Substituted-pyridinyl compounds and uses thereof

Abstract

To provide compounds useful for the treatment and / or enhancement of cognitive dysfunction and negative symptoms associated with CNS disorders where the circuitry involving the production of cortical gamma oscillations is disrupted.SOLUTION: The invention provides compounds represented by formula (I).SELECTED DRAWING: None

Description

Technical Field

[0001] The present disclosure generally relates to compounds useful for treating and / or enhancing cognitive dysfunction and negative symptoms associated with CNS disorders in which the circuitry involved in the generation of fast spiking PV+ interneurons and cortical gamma oscillations is disrupted. The present disclosure enables the manufacture of medicaments and compositions containing the same for use in methods of treating and preventing cognitive dysfunction and negative symptoms.

Background Art

[0002] The Kv3 voltage-gated potassium channels Kv3.1-Kv3.4 encoded by the KCNC1-4 genes are responsible for the neuron's ability for rapid repolarization, thereby facilitating high-frequency action potential firing. Because of these rapid activation properties, Kv3 channels are thought to be important in setting and controlling the firing frequency in fast spiking neurons. Thus, Kv3 channels are thought to play a central role in generating synchronous gamma (γ) frequency oscillations (30-80 Hz) in cortical neuron circuitry. When synchronized across populations of neurons, these γ oscillations are associated with productive cognitive and behavioral responses. Their dysfunction is thought to be associated with cognitive impairment and negative symptoms. Specifically, fast spiking interneurons involved in gamma synchrony express parvalbumin (PV), a calcium-binding protein.

[0003] The Kv3.1 and Kv3.2 subunits are expressed in PV-positive fast spiking GABAergic interneurons and are involved in the rapid action potential firing of these interneurons that organize the activity of the cortical circuitry.

[0004] Studies in patients with schizophrenia and animal models of the condition have shown that the cortical circuitry is unable to generate coherent gamma frequency oscillations. Furthermore, postmortem studies using cortical tissue from schizophrenic patients have reported reduced expression of PV and Kv3.1 channels in the remaining PV+ interneurons. Additionally, PV interneuron dysfunction leading to abnormal gamma oscillations has been associated with cognitive deficits and negative symptoms in several pathologies involving disruption of the circuitry involved in fast-spiking PV+ interneuron and cortical gamma oscillation generation: schizophrenia, Alzheimer's disease, Tourette syndrome, autism, dementia, epilepsy.

[0005] Thus, pharmacological manipulation of the Kv3.1 and / or Kv3.2 channels represents a means of treating the cognitive deficits and negative symptoms associated with CNS disorders in which the circuitry involved in fast-spiking PV+ interneuron and cortical gamma oscillation generation is malfunctioning. Small molecules that positively modulate Kv3.1 and / or Kv3.2 by restoring fast-spiking properties to PV interneurons represent novel therapeutic treatments for cognitive deficits and negative symptoms. SUMMARY OF THE INVENTION

[0006] It is taught from the present disclosure that the compounds of the invention, including the compounds of its partial formula, are activators of the Kv3.1 and / or Kv3.2 channels and are thus therapeutically useful in the treatment of cognitive deficits and negative symptoms associated with CNS disorders such as schizophrenia, Alzheimer's disease, Tourette syndrome, autism, dementia, epilepsy and other disorders in which gamma oscillations are malfunctioning.

[0007] In one aspect, the invention is a method of treating cognitive deficits and negative symptoms associated with a CNS disorder in a subject in need thereof, in which the circuitry involved in fast-spiking PV+ interneuron and cortical gamma oscillation generation is disrupted, the method comprising administering to the patient a compound of formula (I):

Chemical formula

[0008] In another aspect, the present invention relates to a compound of formula (I’): [Chemical formula] [In the formula, X 1 、X 2 、X 3 or X 4 one of them is N, and the others are independently selected from CH, CF, CCF3, CCH3 or COCF3; R 1 is phenyl, CN, F, OCF3, C1-C3 alkoxy or C1-C5 alkyl; R 2 is H, C1-C5 alkyl or C1-C5 alkoxy; R 3 is H or CH3; or R 1 and R 2 together represent an optionally substituted 5- or 6-membered O-containing heterocyclylene, an optionally substituted 5- or 6-membered O-containing heteroarylene, or an optionally substituted 5- or 6-membered arylene; and R 4 and R 5 are independently H or C1-C4 alkyl, or R 4 and R 5 together represent an optionally substituted 4- to 7-membered cycloalkylene or an optionally substituted 5- to 7-membered heterocyclylene] To provide a compound of, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and stereoisomers thereof.

[0009] In certain embodiments, R 1 is CN, F, OCF3, C1-C3 alkoxy or C1-C5 alkyl; R 2 is C1-C5 alkyl or C1-C5 alkoxy; or R 1 and R 2 together represent an optionally substituted 5-membered O-containing heterocyclyl.

[0010] In certain embodiments, the compound of formula (I’) is of formula (I’a), (I’b), (I’c), or (I’d):

Chemical formula

[0011] In certain embodiments, the compound of formula (I’) is a compound of formula (I’a).

[0012] In further embodiments, the compound of formula (I’) is a compound of formula (I’a) to (I’d) [wherein R 4 and R 5 together represent an optionally substituted 4- to 7-membered cycloalkylene or an optionally substituted 5- to 7-membered heterocycle].

[0013] The present invention relates to the use of a compound of formula (I):

Chemical formula

[0014] The present invention relates to the treatment of cognitive dysfunction and negative symptoms associated with CNS disorders in which the fast-spiking PV+ interneurons and the circuitry involved in the generation of cortical gamma oscillations are disrupted, of formula (I):

Chemical formula

[0015] The present disclosure contemplates treating cognitive dysfunction and negative symptoms associated with CNS disorders in which the circuitry involved in fast-spiking PV+ interneuron and cortical gamma oscillation generation is disrupted.

[0016] The present specification presents that the compounds of formula (I) and the compounds of its partial formulae treat cognitive dysfunction and negative symptoms associated with CNS disorders in which the circuitry involved in fast-spiking PV+ interneuron and cortical gamma oscillation generation is disrupted.

[0017] The present invention relates to the following general formula (I): [Chemical formula] [wherein R 1 ~R 5 are as defined above herein] Based on the discovery that certain 1,3 meta-positioned hydantoin-substituted pyridinyl compounds of formula (I) have properties useful as activators of Kv3.1 and / or Kv3.2 channels and can induce effects on the central nervous system. Such compounds have great potential to treat cognitive dysfunction and negative symptoms associated with CNS disorders in which the circuitry involved in fast-spiking PV+ interneuron and cortical gamma oscillation generation is disrupted. For example, in schizophrenia, Alzheimer's disease, Tourette syndrome, autism and other dementias.

[0018] Cognitive dysfunction or impairment refers to a category of mental health disorders that primarily affect cognitive abilities including learning, memory, perception, and problem-solving. They are acquired (as opposed to developmental), typically represent a decline, and are defined by deficits in cognitive abilities that may have an underlying medical condition in the brain.

[0019] This compound has been shown to treat a specific underlying condition, namely the underlying condition in which "the circuit network involved in the generation of fast-spiking PV+ interneurons and cortical gamma oscillations is disrupted."

[0020] The DSM-5 defines six important domains of cognitive function: executive function, learning and memory, sensorimotor function, language, complex attention, and social cognition. Cognitive impairment or dysfunction can be diagnosed and evaluated based on the six-item cognitive impairment test (6-CIT) Kingshill Version 2000.

[0021] "Alkyl" can be linear or branched, preferably having 1 to 5, or more preferably 1 to 4 carbon atoms (i.e., for example, C1-C4 alkyl), and refers to a monovalent saturated hydrocarbon group. Examples of such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, and isobutyl.

[0022] "Alkoxy" refers to an alkyl-O- group, where the alkyl group is as described above, but is limited to C1-C3 alkoxy. Examples include methoxy, ethoxy, and n-propoxy.

[0023] "Heterocyclyl" refers to a monovalent saturated or unsaturated group having a single ring or multiple condensed rings, preferably having 1 to 8 carbon atoms and 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen, selenium, or phosphorus within the ring. The most preferred heteroatom is nitrogen.

[0024] "Heterocyclylene" refers to a divalent heterocyclyl group, where the heterocyclyl group is as described above.

[0025] "Heteroaryl" refers to a monovalent aromatic heterocyclic group that satisfies Hückel's criterion for aromaticity (i.e., contains 4n + 2 π electrons), preferably having 2 to 10 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, selenium, and sulfur (including oxides of sulfur, selenium, and nitrogen) in the ring. Such heteroaryl groups can be monocyclic (e.g., pyridyl, pyrrolyl or its N-oxide, or furyl), or have multiple fused rings (e.g., indolizinyl, benzimidazolyl, coumarinyl, quinolinyl, isoquinolinyl or benzothienyl).

[0026] "Heteroarylene" refers to a divalent heteroaryl group, and the heteroaryl group is as described above.

[0027] "Cycloalkylene" is defined as a divalent saturated cyclic hydrocarbon group, preferably referring to a divalent cycloalkyl group having 3 to 7 or more preferably 4 to 6 carbon atoms. Examples of such groups include cyclopropylene, cyclobutylene, and the like.

[0028] As used herein, "optionally substituted" is understood to mean that the group may or may not be further substituted. The term "optionally substituted" means that the group is independently selected from the group consisting of hydroxy, halogen (especially Cl, Br, F), C 1~6 alkyl, C 1~6 alkoxy, C 2-6 alkenyl, C 1~6 haloalkyl (especially -CF3), C 1~6 haloalkoxy (-OCF3, etc.), arylalkyl (where the alkyl is C 1~6 ), aryloxyalkyl (where the alkyl is C 1~6 ), aryl, cyano, nitro, heteroaryl, trialkylsilyl, amino, mono- and di-alkylamino, mono- and di-(substituted alkyl)amino, and mono- and di-arylamino, and may be substituted 1 to 3 times.

[0029] In yet another embodiment, the term "optionally substituted" is understood to mean that the group is independently selected from the group consisting of hydroxy, halogen (especially Cl, Br, F), hydroxyethyl, hydroxypropyl, methyl, methoxy, cyano, pyridinyl, pyridinylmethyl, pyrazinyl, methylphenyl, benzyl, trimethylsilyl, phenyl, methylpyrazolyl, dimethylamino, fluorophenyl, tert-butyloxycarbonyl, amino or morpholinyl and may be substituted 1 to 3 times.

[0030] R 1 and R 2 together, in the context of being an "optionally substituted" 5-membered O-containing heteroarylene, for example, the present invention contemplates embodiments where R 1 and R 2 together form an optionally substituted furanylene ring. In certain embodiments, R 1 and R 2 together form an optionally substituted furanylene ring, and the optional substituents are selected from F, CH3, and CF3. In certain embodiments, R 1 and R 2 together form formulas (IIa - IIf): [Chemical formula] [wherein R7 and R8 are independently selected from H, F, CH3, and CF3] represent the moiety of.

[0031] In a further embodiment, with respect to sub-formulas II(a) - II(f), R7 and R8 are independently selected from F, CH3, and CF3.

[0032] In certain embodiments, R1 is CH3.

[0033] In certain embodiments, R1 is OCH3.

[0034] In one embodiment, R2 is CH3.

[0035] In one embodiment, R2 is OCH3.

[0036] In one embodiment, R 1 and R 2 together form an optionally substituted furanylene ring.

