WO2025199151A1 - Liants de céréblon à petites molécules qui induisent la dégradation de protéines (kdm4b, vcl) pertinentes pour le cancer - Google Patents

Liants de céréblon à petites molécules qui induisent la dégradation de protéines (kdm4b, vcl) pertinentes pour le cancer

Info

Publication number
WO2025199151A1
WO2025199151A1 PCT/US2025/020443 US2025020443W WO2025199151A1 WO 2025199151 A1 WO2025199151 A1 WO 2025199151A1 US 2025020443 W US2025020443 W US 2025020443W WO 2025199151 A1 WO2025199151 A1 WO 2025199151A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cancer
compound
alkoxy
alkenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/020443
Other languages
English (en)
Inventor
Zoran Rankovic
Gisele A. NISHIGUCHI
Kevin Mcgowan
Jun Yang
Qiong Wu
Henrik Daub
Bjoern SCHWALB
Martin STEGER
Uli OHMAYER
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Neosphere Biotechnologies GmbH
St Jude Childrens Research Hospital
Original Assignee
Neosphere Biotechnologies GmbH
St Jude Childrens Research Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Neosphere Biotechnologies GmbH, St Jude Childrens Research Hospital filed Critical Neosphere Biotechnologies GmbH
Publication of WO2025199151A1 publication Critical patent/WO2025199151A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • KDM4 a membrane-cytoskeletal protein
  • the term covers any treatment of a subject, including a mammal (e.g., a human), and includes: (i) preventing the disease from occurring in a subject that can be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e., arresting its development; or (iii) relieving the disease, i.e., causing regression of the disease.
  • the subject is a mammal such as a primate, and, in a further aspect, the subject is a human.
  • the term “diagnosed” means having been subjected to a physical examination by a person of skill, for example, a physician, and found to have a condition that can be diagnosed or treated by the compounds, compositions, or methods disclosed herein.
  • the terms “administering” and “administration” refer to any method of providing a pharmaceutical preparation to a subject.
  • compositions can contain such amounts or submultiples thereof 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. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. In further various aspects, a preparation can be administered in a “prophylactically effective amount”; that is, an amount effective for prevention of a disease or condition.
  • “dosage form” means a pharmacologically active material in a medium, carrier, vehicle, or device suitable for administration to a subject.
  • a dosage form can comprise a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, in combination with a pharmaceutically acceptable excipient, such as a preservative, buffer, saline, or phosphate buffered saline. Dosage forms can be made using conventional pharmaceutical manufacturing and compounding techniques.
  • Dosage forms can comprise inorganic or organic buffers (e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate) and pH adjustment agents (e.g., hydrochloric acid, sodium or potassium hydroxide, salts of citrate or acetate, amino acids and their salts) antioxidants (e.g., ascorbic acid, alpha-tocopherol), surfactants (e.g., polysorbate 20, polysorbate 80, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-
  • a dosage form formulated for injectable use can have a disclosed compound, a product of a disclosed method of making, or a salt, solvate, or polymorph thereof, suspended in sterile saline solution for injection together with a preservative.
  • kit means a collection of at least two components constituting the kit. Together, the components constitute a functional unit for a given purpose. Individual member components may be physically packaged together or separately. For example, a kit comprising an instruction for using the kit may or may not physically include the instruction with other individual member components. Instead, the instruction can be supplied as a separate member component, either in a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation.
  • instruction(s) means documents describing relevant materials or methodologies pertaining to a kit. These materials may include any combination of the following: background information, list of components and their availability information (purchase information, etc.), brief or detailed protocols for using the kit, trouble-shooting, references, technical support, and any other related documents. Instructions can be supplied with the kit or as a separate member component, either as a paper form or an electronic form which may be supplied on computer readable memory device or downloaded from an internet website, or as recorded presentation. Instructions can comprise one or multiple documents, and are meant to include future updates.
  • therapeutic agent include any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro- drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • 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.
  • aqueous and nonaqueous carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides).
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which
  • Suitable inert carriers can include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more -OCH2CH2O- units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more -CO(CH2)8CO- moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • 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, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen
  • the heteroatoms 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.
  • 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.
  • substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” 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.
  • 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.
  • 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 branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, 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.
  • 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.
  • C1-C4 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, and t-butyl.
  • 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.
  • 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.
  • the term “monohaloalkyl” specifically refers to an alkyl group that is substituted with a single halide, e.g. fluorine, chlorine, bromine, or iodine.
  • 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.
  • alkoxyalkyl specifically refers to an alkyl group that is substituted with one or more alkoxy groups, as described below.
  • aminoalkyl specifically refers to an alkyl group that is substituted with one or more amino groups.
  • hydroxyalkyl specifically refers to an alkyl group that is substituted with one or more hydroxy groups.
  • 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. This practice is also used for other groups described herein.
  • 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.”
  • 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.
  • cycloalkyl is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • cycloalkyl includes monocyclic rings as well as ring systems including more than one cyclic ring, e.g. bicyclic rings. In ring systems including more than one cyclic ring, the rings of the “cycloalkyl” may be fused rings, bridged rings, or spirocyclic rings.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, and the like.
  • 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 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, ⁇ NH2, (C1-C4) alkylamino, (C1-C4)(C1-C4) dialkylamino, ether, halogen, ⁇ OH, C1-C4 hydroxyalkyl, ⁇ NO2, silyl, sulfo-oxo, ⁇ SH, and C1-C4 thioalkyl, as described herein.
  • polyalkylene group as used herein is a group having two or more CH 2 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.
  • 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 —OA 1 where A 1 is 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 —OA 1 —OA 2 or — OA 1 —(OA 2 )a—OA 3 , where “a” is an integer of from 1 to 200 and A 1 , A 2 , and A 3 are alkyl and/or cycloalkyl groups.
  • 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.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • 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 0, 1, 2, 3, or 4 groups independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, C2-C4 alkenyl, C3-C6 cycloalkenyl, C2-C4 alkynyl, aryl, heteroaryl, aldeyhyde, ⁇ NH2, (C1-C4) alkylamino, (C1- C4)(C1-C4) dialkylamino, carboxylic acid, ester, ether, halogen, ⁇ OH, C1-C4 hydroxyalkyl, ketone, azide, ⁇ NO 2 , silyl, sulfo-oxo, ⁇ SH, and C1-C4 thioalkyl, as described herein.
  • 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.
  • 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.
  • cycloalkynyl groups include, but are not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and the like.
  • 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.
  • aromatic group refers to a ring structure having cyclic clouds of delocalized ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477- 497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • 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, ⁇ NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasryl is a specific type of aryl group and is included in the definition of “aryl.”
  • 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.
  • 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.
  • C6-C10 aryl for example includes phenyl and naphthyl.
  • aldehyde as used herein is represented by the formula —C(O)H.
  • amine or “amino” as used herein are represented by the formula —NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is ⁇ NH 2 .
  • alkylamino as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein.
  • ether as used herein is represented by the formula A 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula —(A 1 O-A 2 O)a—, where A 1 and A 2 can 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.
  • 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, 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.
  • 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.
  • 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-triazo
  • 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.
  • 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.
  • 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.
  • a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.
