Development of lysine-specific demethylase 1 (LSD1) inhibitors as Anti-cancer reagents

Abstract

The present disclosure is concerned with substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds in the treatment of various cancers such as, for example, cancers comprising cells that express at least one Sox 2 stem cell marker. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

Description

Attorney Docket No.37474.0110P1 DEVELOPMENT OF LYSINE-SPECIFIC DEMETHYLASE 1 (LSD1) INHIBITORS AS ANTI-CANCER REAGENTS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Application claims the benefit of U.S. Application No.63 / 644,458, filed on May 08, 2024, the contents of which are incorporated herein by reference in their entirety. BACKGROUND

[0002] Methylation of histones plays an important role in regulating transcription and also in chromatin structure and organization (Shi Y. (2007) Nat Rev Genet.8:829; Klose RJ, Zhang Y. (2007) Nat Rev Mol Cell Biol.8:307). Histone methylation and demethylation is dynamically controlled by various histone methyltransferases and demethylases. Lysine-specific demethylase 1 (LSD1) belongs to the flavine dineucleotide (FAD)-dependent amine oxidase family and specifically catalyzes the demethylation of mono- and di-methylated H3K4 through amine oxidation.

[0003] LSD1 protein levels are found at abnormal concentrations in many human cancer cells including teratocarcinoma, embryonic carcinoma, and embryonic stem cells (Saito, Y. et al. (2006) Tetrahedron 62:11599-11607). The elevated expression level of these proteins in various cancers suggests that LSD1 is linked to the proliferation of cancerous cells.

[0004] Demethylation of lysine residues on histones allows for increased levels of gene expression. The demethylation ability of LSD1 proteins can be inhibited by forming covalent FAD adduct with inhibitors such as tranylcypromine (TCP) via single electron transfer. Formation of a FAD covalent adduct with a TCP inhibits the action of LSD1 irreversibly.

[0005] TCP exhibits general cytotoxicity toward the growth of PA-1, F9, HCT116, and NIH3T3 cell lines. CBB3001, a previously prepared mimic of TCP, was found not to have general toxicity toward cancer cell lines such as HCT116 and NIH3T3. See also Hoang et al. (2018) Bioorg. Med. Chem.26(8): 1523-1537. However, the current synthetic route for the preparation of CBB3001 suffers from several limitations, including extremely lowoverall yield. Such limitations have hampered the ability to improve on CBB3001 activity through structure activityAttorney Docket No.37474.0110P1 relationship (SAR) studies. Thus, despite the growing interest in LSD1 inhibitors, and, in particular, specific LSD1 inhibitors such as CBB3001, the development and study of alternative analogs has remained limited. Accordingly, there remains a need for compounds that selectively inhibit LSD1 and methods of making and using same. SUMMARY

[0006] In accordance with the purpose(s) of the invention, as embodied and broadly described herein, the invention, in one aspect, relates to substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds in the treatment of various cancers such as, for example, cancers comprising cells that express at least one Sox2 stem cell marker (e.g., glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer).

[0007] Thus, disclosed are compounds having a structure represented by a formula: ,wherein n is selected from 0, 1, 2, A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4Attorney Docket No.37474.0110P1 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20; wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**.

[0008] Also disclosed are pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0009] Also disclosed are methods of inhibiting lysine-specific demethylase I (LSD1) in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0010] Also disclosed are methods of inhibiting lysine-specific demethylase I (LSD1) in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0011] Also disclosed are methods of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0012] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.Attorney Docket No.37474.0110P1 BRIEF DESCRIPTION OF THE DRAWINGS

[0013] The accompanying figures, which are incorporated in and constitute a part of this specification, illustrate several aspects and together with the description serve to explain the principles of the invention.

[0014] FIG.1 shows a representative scheme illustrating an initial synthesis of CBB3001

[0015] FIG.2A and FIG.2B show a representative scheme illustrating the protecting group effect on the yield of the cyclopropanation reaction.

[0016] FIG.3 shows a representative groups of compounds with variation in the core spacer of CBB0001 analogs.

[0017] FIG.4 shows a representative groups of compounds with variation in the western portion of CBB0001 analogs.

[0018] FIG.5 shows a representative groups of compounds with variation in the eastern portion of CBB0001 analogs.

[0019] Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed. DETAILED DESCRIPTION

[0020] The present invention can be understood more readily by reference to the following detailed description of the invention and the Examples included therein.

[0021] Before the present compounds, compositions, articles, systems, devices, and / or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, example methods and materials are now described.

[0022] While aspects of the present invention can be described and claimed in a particular statutory class, such as the system statutory class, this is for convenience only and one of skill in the art will understand that each aspect of the present invention can be described and claimed in any statutory class. Unless otherwise expressly stated, it is in no way intended that any methodAttorney Docket No.37474.0110P1 or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0023] Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this pertains. The references disclosed are also individually and specifically incorporated by reference herein for the material contained in them that is discussed in the sentence in which the reference is relied upon. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided herein may be different from the actual publication dates, which can require independent confirmation. A. DEFINITIONS

[0024] As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a functional group,” “an alkyl,” or “a residue” includes mixtures of two or more such functional groups, alkyls, or residues, and the like.

[0025] As used in the specification and in the claims, the term “comprising” can include the aspects “consisting of” and “consisting essentially of.”

[0026] Ranges can be expressed herein as from “about” one particular value, and / or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and / or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.Attorney Docket No.37474.0110P1

[0027] As used herein, the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ±10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can 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 or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.

[0028] References in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed. Thus, in a compound containing 2 parts by weight of component X and 5 parts by weight component Y, X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.

[0029] A weight percent (wt. %) of a component, unless specifically stated to the contrary, is based on the total weight of the formulation or composition in which the component is included.

[0030] As used herein, the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0031] As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds. Exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.

[0032] As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example,Attorney Docket No.37474.0110P1 those described below. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this disclosure, the heteroatoms, such as nitrogen, can have hydrogen substituents and / or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This disclosure is not intended to be limited in any manner by the permissible substituents of organic compounds. Also, the terms “substitution” or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0033] In defining various terms, “A1,” “A2,” “A3,” and “A4” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.

[0034] The term “aliphatic” or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1- 20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0035] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t- butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein. A “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms. The term alkyl group can also be a C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.Attorney Docket No.37474.0110P1

[0036] Throughout the specification “alkyl” is generally used to refer to both unsubstituted alkyl groups and substituted alkyl groups; however, substituted alkyl groups are also specifically referred to herein by identifying the specific substituent(s) on the alkyl group. For example, the term “halogenated alkyl” or “haloalkyl” specifically refers to an alkyl group that is substituted with one or more halide, e.g., fluorine, chlorine, bromine, or iodine. Alternatively, the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine. The term “polyhaloalkyl” specifically refers to an alkyl group that is independently substituted with two or more halides, i.e. each halide substituent need not be the same halide as another halide substituent, nor do the multiple instances of a halide substituent need to be on the same carbon. The term “alkoxyalkyl” specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below. The term “aminoalkyl” specifically refers to an alkyl group that is substituted with one or more amino groups. The term “hydroxyalkyl” specifically refers to an alkyl group that is substituted with one or more hydroxy groups. When “alkyl” is used in one instance and a specific term such as “hydroxyalkyl” is used in another, it is not meant to imply that the term “alkyl” does not also refer to specific terms such as “hydroxyalkyl” and the like.

[0037] This practice is also used for other groups described herein. That is, while a term such as “cycloalkyl” refers to both unsubstituted and substituted cycloalkyl moieties, the substituted moieties can, in addition, be specifically identified herein; for example, a particular substituted cycloalkyl can be referred to as, e.g., an “alkylcycloalkyl.” Similarly, a substituted alkoxy can be specifically referred to as, e.g., a “halogenated alkoxy,” a particular substituted alkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.

[0038] The term “cycloalkyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted. The cycloalkyl group and heterocycloalkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.Attorney Docket No.37474.0110P1

[0039] The term “polyalkylene group” as used herein is a group having two or more CH2 groups linked to one another. The polyalkylene group can be represented by the formula —(CH2)a—, where “a” is an integer of from 2 to 500.

[0040] The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl or cycloalkyl group bonded through an ether linkage; that is, an “alkoxy” group can be defined as —OA1where A1is alkyl or cycloalkyl as defined above. “Alkoxy” also includes polymers of alkoxy groups as just described; that is, an alkoxy can be a polyether such as —OA1—OA2or —OA1—(OA2)a—OA3, where “a” is an integer of from 1 to 200 and A1, A2, and A3are alkyl and / or cycloalkyl groups.

[0041] The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond. Asymmetric structures such as (A1A2)C=C(A3A4) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C=C. The alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.

[0042] The term “cycloalkenyl” as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like. The term “heterocycloalkenyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted. The cycloalkenyl group and heterocycloalkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0043] The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon triple bond. The alkynyl group can be unsubstituted or substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.Attorney Docket No.37474.0110P1

[0044] The term “cycloalkynyl” as used herein is a non-aromatic carbon-based ring composed of at least seven carbon atoms and containing at least one carbon-carbon triple bound. Examples of cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like. The term “heterocycloalkynyl” is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkynyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus. The cycloalkynyl group and heterocycloalkynyl group can be substituted or unsubstituted. The cycloalkynyl group and heterocycloalkynyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

[0045] The term “aromatic group” as used herein refers to a ring structure having cyclic clouds of delocalized π electrons above and below the plane of the molecule, where the π clouds contain (4n+2) π electrons. A further discussion of aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference. The term “aromatic group” is inclusive of both aryl and heteroaryl groups.

[0046] The term “aryl” as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, ─NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein. The term “biaryl” is a specific type of aryl group and is included in the definition of “aryl.” In addition, the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond. For example, biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.

[0047] The term “aldehyde” as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C=O.

[0048] The terms “amine” or “amino” as used herein are represented by the formula —NA1A2, where A1and A2can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. A specific example of amino is ─NH2.Attorney Docket No.37474.0110P1

[0049] The term “alkylamino” as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein. Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.

[0050] The term “dialkylamino” as used herein is represented by the formula —N(-alkyl)2where alkyl is a described herein. Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N-methylamino group, N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

[0051] The term “carboxylic acid” as used herein is represented by the formula —C(O)OH.

[0052] The term “ester” as used herein is represented by the formula —OC(O)A1or —C(O)OA1, where A1can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “polyester” as used herein is represented by the formula —(A1O(O)C-A2-C(O)O)a— or —(A1O(O)C-A2-OC(O))a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.

[0053] The term “ether” as used herein is represented by the formula A1OA2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein. The term “polyether” as used herein is represented by the formula —(A1O-A2O)a—, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500. Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.

[0054] The terms “halo,” “halogen,” or “halide” as used herein can be used interchangeably and refer to F, Cl, Br, or I.

[0055] The terms “pseudohalide,” “pseudohalogen,” or “pseudohalo” as used herein can be used interchangeably and refer to functional groups that behave substantially similar to halides. Such functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.Attorney Docket No.37474.0110P1

[0056] The term “heteroalkyl,” as used herein refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized. Heteroalkyls can be substituted as defined above for alkyl groups.

[0057] The term “heteroaryl,” as used herein refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions. The heteroaryl group can be substituted or unsubstituted. The heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein. Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl. Further not limiting examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.

[0058] The terms “heterocycle” or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon. Thus, the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.” Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including 1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine, including 1,2,4-triazine and 1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine, piperidine, piperazine, morpholine, azetidine, tetrahydropyran, tetrahydrofuran, dioxane, and the like. The term heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl. ForAttorney Docket No.37474.0110P1 example, a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like. Alternatively, for example, a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.

[0059] The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as used herein refers to a ring system in which at least one of the ring members is other than carbon. Bicyclic heterocyclyl encompasses ring systems wherein an aromatic ring is fused with another aromatic ring, or wherein an aromatic ring is fused with a non-aromatic ring. Bicyclic heterocyclyl encompasses ring systems wherein a benzene ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms or wherein a pyridine ring is fused to a 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, but are not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H- pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.

[0060] The term “heterocycloalkyl” as used herein refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems. The heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted. Representative heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.

[0061] The term “hydroxyl” or “hydroxyl” as used herein is represented by the formula —OH.

[0062] The term “ketone” as used herein is represented by the formula A1C(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0063] The term “azide” or “azido” as used herein is represented by the formula —N3.

[0064] The term “nitro” as used herein is represented by the formula —NO2.

[0065] The term “nitrile” or “cyano” as used herein is represented by the formula —CN.Attorney Docket No.37474.0110P1

[0066] The term “silyl” as used herein is represented by the formula —SiA1A2A3, where A1, A2, and A3can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0067] The term “sulfo-oxo” as used herein is represented by the formulas —S(O)A1, — S(O)2A1, —OS(O)2A1, or —OS(O)2OA1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. Throughout this specification “S(O)” is a short hand notation for S=O. The term “sulfonyl” is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A1, where A1can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfone” as used herein is represented by the formula A1S(O)2A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein. The term “sulfoxide” as used herein is represented by the formula A1S(O)A2, where A1and A2can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.

[0068] The term “thiol” as used herein is represented by the formula —SH.

[0069] “R1,” “R2,” “R3,” “Rn,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above. For example, if R1is a straight chain alkyl group, one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like. Depending upon the groups that are selected, a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group. For example, with the phrase “an alkyl group comprising an amino group,” the amino group can be incorporated within the backbone of the alkyl group. Alternatively, the amino group can be attached to the backbone of the alkyl group. The nature of the group(s) that is (are) selected will determine if the first group is embedded or attached to the second group.

[0070] As described herein, compounds of the invention may contain “optionally substituted” moieties. In general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogen of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation ofAttorney Docket No.37474.0110P1 stable or chemically feasible compounds. In is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).