[0037] In one embodiment, R 1 and R 2 together form an optionally substituted furanylene ring of formula II(f), wherein R7 and R8 are CH3 and CF3.

[0038] In one embodiment, R4 is CH3 and R5 is CH3.

[0039] In one embodiment, R4 is CH3 and R5 is H.

[0040] In one embodiment, R4 is CH2CH3 and R5 is H.

[0041] In one embodiment, R4 is CH2CH3 and R5 is CH3.

[0042] In one embodiment, n is 1 and R6 is F.

[0043] In certain embodiments, R1 is positioned para to the ether moiety as represented below.

Chemical formula

[0044] In some other embodiments, for the compounds of formula (I), (I’), (I’a), (I’b), (I’c) or (I’d), R1 represents OCH3 or CH3, R2 represents CH3 or OCH3, R3 represents H, R4 represents CH3 or CH2CH3, R5 is CH3 or H, or R4 and R5 together represent cyclopropylene, cyclobutylene, cyclopentylene or cyclohexylene, n is 1 and R6 is F.

[0045] In certain embodiments, representative

Chemical formula

Chemical formula

[0046] In a further embodiment, the present invention provides a compound of formula (II):

Chemical formula

[0047] In a further embodiment, the compound of formula (I) is a compound of formula (I’a):

Chemical formula

[0048] In yet another embodiment, the compound of formula (I) is a compound of formula (I”a):

Chemical formula

[0049] In yet another embodiment, the compound of formula (I) is of formula (I”b):

Chemical formula

[0050] Representative compounds of the present invention and compounds that can be used in the methods of the present invention include not only those exemplified herein,

Chemical formula

[0051] The compounds of the present invention can be prepared based on the following retrosynthetic scheme.

Chemical formula

Chemical formula

[0052] Other compounds of formula (I) or (II) can be prepared by the addition, removal, or modification of existing substituents. This can be achieved by using standard techniques of functional group interconversion well known in the art, for example, the techniques described in "Comprehensive organic transformations: a guide to functional group preparations" by Larock R. C., New York, VCH Publishers, Inc., 1989.

[0053] One skilled in the art will recognize that the synthesis method may require various protecting groups as described herein. As used herein, the term "protecting group" means that in a polyfunctional compound, a specific functional moiety, such as O, S, or N, can be temporarily blocked and a reaction can be selectively carried out at another reaction site. Exemplary protecting groups are described in Protective Groups in Organic Synthesis, 3rd Edition, Greene, T.W. and Wuts, P.G., eds., John Wiley & Sons, New York: 1999, the entire content of which is incorporated herein by reference.

[0054] In the studies conducted by the inventors, it has been revealed that the compounds disclosed herein can treat cognitive impairment (or dysfunction) in an animal model of spatial memory.

[0055] Accordingly, provided herein is the use of a compound of formula (I), (I'), (I'a), (I'b), (I'c) or (I'd) or an embodiment thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a subject in need of treatment for cognitive dysfunction and negative symptoms associated with a CNS disorder in which the circuit involved in the generation of fast-spiking PV+ interneurons and cortical gamma oscillations is disrupted.

[0056] In other embodiments, the compound is administered to a subject in need thereof, in combination with a conventional antipsychotic, for about 2 to 4 weeks to address the symptoms of schizophrenia, although there is also the option to discontinue treatment with the compound while continuing conventional treatment. In other embodiments, the subject is treated during the treatment period with both the compound and one or more conventional medications (sequential or combined administration). Such combination therapy can be particularly useful, for example, when a combination of the compound and one or more conventional antipsychotics alleviates schizophrenia during the acute lag phase of the treatment period and / or when an additive or synergistic antidepressant therapeutic effect is desired.

[0057] "Treat", "treating", or "treatment" in connection with a disorder refers to reducing or suppressing the cause and / or effects of the disorder. As used herein, the terms "treat", "treatment", and "treating" refer to a reduction or improvement in the progression, severity, and / or duration of a condition, or an improvement in one or more symptoms (e.g., one or more distinguishable symptoms) of said condition, resulting from the administration of one or more therapeutic agents (e.g., one or more therapeutic agents such as a compound or composition of the invention), without "curing" the condition (i.e., "managing" the condition). In certain embodiments, the terms "treat", "treatment", and "treating" refer to an improvement in at least one measurable physical parameter of the disorder described herein. In other embodiments, the terms "treat", "treatment", and "treating" refer to suppressing the progression of further cognitive impairment.

[0058] In one embodiment, the compound of formula (I), (Ia), (Ib), (Ic), or (Id) described herein, or an embodiment thereof, or a pharmaceutically acceptable salt thereof, is administered in combination with an antipsychotic compound to the subject.

[0059] The compounds encompassed herein can also be used as combination therapeutic agents with acetylcholinesterase inhibitors (e.g., donepezil, galantamine, rivastigmine), atypical antipsychotics (e.g., risperidone, aripiprazole, quetiapine, olanzapine), and N-methyl-D-aspartic acid receptor (NMDAR) inhibitors (e.g., memantine).

[0060] The compounds encompassed herein are administered to a subject in a therapeutically effective amount. In some embodiments, the therapeutically effective amount is a treatment effective amount. As used herein, the term "treatment effective amount" means the amount of an active compound or pharmaceutical agent that induces a biological or pharmaceutical response in a tissue, system, animal, or human that a researcher, veterinarian, physician, or other clinician is seeking. The treatment effective amount of the compound administered is governed by such considerations and is the minimum amount necessary to ameliorate, cure, or treat one or more of the diseases or disorders or their symptoms. The term "prophylactically effective amount" refers to an amount effective to prevent cognitive impairment before it is acquired, or to substantially reduce the chance of acquiring cognitive impairment, or to reduce the severity of cognitive impairment, or to reduce the severity before symptoms develop. Secondary prevention (the disease or symptoms have already developed, protecting the patient from worsening of this process).

[0061] As used herein, the term "effective amount" relates to the amount of a compound that, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing can be done at intervals of minutes, hours, days, weeks, months or years, or continuously over any one of these periods.

[0062] In certain embodiments, the method comprises administering to a subject in need thereof the compound in a dosage that provides an effective amount in vivo that will result in improved cognition, including but not limited to, the acute phase of treatment (e.g., within 1, 2, 3, or 4 weeks from the start of treatment). Methods for determining the in vitro equivalent concentration of the compound are well known to those of skill in the art.

[0063] Thereafter, treatment with the present compound can be continued throughout the treatment period, or stopped, or replaced with a conventional therapeutic compound.

[0064] As used herein, the terms "administer", "administering", or "administration" with respect to the compounds, compositions, or formulations of the invention mean introducing the compound into the system of an animal in need of treatment. When the compounds of the invention are provided in combination with one or more other active agents, "administration" and variations thereof are understood to include the simultaneous and / or sequential introduction of the compound and the other active agents, respectively.

[0065] In certain embodiments, an effective amount of the compound to be administered once or more times daily to a 70 kg adult can contain from about 0.0001 mg to about 3000 mg, from about 0.0001 mg to about 2000 mg, from about 0.0001 mg to about 1000 mg, from about 0.001 mg to about 1000 mg, from about 0.01 mg to about 1000 mg, from about 0.1 mg to about 1000 mg, from about 1 mg to about 1000 mg, from about 1 mg to about 100 mg, from about 10 mg to about 1000 mg, or from about 100 mg to about 1000 mg of the compound per unit dosage form.

[0066] In certain embodiments, the compounds of the invention can be administered once or more times daily at a dosage level sufficient to obtain the desired therapeutic effect at about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 50 mg / kg, about 0.1 mg / kg to about 40 mg / kg, about 0.5 mg / kg to about 30 mg / kg, about 0.01 mg / kg to about 10 mg / kg, about 0.1 mg / kg to about 10 mg / kg, and about 1 mg / kg to about 25 mg / kg based on the body weight of the subject.

[0067] Suitable dosages and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition, and the general age, health, and weight of the subject. The dosage ranges described herein are recognized as a guide for administering the pharmaceutical composition to adults. For example, (assuming pediatric use is approved) the amount to be administered to a child or adolescent can be determined by a physician or one of ordinary skill in the art and may be less than or equal to the amount administered to an adult.

[0068] The active ingredient can be administered in a single dose or a series of doses. The active ingredient can be administered alone, but is preferably provided as a composition, preferably as a pharmaceutical composition. Formulations of such compositions are well known to those of ordinary skill in the art. The composition can also contain any suitable carrier, diluent, or additive. These include all conventional solvents, dispersion media, fillers, solid carriers, coating agents, antifungal and antibacterial agents, skin penetration enhancers, surfactants, isotonic agents, and absorbents, among others. It will be understood that the compositions of the present invention may also contain other supplementary bioactive agents.

[0069] The compounds and pharmaceutical compositions described herein can be used in combination treatment with one or more additional therapeutic agents. In combination therapy with more than one active agent, when the active agents are in separate dosage formulations, they can be administered separately or together. Further, the administration of one element can be before, at the same time as, or after the administration of the other agent.

[0070] When co-administered with other agents, e.g., when co-administered, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by one of ordinary skill in the art according to the condition of the subject, the type of condition being treated, and the amount of the compounds described herein being used. Where the amount is not specified, an effective amount should be assumed. For example, the compounds described herein can be administered to a subject in a dosage range of about 0.01 to about 10,000 mg / kg body weight / day, about 0.01 to about 5000 mg / kg body weight / day, about 0.01 to about 3000 mg / kg body weight / day, about 0.01 to about 1000 mg / kg body weight / day, about 0.01 to about 500 mg / kg body weight / day, about 0.01 to about 300 mg / kg body weight / day, about 0.01 to about 100 mg / kg body weight / day.

[0071] When "combination therapy" is employed, an effective amount can be achieved using a first amount of a compound of formula (I), (Ia), (Ib), (Ic) or (Id) or a pharmaceutically acceptable salt thereof and a second amount of an additional suitable therapeutic agent.

[0072] In certain embodiments, the compounds of formula (I), (Ia), (Ib), (Ic) or (Id) described herein, or pharmaceutically acceptable salts thereof, and additional therapeutic agents are each administered in an effective amount (i.e., an amount that would be therapeutically effective if administered alone). In other embodiments, the compounds of formula (I), (Ia), (Ib), (Ic) or (Id) described herein, or pharmaceutically acceptable salts thereof, and additional therapeutic agents are each administered in an amount that is not therapeutically effective alone (less than a therapeutic dose). In yet other embodiments, the compounds of formula (I), (Ia), (Ib), (Ic) or (Id) described herein, or pharmaceutically acceptable salts thereof can be administered in an effective amount and the additional therapeutic agent is administered at less than a therapeutic dose. In yet other embodiments, the compounds of formula (I), (Ia), (Ib), (Ic) or (Id) described herein, or pharmaceutically acceptable salts thereof can be administered at less than a therapeutic dose and the additional therapeutic agent is administered in an effective amount.

[0073] As used herein, the terms "in combination" or "co-administration" can be used interchangeably to refer to the use of more than one therapeutic agent (e.g., one or more therapeutic agents). The use of the terms does not limit the order in which the therapeutic agents (e.g., therapeutic agents) are administered to a subject.

[0074] Examples of therapeutic agents that can be administered separately or in the same pharmaceutical composition in combination with the compounds of the present disclosure include, but are not limited to, muscle relaxants, anticonvulsants, hypnotics, anesthetics, analgesics, cholinergic agents, antidepressants, mood stabilizers, anxiolytics, and the like.