  • 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.
  • heterocycloalkyl 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.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • hydroxy or “hydroxyl” as used herein is represented by the formula —OH.
  • ketone as used herein is represented by the formula A 1 C(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • Azide or “azido” as used herein is represented by the formula —N3.
  • nitro as used herein is represented by the formula —NO 2 .
  • nitrile or “cyano” as used herein is represented by the formula —CN or — C ⁇ N.
  • sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula —S(O)2A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 S(O) 2 A 2 is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula —SH.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is 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.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • an alkyl group comprising an amino group the amino group can be incorporated within the backbone of the alkyl group.
  • 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.
  • compounds of the invention may contain “optionally substituted” moieties.
  • 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.
  • 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 those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (i.e., further substituted or unsubstituted).
  • Suitable monovalent substituents on R° are independently halogen, — (CH 2 ) 0–2 R ⁇ , –(haloR ⁇ ), –(CH 2 ) 0–2 OH, –(CH 2 ) 0–2 OR ⁇ , –(CH 2 ) 0–2 CH(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, –(CH 2 ) 0–2 NH 2 , –(CH 2 ) 0–2 NHR ⁇ , –(CH 2 ) 0–2 NR
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: –O(CR * 2 ) 2–3 O–, 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 substituents on the aliphatic group of R * include halogen, –R ⁇ , -(haloR ⁇ ), -OH, – OR ⁇ , –O(haloR ⁇ ), –CN, –C(O)OH, –C(O)OR ⁇ , –NH 2 , –NHR ⁇ , –NR ⁇ 2, or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1–4 aliphat –CH 2 Ph, –O(CH 2 ) 0–1 Ph, or a 5–6–membered saturated, partially unsaturated, or aryl ring having 0–4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • 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)CH 2 C(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, C 1–6 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
  • 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, or –NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently 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.
  • 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.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • hydrolysable group and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues examples 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • a 2,4- thiazolidinedione radical in a particular compound has the structure: regardless of whether thiazolidinedione is used to prepare the compound.
  • the radical for example an alkyl
  • the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
  • Organic radicals 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.
  • 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.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • 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.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • 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.
  • 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.
  • stereoisomers 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 (*).
  • 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.
  • bonds to the chiral carbon 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.
  • 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.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, 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 as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 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.
  • the compounds described in the invention can be present as a solvate.
  • 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.
  • a hydrate which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • the invention includes all such possible solvates.
  • 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.
  • the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates, see e.g.
  • pyrazoles can exist in two tautomeric forms, N 1 - unsubstituted, 3-A 3 and N 1 -unsubstituted, 5-A 3 as shown below.
  • the invention includes all such possible tautomers.
  • 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.
  • a structure of a compound can be represented by a formula: , which is understood to be equivalent to a formula: wherein n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) is halogen, then R n(b) is not necessarily halogen in that instance.
  • 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.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • 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.
  • the invention relates to compounds having a structure represented by a formula: , wherein m is selected from 0 and 1; wherein A is selected from ⁇ SO2 ⁇ and ⁇ C(O) ⁇ ; and wherein Cy 1 is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C10 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, C1-C
  • the invention relates to compounds capable of inducing the degradation of proteins (e.g., KDM4B, VCL) relevant to the treatment of various cancers (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, plasma cell neoplasm (myeloma)).
  • cancers 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
  • the compounds of the invention by way of inducing an altered specificity of an E3 ubiquitin ligase (e.g., cereblon) towards target cancer-associated proteins, such as KDM4 and VCL, are able to induce proteasome-mediated degradation of these proteins in a directed fashion via their recruitment to the E3 ubiquitin ligase and subsequent ubiquitination. Accordingly, the reduction of target cancer-associated protein levels is believed to be mainly attributable to a direct proteasome- mediated degradation of these proteins and not due to secondary changes in gene expression caused by changes in the level and/or activity of regulatory protein substrates of the E3 ubiquitin ligase.
  • E3 ubiquitin ligase e.g., cereblon
  • each disclosed derivative can be optionally further substituted. It is also contemplated that any one or more derivative can be optionally omitted 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 In one aspect, disclosed are compounds having a structure represented by a formula: wherein m is selected from 0 and 1; wherein A is selected from ⁇ SO2 ⁇ and ⁇ C(O) ⁇ ; and wherein Cy 1 is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-
  • the compound has a structure represented by a formula: , wherein Cy 1 is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C10 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl)
  • the compound has a structure represented by a formula: wherein each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen,
  • the compound has a structure represented by a formula: wherein each of R 20a , R 20b , R 20c , and R 20e is independently selected from hydrogen, 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , and R 20e is hydrogen, wherein R 10 is selected from hydrogen and C
  • the compound has a structure represented by a formula: wherein Z 1 is selected from ⁇ O ⁇ , ⁇ S ⁇ , and ⁇ N(R 30 ) ⁇ ; wherein R 30 is selected from hydrogen and C1-C4 alkyl; wherein each of R 21a , R 21b , and R 21c is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl),
  • the compound has a structure represented by a formula: wherein Z 1 is selected from ⁇ O ⁇ , ⁇ S ⁇ , and ⁇ N(R 30 ) ⁇ ; wherein R 30 is selected from hydrogen and C1-C4 alkyl; wherein R 21a is selected from hydrogen, halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , and is substituted with 0, 1, 2,
  • the compound has a structure represented by a formula: wherein Z 2 is selected from ⁇ O ⁇ , ⁇ S ⁇ , and ⁇ N(R 32 ) ⁇ ; wherein R 32 is selected from hydrogen and C1-C4 alkyl; and wherein R 22b is selected from hydrogen, 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , wherein R 10 is selected from hydrogen and
  • the compound is selected from: or a pharmaceutically acceptable salt thereof. In various aspects, the compound is selected from: or a pharmaceutically acceptable salt thereof. In various aspects, the compound is selected from: or a pharmaceutically acceptable salt thereof. In various aspects, m is selected from 0 and 1. In a further aspect, m is 0. In a still further aspect, m is 1. a. A GROUP In one aspect, A is selected from ⁇ SO 2 ⁇ and ⁇ C(O) ⁇ . In a further aspect, A is ⁇ SO 2 ⁇ . In a yet further aspect, A is ⁇ C(O) ⁇ . b. Z 1 GROUPS In one aspect, Z 1 is selected from ⁇ O ⁇ , ⁇ S ⁇ , and ⁇ N(R 30 ) ⁇ .
  • Z 1 is selected from ⁇ O ⁇ and ⁇ S ⁇ . In a still further aspect, Z 1 is selected from ⁇ O ⁇ and ⁇ N(R 30 ) ⁇ . In a yet further aspect, Z 1 is selected from ⁇ S ⁇ and ⁇ N(R 30 ) ⁇ . In an even further aspect, Z 1 is ⁇ O ⁇ . In an even still further aspect, Z 1 is ⁇ S ⁇ . In an even yet further aspect, Z 1 is ⁇ N(R 30 ) ⁇ . c. Z 2 GROUPS In one aspect, Z 2 is selected from ⁇ O ⁇ , ⁇ S ⁇ , and ⁇ N(R 32 ) ⁇ . In a further aspect, Z 2 is selected from ⁇ O ⁇ and ⁇ N(R 32 ) ⁇ .
  • R 10 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, R 10 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 10 is selected from hydrogen and ethyl. In yet a further aspect, R 10 is selected from hydrogen and methyl. In various aspects, R 10 is C1-C4 alkyl. In a further aspect, R 10 is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R 10 is selected from methyl and ethyl. In a still further aspect, R 10 is ethyl. In yet a further aspect, R 10 is methyl.
  • R 10 is hydrogen. f. R 20A , R 20B , R 20C , R 20D , AND R 20E GROUPS
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , provided that at least two of
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, methyl, ethyl, n-propyl, i- propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, – CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, – CH(CH 3 )CH 2 OH,
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, ethyl, ethenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH,– CH 2 CH 2 OH, –OCH 2 F, –OCHF 2 , –OCF 3 , –OCH 2 Cl, –OCHCl 2 , –OCCl 3 , –OCH 2 CH 2 F, – OCH2CH2Cl, –OCH3, –OCH2CH3, —NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH 3 )(CH 2