[0071] The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0072] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; –(CH2)0–4R^; –(CH2)0–4OR^; -O(CH2)0-4Ro, –O– (CH2)0–4C(O)OR°; –(CH2)0–4CH(OR^)2; –(CH2)0–4SR^; –(CH2)0–4Ph, which may be substituted with R°; –(CH2)0–4O(CH2)0–1Ph which may be substituted with R°; –CH=CHPh, which may be substituted with R°; –(CH2)0–4O(CH2)0–1-pyridyl which may be substituted with R°; –NO2; –CN; –N3; -(CH2)0–4N(R^)2; –(CH2)0–4N(R^)C(O)R^; –N(R^)C(S)R^; –(CH2)0–4N(R^)C(O)NR^2; -N(R^)C(S)NR^2; –(CH2)0–4N(R^)C(O)OR^; – N(R^)N(R^)C(O)R^; -N(R^)N(R^)C(O)NR^2; -N(R^)N(R^)C(O)OR^; –(CH2)0–4C(O)R^; – C(S)R^; –(CH2)0–4C(O)OR^; –(CH2)0–4C(O)SR^; -(CH2)0–4C(O)OSiR^3; –(CH2)0–4OC(O)R^; – OC(O)(CH2)0–4SR–, SC(S)SR°; –(CH2)0–4SC(O)R^; –(CH2)0–4C(O)NR^2; –C(S)NR^2; – C(S)SR°; -(CH2)0–4OC(O)NR^2; -C(O)N(OR^)R^; –C(O)C(O)R^; –C(O)CH2C(O)R^; – C(NOR^)R^; -(CH2)0–4SSR^; –(CH2)0–4S(O)2R^; –(CH2)0–4S(O)2OR^; –(CH2)0–4OS(O)2R^; – S(O)2NR^2; -(CH2)0–4S(O)R^; -N(R^)S(O)2NR^2; –N(R^)S(O)2R^; –N(OR^)R^; –C(NH)NR^2; – P(O)2R^; -P(O)R^2; -OP(O)R^2; –OP(O)(OR^)2; SiR^3; –(C1–4straight or branched alkylene)O– N(R^)2; or –(C1–4straight or branched alkylene)C(O)O–N(R^)2, wherein each R^ may be substituted as defined below and is independently hydrogen, C1–6aliphatic, –CH2Ph, –O(CH2)0–1Ph, -CH2-(5-6 membered heteroaryl ring), or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R^, taken together with their intervening atom(s), form a 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0073] Suitable monovalent substituents on R^ (or the ring formed by taking two independent occurrences of R^ together with their intervening atoms), are independently halogen, –(CH2)0–2R^, –(haloR^), –(CH2)0–2OH, –(CH2)0–2OR^, –(CH2)0–2CH(OR^)2; -O(haloR^), –CN, –N3, – (CH2)0–2C(O)R^, –(CH2)0–2C(O)OH, –(CH2)0–2C(O)OR^, –(CH2)0–2SR^, –(CH2)0–2SH, –(CH2)0–2NH2, –(CH2)0–2NHR^, –(CH2)0–2NR^2, –NO2, –SiR^3, –OSiR^3, -C(O)SR^,–(C1–4straight orAttorney Docket No.37474.0110P1 branched alkylene)C(O)OR^, or –SSR^wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1–4 aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R^ include =O and =S.

[0074] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: =O, =S, =NNR*2, =NNHC(O)R*, =NNHC(O)OR*, =NNHS(O)2R*, =NR*, =NOR*, –O(C(R*2))2–3O–, or –S(C(R*2))2–3S–, wherein each independent occurrence of R*is selected from hydrogen, C1–6 aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR*2)2–3O–, wherein each independent occurrence of R*is selected from hydrogen, C1–6aliphatic which may be substituted as defined below, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0075] Suitable substituents on the aliphatic group of R*include halogen, –R^, -(haloR^), -OH, – OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, or –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0076] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include –R†, –NR†2, –C(O)R†, –C(O)OR†, –C(O)C(O)R†, –C(O)CH2C(O)R†, – S(O)2R†, -S(O)2NR†2, –C(S)NR†2, –C(NH)NR†2, or –N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1–6 aliphatic which may be substituted as defined below, unsubstituted –OPh, or an unsubstituted 5–6–membered saturated, partially unsaturated, or aryl ring having 0– 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3–12–membered saturated, partially unsaturated, or aryl mono– or bicyclic ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0077] Suitable substituents on the aliphatic group of R†are independently halogen, – R^, -(haloR^), –OH, –OR^, –O(haloR^), –CN, –C(O)OH, –C(O)OR^, –NH2, –NHR^, –NR^2, orAttorney Docket No.37474.0110P1 –NO2, wherein each R^is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1–4aliphatic, –CH2Ph, –O(CH2)0–1Ph, or a 5–6– membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0078] The term “leaving group” refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons. Examples of suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.

[0079] The terms “hydrolysable group” and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions. Examples of hydrolysable residues include, without limitation, acid halides, activated carboxylic acids, and various protecting groups known in the art (see, for example, “Protective Groups in Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience, 1999).

[0080] The term “organic residue” defines a carbon-containing residue, i.e., a residue comprising at least one carbon atom, and includes but is not limited to the carbon-containing groups, residues, or radicals defined hereinabove. Organic residues can contain various heteroatoms, or be bonded to another molecule through a heteroatom, including oxygen, nitrogen, sulfur, phosphorus, or the like. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc. Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In a further aspect, an organic residue can comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbon atoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

[0081] A very close synonym of the term “residue” is the term “radical,” which as used in the specification and concluding claims, refers to a fragment, group, or substructure of a molecule described herein, regardless of how the molecule is prepared. For example, a 2,4- thiazolidinedione radical in a particular compound has the structure: ,regardless of whether thiazolidinedione is used to prepare the compound. In some embodiments the radical (for example an alkyl) can be further modified (i.e., substituted alkyl) by havingAttorney Docket No.37474.0110P1 bonded thereto one or more “substituent radicals.” The number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.

[0082] “Organic radicals,” as the term is defined and used herein, contain one or more carbon atoms. An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical. One example, of an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical. In some embodiments, an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein. A few non-limiting examples of organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.

[0083] Compounds described herein can contain one or more double bonds and, thus, potentially give rise to cis / trans (E / Z) isomers, as well as other conformational isomers. Unless stated to the contrary, the invention includes all such possible isomers, as well as mixtures of such isomers.

[0084] Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines contemplates each possible isomer, e.g., each enantiomer and diastereomer, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein can contain one or more asymmetric centers and, thus, potentially give rise to diastereomers and optical isomers. Unless stated to the contrary, the present invention includes all such possible diastereomers as well as their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers, and pharmaceutically acceptable salts thereof. Mixtures of stereoisomers, as well as isolated specific stereoisomers, are also included. During the course of the synthetic procedures used to prepare such compounds, or in using racemization or epimerization procedures known to those skilled in the art, the products of such procedures can be a mixture of stereoisomers.Attorney Docket No.37474.0110P1

[0085] Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these compounds, called stereoisomers, are identical except that they are non-superimposable mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

[0086] When the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step can liberate the desired enantiomeric form. Alternatively, specific enantiomers can be synthesized by asymmetricAttorney Docket No.37474.0110P1 synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

[0087] Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.). Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%. In one aspect, the designated enantiomer is substantially free from the other enantiomer. For example, the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms. Conversely, “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.

[0088] When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S) / (R,R) and (R,S) / (S,R)). The pairs of enantiomers (e.g., (S,S) / (R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.

[0089] The compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties. For instance, the hydroxymethyl position may form mono-, di-, or triphosphates and again these phosphates can form prodrugs. Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem.1988, 31, 318; Aligas-Martin et al., PCT WO 2000 / 041531, p.30). The nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.

[0090] “Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, solvates and combinations thereof. The “combinations” mentioned in this context refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radio-actively labeled forms, isomers, and solvates. Examples of radio-actively labeled forms includeAttorney Docket No.37474.0110P1 compounds labeled with tritium, phosphorous-32, iodine-129, carbon-11, fluorine-18, and the like.

[0091] Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance. The disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as2H,3H,13C,14C,15N,18O,17O,35S,18F and36Cl, respectively. Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H, and carbon-14, i.e.,14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.

[0092] The compounds described in the invention can be present as a solvate. In some cases, the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate. The compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution. In this connection, one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates. Unless stated to the contrary, the invention includes all such possible solvates.

[0093] The term “co-crystal” means a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society ofAttorney Docket No.37474.0110P1 Chemistry, 1889-1896, 2004. Examples of co-crystals include p-toluenesulfonic acid and benzenesulfonic acid.

[0094] It is also appreciated that certain compounds described herein can be present as an equilibrium of tautomers. For example, ketones with an α-hydrogen can exist in an equilibrium of the keto form and the enol form.

[0095] Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. As another example, pyrazoles can exist in two tautomeric forms, N1- unsubstituted, 3-A3and N1-unsubstituted, 5-A3as shown below. Unless stated to thetautomers.

[0096] It is known that chemical substances form solids, which are present in different states of order which are termed polymorphic forms or modifications. The different modifications of a polymorphic substance can differ greatly in their physical properties. The compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.

[0097] In some aspects, a structure of a compound can be represented by a formula: ,which is understood to be equivalent to a formula: ,Attorney Docket No.37474.0110P1 wherein n is typically an integer. That is, Rnis understood to represent five independent substituents, Rn(a), Rn(b), Rn(c), Rn(d), Rn(e). By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance Rn(a)is halogen, then Rn(b)is not necessarily halogen in that instance.

[0098] Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Strem Chemicals (Newburyport, MA), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St. Louis, Mo.) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd’s Chemistry of Carbon Compounds, Volumes 1-5 and supplemental volumes (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991); March’s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition); and Larock’s Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0099] Unless otherwise expressly stated, it is in no way intended that any method set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not actually recite an order to be followed by its steps or it is not otherwise specifically stated in the claims or descriptions that the steps are to be limited to a specific order, it is no way intended that an order be inferred, in any respect. This holds for any possible non-express basis for interpretation, including: matters of logic with respect to arrangement of steps or operational flow; plain meaning derived from grammatical organization or punctuation; and the number or type of embodiments described in the specification.

[0100] Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary. Thus, if a class of molecules A, B, and CAttorney Docket No.37474.0110P1 are disclosed as well as a class of molecules D, E, and F and an example of a combination molecule, A-D is disclosed, then even if each is not individually recited each is individually and collectively contemplated meaning combinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considered disclosed. Likewise, any subset or combination of these is also disclosed. Thus, for example, the sub-group of A-E, B-F, and C-E would be considered disclosed. This concept applies to all aspects of this application including, but not limited to, steps in methods of making and using the compositions of the invention. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with any specific embodiment or combination of embodiments of the methods of the invention.

[0101] It is understood that the compounds and compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result. B. COMPOUNDS

[0102] In one aspect, the invention relates to substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds, pharmaceutical compositions comprising the compounds, and methods of using the compounds in the treatment of various cancers such as, for example, cancers comprising cells that express at least one Sox2 stem cell marker (e.g., glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer).

[0103] It is contemplated that each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omittedAttorney Docket No.37474.0110P1 from the invention. It is understood that a disclosed compound can be provided by the disclosed methods. It is also understood that the disclosed compounds can be employed in the disclosed methods of using. 1. STRUCTURE

[0104] In one aspect, disclosed are compounds having a structure represented by a formula: , wherein n is selected from 0, 1, 2,A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20; wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**.

[0105] In various aspects, the compound has a structure represented by a formula: ,wherein n is 1, 2, 3, 4, 5, 6, 7, or 8, or a pharmaceutically acceptable salt thereof.Attorney Docket No.37474.0110P1

[0106] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable

[0107] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable salt

[0108] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable

[0109] In various aspects, the compound has a structure represented by a formula: ,wherein n is 1, 2, 3, 4, 5, 6, 7, or 8, or a acceptable salt thereof.

[0110] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0111] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.Attorney Docket No.37474.0110P1

[0112] In various aspects, the compound has a structure represented by a formula: , wherein each of R21a, R21b, R21c,selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, – SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1, or a pharmaceutically acceptable salt thereof.

[0113] In various aspects, the compound has a structure represented by a formula: R21bR21cR21a, or a pharmaceutically

[0114] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable

[0115] In various aspects, the compound has a structure represented by a formula: ,or a pharmaceutically acceptable salt thereof.

[0116] In various aspects, the compound has a structure represented by a formula:Attorney Docket No.37474.0110P1 , or a pharmaceutically

[0117] In various aspects, the compound has a structure represented by a formula: R21bR21cR21aR1, or a pharmaceutically

[0118] In various aspects, the compound has a structure represented by a formula: , or a pharmaceutically acceptable

[0119] In various aspects, the compound has a structure represented by a formula: R21a 2O OR1b3 ,wherein each of R21a, R21b, R21c, selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, – SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1, or a pharmaceutically acceptable salt thereof.

[0120] In various aspects, the compound has a structure represented by a formula: ,Attorney Docket No.37474.0110P1 or a pharmaceutically acceptable salt thereof.

[0121] In various aspects, compound is selected from: , , or

[0122] In various aspects, the compound is selected from: , or

[0123] In one aspect, n is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8. In a futher aspect, n is selected from 0, 1, 2, 3, 4, 5, 6, and 7. In a still further aspect, n is selected from 0, 1, 2, 3, 4, 5, and 6. In yet a further aspect, n is selected from 0, 1, 2, 3, 4, and 5. In an even further aspect, n is selected from 0, 1, 2, 3, and 4. In an even still further aspect, n is selected from 0, 1, 2, and 3. In yet an even further aspect, n is selected from 0, 1, and 2. In a further aspect, n is selected from 0 and 1. In a still further aspect, n is 0. In yet a further aspect, n is 1. In an even further aspect, n is 2. In an even still further aspect, n is 3. In yet an even further aspect, n is 4. In a further aspect, n is 5. In a still further aspect, n is 6. In yet a further aspect, n is 7. In an even further aspect, n is 8.Attorney Docket No.37474.0110P1

[0124] In various aspects, n is 0 or 1. In a further aspect, n is 0. In a still further aspect, n is 1.