[0075] The compounds and compositions defined herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intraarterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (administered by powders, ointments, creams, and / or drops), mucosal, nasal, buccal, sublingual; by endotracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Particularly contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), local administration via the blood and / or lymphatic supply, and / or direct administration to the affected area. In general, the most appropriate route of administration depends on various factors including the nature of the agent (e.g., its stability in the gastrointestinal environment) and / or the condition of the subject (e.g., whether the subject can tolerate oral administration).

[0076] The exact amount of the compound required to achieve an effective amount will vary from subject to subject and will depend, for example, on the species, age, and general condition of the subject, the severity of side effects or disorders, the identity of the particular compound, the mode of administration, etc. The desired dosage can be administered three times a day, twice a day, once a day, every other day, every three days, weekly, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered by multiple administrations (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or more administrations).

[0077] The carrier must be pharmaceutically "acceptable" in the sense that it is compatible with the other ingredients of the composition and not harmful to the subject. Compositions suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral administration (including subcutaneous, intramuscular, intravenous and intradermal) are contemplated. The compositions can conveniently be provided in unit dosage form and can be prepared by any method well known in the art of pharmacy. Such methods include the step of bringing the active ingredient into association with a carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0078] Pharmaceutically acceptable additives include any and all solvents, diluents, or other liquid vehicles, dispersing agents, suspending aids, surfactants, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, etc. that are suitable for the particular dosage form desired. General considerations of formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington’s Pharmaceutical Sciences, 16th Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005).

[0079] The pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparative methods include bringing the compounds of the invention (the "active ingredients") into association with a carrier and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into the desired single or multiple dose units.

[0080] The pharmaceutical composition can be prepared, packaged, and / or sold in bulk, as single unit doses and / or multiple single unit doses. As used herein, a "unit dose" is an individual quantity of a pharmaceutical composition that contains a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient that should be administered to the subject and / or is a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.

[0081] The relative amounts of the active ingredient, pharmaceutically acceptable additives, and / or any additional ingredients in the pharmaceutical composition of the present invention vary depending on the identity, size, and / or condition of the subject being treated and further depending on the route by which the composition is to be administered. By way of example, the composition can contain from 0.1% to 100% (w / w) of the active ingredient.

[0082] Pharmaceutically acceptable additives used in the manufacture of the pharmaceutical composition include inert diluents, dispersing and / or granulating agents, surfactants and / or emulsifying agents, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. Additives such as cocoa butter, suppository waxes, coloring agents, coating agents, sweetening agents, flavoring agents, and fragrances may also be present in the composition.

[0083] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate, lactose, sucrose, cellulose, crystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dried starch, corn starch, powdered sugar, and mixtures thereof.

[0084] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clay, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, crosslinked poly(vinylpyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose (croscarmellose), methyl cellulose, pregelatinized starch (starch 1500), crystalline starch, water-insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0085] Exemplary surfactants and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long-chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulose derivatives (e.g., sodium carboxymethyl cellulose, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor (trademark)), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether (Brij30)) Poly(vinylpyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, doxart sodium, and / or mixtures thereof.

[0086] Exemplary binders include starch (e.g., corn starch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, Irish moss extract, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, crystalline cellulose, cellulose acetate, poly(vinylpyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginate, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylate, wax, water, alcohol, and / or mixtures thereof.

[0087] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

[0088] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0089] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and its salts and hydrates (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, etc.), citric acid and its salts and hydrates (e.g., citric acid monohydrate), fumaric acid and its salts and hydrates, malic acid and its salts and hydrates, phosphoric acid and its salts and hydrates, and tartaric acid and its salts and hydrates. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0090] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0091] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0092] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0093] Other preservatives include tocopherol, tocopherol acetate, detyroxime mesylate, cetrimide, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium laureth sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0094] Exemplary buffers include citrate buffer, acetate buffer, phosphate buffer, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium gluconate, calcium glucoheptonate, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, calcium hydrogen phosphate, phosphoric acid, tricalcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixture, dipotassium phosphate, potassium dihydrogen phosphate, potassium phosphate mixture, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, sodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixture, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0095] Exemplary lubricants include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0096] Exemplary natural oils include almond oil, cinnamon oil, avocado oil, babassu oil, bergamot oil, blackcurrant seed oil, burdock oil, cade oil, chamomile oil, canola oil, caraway oil, carnauba oil, castor oil, cinnamon oil, cocoa butter oil, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, matricaria oil, fish oil, flaxseed oil, geraniol oil, gourd oil, grape seed oil, hazelnut oil, hyssop oil, isopropyl myristate, jojoba oil, kukui nut oil, lavandin oil, lavender oil, lemon oil, litsea cubeba oil, macadamia nut oil, myrrh oil, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, orange raffia oil, palm oil, palm kernel oil, tangerine oil, peanut oil, safflower oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, camphor oil, sasquana oil, celery oil, sea buckthorn oil, sesame oil, shea butter oil, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, camellia oil, vetiver oil, walnut oil, and malt oil. Exemplary synthetic oils include butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof, but are not limited thereto.

[0097] The compositions of the present invention suitable for oral administration can be provided as individual units such as capsules, sachets or tablets, each containing a predetermined amount of the active ingredient; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as water-in-oil liquid emulsions or oil-in-water liquid emulsions. The active ingredient can also be provided as a bolus, a lozenge or a paste.

[0098] Tablets can be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by mixing the active ingredient in a free-flowing form such as powder or granules with a binder (e.g., an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethylcellulose), a surfactant or a dispersing agent), and compressing with a suitable machine. Molded tablets can be made by molding a mixture of the powdered compound moistened with an inert liquid diluent with a suitable machine. Tablets may be coated or scored. Tablets can be formulated to achieve a sustained or controlled release of the active ingredient therein, for example, by using hydroxypropylmethylcellulose in various proportions to achieve a desired release profile. An enteric coating may be applied to the tablets to effect release in a part of the intestine excluding the stomach.

[0099] The active ingredient can be in the form of microcapsules using one or more additives. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, release control coatings, and other coatings well-known in the pharmaceutical technology field. In such solid dosage forms, the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms can include additional substances other than the inert diluent, for example, lubricants for tableting such as magnesium stearate and crystalline cellulose, and other tableting aids, as is customary. In the case of capsules, tablets, and pills, the dosage form can include buffering agents. They may include opacifying agents and can be compositions that release the active ingredient only or preferentially, optionally with a delay, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0100] For oral and parenteral administration, liquid dosage forms include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form can include inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, solubilizing and emulsifying agents such as polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, and fragrances. In certain embodiments of parenteral administration, the conjugates of the present invention are mixed with solubilizing agents such as Cremophor™, alcohol, oil, modified oil, glycol, polysorbate, cyclodextrin, polymer, and mixtures thereof.

[0101] Compositions suitable for topical administration in the mouth include flavored bases, typically lozenges containing the active ingredient in sucrose and acacia or tragacanth gum; pastilles containing the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia gum; and mouthwashes containing the active ingredient in a suitable liquid carrier.

[0102] Compositions suitable for topical administration to the skin can contain the compound dissolved or suspended in any suitable carrier or base and can take the form of lotions, gels, creams, pastes, ointments, etc. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. The compounds of the present invention can also be administered using transdermal patches.

[0103] Compositions for rectal administration can be provided as suppositories using a suitable base containing, for example, cocoa butter, glycerin, gelatin, or polyethylene glycol.

[0104] Compositions suitable for vaginal administration can be provided as pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing, in addition to the active ingredient, a carrier as is known in the art to be appropriate.

[0105] Compositions suitable for parenteral administration can include aqueous and non-aqueous isotonic sterile injection solutions that can contain an antioxidant, a buffer, a bacteriostatic agent, and a solute that renders the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that can contain a suspending agent and a thickening agent. The compositions can be provided in unit dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) state that requires only the addition of a sterile liquid carrier, such as water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the types described previously. Injectable preparations can be injectable sterile solutions, suspensions, or emulsions in a non-toxic diluent or solvent acceptable for parenteral administration, such as a 1,3-butanediol solution. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution (U.S. Pharmacopeia), and isotonic saline. In addition, sterile fixed oils have conventionally been used as a solvent or suspending medium. For this purpose, any bland fixed oil containing synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating a bacteriostatic agent in the form of a sterile solid composition that can be dissolved or dispersed in sterile water or other injectable sterile medium prior to use.

[0106] In certain embodiments, a unit dosage composition contains the active ingredient in the daily dose or unit, daily fractional dose, or appropriate fraction thereof, as described above herein.

[0107] It should be understood that, in addition to the above active ingredients, the composition of the present invention can include other agents commonly used in the art, taking into account the type of the composition. For example, for those suitable for oral administration, additional agents such as binders, sweeteners, thickeners, flavoring agents, disintegrants, coating agents, preservatives, lubricants and / or time delay agents can be mentioned. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharin. Suitable disintegrants include corn starch, methyl cellulose, polyvinyl pyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavoring agents include peppermint oil, wintergreen oil, strawberry, orange or raspberry flavoring agents. Suitable coating agents include polymers or copolymers of acrylic acid and / or methacrylic acid and / or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulfite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

[0108] As used herein, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt of a defined compound. For use in medicine, the salts of the defined compounds are pharmaceutically acceptable salts. However, other salts may be useful in the preparation of the defined compounds or their pharmaceutically acceptable salts. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. have described pharmaceutically acceptable salts in J. Pharm. Sci. (1977) 66:1-19, which is hereby incorporated by reference in its entirety. A pharmaceutically acceptable salt need contain another molecule such as an acetate ion, a succinate ion or other counterion. The counterion can be any organic or inorganic moiety that stabilizes the charge on the parent compound. Further, a pharmaceutically acceptable salt can have more than one charged atom in its structure. When multiple charged atoms are present in the parent drug, the pharmaceutically acceptable salt can have multiple counterions, which can be examples of the same counterion or several different counterions. Thus, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counterions in the parent compound.

[0109] Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compound. In other embodiments, the salts can be prepared from the free form of the compound in a separate synthetic step.

[0110] When the specified compound is acidic or contains a sufficiently acidic bioequivalent, suitable "pharmaceutically acceptable salts" refer to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, ferric salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. Specific embodiments include ammonium salts, calcium salts, magnesium salts, potassium salts, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc., primary, secondary, and tertiary amines, substituted amines including natural substituted amines, cyclic amines, and salts of basic ion exchange resins. N + (C 1~4 Quaternary ammonium salts such as alkyl)4 are also included.

[0111] When the specified compound is basic or contains a sufficiently basic bioequivalent, salts can be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. Such acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, carbonic acid, boric acid, sulfamic acid, propionic acid, butyric acid, hydroxymaleic acid, mucic acid, phenylacetic acid, sulfanilic acid, aspartic acid, edetic acid, stearic acid, palmitic acid, oleic acid, lauric acid, ascorbic acid, valeric acid, perchloric acid, malonic acid, p-toluenesulfonic acid, etc. Specific embodiments include citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, and tartaric acid.Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharinate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), adipate, alginate, ascorbate, aspartate, cyclopentanepropionate, borate, butyrate, camphorate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactobionate, laurate, laurylsulfate, malonate, 2-naphthalenesulfonate, nicotinate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, and valerate.

[0112] The preparation of the above pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts is described in more detail by Berge et al., "Pharmaceutical Salts", J. Pharm. Sci., 1977:66:1-19.