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO2, methyl, –CH2F, –CH2Cl, –CH2CN, –CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, – OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, –N(CH3)2, –NHCH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO 2 Me, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1- C4 alkyl), and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 C(O)Pr, ⁇ NR 10 CO 2 Me, ⁇ NR 10 CO 2 Et, ⁇ NR 10 CO 2 Pr, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, ⁇ Cl, methyl, ethyl, ethenyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO 2 Me, ⁇ NR 10 CO2Et, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, methyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO 2 Me, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy, and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH3)CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, – OCH 2 CH 2 Cl, –OCH 2 CH 2 CH 2 F, –OCH 2 CH 2 CH 2 Cl, –OCH(CH 3 )CH 2 F, –OCH(CH 3 )CH 2 Cl, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, ⁇ Cl, –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –OCH 2 F, – OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ F, –CH2F, –CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ CN, C1-C4 cyanoalkyl, and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ CN, –CH 2 CN,–CH 2 CH 2 CN, –CH 2 CH 2 CH 2 CN, – CH(CH3)CH2CN, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ CN, –CH 2 CN,–CH 2 CH 2 CN, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ CN, –CH 2 CN, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ OH, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ OH, –CH2OH,–CH2CH2OH, – CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 CH 3 , –OCH(CH 3 )CH 3 , and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ OH, –CH 2 OH,–CH 2 CH 2 OH, –OCH 3 , –OCH 2 CH 3 , and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ OH, –CH 2 OH, –OCH 3 , and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ NH 2 , C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ NH2, –NHCH3, –NHCH2CH3, – NHCH 2 CH 2 CH 3 , —NHCH(CH 3 )CH 3 , –N(CH 3 ) 2 , –N(CH 2 CH 3 ) 2 , –N(CH 2 CH 2 CH 3 ) 2 , – N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, – N(CH(CH3)CH3)2, and —N(CH3)(CH2CH3), —NHCH3, –NHCH2CH3, –NHCH2CH2CH3, – NHCH(CH3)CH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 C(O)Pr
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ NH 2 , –NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 ) 2 , – N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –NHCH3, –NHCH2CH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO 2 Me, ⁇ NR 10 CO 2 Et, and Cy 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, ⁇ NH2, – NHCH 3 , –N(CH 3 ) 2 , –N(CH 3 ) 2 , –NHCH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 CO 2 Me, and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5- membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5-membered heterocycle, a 6-membered aryl, or a 6-membered 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5- membered cycle, a 5-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and is substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl),
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5- membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and is substituted with 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5-membered heterocycle, a 6-membered aryl, or a 6- membered heteroaryl, and is unsubstituted.
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle substituted with 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle and is unsubstituted.
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1- C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 5-membered unsubstituted heterocycle.
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl.
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1- C4 alkyl), and Cy 2 .
  • any adjacent two of R 20a , R 20b , R 20c , R 20d , and R 20e is covalently bonded and, together with the intermediate atoms, comprise a 6-membered unsubstituted heteroaryl.
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 , or wherein any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atom
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, – CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,–CH2CH2CN, – CH 2 CH 2 CH 2 CN, –CH(CH 3 )CH 2 CN, –CH 2 OH,–CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, – CH(CH3)CH2OH, –OCH2F,
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, methyl, ethyl, ethenyl, –CH2F, – CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH,–CH2CH2OH, –OCH2F, – OCHF 2 , –OCF 3 , –OCH 2 Cl, –OCHCl 2 , –OCCl 3 , –OCH 2 CH 2 F, –OCH 2 CH 2 Cl, –OCH 3 , – OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), – N(CH 3 ) 2 ,
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, –CH 2 F, – CH2Cl, –CH2CN, –CH2OH, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, – OCH 3 , –NHCH 3 , –N(CH 3 ) 2 , –N(CH 3 ) 2 , –NHCH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 CO 2 Me, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, , ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 C(O)Pr, ⁇ NR 10 CO2Me, ⁇ NR 10 CO2Et, ⁇ NR 10 CO2Pr, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, ⁇ Cl, methyl, ethyl, ethenyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO2Me, ⁇ NR 10 CO 2 Et, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, methyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO2Me, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy.
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, –CH2F, –CH2Cl, –CH2CH2F, – CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl, –CH(CH 3 )CH 2 F, –CH(CH 3 )CH 2 Cl, –OCH 2 F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, – OCH 2 CH 2 CH 2 F, –OCH 2 CH 2 CH 2 Cl, –OCH(CH 3 ).
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, ⁇ Cl, –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, —OCH 2 F, –OCHF 2 , –OCF 3 , –OCH 2 Cl, – OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ F, –CH 2 F, –CH 2 Cl, –OCH 2 F, – OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ CN, C1-C4 cyanoalkyl, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ CN, ⁇ CH 2 CN,–CH 2 CH 2 CN, –CH 2 CH 2 CH 2 CN, – CH(CH3)CH2CN, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ CN, –CH2CN,–CH2CH2CN, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ CN, – CH2CN, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ OH, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ OH, –CH 2 OH,–CH 2 CH 2 OH, – CH2CH2CH2OH, –CH(CH3)CH2OH, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ OH, –CH2OH,–CH2CH2OH, –OCH3, –OCH2CH3, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ OH, –CH 2 OH, –OCH3, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1- C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ NH2, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, —NHCH(CH 3 )CH 3 , –N(CH 3 ) 2 , –N(CH 2 CH 3 ) 2 , –N(CH 2 CH 2 CH 3 ) 2 , –N(CH(CH 3 )CH 3 ) 2 , – N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, and — N(CH 3 )(CH 2 CH 3 ), —NHCH 3 , –NHCH 2 CH 3 , –NHCH 2 CH 2 CH 3 , –NHCH(CH 3 )CH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ NH 2 , –NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 ) 2 , –N(CH 2 CH 3 ) 2 , –N(CH 3 )(CH 2 CH 3 ), – N(CH3)2, –N(CH2CH3)2, –NHCH3, –NHCH2CH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO 2 Me, ⁇ NR 10 CO 2 Et, and Cy 2 .
  • each of R 21a , R 21b , and R 21c is independently selected from hydrogen, ⁇ NH2, –NHCH3, –N(CH3)2, –N(CH3)2, –NHCH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO 2 Me, and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5-membered heterocycle, a 6-membered aryl, or a 6- membered 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5- membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and is substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and is substituted with 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alky
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle, a 5-membered heterocycle, a 6-membered aryl, or a 6-membered heteroaryl, and is unsubstituted.
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered cycle substituted with 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 5- membered cycle.
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5- membered heterocycle substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 5-membered heterocycle substituted with 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 5-membered heterocycle.
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6- membered aryl.
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6- membered heteroaryl substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • any adjacent two of R 21a , R 21b , and R 21c is covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6-membered heteroaryl.
  • R 22A , R 22B , AND R 33 GROUPS in one aspect, each of R 22a and R 22b is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10
  • each of R 22a and R 22b is independently selected from hydrogen, 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 , and R 33 is selected from hydrogen and C1-C4 alkyl.
  • each of R 22a and R 22b is independently selected from hydrogen, halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, – CH 2 CH 2 CH 2 Cl, —CH(CH 3 )CH 2 F, –CH(CH 3 )CH 2 Cl, –CH 2 CN,–CH 2 CH 2 CN, – CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH,–CH2CH2OH, –CH2CH2CH2OH, – CH(CH 3 )CH 2 OH, –OCH 2 F, –
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, methyl, ethyl, ethenyl, –CH2F, – CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CN,–CH 2 CH 2 CN, –CH 2 OH,–CH 2 CH 2 OH, –OCH 2 F, – OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH2CH2F, –OCH2CH2Cl, –OCH3, — OCH 2 CH 3 , —NHCH 3 , –NHCH 2 CH 3 , –N(CH 3 ) 2 , –N(CH 2 CH 3 ) 2 , –N(CH 3 )(CH 2 CH 3 ), – N(CH3)2,
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, methyl, –CH2F, – CH 2 Cl, –CH 2 CN, –CH 2 OH, –OCH 2 F, –OCHF 2 , –OCF 3 , –OCH 2 Cl, –OCHCl 2 , –OCCl 3 , – OCH3, –NHCH3, –N(CH3)2, –N(CH3)2, –NHCH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO2Me, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, , ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 C(O)Pr, ⁇ NR 10 CO2Me, ⁇ NR 10 CO2Et, ⁇ NR 10 CO2Pr, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, ⁇ Cl, methyl, ethyl, ethenyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO2Me, ⁇ NR 10 CO2Et, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, methyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO2Me, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy.
