US20180161340A1 - Methods and compositions for the prevention and treatment of hearing loss - Google Patents

Methods and compositions for the prevention and treatment of hearing loss Download PDF

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US20180161340A1
US20180161340A1 US15/580,224 US201615580224A US2018161340A1 US 20180161340 A1 US20180161340 A1 US 20180161340A1 US 201615580224 A US201615580224 A US 201615580224A US 2018161340 A1 US2018161340 A1 US 2018161340A1
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hydrogen
further aspect
independently selected
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Jian Zuo
Tai Teitz
Jie Fang
Asli Goktug
Taosheng Chen
Jaeki Min
R. Kiplin Guy
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St Jude Childrens Research Hospital
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Assigned to ST. JUDE CHILDREN'S RESEARCH HOSPITAL reassignment ST. JUDE CHILDREN'S RESEARCH HOSPITAL ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: GOKTUG, Asli, GUY, R. KIPLIN, FANG, Jie, TEITZ, TAL, ZUO, JIAN, CHEN, Taosheng, MIN, JAEKI
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • NIHL Noise-induced hearing loss
  • the World Health Organization recently reported that more than a billion teens and young adults worldwide are at risk of NIHL caused by loud music (http://www.cnn.com/2015/03/06/health/hearing-loss-loud-music/index.html).
  • Acute or chronic acoustic overexposure has put more than 40 million U.S. workers at risk of permanent hearing loss (Kopke et al. (2007) Hear. Res. 226: 114-125).
  • NIHL is also prevalent in military settings, costing more than $2 billion per year in veterans (VA) compensation.
  • PTS threshold shift
  • Cisplatin is known to exhibit toxic effects on hair cells of the inner ear. Indeed, high frequency hearing loss (>8 kHZ) has been reported to be as high as 90% in children undergoing cisplatin therapy (Allen et al. (1998) Otolaryngol Head Neck Surg 118: 584-588). Other clinically important and commonly used drugs also have documented ototoxic effects, including loop diuretics (Greenberg (2000) Am. J. Med. Sci. 319:10-24), antimalarial sesquiterpene lactone endoperoxides (e.g., artemesinins) (Toovey and Jamieson (2004) Trans. R. Soc. Trop. Med. Hyg.
  • ototoxicity to the vestibular system manifests as balance and orientation-related disorders.
  • disorders include, but are not limited to, induced or spontaneous vertigo, dysequilibrium, increased susceptibility to motion sickness, nausea, vomiting, ataxia, labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness, dizziness, increased falling, difficulty walking at night, Meniere's disease, and difficulty in visual tracking and processing.
  • N-acetylcysteine N-acetylcysteine
  • Ebelsen (SPI-1005), a seleno-organic compound with antioxidant activity through glutathione peroxidase-like action, has been tested against TTS in noise-induced excitotoxicity studies but remains unproven in clinical trials (See “Sound Pharmaceuticals Inc. successfully completes its first Phase 2 clinical trial with SPI-1005” (Nov. 5, 2013); Lynch and Kil (2005) Drug Discov. Today 10: 1291-1298). To date, no drugs are FDA-approved for protection against NIHL and traumatic brain injury (TBI)-associated hearing loss. Thus, there remains a need for compositions and methods of preventing and treating hearing loss.
  • TBI traumatic brain injury
  • the invention in one aspect, relates to compositions and methods for use in the prevention and treatment of a hearing impairment.
  • CDK2 cyclin-dependent kinase 2
  • compositions comprising a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; and one or more of: (a) at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof, and (b) at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions comprising a CDK2 inhibitor, wherein the CDK2 inhibitor is not a paullone derivative, or a pharmaceutically acceptable salt thereof; and one or more of: at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof, and at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • Also disclosed are methods of preparing a pharmaceutical composition the method comprising the step of combining a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; and one or more of: (a) at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof; (b) at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof, wherein at least one is present in an effective amount; and a pharmaceutically acceptable carrier.
  • kits comprising a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; and one or more of: (a) at least one agent known to treat a hearing impairment; (b) at least one agent known to prevent a hearing impairment; (c) at least one antibiotic agent; (d) at least one chemotherapeutic agent; (e) instructions for treating a hearing impairment; and (f) instructions for preventing a hearing impairment.
  • kits comprising a compound selected from:
  • FIG. 1 shows a representative plot illustrating the percent activity of the bioactive compounds in a cell-based high-throughput screen.
  • FIG. 2 a - e show representative dose response curves of kenpaullone (compound 4) ( FIG. 2 a ), Olomoucine II (compound 9) ( FIG. 2 b ), CDK2 inhibitor II (compound 12) ( FIG. 2 c ), compound 3 ( FIG. 2 d ), and compound 1 ( FIG. 2 e ), determined using the Caspase-/37 Glo assay and the Promega Cell Titer Glo assay (CTG).
  • CCG Promega Cell Titer Glo assay
  • FIG. 3A-G show representative data illustrating that compounds 4 ( FIG. 3A-E ), 9 (olomoucine II or compound 9, FIG. 3F ), and 12 (CDK2 inhibitor II or compound 12, FIG. 3G ) protect against cisplatin-induced hair cell loss in cochlear explants.
  • FIG. 4A-E show representative data illustrating that compound 4 protects against cisplatin-induced hair cell loss in zebrafish lateral lines in vivo.
  • FIG. 5 shows kenpaullone protects against cisplatin-induced hair cell loss in vivo in mouse.
  • Panel 5a shows experimental diagram. Either ear of the same FVB wild-type mouse at P28 was trans-tympanically injected (in a volume of 5 ⁇ L) with compound (Kenpaullone 250 ⁇ M in 0.5% DMSO) or 0.5% DMSO only, in a double-blinded manner. Two hours later, the mice were treated intraperitoneally (IP) with cisplatin 30 mg/kg body weight, which was expected to damage OHCs equally in both ears.
  • IP intraperitoneally
  • Panel 5b demonstrates that kenpaullone (Ken) significantly reduces cisplatin (Cis)-induced ABR hearing threshold shifts relative to DMSO control at 16 kHz and 32 kHz 14 days post transtympanic injection.
  • Panel 5c shows representative images double stained with phalloidin and myosin 7a which is a hair cell specific marker in the cochlea and illustrates that kenpaullone protects against cisplatin-induced hair cell loss at 32 kHz region 14 days post transtympanic injection.
  • Panel 5d demonstrates kenpaullone significantly increases outer hair cell (OHC) survival in all 11 mice at the 32 kHz region.
  • FIG. 6 shows kenpaullone protects against noise-induced hearing loss.
  • Panel 6a is an experimental design in which adult FVB mice at P28 were exposed to noise (8-16 kHz at 100 dB SPL for 2 hours). Immediately afterward, kenpaullone (250 ⁇ M in 0.5% DMSO) or 0.5% DMSO was delivered (via trans-tympanic injection) to either ear of the same mouse. ABR thresholds were recorded prior, 7 days, or 14 days post noise exposure. Cochlear histology was examined at 14 days. Panel 6b shows that, in a total of 19 mice, kenpaullone significantly protects noise-induced hearing loss at 8 kHz and 16 kHz 14 days post noise damage.
  • Panel 6c also shows that wave 1 amplitudes of ABRs at 16 kHz displayed significant differences between the kenpaullone and DMSO control ears.
  • Panel 6d shows representative images of triple staining with phalloidin, Tuj1 and myosin 7a in the organ of Corti. There are no hair cell loss and no detectable spiral ganglion neuron fiber differences at the 16 kHz region.
  • Panel 6e comparison of the ctbp2 puncta staining and qualification in control (Ctrl) without any treatment, noise damage with DMSO transtympanic injection (DMSO+Noise) and noise damage with kenpaullone transtympanic injection (Ken+Noise). Kenpaullone significantly protects ctbp2 puncta loss comparing with DMSO sample.
  • Inner hair cells (IHCs) are traced by dash line in Panel 6e top figure.
  • FIG. 7 shows kenpaullone inhibits CDK2 kinase activity in vitro.
  • Increasing doses of kenpaullone were tested with Cdk2 immunoprecipitated from HEI—OC cells without (panel 7a) or with (panel 7b) cisplatin treatment and the kinase activity was quantified as the level of phosphorylation of the substrate histone H1.
  • FIG. 8 shows germline CDK2 knockout (KO) cochlear explants confer resistance to cisplatin treatment and kenpaullone administration phenocopies CDK2 knockout resistance to cisplatin ototoxicity.
  • Panels 8a-c show middle turn organs of Corti with actin staining (phalloidin-Alexa Flour 568) in WT and CDK2 KO cochleae without any treatment (Media, panel 8a), with 50 ⁇ M cisplatin treatment (panel 8b) and with 50 ⁇ M cisplatin and 5 ⁇ M kenpaullone (Panel 8c).
  • Outer hair cell (OHCs) numbers of actin-positive cells per 160 ⁇ m of the middle turn cochleae were counted (panel 8d) and data are mean ⁇ s.e.m. Numbers of explants tested in each condition are indicated in the bars. *** P ⁇ 0.001 by one-way ANOVA with Bonferroni's multiple comparison test.
  • FIG. 9 shows testing of kenpaullone toxicity in vivo in adult FVB mice ( ⁇ P28).
  • FVB mice at P28 were administrated kenpaullone at various concentrations (310 ⁇ M, 155 ⁇ M and 77.5 ⁇ M) by transtympanic injection.
  • Basel turn organs of Corti 24 hours post kenpaullone treatments as visualized by DAPI and Parvalbumin show that kenpaullone is toxic at 310 ⁇ M but not at lower doses. Arrows label lost outer hair cells. Two independent mice were tested for each dose.
  • FIG. 10 shows the lack of toxicity of kenpaullone (at 250 ⁇ M by transtymapnic injection) in vivo.
  • Panel 10a shows no significant ABR threshold shifts 7 days, 14 days, 28 days, 56 days and 84 days post kenpaullone or DMSO transtympanic injection at 16 kHz.
  • Panel 10b demonstrates there are no detectable ABR threshold shifts 84 days post kenpaullone or DMSO transtympanic injection at 8 kHz, 16 kHz and 32 kHz.
  • Panel 10c indicates kenpaullone treatment does not affect the length of the cochlea.
  • Panel 10d visualizes organs of Corti 84 days post kenpaullone (Ken) treatment in vivo and demonstrates that kenpaullone lacks ototoxicity at 250 ⁇ M after 84 days in vivo.
  • FIG. 11 addresses interference with cisplatin's killing function in tumors.
  • Four neurosphere lines derived from mouse medulloblastoma (MB) and two human neuroblastoma (NB) cell lines were tested.
  • HEI—OC1 cell line was tested as controls.
  • Viability assay Cell Titer Glo was used 48 hours post treatment of the cells with or without cisplatin (23 ⁇ M, IC 90 ⁇ 10 for all 7 cell lines) and each tested compound (conc. of 3 ⁇ IC 50 ).
  • 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.
  • the terms “optional” or “optionally” means that the subsequently described event or circumstance can or cannot occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • 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.
  • prevent 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.
  • diagnosis 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, polyoxyethylene9-10 nonyl phenol, sodium desoxycholate), solution and/or cryo/lyo stabilizers (e.g., sucrose, lactose, mannitol, trehalose), osmotic adjustment agents (e.g., salts or sugars), antibacterial agents (e.g., benzoic acid, phenol, gentamicin), antifoaming agents (e.g., polydimethylsilozone), preservatives (e.g., thimerosal, 2-phen
  • 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.
  • CDK2 Inhibitor refers to a small molecule chemical compound that binds to CDK2 protein isolated from cochlear cells and cochlear explants, inhibits CDK2 kinase or other activities with IC 50 of ⁇ 10 ⁇ M, and thus prevents cisplatin-induced hair cell loss with IC 50 of ⁇ 10 ⁇ M. See FIGS. 3, 7, and 8 .
  • the term “therapeutic agent” includes any synthetic or naturally occurring biologically active compound or composition of matter which, when administered to an organism (human or nonhuman animal), induces a desired pharmacologic, immunogenic, and/or physiologic effect by local and/or systemic action.
  • the term therefore encompasses those compounds or chemicals traditionally regarded as drugs, vaccines, and biopharmaceuticals including molecules such as proteins, peptides, hormones, nucleic acids, gene constructs and the like.
  • therapeutic agents include, without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or illness; substances that affect the structure or function of the body, or pro-drugs, which become biologically active or more active after they have been placed in a physiological environment.
  • the term “therapeutic agent” includes compounds or compositions for use in all of the major therapeutic areas including, but not limited to, adjuvants; anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations, anorexics, anti-inflammatory agents, anti-epileptics, local and general anesthetics, hypnotics, sedatives, antipsychotic agents, neuroleptic agents, antidepressants, anxiolytics, antagonists, neuron blocking agents, anticholinergic and cholinomimetic agents, antimuscarinic and muscarinic agents, antiadrenergics, antiarrhythmics, antihypertensive agents, hormones, and nutrients, antiarthritics, antiasthmatic agents, anticonvulsants, antihistamines, antinauseants, antineoplastics, antipruritics, antipyretics; antispasmodics, cardiovascular preparations (including calcium channel blockers, beta-blockers, an
  • the agent may be a biologically active agent used in medical, including veterinary, applications and in agriculture, such as with plants, as well as other areas.
