not limited to the particular embodiments described and/or exemplified, but is capable of considerable variation and modification without departure from the scope and spirit of the appended claims.

[00219] Moreover, as used herein, the term "about" means that amounts, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, an amount, size, formulation, parameter, shape or other quantity or characteristic is "about" or "approximate" whether or not expressly stated to be such.

[00220] Furthermore, the transitional terms "comprising", "consisting essentially of and "consisting of, when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s). The term "comprising" is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material. The term "consisting of excludes any element, step or material other than those specified in the claim and, in the latter instance, impurities ordinary associated with the specified material(s). The term "consisting essentially of limits the scope of a claim to the specified elements, steps or material(s) and those that do not materially affect the basic and novel characteristic(s) of the claimed invention. All compounds, compositions, formulations, and methods described herein that embody the present invention can, in alternate embodiments, be more specifically defined by any of the transitional terms "comprising," "consisting essentially of," and "consisting of."

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Claims

CLAIMS It is claimed:

1. A compound of formula (I) or formula (II) or formula (III):

wherein X is a substituent selected from the group consisting of NR³ and O;

R¹ is a substituent selected from the group consisting of optionally substituted alkyl, aryl, and heteroaryl;

R² is a substituent selected from the group consisting of halo and optionally substituted alkyl, aryl, heteroaryl, alkoxy, and aryloxy;

R³ is a substituent selected from the group consisting of H and optionally substituted alkyl, aryl, and heteroaryl; and the pharmaceutically acceptable salts thereof.

2. The compound of claim 1, wherein the compound of formula (I) or formula (II) or formula (III) is an allosteric inhibitor of Mcl-1 protein.

3. A method of treating a disease by inhibiting Mcl-1 protein activity in a patient in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of claim 1 or 2, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

4. The method of claim 3, wherein the disease is selected from the group consisting of pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head-neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, head or neck carcinoma, breast carcinoma, ovarian carcinoma, lung carcinoma, small-cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostatic carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenal cortex carcinoma, malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft-tissue sarcoma, osteogenic sarcoma, primary macroglobulinemia, and retinoblastoma.

5. The method of claim 3, wherein the disease is selected from the group consisting of myeloid leukemia, non-small cell lung cancer, pancreatic cancer, prostate cancer, and ovarian cancer.

6. A pharmaceutical composition for treating a disease alleviated by inhibiting Mcl-1 protein activity, the pharmaceutical composition comprising one or more compounds according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a

pharmaceutically acceptable carrier.