[0113] Basic nitrogen-containing groups can be quaternized with substances such as lower alkyl halides such as methyl chloride, ethyl, propyl, and butyl, methyl bromide, ethyl, propyl, and butyl and methyl iodide, ethyl, propyl, and butyl; and dialkyl sulfates such as dimethyl sulfate and diethyl sulfate.

[0114] The compounds and pharmaceutical formulations described herein can be included in a kit. The kit can include single or multiple doses in which two or more agents are individually packaged or formulated, or single or multiple doses in which two or more agents are packaged or formulated in combination. Thus, one or more agents can be present in a first container, and the kit can optionally include one or more agents in a second container. One or more containers can be placed within a single package, which can optionally include instructions for administration or dosage. The kit can include additional components such as syringes or other means for administering the agent and diluent or other means of formulation. Thus, the kit can include a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle or diluent, and b) a container or packaging container. The kit may include instructions describing how to use the pharmaceutical composition in one or more of the methods described herein (e.g., for preventing or treating one or more of the diseases and disorders described herein). The kit may include a second pharmaceutical composition comprising one or more additional agents, pharmaceutically acceptable carriers, vehicles or diluents described herein for use in combination therapy. The pharmaceutical composition comprising the compound described herein included in the kit and the second pharmaceutical composition may be combined as the same pharmaceutical composition.

[0115] The kit includes a container or packaging container for containing the pharmaceutical composition and can also include a divided container such as a divided bottle or divided foil packet. The container can be, for example, a cardboard or cardboard box, a glass or plastic bottle or jar, a resealable bag (e.g., for holding a “refill” of tablets for placement in a different container), or a blister pack, containing individual doses for extrusion from the pack according to a treatment schedule. Multiple containers can be used together in a single package to enable the marketing of a single dosage form. For example, tablets can be placed in a bottle, and then the bottle can be placed in a box.

[0116] Examples of kits include so-called blister packs. Blister packs are well-known in the packaging industry and are increasingly being used for packaging pharmaceutical unit dosage forms (such as tablets, capsules, etc.). A blister pack generally consists of a sheet of a relatively rigid material, preferably covered with a foil of a transparent plastic material. During the packaging process, depressions are formed in the plastic foil. The depressions have the size and shape of the individual tablets or capsules to be filled, or can have a size and shape that conforms to a plurality of tablets and / or capsules to be filled. Next, the tablets or capsules are placed according to the depressions, and the plastic foil is sealed with the sheet of relatively rigid material on the foil side opposite to the side where the depressions are formed. As a result, the tablets or capsules are individually or collectively sealed as desired in the depressions between the plastic foil and the sheet. Preferably, the strength of the sheet is such that by applying pressure by hand to the depressions, an opening is formed in the sheet at the location of the depressions, so that the tablets or capsules can be removed from the blister pack. Then, the tablets or capsules can be removed via the opening.

[0117] It may be desirable to provide a written memory aid to a physician, pharmacist or subject that includes information and / or instructions regarding the times at which the pharmaceutical should be taken. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. When the kit includes separate compositions, the daily dose of one or more of the compositions of the kit can be one tablet or one capsule, and the daily dose of one or more other compositions of the kit can be a plurality of tablets or capsules. The kit can take the form of a dispenser designed to dispense the daily doses one at a time in the intended order of use. The dispenser can be equipped with a memory aid to further promote compliance with the regimen. An example of such a memory aid is a mechanical counter that displays the number of daily doses dispensed. Another example of such a memory aid is, for example, a battery-powered microchip memory device linked to a liquid crystal readout or reminder audible signal that indicates the date on which the last daily dose was taken and / or reminds of the date on which the next dose should be taken.

[0118] Any compound that is a prodrug of a compound of formula (I), (Ia), (Ib), (Ic) or (Id) is recognized as being within the scope and spirit of the present invention. The term "prodrug" is used in its broadest sense and includes derivatives that are converted in vivo to the compounds of the present invention. Such derivatives are readily envisioned by those skilled in the art and include, for example, compounds in which a free hydroxy group is converted to an ester such as an acetate or phosphate ester, or a compound in which a free amino group is converted to an amide (e.g., an α-amino acid amide). Procedures for esterifying, for example acylating, the compounds of the present invention are well known in the art and may include treating the compound with a suitable carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.

[0119] The compounds of the present invention may be in crystalline form either as the free compound or as a solvate (e.g., hydrate), and both forms are intended to fall within the scope of the present invention. Methods of solvation are generally known in the art.

[0120] It is also recognized that the compounds of the present invention may have chiral centers and thus can exist in the form of more than one stereoisomer. Accordingly, the present invention also relates to compounds in the form of isomers that are substantially pure at one or more chiral centers, e.g., higher than about 90% ee, such as about 95% or 97% ee, or higher than 99% ee, and mixtures thereof including racemic mixtures. Such isomers can be prepared, for example, by asymmetric synthesis using chiral intermediates or can be resolved from mixtures by conventional methods such as chromatography or the use of resolving agents.

[0121] Furthermore, depending on the substitution pattern, the compounds of the present invention may undergo tautomerism. Accordingly, all possible tautomers of the compounds of the present invention fall within the scope and spirit of the present invention.

[0122] Solid-phase synthesis techniques and / or combinatorial chemistry for generating individual compounds or libraries of compounds are applicable to the synthetic methods and processes described herein for preparing the compounds of the present invention.

[0123] Those skilled in the art will appreciate that the present invention described herein is subject to variations and modifications other than those specifically described. It is to be understood that the present invention includes all such variations and modifications that fall within its spirit and scope. The present invention includes all of the steps, features, compositions and compounds referred to or indicated herein, individually or collectively, as well as any and all combinations of any two or more of said steps or features.

[0124] Throughout this specification and the following claims, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", are to be interpreted as including the stated integer or step or group of integers or steps but not excluding any other integer or step or group of integers or steps.

[0125] Any reference in this specification to any prior publication (or information derived therefrom) or to any matter which is known is not, and should not be taken as, an admission or acknowledgment, or any form of suggestion, that that prior publication (or information derived therefrom) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

[0126] Next, certain embodiments of the present invention will be described with reference to the following examples. These examples are intended for illustrative purposes only and are not intended to limit the generality of the foregoing description herein.

Examples

[0127] Chemical synthesis For convenience, many chemical moieties are represented using well-known abbreviations, including but not limited to methyl (Me), ethyl (Et), n-propyl (nPr), isopropyl (iPr), n-butyl (nBu), tert-butyl (tBu), n-hexyl (nHex), cyclohexyl (cHex), phenyl (Ph), methoxy (MeO), ethoxy (EtO), trimethylsilyl (TMS), tert-butyloxycarbonyl (Boc), and acetyl (Ac).

[0128] For the sake of simplicity, many compounds are represented using well-known abbreviations. The abbreviations include methanol (MeOH), ethanol (EtOH), ether or diethyl ether (Et2O), ethyl acetate (EtOAc), triethylamine (TEA, Et3N), N,N-diisopropyl-N-ethylamine (DIEA), dichloromethane (methylene chloride, DCM), trifluoroacetic acid (TFA), trifluoroethanol (TFE), dimethylformamide (DMF), sodium sulfate (Na2SO4), tetrahydrofuran (THF), meta-chloroperbenzoic acid (mCPBA), sodium hexamethyldisilazide (NaHMDS), O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU), dimethyl sulfoxide (DMSO), magnesium sulfate (MgSO4), sodium bicarbonate (NaHCO3), tert-butanol (t-BuOH), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCl.HCl), tetra-n-butylammonium fluoride (TBAF), N,N-diisopropylethylamine (DIPEA), 1-hydroxybenzotriazole (HOBt), benzotriazolium tetramethyluronium hexafluorophosphate (HBTU), trans-dichlorobis(triphenylphosphine)palladium(II) (PdCl2(PPh3)2), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4), tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), tri-t-butylphosphonium tetrafluoroborate (t-Bu3PH.BF4), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), triphenylphosphine (PPh3), diisopropyl azodicarboxylate (DIAD), pyridinium chlorochromate (PCC), dimethyl sulfide borane (BMS), titanium isopropoxide (TiOiPr4), sodium triacetoxyborohydride (NaBH(OAc)3), sodium cyanoborohydride (NaBH3(CN)), ammonium chloride (NH4Cl), chloroform (CHCl3), manganese dioxide (MnO2), potassium carbonate (K2CO3), and 1,2-dichloroethane (DCE), sodium hydride (NaH), dimethylacetamide (DMA), copper(II) oxide (Cu2O), N-methyl-2-pyrrolidone (NMP), cesium carbonate (Cs2CO3), hydrochloric acid (HCl) are mentioned, but not limited thereto.

[0129] General experiments Analytical thin layer chromatography (TLC) was performed on Merck silica gel 60F254 aluminum-backed plates visualized using fluorescence that quenches under UV light. Flash chromatography was performed using a Biotage Isolera One and standard cartridges. Semi-preparative HPLC purification was performed using a Gilson PLC2020 and Princeton SPHER-60, C8, 10μm, 30×150mm as the column.

[0130] Intermediate 1-1: 3-methoxy-4-methyl-phenol

Chemical formula

[0131] <Synthesis of Example 1> Intermediate 1-2: 4-Iodo-2-(3-methoxy-4-methyl-phenoxy)pyridine

Chemical formula

[0132] <Example 1> 3-[2-(3-Methoxy-4-methyl-phenoxy)-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chem.

[0133] <Synthesis of Example 2> Intermediate 1-3: 2-(Benzofuran-6-yloxy)-4-iodo-pyridine

Chem.

[0134] <Example 2> 3-[2-(Benzofuran-6-yloxy)-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical formula

[0135] <Synthesis of Example 3> Intermediate 1-4: 2-Indan-5-yloxy-4-iodo-pyridine [Chemical formula] Using 5-hydroxyindane (200 mg, 1.48 mmol), following basically the procedure described for Intermediate 1-2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50, the title compound was obtained as a white foam (300 mg, 66% yield). 1 1H NMR (300 MHz, CHCl3-d) δ 7.85 (d, J = 5.2 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 6.96 (s, 1H), 6.86 (dd, J = 2.1 and 8.1 Hz, 1H), 3.01 - 2.82 (m, 4H), 2.20 - 2.04 (m, 2H).

[0136] <Example 3> 3-(2-Indan-5-yloxy-4-pyridyl)-5,5-dimethyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 1-4 (300 mg, 0.89 mmol), following basically the procedure described in Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 20:80, the title compound was obtained as a white solid (120 mg, 40% yield). 1 H NMR (300 MHz, DMSO-d6) 8.75 (bs, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.28 (dd, J = 1.6 and 5.5 Hz, 1H), 7.22 (d, J = 8.1 Hz, 1H), 7.14 (d, J = 1.5 Hz, 1H), 6.97 (m, 1H), 6.85 (dd, J = 2.1 and 8.1 Hz, 1H), 2.90 - 2.85 (m, 4H), 2.10 - 1.92 (m, 2H), 1.38 (s, 6H). ESIMS m / z [M+H] + 338.25.

