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WO2024243343A2 - Composés qui réactivent la p53 mutante - Google Patents

Composés qui réactivent la p53 mutante Download PDF

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Publication number
WO2024243343A2
WO2024243343A2 PCT/US2024/030622 US2024030622W WO2024243343A2 WO 2024243343 A2 WO2024243343 A2 WO 2024243343A2 US 2024030622 W US2024030622 W US 2024030622W WO 2024243343 A2 WO2024243343 A2 WO 2024243343A2
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membered
alkyl
hydrogen
compound
cancer
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WO2024243343A3 (fr
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John Karanicolas
Sven Miller
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Individual
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    • 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
    • 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
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • LFS individuals are recommended to undergo neurologic exams, whole -body MRI annually, and abdominal ultrasonography every 3-4 months in childhood and adolescence.
  • Adult women are recommended to commence annual mammogram and breast MRI in their 20s (some patients undergo surgical prophylaxis) (e.g., bilateral mastectomy)); and adult men and women are recommended to have annual skin exams and upper and lower endoscopy every 2-5 years starting at age 25 (Freutz et al. (2020) Eur J Hum Genet.
  • mutant p53 In LFS, by contrast, mutant p53’s degradation by MDM2 is disrupted, such that destabilized mutant p53 accumulates in cells (Ashcroft and Vousden (1999) Oncogene 18:7637-43; Yue et al. (2017) J Mol Biol. 429:1595-606). Third, and finally, certain p53 mutants also acquire gain-of- function (GOF) activities that promote chemoresistance, proliferation, invasion, and metastasis (Yue et al. (2017) J Mol Biol. 429:1595-606; Dittmer et al. (1993) Nat Genet. 4:42-6; Blandino et al. (2016) J Exp Clin Cancer Res.
  • GAF gain-of- function
  • PRIMA-1 MET (APR-246) is thought to directly engage and covalently bind to mutant p53 (Bykov et al. (2005) Oncogene 24:3484-91), and in 2020 was FDA-approved for patients with 77 J 53-mutatcd hematologic malignancies.
  • PK11007 like PRIMA-1 MET , forms a covalent adduct to p53 but also acts in both a p53-dependent and p53 -independent manner (Bauer et al. (2016) Proc Natl Acad Sci USA 113:E5271-80; Synnott et al. (2016) Cancer Lett 414:99-106). Most recently, arsenic trioxide (ATO) was reported as another cysteine -reactive refolder of mutant p53 (Chen et al.
  • ATO arsenic trioxide
  • the invention in one aspect, relates to compounds and compositions for use in restoring p53 activity.
  • Such utility can be useful in, for example, the treatment of cancer (e.g., pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer), the treatment of Li-Fraumeni syndrome (LFS), and the prevention of cancer in a subject having LFS.
  • cancer e.g., pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer
  • LFS Li-Fraumeni syndrome
  • n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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) dial
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10- membered heteroaryl, and a 6- to 10-membered aryl, 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, -CH 2 Cy 3 , and Cy 3 ; wherein Cy 3 , when present, is selected from a 3- to 10-membered cycloalky
  • compositions comprising an effective amount of a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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-C
  • compositions comprising an effective amount of a compound having a structure selected from:
  • Also disclosed are methods of restoring p53 activity in a cell comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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 al
  • Also disclosed are methods of restoring p53 activity in a subject comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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 al
  • methods of treating cancer in a subject in need thereof comprising administering to the subject an effective amount of a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein L is selected from -SO2CH2-, -N(R 2 )SO2-, and -SO2N(R 2 )-; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 groups independently selected from halogen, -CN
  • LFS Li-Fraumeni syndrome
  • kits comprising a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein L is selected from -N(R 2 )SO2- and -SO2N(R 2 )-; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10- membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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, Cl- C4
  • kits comprising a compound having a structure: or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anticancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.
  • FIG. 1A and FIG. IB show representative data illustrating the unfolding and refolding of mutant p53.
  • FIG. 2A and FIG. 2B show representative data illustrating the application of structure -based virtual screening to identify refolders of mutant p53.
  • FIG. 3A-D show representative data generated in cell-based assays for p53 refolding.
  • FIG. 4A and FIG. 4B show representative data illustrating biochemical monitoring of p53 refolding, to drive future optimization.
  • FIG. 5 shows a representative schematic illustrating optimization of computation screening hit JO to arrive at compound SM2.
  • FIG. 6 shows representative data to define rescuable TP53 missense mutations.
  • FIG. 7 shows representative data illustrating the rescue of mutant p53 gain-of- function (GOF).
  • FIG. 8 shows a representative synthetic route to access SM0 and SM0 analogs).
  • FIG. 9 shows a representative schematic illustrating a proposed 4NQO treatment regimen for the efficacy study.
  • FIG. 10A-C show representative data pertaining to the real-time polymerase chain reaction (PCR) of p53 downstream target genes after treatment with JH category compound in BxPC3.
  • PCR polymerase chain reaction
  • FIG. 11A-C show representative data pertaining to the real-time PCT of p53 downstream target genes after treatment with JH category compound in Cal 3.
  • Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.
  • the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ⁇ 10% variation unless otherwise indicated or inferred. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art.
  • an amount, size, formulation, parameter or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is understood that where “about” is used before a quantitative value, the parameter also includes the specific quantitative value itself, unless specifically stated otherwise.
  • references in the specification and concluding claims to parts by weight of a particular element or component in a composition denotes the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such ratio regardless of whether additional components are contained in the compound.
  • a weight percent (wt. %) of a component is based on the total weight of the formulation or composition in which the component is included.
  • IC50 is intended to refer to the concentration of a substance (e.g., a compound or a drug) that is required for 50% inhibition of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • a substance e.g., a compound or a drug
  • an IC50 can refer to the concentration of a substance that is required for 50% inhibition in vivo, as further defined elsewhere herein.
  • IC50 refers to the half-maximal (50%) inhibitory concentration (IC) of a substance.
  • EC50 is intended to refer to the concentration of a substance (e.g. , a compound or a drug) that is required for 50% agonism of a biological process, or component of a process, including a protein, subunit, organelle, ribonucleoprotein, etc.
  • a substance e.g. , a compound or a drug
  • an EC50 can refer to the concentration of a substance that is required for 50% agonism in vivo, as further defined elsewhere herein.
  • EC50 refers to the concentration of agonist that provokes a response halfway between the baseline and maximum response.
  • the term “subject” can be a vertebrate, such as a mammal, a fish, a bird, a reptile, or an amphibian.
  • 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.
  • the subject is a mammal.
  • a patient refers to a subject afflicted with a disease or disorder.
  • patient includes human and veterinary subjects.
  • treatment refers to the medical management of a patient with the intent to cure, ameliorate, stabilize, or prevent a disease, pathological condition, or disorder.
  • This term includes active treatment, that is, treatment directed specifically toward the improvement of a disease, pathological condition, or disorder, and also includes causal treatment, that is, treatment directed toward removal of the cause of the associated disease, pathological condition, or disorder.
  • this term includes palliative treatment, that is, treatment designed for the relief of symptoms rather than the curing of the disease, pathological condition, or disorder; preventative treatment, that is, treatment directed to minimizing or partially or completely inhibiting the development of the associated disease, pathological condition, or disorder; and supportive treatment, that is, treatment employed to supplement another specific therapy directed toward the improvement of the associated disease, pathological condition, or disorder.
  • 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.
  • subject also includes domesticated animals (e.g., cats, dogs, etc.), livestock (e.g., cattle, horses, pigs, sheep, goats, etc.), and laboratory animals (e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.).
  • domesticated animals e.g., cats, dogs, etc.
  • livestock e.g., cattle, horses, pigs, sheep, goats, etc.
  • laboratory animals e.g., mouse, rabbit, rat, guinea pig, fruit fly, etc.
  • the term “prevent” or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • 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.
  • administering refers to any method of providing a pharmaceutical preparation to a subject. 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 be administered prophylactically; that is, administered for prevention of a disease or condition.
  • the terms “effective amount” and “amount effective” refer to an amount that is sufficient to achieve the desired result or to have an effect on an undesired condition.
  • a “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for purposes of administration.
  • 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.
  • 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 forms can comprise inventive 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, polyoxyethyl ene9- 10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g.
  • buffers e.g., sodium or potassium salts of phosphate, carbonate, acetate, or citrate
  • 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
  • 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; anti-cancer and anti-neoplastic agents such as kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HD Ac) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programme
  • 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.
  • the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g. , a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • the term “pharmaceutically acceptable carrier” refers to sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles 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.
  • 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.
  • 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 can have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” include the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., a compound that does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. It is also contemplated that, in certain aspects, unless expressly indicated to the contrary, individual substituents can be further optionally substituted (z.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 (z.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, zz-propyl, isopropyl, //-butyl, isobutyl, s- butyl, t-butyl, //-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be cyclic or acyclic.
  • the alkyl group can be branched or unbranched.
  • the alkyl group can also be substituted or unsubstituted.
  • the alkyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • a “lower alkyl” group is an alkyl group containing from one to six (e.g., from one to four) carbon atoms.
  • alkyl group can also be a Cl 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, Cl -CIO alkyl, and the like up to and including a C1-C24 alkyl.
  • 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.
  • 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.
  • the practice of using a general term, such as “cycloalkyl,” and a specific term, such as “alkylcycloalkyl,” is not meant to imply that the general term does not also include the specific term.
  • cycloalkyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbomyl, 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 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.
  • polyalkylene group as used herein is a group having two or more CH2 groups linked to one another.
  • the polyalkylene group can be represented by the formula — (CH2) a — , where “a” is an integer of from 2 to 500.
  • 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.
  • alkenyl as used herein is a hydrocarbon group of from 2 to 24 carbon atoms with a structural formula containing at least one carbon-carbon double bond.
  • 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.
  • 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 here
  • cycloalkenyl as used herein is a non-aromatic carbon-based ring composed of at least three carbon atoms and containing at least one carbon-carbon double bound, i.e., OC.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbomenyl, 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 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.
  • 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 it electrons above and below the plane of the molecule, where the it clouds contain (4n+2) n 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, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, — NH2, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol
  • 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 carboncarbon 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.
  • amine or “amino” as used herein are represented by the formula — NA 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 — NH2.
  • alkylamino as used herein is represented by the formula — NH(-alkyl) where alkyl is a described herein.