[0125] In various aspects, n is 1, 2, 3, 4, 5, 6, 7, or 8. In a futher aspect, n is 1, 2, 3, 4, 5, 6, or 7. In a still further aspect, n is 1, 2, 3, 4, 5, or 6. In yet a further aspect, n is 1, 2, 3, 4, or 5. In an even further aspect, n is 1, 2, 3, or 4. In an even still further aspect, n is 1, 2, or 3. In yet an even further aspect, n is 1 or 2. a. A GROUPS

[0126] In one aspect, A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1. In a further aspect, A is *– C(O)O–**. In a still further aspect, A is *–SO2–**. b. R1GROUPS

[0127] In one aspect, R1is selected from C1-C8 alkyl and Ar2. In a further aspect, R1is selected from C1-C4 alkyl and Ar2. In a still further aspect, R1is selected from methyl, ethyl, propyl, isopropyl, and Ar2. In yet a further aspect, R1is selected from methyl, ethyl, and Ar2. In yet a further aspect, R1is selected from methyl and Ar2.

[0128] In various aspects, R1is C1-C8 alkyl. In a further aspect, R1is C1-C4 alkyl. In a still further aspect, R1is selected from methyl, ethyl, propyl, and isopropyl. In yet a further aspect, R1is selected from methyl and ethyl. In an even further aspect, R1is ethyl. In an even still further aspect, R1is methyl.

[0129] In various aspects, R1is Ar2. c. R10GROUPS

[0130] In one aspect, R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and – CO2R20. In a further aspect, R10is selected from hydrogen, methyl, ethyl, propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, and –CO2R20. In a still further aspect, R10is selected from hydrogen, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, and –CO2R20. In yet a further aspect, R10is selected from hydrogen, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, and –CO2R20.

[0131] In various aspects, R10is selected from hydrogen, C1-C4 alkyl, and –CO2R20. In a further aspect, R10is selected from hydrogen, methyl, ethyl, propyl, isopropyl and –CO2R20. InAttorney Docket No.37474.0110P1 a still further aspect, R10is selected from hydrogen, methyl, ethyl, and –CO2R20. In yet a further aspect, R10is selected from hydrogen, methyl, and –CO2R20.

[0132] In various aspects, R10is selected from hydrogen, C1-C4 haloalkyl, and –CO2R20. In a further aspect, R10is selected from hydrogen, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, and –CO2R20. In a still further aspect, R10is selected from hydrogen, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, and –CO2R20. In yet a further aspect, R10is selected from hydrogen, −CH2F, −CHF2, −CF3, −CH2Cl, and –CO2R20.

[0133] In various aspects, R10is selected from hydrogen and C1-C4 alkyl. In a further aspect, R10is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R10is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R10is selected from hydrogen and ethyl. In an even further aspect, R10is selected from hydrogen and methyl.

[0134] In various aspects, R10is C1-C4 alkyl. In a further aspect, R10is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R10is selected from methyl and ethyl. In yet a further aspect, R10is ethyl. In an even further aspect, R10is methyl.

[0135] In various aspect, R10is selected from hydrogen and –CO2R20. In a further aspect, R10is hydrogen. In a still further aspect, R10is –CO2R20. d. R11, R12A, AND R12BGROUPS

[0136] In one aspect, each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl. In a further aspect, each of R11, R12a, and R12bis independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, and −CH(CH3)CH2Cl. In a still further aspect, each of R11, R12a, and R12bis independently selected from hydrogen, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, and −CH2CH2Cl. In yet a further aspect, each of R11, R12a, and R12bis independently selected from hydrogen, methyl, −CH2F, −CHF2, −CF3, and −CH2Cl.

[0137] In various aspects, each of R11, R12a, and R12bis independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R11, R12a, and R12bis independently selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a still further aspect, each of R11, R12a, and R12bis independently selected from hydrogen, methyl, and ethyl. In yet a furtherAttorney Docket No.37474.0110P1 aspect, each of R11, R12a, and R12bis independently selected from hydrogen and ethyl. In an even further aspect, each of R11, R12a, and R12bis independently selected from hydrogen and methyl.

[0138] In various aspects, each of R11, R12a, and R12bis independently selected from hydrogen and C1-C4 haloalkyl. In a further aspect, each of R11, R12a, and R12bis independently selected from hydrogen, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, and –CO2R20. In a still further aspect, R10is selected from hydrogen, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, and –CO2R20. In yet a further aspect, R10is selected from hydrogen, −CH2F, −CHF2, −CF3, −CH2Cl, and –CO2R20.

[0139] In various aspect, each of R11, R12a, and R12bis hydrogen. e. R20GROUPS

[0140] In one aspect, R20is selected from hydrogen and C1-C4 alkyl. In a further aspect, R20is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R20is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R20is selected from hydrogen and ethyl. In an even further aspect, R20is selected from hydrogen and methyl.

[0141] In various aspects, R20is C1-C4 alkyl. In a further aspect, R20is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R20is selected from methyl and ethyl. In yet a further aspect, R20is ethyl. In an even further aspect, R20is methyl.

[0142] In various aspect, R20is hydrogen. f. R21A, R21B, R21C, R21D, AND R21EGROUPS

[0143] In one aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, –CN, –N3, methyl, ethyl, n-propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, −CH(CH3)CH2NH2, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, – CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –Attorney Docket No.37474.0110P1 SO2NR12aR12b, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –CN, –N3, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, −CH2OH, −CH2CH2OH, −CH2NH2, −CH2CH2NH2, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, – C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –CN, –N3, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, −CH2OH, −CH2NH2, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, – SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0144] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10,–NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11,– OCONR12aR12b, –CONR12aR12b, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, –CN, –N3, methyl, ethyl, n-propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, −CH(CH3)CH2NH2, –OR10,– NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11,–OCONR12aR12b, –CONR12aR12b, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, – F, –Cl, –CN, –N3, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, −CH2OH, −CH2CH2OH, −CH2NH2, −CH2CH2NH2, –OR10,–NR12aR12b, – P(R11)3, –OCO2R11, –CO2R11, –OCONR12aR12b, –CONR12aR12b, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –CN, –N3, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, −CH2OH, −CH2NH2, –OR10,–NR12aR12b, –P(R11)3, – OCO2R11, –CO2R11–OCONR12aR12b, –CONR12aR12b, and Cy1.

[0145] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, –OR10, –SR11, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, – OSO2R11, –SO2R11, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, –CN, –N3, methyl, ethyl, n-propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH,Attorney Docket No.37474.0110P1 −CH(CH3)CH2OH,–OR10, –SR11, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, – OSO2R11, –SO2R11, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –CN, –N3, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, −CH2OH, −CH2CH2OH, –OR10, – SR11, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –CN, –N3, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, −CH2OH,–OR10, –SR11,– P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, and Cy1.

[0146] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 aminoalkyl,– SR11, –NR12aR12b, –P(R11)3, –CO2R11, –C(O)SR11,–SO2R11, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, –CN, –N3, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, −CH(CH3)CH2NH2,–SR11, –NR12aR12b, –P(R11)3, –CO2R11, –C(O)SR11, –SO2R11, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –CN, –N3, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, −CH2NH2, −CH2CH2NH2, –SR11, –NR12aR12b, –P(R11)3, –CO2R11, –C(O)SR11, – SO2R11, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –CN, –N3, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, −CH2NH2,–SR11, –NR12aR12b, –P(R11)3, –CO2R11, –C(O)SR11, –SO2R11, – CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0147] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, –CN, –N3, methyl, ethyl, n-propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, −CH(CH3)CH2NH2, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –CN, –N3, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2,Attorney Docket No.37474.0110P1 −CH2CF3, −CH2Cl, −CH2CH2Cl, −CH2OH, −CH2CH2OH, −CH2NH2, −CH2CH2NH2, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –CN, –N3, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, −CH2OH, −CH2NH2, and Cy1.

[0148] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, methyl, ethyl, n-propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, −CH2OH, −CH2CH2OH, −CH2CH2CH2OH, −CH(CH3)CH2OH, −CH2NH2, −CH2CH2NH2, −CH2CH2CH2NH2, −CH(CH3)CH2NH2, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, −CH2OH, −CH2CH2OH, −CH2NH2, −CH2CH2NH2, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, −CH2OH, −CH2NH2, and Cy1.

[0149] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 haloalkyl, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, methyl, ethyl, n-propyl, isopropyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, – F, –Cl, methyl, ethyl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, methyl, −CH2F, −CHF2, −CF3, −CH2Cl, and Cy1.

[0150] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, C1-C4 alkyl, and Cy1. In a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, methyl, ethyl, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, methyl, and Cy1.

[0151] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, halogen, C1-C4 haloalkyl, and Cy1. In a further aspect, each of R21a,Attorney Docket No.37474.0110P1 R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, –Br, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2CH2CH2F, −CH2CH2CHF2, −CH2CH2CF3, −CH(CH3)CH2F, −CH(CH3)CHF2, −CH(CH3)CF3, −CH2Cl, −CH2CH2Cl, −CH2CH2CH2Cl, −CH(CH3)CH2Cl, and Cy1. In a still further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, –Cl, −CH2F, −CHF2, −CF3, −CH2CH2F, −CH2CHF2, −CH2CF3, −CH2Cl, −CH2CH2Cl, and Cy1. In yet a further aspect, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –F, −CH2F, −CHF2, −CF3, −CH2Cl, and Cy1.

[0152] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0153] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis independently selected from hydrogen and Cy1.

[0154] In various aspects, each of R21a, R21b, R21c, R21d, and R21eis hydrogen. g. AR1GROUPS

[0155] In one aspect, Ar1is selected from phenyl and monocyclic heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, – P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, – CONR12aR12b, –SO2NR12aR12b, and Cy1. In a further aspect, Ar1is selected from phenyl and monocyclic heteroaryl, and is substituted with 0, 1, or 2 independently selected from halogen, – CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, – OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a still further aspect, Ar1is selected from phenyl and monocyclic heteroaryl, and is substituted with 0 or 1 group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, – OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, – SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In yet a further aspect, Ar1is selected from phenyl and monocyclic heteroaryl, and is monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In an even further aspect, Ar1is selected from phenyl and monocyclic heteroaryl, and is unsubstituted.Attorney Docket No.37474.0110P1

[0156] In various aspects, Ar1is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a further aspect, Ar1is phenyl substituted with 0, 1, or 2 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a still further aspect, Ar1is phenyl substituted with 0 or 1 group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, – P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, – CONR12aR12b, –SO2NR12aR12b, and Cy1. In yet a further aspect, Ar1is phenyl monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In an even further aspect, Ar1is an unsubstituted phenyl.

[0157] In various aspects, Ar1is a monocyclic heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. Examples of monocyclic heteroaryls include, but are not limited to, thiophene, furan, pyrrole, oxazole, isoxazole, isothiazole, pyridine, pyrimidine, pyridazine, and pyrazine. In a further aspect, Ar1is a monocyclic heteroaryl substituted with 0, 1, or 2 independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a still further aspect, Ar1is a monocyclic heteroaryl substituted with 0 or 1 group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, – NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, – OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In yet a further aspect, Ar1is a monocyclic heteroaryl monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, – P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –Attorney Docket No.37474.0110P1 CONR12aR12b, –SO2NR12aR12b, and Cy1. In an even further aspect, Ar1is an unsubstituted monocyclic heteroaryl.

[0158] In various aspects, Ar1is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. Examples of pyridinyls include, but are not limited to, thiophene, furan, pyrrole, oxazole, isoxazole, isothiazole, pyridine, pyrimidine, pyridazine, and pyrazine. In a further aspect, Ar1is a pyridinyl substituted with 0, 1, or 2 independently selected from halogen, –CN, – N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, – NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, – OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1. In a still further aspect, Ar1is a pyridinyl substituted with 0 or 1 group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, – OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, – CONR12aR12b, –SO2NR12aR12b, and Cy1. In yet a further aspect, Ar1is a pyridinyl monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, – CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, – SO2NR12aR12b, and Cy1. In an even further aspect, Ar1is an unsubstituted pyridinyl.

[0159] In various aspects, Ar1is selected from phenyl and monocyclic heteroaryl, and is monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, – CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, – SO2NR12aR12b, and Cy1.

[0160] In various aspects, Ar1is selected from phenyl and monocyclic heteroaryl, and is monosubstituted with a group selected from –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, – CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, – SO2NR12aR12b, and Cy1.

[0161] In various aspects, Ar1is phenyl monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, – OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, – SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.Attorney Docket No.37474.0110P1

[0162] In various aspects, Ar1is phenyl monosubstituted with a group selected from – OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, – SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0163] In various aspects, Ar1is monocyclic heteroaryl monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and

[0164] In selected from– C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0165] In various aspects, Ar1is selected from phenyl and monocyclic heteroaryl, and is para-substituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, – CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, – SO2NR12aR12b, and Cy1.

[0166] In various aspects, Ar1is selected from phenyl and monocyclic heteroaryl, and is para-substituted with a group selected from –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, – CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, – SO2NR12aR12b, and Cy1.

[0167] In various aspects, Ar1is phenyl para-substituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, – OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, – SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0168] In various aspects, Ar1is phenyl para-substituted with a group selected from – OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, – SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0169] In various aspects, Ar1is monocyclic heteroaryl para-substituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

[0170] In various aspects, Ar1is monocyclic heteroaryl para-substituted with a group selected from –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, – C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.Attorney Docket No.37474.0110P1 h. AR2GROUPS

[0171] In one aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1- C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0 or 1 group selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is monosubstituted with a group selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is selected from C6 aryl and 6- membered heteroaryl, and is unsubstituted.