[0137] <Synthesis of Example 4> Intermediate 1-5: 4-Iodo-2-[3-methoxy-4-(trifluoromethyl)phenoxy]pyridine

Chemical Structure

[0138] <Example 4> 3-[2-[3-Methoxy-4-(trifluoromethyl)phenoxy]-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical Structure

[0139] <Synthesis of Example 5> Intermediate 1-6: 2-(3-Fluoro-4-methyl-phenoxy)-4-iodo-pyridine [Chemical formula] Cesium carbonate (1.17 g, 3.59 mmol) was added dropwise to a stirred solution of 3-fluoro-4-methylphenol (250 mg, 1.97 mmol) in DMF (10 mL) at 0 °C under nitrogen. The resulting solution was stirred at 0 °C for 30 minutes, then 2-fluoro-4-iodopyridine (400 mg, 1.80 mmol) was added. The ice bath was removed and the mixture was stirred at room temperature for 18 hours. The mixture was hydrolyzed with water, extracted with Et2O, the organic matter was washed with brine, dehydrated with MgSO4, concentrated in vacuo, and purified by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 70:30 to obtain the title compound as a white foam (420 mg, yield 72%). ESIMS m / z [M+H] + 330.18。

[0140] <Example 5> 3-[2-(3-Fluoro-4-methyl-phenoxy)-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical formula

[0141] <Synthesis of Example 6> Intermediate 1-7: 4-Iodo-2-[3-methoxy-4-fluorophenyl]pyridine

Chemical formula

[0142] <Example 6> 3-[2-[3-Methoxy-4-fluorophenoxy]-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical formula

[0143] <Synthesis of Example 7> Intermediate 1-8: 2-(1,3-Benzodioxol-5-yloxy)-4-iodo-pyridine

Chemical formula

[0144] <Example 7> 3-[2-(1,3-Benzodioxol-5-yloxy)-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical Structure

[0145] <Synthesis of Example 8> Intermediate 1-9: 2-(4-Chloro-3-methoxy-phenoxy)-4-iodo-pyridine

Chem.

[0146] <Example 8> 3-[2-(4-Chloro-3-methoxy-phenoxy)-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chem.

[0147] <Synthesis of Example 9> Intermediate 1-10: (2,2-Difluoro-1,3-benzodioxol-5-yl)boronic acid [Chemical formula] 2.5 M n-Butyllithium in hexane (11.36 mL, 28.40 mmol) was added dropwise to a stirred solution of 5-bromo-2,2-difluoro-1,3-benzodioxole (5.0 g, 21.10 mmol) and triisopropyl borate (6.3 g, 33.50 mmol) in THF (60 mL) at -78 °C under nitrogen. The resulting solution was stirred at -78 °C for 1 h and at room temperature for 3 h. The mixture was hydrolyzed with saturated aqueous ammonium chloride (20 mL), stirred for 30 min, then 3N aqueous HCl (20 mL) was added, and the mixture was extracted with Et2O. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give the title compound as a yellow oil, which was used directly in the next step.

[0148] Intermediate 1-11: 2,2-Difluoro-1,3-benzodioxol-5-ol [Chemical formula] 30% hydrogen peroxide in water (40 mL) was added dropwise to a stirred solution of crude intermediate 1-10 in THF (100 mL) at room temperature. The resulting solution was stirred for 20 h and carefully hydrolyzed with saturated aqueous Na2S2O3 (50 mL). The mixture was extracted with ethyl acetate (3 × 50 mL), the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50 to give the title compound as a yellow oil (3.2 g, 80% yield). 1 1H NMR (300 MHz, CDCl3) δ 9.77 (s, 1H), 7.14 (d, J = 8.8 Hz, 1H), 6.76 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 2.4, 8.8 Hz, 1H).

[0149] Intermediate 1-12: 2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-4-iodo-pyridine

Chemical Structure

[0150] <Example 9> 3-[2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-4-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical Structure

[0151] Intermediate 2-1: (5R)-5-Ethyl-5-methyl-imidazolidine-2,4-dione

Chemical Structure

[0152] <Synthesis of Example 10> <Example 10> (5R)-5-Ethyl-3-[2-(3-methoxy-4-methyl-phenoxy)-4-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chem.

[0153] <Synthesis of Example 11> <Example 11> (5R)-5-Ethyl-3-[2-(3-methoxy-4-fluoro-phenoxy)-4-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chem.

[0154] <Synthesis of Example 12> <Example 12> (5R)-5-Ethyl-3-[2-(3-fluoro-4-methyl-phenoxy)-4-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chemical Structure

[0155] <Synthesis of Example 13> <Example 13> (5R)-5-Ethyl-3-(2-indan-5-yloxy-4-pyridyl)-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 1-4 (220 mg, 0.65 mmol) and Intermediate 2-1 (102 mg, 0.72 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white solid (150 mg, 65% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 8.73 (bs, 1H), 8.18 (d, J = 5.5 Hz, 1H), 7.30 - 7.19 (m, 2H), 7.13 (d, J = 1.5 Hz, 1H), 6.97 (s, 1H), 6.85 (dd, J = 2.2 and 8.0 Hz, 1H), 2.90 - 2.78 (m, 4H), 2.10 - 1.95 (m, 2H), 1.83 - 1.55 (m, 2H), 1.37 (s, 3H), 0.82 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 352.33.

[0156] <Synthesis of Example 14> <Example 14> (5R)-3-[2-(Benzofuran-6-yloxy)-4-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chem.

[0157] <Synthesis of Example 15> <Example 15> (5R)-5-Ethyl-3-[2-(3-methoxy-4-chloro-phenoxy)-4-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chem.

[0158] <Synthesis of Example 16> <Example 16> (5R)-3-[2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-4-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chemical Structure

[0159] <Synthesis of Example 17> Intermediate 2 - 2: 2-(3,4-Dimethylphenoxy)-4-iodo-pyridine [Chemical Structure] Using 3,4-dimethylphenol (135 mg, 1.10 mmol), following basically the procedure described for Intermediate 1 - 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 80:20, the title compound was obtained as a white powder (300 mg, yield 84%). 1 1H NMR (300 MHz, CHCl3-d) δ 7.83 (d, J = 5.3 Hz, 1H), 7.47 (dd, J = 1.2 and 5.3 Hz, 1H), 7.38 (s, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 2.3 Hz, 1H), 6.81 (dd, J = 2.4 and 8.1 Hz, 1H), 2.19 (s, 6H).

[0160] <Example 17> (5R)-3-[2-(3,4-Dimethylphenoxy)-4-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione [Chemical Structure] Using intermediate 2-2 (200 mg, 0.62 mmol) and intermediate 2-1 (105 mg, 0.74 mmol), following basically the procedure described for Example 2, silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100 and purification by lyophilization using water and acetonitrile, the title compound was obtained as a white solid (130 mg, yield 61%). 1 H NMR (300 MHz, DMSO-d6) 8.72 (bs, 1H), 8.17 (d, J = 5.5 Hz, 1H), 7.26 (dd, J = 1.7 and 5.5 Hz, 1H), 7.17 - 7.10 (m, 2H), 6.91 (d, J = 2.5 Hz, 1H), 6.83 (dd, J = 2.5 and 8.1 Hz, 1H), 2.19 (s, 6H), 1.85 - 1.58 (m, 2H), 1.36 (s, 3H), 0.83 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 340.33.

[0161] <Synthesis of Example 18> Intermediate 2-3: 2-Indan-4-yloxy-4-iodo-pyridine

Chemical Structure

[0162] <Example 18> (5R)-5-Ethyl-3-(2-indan-4-yloxy-4-pyridyl)-5-methyl-imidazolidine-2,4-dione

Chemical Structure

[0163] <Synthesis of Example 19> Intermediate 2-4: 2-Chroman-7-yloxy-4-iodo-pyridine

Chemical Structure

[0164] <Example 19> (5R)-3-(2-Chroman-7-yloxy-4-pyridyl)-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chem.

[0165] <Synthesis of Example 20> Intermediate 2-5: 2-(2,3-Dihydrobenzofuran-6-yloxy)-4-iodo-pyridine

Chem.

[0166] <Example 20> (5R)-3-[2-(2,3-Dihydrobenzofuran-6-yloxy)-4-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 2-5 (100 mg, 0.30 mmol) and Intermediate 2-1 (52 mg, 0.36 mmol), following essentially the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 30:70, the title compound was obtained as a white solid (52 mg, 49% yield). 1 H NMR (300 MHz, DMSO-d6) 8.73 (bs, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.28 (dd, J = 1.1 and 5.5 Hz, 1H), 7.21 (d, J = 8.4 Hz, 1H), 7.12 (d, J = 1.1 Hz, 1H), 6.60 - 6.52 (m, 2H), 4.56 (t, J = 8.6 Hz, 2H), 3.15 (t, J = 8.6 Hz, 2H), 1.88 - 1.58 (m, 2H), 1.36 (s, 3H), 0.82 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 354.25.

[0167] <Synthesis of Example 21> Intermediate 2-6: 2-Indan-2-yloxy-4-iodo-pyridine [Chemical formula] Using 2-indanol (160 mg, 1.20 mmol), following basically the procedure described for Intermediate 1-2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white solid (237 mg, 59% yield). ESIMS m / z [M+H] + 338.17.

[0168] [Example 21] (5R)-5-Ethyl-3-(2-indan-2-yloxy-4-pyridyl)-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 2-6 (220 mg, 0.65 mmol) and Intermediate 2-1 (102 mg, 0.72 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white solid (165 mg, 72% yield). 1 H NMR (300 MHz, DMSO-d6) 8.66 (bs, 1H), 8.25 (d, J = 5.6 Hz, 1H), 7.30 - 7.18 (m, 2H), 7.18 - 7.03 (m, 3H), 6.84 (d, J = 1.5 Hz, 1H), 5.80 - 5.68 (m, 1H), 3.36 (dd, J = 6.1 and 17.0 Hz, 2H), 3.00 (dd, J = 2.6 and 17.0 Hz, 2H), 1.80 - 1.50 (m, 2H), 1.34 (s, 3H), 0.79 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 352.17.

[0169] Intermediate 2-7: (5S)-5-Ethyl-5-methyl-imidazolidine-2,4-dione [Chemical formula] (2S)-2-Amino-2-methylbutanoic acid (1.0 g, 6.51 mmol) was used, and following basically the procedure described for Intermediate 2-1, after trituration and filtration in DCM / MeOH (20 / 4 mL), the title compound was obtained as a white solid (920 mg, 99% yield). 1 H NMR (300 MHz, DMSO-d6) 10.55 (bs, 1H), 7.88 (bs, 1H), 1.65 - 1.42 (m, 2H), 1.20 (s, 3H), 0.74 (t, J = 7.4 Hz, 3H).

[0170] [Synthesis of Example 22] [Example 22] (5S)-5-Ethyl-3-[2-(3-methoxy-4-methyl-phenoxy)-4-pyridyl]-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 1-2 (224 mg, 0.66 mmol) and Intermediate 2-7 (280 mg, 1.97 mmol), following basically the procedure described for Example 1-1, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, semi-preparative HPLC, and lyophilization using water and methanol, the title compound was obtained as a white solid (20 mg, 9% yield). 11H NMR (300 MHz, DMSO-d6) δ 8.73 (bs, 1H), 8.20 (d, J = 5.5 Hz, 1H), 7.27 (dd, J = 1.7 and 5.5 Hz, 1H), 7.18 - 7.10 (m, 2H), 6.74 (d, J = 2.2 Hz, 1H), 6.59 (dd, J = 2.2 and 8.0 Hz, 1H), 3.73 (s, 3H), 2.12 (s, 3H), 1.83 - 1.68 (m, 2H), 1.36 (s, 3H), 0.82 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 356.42.

[0171] Intermediate 2 - 8: (5R)-5-Ethylimidazolidine-2,4-dione

Chem.