  • Representative examples include, but are not limited to, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, (sec-butyl)amino group, (tert-butyl)amino group, pentylamino group, isopentylamino group, (tert-pentyl)amino group, hexylamino group, and the like.
  • dialkylamino as used herein is represented by the formula — N(-alkyl)2 where alkyl is a described herein.
  • Representative examples include, but are not limited to, dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)amino group, dipentylamino group, diisopentylamino group, di(tert-pentyl)amino group, dihexylamino group, N-ethyl-N -methylamino group, N-methyl-N -propylamino group, N- ethyl-N-propylamino group and the like.
  • carboxylic acid as used herein is represented by the formula — C(O)OH.
  • esteer as used herein is represented by the formula — OC(O)A 1 or — C(O)OA 1 , where A 1 can be alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • polyester as used herein is represented by the formula — (A 1 O(O)C-A 2 -C(O)O) a — or — (A 1 O(O)C-A 2 -OC(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 from 1 to 500. “Polyester” is as the term used to describe a group that is produced by the reaction between a compound having at least two carboxylic acid groups with a compound having at least two hydroxyl groups.
  • ether as used herein is represented by the formula A 'O A 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.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo halogen
  • halide as used herein can be used interchangeably and refer to F, Cl, Br, or I.
  • pseudohalide pseudohalogen
  • pseudohalo pseudohalogen
  • pseudohalo pseudohalo
  • functional groups include, by way of example, cyano, thiocyanato, azido, trifluoromethyl, trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.
  • heteroalkyl refers to an alkyl group containing at least one heteroatom. Suitable heteroatoms include, but are not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorous and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quatemized. Heteroalkyls can be substituted as defined above for alkyl groups.
  • heteroaryl refers to an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group.
  • heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides, and dioxides are permissible heteroatom substitutions.
  • the heteroaryl group can be substituted or unsubstituted.
  • the heteroaryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • Heteroaryl groups can be monocyclic, or alternatively fused ring systems. Heteroaryl groups include, but are not limited to, furyl, imidazolyl, pyrimidinyl, tetrazolyl, thienyl, pyridinyl, pyrrolyl, A'-mcthylpyrrolyl, quinolinyl, isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl, benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl, benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, and pyrazolopyrimidinyl.
  • heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, bcnzo[ ⁇ 7]oxazolyl, bcnzo[c/]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[l,2-b]pyridazinyl, imidazo[l,2-a]pyrazinyl, benzo[c][l,2,5]thiadiazolyl, benzo[c][l,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.
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2, 3 -thiadiazole, 1,2,5-thiadiazole, and 1,3,4- thiadiazole, triazole, including, 1,2, 3 -triazole, 1,3,4-triazole, tetrazole, including 1, 2,3,4- tetrazole and 1,2,4,5-tetrazole, pyridazine, pyrazine, triazine
  • 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 that has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. It is understood that a heterocyclyl group may be bound either through a heteroatom in the ring, where chemically possible, or one of carbons comprising the heterocyclyl ring.
  • 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[l,5-a]pyridinyl, benzo furanyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-l,4-benzodioxinyl, 3,4-dihydro-2H- chromenyl, lH-pyrazolo[4,3-c]pyridin-3-yl; lH-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.
  • hydroxyl 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.
  • nitro as used herein is represented by the formula — NO2.
  • nitrile or “cyano” as used herein is represented by the formula — CN.
  • sil as used herein is represented by the formula — SiA ⁇ 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.
  • sulfo-oxo is represented by the formulas — S(O)A 1 , — S(O)2A 1 , — OS(O)2A 1 , or — OS(O)2OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, 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)2A 2 is represented by the formula A 1 S(O)2A 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 (z.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 preferably those that result in the formation of stable or chemically feasible compounds.
  • individual substituents can be further optionally substituted (z.e., further substituted or unsubstituted).
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain aspects, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • Suitable monovalent substituents on R° are independently halogen, -(CH 2 )o- 2 R*, -(haloR*), -(CH 2 )o- 2 OH, -(CH 2 )o- 2 OR*, -(CH 2 )o- 2 CH(OR’) 2 ; -O(haloR’), -CN, -N 3 , -(CH 2 )o- 2 C(0)R’, -(CH 2 ) 0-2 C(O)OH, -(CH 2 )o- 2 C(0)OR’, -(CH 2 ) 0 - 2 SR’, -(CH 2 )O- 2 SH, -(CH 2 )O- 2 NH 2 , -(CH 2 )O- 2 NHR*, -(CH 2 )O- 2 NR* 2 , -NO 2 ,
  • 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, Ci-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 Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, 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 -Rt, -NRt 2 , -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C(O)CH 2 C(O)Rt, - S(O) 2 Rt, -S(O) 2 NRt 2 , -C(S)NRt 2 , -C(NH)NRt 2 , or -N(Rt)S(O) 2 R f ; wherein each Rt is independently hydrogen, Ci-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 1 ', taken together with their intervening atom(s
  • Suitable substituents on the aliphatic group of Ri are independently 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 Ci-4 aliphatic, -CH 2 Ph, -0(CH 2 )o iPh, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0 ⁇ 1 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 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. Examples of organic residues include but are not limited alkyl or substituted alkyls, alkoxy or substituted alkoxy, mono or di-substituted amino, amide groups, etc.
  • Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15, carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms.
  • 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, disubstituted 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.
  • the disclosed compounds contain one chiral center, the compounds exist in two enantiomeric forms. Unless specifically stated to the contrary, a disclosed compound includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixture.
  • the enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step can liberate the desired enantiomeric form.
  • specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • Designation of a specific absolute configuration at a chiral carbon in a disclosed compound is understood to mean that the designated enantiomeric form of the compounds can be provided in enantiomeric excess (e.e.).
  • Enantiomeric excess is the presence of a particular enantiomer at greater than 50%, for example, greater than 60%, greater than 70%, greater than 75%, greater than 80%, greater than 85%, greater than 90%, greater than 95%, greater than 98%, or greater than 99%.
  • the designated enantiomer is substantially free from the other enantiomer.
  • the “R” forms of the compounds can be substantially free from the “S” forms of the compounds and are, thus, in enantiomeric excess of the “S” forms.
  • “S” forms of the compounds can be substantially free of “R” forms of the compounds and are, thus, in enantiomeric excess of the “R” forms.
  • a disclosed compound When a disclosed compound has two or more chiral carbons, it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to four optical isomers and two pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)).
  • the pairs of enantiomers e.g.. (S,S)/(R,R)
  • the stereoisomers that are not mirror-images e.g., (S,S) and (R,S) are diastereomers.
  • diastereoisomeric pairs can be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. Unless otherwise specifically excluded, a disclosed compound includes each diastereoisomer of such compounds and mixtures thereof.
  • the compounds according to this disclosure may form prodrugs at hydroxyl or amino functionalities using alkoxy, amino acids, etc., groups as the prodrug forming moieties.
  • the hydroxymethyl position may form mono-, di- or triphosphates and again these phosphates can form prodrugs.
  • Preparations of such prodrug derivatives are discussed in various literature sources (examples are: Alexander et al., J. Med. Chem. 1988, 31, 318; Aligas-Martin et al., PCT WO 2000/041531, p. 30).
  • the nitrogen function converted in preparing these derivatives is one (or more) of the nitrogen atoms of a compound of the disclosure.
  • ‘Derivatives” of the compounds disclosed herein are pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, solvates and combinations thereof.
  • the “combinations” mentioned in this context are refer to derivatives falling within at least two of the groups: pharmaceutically acceptable salts, prodrugs, deuterated forms, radioactively labeled forms, isomers, and solvates.
  • Examples of radioactively labeled forms include compounds labeled with tritium, phosphorous-32, iodine- 129, carbon-11, fluorine- 18, and the like.
  • 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 0, 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.
  • one, two, three or any arbitrary number of solvent or water molecules can combine with the compounds according to the invention to form solvates and hydrates.
  • 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. “Crystal Engineering of the Composition of Pharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a New Path to Improved Medicines?” Almarasson, O., et. al., The Royal Society of Chemistry, 1889-1896, 2004.
  • Examples of co-crystals include p- toluenesulfonic acid and benzenesulfonic acid.
  • ketones with an a-hydrogen can exist in an equilibrium of the keto form and the enol form.
  • amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form.
  • pyrazoles can exist in two tautomeric forms, A 1 -unsubstituted, 3-A 3 and A 1 -unsubstituted, 5-A 3 as shown below.
  • the invention includes all such possible tautomers.
  • polymorphic forms or modifications It is known that chemical substances form solids that are present in different states of order that 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" is understood to represent five independent substituents, R" (a ), By “independent substituents,” it is meant that each R substituent can be independently defined. For example, if in one instance R" (a) is halogen, then R" (b ) is not necessarily halogen in that instance.
  • compositions of the invention Disclosed are the components to be used to prepare the compositions of the invention as well as the compositions themselves to be used within the methods disclosed herein. These and other materials are disclosed herein, and it is understood that when combinations, subsets, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds cannot be explicitly disclosed, each is specifically contemplated and described herein. For example, if a particular compound is disclosed and discussed and a number of modifications that can be made to a number of molecules including the compounds are discussed, specifically contemplated is each and every combination and permutation of the compound and the modifications that are possible unless specifically indicated to the contrary.
  • the invention relates to compounds useful in treating disorders associated with loss of p53 activity such as, for example, cancers including, but not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanomas, gliomas, leukemias, lymphomas, chronic myeloproliferative disorders, myelodysplastic syndromes, myeloproliferative neoplasms, and plasma cell neoplasms (myelomas).
  • cancers including, but not limited to, sarcomas, carcinomas, hematological cancers, solid tumors, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endo
  • the compounds of the invention are useful in the treatment of cancer as further described herein.
  • 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
  • n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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)(C1-C4)(C1-C4)(C1-C4)(C1
  • compositions comprising an effective amount of a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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
  • the compound has a structure as detailed herein above, provided that (a) when R 1 is Cy 1 , Cy 1 is a 5- to 10-membered heteroaryl or a 6- to 10- membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10- membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl and a 6- to 10-membered 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, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 5- to 10- membered heteroaryl and a 6- to 10-membered aryl, 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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -QHCy 3 , and Cy 3 .
  • 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, -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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 , or a pharmaceutically acceptable salt thereof.
  • R 1 is C1-C8 alkyl.
  • R 1 is Cy 1 .