  • therapeutic agent also includes without limitation, medicaments; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of disease or illness; or substances which affect the structure or function of the body; or pro-drugs, which become biologically active or more active after they have been placed in a predetermined physiological environment.
  • pharmaceutically acceptable describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • derivative refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity, would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compounds.
  • exemplary derivatives include salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound.
  • aqueous and nonaqueous carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.
  • These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid and the like. It can also be desirable to include isotonic agents such as sugars, sodium chloride and the like.
  • Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents, such as aluminum monostearate and gelatin, which delay absorption.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide, poly(orthoesters) and poly(anhydrides). Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.
  • 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.
  • hearing impairment refers to a neurologic disorder, oto-neurological in nature, typically sensorineural, but including composite loss (both sensorineural and conductive loss), preferably either a sensory or a neural (8 th nerve related) hearing lost, and most preferably a sensory loss (cochlear related), in which the patient will display, complain of, or is diagnosed to have a hearing loss.
  • Conductive hearing loss is typically related to the external or middle ear.
  • These impairments of interest to the present invention are those associated with hair cell damage. Less preferably such impairments can occur along with conductive hearing loss damage or damage, loss, or degeneration of a neuron of the auditory system.
  • Hair cells are epithelial cells possessing fine projections and located in the maculae and the organ of Corti.
  • hearing impairments and situations in which such hearing impairments can occur encompassed by the term “hearing impairment,” as used herein, include sensory hearing loss due to end-organ lesions, e.g., acoustic trauma, viral endolymphatic labyrinthitis, and Meniere's disease.
  • the impairment can also be a neural hearing loss due to events including cerebellopontine angle tumors of the 8 th nerve.
  • Hearing impairments include tinnitus, this is a perception of sound in the absence of an acoustic stimulus, and may be intermittent or continuous, wherein there is a diagnosed sensorineural loss.
  • Hearing loss may be due to bacterial or viral infection of the 8 th nerve ganglia, such as in herpes zoster oticus, purulent labyrinthitis arising from acute otitis media, purulent meningitis, chronic otitis media, sudden deafness including that of viral origin, e.g., viral endolymphatic labyrinthitis caused by viruses including mumps, measles, influenza, chickenpox, mononucleosis, and adenoviruses.
  • viruses including mumps, measles, influenza, chickenpox, mononucleosis, and adenoviruses.
  • the hearing loss can be congenital, such as that caused by rubella, anoxia during birth, bleeding into the inner ear due to trauma during delivery, ototoxic drugs administered to the mother, erythroblastosis fetalis, and hereditary conditions including Waardenburg's syndrome and Hurler's syndrome.
  • the hearing loss can be noise-induced, generally due to a noise greater than 85 decibels (db) SPL (sound pressure level) that damages the inner ear.
  • Hearing loss includes presbycusis, which is a sensorineural hearing loss occurring as a normal part of aging, fractures of the temporal bone extending into the middle ear and rupturing the tympanic membrane and possibly the ossicular chain, fractures affecting the cochlea, and acoustic neurinoma, which are tumors generally of Shwann cell origin that arise from either the auditory or vestibular divisions of the 8 th nerve.
  • the hearing loss is caused by an ototoxic drug that affects the auditory portion of the inner ear, particularly the organ of Corti.
  • the hearing loss may be due to chemotherapy or to cisplatin.
  • the hearing loss can be related to a vestibular disorder including vertigo, dysequilibrium, increased susceptibility to motion sickness, nausea, vomiting, ataxia, labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness, dizziness, increased falling, difficulty walking at night, Meniere's disease, and difficulty in visual tracking and processing.
  • a vestibular disorder including vertigo, dysequilibrium, increased susceptibility to motion sickness, nausea, vomiting, ataxia, labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness, dizziness, increased falling, difficulty walking at night, Meniere's disease, and difficulty in visual tracking and processing.
  • Incorporated herein by reference are Chapters 196, 197, 198, and 199 of The Merck Index, 14 th Edition (1982), Merck Sharp & Dome Research Laboratories, N.J. and related chapters in the most recent edition, relating to description and diagnosis of
  • Tests are known and available for diagnosing hearing impairments. Neuro-otological, neuro-ophthalmological, neurological examinations, and electra-oculography can be used (Wennmo et al., Acta Otolaryngol 1982, 94, 507). Sensitive and specific measures are available to identify patients with auditory impairments. For example, tuning fork tests can be used to differentiate a conductive from a sensorineural hearing loss and determine whether the loss is unilateral. An audiometer is used to quantitate hearing loss, measured in decibels. With this device the hearing for each ear is measured, typically from 125 to 8000 Hz, and plotted as an audiogram. Speech audiometry can also be performed.
  • the speech recognition threshold the intensity at which speed is recognized as a meaningful symbol, can be determined at various speech frequencies. Speech or phoneme discrimination can also be determined and used as an indicator of sensorineural hearing loss since analysis of speech sounds relies upon the inner ear and 8 th nerve. Tympanometry can be used to diagnose conductive hearing loss and aid in the diagnosis of those patients with sensorineural hearing loss. Electrocochleography, measuring the cochlear microphonic response and action potential of the 8 th nerve, and evoked response audiometry, measuring evoked response from the brainstem and auditory cortex, to acoustic stimuli can be used in patients, particularly infants and children or patients with sensorineural hearing loss of obscure etiology. Auditory brainstem responses (ABRs) or distortion products otoacoustic emissions (DPOAEs) are most commonly used audiometry methods. These tests serve a diagnostic function as well as a clinical function in assessing response to therapy.
  • ABRs auditory brainstem responses
  • DPOAEs distortion products
  • a residue of a chemical species refers to the moiety that is the resulting product of the chemical species in a particular reaction scheme or subsequent formulation or chemical product, regardless of whether the moiety is actually obtained from the chemical species.
  • an ethylene glycol residue in a polyester refers to one or more —OCH 2 CH 2 O— units in the polyester, regardless of whether ethylene glycol was used to prepare the polyester.
  • a sebacic acid residue in a polyester refers to one or more —CO(CH 2 ) 8 CO— moieties in the polyester, regardless of whether the residue is obtained by reacting sebacic acid or an ester thereof to obtain the polyester.
  • the term “substituted” is contemplated to include all permissible substituents of organic compounds.
  • the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, and aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described below.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms, such as nitrogen 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 (i.e., further substituted or unsubstituted).
  • a 1 ,” “A 2 ,” “A 3 ,” and “A 4 ” are used herein as generic symbols to represent various specific substituents. These symbols can be any substituent, not limited to those disclosed herein, and when they are defined to be certain substituents in one instance, they can, in another instance, be defined as some other substituents.
  • aliphatic or “aliphatic group,” as used herein, denotes a hydrocarbon moiety that may be straight-chain (i.e., unbranched), branched, or cyclic (including fused, bridging, and spirofused polycyclic) and may be completely saturated or may contain one or more units of unsaturation, but which is not aromatic. Unless otherwise specified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groups include, but are not limited to, linear or branched, alkyl, alkenyl, and alkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
  • alkyl as used herein is a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like.
  • the alkyl group can be 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 C1 alkyl, C1-C2 alkyl, C1-C3 alkyl, C1-C4 alkyl, C1-C5 alkyl, C1-C6 alkyl, C1-C7 alkyl, C1-C8 alkyl, C1-C9 alkyl, C1-C10 alkyl, and the like up to and including a C1-C24 alkyl.
  • 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, norbornyl, and the like.
  • heterocycloalkyl is a type of cycloalkyl group as defined above, and is included within the meaning of the term “cycloalkyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkyl group and heterocycloalkyl group can be substituted or unsubstituted.
  • the cycloalkyl group and heterocycloalkyl group can be substituted with 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 CH 2 groups linked to one another.
  • the polyalkylene group can be represented by the formula —(CH 2 ) 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 —A 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.
  • Asymmetric structures such as (A 1 A 2 )C ⁇ C(A 3 A 4 ) are intended to include both the E and Z isomers. This can be presumed in structural formulae herein wherein an asymmetric alkene is present, or it can be explicitly indicated by the bond symbol C ⁇ C.
  • the alkenyl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, as described herein.
  • 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., C ⁇ C.
  • Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, norbornenyl, and the like.
  • heterocycloalkenyl is a type of cycloalkenyl group as defined above, and is included within the meaning of the term “cycloalkenyl,” where at least one of the carbon atoms of the ring is replaced with a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted or unsubstituted.
  • the cycloalkenyl group and heterocycloalkenyl group can be substituted with 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 ⁇ electrons above and below the plane of the molecule, where the ⁇ clouds contain (4n+2) ⁇ electrons.
  • aromaticity is found in Morrison and Boyd, Organic Chemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages 477-497, incorporated herein by reference.
  • aromatic group is inclusive of both aryl and heteroaryl groups.
  • aryl as used herein is a group that contains any carbon-based aromatic group including, but not limited to, benzene, naphthalene, phenyl, biphenyl, anthracene, and the like.
  • the aryl group can be substituted or unsubstituted.
  • the aryl group can be substituted with one or more groups including, but not limited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl, aldehyde, —NH 2 , carboxylic acid, ester, ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol as described herein.
  • biasryl is a specific type of aryl group and is included in the definition of “aryl.”
  • the aryl group can be a single ring structure or comprise multiple ring structures that are either fused ring structures or attached via one or more bridging groups such as a carbon-carbon bond.
  • biaryl can be two aryl groups that are bound together via a fused ring structure, as in naphthalene, or are attached via one or more carbon-carbon bonds, as in biphenyl.
  • aldehyde as used herein is represented by the formula —C(O)H. Throughout this specification “C(O)” is a short hand notation for a carbonyl group, i.e., C ⁇ O.
  • amine or “amino” as used herein are represented by the formula —NA 1 A 2 , where A 1 and A 2 can be, independently, hydrogen or alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a specific example of amino is —NH 2 .
  • alkylamino as used herein is represented by the formula —NH(-alkyl) where alkyl is a described herein.
  • 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.
  • esters 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 1 OA 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein.
  • polyether as used herein is represented by the formula -(A 1 O-A 2 O) a —, where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and “a” is an integer of from 1 to 500.
  • Examples of polyether groups include polyethylene oxide, polypropylene oxide, and polybutylene oxide.
  • halo halogen
  • halide halogen
  • pseudohalide 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 quaternized. 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, N-methylpyrrolyl, 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, benzo [d]oxazolyl, benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, and pyrido[2,3-b]pyrazinyl.
  • heterocycle or “heterocyclyl,” as used herein can be used interchangeably and refer to single and multi-cyclic aromatic or non-aromatic ring systems in which at least one of the ring members is other than carbon.
  • the term is inclusive of, but not limited to, “heterocycloalkyl”, “heteroaryl”, “bicyclic heterocycle” and “polycyclic heterocycle.”
  • Heterocycle includes pyridine, pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole, 1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including, 1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole, including, 1,2,3-triazole
  • heterocyclyl group can also be a C2 heterocyclyl, C2-C3 heterocyclyl, C2-C4 heterocyclyl, C2-C5 heterocyclyl, C2-C6 heterocyclyl, C2-C7 heterocyclyl, C2-C8 heterocyclyl, C2-C9 heterocyclyl, C2-C10 heterocyclyl, C2-C11 heterocyclyl, and the like up to and including a C2-C18 heterocyclyl.
  • a C2 heterocyclyl comprises a group which has two carbon atoms and at least one heteroatom, including, but not limited to, aziridinyl, diazetidinyl, dihydrodiazetyl, oxiranyl, thiiranyl, and the like.
  • a C5 heterocyclyl comprises a group which has five carbon atoms and at least one heteroatom, including, but not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, diazepanyl, pyridinyl, and the like. 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[1,5-a]pyridinyl, benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl, 2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl, 1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and 1H-pyrazolo[3,2-b]pyridin-3-yl.
  • heterocycloalkyl refers to an aliphatic, partially unsaturated or fully saturated, 3- to 14-membered ring system, including single rings of 3 to 8 atoms and bi- and tricyclic ring systems.
  • the heterocycloalkyl ring-systems include one to four heteroatoms independently selected from oxygen, nitrogen, and sulfur, wherein a nitrogen and sulfur heteroatom optionally can be oxidized and a nitrogen heteroatom optionally can be substituted.
  • heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl.
  • 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.
  • azide or “azido” as used herein is represented by the formula —N 3 .
  • nitro as used herein is represented by the formula —NO 2 .
  • nitrile or “cyano” as used herein is represented by the formula —CN.
  • sil as used herein is represented by the formula —SiA 1 A 2 A 3 , where A 1 , A 2 , and A 3 can be, independently, hydrogen or an alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfo-oxo as used herein is represented by the formulas —S(O)A 1 , —S(O) 2 A 1 , —OS(O) 2 A 1 , or —OS(O) 2 OA 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • S(O) is a short hand notation for S ⁇ O.
  • sulfonyl is used herein to refer to the sulfo-oxo group represented by the formula —S(O) 2 A 1 , where A 1 can be hydrogen or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • a 1 S(O) 2 A 2 is represented by the formula A 1 S(O) 2 A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • sulfoxide as used herein is represented by the formula A 1 S(O)A 2 , where A 1 and A 2 can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.
  • thiol as used herein is represented by the formula —SH.
  • R 1 ,” “R 2 ,” “R 3 ,” “R n ,” where n is an integer, as used herein can, independently, possess one or more of the groups listed above.