[0172] <Synthesis of Example 23> <Example 23> (5R)-5-Ethyl-3-[2-(3-methoxy-4-methyl-phenoxy)-4-pyridyl]imidazolidine-2,4-dione

Chem.

[0173] <Synthesis of Example 24> <Example 24> 3-[2-(3-Methoxy-4-methyl-phenoxy)-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0174] <Synthesis of Example 25> <Example 25> 3-[2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0175] <Synthesis of Example 26> <Example 26> 3-[2-(4-Fluoro-3-methoxy-phenoxy)-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0176] <Synthesis of Example 27> Intermediate 3-1: 2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)-4-iodo-pyridine

Chemical Structure

[0177] <Example 27> 3-[2-(2,3-Dihydro-1,4-benzodioxin-6-yloxy)-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical formula

[0178] <Synthesis of Example 28> Intermediate 3-2: 2-(3,4-Dimethoxyphenoxy)-4-iodo-pyridine

Chem.

[0179] <Example 28> 3-[2-(3,4-Dimethoxyphenoxy)-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chem.

[0180] <Synthesis of Example 29> Intermediate 3 - 3: 4 - Methyl - 3 - (trifluoromethoxy)phenol

Chem.

[0181] Intermediate 3 - 4: 4 - Iodo - 2 - [4 - methyl - 3 - (trifluoromethoxy)phenoxy]pyridine

Chem.

[0182] <Example 29> 3-[2-[4-Methyl-3-(trifluoromethoxy)phenoxy]-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0183] <Synthesis of Example 30> <Example 30> 3-[2-(3-Methoxy-4-methyl-phenoxy)-4-pyridyl]-8-methyl-1,3,8-triazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0184] <Synthesis of Example 31> <Example 31> 3-[2-(3-Methoxy-4-methyl-phenoxy)-4-pyridyl]-8-thia-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0185] <Synthesis of Example 32> Intermediate 3-5: 8-oxa-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0186] <Example 32> 3-[2-(3-Methoxy-4-methyl-phenoxy)-4-pyridyl]-8-oxa-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0187] <Synthesis of Example 33> <Example 33> 3-[2-(3-Methoxy-4-methyl-phenoxy)-4-pyridyl]-1,3-diazaspiro[4.4]nonane-2,4-dione

Chem.

[0188] <Synthesis of Example 34> Intermediate 3-6: 5,7-Diazaspiro[3.4]octane-6,8-dione

Chem.

[0189] <Example 34> 7-[2-(3-Methoxy-4-methyl-phenoxy)-4-pyridyl]-5,7-diazaspiro[3.4]octane-6,8-dione

Chem.

[0190] <Synthesis of Example 35> <Example 35> 3-[2-(1,3-Benzodioxol-5-yloxy)-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chem.

[0191] <Synthesis of Example 36> <Example 36> 3-[2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-4-pyridyl]-1,3-diazaspiro[4.4]nonane-2,4-dione

Chemical Structure

[0192] <Synthesis of Example 37> <Example 37> 7-[2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-4-pyridyl]-5,7-diazaspiro[3.4]octane-6,8-dione

Chemical Structure

[0193] <Synthesis of Example 38> Intermediate 4-1: 3-Bromo-5-(3-methoxy-4-methyl-phenoxy)pyridine [Chemical Structure] To a reaction vessel charged with Intermediate 1-1 (528 mg, 3.82 mmol) and 3,5-dibromopyridine (905 mg, 3.82 mmol) in NMP (15 mL), Cs2CO3 (1.24 g, 3.82 mmol) was added. The vessel was sealed and the mixture was stirred at 100 °C for 24 h. The mixture was diluted with EtOAc, washed with saturated aqueous solution of NH4Cl and brine, dehydrated over MgSO4, concentrated in vacuo, and then purified by silica flash chromatography eluting with cyclohexane followed by gradient elution with 0%-50% EtOAc / cyclohexane mixture to afford the title compound as a colorless oil (440 mg, 39% yield). 11H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 2.0 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 7.62 (dd, J = 2.0 and 2.4 Hz, 1H), 7.18 (dd, J = 0.7 and 8.1 Hz, 1H), 6.80 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 2.3 and 8.1 Hz, 1H), 3.77 (s, 3H), 2.13 (s, 3H).

[0194] Intermediate 4-2: tert-Butyl N-[5-(3-Methoxy-4-methyl-phenoxy)-3-pyridyl]carbamate [Chemical Structure] To a reaction vessel charged with Intermediate 4-1 (430 mg, 1.46 mmol) in dioxane (15 mL) were added tert-butyl carbamate (205 mg, 1.75 mmol) and Cs2CO3 (666 mg, 2.04 mmol). The mixture was degassed with argon for 15 minutes, then Xantphos (12 mg, 0.02 mmol) and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (7.5 mg, 0.007 mmol) were added. The vessel was sealed and the mixture was stirred at 100 °C for 24 hours. The mixture was hydrolyzed with water, extracted with EtOAc, the organic matter was washed with brine, dehydrated with MgSO4, concentrated in vacuo, and purified by silica flash chromatography eluting with cyclohexane and then with a gradient of 0%-100% EtOAc / cyclohexane mixture to give the title compound as a yellow gum (460 mg, 92% yield). 11H NMR (300 MHz, CHCl3-d) δ 8.19 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 2.5 Hz, 1H), 7.65 (bs, 1H), 7.08 (bs, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.56 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 2.3 and 8.0 Hz, 1H), 3.77 (s, 3H), 2.17 (s, 3H), 1.47 (s, 9H).

[0195] Intermediate 4-3: 5-(3-Methoxy-4-methyl-phenoxy)pyridin-3-amine hydrochloride

Chemical Structure

[0196] Intermediate 4-4: tert-Butyl N-[(1R)-1-[[5-(3-Methoxy-4-methyl-phenoxy)-3-pyridyl]carbamoyl]propyl]carbamate

Chemical Structure

[0197] Intermediate 4-5: (2R)-2-Amino-N-[5-(3-methoxy-4-methyl-phenoxy)-3-pyridyl]butanamide

Chemical Structure

[0198] <Example 38> (5R)-5-Ethyl-3-[5-(3-methoxy-4-methyl-phenoxy)-3-pyridyl]imidazolidine-2,4-dione [Chemical formula] To a solution of intermediate 4-5 (280 mg, 0.88 mmol) in DCM (20 mL) at 0 °C was added TEA (617 μL, 4.43 mmol), and a solution of triphosgene (127 mg, 0.39 mmol) in DCM (6 mL). The mixture was stirred at 0 °C for 30 min. The mixture was hydrolyzed with water, extracted with DCM, dried over MgSO4, and concentrated in vacuo. The residue was triturated in EtOAc / MeOH (1 mL / 1 mL), and Et2O was added until precipitation occurred. After filtration, the title compound was obtained as a beige solid (85 mg, 28% yield). 11H NMR (300 MHz, DMSO-d6) δ 8.66 (bs, 1H), 8.37 (d, J = 2.4 Hz, 1H), 7.45 (m, 1H), 7.18 (d, J = 8.1 Hz, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.58 (dd, J = 2.3 and 8.1 Hz, 1H), 4.16 (t, J = 2.9 Hz, 1H), 3.77 (s, 3H), 2.13 (s, 3H), 1.84 - 1.62 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 342.17.

[0199] <Synthesis of Example 39> <Example 39> 3-[5-(3-Methoxy-4-methyl-phenoxy)-3-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical Structure

[0200] <Synthesis of Example 40> <Example 40> (5R)-5-Ethyl-3-[5-(3-methoxy-4-methyl-phenoxy)-3-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chem.

[0201] <Synthesis of Example 41> Intermediate 5-1: 4-(3-Methoxy-4-methyl-phenoxy)pyridin-2-amine

Chem.

[0202] Intermediate 5-2: tert-Butyl N-[(1R)-1-[[4-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]carbamoyl]propyl]carbamate

Chemical Structure

[0203] Intermediate 5-3: (2R)-2-Amino-N-[4-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]butanamide

Chemical Structure

[0204] <Example 41> (5R)-5-Ethyl-3-[4-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]imidazolidine-2,4-dione [Chemical formula] To a solution of intermediate 5-3 (160 mg, 0.51 mmol) in DCM (10 mL) at room temperature, TEA (430 μL, 3.04 mmol) and carbonyldiimidazole (250 mg, 1.52 mmol) were added. The mixture was stirred at room temperature for 3 h. The mixture was hydrolyzed with water, extracted with DCM, dehydrated over MgSO4, concentrated in vacuo, and purified by silica flash chromatography eluting with cyclohexane followed by gradient elution with a 0%-100% EtOAc / cyclohexane mixture to give the title compound as a white foam (85 mg, yield 49%). 11H NMR (300 MHz, DMSO-d6) δ 8.49 (bs, 1H), 8.39 (d, J = 5.7 Hz, 1H), 7.22 (d, J = 8.6 Hz, 1H), 6.96 (m, 1H), 6.91 (d, J = 2.3 Hz, 1H), 6.81 (d, J = 2.3 Hz, 1H), 6.67 (dd, J = 2.3 and 8.0 Hz, 1H), 4.15 (m, 1H), 3.75 (s, 3H), 2.13 (s, 3H), 1.76 - 1.61 (m, 2H), 0.91 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 342.0

[0205] <Synthesis of Example 42> Intermediate 5-4: 4-(2-Naphthyloxy)pyridin-2-amine [Chemical Structure] Using 2-naphthol (467 mg, 3.24 mmol), following basically the procedure described for Example 5-1, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white powder (580 mg, 75% yield). ESIMS m / z [M+H] + 237.3

[0206] Intermediate 5-5: tert-Butyl N-[(1R)-1-[[4-(2-naphthyloxy)-2-pyridyl]carbamoyl]propyl]carbamate [Chemical Structure] To a solution of Intermediate 5-4 (580 mg, 2.40 mmol) in DMF (20 mL) were added Boc-D-Abu-OH (490 mg, 2.40 mmol), 1-hydroxybenzotriazole (442 mg, 2.89 mmol), EDC (553 mg, 2.89 mmol) and DIEA (930 μL, 9.62 mmol). The mixture was stirred at 80 °C for 48 h. The mixture was hydrolyzed with water, extracted with Et2O, the organics were washed with brine, dried over MgSO4 and concentrated in vacuo, and then purified by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 30:70 to give the title compound as a yellow oil (233 mg, 23% yield). ESIMS m / z [M+H] + 422.2。

[0207] Intermediate 5-6: (2R)-2-Amino-N-[4-(2-naphthyloxy)-2-pyridyl]butanamide

Chemical Structure

[0208] <Example 42> (5R)-5-Ethyl-3-[4-(2-naphthyloxy)-2-pyridyl]imidazolidine-2,4-dione

Chemical Structure

[0209] <Synthesis of Example 43> Intermediate 5 - 7: 4-(2-Phenylphenoxy)pyridin-2-amine [Chemical Structure] Using 2-phenylphenol (550 mg, 3.24 mmol), following basically the procedure described for Example 5-1, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white solid (600 mg, yield 70%). ESIMS m / z [M+H] + 236.3

[0210] Intermediate 5 - 8: tert-Butyl N-[(1R)-1-[[4-(2-phenylphenoxy)-2-pyridyl]carbamoyl]propyl]carbamate [Chemical Structure] Using intermediate 5-7 (600 mg, 2.29 mmol), following basically the procedure described for intermediate 5-5, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 70:30, the title compound was obtained as a white solid (200 mg, yield 17%). ESIMS m / z [M+H] + 448.4。

[0211] Intermediate 5-9: (2R)-2-Amino-N-[4-(2-phenylphenoxy)-2-pyridyl]butanamide

Chemical Structure

[0212] <Example 5-3> (5R)-5-Ethyl-3-[4-(2-phenylphenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chemical Structure

[0213] <Synthesis of Example 44> Intermediate 5-10: 2-Bromo-4-(3-bromo-5-methoxy-4-methyl-phenoxy)pyridine

Chemical formula

[0214] Intermediate 5-11: 3-[4-(3-Bromo-5-methoxy-4-methyl-phenoxy)-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical formula

[0215] <Example 44> 3-[4-(3-Methoxy-4-methyl-phenoxy)-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chem.