  • 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, -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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 , wherein each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, -NH2, -OH,
  • the compound has a structure represented by a formula: wherein each of R 21a , R 21b , R 21c , R 21d , and R 21e 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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -CO2R 10 , or a pharmaceutically acceptable salt thereof.
  • the compound has a structure represented by a formula: or a pharmaceutically acceptable salt thereof.
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl and a 6- to 10-membered 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, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 5- to 10- membered heteroaryl and a 6- to 10-membered aryl, 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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -QHCy 3 , and Cy 3 .
  • 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, -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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 , or a pharmaceutically acceptable salt thereof.
  • R 1 is C1-C8 alkyl.
  • R 1 is Cy 1 .
  • 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, -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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 , wherein each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, -NH2, -OH,
  • the compound has a structure represented by a formula: wherein each of R 21a , R 21b , R 21c , R 21d , and R 21e 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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, and -CO2R 10 , or a pharmaceutically acceptable salt thereof.
  • the compound is selected from:
  • the compound is selected from:
  • the compound is: or a pharmaceutically acceptable salt thereof.
  • n is selected from 0 and 1. In a further aspect, n is 0. In a still further aspect, n is 1. a. R 1 GROUPS
  • R 1 is selected from C1-C8 alkyl and Cy 1 . In a further aspect, R 1 is selected from C1-C4 alkyl and Cy 1 . In a still further aspect, R 1 is selected from methyl, ethyl, n-propyl, isopropyl, and Cy 1 . In yet a further aspect, R 1 is selected from methyl, ethyl, and Cy 1 . In an even further aspect, R 1 is selected from methyl and Cy 1 .
  • R 1 is C1-C8 alkyl. In a further aspect, R 1 is C1-C4 alkyl. In a still further aspect, R 1 is selected from methyl, ethyl, n-propyl, and isopropyl. In yet a further aspect, R 1 is selected from methyl and ethyl. In an even further aspect, R 1 is methyl.
  • R 1 is Cy 1 .
  • R 2 GROUPS independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C
  • R 2 is selected from hydrogen and C1-C4 alkyl. In a further aspect, R 2 is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 2 is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 2 is selected from hydrogen and methyl.
  • R 2 is C 1 -C4 alkyl. In a further aspect, R 2 is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 2 is selected from methyl and ethyl. In yet a further aspect, R 2 is methyl.
  • R 2 is a hydrogen. c. R 3 AND R 4 GROUPS
  • one of R 3 and R 4 is hydrogen and one of R 3 and R 4 is -N(R n )CH2C(O)N(R 12 )Cy 2 .
  • R 3 is hydrogen and R 4 is -N(R n )CH2C(O)N(R 12 )Cy 2 .
  • R 3 is hydrogen and R 4 is -NHCH2C(O)NHCy 2 .
  • R 4 is hydrogen and R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 .
  • R 4 is hydrogen and R 3 is -NHCH 2 C(O)NHCy 2 . d.
  • each of R 5a , R 5b , and R 5c 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, and C1-C4 aminoalkyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, //-propyl, z-propyl, ethenyl, propenyl, isopropenyl, -CH2F, -CH2CI, - CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH 3 )CH 2 F, - CH(CH 3 )CH 2 C1, -CH 2 CN, -CH2CH2CN, -CH2CH2CH2CN, -CH(CH 3 )CH 2 CN, -CH2OH, - CH2CH2OH, -CH2CH2CH2OH, -CH(CH 3 )CH 2 OH, -OCF 3 , -OCH 2 CF
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH 2 F, -CH 2 C1, -CH2CH2F, -CH2CH2CI, -CH2CN -CH2CH2CN, -CH 2 OH, - CH2CH2OH, -OCF 3 , -OCH 2 CF 3 , -OCH 3 , -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 ), -CH2NH2, and -CH 2 CH 2 NH 2 .
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, - OH, -NO2, methyl, -CH 2 F, -CH 2 C1, -CH 2 CN, -CH 2 OH, -OCF 3 , -OCH 2 CF 3 , -OCH 3 , - NHCH 3 , -N(CH 3 ) 2 , and -CH2NH2.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, - CN, -OH, -NO2, methyl, ethyl, zz -propyl, z-propyl, ethenyl, propenyl, and isopropenyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, - NH2, -CN, -OH, -NO2, methyl, ethyl, and ethenyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, and methyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, //-propyl, z-propyl, -OCH 3 , -OCI FCI l 3 , -OCI FCI FCI l 3 , and -OCH(CH 3 )CH 3 .
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -OCH3, and -OCH2CH3.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH3.
  • each of R 5a , R 5b , and R 5c is independently independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R 5a , R 5b , and R 5c is independently selected from hydrogen, methyl, ethyl, //-propyl, and z-propyl. In a further aspect, each of R 5a , R 5b , and R 5c is independently selected from hydrogen, methyl, and ethyl. In a still further aspect, each of R 5a , R 5b , and R 5c is independently selected from hydrogen and methyl.
  • each of R 5a , R 5b , and R 5c is independently Cl -C4 alkyl. In a further aspect, each of R 5a , R 5b , and R 5c is independently selected from methyl, ethyl, n- propyl, and z-propyl. In a further aspect, each of R 5a , R 5b , and R 5c is independently selected from methyl and ethyl. In a still further aspect, each of R 5a , R 5b , and R 5c is methyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, - NH 2 , -CN, -OH, -NO2, -CH 2 F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, - CH2CH2CH2CI, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 C1, -CH2CN, -CH2CH2CN, - CH2CH2CH2CN, and -CH(CH3)CH2CN.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2CI, - CH2CH2F, -CH2CH2CI, -CH2CN, and -CH2CH2CN.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, - CH 2 F, -CH2CI, and -CH 2 CN.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C 1 -C4 alkoxy.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO2, -CH 2 OH, -CH2CH2OH, -CH 2 CH 2 CH 2 OH, - CH(CH 3 )CH 2 OH, -OCF3, -OCH2CF3, -OCH2CH2CF3, -OCH(CH 3 )CF 3 , -OCH3, - OCH2CH3, -OCH2CH2CH3, and -OCH(CH3)CH3.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, - CH2CH2OH, -OCF3, -OCH2CF3, -OCH3, and -OCH2CH3.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -OCF3, -OCH2CF3, and -OCH3.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -NHCH3, - NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH 3 )CH3, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 2 CH 2 CH3) 2 , -N(CH(CH 3 )CH 3 )2, -N(CH 3 )(CH 2 CH 3 ), -CH2NH2, -CH2CH2NH2, - CH2CH2CH2NH2, and -CH(CH3)CH2NH2.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -NHCH3, - NHCH2CH3, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH3)(CH 2 CH 3 ), -CH2NH2, and -CH2CH2NH2.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO2, -NHCH3, -N(CH 3 ) 2 , and -CH2NH2.
  • each of R 5a , R 5b , and R 5c is independently selected from hydrogen and halogen. In a further aspect, each of R 5a , R 5b , and R 5c is independently selected from hydrogen, -F, and -Cl. In a further aspect, each of R 5a , R 5b , and R 5c is independently selected from hydrogen and -Cl. In a still further aspect, each of R 5a , R 5b , and R 5c is independently selected from hydrogen and -F.
  • each of R 5a , R 5b , and R 5c is independently halogen. In a further aspect, each of R 5a , R 5b , and R 5c is independently selected from -F and -Cl. In a further aspect, each of R 5a , R 5b , and R 5c is -Cl. In a still further aspect, each of R 5a , R 5b , and R 5c is -F.
  • each of R 5a , R 5b , and R 5c is hydrogen.
  • R 10 when present, is selected from hydrogen and C 1 -C4 alkyl. In a further aspect, R 10 , when present, is selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 10 , when present, is selected from hydrogen, methyl, and ethyl. In yet a further aspect, R 10 , when present, is selected from hydrogen and methyl.
  • R 10 when present, is C1-C4 alkyl. In a further aspect, R 10 , when present, is selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, R 10 , when present, is selected from methyl and ethyl. In yet a further aspect, R 10 , when present, is methyl.
  • R 10 when present, is a hydrogen. f. R 11 AND R 12 GROUPS
  • each of R 11 and R 12 is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R 11 and R 12 is independently selected from hydrogen, methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R 11 and R 12 is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 11 and R 12 is independently selected from hydrogen and methyl.
  • each of R 11 and R 12 is independently C1-C4 alkyl. In a further aspect, each of R 11 and R 12 is independently selected from methyl, ethyl, n-propyl, and isopropyl. In a still further aspect, each of R 11 and R 12 is independently selected from methyl and ethyl. In yet a further aspect, each of R 11 and R 12 is methyl.
  • each of R 11 and R 12 is hydrogen. g. 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, -CI FCy', and Cy 3 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, n-propyl, z -propyl, ethenyl, propenyl, isopropenyl, -CH2F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, - CH2CH2CH2CI, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 C1, -CH 2 CN, -CH2CH2CN, - CH2CH2CH2CN, -CH(CH 3 )CH 2 CN, -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, -NH2, -CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH 2 F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CN -CH2CH2CN, -CH2OH, - CH2CH2OH, -OCF 3 , -OCH 2 CF 3 , -OCH 3 , -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 ), -CH2NH2, -CH2CH2NH2, -CH 2 Cy 3 , and Cy 3 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , methyl, -CH 2 F, -CH 2 C1, -CH 2 CN, -CH 2 OH, - OCF 3 , -OCH 2 CF 3 , -OCH3, -NHCH3, -N(CH 3 ) 2 , -CH 2 NH 2 , -CH 2 Cy 3 , and Cy 3 .
  • 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, and C2-C4 alkenyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , methyl, ethyl, //-propyl, z-propyl, ethenyl, propenyl, and isopropenyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , methyl, ethyl, and ethenyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , and methyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, //-propyl, z-propyl, -OCH3, C)C I 1 2 C I I , , -OCH 2 CH 2 CH3, and - OCH(CH3)CH3.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -OCH3, and -OCH 2 CH3.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH3.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently independently selected from hydrogen and C1-C4 alkyl.
  • y selected from hydrogen, methyl, ethyl, //-propyl, and z-propyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, methyl, and ethyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen and methyl.
  • 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 haloalkyl, and C1-C4 cyanoalkyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , -CH 2 F, -CH 2 C1, -CH 2 CH 2 F, - CH 2 CH 2 C1, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 C1, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 C1, -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, and -CH(CH3)CH 2 CN.