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, –CH 2 F, –CH 2 Cl, –CH 2 CH 2 F, – CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –OCH2F, –OCHF 2 , –OCF 3 , –OCH 2 Cl, –OCHCl 2 , –OCCl 3 , –OCH 2 CH 2 F, –OCH 2 CH 2 Cl, – OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH(CH3)CH2F,
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, ⁇ Cl, – CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, – OCCl 3 , –OCH 2 CH 2 F, –OCH 2 CH 2 Cl, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ F, –CH2F, –CH2Cl, –OCH2F, –OCHF2, –OCF3, – OCH 2 Cl, –OCHCl 2 , –OCCl 3 , and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ CN, C1-C4 cyanoalkyl, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ CN, –CH 2 CN,–CH 2 CH 2 CN, –CH 2 CH 2 CH 2 CN, –CH(CH 3 )CH 2 CN, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ CN, –CH 2 CN,–CH 2 CH 2 CN, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ CN, –CH2CN, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ OH, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ OH, –CH 2 OH,–CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, – CH(CH3)CH2OH, –OCH3, –OCH2CH3, –OCH2CH2CH3, –OCH(CH3)CH3, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ OH, – CH2OH,–CH2CH2OH, –OCH3, –OCH2CH3, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ OH, –CH 2 OH, –OCH 3 , and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ NH2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ NH2, –NHCH3, –NHCH2CH3, –NHCH2CH2CH3, – NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, – N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, –N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, and — N(CH 3 )(CH 2 CH 3 ), —NHCH 3 , –NHCH 2 CH 3 , –NHCH 2 CH 2 CH 3 , –NHCH(CH 3 )CH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 C(O)Pr, ⁇ NR 10 CO2Me, ⁇ NR 10 CO2Et, ⁇ NR
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ NH2, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, – N(CH 2 CH 3 ) 2 , –NHCH 3 , –NHCH 2 CH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO 2 Me, ⁇ NR 10 CO2Et, and Cy 2 .
  • each of R 22a and R 22b is independently selected from hydrogen, ⁇ NH 2 , –NHCH 3 , –N(CH 3 ) 2 , –N(CH 3 ) 2 , –NHCH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 CO2Me, and Cy 2 .
  • R 33 is selected from hydrogen and C1-C4 alkyl.
  • R 32 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl.
  • R 33 is selected from hydrogen, methyl, and ethyl.
  • R 33 is selected from hydrogen and ethyl.
  • R 33 is selected from hydrogen and methyl. In various aspects, R 33 is C1-C4 alkyl. In a further aspect, R 33 is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R 33 is selected from methyl and ethyl. In a still further aspect, R 33 is ethyl. In yet a further aspect, R 33 is methyl. In various aspects, R 33 is hydrogen.
  • R 22b is 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 , and R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl or a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH
  • R 22b is selected from hydrogen, 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, methyl, ethyl, n- propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, –CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, –CH(CH3)CH2Cl, –CH2CN,– CH2CH2CN, –CH2CH2CH2CN, –CH(CH3)CH2CN, –CH2OH,–CH2CH2OH, – CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, –OCH 2 F, –OCHF 2 , –OCF 3 , –CH 2 ,
  • R 22b is selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, ethyl, ethenyl, – CH2F, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CN,–CH2CH2CN, –CH2OH,–CH2CH2OH, – OCH 2 F, –OCHF 2 , –OCF 3 , –OCH 2 Cl, –OCHCl 2 , –OCCl 3 , –OCH 2 CH 2 F, –OCH 2 CH 2 Cl, – OCH3, –OCH2CH3, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, –N(CH3)(CH2CH3), –N(CH3)(CH2CH3), – N(CH 3 ) 2 , –N(CH 2 CH 3
  • R 22b is selected from hydrogen, ⁇ F, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , methyl, –CH 2 F, –CH 2 Cl, –CH 2 CN, –CH 2 OH, –OCH 2 F, – OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, –OCH3, –NHCH3, –N(CH3)2, –N(CH3)2, – NHCH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO2Me, and Cy 2 .
  • R 22b is selected from hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, methyl, ethyl, n-propyl, i-propyl, ethenyl, n-propenyl, i-propenyl, , ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 C(O)Pr, ⁇ NR 10 CO 2 Me, ⁇ NR 10 CO 2 Et, ⁇ NR 10 CO2Pr, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ F, ⁇ Cl, methyl, ethyl, ethenyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO 2 Me, ⁇ NR 10 CO 2 Et, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ F, methyl, ⁇ NR 10 C(O)Me, ⁇ NR 10 CO 2 Me, and Cy 2 .
  • R 22b is selected from hydrogen, halogen, C1-C4 haloalkyl, C1-C4 haloalkoxy.
  • R 22b is selected from hydrogen, ⁇ F, ⁇ Cl, ⁇ Br, –CH 2 F, – CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl, –CH(CH3)CH2F, – CH(CH 3 )CH 2 Cl, –OCH 2 F, –OCHF 2 , –OCF 3 , –OCH 2 Cl, –OCHCl 2 , –OCCl 3 , –OCH 2 CH 2 F, – OCH2CH2Cl, –OCH2CH2CH2F, –OCH2CH2CH2Cl, –OCH(CH3)CH2F, –OCH(CH3)CH2Cl, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ F, ⁇ Cl, –CH2F, –CH2Cl, – CH2CH2F, –CH2CH2Cl, –OCH2F, –OCHF2, –OCF3, –OCH2Cl, –OCHCl2, –OCCl3, – OCH2CH2F, –OCH2CH2Cl, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ F, –CH 2 F, –CH 2 Cl, –OCH 2 F, –OCHF 2 , –OCF 3 , –OCH 2 Cl, –OCHCl 2 , –OCCl 3 , and Cy 2 .
  • R 22b is selected selected from hydrogen, ⁇ CN, C1-C4 cyanoalkyl, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ CN, –CH 2 CN,–CH 2 CH 2 CN, – CH2CH2CH2CN, –CH(CH3)CH2CN, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ CN, –CH 2 CN,–CH 2 CH 2 CN, and Cy 2 . In a yet further aspect, R 22b is selected from hydrogen, ⁇ CN, –CH2CN, and Cy 2 . In various aspects, R 22b is selected from hydrogen, ⁇ OH, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ OH, –CH2OH,– CH 2 CH 2 OH, –CH 2 CH 2 CH 2 OH, –CH(CH 3 )CH 2 OH, –OCH 3 , –OCH 2 CH 3 , –OCH 2 CH 2 CH 3 , – OCH(CH3)CH3, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ OH, – CH 2 OH,–CH 2 CH 2 OH, –OCH 3 , –OCH 2 CH 3 , and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ OH, –CH2OH, –OCH3, and Cy 2 .
  • R 22b is selected from hydrogen, ⁇ NH 2 , C1-C4 alkylamino, (C1- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22b is selected selected from hydrogen, ⁇ NH 2 , –NHCH 3 , –NHCH2CH3, –NHCH2CH2CH3, –NHCH(CH3)CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH2CH2CH3)2, –N(CH(CH3)CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH3)(CH2CH3), –N(CH3)2, –N(CH2CH3)2, – N(CH 2 CH 2 CH 3 ) 2 , –N(CH(CH 3 )CH 3 ) 2 , and —N(CH 3 )(CH 2 CH 3 ), —NHCH 3 , –NHCH 2 CH 3 , – NHCH2CH2CH3, –NHCH(CH3)CH3, ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 C(O)Pr, ⁇ NR 10 CO
  • R 22b is selected from hydrogen, ⁇ NH2, –NHCH3, –NHCH2CH3, –N(CH3)2, –N(CH2CH3)2, – N(CH 3 )(CH 2 CH 3 ), –N(CH 3 ) 2 , –N(CH 2 CH 3 ) 2 , –NHCH 3 , –NHCH 2 CH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 C(O)Et, ⁇ NR 10 CO2Me, ⁇ NR 10 CO2Et, and Cy 2 .
  • R 22b is selected selected from hydrogen, ⁇ NH 2 , –NHCH 3 , –N(CH 3 ) 2 , –N(CH 3 ) 2 , –NHCH 3 , ⁇ NR 10 C(O)Me, ⁇ NR 10 CO2Me, and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl or a 6-membered heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6- membered aryl or a 6-membered 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl or a 6- membered heteroaryl, and is substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl or a 6-membered heteroaryl, and is substituted with 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6- membered aryl or a 6-membered heteroaryl, and is unsubstituted.
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl, ⁇ NR 10 C
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 0 or 1 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered aryl substituted with 1 group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6-membered aryl.
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C1-C
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1- C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise a 6-membered heteroaryl substituted with 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • R 22a and R 33 are covalently bonded and, together with the intermediate atoms, comprise an unsubstituted 6-membered heteroaryl.
  • R 30 GROUPS In one aspect, R 30 is selected from hydrogen and C1-C4 alkyl. In a further aspect, R 30 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, R 30 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 30 is selected from hydrogen and ethyl. In yet a further aspect, R 30 is selected from hydrogen and methyl. In various aspects, R 30 is C1-C4 alkyl.
  • R 30 is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R 30 is selected from methyl and ethyl. In a still further aspect, R 30 is ethyl. In yet a further aspect, R 30 is methyl. In various aspects, R 30 is hydrogen. j. R 32 GROUPS In one aspect, R 32 is selected from hydrogen and C1-C4 alkyl. In a further aspect, R 32 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl. In a further aspect, R 32 is selected from hydrogen, methyl, and ethyl.
  • R 32 is selected from hydrogen and ethyl. In yet a further aspect, R 32 is selected from hydrogen and methyl. In various aspects, R 32 is C1-C4 alkyl. In a further aspect, R 32 is selected from methyl, ethyl, propyl, and isopropyl. In a further aspect, R 32 is selected from methyl and ethyl. In a still further aspect, R 32 is ethyl. In yet a further aspect, R 32 is methyl. In various aspects, R 32 is hydrogen. k.
  • Cy 1 is selected from a C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6- C10 aryl, and C2-C10 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from a C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from a C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C10 heteroaryl, and is substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from a C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C10 heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from a C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C6-C10 aryl, and C2-C10 heteroaryl, and is unsubstituted.
  • Cy 1 is selected from a C3-C10 cycloalkyl and a C2-C9 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C