[0216] <Synthesis of Example 45> Intermediate 5-12: (5R)-3-[4-(3-Bromo-5-methoxy-4-methyl-phenoxy)-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chem.

[0217] <Example 45> (5R)-5-Ethyl-3-[4-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chem.

[0218] <Synthesis of Example 46> Intermediate 5-13: (5S)-3-[4-(3-bromo-5-methoxy-4-methyl-phenoxy)-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chem.

[0219] <Example 46> (5S)-5-Ethyl-3-[4-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chem.

[0220] <Synthesis of Example 47> Intermediate 5-14: 4-Hydroxy-2-isopropyl-benzonitrile

Chem.

[0221] Intermediate 5-15: 3-(4-Chloro-2-pyridyl)-5,5-dimethyl-imidazolidine-2,4-dione

Chem.

[0222] <Example 47> 4-[[2-(4,4-Dimethyl-2,5-dioxo-imidazolidin-1-yl)-4-pyridyl]oxy]-2-isopropyl-benzonitrile

Chemical formula

[0223] <Synthesis of Example 48> Intermediate 6-1: 6-(3-Methoxy-4-methyl-phenoxy)pyridin-2-amine [Chemical formula] To a microwave reaction vessel charged with 3-methoxy-4-methyl-phenol (200 mg, 1.44 mmol) and 2-amino-6-fluoropyridine (200 mg, 1.73 mmol) in NMP (3 mL), Cs2CO3 (565 mg, 1.73 mmol) was added. The vessel was sealed and the mixture was stirred at 220 °C for 1 hour. The mixture was diluted with Et2O, washed with H2O and brine, dehydrated over MgSO4, concentrated in vacuo, and purified by silica flash chromatography eluting with cyclohexane and then gradient eluting with a 0%-50% EtOAc / cyclohexane mixture to afford the title compound as a yellow oil (300 mg, 90% yield). 1 H NMR (300 MHz, CHCl3-d) 7.38 (apparent t, J = 7.9 Hz, 1H), 7.09 (d, J = 8.3 Hz, 1H), 6.62 (m, 2H), 6.19 (d, J = 7.9 Hz, 1H), 6.02 (d, J = 7.9 Hz, 1H), 3.78 (s, 3H), 2.19 (s, 3H).

[0224] Intermediate 6-2: tert-Butyl N-[(1R)-1-[[6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]carbamoyl]propyl]carbamate [Chemical formula] To a solution of Boc-D-Abu-OH (1.14 g, 5.63 mmol) in DMF (10 mL) was added DIEA (1.9 mL, 11.26 mmol), followed by HATU (2.14 g, 5.63 mmol), and the mixture was stirred at room temperature for 30 minutes. Then, a solution of 6-(3-methoxy-4-methyl-phenoxy)pyridin-2-amine (865 mg, 3.76 mmol) in THF (10 mL) was added, and the mixture was stirred at 50 °C for 24 hours. An additional amount of Boc-D-Abu-OH (1.14 g, 5.63 mmol), DIEA (1.9 mL, 11.26 mmol), and HATU (2.14 g, 5.63 mmol) were added, and the mixture was stirred at 50 °C for 24 hours. The mixture was hydrolyzed with saturated aqueous NH4Cl, extracted with EtOAc, the organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by silica flash chromatography eluting with cyclohexane followed by gradient elution with a 0%-60% EtOAc / cyclohexane mixture to afford the title compound as a yellow oil (1.0 g, 68% yield). ESIMS m / z [M+H] + 416.1。

[0225] Intermediate 6-3: (2R)-2-Amino-N-[6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]butanamide trifluoroacetate

Chemical Structure

[0226] <Example 48> (5R)-5-Ethyl-3-[6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chem.

[0227] <Synthesis of Example 49> Intermediate 6-4: 6-(2-Naphthyloxy)pyridin-2-amine

Chem.

[0228] Intermediate 6-5: tert-Butyl N-[(1R)-1-[[6-(2-Naphthyloxy)-2-pyridyl]carbamoyl]propyl]carbamate

Chemical Structure

[0229] Intermediate 6-6: (2R)-2-Amino-N-[6-(2-naphthyloxy)-2-pyridyl]butanamide

Chem.

[0230] <Example 49> (5R)-5-Ethyl-3-[6-(2-naphthyloxy)-2-pyridyl]imidazolidine-2,4-dione

Chem.

[0231] <Synthesis of Example 50> Intermediate 6 - 7: 6-(2-Phenylphenoxy)pyridin-2-amine [Chemical Structure] Using 2-phenylphenol (910 mg, 5.35 mmol), following basically the procedure described for Intermediate 6 - 1, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 75:25, the title compound was obtained as an off-white solid (1.29 g, 92% yield). 1 1H NMR (300 MHz, CHCl3-d) δ 7.55 - 7.42 (m, 3H), 7.38 - 7.23 (m, 6H), 7.17 (dd, J = 1.4 and 8.0 Hz, 1H), 6.23 (d, J = 7.9 Hz, 1H), 6.10 (d, J = 7.9 Hz, 1H), 4.33 (bs, 2H).

[0232] Intermediate 6 - 8: tert-Butyl N-[(1R)-1-[[6-(2-phenylphenoxy)-2-pyridyl]carbamoyl]propyl]carbamate [Chemical Structure] Using intermediate 6-7 (750 mg, 2.86 mmol), following basically the procedure described for intermediate 6-2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 80:20, the title compound was obtained as a white foam (775 mg, 61% yield). 1 H NMR (300 MHz, CHCl3-d) 8.19 (bs, 1H), 7.92 (d, J = 7.9 Hz, 1H), 7.89 - 7.82 (m, 2H), 7.81 - 7.74 (m, 1H), 7.14 (apparently t, J = 8.0 Hz, 1H), 7.55 - 7.41 (m, 3H), 7.30 - 7.23 (m, 2H), 6.52 (d, J = 8.0 Hz, 1H), 5.03 - 4.82 (m, 1H), 4.25 - 4.03 (m, 1H), 2.03 - 1.87 (m, 1H), 1.75 - 1.56 (m, 1H), 1.58 (s, 1H), 1.38 (s, 9H), 0.96 (t, J = 7.4 Hz, 3H).

[0233] Intermediate 6-9: (2R)-2-Amino-N-[6-(2-phenylphenoxy)-2-pyridyl]butanamide

Chemical Structure

[0234] <Example 50> (5R)-5-Ethyl-3-[6-(2-phenylphenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chem.

[0235] <Synthesis of Example 51> Intermediate 6-10: 6-(4-Methoxy-3-methyl-phenoxy)pyridin-2-amine

Chem.

[0236] Intermediate 6-11: tert-Butyl N-[(1R)-1-[[6-(4-Methoxy-3-methyl-phenoxy)-2-pyridyl]carbamoyl]propyl]carbamate

Chemical Structure

[0237] Intermediate 6-12: (2R)-2-Amino-N-[6-(4-Methoxy-3-methyl-phenoxy)-2-pyridyl]butanamide

Chemical Structure

[0238] <Example 51> (5R)-5-Ethyl-3-[6-(4-Methoxy-3-methyl-phenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chemical Structure

[0239] <Synthesis of Example 52> Intermediate 6 - 13: 6-(5 - Methoxy - 2 - methyl - phenoxy)pyridin - 2 - amine [Chemical Structure Diagram] Using 5 - methoxy - 2 - methylphenol (500 mg, 3.62 mmol), following basically the procedure described for Intermediate 6 - 1, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50, the title compound was obtained as a yellow oil (530 mg, yield 64%). ESIMS m / z [M+H] + 231.17

[0240] Intermediate 6 - 14: tert - Butyl N - [(1R)-1 - [[6-(5 - methoxy - 2 - methyl - phenoxy)-2 - pyridyl]carbamoyl]propyl]carbamate [Chemical Structure Diagram] Using Intermediate 6 - 13 (530 mg, 2.30 mmol), following basically the procedure described for Intermediate 6 - 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50, the title compound was obtained as a white foam (720 mg, yield 75%). ESIMS m / z [M+H] + 416.4

[0241] Intermediate 6-15: (2R)-2-Amino-N-[6-(5-methoxy-2-methyl-phenoxy)-2-pyridyl]butanamide

Chem.

[0242] <Example 52> (5R)-5-Ethyl-3-[6-(5-methoxy-2-methyl-phenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chem.

[0243] <Synthesis of Example 53> Intermediate 6-16: 6-(4-Methoxy-phenoxy)pyridin-2-amine

Chem.

[0244] Intermediate 6-17: tert-Butyl N-[(1R)-1-[[6-(4-Methoxy-phenoxy)-2-pyridyl]carbamoyl]propyl]carbamate

Chem.

[0245] Intermediate 6-18: (2R)-2-Amino-N-[6-(4-Methoxy-phenoxy)-2-pyridyl]butanamide

Chem.

[0246] <Example 53> (5R)-5-Ethyl-3-[6-(4-methoxy-phenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chem.

[0247] <Synthesis of Example 54> Intermediate 6-19: 6-(5-Methoxy-3-methyl-phenoxy)pyridin-2-amine

Chem.

[0248] Intermediate 6-20: tert-Butyl N-[(1R)-1-[[6-(5-methoxy-3-methyl-phenoxy)-2-pyridyl]carbamoyl]propyl]carbamate [Chemistry] Using Intermediate 6-19 (520 mg, 2.24 mmol), following basically the procedure described for Intermediate 6-2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50, the title compound was obtained as a white foam (800 mg, 86% yield). ESIMS m / z [M+H] + 416.1.

[0249] Intermediate 6-21: (2R)-2-Amino-N-[6-(5-methoxy-3-methyl-phenoxy)-2-pyridyl]butanamide [Chemistry] Using Intermediate 6-20 (800 mg, 1.93 mmol), following basically the procedure described for Intermediate 6-6, after evaporation under reduced pressure, the title compound was obtained as a yellow oil (570 mg, 94% yield). ESIMS m / z [M+H] + 316.1.

[0250] <Example 54> (5R)-5-Ethyl-3-[6-(5-methoxy-3-methyl-phenoxy)-2-pyridyl]imidazolidine-2,4-dione [Chemistry] Using Intermediate 6-21 (570 mg, 1.80 mmol), following basically the procedure described for Example 6-1, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white foam (244 mg, 39% yield). 11H NMR (300 MHz, DMSO-d6) δ 8.54 (bs, 1H), 7.98 (apparent t, J = 7.9 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.62 - 6.48 (m, 3H), 4.22 - 4.15 (m, 1H), 3.70 (s, 3H), 2.24 (s, 3H), 1.84 - 1.55 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 342.33

[0251] <Synthesis of Example 55> Intermediate 6 - 22: 6-(3 - Methoxy - phenoxy)pyridin - 2 - amine

Chem.