[0172] In various aspects, Ar2is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Ar2is C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is C6 aryl substituted with 0 or 1 group selected from halogen, –OH, – NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is C6 aryl monosubstituted with a group selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is an unsubstituted C6 aryl.

[0173] In various aspects, Ar2is a 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1- C4) dialkylamino. Examples of 6-membered heteroaryls include, but are not limited to, pyridine, pyrimidine, pyridazine, and pyrazine. In a further aspect, Ar2is a 6-memberedAttorney Docket No.37474.0110P1 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is 6-membered heteroaryl substituted with 0 or 1 group selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is 6-membered heteroaryl monosubstituted with a group selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1- C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is an unsubstituted 6-membered heteroaryl.

[0174] In various aspects, Ar2is a pyridinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. Examples of pyridinyls include, but are not limited to, pyridine, pyrimidine, pyridazine, and pyrazine. In a further aspect, Ar2is a pyridinyl substituted with 0, 1, or 2 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a still further aspect, Ar2is pyridinyl substituted with 0 or 1 group selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet a further aspect, Ar2is pyridinyl monosubstituted with a group selected from halogen, –OH, – NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In an even further aspect, Ar2is an unsubstituted pyridinyl.

[0175] In various aspects, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 C1-C4 alkyl groups. In a further aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, or 2 C1-C4 alkyl groups. In a still further aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0 or 1 C1-C4 alkyl group. In yet a further aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is monosubstituted with a C1-C4 alkyl group. In an even further aspect, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is unsubstituted.

[0176] In various aspects, Ar2is C6 aryl substituted with 0, 1, 2, or 3 C1-C4 alkyl groups. In a further aspect, Ar2is C6 aryl substituted with 0, 1, or 2 C1-C4 alkyl groups. In a still further aspect, Ar2is C6 aryl substituted with 0 or 1 C1-C4 alkyl group. In yet a furtherAttorney Docket No.37474.0110P1 aspect, Ar2is C6 aryl monosubstituted with a C1-C4 alkyl group. In an even further aspect, Ar2is an unsubstituted C6 aryl.

[0177] In various aspects, Ar2is a 6-membered heteroaryl substituted with 0, 1, 2, or 3 C1-C4 alkyl groups. In a further aspect, Ar2is a 6-membered heteroaryl substituted with 0, 1, or 2 C1-C4 alkyl groups. In a still further aspect, Ar2is a 6-membered heteroaryl substituted with 0 or 1 C1-C4 alkyl group. In yet a further aspect, Ar2is a 6-membered heteroaryl monosubstituted with a C1-C4 alkyl group. In an even further aspect, Ar2is an unsubstituted 6- membered heteroaryl.

[0178] In various aspects, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is para-substituted with a C1-C4 alkyl group. In a further aspect, Ar2is C6 aryl para-substituted with a C1-C4 alkyl group. In a still further aspect, Ar2is a 6-membered heteroaryl para- substituted with a C1-C4 alkyl group.

[0179] In various aspects, Ar2is selected from C6 aryl and 6-membered heteroaryl, and is para-substituted with a methyl group. In a further aspect, Ar2is C6 aryl para-substituted with a methyl group. In a still further aspect, Ar2is a 6-membered heteroaryl para-substituted with a methyl group. i. CY1GROUPS

[0180] In one aspect, Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In a further aspect, Cy1is selected from a C3-C6 cycloalkyl, a C2-C5 heterocycloalkyl, a C6 aryl, and a C2-C5 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy1is selected from a C3-C6 cycloalkyl, a C2-C5 heterocycloalkyl, a C6 aryl, and a C2-C5 heteroaryl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Cy1is selected from a C3-C6 cycloalkyl, a C2-C5 heterocycloalkyl, a C6 aryl, and a C2-C5 heteroaryl, and is monosubstituted with a group independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4Attorney Docket No.37474.0110P1 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy1is selected from a C3-C6 cycloalkyl, a C2-C5 heterocycloalkyl, a C6 aryl, and a C2-C5 heteroaryl, and is unsubstituted.

[0181] In various aspects, Cy1is selected from a C3-C6 cycloalkyl and a C2-C5 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Cy1is selected from a C3-C6 cycloalkyl and a C2-C5 heterocycloalkyl, and is substituted with with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy1is selected from a C3-C6 cycloalkyl and a C2-C5 heterocycloalkyl, and is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Cy1is selected from a C3-C6 cycloalkyl and a C2-C5 heterocycloalkyl, and is monosubstituted with a group independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy1is selected from a C3-C6 cycloalkyl and a C2-C5 heterocycloalkyl, and is unsubstituted.

[0182] In various aspects, Cy1is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C3-C6 cycloalkyl include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, and cyclohexane. In a further aspect, Cy1is a C3-C6 cycloalkyl substituted with with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy1is a C3-C6 cycloalkyl substituted with 0 or 1 group selected from halogen, ‒ CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-Attorney Docket No.37474.0110P1 C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Cy1is a C3-C6 cycloalkyl monosubstituted with a group independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy1is an unsubstituted C3-C6 cycloalkyl.

[0183] In various aspects, Cy1is a C2-C5 heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C5 heterocycloalkyls include, but are not limited to, thiirane, oxirane, aziridine, thietane, azetidine, oxetane, pyrrolidine, imidazolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, piperazine, thiane, and morpholine. In a further aspect, Cy1is a C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy1is a C2-C5 heterocycloalkyl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Cy1is a C2-C5 heterocycloalkyl monosubstituted with a group independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1- C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy1is an unsubstituted C2-C5 heterocycloalkyl.

[0184] In various aspects, Cy1is selected from a C6 aryl and a C2-C5 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Cy1is selected from a C6 aryl and a C2-C5 heteroaryl, and is substituted with with 0, 1, or 2 groups independently selected from halogen, ‒CN‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy1is selected from a C6 aryl and a C2-C5 heteroaryl, andAttorney Docket No.37474.0110P1 is substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Cy1is selected from a C6 aryl and a C2-C5 heteroaryl, and is monosubstituted with a group independently selected from halogen, ‒CN‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy1is selected from a C6 aryl and a C2-C5 heteroaryl, and is unsubstituted.

[0185] In various aspects, Cy1is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a further aspect, Cy1is a C6 aryl substituted with with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy1is a C6 aryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Cy1is a C6 aryl monosubstituted with a group independently selected from halogen, ‒CN, ‒NH2, ‒ OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy1is an unsubstituted C6 aryl.

[0186] In various aspects, Cy1is a C2-C5 heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. Examples of C2-C5 heteroaryls include, but are not limited to, thiophene, furan, pyrrole, oxazole, isoxazole, isothiazole, pyridine, pyrimidine, pyridazine. In a further aspect, Cy1is a C2-C5 heteroaryl substituted with with 0, 1, or 2 groups independently selected from halogen, ‒CN, ‒NH2, ‒OH, ‒ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a still further aspect, Cy1is a C2-C5 heteroaryl substituted with 0 or 1 group selected from halogen, ‒CN, ‒NH2, ‒OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl,Attorney Docket No.37474.0110P1 C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In a yet further aspect, Cy1is a C2-C5 heteroaryl monosubstituted with a group independently selected from halogen, ‒CN, ‒NH2, ‒ OH, ‒NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl. In an even further aspect, Cy1is an unsubstituted C2-C5 heteroaryl. 2. EXEMPLARY COMOPUUNDS

[0187] In one aspect, a compound can be present as: , or3. PROPHETIC COMPOUND EXAMPLES

[0188] The following compound examples are prophetic, and can be prepared using the synthesis methods described herein above and other general methods as needed as would be known to one skilled in the art. It is anticipated that the prophetic compounds would be useful in the treatment of various cancers such as, for example, cancers comprising cells that express at least one Sox2 stem cell marker (e.g., glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer,Attorney Docket No.37474.0110P1 pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer)., and such utility can be determined using the methods described herein.

[0189] In one aspect, a compound can be selected from: , , orC. METHODS OF MAKING A COMPOUND

[0190] The compounds of this invention can be prepared by employing reactions as shown in the following schemes, in addition to other standard manipulations that are known in the literature, exemplified in the experimental sections or clear to one skilled in the art. For clarity, examples having a single substituent are shown where multiple substituents are allowed under the definitions disclosed herein.

[0191] Reactions used to generate the substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below. In certain specific examples, the disclosed compounds can be prepared by Route I, as described and exemplified below. The following examples are provided so that the invention might be more fully understood, are illustrative only, and should not be construed as limiting. 1. ROUTE IAttorney Docket No.37474.0110P1

[0192] In one aspect, substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds can be prepared as shown below. SCHEME 1A.

[0193] Compounds are represented in generic form, wherein R’ is a C1-C4 alkyl and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 1B.

[0194] In one aspect, compounds of type 1.8, and similar compounds, can be prepared according to reaction Scheme 1B above. Compounds of type 1.6 can be prepared by, forAttorney Docket No.37474.0110P1 example, Corey-Chaykovsky cyclopronation of a suitable alkene, e.g., 1.5 as shown above. Suitable alkenes are commercially available or or prepared by methods known to one skilled in the art. The Corey-Chaykovsky cycloproanation is carried out in the presence of an appropriate cyclopropanation agent, e.g., trimethyl sulfonium iodide, and an appropriate base, e.g., sodium hydride, in an appropriate solvent, e.g., dimethylsulfoxide. Compounds of type 1.7 can be prepared by hydrolysis of an appropriate ester, e.g., 1.6 as shown above. The hydrolysis is carried out in the presence of an appropriate base, e.g., lithium hydroxide, in an appropriate solvent system, e.g., tertrahydrofuran and water. Compounds of type 1.8 can be prepared by formation of an acyl azide from an appropriate carboxylic acid, e.g., 1.7 as shown above, followed by a Curtious rearrangement, for example. The reaction is carried out in the presence of an appropriate azide acylating agent, e.g., diphenylphosphoryl azide (DPPA), and an appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., toluene, followed by heating the in situ formed azide in the presense of an appropriate alcohol, e.g., tert-butanol. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1, 1.2, and 1.3), can be substituted in the reaction to provide substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds analogs similar to Formula 1.4. 2. ROUTE II

[0195] In one aspect, substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds can be prepared as shown below. SCHEME 2A.Attorney Docket No.37474.0110P1

[0196] Compounds are represented in generic form with substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 2B.according to reaction Scheme 2B above. Compounds of type 2.6 can be prepared by deprotection of an appropriate amine, e.g., 2.5 as shown above. The deprotection is carried out in the presence of an appropriate acid, e.g., trifluoroacetic acid, in an appropriate solvent, e.g., dichloromethane. Compounds of type 2.8 can be prepared by reaction of an appropriate free amine, e.g., 2.6 as shown above, with an appropriate acid chloride or sulfonyl chloride, e.g., 2.7 as shown above. Suitable acid chlorides and sulfonyl chlorides are commercially available or prepared by methods known to one skilled in the art. The reaction is carried out in the presence of an appropriate base, e.g., triethylamine, in an appropriate solvent, e.g., dichloromethane. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1, 2.2, and 2.3), can be substituted in the reaction to provide substituted cyclopropyl carbamate and cyclopropyl sulfonamide compounds similar to Formula 2.4. 3. ROUTE III

[0198] In one aspect, substituted unsaturated ester compounds can be prepared as shown below.Attorney Docket No.37474.0110P1 SCHEME 3A.

[0199] C4 alkyl and with other substituents as noted in compound descriptions elsewhere herein. A more specific example is set forth below. SCHEME 3B.

[0200] be prepared according to reaction Scheme 3B above. Compounds of type 3.6 can be prepared by a Wittig reaction of an appropriate aldehyde, e.g., 3.4 as shown above and a phosphonium ylide, e.g., 3.5 as shown above. Appropriate aldehydes and appropriate phosphonium ylides are commercially available or or prepared by methods known to one skilled in the art. The Wiitig reaction is carried out in the presence of an appropriate base, e.g., 62 °C, for an appropriate amount of time, e.g., 12 h. As can be appreciated by one skilled in the art, the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.1 and 3.2), can be substituted in the reaction to provide substituted unsaturated ester compounds similar to Formula 3.3.

[0201] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the inventionAttorney Docket No.37474.0110P1 concepts as expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0202] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls. D. PHARMACEUTICAL COMPOSITIONS

[0203] In one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0204] Thus, in one aspect, disclosed are pharmaceutical compositions comprising an effective amount of a compound having a structure represented by a formula: ,wherein n is selected from 0, 1, 2, 3, A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20;Attorney Docket No.37474.0110P1 wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**, and a pharmaceutically acceptable carrier.

[0205] In various aspects, the compounds and compositions of the invention can be administered in pharmaceutical compositions, which are formulated according to the intended method of administration. The compounds and compositions described herein can be formulated in a conventional manner using one or more physiologically acceptable carriers or excipients. For example, a pharmaceutical composition can be formulated for local or systemic administration, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.

[0206] The nature of the pharmaceutical compositions for administration is dependent on the mode of administration and can readily be determined by one of ordinary skill in the art. In various aspects, the pharmaceutical composition is sterile or sterilizable. The therapeutic compositions featured in the invention can contain carriers or excipients, many of which are known to skilled artisans. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol. The nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration. For example, administration can be parenteral, intravenous, subcutaneous, or oral. A modulatory compound can be formulated in various ways, according to the corresponding route of administration. For example, liquid solutions can be made for administration by drops into the ear, for injection, or for ingestion; gels or powders can be made for ingestion or topical application. Methods for making such formulations are well known and can be found in, for example, Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA 1990.

[0207] In various aspects, the disclosed pharmaceutical compositions comprise the disclosed compounds (including pharmaceutically acceptable salt(s) thereof) as an active ingredient, a pharmaceutically acceptable carrier, and, optionally, other therapeutic ingredients orAttorney Docket No.37474.0110P1 adjuvants. The instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0208] In various aspects, the pharmaceutical compositions of this invention can include a pharmaceutically acceptable carrier and a compound or a pharmaceutically acceptable salt of the compounds of the invention. The compounds of the invention, or pharmaceutically acceptable salts thereof, can also be included in pharmaceutical compositions in combination with one or more other therapeutically active compounds.