  • Cy 1 is selected from a C3-C10 cycloalkyl and a C2-C9 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from a C3-C10 cycloalkyl and aC2- C9 heterocycloalkyl, and is substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from a C3-C10 cycloalkyl and a C2- C9 heterocycloalkyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from a C3-C10 cycloalkyl and a C2-C9 heterocycloalkyl, and is unsubstituted.
  • Cy 1 is a C3-C10 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C3-C10 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C3-C10 cycloalkyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C3-C10 cycloalkyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is an unsubstituted C3-C10 cycloalkyl.
  • Cy 1 is a C2-C9 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C2-C9 heterocycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C2-C9 heterocycloalkyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C2-C9 heterocycloalkyl monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • Cy 1 is an unsubstituted C2-C9 heterocycloalkyl.
  • Cy 1 is a 2,3-dihydrobenzo[b][1,4]dioxinyl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a 2,3- dihydrobenzo[b][1,4]dioxinyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a 2,3-dihydrobenzo[b][1,4]dioxinyl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a 2,3-dihydrobenzo[b][1,4]dioxinyl monosubstituted with a 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • halogen ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C
  • Cy 1 is an unsubstituted 2,3-dihydrobenzo[b][1,4]dioxinyl.
  • Cy 1 is selected from C6-C10 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from C6-C10 aryl and C2-C10 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from C6-C10 aryl and C2-C10 heteroaryl, and is substituted with 0 or 1 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from C6-C10 aryl and C2-C10 heteroaryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is selected from C6-C10 aryl and C2-C10 heteroaryl, and is unsubstituted.
  • Cy 1 is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C6-C10 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C6-C10 aryl substituted with 0 or 1 group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C6-C10 aryl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • Cy 1 is an unsubstituted C6-C10 aryl.
  • Cy 1 is a phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a phenyl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a phenyl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is phenyl, and is monosubstituted with a group selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • halogen ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl
  • Cy 1 is an unsubstituted C6-C10 aryl.
  • Cy 1 is a C2-C10 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C2-C10 heteroaryl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C2-C10 heteroaryl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • Cy 1 is a C2-C10 heteroaryl monosubstituted with a 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • halogen ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4
  • Cy 1 is an unsubstituted C2-C10 heteroaryl. l.
  • Cy 2 is selected from a C3-C6 cycloalkyl, a C2-C5 heterocycloalkyl, 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.
  • Cy 2 is 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, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is 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, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is 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- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 2 is selected from a C3-C6 cycloalkyl, a C2-C5 heterocycloalkyl, a C6 aryl, and a C2-C5 heteroaryl, and is unsubstituted.
  • Cy 2 is 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.
  • Cy 2 is selected from a C3-C6 cycloalkyl and 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.
  • Cy 2 is 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.
  • halogen ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1
  • Cy 2 is 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.
  • Cy 2 is selected from a C3- C6 cycloalkyl and a C2-C5 heterocycloalkyl, and is unsubstituted.
  • Cy 2 is a C3-C6 cycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is a C3-C6 cycloalkyl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is 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-C4 hydroxyalkyl, C1- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 2 is a C3-C6 cycloalkyl monosubstituted with a group independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is an unsubstituted C3-C6 cycloalkyl.
  • Cy 2 is 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.
  • C2- C5 heterocycloalkyls include, but are not limited to, thiirane, oxirane, aziridine, thietane, azetidine, oxetane, pyrrolidine, imidazolidine, tetrahydrothiophene, tetrahydrofuran, piperidine, piperazine, thiane, and morpholine.
  • Cy 2 is a C2-C5 heterocycloalkyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is 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.
  • Cy 2 is a C2-C5 heterocycloalkyl monosubstituted with a group independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is an unsubstituted C2-C5 heterocycloalkyl.
  • Cy 2 is 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, ⁇ NO 2 , 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.
  • Cy 2 is selected from a C6 aryl and a C2-C5 heteroaryl, and is substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is selected from 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.
  • halogen ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy
  • Cy 2 is 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.
  • Cy 2 is selected from a C6 aryl and a C2-C5 heteroaryl, and is unsubstituted.
  • Cy 2 is a C6 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is a C6 aryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is 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.
  • Cy 2 is a C6 aryl monosubstituted with a group independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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.
  • Cy 2 is an unsubstituted C6 aryl.
  • Cy 2 is 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.
  • C2- C5 heteroaryls include, but are not limited to, thiophene, furan, pyrrole, oxazole, isoxazole, isothiazole, pyridine, pyrimidine, pyridazine.
  • Cy 2 is a C2-C5 heteroaryl substituted with 0, 1, or 2 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ 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.
  • Cy 2 is 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, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 2 is 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.
  • Cy 2 is an unsubstituted C2-C5 heteroaryl.
  • m is 0 and A is ⁇ SO2 ⁇ .
  • m is 0, A is ⁇ SO 2 ⁇
  • Cy 1 is selected from a C3-C10 cycloalkyl and a C2-C9 heterocycloalkyl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2
  • m is 0,
  • A is ⁇ SO2 ⁇
  • Cy 1 is a C2-C9 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • m is 0,
  • A is ⁇ SO 2 ⁇
  • Cy 1 is a 2,3-dihydrobenzo[b][1,4]dioxinyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH2, ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • m is 0,
  • A is ⁇ SO 2 ⁇
  • Cy 1 is selected from a C6-C10 aryl and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • m is 0,
  • A is ⁇ SO2 ⁇
  • Cy 1 is a C6-C10 aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO2(C1-C4 alkyl), and Cy 2 .
  • m is 0,
  • A is ⁇ SO 2 ⁇
  • Cy 1 is phenyl 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, C1-C4 aminoalkyl, ⁇ NR 10 C(O)(C1-C4 alkyl), ⁇ NR 10 CO 2 (C1-C4 alkyl), and Cy 2 .
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof, wherein R 20a , R 20b , R 20c , R 20d , R 20e , Z 1 , R 21a , R 21b , R 21c , Z 2 , Z 2 , R 21a , and R 21b are as defined herein. 2.
  • a compound can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof.
  • a compound can be present as one or more of the following structures: or a pharmaceutically acceptable salt thereof. 3.
  • PROPHETIC EXAMPLE COMPOUNDS The following compound examples are prophetic, and can be prepared using the synthesis methods described herein below 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 capable of inducing the degradation of proteins (e.g., KDM4B, VCL) relevant to the treatment of various cancers as further detailed herein, and such activity can be determined using the assay methods described herein below.
  • a compound is: or a pharmaceutically acceptable salt thereof. It is contemplated that one or more compounds can optionally be omitted from the disclosed invention. It is understood that the disclosed compounds can be used in connection with the disclosed methods, compositions, kits, and uses.
  • pharmaceutical acceptable derivatives of the disclosed compounds can be used also in connection with the disclosed methods, compositions, kits, and uses.
  • the pharmaceutical acceptable derivatives of the compounds can include any suitable derivative, such as pharmaceutically acceptable salts as discussed below, isomers, radiolabeled analogs, tautomers, and the like.
  • C. METHODS OF MAKING A COMPOUND 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.
  • Reactions used to generate the compounds of this invention are prepared by employing reactions as shown in the following Reaction Schemes, as described and exemplified below.
  • the disclosed compounds can be prepared by Routes I-IV, 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 I In one aspect, the compounds disclosed herein can be prepared as shown below. SCHEME 1A.
  • compounds of type 1.8 can be prepared by a coupling reaction between an aryl halide, e.g., 1.6 as shown above, and an appropriate boronic acid or ester, e.g., 1.7 as shown above.
  • an aryl halide e.g., 1.6 as shown above
  • an appropriate boronic acid or ester e.g., 1.7 as shown above.
  • Appropriate aryl halides and appropriate boronic acids or esters are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate catalyst, e.g., bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane, and an appropriate base, e.g., potassium phosphate tribasic, in an appropriate solvent, e.g., dioxane/water, at an appropriate temperature, e.g., 110 °C, for an appropriate period of time, e.g., 12 hours.
  • an appropriate catalyst e.g., bis(diphenylphosphino)ferrocene]dichloropalladium(II)
  • dichloromethane e.g., dichloromethane
  • an appropriate base e.g., potassium phosphate tribasic
  • an appropriate solvent e.g., dioxane/water