  • R 1 is a straight chain alkyl group
  • one of the hydrogen atoms of the alkyl group can optionally be substituted with a hydroxyl group, an alkoxy group, an alkyl group, a halide, and the like.
  • a first group can be incorporated within second group or, alternatively, the first group can be pendant (i.e., attached) to the second group.
  • 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 (i.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 a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH 2 ) 0-4 R o ; —(CH 2 ) 0-4 OR o ; —O(CH 2 ) 0-4 R o , —O—(CH 2 ) 0-4 C(O)OR o ; —(CH 2 ) 0-4 CH(OR o 2 ; —(CH 2 ) 0-4 SR o ; —(CH 2 ) 0-4 Ph, which may be substituted with R o ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 Ph which may be substituted with R o ; —CH ⁇ CHPh, which may be substituted with R o ; —(CH 2 ) 0-4 O(CH 2 ) 0-1 -pyridyl which may be substituted with R o ; —NO 2 ; —CN; —N
  • Suitable monovalent substituents on R o are independently halogen, —(CH 2 ) 0-2 R ⁇ , -(haloR ⁇ ), —(CH 2 ) 0-2 OH, —(CH 2 ) 0-2 OR ⁇ , —(CH 2 ) 0-2 CH(OR ⁇ ) 2 ; —O(haloR ⁇ ), —CN, —N 3 , —(CH 2 ) 0-2 C(O)R ⁇ , —(CH 2 ) 0-2 C(O)OH, —(CH 2 ) 0-2 C(O)OR ⁇ , —(CH 2 ) 0-2 SR ⁇ , —(CH 2 ) 0-2 SH, —(CH 2 ) 0-2 NH 2 , —(CH 2 ) 0-2 NHR ⁇ , —(CH 2
  • Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ⁇ O, ⁇ S, ⁇ NNR* 2 , ⁇ NNHC(O)R*, ⁇ NNHC(O)OR*, ⁇ NNHS(O) 2 R*, ⁇ NR*, ⁇ NOR*, —O(C(R* 2 )) 2-3 O—, or —S(C(R* 2 )) 2-3 S—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR* 2 ) 2-3 O—, wherein each independent occurrence of R* is selected from hydrogen, C 1-6 aliphatic which may be substituted as defined below, or an unsubstituted 5-6membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on the aliphatic group of R* include halogen, R ⁇ , -(haloR ⁇ ), —OH, OR ⁇ , —O(haloR ⁇ ), —CN, —C(O)OH, —C(O)OR ⁇ , —NH 2 , —NHR ⁇ , —NR ⁇ 2 , or —NO 2 , wherein each R ⁇ is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R ⁇ , —NR ⁇ 2 , —C(O)R ⁇ , —C(O)OR ⁇ , —C(O)C(O)R ⁇ , —C(O)CH 2 C(O)R ⁇ , —S(O) 2 R ⁇ , —S(O) 2 NR ⁇ 2 , —C(S)NR ⁇ 2 , —C(NH)NR ⁇ 2 , or —N(R ⁇ )S(O) 2 R ⁇ ; wherein each R ⁇ is independently hydrogen, C 1-6 aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6membered 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
  • Suitable substituents on the aliphatic group of R ⁇ 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 C 1-4 aliphatic, —CH 2 Ph, —O(CH 2 ) 0-1 Ph, or a 5-6membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
  • leaving group refers to an atom (or a group of atoms) with electron withdrawing ability that can be displaced as a stable species, taking with it the bonding electrons.
  • suitable leaving groups include halides and sulfonate esters, including, but not limited to, triflate, mesylate, tosylate, and brosylate.
  • hydrolysable group and “hydrolysable moiety” refer to a functional group capable of undergoing hydrolysis, e.g., under basic or acidic conditions.
  • hydrolysable residues 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.
  • radical for example an alkyl
  • substituted alkyl can be further modified (i.e., substituted alkyl) by having bonded thereto one or more “substituent radicals.”
  • the number of atoms in a given radical is not critical to the present invention unless it is indicated to the contrary elsewhere herein.
  • Organic radicals contain one or more carbon atoms.
  • An organic radical can have, for example, 1-26 carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms.
  • an organic radical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbon atoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms.
  • Organic radicals often have hydrogen bound to at least some of the carbon atoms of the organic radical.
  • an organic radical that comprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthyl radical.
  • an organic radical can contain 1-10 inorganic heteroatoms bound thereto or therein, including halogens, oxygen, sulfur, nitrogen, phosphorus, and the like.
  • organic radicals include but are not limited to an alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, mono-substituted amino, di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide, substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl, thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl, substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclic radicals, wherein the terms are defined elsewhere herein.
  • organic radicals that include heteroatoms include alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals, dimethylamino radicals and the like.
  • Inorganic radicals contain no carbon atoms and therefore comprise only atoms other than carbon.
  • Inorganic radicals comprise bonded combinations of atoms selected from hydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, and halogens such as fluorine, chlorine, bromine, and iodine, which can be present individually or bonded together in their chemically stable combinations.
  • Inorganic radicals have 10 or fewer, or preferably one to six or one to four inorganic atoms as listed above bonded together. Examples of inorganic radicals include, but not limited to, amino, hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonly known inorganic radicals.
  • the inorganic radicals do not have bonded therein the metallic elements of the periodic table (such as the alkali metals, alkaline earth metals, transition metals, lanthanide metals, or actinide metals), although such metal ions can sometimes serve as a pharmaceutically acceptable cation for anionic inorganic radicals such as a sulfate, phosphate, or like anionic inorganic radical.
  • Inorganic radicals do not comprise metalloids elements such as boron, aluminum, gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gas elements, unless otherwise specifically indicated elsewhere herein.
  • 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.
  • the products of such procedures can be a mixture of stereoisomers.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture.
  • Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the disclosed formulas, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the formula.
  • one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane).
  • the Cahn-Ingold-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.
  • Compounds described herein comprise atoms in both their natural isotopic abundance and in non-natural abundance.
  • the disclosed compounds can be isotopically-labeled or isotopically-substituted compounds identical to those described, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 35 S, 18 F and 36 Cl, respectively.
  • Compounds further comprise prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention.
  • Certain isotopically-labeled compounds of the present invention for example those into which radioactive isotopes such as 3 H and 14 C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • isotopically labeled compounds of the present invention and prodrugs thereof can generally be prepared by carrying out the procedures below, by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent.
  • the compounds described in the invention can be present as a solvate.
  • the solvent used to prepare the solvate is an aqueous solution, and the solvate is then often referred to as a hydrate.
  • the compounds can be present as a hydrate, which can be obtained, for example, by crystallization from a solvent or from aqueous solution.
  • 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 ⁇ -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, N 1 -unsubstituted, 3-A 3 and M-unsubstituted, 5-A 3 as shown below.
  • the invention includes all such possible tautomers.
  • polymorphic forms It is known that chemical substances form solids which are present in different states of order which are termed polymorphic forms or modifications.
  • the different modifications of a polymorphic substance can differ greatly in their physical properties.
  • the compounds according to the invention can be present in different polymorphic forms, with it being possible for particular modifications to be metastable. Unless stated to the contrary, the invention includes all such possible polymorphic forms.
  • a structure of a compound can be represented by a formula:
  • n is typically an integer. That is, R n is understood to represent five independent substituents, R n(a) , R n(b) , R n(c) , R n(d) , R n(e) .
  • independent substituents it is meant that each R substituent can be independently defined. For example, if in one instance R n(a) halogen, then R n(b) is not necessarily halogen in that instance.
  • Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art.
  • the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), Acros Organics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), or Sigma (St.
  • compositions 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.
  • compositions disclosed herein have certain functions. Disclosed herein are certain structural requirements for performing the disclosed functions, and it is understood that there are a variety of structures that can perform the same function that are related to the disclosed structures, and that these structures will typically achieve the same result.
  • the disclosed compounds exhibit inhibition of CDK2.
  • the disclosed compounds exhibit antagonism of CDK2.
  • the compounds of the invention are useful in the treatment or prevention of hearing disorders associated with CDK2 dysfunction and other diseases in which CDK2s are involved, 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.
  • the compound is a paullone derivative, or a pharmaceutically acceptable solvate, salt, or polymorph thereof.
  • Paullones are a family of benzazepinones characterized by a core framework represented by a structure:
  • CDK cyclin-dependent kinase
  • Inhibitors of CDK could potentially serve as pharmacological agents to treat diseases of proliferation such as cancer, psoriasis, and restenosis (Sharma, V. M., et al. (2008) Indian J. of Biochem. & Biophysics 45, 416; Leost, M., et al. (2000) Eur. J. Biochem. 267, 5983-5994).
  • paullone derivatives having a structure represented by a formula:
  • R 1 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , —(S ⁇ O)R 3 , —SO 2 R 3 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino; wherein R 3 , when present, is selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ; wherein R 2 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , —(S ⁇ O)
  • the paullone derivative has a structure represented by a formula selected from:
  • the paullone derivative has a structure represented by a formula selected from:
  • the paullone derivative has a structure represented by a formula:
  • the paullone derivative has a structure represented by a formula selected from:
  • the paullone derivative has a structure represented by a formula:
  • the paullone derivative has a structure represented by a formula:
  • R 1 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , —(S ⁇ O)R 3 , —SO 2 R 3 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino.
  • R 1 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , —(S ⁇ O)R 3 , —SO 2 R 3 , C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino.
  • R 1 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino.
  • R 1 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino.
  • R 1 is selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 1 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino.
  • R 1 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino.
  • R 1 is selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 1 is selected from hydrogen, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl. In a still further aspect, R 1 is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In yet a further aspect, R 1 is selected from hydrogen, —CClH 2 , —CCl 2 H, —CCl 3 , —CFH 2 , —CF 2 H, and —CF 3 . In an even further aspect, R 1 is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 1 is selected from hydrogen and C1-C6 alkyl. In a still further aspect, R 1 is selected from hydrogen, methyl, ethyl, iso-propyl, n-propyl, tert-butyl, sec-butyl, iso-butyl, and n-butyl. In yet a further aspect, R 1 is selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In an even further aspect, R 1 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 1 is selected from hydrogen and methyl. In yet a further aspect, R 1 is selected from hydrogen and ethyl. In an even further aspect, R 1 is hydrogen. In a still further aspect, R 1 is methyl. In yet a further aspect, R 1 is ethyl. In an even further aspect, R 1 is hydrogen. In a still further aspect, R 1 is methyl. In yet a further aspect, R 1 is
  • R 1 is selected from hydrogen and halogen. In a still further aspect, R 1 is selected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, R 1 is selected from hydrogen, —F, and —Cl. In an even further aspect, R 1 is selected from hydrogen and —F. In a still further aspect, R 1 is selected from hydrogen and —Cl.
  • R 1 is halogen. In a still further aspect, R 1 is selected from —F, —Cl, and —Br. In yet a further aspect, R 1 is selected from —F and —Cl. In an even further aspect, R 1 is —Br. In a still further aspect, R 1 is —Cl. In yet a further aspect, R 1 is —F.
  • R 2 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , —(S ⁇ O)R 4 , —SO 2 R 4 , C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino.
  • R 2 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , —(S ⁇ O)R 4 , —SO 2 R 4 , C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino.
  • R 2 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino.
  • R 2 is selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino.
  • R 2 is selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 2 is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 cyanoalkyl, C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino.
  • R 2 is selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, C1-C3 alkoxy, C1-C3 cyanoalkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 monoalkylamino, and C1-C3 dialkylamino.
  • R 2 is selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 2 is selected from hydrogen, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl. In a still further aspect, R 2 is selected from hydrogen, C1-C3 monohaloalkyl, and C1-C3 polyhaloalkyl. In yet a further aspect, R 2 is selected from hydrogen, —CClH 2 , —CCl 2 H, —CCl 3 ,—CFH 2 , —CF 2 H, and —CF 3 . In an even further aspect, R 2 is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 2 is selected from hydrogen and C1-C6 alkyl. In a still further aspect, R 2 is selected from hydrogen, methyl, ethyl, iso-propyl, n-propyl, tert-butyl, sec-butyl, iso-butyl, and n-butyl. In yet a further aspect, R 2 is selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In an even further aspect, R 2 is selected from hydrogen, methyl, and ethyl. In a still further aspect, R 2 is selected from hydrogen and methyl. In yet a further aspect, R 2 is selected from hydrogen and ethyl. In an even further aspect, R 2 is hydrogen. In a still further aspect, R 2 is methyl. In yet a further aspect, R 2 is ethyl. In an even further aspect, R 2 is hydrogen. In a still further aspect, R 2 is methyl. In yet a further aspect, R 2 is
  • R 2 is selected from hydrogen and halogen. In a still further aspect, R 2 is selected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, R 2 is selected from hydrogen, —F, and —Cl. In an even further aspect, R 2 is selected from hydrogen and —F. In a still further aspect, R 2 is selected from hydrogen and —Cl.
  • R 2 is halogen. In a still further aspect, R 2 is selected from —F, —Cl, and —Br. In yet a further aspect, R 2 is selected from —F and —Cl. In an even further aspect, R 2 is —Br. In a still further aspect, R 2 is —Cl. In yet a further aspect, R 2 is —F.