  • each of R 20a , R 20b , R 20C , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, - OH, -NO 2 , -CH 2 F, -CH 2 C1, -CH 2 CH 2 F, -CH 2 CH 2 C1, -CH 2 CN, and -CH 2 CH 2 CN.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , -CH 2 F, -CH 2 C1, and -CH 2 CN.
  • 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 hydroxyalkyl, C1-C4 haloalkoxy, and C 1 -C4 alkoxy.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , -CH 2 OH, - CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, -CH(CH 3 )CH 2 OH, -OCF3, -OCH 2 CF 3 , -OCH 2 CH 2 CF 3 , - OCH(CH 3 )CF 3 , -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , and -OCH(CH 3 )CH 3 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, - Cl, -NH 2 , -CN, -OH, -NO 2 , -CH 2 OH, -CH 2 CH 2 OH, -OCF 3 , -OCH 2 CF 3 , -OCH 3 , and - OCH 2 CH 3 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , -CH 2 OH, -OCF 3 , -OCH 2 CF 3 , and -OCH 3 .
  • 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 alkylamino, (C1-C4)(C1- C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , - NHCH 3 , -NHCH 2 CH 3 , -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(CH 3 )CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -CH 2 NH 2 , -CH 2 CH 2 NH 2 , - CH 2 CH 2 CH 2 NH 2 , and -CH(CH 3 )CH 2 NH 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , - NHCH 3 , -NHCH 2 CH 3 , -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -CH 2 NH 2 , and - CH 2 CH 2 NH 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , -NHCH 3 , -N(CH 3 ) 2 , and - CH 2 NH 2 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen and halogen.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -F, and -Cl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e selected from hydrogen and -Cl.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen and - F.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen, -CH 2 Cy 3 , and Cy 3 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen and -Cl FCy'.
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is independently selected from hydrogen and Cy 3 .
  • each of R 20a , R 20b , R 20c , R 20d , and R 20e is hydrogen. h. R 21A , R 21B , R 21c , R 21D , AND R 21E GROUPS
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e 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, and -CO2R 10 .
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, - Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, //-propyl, z-propyl, ethenyl, propenyl, isopropenyl, -CH 2 F, -CH 2 C1, -CH2CH2F, -CH2CH2CI, -CH 2 CH 2 CH 2 F, -CH2CH2CH2CI, - CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 C1, -CH 2 CN, -CH2CH2CN, -CH2CH2CH2CN, - CH(CH 3 )CH 2 CN, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH(CH 3 )CH 2 OH, -OCF 3
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, - CN, -OH, -NO2, methyl, ethyl, ethenyl, -CH 2 F, -CH 2 C1, -CH2CH2F, -CH2CH2CI, - CH2CN -CH2CH2CN, -CH2OH, -CH2CH2OH, -OCF 3 , -OCH 2 CF 3 , -OCH 3 , -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 ), -CH2NH2, - CH2CH2NH2, and -CO2R 10 .
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, -CH2F, - CH2CI, -CH 2 CN, -CH2OH, -OCF 3 , -OCH 2 CF 3 , -OCH 3 , -NHCH 3 , -N(CH 3 ) 2 , -CH2NH2, and -CO2R 10 .
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, and C2-C4 alkenyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, //-propyl, z-propyl, ethenyl, propenyl, and isopropenyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, methyl, ethyl, and ethenyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, and methyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, C1-C4 alkyl, and C1-C4 alkoxy.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, //-propyl, z-propyl, -OCH3, -OCH2CH3, -OCH2CH2CH3, and - OCH(CH3)CH3.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -CN, methyl, ethyl, -OCH3, and -OCH2CH3.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -CN, methyl, and -OCH3.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently independently selected from hydrogen and C1-C4 alkyl.
  • each of R 21a , R 2 ⁇ , R 21C , R 21d , and R 21e is independently selected from hydrogen, methyl, ethyl, //-propyl, and z-propyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, methyl, and ethyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen and methyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 haloalkyl, and C1-C4 cyanoalkyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2F, -CH2CI, -CH2CH2F, - CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CH(CH 3 )CH 2 F, -CH(CH 3 )CH 2 C1, -CH2CN, -CH2CH2CN, -CH2CH2CH2CN, and -CH(CH3)CH2CN.
  • each of R 21a , R 2 ⁇ , R 21C , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, - OH, -NO2, -CH 2 F, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH 2 CN, and -CH2CH2CN.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH 2 , -CN, -OH, -NO 2 , -CH 2 F, -CH 2 C1, and -CH 2 CN.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, and C1-C4 alkoxy.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, - CH2CH2OH, -CH2CH2CH2OH, -CH(CH 3 )CH 2 OH, -OCF3, -OCH2CF3, -OCH2CH2CF3, - OCH(CH 3 )CF 3 , -OCH3, -OCH2CH3, -OCH2CH2CH3, and -OCH(CH 3 )CH 3 .
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, - Cl, -NH 2 , -CN, -OH, -NO2, -CH2OH, -CH2CH2OH, -OCF3, -OCH2CF3, -OCH3, and - OCH2CH3.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -CH2OH, -OCF3, -OCH2CF3, and -OCH3.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkylamino, (C1-C4)(C1- C4) dialkylamino, and C1-C4 aminoalkyl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, - NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH 3 )CH3, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , - N(CH 2 CH 2 CH3) 2 , -N(CH(CH 3 )CH 3 )2, -N(CH 3 )(CH 2 CH 3 ), -CH2NH2, -CH2CH2NH2, - CH2CH2CH2NH2, and -CH(CH3)CH2NH2.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, - NHCH3, -NHCH2CH3, -N(CH 3 ) 2 , -N(CH 2 CH 3 ) 2 , -N(CH 3 )(CH 2 CH 3 ), -CH2NH2, and - CH2CH2NH2.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, -Cl, -NH2, -CN, -OH, -NO2, -NHCH3, -N(CHs)2, and - CH2NH2.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen and halogen.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen, -F, and -Cl.
  • each of R 21a , R 21b , R 21C , R 21d , and R 21e is independently selected from hydrogen and -Cl.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen and - F.
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is independently selected from hydrogen and -CO2R 10 .
  • each of R 21a , R 21b , R 21c , R 21d , and R 21e is hydrogen. i. CY 1 GROUPS
  • Cy 1 when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is unsubstituted.
  • Cy 1 when present, is selected from a 3- to 10-membered cycloalkyl and a 3- to 10-membered heterocycloalkyl, and is monosubstituted with a group
  • 3- to 10-membered cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2,2]pentanyl, norbomyl, adamantly, and camphor.
  • Cy 1 when present, is an unsubstituted 3- to 10-membered cycloalkyl.
  • Cy 1 is an unsubstituted C3-C6 cycloalkyl.
  • Cy 1 is selected from norbomyl, adamantly, and camphor, and is unsubstituted.
  • 3- to 10-membered heterocyclyls include, but are not limited to, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, thiazolidine, oxazolidine, imidazolidine, tetrahydropyran, tetrahydrothiopyran, piperazine, piperidine, and morpholine.
  • Cy 1 when present, is an unsubstituted 3- to 10-membered heterocycloalkyl.
  • Cy 1 when present, is an unsubstituted piperidinyl.
  • Cy 1 when present, is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.
  • 5- to 10-membered heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, benzothiazole, benzoxazole, quinolone, isoquinoline, pyridine, and pyrazine.
  • Cy 1 when present, is an unsubstituted 5- to 10-membered heteroaryl.
  • Cy 1 when present, is an unsubstituted 6- to 10-membered aryl.
  • Cy 1 when present, is an unsubstituted 6-membered aryl.
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl, a 6- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl, a 6- to 10-membered heterocycloalkyl, a 5- to 10- membered heteroaryl, and a 6- to 10-membered aryl, 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl, a 6- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, 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, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10- membered cycloalkyl, a 6- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is monosubstituted with a group 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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl, a 6- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is unsubstituted.
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl and a 6- to 10-membered 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, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl and a 6- to 10- membered 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, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CHzCy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl and a 6- to 10-membered 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, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10-membered cycloalkyl and a 6- to 10-membered heterocycloalkyl, and is 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 6- to 10- membered cycloalkyl and a 6- to 10-membered heterocycloalkyl, and is unsubstituted.
  • Cy 2 is a 6- to 10-membered 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, -CH2Cy 3 , and Cy 3 .
  • 6- to 10-membered cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2,2]pentanyl, norbomyl, adamantly, and camphor
  • Cy 2 is a 6- to 10-membered cycloalkyl 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, -CH2Cy 3
  • Cy 2 is a 6- to 10-membered 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, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is a 6- to 10-membered cycloalkyl 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is an unsubstituted 6- to 10-membered cycloalkyl.
  • Cy 2 is selected from norbomyl, adamantly, and camphor, 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from norbomyl, adamantly, and camphor, 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from norbomyl, adamantly, and camphor, 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, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from norbomyl, adamantly, and camphor, and is monosubstituted with a group 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is selected from norbomyl, adamantly, and camphor, and is unsubstituted.
  • Cy 2 is a 6- to 10-membered heterocycloalkyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, Cl- 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, -CH2Cy 3 , and Cy 3 .
  • 6- to 10-membered heterocyclyls include, but are not limited to, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, thiazolidine, oxazolidine, imidazolidine, tetrahydropyran, tetrahydrothiopyran, piperazine, piperidine, and morpholine.
  • Cy 2 is a 6- to 10-membered heterocycloalkyl 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is a 6- to 10-membered 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, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is a 6- to 10-membered heterocycloalkyl monosubstituted with a group 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, -Cl hCy 3 , and Cy 3 .
  • Cy 2 is an unsubstituted 6- to 10-membered heterocycloalkyl.
  • Cy 2 is selected a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, 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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, 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, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH 2 , -OH, -NO 2 , C1-C4 alkyl, C2-C4 alkenyl, Cl- 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, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered 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, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.
  • Cy 2 is a 5- to 10-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, -CH 2 Cy 3 , and Cy 3 .
  • 5- to 10-membered heteroaryls include, but are not limited to, oxazole, oxadiazole, indole, indazole, isoindole, benzothiazole, benzoxazole, quinoline, isoquinoline, pyridine, and pyrazine.
  • Cy 2 is a 5- to 10- 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, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is a 5- to 10-membered heteroaryl 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, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is a 5- to 10-membered heteroaryl 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, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is an unsubstituted 5- to 10-membered heteroaryl.
  • Cy 2 is a 6- to 10-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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 .
  • 6- to 10-membered aryls include, but are not limited to, phenyl and naphthyl.