  • the deprotection and reduction is carried out under hydrogen gas at an appropriate pressure, e.g., 0.5 Mpa, in the presences on an appropriate catalyst, e.g., palladium on carbon, in an appropriate solvent, e.g., tetrahydrofuran (THF) and isopropyl alcohol (IPA) (3:1), at an appropriate temperature, e.g., 50 °C, for an appropriate period of time, e.g., 12h.
  • an appropriate pressure e.g., 0.5 Mpa
  • an appropriate catalyst e.g., palladium on carbon
  • an appropriate solvent e.g., tetrahydrofuran (THF) and isopropyl alcohol (IPA) (3:1)
  • THF tetrahydrofuran
  • IPA isopropyl alcohol
  • Compounds of type 1.10 can be prepared by deprotection of an appropriate protected amine, e.g.1.9 as shown above.
  • the deprotection is carried out in the presence of an appropriate cleavage agent, e.g., hydrogen chloride, in an appropriate solvent, e.g., ethyl acetate, at an appropriate temperature, e.g., 25 °C, for an appropriate period of time, e.g., 2 hours.
  • an appropriate cleavage agent e.g., hydrogen chloride
  • an appropriate solvent e.g., ethyl acetate
  • compounds of type 2.6 can be prepared according to reaction Scheme 2B above.
  • compounds of type 2.6 can be prepared by coupling an appropriate amine, e.g., 2.4 as shown above, and an appropriate sulfonic chloride or acyl chloride, e.g., 2.5 as shown above.
  • Appropriate sulfonic chlorides or acyl chlorides are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate base, e.g., triethyl amine, in an appropriate solvent, e.g., dimethylformamide (DMF), at an appropriate temperature, e.g., room temperature, for an appropriate period of time, e.g., 18 hours.
  • an appropriate base e.g., triethyl amine
  • an appropriate solvent e.g., dimethylformamide (DMF)
  • an appropriate temperature e.g., room temperature
  • the coupling reaction is carried out in the presence of an appropriate catalyst, e.g., added methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy- 2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (BrettPhos Pd Gen 3), in the presence of an appropriate base, e.g., cesium carbonate, in an appropriate solvent, e.g., 1,4 dioxane, at an appropriate temperature, e.g., 105 °C, for an appropriate period of time, e.g., 18 hours.
  • an appropriate catalyst e.g., added methanesulfonato(2-dicyclohexylphosphino-3,6-dimethoxy- 2',4',6'-tri-i-propyl-1,1
  • compounds of type 4.6 can be prepared by coupling an appropriate aryl halide, e.g., 4.4 as shown above, and an appropriate amine, e.g., 4.5 as shown above.
  • Appropriate amines are commercially available or prepared by methods known to one skilled in the art.
  • the coupling reaction is carried out in the presence of an appropriate catalyst, e.g., (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulfonate (RuPhos Pd Gen 3), in the presence of an appropriate base, e.g., cesium carbonate, in an appropriate solvent, e.g., 1,4-dioxane, at an appropriate temperature, e.g., 105 °C, for an appropriate period of time, e.g., 18 hours.
  • an appropriate catalyst e.g., (2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′- biphenyl)]palladium(II) methanesulf
  • compositions comprising an effective amount of a disclosed compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising an effective amount of a compound having a structure represented by a formula: wherein m is selected from 0 and 1; wherein A is selected from ⁇ SO 2 ⁇ and ⁇ C(O) ⁇ ; and wherein Cy 1 is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C10 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) dialkylamin
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 or adjuvants.
  • 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.
  • 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.
  • the pharmaceutical carrier employed can be, for example, a solid, liquid, or gas.
  • solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid.
  • liquid carriers are sugar syrup, peanut oil, olive oil, and water.
  • gaseous carriers include carbon dioxide and nitrogen.
  • oral liquid preparations such as suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like
  • oral solid preparations such as powders, capsules and tablets.
  • tablets and capsules are the preferred oral dosage units whereby solid pharmaceutical carriers are employed.
  • tablets can be coated by standard aqueous or nonaqueous techniques
  • 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.
  • 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.
  • compositions 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.
  • 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.
  • compositions of the present invention suitable for injectable use include sterile aqueous solutions or dispersions.
  • the compositions can be in the form of sterile powders for the extemporaneous preparation of such sterile injectable solutions or dispersions.
  • 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.
  • 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.
  • 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.
  • 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.
  • additional carrier ingredients such as diluents, buffers, flavoring agents, binders, surface-active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like.
  • 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.
  • an effective amount is a therapeutically effective amount.
  • an effective amount is a prophylactically effective amount.
  • the pharmaceutical composition is administered to a mammal.
  • the mammal is a human.
  • the human is a patient.
  • the pharmaceutical composition is used for inducing the degradation of proteins (e.g., KDM4B, VCL) that are relevant to cancer.
  • the disclosed compounds and compositions can be useful in the treatment of a variety of different cancers including, but not limited to, 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).
  • 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
  • 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 DEGRADING A TARGET PROTEIN IN A CELL In one aspect, disclosed are methods of degrading a target protein (e.g., KDM4B, VCL) in a cell, the method comprising contacting the cell with an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.
  • a target protein e.g., KDM4B, VCL
  • the target protein is KDM4B or VCL.
  • the cell is mammalian. In a further aspect, the cell is human. In various aspects, the cell has been isolated from a mammal prior to the contacting step. In various aspects, the contacting is ex vivo. In various aspects, the contacting is in vitro. In various aspects, contacting is via administration to a mammal. In a further aspect, the mammal has been diagnosed with a need for degrading the target protein prior to the administering step. In a still further aspect, the mammal has been diagnosed with a need for treatment of a cancer related to activity of the target protein prior to the administering step. F.
  • a target protein e.g., KDM4B, VCL
  • the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.
  • the subject is a mammal. In a further aspect, the subject is a human. In various aspects, the subject has been diagnosed with a need for degrading the target protein prior to the administering step. In various aspects, the method further comprising identifying a subject in need of degradation of the target protein. G. METHODS OF TREATING A CANCER IN A SUBJECT In one aspect, disclosed are methods of treating a cancer in a subject, the method comprising administering to the subject an effective amount of a disclosed compound or a pharmaceutically acceptable salt thereof.
  • a cancer in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein m is selected from 0 and 1; wherein A is selected from ⁇ SO2 ⁇ and ⁇ C(O) ⁇ ; and wherein Cy 1 is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamin
  • the subject is a mammal. In a further aspect, the subject is a human. In various aspects, the subject has been diagnosed with a need for treatment of the cancer prior to the administering step. In various aspects, the method further comprising the step of identifying a subject in need of treatment of the cancer. In a further aspect, the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount. In a further aspect, the cancer is associated with activity of a protein selected from KDM4B and VCL.
  • the cancer is selected from 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).
  • the cancer is leukemia. H.
  • the compounds and pharmaceutical compositions of the invention are useful in inducing the degradation of proteins (e.g., KDM4B, VCL) relevant to cancer.
  • cancer include, but are not limited to, 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).
  • 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.
  • 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.
  • the subject 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)).
  • 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
  • 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 not 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.
  • 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.
  • 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.
  • the invention relates to a method for the manufacture of a medicament for inducing the degradation of proteins (e.g., KDM4B, VCL) relevant to 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. Also disclosed herein is the use of the disclosed compounds or a pharmaceutically acceptable salt thereof, together with a compound or agent known for inducing the degradation of proteins (e.g., KDM4B, VCL) relevant to cancer, in the manufacture of a medicament.
  • proteins e.g., KDM4B, VCL
  • 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.
  • chemotherapeutic agents include, but are not limited to, alkylating agents, antimetabolite agents, antineoplastic antibiotic agents, mitotic inhibitor agents, and mTor inhibitor agents.
  • the method for the manufacture of a medicament comprises combining a therapeutically effective amount of the disclosed compounds, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or diluent and/or with a compound known for treating cancer.
  • a method for the manufacture of a medicament for treating cancer 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.
  • a use relates to the manufacture of a medicament for inducing the degradation of proteins (e.g., KDM4B, VCL) relevant to cancer.
  • a use relates to the manufacture of a medicament for treating 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, plasma cell neoplasm (myeloma)).