  • R 3 when present, is selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 3 when present, is selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 3 when present, is selected from hydrogen, —CH 3 , —CFH 2 , —NH 2 , and —NH(CH 3 ).
  • R 3 when present, is selected from hydrogen, —CH 3 , and —NH 2 . In an even further aspect, R 3 , when present, is selected from hydrogen and —CH 3 . In a still further aspect, R 3 , when present, is selected from hydrogen and —NH 2 . In yet a further aspect, R 3 , when present, is hydrogen.
  • R 4 when present, is selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 4 when present, is selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 4 when present, is selected from hydrogen, —CH 3 , —CFH 2 , —NH 2 , and —NH(CH 3 ).
  • R 4 when present, is selected from hydrogen, —CH 3 , and —NH 2 . In an even further aspect, R 4 , when present, is selected from hydrogen and —CH 3 . In a still further aspect, R 4 , when present, is selected from hydrogen and —NH 2 . In yet a further aspect, R 4 , when present, is hydrogen.
  • purine derivatives having a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein each of R 5a and R 5b is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; wherein q, when present, is an integer selected from 1, 2, 3, and 4; wherein R 8 , when present, is selected from hydrogen, —OH, —SH, —NH 2 , C1-C4 alkoxy, C1-C4 thioal
  • q, when present, is an integer selected from 1, 2, 3, and 4. In a further aspect, q, when present, is an integer selected from 1, 2, and 3. In a still further aspect, q, when present, is an integer selected from 2, 3, and 4. In yet a further aspect, q, when present, is an integer selected from 1, 2, and 4. In an even further aspect, q, when present, is an integer selected from 1, 3, and 4. In a still further aspect, q, when present, is an integer selected from 1 and 2. In yet a further aspect, q, when present, is an integer selected from 1 and 3. In an even further aspect, q, when present, is an integer selected from 1 and 4. In a still further aspect, q, when present, is an integer selected from 2 and 3.
  • q, when present, is an integer selected from 2 and 4. In an even further aspect, q, when present, is an integer selected from 3 and 4. In a still further aspect, q, when present, is 1. In yet a further aspect, q, when present, is 2. In an even further aspect, q, when present, is 3. In a still further aspect, q, when present, is 4.
  • p when present, is an integer selected from 0, 1, 2, and 3. In a further aspect, p, when present, is an integer selected from 0, 1, and 2. In a still further aspect, p, when present, is an integer selected from 0, 1, and 3. In yet a further aspect, p, when present, is an integer selected from 0, 2, and 3. In an even further aspect, p, when present, is an integer selected from 1, 2, and 3. In a still further aspect, p, when present, is an integer selected from 0 and 1. In yet a further aspect, p, when present, is an integer selected from 0 and 2. In an even further aspect, p, when present, is an integer selected from 0 and 3. In a still further aspect, p, when present, is an integer selected from 1 and 2.
  • p, when present, is an integer selected from 1 and 3. In an even further aspect, p, when present, is an integer selected from 2 and 3. In a still further aspect, p, when present, is 0. In yet a further aspect, p, when present, is 1. In an even further aspect, p, when present, is 2. In a still further aspect, p, when present, is 3.
  • r when present, is an integer selected from 0, 1, 2, and 3. In a further aspect, r, when present, is an integer selected from 0, 1, and 2. In a still further aspect, r, when present, is an integer selected from 0, 1, and 3. In yet a further aspect, r, when present, is an integer selected from 0, 2, and 3. In an even further aspect, r, when present, is an integer selected from 1, 2, and 3. In a still further aspect, r, when present, is an integer selected from 0 and 1. In yet a further aspect, r, when present, is an integer selected from 0 and 2. In an even further aspect, r, when present, is an integer selected from 0 and 3. In a still further aspect, r, when present, is an integer selected from 1 and 2.
  • r, when present, is an integer selected from 1 and 3. In an even further aspect, r, when present, is an integer selected from 2 and 3. In a still further aspect, r, when present, is 0. In yet a further aspect, r, when present, is 1. In an even further aspect, r, when present, is 2. In a still further aspect, r, when present, is 3.
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula:
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula:
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula selected from:
  • the purine derivative has a structure represented by a formula:
  • each of R 5a and R 5b is independently selected from hydrogen, C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein each of R 5a and R 5b is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 5a and R 5b is independently selected from hydrogen, C1-C4 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein each of R 5a and R 5b is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 5a and R 5b is independently selected from hydrogen, C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein each of R 5a and R 5b is independently substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 5a and R 5b is independently selected from hydrogen, C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein each of R 5a and R 5b is independently substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 5a and R 5b is independently selected from hydrogen, C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein each of R 5a and R 5b is independently monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 5a and R 5b is independently selected from hydrogen, C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein each of R 5a and R 5b is unsubstituted.
  • R 5a when present, is hydrogen and R 5b is selected from C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from C1-C4 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5b is selected from C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is monosubstituted with a group selected from halogen, —OH, —CN,
  • R 5a when present, is hydrogen and R 5b is selected from C1-C8 alkyl, (CH 2 ) q R 8 , and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is unsubstituted.
  • R 5a when present, is hydrogen and R 5b is selected from (CH 2 ) q R 8 and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from (CH 2 ) q R 8 and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from (CH 2 ) q R 8 and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from (CH 2 ) q R 8 and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from (CH 2 ) q R 8 and C ⁇ O(CH 2 ) q R 8 and wherein R 5b is unsubstituted.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C
  • R 5a when present, is hydrogen and R 5b is C1-C4 alkyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is C1-C4 alkyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C
  • R 5a when present, is hydrogen and R 5b is selected from methyl, ethyl, n-propyl, and iso-propyl and wherein R 5b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is selected from methyl and ethyl and wherein R 5b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is ethyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is ethyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl,
  • R 5a when present, is hydrogen and R 5b is methyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 amino
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 amino
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is unsubstituted C1-C8 alkyl.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 amino
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 amino
  • R 5a when present, is hydrogen and R 5b is C1-C8 alkyl monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C2 monohaloalkyl
  • C1-C2 polyhaloalkyl C1-C2 alkoxy
  • C1-C2 cyanoalkyl C1-C2 aminoalkyl
  • C1-C2 hydroxyalkyl C1-C2 monoalkylamino
  • R 5a when present, is hydrogen and R 5b is n-propyl monosubstituted with a C1-C4 hydroxyalkyl group. In a still further aspect, R 5a , when present, is hydrogen and R 5b is n-propyl monosubstituted with a C1-C2 hydroxyalkyl group. In yet a further aspect, R 5a , when present, is hydrogen and R 5b is n-propyl monosubstituted with a CH 2 OH group.
  • R 6 is selected from halogen, OR 9 , and NR 10a R 10b .
  • R 2 is selected from OR 9 and NR 10a R 10b .
  • R 2 is selected from halogen and OR 9 .
  • R 2 is selected from halogen and NR 10a R 10b .
  • R 2 is halogen.
  • R 2 is OR 9 .
  • R 2 is NR 10a R 10b .
  • R 7 when present, is selected from hydrogen and C1-C8 alkyl. In a further aspect, R 7 , when present, is selected from hydrogen and C1-C4 alkyl. In a still further aspect, R 7 , when present, is hydrogen.
  • R 7 when present, is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In a still further aspect, R 7 , when present, is selected from hydrogen, methyl, ethyl, n-propyl, and iso-propyl. In yet a further aspect, R 7 , when present, is selected from hydrogen, methyl, and ethyl. In an even further aspect, R 7 , when present, is selected from hydrogen and methyl. In a still further aspect, R 7 , when present, is selected from hydrogen and ethyl.
  • R 7 when present, is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In a still further aspect, R 7 , when present, is selected from methyl, ethyl, n-propyl, and iso-propyl. In yet a further aspect, R 7 , when present, is selected from methyl, and ethyl. In an even further aspect, R 7 , when present, is methyl. In a still further aspect, R 7 , when present, is ethyl. In yet a further aspect, R 7 , when present, is n-propyl. In an even further aspect, R 7 , when present, is iso-propyl.
  • R 8 when present, is selected from hydrogen, —OH, —SH, —NH 2 , C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino.
  • R 8 when present, is selected from hydrogen, —OH, —SH, —NH 2 , C1-C4 alkoxy, C1-C2 thioalkoxy, C1-C2 alkylamino, and C1-C2 dialkylamino.
  • R 8 when present, is hydrogen.
  • R 8 when present, is selected from hydrogen, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and C1-C4 dialkylamino. In a still further aspect, R 8 , when present, is selected from hydrogen, C1-C2 alkoxy, C1-C2 thioalkoxy, C1-C2 alkylamino, and C1-C2 dialkylamino.
  • R 8 when present, is selected from hydrogen, —OH, —SH, and —NH 2 . In a still further aspect, R 8 , when present, is selected from hydrogen, —OH, and —SH. In yet a further aspect, R 8 , when present, is selected from hydrogen, —OH and —NH 2 . In an even further aspect, R 8 , when present, is selected from hydrogen and —OH. In a still further aspect, R 8 , when present, is selected from hydrogen and —SH. In yet a further aspect, R 8 , when present, is selected from hydrogen and —NH 2 .
  • R 9 when present, is selected from C1-C8 alkyl, (CH 2 ) p Cy 1 , and (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is selected from C1-C4 alkyl, (CH 2 ) p Cy 1 , and (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is selected from C1-C8 alkyl, (CH 2 ) p Cy 1 , and (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is selected from C1-C8 alkyl, (CH 2 ) p Cy 1 , and (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is selected from C1-C8 alkyl, (CH 2 ) p Cy 1 , and (CH 2 ) p Ar 1 and wherein R 9 , when present, is monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is selected from C1-C8 alkyl, (CH 2 ) p Cy 1 , and (CH 2 ) p Ar 1 and wherein R 9 , when present, is unsubstituted.
  • R 9 when present, is selected from (CH 2 ) p Cy 1 and (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is selected from (CH 2 ) p Cy 1 and (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-
  • R 9 when present, is selected from (CH 2 ) p Cy 1 and (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C
  • R 9 when present, is selected from (CH 2 ) p Cy 1 and (CH 2 ) p Ar 1 and wherein R 9 , when present, is monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is selected from (CH 2 ) p Cy 1 and (CH 2 ) p Ar 1 and wherein R 9 , when present, is unsubstituted.
  • R 9 when present, is (CH 2 ) p Cy 1 and wherein R 9 , when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is (CH 2 ) p Cy 1 and wherein R 9 , when present, is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C
  • R 9 when present, is (CH 2 ) p Cy 1 and wherein R 9 , when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
  • R 9 when present, is (CH 2 ) p Cy 1 and wherein R 9 , when present, is substituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is (CH 2 ) p Cy 1 and wherein R 9 , when present, is unsubstituted.
  • R 9 when present, is (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C
  • R 9 when present, is (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
  • R 9 when present, is (CH 2 ) p Ar 1 and wherein R 9 , when present, is substituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is (CH 2 ) p Ar 1 and wherein R 9 , when present, is unsubstituted.
  • R 9 when present, is C1-C8 alkyl and wherein R 9 , when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4
  • R 9 when present, is C1-C8 alkyl and wherein R 9 , when present, is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4
  • R 9 when present, is C1-C8 alkyl and wherein R 9 , when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxy
  • R 9 when present, is C1-C8 alkyl and wherein R 9 , when present, is substituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 9 when present, is C1-C8 alkyl and wherein R 9 , when present, is unsubstituted.
  • R 9 when present, is C1-C8 alkyl. In a still further aspect, R 9 , when present, is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. In yet a further aspect, R 9 , when present, is selected from methyl, ethyl, n-propyl, and iso-propyl. In an even further aspect, R 9 , when present, is selected from methyl and ethyl. In a still further aspect, R 9 , when present, is ethyl. In yet a further aspect, R 9 , when present, is methyl.
  • each of R 10a and R 10b when present, is independently selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein each of R 10a and R 10b is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 10a and R 10b when present, is independently selected from C1-C4 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein each of R 10a and R 10b is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 10a and R 10b when present, is independently selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein each of R 10a and R 10b is independently substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 10a and R 10b when present, is independently selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein each of R 10a and R 10b is independently substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 10a and R 10b when present, is independently selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein each of R 10a and R 10b is independently monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each of R 10a and R 10b when present, is independently selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein each of R 10a and R 10b is unsubstituted.
  • R 10a when present, is hydrogen and R 10b , when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0, 1, or 2
  • R 10a when present, is hydrogen and R 10b , when present, is selected from C1-C4 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from C1-C4 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0, 1, or 2
  • R 10a when present, is hydrogen and R 10b , when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 1 or 2 groups independently
  • R 10a when present, is hydrogen and R 10b , when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0 or 1 group
  • R 10a when present, is hydrogen and R 10b , when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is monosubstituted
  • R 10a when present, is hydrogen and R 10b , when present, is selected from C1-C8 alkyl, Cy 2 , Ar 2 , (CH 2 ) r Cy 2 , and (CH 2 ) r Ar 2 and wherein R 10b is unsubstituted.