  • Cy 2 is a 6- to 10-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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is a 6- to 10-membered 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, -CH 2 Cy 3 , and Cy 3 .
  • Cy 2 is a 6- to 10-membered aryl 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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH 2 Cy 3 , and Cy 3 .
  • halogen -CN, -NH 2 , -OH, -NO 2
  • C1-C4 alkyl C2-C4 alkenyl
  • C1-C4 haloalkyl C1-C4 cyanoalkyl
  • C1-C4 hydroxyalkyl C
  • Cy 2 is an unsubstituted 6- to 10-membered aryl.
  • Cy 2 is 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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CfrhCy 3 , and Cy 3 .
  • Cy 2 is 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is a 6-membered 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, (Cl- C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is a 6-membered aryl 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, -CH2Cy 3 , and Cy 3 .
  • Cy 2 is an unsubstituted 6-membered aryl.
  • Cy 2 is a 6-membered aryl para-substituted a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4 aminoalkyl, -QHCy 3 , and Cy 3 .
  • Cy 2 is a 6-membered aryl para-substituted a group selected from -CH2Cy 3 and Cy 3 . k. CY 3 GROUPS
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, 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, (Cl- C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, 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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, 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, Cl- C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is monosubstituted with a group 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 Cl -C4 aminoalkyl.
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is unsubstituted.
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl and a 3- to 10-membered 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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl and a 3- to 10-membered 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 3 when present, is selected from a 3- to 10-membered cycloalkyl and a 3- to 10-membered 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.
  • Cy 3 when present, is selected from a 3- to 10-membered cycloalkyl and a 3- to 10-membered heterocycloalkyl, and is 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, and C1-C4 aminoalkyl.
  • Cy 3 when present, is selected from a 3- to 10- membered cycloalkyl and a 3- to 10-membered heterocycloalkyl, and is unsubstituted.
  • Cy 3 when present, is a 3- to 10-membered cycloalkyl substituted with 0, 1 , 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • 3- to 10-membered cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, spiro[2,2]pentanyl, norbomyl, adamantly, and camphor.
  • Cy 3 when present, is a 3 - to 10- membered cycloalkyl 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 3 when present, is a 3- to 10-membered 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 3 when present, is a 3- to 10-membered cycloalkyl 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, and Cl -C4 aminoalkyl.
  • Cy 3 when present, is an unsubstituted 3- to 10-membered cycloalkyl.
  • Cy 3 when present, is a 3- to 10-membered heterocycloalkyl 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, and C1-C4 aminoalkyl.
  • 3- to 10-membered heterocyclyls include, but are not limited to, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, thiazolidine, oxazolidine, imidazolidine, tetrahydropyran, tetrahydrothiopyran, piperazine, piperidine, and morpholine.
  • Cy 3 when present, is a 3- to 10-membered heterocycloalkyl 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 3 when present, is a 3- to 10-membered 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, and C1-C4 aminoalkyl.
  • Cy 3 when present, is a 3- to 10-membered 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, and Cl -C4 aminoalkyl.
  • Cy 3 when present, is an unsubstituted 3- to 10-membered heterocycloalkyl.
  • Cy 3 when present, is triazo lyl 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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 3 when present, is triazolyl 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 3 when present, is triazolyl 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 3 when present, is triazolyl 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, and C1-C4 aminoalkyl.
  • Cy 3 when present, is an unsubstituted triazolyl.
  • Cy 3 when present, is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, 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, C 1 -C4 alkylamino, (C 1 -C4)(C 1 -C4) dialkylamino, and C 1 -C4 aminoalkyl.
  • Cy 3 when present, is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, 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 3 when present, is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is substituted with 0 or 1 group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, Cl- C4 haloalkyl, C1-C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C 1 -C4 alkoxy, C 1 -C4 alkylamino, (C 1 -C4)(C 1 -C4) dialkylamino, and C 1 -C4 aminoalkyl.
  • Cy 3 when present, is selected from a 5- to 10-membered heteroaryl and a 6- to 10- membered aryl, and is 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, and Cl -C4 aminoalkyl.
  • Cy 3 when present, is selected from a 5- to 10-membered heteroaryl and a 6- to 10-membered aryl, and is unsubstituted.
  • Cy 3 when present, is a 5- to 10-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, and C1-C4 aminoalkyl.
  • 5- to 10-membered heteroaryls include, but are not limited to, furan, triazole, benzoimidazole, oxazole, oxadiazole, indole, indazole, isoindole, benzothiazole, benzoxazole, quinoline, isoquinoline, pyridine, and pyrazine.
  • Cy 3 when present, is a 5- to 10-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, Cl- C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 3 when present, is a 5- to 10-membered heteroaryl substituted with 0 or 1 group 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 3 when present, is a 5- to 10-membered heteroaryl monosubstituted with a group selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 haloalkyl, Cl- C4 cyanoalkyl, C1-C4 hydroxyalkyl, C1-C4 haloalkoxy, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, and C1-C4 aminoalkyl.
  • Cy 3 when present, is an unsubstituted a 5- to 10-membered heteroaryl.
  • Cy 3 when present, is a 6- to 10-membered aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, Cl- 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 3 when present, is a 6- to 10-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, and C1-C4 aminoalkyl.
  • Cy 3 when present, is a 6- to 10-membered 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 3 when present, is a 6- to 10-membered aryl 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, and C1-C4 aminoalkyl.
  • Cy 3 when present, is an unsubstituted 6- to 10- membered aryl.
  • a compound can be present as:
  • a compound can be present as: or a pharmaceutically acceptable salt thereof.
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as:
  • a compound can be present as: or a pharmaceutically acceptable salt thereof.
  • a compound can be present as:
  • a compound can be present as: or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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 and II, 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.
  • a disclosed compound can be prepared as shown below.
  • R 3 is hydrogen and R 4 is -NHCH2C(O)N(R 12 )Cy 2 , however, as would be appreciated by one of ordinary skill in the art, the same synthetic protocol could be utilized to access compounds in which R 3 is -NHCH2C(O)N(R 12 )Cy 2 and R 4 is hydrogen.
  • R 4 is hydrogen.
  • compounds of type 1.14 can be prepared according to reaction Scheme IB above.
  • compounds of type 1.10 can be prepared by a coupling reaction between an appropriate sulfonyl halide, e.g., 1.8 as shown above, and appropriate amine, e.g., 1.9 as shown above.
  • Appropriate sulfonyl halides and 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 base, e.g., pyridine as shown above, for an appropriate period of time, e.g., 16 hours as shown above.
  • Compounds of type 1.11 can be prepared by reduction of of an appropriate nitrobenzene derivative, e.g., 1.10 as shown above. The reduction is carried out in the presence of an appropriate reducing agent, e.g., tetrahydroxydiboron as shown above, and an appropriate base, e.g., sodium hydroxide as shown above, in an appropriate solvent system, e.g., 3:1 methanokwater, for an appropriate period of time, e.g., 1 to 3 hours.
  • Compounds of type 1.12 can be prepared by reductive amination of an appropriate aniline derivative, e.g., 1.12 as shown above.
  • reaction is carried out in the presence of an appropriate carboxylic acid, e.g, glyoxylic acid as shown above, an appropriate reducing agent, e.g., sodium cyanoborohydride as shown above, in an appropriate solvent, e.g., ethanol, for an appropriate period time, e.g., 1 to 6 hours.
  • an appropriate carboxylic acid e.g., glyoxylic acid as shown above
  • an appropriate reducing agent e.g., sodium cyanoborohydride as shown above
  • an appropriate solvent e.g., ethanol
  • an appropriate period time e.g., 1 to 6 hours.
  • Compounds of type 1.14 can be prepared by a coupling reaction between an appropriate carboxylic acid, e.g., 1.12 as shown above, and an appropriate amine, e.g., 1.13 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 coupling agent, e.g., N,N’- dicyclohexylcarbodiimide (DCC) as shown above, in an appropriate solvent, e.g., dichloromethane (DCM) as shown above, for an appropriate period time, e.g., 16 hours.
  • an appropriate coupling agent e.g., N,N’- dicyclohexylcarbodiimide (DCC) as shown above
  • an appropriate solvent e.g., dichloromethane (DCM) as shown above
  • an appropriate period time e.g. 16 hours.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 1.1, 1.2, 1.3, 1.4, 1.5, and 1.6), can be substituted in the reaction to provide substituted compounds similar to Formula 1.7.
  • a disclosed compound can be prepared as shown below.
  • R 3 is hydrogen and R 4 is -NHR 11 , however, as would be appreciated by one of ordinary skill in the art, the same synthetic protocol could be utilized to access compounds in which R 3 is -NR 11 and R 4 is hydrogen. A more specific example is set forth below.
  • compounds of type 2.6 can be prepared according to reaction Scheme 2B above.
  • compounds of type 2.6 can be prepared by alkylation of an appropriate aniline derivative, e.g. , 2.4 as shown above, using an appropriate alkyl halide, e..g, 2.5 as shown above.
  • Appropriate alkyl halides are commercially available or prepared by methods known to one skilled in the art.
  • the alkylation reaction is carried out in the presence of an appropriate base, e.g., cesium carbonate as shown above, in an appropriate solvent, e.g., dimethylformamide.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1 and 2.2), can be substituted in the reaction to provide substituted compounds similar to Formula 2.3.
  • compositions comprising a disclosed compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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, (
  • compositions comprising an effective amount of a compound having a structure selected from:
  • the compound has a structure as disclosed herein above, provided that (a) when R 1 is Cy 1 , Cy 1 is a 5- to 10-membered heteroaryl or a 6- to 10- membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10- membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • the compound is selected from:
  • 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, 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. Excipients that can be used include buffers (for example, citrate buffer, phosphate buffer, acetate buffer, and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, polypeptides (for example, serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, water, and glycerol.
  • nucleic acids, polypeptides, small molecules, and other modulatory compounds featured in the invention can be administered by any standard route of administration.
  • administration can be parenteral, intravenous, subcutaneous, or oral.
  • a modulatory compound can be formulated in various ways, according to the corresponding route of administration.
  • 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.
  • the instant compositions include those suitable for oral, rectal, topical, and parenteral (including subcutaneous, intramuscular, and intravenous) administration, although the most suitable route in any given case will depend on the particular host, and nature and severity of the conditions for which the active ingredient is being administered.
  • the pharmaceutical compositions can be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of pharmacy.
  • 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.
  • any convenient pharmaceutical media can be employed.