  • cancer e.g., a sarcoma, a carcinoma, a hematological cancer, a solid tumor, breast cancer, cervical cancer,
  • the compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders associated with overexpression of KDM4B. Also provided are the uses of the disclosed compounds and products.
  • the invention relates to use of at least one disclosed compound, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the compound used is a product of a disclosed method of making.
  • 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.
  • the use relates to a process for preparing a pharmaceutical composition
  • 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.
  • the disclosed uses can be employed in connection with the disclosed compounds, products of disclosed methods of making, methods, compositions, and kits.
  • 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 KDM4B. 3.
  • kits comprising a disclosed compound, or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an agent known to treat a cancer; (b) instructions for administering the compound in connection with treating a cancer; and (c) instructions for treating a cancer.
  • kits comprising a compound having a structure represented by a formula: , wherein m is selected from 0 and 1; wherein A is selected from ⁇ SO2 ⁇ and ⁇ C(O) ⁇ ; and wherein Cy 1 is selected from a C3-C10 cycloalkyl, a C2-C9 heterocycloalkyl, a C6-C10 aryl, and a C2-C10 heteroaryl, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, ⁇ CN, ⁇ NH 2 , ⁇ OH, ⁇ NO 2 , 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
  • the agent known to treat a cancer is a chemotherapeutic agent.
  • the chemotherapeutic agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, and a mTor inhibitor agent.
  • the antineoplastic antibiotic agent is selected from doxorubicin, mitoxantrone, bleomycin, daunorubicin, dactinomycin, epirubicin, idarubicin, plicamycin, mitomycin, pentostatin, and valrubicin, or a pharmaceutically acceptable salt thereof.
  • the antimetabolite agent is selected from gemcitabine, 5- fluorouracil, capecitabine, hydroxyurea, mercaptopurine, pemetrexed, fludarabine, nelarabine, cladribine, clofarabine, cytarabine, decitabine, pralatrexate, floxuridine, methotrexate, and thioguanine, or a pharmaceutically acceptable salt thereof.
  • the alkylating agent is selected from carboplatin, cisplatin, cyclophosphamide, chlorambucil, melphalan, carmustine, busulfan, lomustine, dacarbazine, oxaliplatin, ifosfamide, mechlorethamine, temozolomide, thiotepa, bendamustine, and streptozocin, or a pharmaceutically acceptable salt thereof.
  • the mitotic inhibitor agent is selected from irinotecan, topotecan, rubitecan, cabazitaxel, docetaxel, paclitaxel, etopside, vincristine, ixabepilone, vinorelbine, vinblastine, and teniposide, or a pharmaceutically acceptable salt thereof.
  • mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the compound and the agent known to treat cancer are co-packaged.
  • 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.
  • 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.
  • 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.
  • each dose of the compound and the agent are co-packaged.
  • each dose of the compound and the agent are co- formulated. 4.
  • the subject of the herein disclosed methods is a vertebrate, e.g., a mammal.
  • 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.
  • patient includes human and veterinary subjects.
  • the subject has been diagnosed with a need for treatment prior to the administering step.
  • the subject has been diagnosed with a disorder of uncontrolled cellular proliferation prior to the administering step.
  • a subject has been identified with a need for treatment prior to the administering step.
  • a subject can be treated prophylactically with a compound or composition disclosed herein, as discussed herein elsewhere.
  • DOSAGE 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 LD 50 (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. 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.
  • 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 per 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.
  • 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.
  • the dosage facilitates an intended purpose for both prophylaxis and treatment without undesirable side effects, such as toxicity, irritation or allergic response.
  • 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).
  • the dosage required to provide an effective amount of a formulation 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 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.
  • the route of administration can be determined by a patient's health care provider or clinician, for example following an evaluation of the patient.
  • 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.
  • 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.
  • 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).
  • 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
  • reaction mixture was heated to 105 °C and stirred overnight. Crude reaction mixture was filtered through a plug of Celite and washed with EtOAc (5 mL). Filtrate was concentrated then taken up in DMSO and purified by the Waters purification/analytical LC/UV/ELSD system and the gradient program started at 95% (0.1% formic acid in MilliQ H 2 O), changed to 90% (0.1% formic acid in Acetonitrile) over 14 min.
  • KASUMI-1 cell line is maintained in RPMI1640 medium, supplemented with 20% FBS, 100 U/mL penicillin– streptomycin.
  • SKNO-1 cell line is maintained in RPMI1640 medium, supplemented with 10% FBS, 100 U/mL penicillin–streptomycin, 10 ng/ml GM-CSF.
  • CAKI-1 cell line is maintained in McCoy’s 5A medium supplemented with 10% FBS, 100 U/mL penicillin– streptomycin, 10 ng/ml GM-CSF.
  • WESTERN BLOT Cells were lysed on ice using a lysis buffer (0.1 M Tris-HCl, pH 6.8, 200 mM dithiothreitol, 0.01% bromophenol blue, 4% sodium dodecyl sulfate and 20% glycerol). Samples were sonicated at 4 °C for 10 s, and then boiled at 95 °C for 10 min. Cell lysates were separated on 4–15% precast polyacrylamide gel and transferred to PVDF membranes pre-activated with methanol. Membranes were blocked in a solution of 5% milk in PBST buffer and incubated for 1 hour at room temperature and incubated overnight with primary antibodies at 4 °C under gentle horizontal shaking.
  • a lysis buffer 0.1 M Tris-HCl, pH 6.8, 200 mM dithiothreitol, 0.01% bromophenol blue, 4% sodium dodecyl sulfate and 20% glycerol.
  • membranes were washed with PBST buffer and incubated with anti-mouse or anti-rabbit HRP-conjugated secondary antibodies (1:5,000). Membranes were washed with PBST buffer, incubated with SuperSignal West Pico PLUS Chemiluminescent Substrate and developed using an Odyssey Fc Imaging System (LI-COR Corp.).
  • KDM4A (Abclonal, A7953), KDM4B (Bethyl, A301- 478A), KDM4C (Abclonal, A8485), KDM4D (ProteinTech, 22591-1-AP), GAPDH (Cell Signaling, 3683S), ⁇ -Tubulin (Santa cruz, sc-69969), CRBN (CST, 71810S), VCL (Cell Signaling, 13901S), Flag M2 (SIGMA, 080M6035). 3. EVALUATION OF THE ABILITY OF EXEMPLARY COMPOUNDS TO INDUCE PROTEIN DEGRADATION A list of exemplary compounds is shown in Table 1 below. Compounds were prepared using the synthetic methods described herein.
  • FIG.2B shows immunoblots for KDM4B protein after the treatment of BE2C cells with 100 nM of compound 6 over 48 h, and proteins were harvested at 0, 1, 2, 4, 8, 24, and 48 hours after treatment.
  • FIG.2C shows immunoblots for KDM4B protein after the treatment of BE2C wild-type and CRBN knockout cells with compounds 6 for 24 h.
  • compound 6 selectively targets KDM4B and degrades KDM4B in multiple cell lines.
  • FIG.3A shows immunoblots for KDM4A-D proteins after the treatment of BE2C cells with 1 and 10 ⁇ M of compounds 6 for 24 h.
  • FIG.4A-C shows immunoblots for KDM4B protein after the treatment of neuroblastoma (BE2C, SIMA), rhabdomyosarcoma (RH30, RH4), leukemia (KASUMI-1, SKNO-1), Ewing sarcoma (EW-8) cells with 1 ⁇ M and 10 ⁇ M of compounds 6 for 24 h.
  • FIG.4A-C shows immunoblots demonstrating how compound 5 degrades vinculin in a time-, concentration-, and lenalidomide dependent manner.
  • FIG.4A shows imunoblots for vinculin protein after the treatment of CAKI-1 cells with increasing concentrations of compound 5 for 24 h.
  • FIG.4B shows immunoblots for vinculin protein after the treatment of CAKI-1 cells with 1 ⁇ M compound 5 over 48 h, and proteins were harvested at 0, 1, 2, 4, 8, 24, and 48 hours after treatment.
  • FIG.4C shows immunoblots for vinculin protein after the treatment of CAKI-1 cells with compound 5 for 24 h in the presence and absence of lenalidomide.
  • FIG.5 immunoblots for vinculin protein after the treatment of kidney tumor cell lines (786-O, WiT49) and neuroblastoma cell lines (SKNAS, BE2C, SKNSH) cells with 1 and 10 ⁇ M of compounds 5 for 24 h are shown.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente divulgation concerne des composés et des compositions, et des procédés d'utilisation des composés et des compositions pour induire la dégradation de protéines qui sont pertinentes pour le cancer tel que. par exemple. KDM4B et VCL. La présente divulgation concerne également des méthodes de traitement du cancer (par exemple, un sarcome, un carcinome, un cancer hématologique, une tumeur solide, un cancer du sein, un cancer du col de l'utérus, un cancer gastro-intestinal, un cancer colorectal, un cancer du cerveau, un cancer de la peau, un cancer de la prostate, un cancer de l'ovaire, un carcinome pulmonaire non à petites cellules, un cancer de la thyroïde, un cancer du testicule, un cancer du pancréas, un cancer du foie, un cancer de l'endomètre, un mélanome, un gliome, une leucémie, un lymphome, un trouble myéloprolifératif chronique, un syndrome myélodysplasique, un néoplasme myéloprolifératif, un néoplasme cellulaire plasmatique (myélome)) à l'aide des composés et des compositions divulgués. Le présent abrégé est destiné à être utilisé comme outil d'exploration à des fins de recherche dans ce domaine technique particulier, et ne se limite pas à la présente divulgation.
PCT/US2025/020443 2024-03-19 2025-03-18 Liants de céréblon à petites molécules qui induisent la dégradation de protéines (kdm4b, vcl) pertinentes pour le cancer Pending WO2025199151A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202463567094P 2024-03-19 2024-03-19
US63/567,094 2024-03-19