  • R 10a when present, is hydrogen and R 10b , when present, is C1-C8 alkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is C1-C4 alkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is C1-C4 alkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C
  • R 10a when present, is hydrogen and R 10b , when present, is selected from methyl, ethyl, n-propyl, and iso-propyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is selected from methyl and ethyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is ethyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is ethyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl,
  • R 10a when present, is hydrogen and R 10b , when present, is methyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is methyl substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 amino
  • R 10a when present, is hydrogen and R 10b , when present, is C1-C8 alkyl and substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-
  • R 10a when present, is hydrogen and R 10b , when present, is C1-C8 alkyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 monohaloalkyl
  • C1-C4 polyhaloalkyl C1-C4 alkoxy
  • C1-C4 cyanoalkyl C1-C4 aminoalkyl
  • C1-C4 hydroxyalkyl C1-C4 monoalkylamino
  • R 10a when present, is hydrogen and R 10b , when present, is C1-C8 alkyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is unsubstituted C1-C8 alkyl.
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1
  • R 10a when present, is hydrogen and R 10b when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Cy 2 and (CH 2 ) r Cy 2 and wherein R 10b is unsubstituted.
  • R 10a when present, is hydrogen and R 10b , when present, is Cy 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is Cy 2 and substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkyla
  • R 10a when present, is hydrogen and R 10b , when present, is Cy 2 and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 monohaloalkyl
  • C1-C4 polyhaloalkyl C1-C4 alkoxy
  • C1-C4 cyanoalkyl C1-C4 aminoalkyl
  • C1-C4 hydroxyalkyl C1-C4 monoalkylamino
  • R 10a when present, is hydrogen and R 10b , when present, is Cy 2 and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is unsubstituted Cy 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Cy 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Cy 2 and substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Cy 2 and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Cy 2 and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is unsubstituted (CH 2 ) r Cy 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is CH 2 Cy 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is CH 2 Cy 2 and substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is CH 2 Cy 2 and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is CH 2 Cy 2 and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is unsubstituted CH 2 Cy 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl,
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1
  • R 10a when present, is hydrogen and R 10b when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10b when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is selected from Ar 2 and (CH 2 ) r Ar 2 and wherein R 10b is unsubstituted.
  • R 10a when present, is hydrogen and R 10b , when present, is Ar 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is Ar 2 and substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkyla
  • R 10a when present, is hydrogen and R 10b , when present, is Ar 2 and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 monohaloalkyl
  • C1-C4 polyhaloalkyl C1-C4 alkoxy
  • C1-C4 cyanoalkyl C1-C4 aminoalkyl
  • C1-C4 hydroxyalkyl C1-C4 monoalkylamino
  • R 10a when present, is hydrogen and R 10b , when present, is Ar 2 and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is unsubstituted Ar 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Ar 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Ar 2 and substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Ar 2 and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 ) r Ar 2 and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is unsubstituted (CH 2 ) r Ar 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • 1 or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • R 10a when present, is hydrogen and R 10b , when present, is unsubstituted (CH 2 )Ar 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , and —NH 2 .
  • R ma when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, and —NH 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 0, 1, or 2 groups independently selected from —OH and —NH 2 .
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 0, 1, or 2 OH groups.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 and substituted with 0, 1, or 2 —NH 2 groups.
  • R 10a when present, is hydrogen and R 10b , when present, is (CH 2 )Ar 2 monosubstituted with an —OH group.
  • Cy 1 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Cy 1 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C
  • Cy 1 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and unsubstituted.
  • Cy 1 when present, is C3-C6 cycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is C3-C6 cycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Cy 1 when present, is C3-C6 cycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is C3-C6 cycloalkyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C
  • Cy 1 when present, is C3-C6 cycloalkyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is unsubstituted C3-C6 cycloalkyl.
  • Cy 1 when present, is C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Cy 1 when present, is C3-C6 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is C3-C6 heterocycloalkyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C
  • Cy 1 when present, is C3-C6 heterocycloalkyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 1 when present, is unsubstituted C3-C6 heterocycloalkyl.
  • Cy 2 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Cy 2 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C
  • Cy 2 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is selected from C3-C6 cycloalkyl and C3-C6 heterocycloalkyl and unsubstituted.
  • Cy 2 when present, is C3-C6 cycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is C3-C6 cycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Cy 2 when present, is C3-C6 cycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is C3-C6 cycloalkyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C
  • Cy 2 when present, is C3-C6 cycloalkyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is unsubstituted C3-C6 cycloalkyl.
  • Cy 2 when present, is C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is C3-C6 heterocycloalkyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Cy 2 when present, is C3-C6 heterocycloalkyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is C3-C6 heterocycloalkyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C
  • Cy 2 when present, is C3-C6 heterocycloalkyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Cy 2 when present, is unsubstituted C3-C6 heterocycloalkyl.
  • Ar 1 when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Ar 1 when present, is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is selected from aryl and heteroaryl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 mono
  • Ar 1 when present, is selected from aryl and heteroaryl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is selected from aryl and heteroaryl and unsubstituted.
  • Ar 1 when present, is aryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-
  • Ar 1 when present, is aryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-
  • Ar 1 when present, is aryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is aryl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,
  • Ar 1 when present, is aryl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is unsubstituted aryl.
  • Ar 1 when present, is phenyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1
  • Ar 1 when present, is phenyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1
  • Ar 1 when present, is phenyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is phenyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino
  • Ar 1 when present, is phenyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is unsubstituted phenyl.
  • Ar 1 when present, is heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-
  • Ar 1 when present, is heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-
  • Ar 1 when present, is heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino
  • Ar 1 when present, is heteroaryl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,
  • Ar 1 when present, is heteroaryl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is unsubstituted heteroaryl.
  • Ar 1 when present, is pyridinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
  • Ar 1 when present, is pyridinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl,
  • Ar 1 when present, is pyridinyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalky
  • Ar 1 when present, is pyridinyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkyla
  • Ar 1 when present, is pyridinyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 1 when present, is unsubstituted pyridinyl.
  • Ar 2 when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 2 when present, is selected from aryl and heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • Ar 2 when present, is selected from aryl and heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 2 when present, is selected from aryl and heteroaryl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 mono
  • Ar 2 when present, is selected from aryl and heteroaryl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 2 when present, is selected from aryl and heteroaryl and unsubstituted.
  • Ar 2 when present, is aryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-
  • Ar 2 when present, is aryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-
  • Ar 2 when present, is aryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino
  • Ar 2 when present, is aryl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,
  • Ar 2 when present, is aryl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 2 when present, is unsubstituted aryl.
  • Ar 2 when present, is phenyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1
  • Ar 2 when present, is phenyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1
  • Ar 2 when present, is phenyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamin
  • Ar 2 when present, is phenyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino
  • Ar 2 when present, is phenyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar e when present, is unsubstituted phenyl.
  • Ar 2 when present, is heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-
  • Ar 2 when present, is heteroaryl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-
  • Ar 2 when present, is heteroaryl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino
  • Ar 2 when present, is heteroaryl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino,
  • Ar 2 when present, is heteroaryl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar 2 when present, is unsubstituted heteroaryl.
  • Ar 2 when present, is pyridinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl,
  • Ar 2 when present, is pyridinyl and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylaminomethyl.
  • groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl,
  • Ar 2 when present, is pyridinyl and substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalky
  • Ar 2 when present, is pyridinyl and substituted with 0 or 1 group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • halogen —OH, —CN, —NO 2
  • —NH 2 C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkyla
  • Ar 2 when present, is pyridinyl and monosubstituted with a group selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • Ar e when present, is unsubstituted pyridinyl.
  • 3-(2-phenylhydrazono)indolin-2-one derivatives having a structure represented by a formula:
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 ; wherein each occurrence of R 15 , when present, is independently selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 ; wherein each of R 12 and R 13 is independently selected from hydrogen and C
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula selected from:
  • the 3-(2-phenylhydrazono)indolin-2-one derivative has a structure represented by a formula:
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • each of R 11a , R 11b , R 11c , and R 11d is hydrogen.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • each of R 11a , R 11b , R 11c , and R 11d is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen and methyl. In a still further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen and ethyl.
  • each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen and halogen. In a still further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, and —Cl. In an even further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen and —F. In a still further aspect, each of R 11a , R 11b , R 11c , and R 11d is independently selected from hydrogen and —Cl.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen and methyl. In a still further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen and ethyl.
  • R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen and halogen. In a still further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen, —F, and —Cl. In an even further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen and —F. In a still further aspect, R 11a is hydrogen and each of R 11b , R 11c , and R 11d is independently selected from hydrogen and —Cl.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, SO 2 R 15 , and —CO 2 R 15 .
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a further aspect, R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen and methyl. In a still further aspect, R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen and ethyl.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen and halogen.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, —F, —Cl, and —Br.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen, —F, and —Cl.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen and —F.
  • R 11b is hydrogen and each of R 11a , R 11c , and R 11d is independently selected from hydrogen and —Cl.
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11c is hydrogen and each of R 11a , R 11b, and R 11d is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen and methyl. In a still further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen and ethyl.
  • R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen and halogen. In a still further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen, —F, and —Cl. In an even further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen and —F. In a still further aspect, R 11c is hydrogen and each of R 11a , R 11b , and R 11d is independently selected from hydrogen and —Cl.
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 11a is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c independently selected from hydrogen and C1-C4 alkyl. In a still further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl. In yet a further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, methyl, and ethyl. In an even further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen and methyl. In a still further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen and ethyl.
  • R 11d is hydrogen and each of R 11a , R 11b , and R 11c independently selected from hydrogen and halogen. In a still further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, —F, —Cl, and —Br. In yet a further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen, —F, and —Cl. In an even further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen and —F. In a still further aspect, R 11d is hydrogen and each of R 11a , R 11b , and R 11c is independently selected from hydrogen and —Cl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d is independently selected from —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d is independently selected from —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from —CFH 2 , —CF 2 H, and —CF 3 .
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from C1-C4 alkyl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from methyl, ethyl, iso-propyl, and n-propyl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from methyl and ethyl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are methyl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are ethyl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from halogen.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from —F, —Cl, and —Br.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are independently selected from —F and —Cl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are —F.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are —Cl.
  • two of R 11a , R 11b , R 11c , and R 11d are hydrogen and two of R 11a , R 11b , R 11c , and R 11d are —Br.
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R11c, and R 11d is selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl.
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from —CFH 2 , —CF 2 H, and —CF 3 .
  • R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from C1-C4 alkyl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from methyl, ethyl, iso-propyl, and n-propyl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from methyl and ethyl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is methyl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is ethyl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from halogen.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from —F, —Cl, and —Br.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is selected from —F and —Cl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is —F.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is —Cl.
  • three of R 11a , R 11b , R 11c , and R 11d are hydrogen and one of R 11a , R 11b , R 11c , and R 11d is —Br.
  • each of R 12 and R 13 is independently selected from hydrogen and C1-C4 alkyl. In a further aspect, each of R 12 and R 13 is hydrogen.
  • each of R 12 and R 13 is independently selected from hydrogen, methyl, ethyl, n-propyl, and iso-propyl. In a still further aspect, each of R 12 and R 13 is independently selected from hydrogen, methyl, and ethyl. In yet a further aspect, each of R 12 and R 13 is independently selected from hydrogen and ethyl. In an even further aspect, each of R 12 and R 13 is independently selected from hydrogen and methyl.
  • R 12 is hydrogen and R 13 is C1-C4 alkyl. In a still further aspect, R 12 is hydrogen and R 13 is selected from methyl, ethyl, n-propyl, and iso-propyl. In yet a further aspect, R 12 is hydrogen and R 13 is selected from methyl and ethyl. In an even further aspect, R 12 is hydrogen and R 13 is ethyl. In a still further aspect, R 12 is hydrogen and R 13 is methyl.
  • R 13 is hydrogen and R 12 is C1-C4 alkyl. In a still further aspect, R 13 is hydrogen and R 12 is selected from methyl, ethyl, n-propyl, and iso-propyl. In yet a further aspect, R 13 is hydrogen and R 12 is selected from methyl and ethyl. In an even further aspect, R 13 is hydrogen and R 12 is ethyl. In a still further aspect, R 13 is hydrogen and R 12 is methyl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • each of R 14a , R 14b , R 14c , R 14d and R 14e is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • each of R 14a , R 14b , R 14c , R 14d and R 14e is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and C1-C4 alkyl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, methyl, and ethyl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and methyl. In a still further aspect, each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and ethyl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and halogen.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, and —Br.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, and —Cl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —F.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —Cl.
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —SO 2 R 16 .
  • each of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —CO 2 R 16 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and C1-C4 alkyl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, methyl, and ethyl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and methyl. In a still further aspect, R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and ethyl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and halogen.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, and —Br.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, and —Cl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —F.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —Cl.
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —SO 2 R 16 .
  • R 14a is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and —CO 2 R 16 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen and C1-C4 alkyl.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
  • R 14b is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen, methyl, and ethyl.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen and methyl. In a still further aspect, R 14b is hydrogen and each of R 14b , R 14c , R 14d , and R 14e is independently selected from hydrogen and ethyl.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen and halogen.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, and —Br.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, —F, and —Cl.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen and —F.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen and —Cl.
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen and —SO 2 R 16 .
  • R 14b is hydrogen and each of R 14a , R 14c , R 14d , and R 14e is independently selected from hydrogen and —CO 2 R 16 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14 c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C I -C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and C1-C4 alkyl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, methyl, and ethyl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and methyl. In a still further aspect, R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and ethyl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and halogen.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, —F, —Cl, and —Br.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, —F, and —Cl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and —F.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and —Cl.