[0209] The pharmaceutical carrier employed can be, for example, a solid, liquid, or gas. Examples of solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid carriers are sugar syrup, peanut oil, olive oil, and water. Examples of gaseous carriers include carbon dioxide and nitrogen.

[0210] In preparing the compositions for oral dosage form, any convenient pharmaceutical media can be employed. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets. Because of their ease of administration, tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed. Optionally, tablets can be coated by standard aqueous or nonaqueous techniques

[0211] A tablet containing the composition of this invention can be prepared by compression or molding, optionally with one or more accessory ingredients or adjuvants. 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 a binder, lubricant, inert diluent, 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.

[0212] The pharmaceutical compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants. The instant compositions include compositions suitable for oral, rectal, topical, andAttorney Docket No.37474.0110P1 parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered. The pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.

[0213] Pharmaceutical compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water. A suitable surfactant can be included such as, for example, hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.

[0214] Pharmaceutical compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions. Furthermore, the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions. In all cases, the final injectable form must be sterile and must be effectively fluid for easy syringability. The pharmaceutical compositions must be stable under the conditions of manufacture and storage; thus, preferably should be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), vegetable oils, and suitable mixtures thereof.

[0215] Pharmaceutical compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.

[0216] In addition to the aforementioned carrier ingredients, the pharmaceutical formulations described above can include, as appropriate, one or more additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like. Furthermore, other adjuvants can be included to render the formulation isotonic with the blood of the intended recipient. Compositions containing a compound of the invention, and / or pharmaceutically acceptable salts thereof, can also be prepared in powder or liquid concentrate form.Attorney Docket No.37474.0110P1

[0217] In a further aspect, an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.

[0218] In a further aspect, the pharmaceutical composition is administered to a mammal. In a still further aspect, the mammal is a human. In an even further aspect, the human is a patient.

[0219] In a further aspect, the pharmaceutical composition is used for the inhibition of lysine-specific demethylase I (LSD1) that are relevant to cancer. The disclosed compounds and compositions can be useful in the treatment of a variety of different cancers including, glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer.

[0220] It is understood that the disclosed compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using. E. Methods of Inhibiting Lysine-Specific Demethylase I (LSD1) in a Cell

[0221] In one aspect, disclosed are methods of inhibiting lysine-specific demethylase I (LSD1) in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0222] Thus, in one aspect, disclosed are methods of degrading a target protein in a cell, the method comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: ,Attorney Docket No.37474.0110P1 wherein n is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20; wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**.

[0223] In various aspects, the cell is mammalian. In a further aspect, the cell is human.

[0224] In various aspects, the cell is selected from a cancer stem cell and a cancer- initiating cell.

[0225] In various aspects, the cell expresses at least one Sox2 stem cell marker. In a further aspect, the cancer stem cell is an embryonic cancer stem cell with germ tumor cell properties.

[0226] In various aspects, contacting is via administration to a mammal. In a further aspect, the mammal has been diagnosed with a need for treatment of cancer prior to the administering step.

[0227] In various aspects, the compound exhibits an IC50 of less than about 40 mM. In a further aspect, the compound exhibits an IC50of less than about 30 mM. F. METHODS OF INHIBITING LYSINE-SPECIFIC DEMETHYLASE I (LSD1) IN A SUBJECT

[0228] In one aspect, disclosed are methods of inhibiting lysine-specific demethylase I (LSD1) in a subject, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.Attorney Docket No.37474.0110P1

[0229] Thus, in one aspect, disclosed are methods of inhibiting lysine-specific demethylase I (LSD1) in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: , wherein n is selected from 0, 1, 2,A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20; wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**.

[0230] In a further aspect, the cancer comprises cells expressing at least one Sox2 stem cell marker.

[0231] In a further aspect, the mammal is a human. In a still further aspect, the mammal has been diagnosed with a need for treatment of a cancer prior to the administering step. In yet a further aspect, the method further comprises the step of identifying a mammal in need of treatment of a cancer.

[0232] In a further aspect, the cancer is selected from a lymphoma, sarcoma, and a carcinoma. In a still further aspect, the carcinoma is a squamous cell carcinoma.Attorney Docket No.37474.0110P1

[0233] In a further aspect, the cancer is characterized by the presence of Sox2. In a still further aspect, the cancer is selected from glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer.

[0234] In a further aspect, the cancer is associated with gene amplification of Sox2. In a still further aspect, the gene amplification occurs at 3q22.33. G. METHODS OF TREATING CANCER IN A SUBJECT

[0235] In one aspect, disclosed are methods of treating cancer in a subject, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.

[0236] Thus, in one aspect, disclosed are methods of treating cancer in a subject, the method comprising administering to the subject an effective amount of a compound having a structure represented by a formula: ,wherein n is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; wherein A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3Attorney Docket No.37474.0110P1 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20; wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**.

[0237] In various aspects, the cancer comprises cells expressing at least one Sox2 stem cell marker.

[0238] In various aspects, the subject is a mammal. In a further aspect, the subject is a human.

[0239] In various aspects, the subject has been diagnosed with a need for treatment of the cancer prior to the administering step.

[0240] In various aspects, the method further comprising the step of identifying a subject in need of treatment of the cancer.

[0241] In various aspects, the cancer is selected from a lymphoma, sarcoma, and a carcinoma. In a further aspect, the carcinoma is a squamous cell carcinoma.

[0242] In various aspects, the cancer is characterized by the presence of Sox2. In a further aspect, the cancer is selected from glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer.Attorney Docket No.37474.0110P1

[0243] In various aspects, the cancer is associated with gene amplification of Sox2. In a further aspect, the gene amplification occurs at 3q22.33. H. ADDITIONAL METHODS OF USING THE COMPOUNDS

[0244] The compounds and pharmaceutical compositions of the invention are useful in inhibiting lysine-specific demethylase I (LSD1) relevant to cancer. Examples of cancers for which the disclosed compounds may be useful include, but are not limited to, glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer.

[0245] To treat or control the condition, the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian. The subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig, or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. The subject is preferably a mammal, such as a human. Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of cancer (e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, non-small cell lung carcinoma, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma)).

[0246] The compounds or compositions can be administered to the subject according to any method. Such methods are well known to those skilled in the art and include, but are notAttorney Docket No.37474.0110P1 limited to, oral administration, transdermal administration, administration by inhalation, nasal administration, topical administration, intravaginal administration, ophthalmic administration, intraaural administration, intracerebral administration, rectal administration, sublingual administration, buccal administration and parenteral administration, including injectable such as intravenous administration, intra-arterial administration, intramuscular administration, and subcutaneous administration. Administration can be continuous or intermittent. A preparation can be administered therapeutically; that is, administered to treat an existing disease or condition. A preparation can also be administered prophylactically; that is, administered for prevention of cancer.

[0247] The therapeutically effective amount or dosage of the compound can vary within wide limits. Such a dosage is adjusted to the individual requirements in each particular case including the specific compound(s) being administered, the route of administration, the condition being treated, as well as the patient being treated. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded. The daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. 1. MANUFACTURE OF A MEDICAMENT

[0248] In one aspect, the invention relates to a method for the manufacture of a medicament for treating cancer in a subject in need thereof, the method comprising combining a therapeutically effective amount of a disclosed compound or product of a disclosed method with a pharmaceutically acceptable carrier or diluent.

[0249] As regards these applications, the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of treatment of various cancers such as, for example, cancers comprising cells that express at least one Sox2 stem cell marker (e.g., glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma,Attorney Docket No.37474.0110P1 medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer).

[0250] The total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 0.05 mg / kg and about 100 mg / kg of body weight for mice, and more preferably between 0.05 mg / kg and about 50 mg / kg of body weight for mice, and between about 100 mg / kg and about 500 mg / kg of body weight for humans, and more preferably between 200 mg / kg and about 400 mg / kg of body weight for humans per daily dose. This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.

[0251] The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.

[0252] Thus, in one aspect, the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.

[0253] In one aspect, the manufacture of the medicament can comprise co-formulating or co-packaging the disclosed compounds, or a pharmaceutically acceptable salt thereof, together with a chemotherapeutic agent. Non-limiting of chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolite agents, antineoplastic antibiotic agents, mitotic inhibitor agents, and mTor inhibitor agents.

[0254] In various aspects, the method for the manufacture of a medicament comprises combining a therapeutically effective amount of the disclosed compounds, or a pharmaceuticallyAttorney Docket No.37474.0110P1 acceptable salt thereof, with a pharmaceutically acceptable carrier or diluent and / or with a compound known for treating cancer. In a further aspect, disclosed is a method for the manufacture of a medicament for treating cancer, the method comprising combining a therapeutically effective amount of a disclosed compounds or a pharmaceutically acceptable salt thereof with a therapeutically effective amount of a compound known for treating cancer, together with a pharmaceutically acceptable carrier or diluent. 2. USE OF COMPOUNDS AND COMPOSITIONS

[0255] In one aspect, the invention relates to the use of a disclosed compound, a disclosed composition, or a product of a disclosed method. In a further aspect, a use relates to the manufacture of a medicament for inhibiting lysine-specific demethylase I (LSD1) relevant to cancer. In a still further aspect, a use relates to the manufacture of a medicament for treating cancer (e.g., glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer).

[0256] The compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with overexpression of LSD1.

[0257] Also provided are the uses of the disclosed compounds and products. In one aspect, the invention relates to use of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof. In a further aspect, the compound used is a product of a disclosed method of making.

[0258] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, for use as a medicament.Attorney Docket No.37474.0110P1

[0259] In a further aspect, the use relates to a process for preparing a pharmaceutical composition comprising a therapeutically effective amount of a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the compound or the product of a disclosed method of making.

[0260] It is understood that the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits. In a further aspect, the invention relates to the use of a disclosed compound or a disclosed product in the manufacture of a medicament for the treatment of a disorder associated with overexpression of LSD1. 3. KITS

[0261] In one aspect, disclosed are kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent known to inhibit LSD1; (b) an agent known to inhibit HDAC1; (c) an anticancer agent; (d) instructions for detecting a cancer; and (e) instructions for treating a cancer.

[0262] Thus, in one aspect, disclosed are kits comprising a compound having a structure represented by a formula: ,wherein n is selected from 0, 1, 2, A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, – OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20; wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bisAttorney Docket No.37474.0110P1 independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, – CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1- C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**, and one or more selected from: (a) an agent known to inhibit LSD1; (b) an agent known to inhibit HDAC1; (c) an anticancer agent; (d) instructions for detecting a cancer; and (e) instructions for treating a cancer.

[0263] In various aspects, the compound and the agent are co-packaged.

[0264] In various aspects, the compound and the agent are co-forumulated.

[0265] In various aspects, kit comprises the agent known to inhibit LSD1. In a further aspect, the agent known to inhibit LSD1 is a monoamine oxidase inhibitor. In a still further aspect, the monoamine oxidase inhibitor is selected from a MAO-A inhibitor and a MOA-B inhibitor. In yet a further aspect, the monoamine oxidase inhibitor is selected from pargyline and phenelzine. In an even further aspect, the monoamine oxidase is trans-2- phenylcyclopropylamine. In a still further aspect, the trans-2-phenylcyclopropylamine is selected from tranylcypromine, 2-PCPA, parnate, tranylcypromine (TCP), S2101, and RN-1.

[0266] In various aspects, the kit comprises the agent known to inhibit HDAC1. In a further aspect, the agent known to inhibit HDAC1 is vorinostat (SAHA), romidepsin (FK228), belinostat (PXD-101), panobinostat (LBH589), Pracinostat (SB939) and chidamid.

[0267] In various aspects, the kit comprises the anticancer agent. In a further aspect, the anticancer agent is selected from: (a) a hormone therapy agent; (b) an alkylating agent; (c) an antineoplastic antimetabolite agent; (d) a mitotic inhibitor agent; and (e) an antineoplastic antibiotic agent.

[0268] In a further aspect, the hormone therapy agent is selected from one or more of the group consisting of leuprolide, tamoxifen, raloxifene, megestrol, fulvestrant, triptorelin, medroxyprogesterone, letrozole, anastrozole, exemestane, bicalutamide, goserelin, histrelin, fluoxymesterone, estramustine, flutamide, toremifene, degarelix, nilutamide, abarelix, and testolactone, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0269] In a further aspect, the alkylating agent is selected from one or more of the group consisting of carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide,Attorney Docket No.37474.0110P1 thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0270] In a further aspect, the antineoplastic antimetabolite agent is selected from one or more of the group consisting of gemcitabine, 5-fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0271] In a further aspect, the mitotic inhibitor agent is selected from one or more of the group consisting of irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0272] In a further aspect, the antineoplastic antibiotic agent is selected from one or more of the group consisting of doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.

[0273] In various further aspects, a disclosed compound or a pharmaceutically-acceptable salt thereof, the instructions for the use thereof (when present) and / or a combination therapy including a compound known for treating the target condition can be co-packaged and / or co- formulated. In a still further aspect, the compound or pharmaceutically-acceptable salt thereof, the instructions (when present), and / or the compound known for treating the target condition are not co-packaged.

[0274] The kits can also comprise compounds and / or products co-packaged, co- formulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.

[0275] It is understood that the disclosed kits can be prepared from the disclosed compounds and pharmaceutical formulations. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using the compounds and pharmaceutical formulations.