Publications (1)

Publication Number Publication Date
WO2025199151A1 true WO2025199151A1 (fr) 2025-09-25

Family

ID=97140138

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2025/020443 Pending WO2025199151A1 (fr) 2024-03-19 2025-03-18 Liants de céréblon à petites molécules qui induisent la dégradation de protéines (kdm4b, vcl) pertinentes pour le cancer

Country Status (1)

Country Link
WO (1) WO2025199151A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020014489A2 (fr) * 2018-07-11 2020-01-16 H. Lee Moffitt Cancer Center And Research Institute, Inc. Composés immunomodulateurs dimères visant des mécanismes à base de céréblon
US10849982B2 (en) * 2016-05-10 2020-12-01 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2022217010A1 (fr) * 2021-04-09 2022-10-13 Endotarget Inc. Composés et procédés pour la dégradation ciblée de récepteurs d'œstrogène

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10849982B2 (en) * 2016-05-10 2020-12-01 C4 Therapeutics, Inc. C3-carbon linked glutarimide degronimers for target protein degradation
WO2020014489A2 (fr) * 2018-07-11 2020-01-16 H. Lee Moffitt Cancer Center And Research Institute, Inc. Composés immunomodulateurs dimères visant des mécanismes à base de céréblon
WO2022217010A1 (fr) * 2021-04-09 2022-10-13 Endotarget Inc. Composés et procédés pour la dégradation ciblée de récepteurs d'œstrogène

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Pubchem Substance 17 February 2021 (2021-02-17), ANONYMOUS: "CHEMBL4585625", XP093360507, retrieved from NCBI Database accession no. 440223093 *

Similar Documents

Publication Publication Date Title
CN103889962B (zh) 作为受体酪氨酸激酶btk抑制剂的取代的n‑(3‑(嘧啶‑4‑基)苯基)丙烯酰胺类似物
EP2916840B1 (fr) Analogues arylamides substitués de gemcitabine
WO2021022076A1 (fr) Molécules et procédés se rapportant au traitement de la prolifération incontrôlée de cellules
WO2014055928A2 (fr) Analogues de n-(3-(pyrimidin-4-yl)phényl) substitué utilisés en tant qu'inhibiteurs de récepteur tyrosine kinase btk
EP4031144A1 (fr) Benzimidazoles et leurs procédés d'utilisation
EP3518925A1 (fr) Inhibiteurs doubles de clk/cdk1 destinés au traitement du cancer
WO2020198526A2 (fr) Modulateurs à petites molécules de pank
WO2024173718A2 (fr) Liants hétérobifonctionnels de klhdc2
US20250375450A1 (en) Smarca2/4 inhibition as a strategy to treat tumors that harbor aberrant baf assemblies
WO2025199151A1 (fr) Liants de céréblon à petites molécules qui induisent la dégradation de protéines (kdm4b, vcl) pertinentes pour le cancer
WO2022150314A1 (fr) Modulateurs de mort programmée-ligand-1
WO2023205344A1 (fr) Modulateurs à petites molécules du récepteur de prégnane x humain
US20200079739A1 (en) Tetrahydroquinoline-based bromodomain inhibitors
US12215108B2 (en) Development of potential antidotes for arsenicals
US12098216B2 (en) Modulators of programmed death-ligand-1 and/or programmed death-ligand-2
WO2026072967A1 (fr) Ubiquitylation de p85a médiée par fbxo21 comme cible thérapeutique dans le cancer
US20240342139A1 (en) Development and optimization of thiochromenothiazole-based msut2 inhibitors as candidates for the treatment of tauopathy
WO2024192144A1 (fr) Pyrazolopyrimidines utilisées comme antidotes pour des arsénicaux
EP4705307A1 (fr) Molécule de liaison à l'adn à sélection de séquence (syngrader)
WO2024050062A1 (fr) Aminopipérazines ayant une activité antimicrobienne à large spectre
WO2023244691A1 (fr) Compositions et procédés d'inhibition d'interaction dcn1-ubc12
WO2023004138A1 (fr) Agonistes de tyro3 en tant que protection contre une lésion des podocytes dans une maladie glomérulaire rénale
EP4447949A1 (fr) Dimères de phényléthylidènehydrazine et leurs procédés d'utilisation
EP4626419A1 (fr) Inhibiteurs eif4a1 à activité antitumorale
US20160052896A1 (en) Isoxazole analogs as mediators of transcriptional induction of e-cadherin

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 25774377

Country of ref document: EP

Kind code of ref document: A1