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and —SO 2 R 16 .
  • R 14c is hydrogen and each of R 14a , R 14b , R 14d , and R 14e is independently selected from hydrogen and —CO 2 R 16 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen and C1-C4 alkyl.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, methyl, and ethyl.
  • R 14d is hydrogen and each of R 14a , R 14c , and R 14e is independently selected from hydrogen and methyl. In a still further aspect, R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen and ethyl.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen and halogen.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, —F, —Cl, and —Br.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, —F, and —Cl.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen and —F.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen and —Cl.
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen and —SO 2 R 16 .
  • R 14d is hydrogen and each of R 14a , R 14b , R 14c , and R 14e is independently selected from hydrogen and —CO 2 R 16 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, C1-C2 monohaloalkyl, and C1-C2 polyhaloalkyl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently is selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and C1-C4 alkyl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, methyl, ethyl, iso-propyl, and n-propyl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, methyl, and ethyl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and methyl. In a still further aspect, R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and ethyl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and halogen.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, —F, —Cl, and —Br.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, —F, and —Cl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and —F.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and —Cl.
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and —SO 2 R 16 .
  • R 14e is hydrogen and each of R 14a , R 14b , R 14c , and R 14d is independently selected from hydrogen and —CO 2 R 16 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from —CFH 2 , —CF 2 H, and —CF 3 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from C1-C4 alkyl.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from methyl, ethyl, iso-propyl, and n-propyl.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from methyl and ethyl.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are methyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are ethyl.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from —F, —Cl, and —Br.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from —F and —Cl.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are —F.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are —Cl.
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are —Br.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen and —SO 2 R 16 .
  • two of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and three of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen and —CO 2 R 16 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e is independently selected from —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl.
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from —CFH 2 , —CF 2 H, and —CF 3 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from C1-C4 alkyl.
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are selected from methyl, ethyl, iso-propyl, and n-propyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from methyl and ethyl.
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are methyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are ethyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from halogen.
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from —F, —Cl, and —Br.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from —F and —Cl.
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are —F.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are —Cl.
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are —Br.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen, —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen, —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen, —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen and —SO 2 R 16 .
  • three of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and two of R 14a , R 14b , R 14c , R 14d , and R 14e are independently selected from hydrogen and —CO 2 R 16 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, C1-C4 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from halogen, —OH, —SH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, C1-C2 dialkylamino, —SO 2 R 15 , and —CO 2 R 15 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —F, —Cl, —Br, —OH, —CN, —NO 2 , —NH 2 , —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from halogen, C1-C4 alkyl, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from halogen, C1-C2 alkyl, C1-C2 monohaloalkyl, C1-C2 polyhaloalkyl, C1-C2 alkoxy, C1-C2 cyanoalkyl, C1-C2 aminoalkyl, C1-C2 hydroxyalkyl, C1-C2 monoalkylamino, and C1-C2 dialkylamino.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —F, —Cl, —Br, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —OCH 3 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from C1-C4 monohaloalkyl and C1-C4 polyhaloalkyl.
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from C1-C2 monohaloalkyl and C1-C2 polyhaloalkyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —CFH 2 , —CF 2 H, and —CF 3 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from C1-C4 alkyl.
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from methyl, ethyl, iso-propyl, and n-propyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from methyl and ethyl.
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is methyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is ethyl.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from halogen.
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —F, —Cl, and —Br.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —F and —Cl.
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is —F.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is —Cl.
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is —Br.
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —OH, —SH, —CN, —NO 2 , —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —OH, —SH, —NH 2 , —SO 2 R 16 , and —CO 2 R 16 .
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is selected from —SO 2 R 16 and —CO 2 R 16 .
  • R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is —SO 2 R 16 .
  • four of R 14a , R 14b , R 14c , R 14d , and R 14e are hydrogen and one of R 14a , R 14b , R 14c , R 14d , and R 14e is —CO 2 R 16 .
  • each occurrence of R 15 when present, is independently selected from hydrogen, —CH 3 , —CFH 2 , —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • each occurrence of R 15 when present, is hydrogen.
  • each occurrence of R 15 when present, is independently selected from hydrogen and —CH 3 . In a still further aspect, each occurrence of R 15 , when present, is —CH 3 .
  • each occurrence of R 15 when present, is independently selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 . In a still further aspect, each occurrence of R 15 , when present, is independently selected from hydrogen, —CFH 2 , and —CF 2 H. In yet a further aspect, each occurrence of R 15 , when present, is independently selected from hydrogen and —CFH 2 . In an even further aspect, each occurrence of R 15 , when present, is —CF 3 . In a still further aspect, each occurrence of R 15 , when present, is —CF 2 H. In yet a further aspect, each occurrence of R 15 , when present, is —CFH 2 .
  • each occurrence of R 15 when present, is independently selected from hydrogen, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 . In a still further aspect, each occurrence of R 15 , when present, is independently selected from hydrogen, —NH 2 , and —NH(CH 3 ). In yet a further aspect, each occurrence of R 15 , when present, is independently selected from hydrogen and —NH 2 . In an even further aspect, each occurrence of R 15 , when present, is —N(CH 3 ) 2 . In a still further aspect, each occurrence of R 15 , when present, is —NH(CH 3 ). In yet a further aspect, each occurrence of R 15 , when present, is —NH 2 .
  • each occurrence of R 16 when present, is independently selected from hydrogen, —CH 3 , —CFH 2 , —CF 2 H, —CF 3 , —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 .
  • each occurrence of R 16 when present, is hydrogen.
  • each occurrence of R 16 when present, is independently selected from hydrogen and —CH 3 . In a still further aspect, each occurrence of R 16 , when present, is —CH 3 .
  • each occurrence of R 16 when present, is independently selected from hydrogen, —CFH 2 , —CF 2 H, and —CF 3 . In a still further aspect, each occurrence of R 16 , when present, is independently selected from hydrogen, —CFH 2 , and —CF 2 H. In yet a further aspect, each occurrence of R 16 , when present, is independently selected from hydrogen and —CFH 2 . In an even further aspect, each occurrence of R 16 , when present, is —CF 3 . In a still further aspect, each occurrence of R 16 , when present, is —CF 2 H. In yet a further aspect, each occurrence of R 16 , when present, is —CFH 2 .
  • each occurrence of R 16 when present, is independently selected from hydrogen, —NH 2 , —NH(CH 3 ), and —N(CH 3 ) 2 . In a still further aspect, each occurrence of R 16 , when present, is independently selected from hydrogen, —NH 2 , and —NH(CH 3 ). In yet a further aspect, each occurrence of R 16 , when present, is independently selected from hydrogen and —NH 2 . In an even further aspect, each occurrence of R 16 , when present, is —N(CH 3 ) 2 . In a still further aspect, each occurrence of R 16 , when present, is —NH(CH 3 ). In yet a further aspect, each occurrence of R 16 , when present, is —NH 2 .
  • CDK2 inhibitors having a structure represented by a formula:
  • R 20 is selected from —SO 2 R 20a , —OH, NH 2 , substituted amide, C1-C4 alkyl carbonyl, C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; wherein each of R 21 , R 23 , and R 25 is independently selected from hydrogen, halogen, —OH, NH 2 , C1-C4 monoalkylamino, C1-C4 dialky
  • a CDK2 inhibitor can have a structure represented by a formula:
  • R 20a is selected from —OH, NH 2 , C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; wherein each of R 21 , R 23 , and R 25 is independently selected from hydrogen, halogen, —OH, NH 2 , C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups
  • each occurrence of R 20 when present, is selected from —OH, NH 2 , C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino, or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino, methylethylamino, methylpropylamino, methylbutylamino, diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl
  • each occurrence of R 20a can be selected from —OH, NH 2 , C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl.
  • each occurrence of R 20 and R 20a can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 21 when present, is selected from hydrogen, halogen (e.g., fluoride, chloride, bromide, or iodide), —OH, NH 2 , C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino, or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino, methylethylamino, methylpropylamino, methylbutylamino, diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or oct
  • each occurrence of R 21 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 22 when present, is selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
  • each occurrence of R 22 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 23 when present, is selected from hydrogen, halogen (e.g., fluoride, chloride, bromide, or iodide), —OH, NH 2 , C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino, or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino, methylethylamino, methylpropylamino, methylbutylamino, diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or oct
  • each occurrence of R 23 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 24 when present, is selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
  • each occurrence of R 24 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 25 when present, is selected from hydrogen, halogen (e.g., fluoride, chloride, bromide, or iodide), —OH, NH 2 , C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino, or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino, methylethylamino, methylpropylamino, methylbutylamino, diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or oct
  • each occurrence of R 25 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • CDK2 inhibitors having a structure represented by a formula:
  • each occurrence of R 30 is independently selected from substituted phenyl, C1-C8 alkyl, carbocyclic, substituted cyclohexyl, piperidine wherein each of R 31 , R 32 , and R 33 is independently selected from hydrogen and C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein R 34 is selected from hydroxy alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl or a pharmaceutically acceptable salt thereof.
  • CDK2 inhibitors having a structure represented by a formula:
  • each occurrence of X is independently a halogen (e.g., fluoride, chloride, bromide, or iodide), wherein each of R 30 , R 31 , R 32 , and R 33 is independently selected from hydrogen and C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein R 34 is selected from —OH, NH 2 , C1-C4 monoalkylamino, C1-C4 dialkylaminomethyl, and C1-C8 alkyl and is substituted
  • a CDK2 inhibitor is provided as a compound having the formula:
  • This compound is a multi-CDK inhibitor for CDK1, 2, 4, 6 and 9 with IC50 of 10-210 nM. In certain aspects, this compound can have a low oral bioavailability ( ⁇ 1%). This compound is a potent cell cycle inhibitor and can be useful for the treatment of chronic lymphocytic leukemia and for the treatment of mantle cell lymphoma.
  • each occurrence of R 30 when present, is selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
  • each occurrence of R 30 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 31 when present, is selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
  • each occurrence of R 31 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 32 when present, is selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
  • each occurrence of R 32 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 33 when present, is selected from hydrogen and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl, C1-C4 alkyl, or C1-C2 alkyl.
  • each occurrence of R 33 can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • each occurrence of R 30 is independently selected from substituted phenyl, C1-C8 alkyl, carbocyclic, substituted cyclohexyl, piperidine wherein each of R 31 , R 32 , and R 33 is independently selected from hydrogen and C1-C8 alkyl and is independently substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO 2 , —NH 2 , C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl; and wherein R 34 is selected from hydroxy alkyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl or a pharmaceutically acceptable salt thereof
  • each occurrence of R 34a when present, is selected from —OH, NH 2 , C1-C4 monoalkylamino (e.g., methylamino, ethylamino, propylamino, or butylamino), C1-C4 dialkylaminomethyl (e.g., dimethylamino, methylethylamino, methylpropylamino, methylbutylamino, diethylamino, ethylpropylamino, ethylbutylamino, dipropylamino, propylbutylamino, or dibutylamino), and C1-C8 alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, or octyl).
  • C1-C8 alkyl can be selected to be C1-C6 alkyl
  • each occurrence of R 34 and R 34a can be substituted with 0, 1, or 2 groups independently selected from halogen, —OH, —CN, —NO2, —NH2, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkoxy, C1-C4 cyanoalkyl, C1-C4 aminoalkyl, C1-C4 hydroxyalkyl, C1-C4 monoalkylamino, and C1-C4 dialkylaminomethyl.
  • a compound can be present as one or more of the following structures:
  • a compound can be present as one or more of the following structures:
  • a compound can be present as one or more of the following structures:
  • 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 Route I and Route 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.
  • paullone derivatives can be prepared as shown below.
  • compounds of type 1.3 can be prepared according to reaction Scheme 1B above.
  • compounds of type 1.6 can be prepared by a cyclization reaction (e.g., Fischer indole reaction) of an appropriate hydrazine, e.g., 1.4 as shown above, with an appropriate benzazepine, e.g., 1.5 as shown above.
  • a cyclization reaction e.g., Fischer indole reaction
  • an appropriate benzazepine e.g., 1.5 as shown above.
  • Appropriate hydrazines and appropriate benzazepines are commercially available or prepared by methods known to one skilled in the art.
  • the cyclization reaction is carried out in the presence of an appropriate base, e.g., sodium acetate, in an appropriate protic solvent, e.g., acetic acid, at an appropriate temperature, e.g., 70° C., for an appropriate period of time, e.g., 1 hour.
  • an appropriate base e.g., sodium acetate
  • an appropriate protic solvent e.g., acetic acid
  • each disclosed method can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using.
  • purine derivatives can be prepared as shown below.
  • compounds of type 2.7 can be prepared according to reaction Scheme 2B above.
  • compounds of type 2.9 can be prepared by a substitution reaction of an appropriate aryl halide, e.g., 2.7 as shown above.
  • Appropriate aryl halides are commercially available or prepared by methods known to one skilled in the art.
  • the substitution reaction is carried out in the presence of an appropriate amine, e.g., 2.8 as shown above, in an appropriate solvent, e.g., ethanol.
  • Compounds of type 2.11 can be prepared an alkylation reaction of an appropriate amine, e.g., 2.9 as shown above.
  • the alkylation reaction is carried out in the presence of an appropriate alkyl halide, e.g., 2.10, and an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., dimethylsulfoxide.