  • water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used to form oral liquid preparations such as suspensions, elixirs and solutions; while carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets.
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like can be used to form oral solid preparations such as powders, capsules and tablets.
  • 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.
  • compositions of the present invention comprise a compound of the invention (or pharmaceutically acceptable salts thereof) as an active ingredient, a pharmaceutically acceptable carrier, and optionally one or more additional therapeutic agents or adjuvants.
  • the instant compositions include compositions suitable for oral, rectal, topical, 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.
  • compositions of the present invention suitable for parenteral administration can be prepared as solutions or suspensions of the active compounds in water.
  • a suitable surfactant can be included such as, for example, hydroxypropylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, a preservative can be included to prevent the detrimental growth of microorganisms.
  • 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.
  • compositions of the present invention can be in a form suitable for topical use such as, for example, an aerosol, cream, ointment, lotion, dusting powder, mouth washes, gargles, and the like. Further, the compositions can be in a form suitable for use in transdermal devices. These formulations can be prepared, utilizing a compound of the invention, or pharmaceutically acceptable salts thereof, via conventional processing methods. As an example, a cream or ointment is prepared by mixing hydrophilic material and water, together with about 5 wt% to about 10 wt% of the compound, to produce a cream or ointment having a desired consistency.
  • compositions of this invention can be in a form suitable for rectal administration wherein the carrier is a solid. It is preferable that the mixture forms unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art. The suppositories can be conveniently formed by first admixing the composition with the softened or melted carrier(s) followed by chilling and shaping in molds.
  • 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.
  • 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
  • an effective amount is a therapeutically effective amount. In a still further aspect, 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 to treat cancer such as, for example, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • cancer such as, for example, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer
  • n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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-
  • the compound has a structure as disclosed herein above, provided that (a) when R 1 is Cy 1 , Cy 1 is a 5- to 10-membered heteroaryl or a 6- to 10- membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10- membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • the subject has been diagnosed with a need for treatment of a disorder related to loss of p53 activity prior to the administering step.
  • the disorder is cancer.
  • 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, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
  • the cancer is a solid tumor.
  • the cancer is breast cancer.
  • the subject has been diagnosed with a need for restoration
  • the subject is a mammal.
  • the mammal is a human.
  • the method further comprises the step of identifying a subject in need of treatment of a disorder related to loss of p53 activity prior to the administering step.
  • the disorder is cancer.
  • 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, bladder cancer, thyroid cancer, testicular cancer, pancreatic cancer, endometrial cancer, melanoma, glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, and plasma cell neoplasm (myeloma).
  • the cancer is a solid tumor.
  • the cancer is breast cancer.
  • the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the method further comprises the step of administering a therapeutically effective amount of at least one agent associated with the treatment of cancer.
  • the at least one agent 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 at least one agent is a chemotherapeutic agent or an antineoplastic agent.
  • the chemotherapeutic agent or anti-neoplastic agent is selected from kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HD Ac) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-l)/programmed cell death-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB
  • CTLA-4
  • 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.
  • the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the kinase inhibitor is selected from p38 inhibitors, CDK inhibitors, TNF inhibitors, matrixmetallo proteinase (MMP) inhibitors, COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, SOD mimics, and a v [33 -inhibitors.
  • MMP matrixmetallo proteinase
  • the PARP inhibitor is selected from iniparib, talazoparib, olaparib, rucapariv, veliparib, CEP 9722, AK 4827, BGB-290 and 3 -aminobenzamide.
  • the epigenetic agent is selected from a histone deacetylase inhibitor and a DNA methylation inhibitor.
  • the epigenetic agent is a BET inhibitor.
  • the BET inhibitor is selected from JQ1, 1-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010 (Tensha therapeutics), CPI- 203, RVX-208 (Resverlogix Corp), LY294002, MK-8628 (Merck/Mitsubishi Tanabe), BMS- 986158 (Bristol-Myers Squibb), INCB54329 (Incyte Pharmaceuticals), ABBV-075 (Abb Vie, also called ABV-075), CPI-0610 (Constellation Pharmaceuticals/Roche), FT-1101 (Forma Therapeutics/Celgene), GS-5829 (Gilead Sciences), and
  • the HD Ac inhibitor is selected from pracinostat and panobinostat.
  • the ribonuclotide reductase inhibitor is selected from fludarabine, cladribine, gemcitabine, tezacitabine, triapine, motexafrn gadolinium, hydroxyurea, gallium maltolate, and gallium nitrate.
  • the ribonuclotide reductase inhibitor is an iron chelator.
  • the proteasome inhibitor is selected from lactacystin and bortezomib.
  • the NAE inhibitor is a 1 -substituted methyl sulfamate. In a still further aspect, the NAE inhibitor is MLN4924.
  • the immune checkpoint blockade agent is selected from anti-PD-Ll antibodies, anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, anti-TEVI3 antibodies, antibodies to PD-1, CTLA-4, BTLA, TIM-3, LAG-3, CD 160, TIGIT, LAIR1, and 2B4, antibodies to the corresponding ligands for these receptors including, but not limited to, PD-L1 (for PD-1), PD-L2 (for PD-1), CD80 and CD86 (for CTLA-4), HVEM (for BTLA), Galectin-9 and HMGB1 (for TIM-3), MHC II (for LAG-3), HVEM (for CD 160), CD 155, CD112, and CD113 (for TIGIT), Clq and collagen (for LAIR1), and CD48 (for 2B4).
  • the immune checkpoint blockade agent is selected from CTL-4 mAb
  • the TLR agonist is selected from CRX-527 and OM-174.
  • the cell therapeutic is selected from CAR-T cell therapy and
  • the compound and the agent are administered sequentially. In a still further aspect, the compound and the agent are administered simultaneously.
  • the compound and the agent are co-formulated. In a still further aspect, the compound and the agent are co-packaged.
  • disclosed are methods of restoring p53 activity in a cell comprising the step of contacting the cell with an effective amount of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.
  • methods of restoring p53 activity in a cell comprising contacting the cell with an effective amount of a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10- membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 groups independently selected from halogen, -CN, -NH 2 , -OH, -NO 2 , C1-C4 alkyl, C2-
  • Also disclosed are methods of restoring p53 activity in a cell the method comprising contacting the cell with an effective amount of a compound having a structure selected from: or a pharmaceutically acceptable salt thereof.
  • the compound has a structure as disclosed herein above, provided that (a) when R 1 is Cy 1 , Cy 1 is a 5- to 10-membered heteroaryl or a 6- to 10- membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10- membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • the cell is a cancer cell.
  • the cell is present in a tissue sample.
  • the tissue sample is a malignant tissue sample.
  • the cell is human. In a further aspect, the cell has been isolated from a human prior to the administering step.
  • contacting is via administration to a subject.
  • the subject has been diagnosed with a need for restoration of p53 activity prior to the administering step.
  • the subject has been diagnosed with a need for treatment of cancer prior to the administering step.
  • cancers include, but are not limited to, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a sarcoma a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer,
  • n is selected from 0 and 1; wherein L is selected from -SO2CH2-, -N(R 2 )SO2-, and -SO2N(R 2 )-; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl, C1-
  • the compound has a structure as detailed herein above, provided that (a) when R 1 is Cy 1 , Cy 1 is a 5- to 10-membered heteroaryl or a 6- to 10- membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10- membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • L is -N(R 2 )SO2- In a further aspect, L is -SO2N(R 2 )-. In a still further aspect, one of R 3 and R 4 is N(R n )CH2C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 )mN(R 12 )Cy 2 , or -CH 2 N(R n )C(O)N(R 12 )Cy 2 .
  • R 3 is N(R n )CH2C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 )mN(R 12 )Cy 2 , or -CH 2 N(R n )C(O)N(R 12 )Cy 2 .
  • R 4 is N(R n )CH 2 C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 ) m N(R 12 )Cy 2 , or -CH2N(R n )C(O)N(R 12 )Cy 2 .
  • each of R 3 and R 4 is hydrogen and R 6 is -CH 2 N(R 11 )C(O)N( R 12 )Cy 2 .
  • the compound has a structure represented by a formula: wherein one of R 3 and R 4 is hydrogen and one of R 3 and R 4 is -N(R n )CH2C(O)N(R 12 )Cy 2 ; wherein each of R 5a , R 5b , and R 5c 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, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.
  • the compound is not: or a pharmaceutically acceptable salt thereof. [00317] In various aspects, the compound is selected from:
  • the compound is selected from:
  • the subject has been diagnosed with a need for treatment of cancer prior to the administering step.
  • the subject has been diagnosed with Li-Fraumeni syndrome (LFS) prior to the administering step.
  • LFS Li-Fraumeni syndrome
  • the subject is a mammal.
  • the mammal is a human.
  • the method further comprises the step of identifying a subject in need of treatment of cancer.
  • the cancer is a primary or secondary tumor.
  • the primary or secondary tumor is within the subject’s brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.
  • the cancer is selected from a sarcoma, a carcinoma, a head- and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a sarcoma a carcinoma, a head- and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer,
  • the cancer is selected from pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer.
  • lung cancer is small cell lung carcinoma.
  • the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the cancer is associated with loss of p53 activity.
  • the cancer is associated with cells that express a mutant p53.
  • the mutant p53 is a somatic mutation.
  • the mutant p53 contains a mutation at an amino acid residue selected from V157F, R175, H179, R213, Y220, M237 G245, R248, R249, R273, and R282.
  • the mutant p53 is a mutation associated with LFS.
  • the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R248Q, R248W, R273H, R282W, Y220C, V157F, R337H, and R175H. In an even further aspect, the mutant p53 contains a mutation selected from Y220C, Y107H, A138V, V157F, and R175H.
  • administering is oral or parental administration.
  • parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.
  • the method further comprises administering a therapeutically effective amount of an anti-cancer agent or radiotherapy to the subject.
  • the anti-cancer agent or radiotherapy is administered prior to administration of the compound.
  • the anti-cancer agent or radiotherapy is administered subsequent to administration of the compound.
  • the method further comprises the step of administering a therapeutically effective amount of at least one agent associated with the treatment of cancer.
  • the at least one agent 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 at least one agent is a chemotherapeutic agent or an antineoplastic agent.