[0276] In a further aspect, the kit further comprises a plurality of dosage forms, the plurality comprising one or more doses; wherein each dose comprises an effective amount of the compound and the agent. In an even further aspect, each dose of the compound and the agent are co-packaged. In a still further aspect, each dose of the compound and the agent are co- formulated.Attorney Docket No.37474.0110P1 4. SUBJECTS

[0277] In various aspects, the subject of the herein disclosed methods is a vertebrate, e.g., a mammal. Thus, the subject of the herein disclosed methods can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent. The term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered. A patient refers to a subject afflicted with a disease or disorder. The term “patient” includes human and veterinary subjects.

[0278] In some aspects of the disclosed methods, the subject has been diagnosed with a need for treatment prior to the administering step. In some aspects of the disclosed method, the subject has been diagnosed with cancer prior to the administering step. In some aspects of the disclosed methods, the subject has been identified with a need for treatment prior to the administering step. In one aspect, a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere. a. DOSAGE

[0279] Toxicity and therapeutic efficacy of the agents and pharmaceutical compositions described herein can be determined by standard pharmaceutical procedures, using either cells in culture or experimental animals to determine the LD50 (the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio LD50 / ED50.

[0280] Data obtained from cell culture assays and further animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity, and with little or no adverse effect on a human's ability to hear. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. For any agents used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve a circulating plasma concentration range that includes the IC50 (that is, the concentration of the test compound which achieves a half-maximal inhibition of symptoms) as determined in cell culture. Such information can be used to more accurately determine useful doses in humans. Exemplary dosage amounts of a differentiation agent are at least from about 0.01 to 3000 mg perAttorney Docket No.37474.0110P1 day, e.g., at least about 0.00001, 0.0001, 0.001, 0.01, 0.1, 1, 2, 5, 10, 25, 50, 100, 200, 500, 1000, 2000, or 3000 mg per kg per day, or more.

[0281] The formulations and routes of administration can be tailored to the disease or disorder being treated, and for the specific human being treated. For example, a subject can receive a dose of the agent once or twice or more daily for one week, one month, six months, one year, or more. The treatment can continue indefinitely, such as throughout the lifetime of the human. Treatment can be administered at regular or irregular intervals (once every other day or twice per week), and the dosage and timing of the administration can be adjusted throughout the course of the treatment. The dosage can remain constant over the course of the treatment regimen, or it can be decreased or increased over the course of the treatment.

[0282] In various aspects, the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation or allergic response. Although individual needs may vary, the determination of optimal ranges for effective amounts of formulations is within the skill of the art. Human doses can readily be extrapolated from animal studies (Katocs et al., (1990) Chapter 27 in Remington's Pharmaceutical Sciences, 18th Ed., Gennaro, ed., Mack Publishing Co., Easton, PA). In general, the dosage required to provide an effective amount of a formulation, which can be adjusted by one skilled in the art, will vary depending on several factors, including the age, health, physical condition, weight, type and extent of the disease or disorder of the recipient, frequency of treatment, the nature of concurrent therapy, if required, and the nature and scope of the desired effect(s) (Nies et al., (1996) Chapter 3, In: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 9th Ed., Hardman et al., eds., McGraw-Hill, New York, NY). b. ROUTES OF ADMINISTRATION

[0283] Also provided are routes of administering the disclosed compounds and compositions. The compounds and compositions of the present invention can be administered by direct therapy using systemic administration and / or local administration. In various aspects, the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient. In various aspects, an individual patient's therapy may be customized, e.g., the type of agent used, the routes of administration, and the frequency of administration can be personalized. Alternatively, therapy may be performed using a standard course of treatment, e.g., using pre-selected agents and pre-selected routes of administration and frequency of administration.Attorney Docket No.37474.0110P1

[0284] Systemic routes of administration can include, but are not limited to, parenteral routes of administration, e.g., intravenous injection, intramuscular injection, and intraperitoneal injection; enteral routes of administration e.g., administration by the oral route, lozenges, compressed tablets, pills, tablets, capsules, drops (e.g., ear drops), syrups, suspensions and emulsions; rectal administration, e.g., a rectal suppository or enema; a vaginal suppository; a urethral suppository; transdermal routes of administration; and inhalation (e.g., nasal sprays).

[0285] In various aspects, the modes of administration described above may be combined in any order.

[0286] The foregoing description illustrates and describes the disclosure. Additionally, the disclosure shows and describes only the preferred embodiments but, as mentioned above, it is to be understood that it is capable to use in various other combinations, modifications, and environments and is capable of changes or modifications within the scope of the invention concepts as expressed herein, commensurate with the above teachings and / or the skill or knowledge of the relevant art. The embodiments described herein above are further intended to explain best modes known by applicant and to enable others skilled in the art to utilize the disclosure in such, or other, embodiments and with the various modifications required by the particular applications or uses thereof. Accordingly, the description is not intended to limit the invention to the form disclosed herein. Also, it is intended to the appended claims be construed to include alternative embodiments.

[0287] All publications and patent applications cited in this specification are herein incorporated by reference, and for any and all purposes, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. In the event of an inconsistency between the present disclosure and any publications or patent application incorporated herein by reference, the present disclosure controls. I. EXAMPLES

[0288] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how the compounds, compositions, articles, devices and / or methods claimed herein are made and evaluated, and are intended to be purely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.Attorney Docket No.37474.0110P1

[0289] The Examples are provided herein to illustrate the invention, and should not be construed as limiting the invention in any way. Examples are provided herein to illustrate the invention and should not be construed as limiting the invention in any way. 1. CHEMISTRY EXPERIMENTALS a. GENERAL EXPERIMENTALS

[0290] Infrared spectra were recorded neat unless otherwise indicated and are reported in cm-1.1H NMR spectra were recorded in deuterated solvents and are reported in ppm relative to tetramethylsilane and referenced internally to the residually protonated solvent.13C NMR spectra were recorded in deuterated solvents and are reported in ppm relative to tetramethylsilane and referenced internally to the residually protonated solvent.

[0291] Routine monitoring of reactions was performed using EM Science DCAlufolien silica gel, aluminum-backed TLC plates. Flash chromatography was performed with the indicated eluents on EM Science Gedurian 230-400 mesh silica gel.

[0292] Air and / or moisture sensitive reactions were performed under usual inert atmosphere conditions. Reactions requiring anhydrous conditions were performed under a blanket of argon, in glassware dried in an oven at 120 °C or by flame, then cooled under argon. Dry THF, CH2Cl2, and toluene were obtained via a solvent purification system. All other solvents and commercially available reagents were either purified via literature procedures or used without further purification. b. SYNTHESIS OF TERT-BUTYL-2-(4-(TERT-BUTOXYCARBONYLOXY) PHENYL)CYCLOPROPYLCARBAMATE (CBB3001)Attorney Docket No.37474.0110P1 i. ETHYL (2E)-3-[4-(PHENYLMETHOXY)PHENYL]-2- PROPENOATE (2)

[0293] mL) in a 100 mL round bottom flask. Benzyl bromide (0.42 mL, 3.5 mmol) and K2CO3(499 mg, 3.5 mmol) were added to the reaction mixture. The mixture was stirred under argon for 5 minutes, and then left to stir at room temperature for an additional 20 hours. Mixture was filtered and then purified through column using hexanes / ethyl acetate 9 / 1. Reaction was concentrated down and then high-vacuumed to yield a white solid 2 (810.6 mg, 89%). ii. REL-ETHYL (1R,2R)-2-[4- (PHENYLMETHOXY)PHENYL]CYCLOPROPANECARBOXYLATE (3)

[0294] mg, mg, mmol) were dissolved in dry DMSO (14 mL) in a 50 mL round bottom flask. The mixture was stirred for 1 hour under argon at room temperature. After 1 hour, ethyl (2E)-3-[4- (phenylmethoxy)phenyl]-2-propenoate (2) (1,265 mg, 2.8 mmol) was dissolved in dry DMSO (2.7 mL) in a 20-dram vial and then added to the mixture dropwise. After addition of 2, the reaction was refluxed at 60 °C for 16 hours. The reaction was extracted with Ethyl acetate and purified through column using hexanes / ethyl acetate 7 / 3. The product was concentrated down and high vacuumed to obtain a white solid 3 (568.7 mg, 69%).Attorney Docket No.37474.0110P1 iii. REL-(1R,2R)-2-[4- (PHENYLMETHOXY)PHENYL]CYCLOPROPANECARBOXYLIC ACID (4)

[0295] (3) (566.7 mg, 1.9 mmol) was dissolved in THF (7.6 mL) in a 20-dram vial and then transferred to a 50 mL round bottom flask with a pipette. LiOH (182 mg, 7.6 mmol) was dissolved with H2O (7.6 mL) in a beaker and then added to reaction mixture with a pipette. Mixture was stirred at room temperature for 22 hours. Initially, the reaction was a white cloudy liquid but turned into a yellow homogenous liquid overnight. After 22 hours, the mixture was acidified with 12 mL HCl / H2O (11 mL / 1 mL). The mixture was extracted with dichloromethane and then filtered to obtain a white solid 4 (513.2 mg, 99%). iv. REL-1,1-DIMETHYLETHYL N-[(1R,2S)-2-[4 (PHENYLMETHOXY) PHENYL] CYCLOPROPYL] CARBAMATE (5)

[0296] - (4)(297 mg, 1.1 mmol) was dissolved in toluene(14.4 mL, 132 mmol) in a 50 mL round bottom flask. Diphenyl phosphoryl azide (DPPA) (0.28 mL, 1.3 mmol), and then triethylamine (0.18 mL, 1.32 mmol) was added dropwise to the reaction mixture under an ice bath at 0 °C. The reaction mixture was refluxed at 100 °C for 5 hours. After 5 hours, t-BuOH (2.1 mL, 22 mmol) was added to the mixture. The mixture was refluxed for an additional 18 hours. After 18 hours, the reaction was purified through column. The column was neutralized by flushing with 2% Et3N (hexanes / ethyl acetate: 98 / 2 mL). The column was eluted with hexanes / ethyl acetate 9 / 1. The desired product was concentrated down and high vacuumed to obtain a white solid 5 (227.4 mg, 61%).Attorney Docket No.37474.0110P1 v. REL-4-[(1R,2S)-2-AMINOCYCLOPROPYL]PHENOL (CBB3001)

[0297] cyclopropyl] carbamate (5) (20 mg, 0.06mmol) was added to a 2-dram vial and dissolved with DCM (1.0 mL, 16 mmol). Solution was stirred under argon for 5 minutes. Reaction vial was put in a dry ice bath with acetone to lower the temperature to -78 °C. BBr3 (0.01 mL, 0.12 mmol) was then added to reaction mixture and allowed to stir for 20 minutes. Upon addition of BBr3, the color changed from yellow to red. After 20 minutes, the reaction was quenched with MeOH (1 mL) and stirred for a remaining 10 minutes at room temperature. The reaction was concentrated down, and then high vacuumed for 30 minutes. No further purification was done due to high polarity of the desired product. The product obtained was a dark brown solid CBB3001 (9.6 mg, 99%). vi. 1,1-DIMETHYLETHYL 4-[(1S,2R)-2-[[(1,1- DIMETHYLETHOXY) CARBONYL]AMINO] CYCLOPROPYL]PHENYLESTER CARBONIC ACID (CBB3001)- mg, was dissolved with THF (2.4 mL) in a 2-dram vial at room temperature. Boc2O (0.06 mL, 0.24 mmol) was added dropwise to the mixture, followed by the addition of Et3N (0.03 mL, 0.24 mmol). After 1 hour, DMAP (1.4mg) was added to the mixture and stirred for an additional hour. After 2 hours, the reaction mixture was purified using hexanes / ethyl acetate: 9 / 1. The product was concentrated down and high vacuumed to obtain a white solid 7 (18.4 mg, 86%). (CL-1- 172)Attorney Docket No.37474.0110P1 c. SYNTHESIS OF OPEN RING-BUTYL-2(4-(TERT- BUTOXYCARBONYLOXY)PHENYL)CYCLOPROPYLCARBAMATE (OPCBB3001)

[0299] rel-1,1-Dimethylethyl N-[(1R,2S)-2-[4 (phenylmethoxy)phenyl]cyclopropyl] carbamate (5) (60 mg, 0.18 mmol) was dissolved in distilled MeOH (1.9 mL, 48 mmol) in a 5 mL round bottom flask. Pd (8 mg, 0.07 mmol) was then added to reaction solution and stirred at room temperature under a hydrogen atmosphere for 4 hours. After 4 hours, the reaction was filtered with a 5 mL syringe and filter top, to obtain a colorless oil 6 (44.7 mg, 99%).6 (44.2 mg, 0.18 mmol) was dissolved in dichloromethane (0.64 mL, 10 mmol) in a 2-dram vial. Di-tert- butyl dicarbonate (0.62 mL, 0.27 mmol) was added dropwise to the mixture, followed by the addition of 4-dimethylaminopyridine (4.0 mg, 0.02 mmol). The mixture was stirred at roomAttorney Docket No.37474.0110P1 temperature for 1 hour. After 1 hour, the reaction mixture was purified using hexanes / ethyl acetate: 9 / 1. The product was concentrated down and high vacuumed to obtain OPCBB3001 (29.7 mg, 48%).1H NMR (400 MHz, CDCl3) δ 7.16-7.14 (d, 2H, J = 8.4 Hz), 7.08-7.06 (d, 2H, J = 8.4 Hz), 4.36 (s, 1H), 3.87 (s, 1H), 2.83-2.78 (dd, 1H, J = 13.6 Hz, J = 5.2 Hz), 2.65-2.60 (dd, 1H, J = 13.2 Hz, J = 7.2 Hz), 1.53 (s, 9H), 1.41 (s, 9H), 1.06-1.04 (d, 1H, J = 6.8 Hz) ppm;13C NMR (100 MHz, CDCl3) δ 155.1, 151.9, 144.6, 130.3, 121.0, 83.4, 42.4, 28.3, 27.7, 19.9 ppm. d. SYNTHESIS OF TRANS-2-(4-METHOXYMETHOXYPHENYL)CYCLOPROPYL TERT-BUTYLCARBAMATE (CL-1-128)- mg, was in dichloromethane (3.6 mL) in a 25 mL round bottom flask. Chloromethyl methyl ether (MOM chloride) (5.4 mL, 5.4 mmol) and N,N-diisopropylethylamine (Hunigs base) (1.3 mL, 7.2 mmol) were added to reaction mixture and stirred at room temperature for 20 hours. After 20 hours, the mixture was extracted with ethyl acetate and purified through column using hexanes / ethyl acetate 8 / 2. Product was concentrated down and high vacuumed to obtain 2 (536.8 mg, 63%).Attorney Docket No.37474.0110P1 ii. ETHYL TRANS-2-(4- METHOXYMETHOXYPHENYL)CYCLOPROPANECARBOXYLAT E (3)and sodium hydride (182 mg, 4.5 mmol) was dissolved in dry dimethyl sulfoxide (10 mL) in a 50 mL round bottom flask. The mixture was stirred for 1 hour under argon at room temperature. After 1 hour, ethyl trans-3-(4-Methoxymethoxyphenyl)propenoate (2) (1,265 mg, 2.8 mmol) was dissolved in dry dimethyl sulfoxide (1.5 mL) in a 20-dram vial and then added to the mixture dropwise. After addition of 2, the reaction was refluxed at 60 °C for 24 hours. The reaction was extracted with ethyl acetate and purified through column using hexanes / ethyl acetate 9 / 1. The product was concentrated down and high vacuumed to obtain 3 (296.7 mg, 52%). iii. TRANS-2-(4- METHOXYMETHOXYPHENYL)CYCLOPROPANECARBOXYLIC ACID (4)