  • Compounds of type 2.13 can be prepared by a substitution reaction of an appropriate aryl halide, e.g., 2.11 as shown above.
  • the substitution reaction is carried out in the presence of an appropriate amine, e.g., 2.12 as shown above, in an appropriate solvent, e.g., ethanol.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 2.1, 2.2, 2.3, 2.4, 2.5, and 2.6), can be substituted in the reaction to provide purine derivatives similar to Formula 2.7.
  • each disclosed method can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using.
  • purine derivatives can be prepared as shown below.
  • compounds of type 3.5 can be prepared according to reaction Scheme 3B above.
  • compounds of type 3.8 can be prepared by a displacement reaction of an appropriate guanine derivative, e.g., 3.6 as shown above.
  • Appropriate guanine derivatives are commercially available or prepared by methods known to one skilled in the art.
  • the displacement reaction is carried out in the presence of an appropriate acetate, e.g., 3.7 as shown above, and an appropriate base, e.g., 1,8-diazobicyclo[5.4.0] undec-7-ene (DBU), in an appropriate solvent, e.g., acetonitrile, at an appropriate temperature, e.g., 0° C., for an appropriate period of time, e.g., thirty minutes.
  • DBU 1,8-diazobicyclo[5.4.0] undec-7-ene
  • an appropriate solvent e.g., acetonitrile
  • Compounds of type 3.10 can be prepared by an alkylation reaction of an appropriate amine, e.g., 3.8 as shown above.
  • the alkylation reaction is carried out in the presence of an appropriate alkyl halide, e.g., 3.9 as shown above, and an appropriate base, e.g., potassium carbonate, in an appropriate solvent, e.g., dimethylsulfoxide.
  • an appropriate alkyl halide e.g., 3.9 as shown above
  • an appropriate base e.g., potassium carbonate
  • an appropriate solvent e.g., dimethylsulfoxide
  • each disclosed method can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using.
  • purine derivatives can be prepared as shown below.
  • compounds of type 4.9, and similar compounds can be prepared according to reaction Scheme 4B above.
  • compounds of type 4.1 can be prepared by protection of an appropriate purine derivative, e.g., 3.6 as shown above.
  • Appropriate purine derivatives are commercially available or prepared by methods known to one skilled in the art. The protection is carried out in the presence of an appropriate protecting group, e.g., di-tert-butyldicarbonate as shown above, and an appropriate catalytic base, e.g., DMAP as shown above, in an appropriate solvent, e.g., dimethylsulfoxide, at an appropriate temperature, e.g., 0° C.
  • Compounds of type 4.2 can be prepared by protection of an appropriate amine, e.g., 4.1 as shown above. The protection is carried out in the presence of an appropriate base, e.g., sodium hydride, in an appropriate solvent, e.g., tetrahydrofuran.
  • Compounds of type 4.11 can be prepared by a displacement reaction of an appropriate amine, e.g., 4.2 as shown above.
  • the displacement reaction is carried out in the presence of an appropriate alcohol, e.g., 4.10 as shown above, and an appropriate nucleophile, e.g., triphenylphosphine, followed by the addition of an appropriate azodicarboxylate, e.g., diisopropyl azodicarboxylate.
  • an appropriate alcohol e.g., 4.10 as shown above
  • an appropriate nucleophile e.g., triphenylphosphine
  • an appropriate azodicarboxylate e.g., diisopropyl azodicarboxylate.
  • Compounds of type 4.13 can be prepared by a displacement reaction of an appropriate amine, e.g., 4.11 as shown above.
  • the displacement reaction is carried out in the presence of an appropriate alcohol, e.g., 4.12 as shown above, and an appropriate nucleophile, e.g., triphenylphosphine, followed by the addition of an appropriate azodicarboxylate, e.g., diisopropyl azodicarboxylate.
  • an appropriate alcohol e.g., 4.12 as shown above
  • an appropriate nucleophile e.g., triphenylphosphine
  • an appropriate azodicarboxylate e.g., diisopropyl azodicarboxylate.
  • Compounds of type 4.15 can be prepared by a displacement reaction of an appropriate halide, e.g., 4.13 as shown above.
  • the displacement reaction is carried out in the presence of an appropriate alcohol, e.g., 4.14 as shown above, and an appropriate nucleophile, e.g., triphenylphosphine, followed by the addition of an appropriate azodicarboxylate, e.g., diisopropyl azodicarboxylate.
  • an appropriate alcohol e.g., 4.14 as shown above
  • an appropriate nucleophile e.g., triphenylphosphine
  • an appropriate azodicarboxylate e.g., diisopropyl azodicarboxylate.
  • Compounds of type 4.16 can be prepared by deprotection of an appropriate amine, e.g., 4.15 as shown above.
  • the deprotection is carried out in the presence of an appropriate acid, e.g., trifluoroacetic acid.
  • the above reaction provides an example of a generalized approach wherein compounds similar in structure to the specific reactants above (compounds similar to compounds of type 3.6, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, and 4.8), can be substituted in the reaction to provide purine derivatives similar to Formula 4.9.
  • each disclosed method can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using.
  • 3-(2-phenylhydrazono)indolin-2-one derivatives can be prepared as shown below.
  • compounds of type 5.3 can be prepared according to reaction Scheme 5B above.
  • compounds of type 5.6 can be prepared by a hydrolysis reaction of an appropriate hydrazone, e.g., 5.4 as shown above.
  • Appropriate hydrazones are commercially available or prepared by methods known to one skilled in the art.
  • the hydrolysis reaction is carried out in the presence of an appropriate hydrazine, e.g., 5.5 as shown above, which are commercially available or prepared by methods known to one skilled in the art, in an appropriate solvent, e.g., ethanol, at an appropriate temperature, e.g., refluxing conditions, for an appropriate period of 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 5.1 and 5.2), can be substituted in the reaction to provide 3-(2-phenylhydrazono)indolin-2-one derivatives similar to Formula 5.3.
  • each disclosed method can further comprise additional steps, manipulations, and/or components. It is also contemplated that any one or more step, manipulation, and/or component can be optionally omitted from the invention. It is understood that a disclosed method can be used to provide the disclosed compounds. It is also understood that the products of the disclosed methods can be employed in the disclosed methods of using.
  • 4-(1H-imidazol-5-yl)-N-(phenyl)pyrimidin-2-amine derivatives can be prepared as shown below.
  • compounds of type 6.3 can be prepared according to reaction Scheme 6B above.
  • compounds of type 6.6 can be prepared by a coupling reaction between appropriate aryl halide and amino pyrimidines, e.g., 6.4 and 6.5 respectively as shown above.
  • Appropriate aryl halides 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 imidazoly pyrimidines, e.g., 6.5 as shown above, which are commercially available or prepared by methods known to one skilled in the art, in an appropriate solvent, e.g., dioxane, at an appropriate temperature, e.g., refluxing conditions, for an appropriate period of time, e.g., 16 hours.
  • an appropriate imidazoly pyrimidines e.g., 6.5 as shown above, which are commercially available or prepared by methods known to one skilled in the art
  • an appropriate solvent e.g., dioxane
  • 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 6.1 and 6.2), can be substituted in the reaction to provide 4-(1H-imidazol-5-yl)-N-(phenyl)pyrimidin-2-amine derivatives similar to Formula 6.3.
  • compositions comprising a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof; and one or more of: (a) at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof; and (b) at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
  • compositions comprising a compound selected from:
  • a pharmaceutically acceptable salt thereof and one or more of: at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof; at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof; wherein at least one is present in an effective amount; and a pharmaceutically acceptable carrier.
  • compositions comprising a compound 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, e.g., administration by drops or injection into the ear, insufflation (such as into the ear), intravenous, topical, or oral administration.
  • 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.
  • 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
  • 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
  • the CDK2 inhibitor is selected from a paullone derivative, a purine derivative, and a 3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceutically acceptable salt thereof.
  • the CDK2 inhibitor is selected from:
  • 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 agent known to treat hearing impairment is selected from an antiepileptic drug blocking T-type calcium channels; an anticonvulsant; a synthetic glucocorticoid; a loop diuretic; an anti-oxidant; a proton pump inhibitor; a PDES inhibitor; and a mGluR7 inhibitor.
  • the agent known to treat a hearing impairment is selected from trimethadione; mibefrabil; ethosuximide; 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2); NNC 55-0396; ML 218; nilvadipine; valproic acid; oxcarbazepine; phenobarbital; phenytoin; zonisamide; nicardipine; chlordiazepoxide; sipatrigine; halothane; octanol; pimozide; penfluridol; fluspirilene; thioridazine; clozapine; haloperidol; tetramethrin; tetrandrine; amiodarone; bepridil; cinnarizine
  • the chemotherapeutic agent is selected from a platinum-based agent.
  • the platinum-based agent is selected from carboplatin, cisplatin, transplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, transplatin, and triplatin.
  • the platinum-based agent is cisplatin.
  • the ototoxic agent is selected from one or more of an antibiotic, a loop diuretic, an antimetabilite, and a salicyclate.
  • the antibiotic agent is selected from one or more of daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, and mitomycin-C, or a pharmaceutically acceptable salt thereof.
  • the antibiotic agent is an aminoglycoside.
  • the aminoglycoside is selected from one or more of amikacin, apramycin, arbekacin, astromicin, bekanamycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin, or a pharmaceutically acceptable salt thereof.
  • the loop diuretic is selected from one or more of furosemide; ethacrynic acid; or bumetanide, or a pharmaceutically acceptable salt thereof.
  • the antimetabilite is selected one or more of an anti-folate, a fluoropyridimidine, a deoxynucleoside analogue, and a thiopurine.
  • the antimetabolite is selected from one or more of methotrexate, pemetrexed, fluorouracil, capecitabine, cytarabine, gemcitabine, decitabine, 5-azacytidine, fludarabine, nelarabine, cladribine, clofarabine, pentostatin, thioguanine, and mercaptopurine, or a pharmaceutically acceptable salt thereof.
  • the salicylate is selected from one or more of salicylic acid, methyl salicylate, and trolamine salicylate, or pharmaceutically acceptable salts thereof.
  • the agent known to prevent hearing impairment is selected from one or more of fish oil, an omega-3 fatty acid, magnesium, folic acid, vitamin A, vitamin C, vitamin E, rebamipide, alpha-lipoic acid, N-acetylcysteine (NAC), Elselen, D-methionine, magnesium, ABC magnesium (vitamins A, B, and C, plus magnesium).
  • Molecular hydrogen (hydrogen-rich water), dexamethasone, Acuval, CoQ10, L-arginine, Ginko biloba, coenzyme Q10, Z-VAD-fmk, thymidylate kinase (TMK, AM111), retinoic acid, calcium, calcineurin inhibitors, or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition is used to treat hearing impairment.
  • the pharmaceutical composition is used to prevent a hearing impairment.
  • compositions can be prepared from the disclosed compounds. It is also understood that the disclosed compositions can be employed in the disclosed methods of using.
  • a pharmaceutical composition comprising the step of combining a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof and one or more of: (a) at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof (b) at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof wherein at least one is present in an effective amount; and a pharmaceutically acceptable carrier.
  • the effective amount is a prophylactically effective amount. In a still further aspect, the effective amount is a therapeutically effective amount.
  • a pharmaceutically acceptable salt thereof and one or more of: at least one agent known to treat hearing impairment, or a pharmaceutically acceptable salt thereof; at least one agent known to prevent hearing impairment, or a pharmaceutically acceptable salt thereof; wherein at least one is present in an effective amount; and a pharmaceutically acceptable carrier.
  • the CDK2 inhibitor is selected from a paullone derivative, a purine derivative, and a 3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceutically acceptable salt thereof.
  • the CDK2 inhibitor is selected from:
  • an effective amount is a therapeutically effective amount. In a still further aspect, an effective amount is a prophylactically effective amount.
  • combining is co-formulation of the CDK2 inhibitor, the agent known to treat hearing impairment and/or the agent known to prevent hearing impairment with the pharmaceutically acceptable carrier.
  • co-formulation is an oral solid dosage form comprising the CDK2 inhibitor, the agent known to treat hearing impairment, and/or the agent known to prevent hearing impairment, and the pharmaceutically acceptable carrier.
  • the solid dosage form is a tablet.
  • the solid dosage dorm is a capsule.
  • co-formulation is an inhaled dosage form comprising the CDK2 inhibitor, the agent known to treat hearing impairment, and/or the agent known to prevent hearing impairment, and the pharmaceutically acceptable carrier.
  • co-formulation is an injectable dosage form comprising the CDK2 inhibitor, the agent known to treat hearing impairment, and/or the agent known to prevent hearing impairment, and the pharmaceutically acceptable carrier.
  • the pharmaceutical composition is used to treat hearing impairment. In a further aspect, the pharmaceutical composition is used to prevent hearing impairment.
  • a method of treating hearing impairment comprising administering to a subject diagnosed with a need for treatment of hearing impairment a therapeutically effective amount of a cyclin-dependent kinase 2 (CDK2) inhibitor, or a pharmaceutically acceptable salt thereof.