  • the chemotherapeutic agent or anti-neoplastic agent is selected from kinase inhibitors, poly ADP ribose polymerase (PARP) inhibitors and other DNA damage response modifiers, epigenetic agents such as bromodomain and extra-terminal (BET) inhibitors, histone deacetylase (HD Ac) inhibitors, iron chelotors and other ribonucleotides reductase inhibitors, proteasome inhibitors and Nedd8-activating enzyme (NAE) inhibitors, mammalian target of rapamycin (mTOR) inhibitors, traditional cytotoxic agents such as paclitaxel, dox, irinotecan, and platinum compounds, immune checkpoint blockade agents such as cytotoxic T lymphocyte antigen-4 (CTLA-4) monoclonal antibody (mAB), programmed cell death protein 1 (PD-l)/programmed cell death-ligand 1 (PD-L1) mAB, cluster of differentiation 47 (CD47) mAB
  • CTLA-4
  • 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.
  • the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the kinase inhibitor is selected from p38 inhibitors, CDK inhibitors, TNF inhibitors, matrixmetallo proteinase (MMP) inhibitors, COX-2 inhibitors, including celecoxib, rofecoxib, parecoxib, valdecoxib, and etoricoxib, SOD mimics, and a v [33 -inhibitors.
  • MMP matrixmetallo proteinase
  • the PARP inhibitor is selected from iniparib, talazoparib, olaparib, rucapariv, veliparib, CEP 9722, AK 4827, BGB-290 and 3 -aminobenzamide.
  • the epigenetic agent is selected from a histone deacetylase inhibitor and a DNA methylation inhibitor. In a still further aspect, the epigenetic agent is a BET inhibitor.
  • the BET inhibitor is selected from JQ1, 1-BET 151 (GSK1210151A), I-BET 762 (GSK525762), OTX-015, TEN-010 (Tensha therapeutics), CPI- 203, RVX-208 (Resverlogix Corp), LY294002, MK-8628 (Merck/Mitsubishi Tanabe), BMS- 986158 (Bristol-Myers Squibb), INCB54329 (Incyte Pharmaceuticals), ABBV-075 (Abb Vie, also called ABV-075), CPI-0610 (Constellation Pharmaceuticals/Roche), FT-1101 (Forma Therapeutics/Celgene), GS-5829 (Gilead Sciences), and PLX51107 (Daiichi Sankyo).
  • the HD Ac inhibitor is selected from pracinostat and panobinostat.
  • the ribonuclotide reductase inhibitor is selected from fludarabine, cladribine, gemcitabine, tezacitabine, triapine, motexafrn gadolinium, hydroxyurea, gallium maltolate, and gallium nitrate.
  • the ribonuclotide reductase inhibitor is an iron chelator.
  • the proteasome inhibitor is selected from lactacystin and bortezomib.
  • the NAE inhibitor is a 1 -substituted methyl sulfamate. In a still further aspect, the NAE inhibitor is MLN4924.
  • the immune checkpoint blockade agent is selected from anti-PD-Ll antibodies, anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-LAG3 antibodies, anti-B7-H3 antibodies, anti-TEVI3 antibodies, antibodies to PD-1, CTLA-4, BTLA, TIM-3, LAG-3, CD 160, TIGIT, LAIR1, and 2B4, antibodies to the corresponding ligands for these receptors including, but not limited to, PD-L1 (for PD-1), PD-L2 (for PD-1), CD80 and CD86 (for CTLA-4), HVEM (for BTLA), Galectin-9 and HMGB1 (for TIM-3), MHC II (for LAG-3), HVEM (for CD 160), CD 155, CD112, and CD113 (for TIGIT), Clq and collagen (for LAIR1), and CD48 (for 2B4).
  • the immune checkpoint blockade agent is selected from CTL-4 mAb
  • the TLR agonist is selected from CRX-527 and OM-174.
  • the cell therapeutic is selected from CAR-T cell therapy and CAR-NK cell therapy.
  • the compound and the agent are administered sequentially. In a still further aspect, the compound and the agent are administered simultaneously. [00345] In a further aspect, the compound and the agent are co-formulated. In a still further aspect, the compound and the agent are co-packaged.
  • n is selected from 0 and 1; wherein L is selected from -SO2CH2-, -N(R 2 )SO2-, and -SO2N(R 2 )-; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 hal
  • LFS Li-Fraumeni syndrome
  • R 1 when R 1 is Cy 1 , Cy 1 is a 5- to 10- membered heteroaryl or a 6- to 10-membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • the effective amount is a therapeutically effective amount. In a further aspect, the effective amount is a prophylactically effective amount. [00350] In various aspects, the subject is a mammal. In a further aspect, the mammal is a human.
  • the subject has been diagnosed with a need for treatment of cancer prior to the administering step.
  • the cancer is selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer.
  • the subject has not been diagnosed with a need for treatment of cancer prior to the administering step.
  • the subject has been diagnosed with LFS prior to the administering step.
  • the method further comprises the step of identifying a subject in need of treatment of LFS.
  • LFS is associated with loss of p53 activity.
  • the LFS is associated with cells that express a mutant p53.
  • the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R248Q, R248W, R273H, R282W, Y220C, V157F, R337H, and R175H.
  • administering is oral or parental administration.
  • parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.
  • L is -N(R 2 )SO2- In a further aspect, L is -SO2N(R 2 )-.
  • one of R 3 and R 4 is N(R n )CH2C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 ) m N(R 12 )Cy 2 , or -CH 2 N(R n )C(O)N(R 12 )Cy 2 .
  • R 3 is N(R n )CH 2 C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 ) m N(R 12 )Cy 2 , or -CH2N(R n )C(O)N(R 12 )Cy 2 .
  • R 4 is N(R n )CH 2 C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 ) m N(R 12 )Cy 2 , or -CH2N(R n )C(O)N(R 12 )Cy 2 .
  • each of R 3 and R 4 is hydrogen and R 6 is -CH 2 N(R 11 )C(O)N( R 12 )Cy 2 .
  • the compound has a structure represented by a formula: wherein one of R 3 and R 4 is hydrogen and one of R 3 and R 4 is -N(R n )CH2C(O)N(R 12 )Cy 2 ; wherein each of R 5a , R 5b , and R 5c is independently selected from hydrogen, 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, or a pharmaceutically acceptable salt thereof. or a pharmaceutically acceptable salt thereof.
  • the compound is selected from:
  • the compound is selected from:
  • n is selected from 0 and 1; wherein L is selected from -SO2CH2-, -N(R 2 )SO2-, and -SO2N(R 2 )-; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 groups independently selected from halogen, -CN, -NH2, -OH, -NO2, C1-C4 alkyl, C2- C4 alkenyl, C1-C4 haloalkyl
  • the subject has not yet been diagnosed as having cancer.
  • the compound has a structure as detailed herein above, provided that (a) when R 1 is Cy 1 , Cy 1 is a 5- to 10-membered heteroaryl or a 6- to 10- membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10- membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • L is -N(R 2 )SO2- In a further aspect, L is -SO2N(R 2 )-. In a still further aspect, one of R 3 and R 4 is N(R n )CH2C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 ) m N(R 12 )Cy 2 , or -CH 2 N(R n )C(O)N(R 12 )Cy 2 .
  • R 3 is N(R n )CH2C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 ) m N(R 12 )Cy 2 , or -CH 2 N(R n )C(O)N(R 12 )Cy 2 .
  • R 4 is N(R n )CH 2 C(O)N(R 12 )Cy 2 , -N(R n )C(O)(CH 2 ) m N(R 12 )Cy 2 , or -CH2N(R n )C(O)N(R 12 )Cy 2 .
  • each of R 3 and R 4 is hydrogen and R 6 is -CH 2 N(R 11 )C(O)N( R 12 )Cy 2 .
  • the compound has a structure represented by a formula: wherein one of R 3 and R 4 is hydrogen and one of R 3 and R 4 is -N(R n )CH2C(O)N(R 12 )Cy 2 ; wherein each of R 5a , R 5b , and R 5c 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, and C1-C4 aminoalkyl, or a pharmaceutically acceptable salt thereof.
  • the compound is not:
  • the compound is selected from:
  • the compound is selected from: or a pharmaceutically acceptable salt thereof.
  • the subject has been diagnosed with a need for prevention and/or treatment of cancer prior to the administering step.
  • the subject has been diagnosed with Li-Fraumeni syndrome (LFS) prior to the administering step.
  • LFS Li-Fraumeni syndrome
  • the subject is a mammal.
  • the mammal is a human.
  • the method further comprises the step of identifying a subject in need of cancer treatment (z.e., a subject having LFS who has not yet been diagnosed as having cancer).
  • the subject is at risk for developing cancer such as, for example, a primary or secondary tumor.
  • subject is at risk for developing a primary or secondary tumor within their brain, breast, kidney, pancreas, lung, colon, prostate, lymphatic system, liver, ovary, or cervix.
  • the subject is at risk for developing a cancer selected from a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, nonsmall cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a cancer selected from a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer,
  • the subject is at risk for developing a cancer selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer.
  • a cancer selected from pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer.
  • lung cancer is small cell lung carcinoma.
  • the effective amount is a therapeutically effective amount. In a still further aspect, the effective amount is a prophylactically effective amount.
  • the cancer is associated with loss of p53 activity.
  • the cancer is associated with cells that express a mutant p53.
  • the mutant p53 is a somatic mutation.
  • the mutant p53 contains a mutation at an amino acid residue selected from V157F, R175, H179, R213, Y220, M237 G245, R248, R249, R273, and R282.
  • the mutant p53 is a mutation associated with LFS.
  • the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R248Q, R248W, R273H, R282W, Y220C, V157F, R337H, and R175H. In an even further aspect, the mutant p53 contains a mutation selected from Y220C, V157F, and R175H.
  • administering is oral or parental administration.
  • parenteral administration is intravenous, subcutaneous, intramuscular, or via direct injection.
  • the compounds and pharmaceutical compositions of the invention are useful in treating or controlling disorders related to restoration of p53 activity, and, in particular, cancer.
  • cancers for which the compounds and compositions can be useful in treating include, but are not limited to, a sarcoma, a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a sarcoma a carcinoma, a head-and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer
  • the compounds and pharmaceutical compositions comprising the compounds are administered to a subject in need thereof, such as a vertebrate, e.g., a mammal, a fish, a bird, a reptile, or an amphibian.
  • the subject can be a human, non-human primate, horse, pig, rabbit, dog, sheep, goat, cow, cat, guinea pig or rodent.
  • the term does not denote a particular age or sex. Thus, adult and newborn subjects, as well as fetuses, whether male or female, are intended to be covered.
  • the subject is preferably a mammal, such as a human.