[0302] Ethyl trans-2-(4-Methoxymethoxyphenyl)cyclopropanecarboxylate (3) (297 mg, 1.2 mmol) was dissolved in tetrahydrofuran (4.8 mL) in a 20-dram vial and then transferred to a 50 mL round bottom flask with a pipette. Lithium hydroxide (118 mg, 4.8 mmol) was dissolved with water (4.8 mL) in a beaker and then added to reaction mixture with a pipette. Mixture was stirred at room temperature for 24 hours. After 22 hours, the mixture was acidified with 12 mL HCl / H2O (11 mL / 1 mL). The mixture was extracted with dichloromethane and then filtered to obtain 4 (218 mg, 83%).Attorney Docket No.37474.0110P1 iv. TRANS-2-(4-METHOXYMETHOXYPHENYL)CYCLOPROPYL TERT-BUTYLCARBAMATE (CL-1-128) O O Et N Omg, 0.5 mmol) was dissolved in cyclohexane (5 mL, 0.05 mmol) in a 2-dram vial. Diphenyl phosphoryl azide (DPPA) (0.12 mL, 0.6 mmol), and then triethylamine (0.08 mL, 0.6 mmol) was added dropwise to the reaction mixture under an ice bath at 0 °C. The reaction mixture was refluxed at 100 °C for 3 hours. After 3 hours, t-butanol (0.1 mL, 0.98 mmol) was added to the mixture. The mixture was refluxed for an additional 22 hours. After 22 hours, the reaction was purified through column. The column was eluted with hexanes / ethyl acetate 7 / 3. The desired product was concentrated down and high vacuumed to obtain CL-1-128 (44.5 mg, 31%). e. SYNTHESIS OF REL-1,1-DIMETHYLETHYL N-[TRANS-2-(4- CHLOROPHENYL)CYCLOPROPYL]CARBAMATE (CL-1-169)Attorney Docket No.37474.0110P1

[0304] p-Chloro benzaldehyde (1) (144 mg, 0.76 mmol), sodium bicarbonate (NaHCO3) (5.0 mL, 1131 mmol), ethyl bromoacetate (0.20 mL, 1.8 mmol), and triphenyl phosphine (PPh3) (398 mg, 1.5 mmol) were added to a 20 mL vial with a stir bar. Mixture was stirred at room temperature for 4 hours. After stirring for 4 hours, mixture was acidified with 1M H2SO4(11 / 1 H2O / H2SO4) and stirred for an additional 10 minutes. Mixture was extracted with ethyl acetate and purified through column using hexanes / ethyl acetate 7 / 3. Product was concentrated down and high vacuumed to obtain 2 (48.5 mg, 23%). ii. ETHYL TRANS-2-(4- CHLOROPHENYL)CYCLOPROPANECARBOXYLATE (3)

[0305] and sodium hydride (NaH) (17.9 mg, 0.42 mmol) were dissolved in dry DMSO (1.1 mL) in a 5 mL round bottom flask. The mixture was stirred for 1 hour under argon at room temperature. After 1 hour, 2-propenoic acid, 3-(4-chlorophenyl)-ethyl ester (2) (44 mg, 0.21 mmol) was dissolved in dry DMSO (0.5 mL) then added to the mixture dropwise. After addition of 7, the reaction was refluxed at 60 °C for 24 hours. The reaction was extracted with ethyl acetate and filtered. The product was concentrated down and high vacuumed to obtain 3 (37.6 mg, 80%). iii. TRANS-2-(4-CHLOROPHENYL)CYCLOPROPANECARBOXYLIC ACID (4)

[0306] Ethyl trans-2-(4-chlorophenyl)cyclopropanecarboxylate (3) (37.6 mg, 0.17 mmol) was dissolved in tetrahydrofuran (1.2 mL) in a 20-dram vial and then transferred to a 50 mL round bottom flask with a pipette. LiOH (29.5 mg, 1.2 mmol) was dissolved with H2O (1.2 mL) in a beaker and then added to reaction mixture with a syringe. Mixture was stirred at room temperature for 19 hours. After 19 hours, the mixture was acidified with 12 mL HCl / H2O (11Attorney Docket No.37474.0110P1 mL / 1 mL). The mixture was extracted with ethyl acetate and then filtered to obtain 4 (29.1 mg, 88%). iv. REL-1,1-DIMETHYLETHYL N-[TRANS-2-(4- CHLOROPHENYL)CYCLOPROPYL]CARBAMATE (CL-1-169)

[0307] 0.2 mmol) was dissolved in toluene (1.7 mL, 18 mmol) in a 2-dram vial. Diphenyl phosphoryl azide (DPPA) (0.04 mL, 0.17 mmol), and then triethylamine (0.03 mL, 0.18 mmol) was added dropwise to the reaction mixture under an ice bath at 0 °C. The reaction mixture was refluxed at 100 °C for 3 hours. After 3 hours, t-butanol (0.29 mL, 3 mmol) was added to the mixture. The mixture was refluxed for an additional 24 hours. After 24 hours, the reaction was purified through column. The column was eluted with hexanes / ethyl acetate 9 / 1. The desired product was concentrated down and high vacuumed to obtain CL-1-169 (4.6 mg, 12%). f. SYNTHESIS OF 4-TRANS-2-((4- METHYLPHENYL)SULFONAMIDO)CYCLOPROPYL)PHENYL 4- METHYLBENZENESULFONATE (CL-1-178)Attorney Docket No.37474.0110P1 i. 4-TRANS-2-((4- METHYLPHENYL)SULFONAMIDO)CYCLOPROPYL)PHENYL 4- METHYLBENZENESULFONATE (CL-1-178)

[0308] dissolved in dichloromethane (1 mL, 16 mmol) under argon. Solution was cooled to 0 °C by adding an ice bath. Triethylamine (0.09 mL, 0.71 mmol) and tosyl chloride (15.4 mg, 0.08 mmol) were added to the reaction under argon. Mixture was then warmed to room temperature and stirred at room temperature for 72 hours. After 3 days, the reaction was quenched with H2O (1 mL) and stirred for an additional 10 minutes. Mixture was extracted with dichloromethane and purified through column using hexanes / ethyl acetate 8 / 2. Column was washed with 1% triethylamine before use. Product was concentrated down and high vacuumed to obtain CL-1-178 (9 mg, 22%). g. SYNTHESIS OF 4-(TRANS-2- (METHYLSULFONAMIDO)CYCLOPROPYL)PHENYL METHANESULFONATE (CL2-4)

[0309] To a solution of 4-((2-aminocyclopropyl)phenol (6) (0.06 mmol) in dichloromethane (1.0 mL) was added triethyl amine (0.2 mmol) and methanesulfonyl chloride (0.2 mmol) dropwise and stirred for 24 h. Water was added to the reaction, and then the reaction was extracted with dichloromethane (3x). The organic layer was washed with brine and driedAttorney Docket No.37474.0110P1 over sodium sulfate. The dried organic extract was then concentrated under reduced pressure and directly purified by column chromatography (7:3 Hexane:EtOAc) to give Cl-2-4 (6.1 mg, 32%). h. SYNTHESIS OF TERT-BUTYL-TRANS-2- PHENETHYLCYCLOPROPYL)CARBAMATE (AA-1-43)and triethyl amine (6.0 mmol) in CHCl3 (20.0 mL) was stirred for 2 h under an argon atmosphere at room temperature.3-Phenylpropanal (1) (4.0 mmol) was slowly added and the reaction mixture was refluxed for 12 h. The reaction was quenched with water and extracted with ethyl acetate (3x). The organic layer was washed with brine and dried over sodium sulfate. The dried organic extract was then concentrated under reduced pressure and purified by column chromatography (7:3 Hexane:dichloromethane) to obtain 2 (619.2 mg, 76%). ii. ETHYL TRANS-2-PHENETHYLCYCLOPROPANE-1- CARBOXYLATE (3)Attorney Docket No.37474.0110P1

[0311] A solution of TMSI (3.0 mmol) and NaH (3.0 mmol) in DMSO (7.5 mL) was stirred for 45 minutes under an argon atmosphere at room temperature. A solution of ethyl (E)-5- phenylpent-2-enoate (2) (2.0 mmol in DMSO (2.5 mL) was added dropwise and the reaction was heated to 80 °C for 12 h. The reaction was quenched with water and extracted with dichloromethane (3x). The organic layer was washed with brine and dried over sodium sulfate. The dried organic extract was then concentrated under reduced pressure and purified by column chromatography. (7:3 Hexane:dichloromethane) to obtain 3 (162.6 mg, 37%). iii. TRANS-2-PHENETHYLCYCLOPROPANE-1-CARBOXYLIC ACID (4)

[0312] (0.2 mmol) in tetrahydrofuran / H2O (1.0 mL) was added LiOH (1.0 mmol) and heated at 70 °C for 1 h. The reaction was acidified using 1 M HCl and extracted with ethyl acetate (3x). The organic layer was washed with brine and dried over sodium sulfate. The dried organic extract was then concentrated under reduced pressure to give 4 (30.3 mg, 80%). iv. TERT-BUTYL-TRANS-2-

[0313] To a solution of trans-2-phenethylcyclopropane-1-carboxylic acid (4) in toluene (1.5 mL) was added triethylamine (0.19 mmol) and diphenyl phosphoryl azide (DPPA)(0.18 mmol) under argon conditions. The reaction was then heated at 100 °C for 3 h. The reaction was allowed to cool to room temperature and tert butanol (0.3 mL) was added and the reaction was heated at 100 °C overnight. The reaction was concentrated under reduced pressure and directly purified by column chromatography (9:1 Hexane:EtOAc) to give AA-1-43 (16.0 mg, 53%).Attorney Docket No.37474.0110P1 2. CHALLENGES IN THE ORIGINAL SYNTHETIC ROUTE TO ACCESS CBB3001

[0314] The original synthesis of CBB3001 is shown in FIG.1. This route suffers from several key issues; namely, the cyclopropanation step is low yielding (yields around 20%) and the overall yield is quite low (~8%). Further, the low yield makes it difficult to analyze the resultant product. Thus, an improved synthetic route, which would allow access to additional analogs that may offer improvements in potency and pharmacokinetic properties, is desirable.

[0315] To this end, a new route was explored, focusing on optimizing the cyclopropanation and alternative techniques to access the carbamate. 3. EFFECT OF THE PROTECTING GROUP ON CYCLOPROPANATION

[0316] The effect of a variety of protecting groups on the cyclopropanation reaction was explored, including fluorenylmethyloxycarbonyl (Fmoc), tert-butyldimethyl silyl (TBS), methoxymethyl ether (MOM), and benzyl (Bn). See FIG.2A and FIG.2B. As shown, benzyl protection of the phenol provided a significantly improved yield (more than three-fold improvement) over the original synthesis. 4. CURTIUS REARRANGEMENT

[0317] In order to arrive at the desired Boc-protected intermediate, a Curtius rearrangement was attempted. The (benzyloxy)phenyl)cyclopropane-1-carboxylic acid 3.1 was reacted with diphenylphosphoryl azide and subsequent heating in the presence of tert-butanol provided the Boc protected amine 3.2 as shown in Scheme 3. This reaction beneficially avoids a free amine intermediate, which is difficult to isolate. For purification, the column was neutralized using 1% triethylamine to avoid decomposition. SCHEME 3.5. SYNTHESIS OF AN OPEN RING PRODUCT

[0318] Debenzylation of the benzyl protected hydroxyl group 4.1 using palladium catalyzed hydrogenation also resulted in the opening of the cyclopropane ring to provide 4.2 asAttorney Docket No.37474.0110P1 shown in Scheme 4 with none of the expected product 4.3. Subsequent protection of the hydroxyl group with di-tert-butyl dicarbonate provided the open ring analog 4.4 (OPCBB3001). Although no inhibition of LSD1 was observed with this compound, it does allow for testing of the reaction mechanism. SCHEME 4.6.