  • CDK2 cyclin-dependent kinase 2
  • the compounds and compositions disclosed herein are useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of hearing impairments and disorders, including hearing loss, deafness, tinnitus, ringing, Presbyacusis, auditory neuropathy, acoustic trauma, acoustic neuroma, Pendred syndrome, Usher syndrome, Wardenburg syndrome, non-syndromic sensorineural deafness, otitis media, otosclerosis, Meniere's disease, ototoxicity, labyrinthitis, as well as hearing impairments caused by infection (i.e., measles, mumps, or meningitis), medicines such as antibiotics, and some cancer treatments (i.e., chemotherapy and radiation therapy).
  • infections i.e., measles, mumps, or meningitis
  • medicines such as antibiotics
  • cancer treatments i.e., chemotherapy and radiation therapy.
  • NIHL Noise-induced hearing loss caused by intense or constant noise exposure is irreversible, resulting in a permanent disability to military personnel.
  • NIHL is the No. 1 diagnosis among U.S. soldiers who served in Afghanistan (http://issuu.com/hearinghealthmagazine/docs/hearinghealthwinter2010issuurev3). Of 1,250 Marine Commandos who served in Afghanistan, 69% suffered hearing loss due to the intense noise of combat. Hearing impairment significantly affects performance (Consideration of Hazardous Noise in the Acquisition of Selected Major Department of the Navy Weapon Systems and Platforms N2010-0038, 22 June 2010). Given the importance of auditory acuity in perceiving commands and sensing enemy activity, it is clear that even mild loss of hearing increases the risk to soldiers.
  • TBI Traumatic brain injury
  • TBI is often accompanied by a diverse range of disruption or damage to the auditory sensory system, which is highly vulnerable to blast injury. Extreme physical blast force can cause damage of various types to the peripheral auditory system, including rupture of the tympanic membrane (TM, eardrum), fracture of the middle ear bones, dislocation of sensory hair cells from the basilar membrane, and loss of spiral ganglia that innervate hair cells.
  • TM tympanic membrane
  • TM tympanic membrane
  • the disclosed compounds can be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of hearing impairments and disorders for which disclosed compounds or the other drugs can have utility, where the combination of the drugs together are safer or more effective than either drug alone.
  • Such other drug(s) can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present invention.
  • a pharmaceutical composition in unit dosage form containing such other drugs and a disclosed compound is preferred.
  • the combination therapy can also include therapies in which a disclosed compound and one or more other drugs are administered on different overlapping schedules.
  • the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions include those that contain one or more other active ingredients, in addition to a compound of the present invention.
  • the subject e.g., human or other animal
  • Methods for measuring hearing are well-known and include pure tone audiometry, air conduction, and bone conduction tests. These exams measure the limits of loudness (intensity) and pitch (frequency) that a human can hear.
  • Hearing tests in humans include behavioral observation audiometry (for infants to seven months), visual reinforcement orientation audiometry (for children 7 months to 3 years) and play audiometry for children older than 3 years.
  • Oto-acoustic emission testing can be used to test the functioning of the cochlear hair cells, and electro-cochleography provides information about the functioning of the cochlea and the first part of the nerve pathway to the brain.
  • treatment can be continued with or without modification or can be stopped.
  • the CDK2 inhibitor is selected from a paullone derivative, a purine derivative, and a 3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceutically acceptable salt thereof.
  • the CDK2 inhibitor is selected from:
  • the subject is a mammal.
  • the mammal is human.
  • the subject has been diagnosed with a need for treatment of a hearing impairment prior to the administering step. In a still further aspect, the subject is at risk for developing a hearing impairment prior to the administering step.
  • the CDK2 inhibitor is administered locally. In a still further aspect, the CDK2 inhibitor is administered systemically. In yet a further aspect, the CDK2 inhibitor is administered locally to the inner ear of the subject. In an even further aspect, the CDK2 inhibitor is administered via injection into one or more of the scala tympani, cochlear duct, scala vestibule of the cochlea, into the auditory nerve trunk in the internal auditory meatus, or into the middle ear space across the transtympanic membrane/ear drum.
  • the CDK2 inhibitor is administered in an amount of from about 0.001 ⁇ M to about 1.0 ⁇ 10 4 ⁇ M. In a still further aspect, the CDK2 inhibitor is administered in an amount of from about 0.001 ⁇ M to about 1.0 ⁇ 10 2 ⁇ M. In yet a further aspect, the CDK2 inhibitor is administered in an amount of from about 0.001 ⁇ M to about 10 ⁇ M. In an even further aspect, the CDK2 inhibitor is administered in an amount of from about 0.01 ⁇ M to about 1.0 ⁇ 10 4 ⁇ M. In a still further aspect, the CDK2 inhibitor is administered in an amount of from about 0.1 ⁇ M to about 1.0 ⁇ 10 4 ⁇ M. In yet a further aspect, the CDK2 inhibitor is administered in an amount of from about 1.0 ⁇ M to about 1.0 ⁇ 10 4 ⁇ M.
  • the CDK2 inhibitor is administered locally. In a still further aspect, the CDK2 inhibitor is administered systemically.
  • the CDK2 inhibitor is administered at least once every three weeks. In a still further aspect, the CDK2 inhibitor is administered at least once every week. In yet a further aspect, the CDK2 inhibitor is administered at least once every 24 h. In an even further aspect, the CDK2 inhibitor is administered at least once every four hours. In a still further aspect, the CDK2 inhibitor is administered at least once every one hour.
  • the CDK2 inhibitor is administered in an amount of from about 0.001 ⁇ M to about 1.0 ⁇ 10 4 ⁇ M at least once every three weeks.
  • the hearing impairment is noise-induced.
  • the noise-induced hearing loss is temporary.
  • the noise-induced hearing loss is permanent.
  • the hearing impairment is drug-induced.
  • the drug is a chemotherapeutic agent.
  • the chemotherapeutic agent is platinum-based.
  • the platinum-based chemotherapeutic agent is selected from carboplatin, cisplatin, transplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, transplatin, and triplatin, or a pharmaceutically acceptable salt thereof.
  • the platinum-based chemotherapeutic agent is cisplatin, or a pharmaceutically acceptable salt thereof.
  • the drug is an antibiotic.
  • the antibiotic is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, amikacin, apramycin, arbekacin, astromicin, bekanamycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin, or a pharmaceutically acceptable salt thereof.
  • the hearing impairment is age-related.
  • the hearing impairment is related to a balance or orientation-related disorder.
  • balance disorders include, but are not limited to, induced or spontaneous vertigo, dysequilibrium, increased susceptibility to motion sickness, nausea, vomiting, ataxia, labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness, dizziness, increased falling, difficulty walking at night, Meniere's disease, and difficulty in visual tracking and processing.
  • the subject has been diagnosed with a need for prevention of hearing impairment prior to the administering step.
  • the method further comprises identifying a subject at risk for developing a hearing impairment prior to the administering step.
  • a CDK2 inhibitor in an amount of from about 0.001 ⁇ M to about 1.0 ⁇ 10 4 ⁇ M at least once every three weeks, or a pharmaceutically acceptable salt thereof.
  • hearing impairment examples include, but are not limited to, hearing loss, deafness, tinnitus, ringing, Presbyacusis, auditory neuropathy, acoustic trauma, acoustic neuroma, Pendred syndrome, Usher syndrome, Wardenburg syndrome, non-syndromic sensorineural deafness, otitis media, otosclerosis, Meniere's disease, ototoxicity, labyrinthitis, as well as hearing impairments caused by infection (i.e., measles, mumps, or meningitis), medicines such as antibiotics, and some cancer treatments (i.e., chemotherapy and radiation therapy).
  • infection i.e., measles, mumps, or meningitis
  • medicines such as antibiotics
  • cancer treatments i.e., chemotherapy and radiation therapy
  • the CDK2 inhibitor is selected from a paullone derivative, a purine derivative, and a 3-(2-phenylhydrazono)indolin-2-one derivative, or a pharmaceutically acceptable salt thereof.
  • the CDK2 inhibitor is selected from:
  • the subject is a mammal.
  • the mammal is human.
  • the CDK2 inhibitor is administered locally. In a still further aspect, the CDK2 inhibitor is administered systemically. In yet a further aspect, the CDK2 inhibitor is administered locally to the inner ear of the subject. In an even further aspect, the CDK2 inhibitor is administered via injection into one or more of the scala tympani, cochlear duct, scala vestibule of the cochlea, into the auditory nerve trunk in the internal auditory meatus, or into the middle ear space across the transtympanic membrane/ear drum.
  • the hearing impairment is noise-induced.
  • the noise-induced hearing loss is temporary.
  • the noise-induced hearing loss is permanent.
  • the hearing impairment is drug-induced.
  • the drug is a chemotherapeutic agent.
  • the chemotherapeutic agent is platinum-based.
  • the platinum-based chemotherapeutic agent is selected from carboplatin, cisplatin, transplatin, nedaplatin, oxaliplatin, picoplatin, satraplatin, transplatin, and triplatin, or a pharmaceutically acceptable salt thereof.
  • the platinum-based chemotherapeutic agent is cisplatin, or a pharmaceutically acceptable salt thereof.
  • the drug is an antibiotic.
  • the antibiotic is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, actinomycin-D, bleomycin, mitomycin-C, amikacin, apramycin, arbekacin, astromicin, bekanamycin, dibekacin, framycetin, gentamicin, hygromycin B, isepamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, ribostamycin, sisomicin, spectinomycin, streptomycin, tobramycin, and verdamicin, or a pharmaceutically acceptable salt thereof.
  • the hearing impairment is age-related.
  • the hearing impairment is related to a balance or orientation-related disorder.
  • balance disorders include, but are not limited to, induced or spontaneous vertigo, dysequilibrium, increased susceptibility to motion sickness, nausea, vomiting, ataxia, labyrinthitis, oscillopsia, nystagmus, syncope, lightheadedness, dizziness, increased falling, difficulty walking at night, Meniere's disease, and difficulty in visual tracking and processing.
  • the compounds and compositions are further useful in methods for the prevention, treatment, control, amelioration, or reduction of risk of the hearing impairments and disorders noted herein.
  • the compounds and compositions are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned hearing impairments and disorders in combination with other agents.
  • the method of use is directed to the treatment of a disorder.
  • the disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone.
  • the other drug(s) can be administered by a route and in an amount commonly used therefore, contemporaneously or sequentially with a disclosed compound.
  • a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound is preferred.
  • the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent.
  • compositions and methods of the present invention can further comprise other therapeutically active compounds as noted herein which are usually applied in the treatment of the above mentioned pathological conditions.
  • the invention relates to a medicament comprising a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof and one or more of at least one agent known to treat a hearing impairment, or a pharmaceutically acceptable salt thereof, and at least one agent known to prevent a hearing impairment, or a pharmaceutically acceptable salt thereof.
  • the invention relates methods for the manufacture of a medicament for treating and/or preventing hearing impairment comprising combining one or more disclosed compounds, products, or compositions or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier. It is understood that the disclosed methods can be performed with the disclosed compounds, products, and pharmaceutical compositions. It is also understood that the disclosed methods can be employed in connection with the disclosed methods of using.
  • the invention relates to the uses of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof and one or more of at least one agent known to treat a hearing impairment, or a pharmaceutically acceptable salt thereof, and at least one agent known to prevent a hearing impairment, or a pharmaceutically acceptable salt thereof.
  • the invention relates to the use of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a hearing impairment or disorder.
  • the use relates to a process for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, and one or more of at least one agent known to treat a hearing impairment, or a pharmaceutically acceptable salt thereof, and at least one agent known to prevent a hearing impairment, or a pharmaceutically acceptable salt 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 CDK2 inhibitor, or a pharmaceutically acceptable salt thereof, and one or more of at least one agent known to treat a hearing impairment, or a pharmaceutically acceptable salt thereof, and at least one agent known to prevent a hearing impairment, or a pharmaceutically acceptable salt thereof, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of the CDK2 inhibitor, the at least one agent known to treat a hearing impairment, or the at least one agent known to prevent a hearing impairment.
  • the use relates to the treatment of a hearing impairment or disorder in a vertebrate animal. In a further aspect, the use relates to the treatment of a hearing impairment or disorder in a human subject.
  • the use is the treatment of a hearing impairment or disorder. In a still further aspect, the use is the treatment of a hearing impairment. In yet a further aspect, the use is the treatment of a hearing disorder.
  • the disclosed uses can be employed in connection with the disclosed compounds, methods, compositions, and kits.
  • the invention relates to the use of a disclosed compound or composition of a medicament for the treatment of a hearing impairment or disorder in a mammal.
  • the invention relates to the use of a disclosed compound or composition in the manufacture of a medicament for the treatment of a hearing impairment or disorder selected from hearing loss, deafness, tinnitus, ringing, Presbyacusis, auditory neuropathy, acoustic trauma, acoustic neuroma, Pendred syndrome, Usher syndrome, Wardenburg syndrome, non-syndromic sensorineural deafness, otitis media, otosclerosis, Meniere's disease, ototoxicity, labyrinthitis, as well as hearing impairments caused by infection (i.e., measles, mumps, or meningitis), medicines such as antibiotics, and some cancer treatments (i.e., chemotherapy and radiation therapy).
  • a hearing impairment or disorder selected from hearing loss, deafness, tinnitus, ringing, Presbyacusis, auditory neuropathy, acoustic trauma, acoustic neuroma, Pendred syndrome, Usher syndrome
  • the invention relates to the use of a disclosed compound or composition in the manufacture of a medicament for the treatment of a hearing impairment or disorder.

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