  • the subject Prior to administering the compounds or compositions, the subject can be diagnosed with a need for treatment of cancer.
  • 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. In general, in the case of oral or parenteral administration to adult humans weighing approximately 70 Kg or more, a daily dosage of about 10 mg to about 10,000 mg, preferably from about 200 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, as a continuous infusion. Single dose compositions can contain such amounts or submultiples thereof of the compound or composition to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days.
  • the invention relates to the use of a disclosed compound or a product of a disclosed method.
  • a use relates to the manufacture of a medicament for the treatment of cancer in a subject.
  • 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
  • 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 use relates to a treatment of cancer in a subject.
  • the use is characterized in that the subject is a human.
  • the use is characterized in that the cancer is pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, or ovarian cancer.
  • the use relates to the manufacture of a medicament for the treatment of cancer in a subject.
  • 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 of uncontrolled cellular proliferation in a mammal.
  • the invention relates to a method for the manufacture of a medicament for treating cancer in a subject having the disorder, 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.
  • the present method includes the administration to an animal, particularly a mammal, and more particularly a human, of a therapeutically effective amount of the compound effective in the treatment of cancer.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to affect a therapeutic response in the animal over a reasonable time-frame.
  • dosage will depend upon a variety of factors including the condition of the animal and the body weight of the animal.
  • the total amount of the compound of the present disclosure administered in a typical treatment is preferably between about 0.05 mg/kg and about 100 mg/kg of body weight for mice, and more preferably between 0.05 mg/kg and about 50 mg/kg of body weight for mice, and between about 100 mg/kg and about 500 mg/kg of body weight, and more preferably between 200 mg/kg and about 400 mg/kg of body weight for humans per daily dose.
  • This total amount is typically, but not necessarily, administered as a series of smaller doses over a period of about one time per day to about three times per day for about 24 months, and preferably over a period of twice per day for about 12 months.
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature and extent of any adverse side effects that might accompany the administration of the compound and the desired physiological effect. It will be appreciated by one of skill in the art that various conditions or disease states, in particular chronic conditions or disease states, may require prolonged treatment involving multiple administrations.
  • the invention relates to the manufacture of a medicament comprising combining a disclosed compound or a product of a disclosed method of making, or a pharmaceutically acceptable salt, solvate, or polymorph thereof, with a pharmaceutically acceptable carrier or diluent.
  • kits comprising an effective amount of a disclosed compound, and one or more selected from: (a) an anti-cancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.
  • kits comprising a compound having a structure represented by a formula: wherein n is selected from 0 and 1; wherein L is selected from -N(R 2 )SO2- and -SO2N(R 2 )-; wherein R 1 is selected from C1-C8 alkyl and Cy 1 ; wherein Cy 1 , when present, is selected from a 3- to 10-membered cycloalkyl, a 3- to 10-membered heterocycloalkyl, a 5- to 10- membered heteroaryl, and a 6- to 10-membered aryl, and is substituted with 0, 1, 2, 3, or 4 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 haloalk
  • kits comprising a compound having a structure: or a pharmaceutically acceptable salt thereof, and one or more selected from: (a) an anticancer agent; (b) instructions for administering the compound in connection with treating cancer; and (c) instructions for treating cancer.
  • the compound has a structure as disclosed herein above, provided that (a) when R 1 is Cy 1 , Cy 1 is a 5- to 10-membered heteroaryl or a 6- to 10- membered aryl, R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , and R 4 is hydrogen, then Cy 2 is a 6- to 10- membered cycloalkyl or a 6- to 10-membered heterocycloalkyl; or (b) when R 1 is Cy 1 , R 3 is -N(R n )CH2C(O)N(R 12 )Cy 2 , R 4 is hydrogen, and Cy 2 is a 5- to 10-membered heteroaryl or a 6- to 10-membered aryl, then Cy 1 is a 6- to 10-membered cycloalkyl or a 6- to 10-membered heterocycloalkyl.
  • the cancer is selected from a sarcoma, a carcinoma, a head- and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer, pancreatic cancer, liver cancer, endometrial cancer, melanoma, a glioma, leukemia, lymphoma, chronic myeloproliferative disorder, myelodysplastic syndrome, myeloproliferative neoplasm, non-small cell lung carcinoma, small cell lung carcinoma, renal cancer, lung cancer, colon cancer, cervical cancer, and plasma cell neoplasm (myeloma).
  • a sarcoma a carcinoma, a head- and-neck cancer, hematological cancer, a solid tumor, breast cancer, cervical cancer, gastrointestinal cancer, colorectal cancer, brain cancer, skin cancer, prostate cancer, ovarian cancer, thyroid cancer, testicular cancer,
  • the cancer is selected from osteosarcoma, soft tissue sarcoma, acute leukemia, breast cancer, brain cancer, an adrenal cortical tumor, stomach cancer, melanoma, Wilms’ tumor, colon cancer, pancreatic cancer, esophageal cancer, lung cancer, and a gonadal germ cell cancer.
  • the cancer is selected from pancreatic cancer, head-and-neck cancer, lung cancer, breast cancer, and ovarian cancer.
  • lung cancer is small cell lung carcinoma.
  • the cancer is associated with loss of p53 activity.
  • the cancer is associated with cells that express a mutant p53.
  • the mutant p53 is a somatic mutation.
  • the mutant p53 contains a mutation at an amino acid residue selected from V157F, R175, H179, R213, Y220, M237 G245, R248, R249, R273, and R282.
  • the mutant p53 is a mutation associated with LFS.
  • the mutant p53 contains a mutation selected from T125M, R181H, R213Q, G245S, R248Q, R248W, R273H, R282W, Y220C, V157F, R337H, and R175H. In an even further aspect, the mutant p53 contains a mutation selected from Y220C, V157F, and R175H.
  • the anti-cancer agent is selected from an alkylating agent, an antimetabolite agent, an antineoplastic antibiotic agent, a mitotic inhibitor agent, a DNA damage-inducing 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.
  • the mTor inhibitor agent is selected from everolimus, siroliumus, and temsirolimus, or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
  • the DNA damage-inducing agent is selected from doxorubicin, cisplatin, 5-Fluorouracin, etoposide, daunorubicin, camptothesin, methotrexate, carboplatin, oxaliplatin, or ionizing radiation.
  • the compound and the anti-cancer agent are co-formulated. In a further aspect, the compound and the anti-cancer agent are co-packaged.
  • kits can also comprise compounds and/or products co-packaged, coformulated, and/or co-delivered with other components.
  • 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, products, and pharmaceutical compositions. It is also understood that the disclosed kits can be employed in connection with the disclosed methods of using. [00411] The foregoing description illustrates and describes the disclosure.
  • Step 1 Compound (1) was dissolved in pyridine to a concentration of 2.5M, followed by addition of 1.2eq compound (2). This reaction was left for 16 hrs at 25 °C.
  • Step 2 Compound (3) was dissolved to a concentration of 0. IM in 3: 1 (MeOH:water) followed by addition of lOeq. NaOH and 4eq. B2(OH4). Reactions were monitored by TLC (50:50, Hexane:EtOAc) for progress; typically, ⁇ 1 hour. Reactions were dried down prior to extraction of compound (4) using EtOAc. Crude product was then purified with normal phase chromatography using a Hexane :EtO Ac gradient and verified
  • Step 3 Compound (4) was dissolved in dry EtOH ( ⁇ 30 mL/g) under nitrogen, followed by addition of leq. glyoxylic acid (5). Sodium cyanob orohydride (1.2eq) was then slowly added. Reactions were monitored by TLC (10:90, MeOH:DCM) for progress; typically, ⁇ 3 hours. Reactions were quenched by addition of excess water and dried onto silica. Compound (6) was then purified with normal phase chromatography using a DCM:MeOH gradient and verified using LC-MS.
  • Step 4 Compound (6) was dissolved in dry DCM under nitrogen along with leq. HOBt then placed on ice with stirring. DCC (1.4eq) was added and left to stir for 30 minutes. Compound (7) was then added slowly (1 eq). Reactions were allowed to reach 25 °C over a 16 hour period. Reactions were filtered and washed with DCM, followed by 0. IM CuSCC washes and dried using brine then MgSCU. Compound (8) was then purified with normal phase chromatography using a Hexane:EtOAc gradient and verified using LC-MS. a.
  • the resulting mixture was concentrated under reduced pressure.
  • the crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Prep Cis OBD Column 30 X 150 mm, 5pm; Mobile Phase A: Water(10mmol/L NH4HCO3+0.1%NH3H2O), Mobile Phase B: MeCN; Flow rate: 60 mL/min; Gradient: 30% B to 46% B in 9 min; Wave Length: 254nm/220nm; RTl(min): 8.33) to afford 2- ⁇ [2-(phenylsulfamoyl)phenyl]amino ⁇ -7V-(lH- pyrrol-2-yl)acetamide (25.5 mg, 9.14%) as a white solid.
  • the crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep Cis OBD Column 30 X 150 mm, 5pm; Mobile Phase A: Water(10mmol/L NH4HC03+0.05%NH3H20), Mobile Phase B: CH3CN; Flow rate: 60 mL/min; Gradient: 37% B to 49%B in 8 min; Wave Length: 254nm/220nm;) to afford N- (5-chloro-2-methoxyphenyl)-2- ⁇ [2-( ⁇ l/7-pyrrolo[2,3-6]pyridin-5- yl ⁇ sulfamoyl)phenyl]amino ⁇ acetamide (20.3 mg, 7.23%yield, 99.4%purity) as a white solid.

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Abstract

La présente invention concerne des composés qui restaurent l'activité de p53 et des méthodes d'utilisation des composés dans le traitement de divers troubles liés à la perte d'activité de p53 tels que, par exemple, le cancer (par exemple, un sarcome, un carcinome, un cancer de la tête et du cou, 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 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, une maladie myéloproliférative chronique, un syndrome myélodysplasique, un néoplasme myéloprolifératif, un carcinome pulmonaire non à petites cellules, un carcinome pulmonaire à petites cellules, un cancer du rein, un cancer du poumon, un cancer du côlon, un cancer du col de l'utérus, et un néoplasme plasmocytaire (myélome)). Le présent abrégé est proposé à titre d'outil d'exploration à des fins de recherche dans cette technique particulière et n'est pas destiné à limiter la présente invention.
PCT/US2024/030622 2023-05-23 2024-05-22 Composés qui réactivent la p53 mutante Pending WO2024243343A2 (fr)

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