[0319] Succcesful selective debenzylation of 5.1 using boron tribromide led to high quantitative yield (99%) of the free amine 5.2 as shown in Scheme 5. It is noted that this Lewis acid deprotects both the benzyl and the Boc protecting groups in a single step. The amine can then be re-protected using standard conditions to afford the desired product 5.3 (CBB3001). SCHEME 5.Attorney Docket No.37474.0110P17. IMPROVED SYNTHESIS OF CBB3001

[0320] The complete improved synthetic route is illustrated in Scheme 6. As shown, the yield for the cyclopropanation step was improved to 69% and the overall yield was improved to 33%. SCHEME 6.8. SYNTHESIS OF CBB3001 ANALOGS

[0321] A list of the compounds synthesized using the procedures described herein is shown in Table 1 below. TABLE 1.Attorney Docket No.37474.0110P1 No. Structure 9. SCY AND SELECTIVITY

[0322] A rigorous analysis of the reported crystal structures of FAD-dependent enzymes in their active sites revealed that the activity pocket of LSD1 is larger and more hydrophilic than those of the other enzymes such as LSD2, MAO-A, and MAO-B.1 (Fang et al. (2013) Molecular Cell 49: 558-570; Son et al. (2008) Proceedings of the National Academy of Sciences 105: 5739-5744; De Colibus et al. (2005) Proceedings of the National Academy of Sciences 102: 12684-12689; Li et al. (2022) Journal of Medicinal Chemistry 65: 4335-4349). This structural information provides important insights into the optimum design of highly selective LSD1 inhibitors. Without wishing to be bound by theory, the information from the crystal structures, indicated various space linkers between the cyclopropane core and the aryl group will help to understand the size of the activity pocket. In addition, a large hydrophobic activity pocket ofAttorney Docket No.37474.0110P1 LSD1 can be explored by installing bulky substituents on the phenyl group of the western part of CBB3001. Further, sulfoxide substituents on the cyclopropylamine can stabilize the sulfonamidyl radical cation intermediate and thus induces a high affinity to form a covalent adduct with FAD.

[0323] With a large activity pocket revealed by the crystal structure studies of LSD1 adduct, well-fitted substrates are expected to increase not only the potency but also the selectivity against other enzymes sharing similar structures such as LSD2, MAO-A, and MAO-B (Mimasu et al. (2008) Biochemical and Biophysical Research Communications 366: 15-22). To exploit the size of the activity pocket, CBB3001 derivatives with various spacer lengths are being studied. See, e.g., compound no. AA-1-43 above.

[0324] In addition, it has been previously disclosed that bulky hydrophobic substituents on the TCP benzene ring exhibited good selectivity for LSD1 over MAO-A and MAO-B (Son et al. (2008) Proceedings of the National Academy of Sciences 105: 5739-5744). In 2015, it was the significant effect of bulky benzoyl substituents on the phenyl group was further realized by achieving high LSD1 inhibitory potency (IC50 = 32 nM) (Rodriguez et al. (2015) MedChemComm 6: 665-670). To optimize the CBB3001 compound, the hydrophobic site will be explored with bulky substituents on the para-position of the phenyl group to improve its potency and specificity.

[0325] Furthermore, the proposed inhibitory mechanism of FAC-TCP adduct via covalent bond formation suggests that the cyclopropylamine undergoes sequential reactions to form the adduct via single electron transfer (SET), homolytic bond cleavage of the cyclopropane, and hydrolysis which converts the amine group into an aldehyde (Mimasu et al. (2008) Biochemical and Biophysical Research Communications 366:15-22; Yang et al. (2007) Biochemistry 46: 8058-8065; Binda et al. (2010) J. of the Amer. Chem. Soc.132: 6827-6833; Dai et al. (2020) J. Med. Chem.63: 14197-14215). Based on this covalent adduct formation of the inhibitory mechanism, the amine group of TCP is converted into an iminium intermediate via SET followed by hydrolysis. Whether the formation of a stabilized-amine cation radical intermediate could be beneficial to induce this sequential mechanism rapidly is being studied by introducing sulfonamide groups to stabilize the amine cation radical intermediate (Zhu et al. (2018) J. Amer. Chem. Soc.140: 741-747). See, e.g., bis-mesyl (Ms) and bis-tosyl (Ts) analogs CL-1-178 and CL-2-4.

[0326] It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention without departing from the scope or spirit of the invention. Other embodiments of the invention will be apparent to those skilled in the art fromAttorney Docket No.37474.0110P1 consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

Attorney Docket No.37474.0110P1 CLAIMS What is claimed is:

1. A compound having a structure represented by a formula: , wherein n is selected from 0, 1,wherein A is selected from *–C(O)O–** and *–SO2–**, wherein * denotes a bond connected to NH and ** denotes a bond connected to R1; wherein R1is selected from C1-C8 alkyl and Ar2; wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, – P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, – CONR12aR12b, –SO2NR12aR12b, and Cy1; wherein R10is selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, and –CO2R20; wherein R20is selected from hydrogen and C1-C4 alkyl; wherein each of R11, R12a, and R12bis independently selected from hydrogen, C1-C4 alkyl, and C1-C4 haloalkyl; wherein Cy1is selected from C3-C6 cycloalkyl, C2-C5 heterocycloalkyl, C6 aryl, and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C4-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, or a pharmaceutically acceptable salt thereof,Attorney Docket No.37474.0110P1 provided that either n is 1, 2, 3, 4, 5, 6, 7, or 8 or A is *–SO2–**.

2. The compound of claim 1, wherein n is 1, 2, 3, 4, 5, 6, 7, or 8.

3. The compound of claim 1, wherein n is 0 or 1.

4. The compound of claim 1, wherein n is 1.

5. The compound of any one of claims 1 to 4, wherein A is *–C(O)O–**.

6. The compound of any one of claims 1 to 4, wherein A is *–SO2–**.

7. The compound of any one of claims 1 to 6, wherein R1is C1-C8 alkyl.

8. The compound of any one of claims 1 to 6, wherein R1is C1-C4 alkyl.

9. The compound of any one of claims 1 to 6, wherein R1is methyl.

10. The compound of any one of claims 1 to 6, wherein R1is Ar2.

11. The compound of claim 10, wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 C1-C4 alkyl groups.

12. The compound of claim 10, wherein Ar2is selected from C6 aryl and 6-membered heteroaryl, and is para-substituted with a methyl group.

13. The compound of claim 10, wherein Ar2is C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, –OH, –NH2, –CN, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino.

14. The compound of claim 10, wherein Ar2is C6 aryl substituted with 0, 1, 2, or 3 groups C1-C4 alkyl groups.

15. The compound of claim 10, wherein Ar2is C6 aryl para-substituted with a methyl group.

16. The compound of any one of claims 1 to 15, wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is monosubstituted with a group selected from halogen, – CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –Attorney Docket No.37474.0110P1 OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

17. The compound of any one of claims 1 to 15, wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is monosubstituted with a group selected from –OR10, – SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

18. The compound of any one of claims 1 to 15, wherein Ar1is selected from phenyl and monocyclic heteroaryl and wherein Ar1is para-substituted with a group selected from –OR10, – SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

19. The compound of any one of claims 1 to 15, wherein Ar1is phenyl monosubstituted with a group selected from halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, – C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

20. The compound of any one of claims 1 to 15, wherein Ar1is phenyl monosubstituted with a group selected from –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, – C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

21. The compound of any one of claims 1 to 15, wherein Ar1is phenyl para-substituted with a group selected from –OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, – C(O)SR11, –OSO2R11, –SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1.

22. The compound of claim 1, wherein the compound has a structure represented by a formula: , wherein n is 1, 2, 3, 4, 5, 6, 7,or a pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound has a structure represented by a formula: ,Attorney Docket No.37474.0110P1 or a pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable25. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable26. The compound of claim 1, wherein the compound has a structure represented by a formula: , wherein n is 1, 2, 3, 4, 5, 6, 7, oror a pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound has a structure represented by a formula: , or a pharmaceutically acceptable28. The compound of claim 1, wherein the compound has a structure represented by a formula: ,or a pharmaceutically 29. The compound of claim 1, wherein the compound has a structure represented by a formula:Attorney Docket No.37474.0110P1 , wherein each of R21a, R21b,selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, – OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, – SO2R11, –OCONR12aR12b, –CONR12aR12b, –SO2NR12aR12b, and Cy1, or a pharmaceutically acceptable salt thereof.

30. The compound of claim 29, wherein the compound has a structure represented by a formula: R21bR21cR21aR1, or a pharmaceutically31. The compound of claim 29, wherein the compound has a structure represented by a formula: , or a pharmaceutically32. The compound of claim 29, wherein the compound has a structure represented by a formula: ,or a pharmaceutically 33. The compound of claim 29, wherein the compound has a structure represented by a formula:Attorney Docket No.37474.0110P1 , or a pharmaceutically34. The compound of claim 29, wherein the compound has a structure represented by a formula: R21bR21cR21a, or a pharmaceutically35. The compound of claim 29, wherein the compound has a structure represented by a formula: , or a pharmaceutically36. The compound of claim 1, wherein the compound has a structure represented by a formula: R21a 2O OR1b3 , wherein each of R21a, R21b,selected from hydrogen, halogen, –CN, –N3, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 aminoalkyl, – OR10, –SR11, –NR12aR12b, –P(R11)3, –OCO2R11, –CO2R11, –OC(O)SR11, –C(O)SR11, –OSO2R11, –37. The compound of claim 36, wherein the compound has a structure represented by a formula:Attorney Docket No.37474.0110P1 , or a pharmaceutically38. The compound of claim 1, wherein the compound is selected from: Oor a 39. The compound of claim 1, wherein the compound is selected from: ,or a pharmaceutically acceptable salt thereof.

40. A pharmaceutical composition comprising a therapeutically effective amount of theAttorney Docket No.37474.0110P1 compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

41. A method of inhibiting lysine-specific demethylase I (LSD1) in a cell, the method comprising contacting the cell with an effective amount of the compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein the cell is a mammalian cell.

43. The method of claim 41, wherein the cell is a human cell.

44. The method of claim 41, wherein the cell is selected from a cancer stem cell and a cancer-initiating cell.

45. The method of claim 41, wherein the cell expresses at least one Sox2 stem cell marker.

46. The method of claim 45, wherein the cancer stem cell is an embryonic cancer stem cell with germ tumor cell properties.

47. The method of any one of claims 41 to 46, wherein contacting is via administration to a mammal.

48. The method of claim 47, wherein the mammal has been diagnosed with a need for treatment of cancer prior to the administering step.

49. The method of any one of claims 41 to 48, wherein the compound exhibits an IC50of less than about 40 mM.

50. The method of any one of claims 41 to 48, wherein the compound exhibits an IC50of less than about 30 mM.

51. A method of inhibiting lysine-specific demethylase I (LSD1) in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.

52. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective amount of the compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.Attorney Docket No.37474.0110P1 53. The method of claim 52, wherein the cancer comprises cells expressing at least one Sox2 stem cell marker.

54. The method of claim 52 or claim 53, wherein the subject is a mammal.

55. The method of claim 52 or claim 53, wherein the subject is a human.

56. The method of any one of claims 52 to 55, wherein the subject has been diagnosed with a need for treatment of cancer prior to the administering step.

57. The method of any one of claims 52 to 56, further comprising the step of identifying a subject in need of treatment of cancer.

58. The method of any one of claims 52 to 57, wherein the cancer is selected from a lymphoma, sarcoma, and a carcinoma.

59. The method of claim 58, wherein the carcinoma is a squamous cell carcinoma.

60. The method of claim 52, wherein the cancer is characterized by the presence of Sox2.

61. The method of claim 60, wherein the cancer is selected from glioblastoma multiforme, breast cancer, lung cancer, skin cancer, neuroblastoma, leukemia, lymphoma, prostate cancer, glioma, bladder cancer, colon and rectal cancer, gastric cancer, liver cancer, germ cell tumor, endometrial cancer, cervical cancer, retinoblastoma, medulloblastoma, medulloepithelioma, bronchial cancer, brain cancer, mesothelioma, kidney cancer, pancreatic cancer, lip and oral cancer, laryngeal and pharyngeal cancer, melanoma, pituitary cancer, penile cancer, parathyroid cancer, thyroid cancer, pheochromocytoma and paraganglioma, thymoma and thymic carcinoma, plasma cell neoplasms, myeloproliferative disorders, islet cell tumor, small intestine cancer, transitional cell cancer, pleuropulmonary blastoma, gestational trophoblastic cancer, esophageal cancer, central nervous system cancer, head and neck cancer, endocrine cancer, cardiovascular cancer, rhabdomyosarcoma, soft tissue carcinomas, carcinomas of bone, cartilage, fat, vascular, neural, and hematopoietic tissues and AIDS-related cancers, and ovarian cancer.

62. The method of any one of claims 52 to 57, wherein the cancer is associated with gene amplification of Sox2.

63. The method of claim 62, wherein the gene amplification occurs at 3q22.33.Attorney Docket No.37474.0110P1 64. A kit comprising the compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent known to inhibit LSD1; (b) an agent known to inhibit HDAC1; (c) an anticancer agent; (d) instructions for detecting a cancer; and (e) instructions for treating a cancer.

65. The kit of claim 64, wherein the compound and the agent are co-formulated.

66. The kit of claim 64, wherein the compound and the agent are co-packaged.

67. The kit of claim 64, wherein the agent known to inhibit LSD1 is a monoamine oxidase inhibitor.

68. The kit of claim 67, wherein the monoamine oxidase inhibitor is selected from a MAO-A inhibitor and a MOA-B inhibitor.

69. The kit of claim 67, wherein the monoamine oxidase inhibitor is selected from pargyline and phenelzine.

70. The kit of claim 64, wherein the monoamine oxidase is a trans-2- phenylcyclopropylamine.

71. The kit of claim 70, wherein the trans-2-phenylcyclopropylamine is selected from tranylcypromine, 2-PCPA, parnate, tranylcypromine (TCP), S2101, and RN-1.Attorney Docket No.37474.0110P1 72. The kit of claim 64, wherein the anticancer agent is selected from: (a) a hormone therapy agent; (b) an alkylating agent; (c) an antineoplastic antimetabolite agent; (d) a mitotic inhibitor agent; and (e) an antineoplastic antibiotic agent.

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