[0252] Intermediate 6 - 23: tert - Butyl N - [(1R)-1 - [[6-(3 - Methoxy - phenoxy)-2 - pyridyl]carbamoyl]propyl]carbamate

Chem.

[0253] Intermediate 6-24: (2R)-2-Amino-N-[6-(3-methoxy-phenoxy)-2-pyridyl]butanamide

Chem.

[0254] <Example 55> (5R)-5-Ethyl-3-[6-(3-methoxy-phenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chem.

[0255] <Synthesis of Example 56> Intermediate 6-25: 2-Methoxy-3-methyl-benzaldehyde and 2,3-dimethoxy-benzaldehyde [Chem.] To a stirred solution of 2,3-dihydroxybenzaldehyde (2.0 g, 14.48 mmol) in DMF (25 mL) was added potassium carbonate (2.2 g, 15.90 mmol). The mixture was stirred at room temperature for 30 minutes, and iodomethane (1.0 mL, 15.90 mmol) was added dropwise. The resulting solution was stirred at room temperature for 18 hours. The mixture was hydrolyzed with saturated aqueous NH4Cl, extracted with ethyl acetate, the organic matter was washed with brine, dehydrated with MgSO4, concentrated in vacuo, and then purified by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 75:25 to give 2,3-dimethoxy-benzaldehyde, the first eluted compound, as a colorless gum (450 mg, 19% yield), and 2-methoxy-3-methyl-benzaldehyde, the last eluted compound, as a white solid (1.27 g, 57% yield). 2,3-Dimethoxy-benzaldehyde: 1 H NMR (300 MHz, CHCl3-d) 10.43 (s, 1H), 7.45 - 7.38 (m, 1H), 7.18 - 7.10 (m, 2H), 3.98 (s, 3H), 3.91 (s, 3H). 2-Methoxy-3-methyl-benzaldehyde: 1 H NMR (300 MHz, CHCl3-d) 10.26 (s, 1H), 7.45 - 7.38 (dd, J = 1.8 and 7.6 Hz, 1H), 7.26 - 7.10 (m, 2H), 5.79 (s, 1H), 3.97 (s, 3H).

[0256] Intermediate 6 - 26: 2-Methoxy-3-methyl-phenol [Chem.] Using 2-methoxy-3-methylbenzaldehyde (1.27 g, 8.34 mmol), following essentially the procedure described for Intermediate 1-1, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 80:20, the title compound was obtained as a colorless oil (975 mg, 84% yield). 1 H NMR (300 MHz, CHCl3-d) 6.91 (apparent t, J = 7.8 Hz, 1H), 6.80 (dd, J = 1.6 and 8.0 Hz, 1H), 6.69 (dd, J = 0.7 and 7.5 Hz, 1H), 5.62 (bs, 1H), 3.80 (s, 3H), 2.30 (s, 3H).

[0257] Intermediate 6-27: 6-(2-Methoxy-3-methyl-phenoxy)pyridin-2-amine

Chemical Structure

[0258] Intermediate 6-28: Methyl (2R)-2-(tert-butoxycarbonylamino)butanoate

Chemical Structure

[0259] Intermediate 6 - 29: tert-Butyl N-[(1R)-1-[[6-(2-Methoxy-3-methyl-phenoxy)-2-pyridyl]carbamoyl]propyl]carbamate

Chemical Structure

[0260] Intermediate 6-30: (2R)-2-Amino-N-[6-(2-methoxy-3-methyl-phenoxy)-2-pyridyl]butanamide

Chemical formula

[0261] <Example 56> (5R)-5-Ethyl-3-[6-(2-methoxy-3-methyl-phenoxy)-2-pyridyl]imidazolidine-2,4-dione

Chemical formula

[0262] <Synthesis of Example 57> Intermediate 6-31: 4-[(6-Bromo-2-pyridyl)oxy]-3-tert-butyl-benzonitrile

Chemical Structure

[0263] <Example 57> 3-tert-Butyl-4-[[6-[(4R)-4-ethyl-2,5-dioxo-imidazolidin-1-yl]-2-pyridyl]oxy]benzonitrile

Chemical Structure

[0264] <Synthesis of Example 58> Intermediate 6-32: 2-Bromo-6-(3-methoxy-4-methyl-phenoxy)pyridine [Chemistry] Using Intermediate 1-1 (120 mg, 0.87 mmol), following basically the procedure described for Intermediate 6-31, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:dichloromethane from 100:0 to 50:50, the title compound was obtained as a colorless oil (185 mg, 72% yield). 1 H NMR (300 MHz, CDCl3-d) 7.49 (dd, J = 7.6 and 8.1 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 8.1 Hz, 1H), 6.70 - 6.58 (m, 2H), 3.80 (s, 3H), 2.21 (s, 3H).

[0265] [Example 58] (5R)-5-Ethyl-3-[6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-5-methyl-imidazolidine-2,4-dione [Chemistry] Using Intermediate 6-32 (180 mg, 0.61 mmol) and Intermediate 2-1 (90 mg, 0.63 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with gradients of cyclohexane:dichloromethane from 100:0 to 0:100 and dichloromethane:ethyl acetate from 100:0 to 0:100, and freeze-drying using water and acetonitrile, the title compound was obtained as a white foam (83 mg, 38% yield). 11H NMR (300 MHz, DMSO-d6) δ 8.52 (bs, 1H), 7.99 (dd, J = 7.8 and 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), 6.65 (dd, J = 2.1 and 8.0 Hz, 1H), 3.76 (s, 3H), 2.13 (s, 3H), 1.85 - 1.55 (m, 2H), 1.35 (s, 3H), 0.82 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 356.0.

[0266] <Synthesis of Example 59> Intermediate 6-33: 2-Bromo-6-(4-fluoro-3-methoxy-phenoxy)pyridine [Chemical Structure] Using 4-fluoro-3-methoxyphenol (115 mg, 0.81 mmol), following basically the procedure described for Intermediate 6-31, the title compound was obtained as a brown solid without purification (215 mg, yield 74%). ESIMS m / z [M+H] + 300.17。

[0267] <Example 59> (5R)-5-Ethyl-3-[6-(4-fluoro-3-methoxy-phenoxy)-2-pyridyl]-5-methyl-imidazolidine-2,4-dione [Chemical Structure] Using intermediate 6-33 (205 mg, 0.57 mmol) and intermediate 2-1 (110 mg, 0.67 mmol), following basically the procedure described in Example 2, silica gel flash chromatography was carried out with elution in a gradient from 100:0 to 50:50 of dichloromethane:ethyl acetate for the first time and from 100:0 to 0:100 of cyclohexane:ethyl acetate for the second time, and after two purifications by lyophilization using water and methanol, the title compound was obtained as a white solid (125 mg, yield 59%). 1 H NMR (300 MHz, DMSO-d6) 8.52 (bs, 1H), 8.01 (dd, J = 7.7 and 8.1 Hz, 1H), 7.24 (dd, J = 8.8 and 11.3 Hz, 1H), 7.16 (d, J = 7.1 Hz, 1H), 7.09 (dd, J = 2.8 and 7.5 Hz, 1H), 7.02 (d, J = 8.1 Hz, 1H), 6.80 - 6.69 (m, 1H), 3.82 (s, 3H), 1.80 - 1.55 (m, 2H), 1.35 (s, 3H), 0.81 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 360.33

[0268] <Synthesis of Example 60> Intermediate 6-34: 2-Bromo-6-(4-fluoro-3-methyl-phenoxy)pyridine

Chemical Structure

[0269] <Example 60> (5R)-5-Ethyl-3-[6-(4-fluoro-3-methyl-phenoxy)-2-pyridyl]-5-methyl-imidazolidine-2,4-dione

Chem.

[0270] <Synthesis of Example 61> Intermediate 6-35: 2-Bromo-6-indan-5-yloxy-pyridine

Chem.

[0271] <Example 61> (5R)-5-Ethyl-3-(6-indan-5-yloxy-2-pyridyl)-5-methyl-imidazolidine-2,4-dione

Chemical Structure

[0272] <Synthesis of Example 62> Intermediate 6-36: 2-Bromo-6-(4-chloro-3-methoxy-phenoxy)pyridine [Chemical formula] Using 4-chloro-3-methoxyphenol (300 mg, 1.89 mmol), following basically the procedure described for Intermediate 6-31, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:dichloromethane from 100:0 to 50:50, the title compound was obtained as a colorless oil (426 mg, yield 72%). 1 H NMR (300 MHz, CDCl3-d) 7.53 (dd, J = 7.6 and 8.0 Hz, 1H), 7.35 (d, J = 8.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 6.84 - 6.75 (m, 2H), 6.69 (dd, J = 2.6 and 8.6 Hz, 1H), 3.88 (s, 3H).

[0273] [Example 62] (5R)-3-[6-(4-chloro-3-methoxy-phenoxy)-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 6-36 (200 mg, 0.64 mmol) and Intermediate 2-1 (90 mg, 0.64 mmol) in toluene, following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of dichloromethane:ethyl acetate from 100:0 to 0:100 and freeze-drying using water and acetonitrile, the title compound was obtained as a white foam (58 mg, yield 24%). 11H NMR (300 MHz, DMSO-d6) δ 8.51 (bs, 1H), 8.01 (dd, J = 7.8 and 8.0 Hz, 1H), 7.41 (d, J = 8.6 Hz, 1H), 7.17 (d, J = 7.5 Hz, 1H), 7.09 - 7.03 (m, 2H), 6.76 (dd, J = 2.6 and 8.6 Hz, 1H), 3.82 (s, 3H), 1.78 - 1.54 (m, 2H), 1.33 (s, 3H), 0.79 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 376.33

[0274] <Synthesis of Example 63> Intermediate 6 - 37: 2-(Benzofuran - 6 - yloxy)-6 - bromo - pyridine [Chemical Structure] Using benzofuran - 6 - ol (143 mg, 1.07 mmol), following basically the procedure described for Intermediate 6 - 31, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:dichloromethane from 100:0 to 0:100, the title compound was obtained as a colorless oil (266 mg, yield 87%). 1 1H NMR (300 MHz, CDCl3 - d) δ 7.64 (d, J = 2.2 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 7.6 and 8.1 Hz, 1H), 7.32 (d, J = 1.6 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.05 (dd, J = 2.1 and 8.4 Hz, 1H), 6.81 - 6.74 (m, 2H).

[0275] <Example 63> (5R)-3 - [6-(Benzofuran - 6 - yloxy)-2 - pyridyl]-5 - ethyl - 5 - methyl - imidazolidine - 2,4 - dione [Chemical Structure] Using intermediate 6-37 (260 mg, 0.90 mmol) and intermediate 2-1 (127 mg, 0.90 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white foam (180 mg, 57% yield). 1 H NMR (300 MHz, DMSO-d6) 8.48 (bs, 1H), 8.02 - 7.93 (m, 2H), 7.65 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 1.6 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 7.09 (dd, J = 2.0 and 8.4 Hz, 1H), 7.02 - 6.93 (m, 2H), 1.78 - 1.52 (m, 2H), 1.32 (s, 3H), 0.77 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 352.25

[0276] <Synthesis of Example 64> Intermediate 6-38: 2-Bromo-6-chroman-7-yloxy-pyridine [Chemical formula] Using chroman-7-ol (160 mg, 1.07 mmol), following basically the procedure described for intermediate 6-31, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:dichloromethane from 100:0 to 0:100, the title compound was obtained as a colorless oil (82 mg, 25% yield). 11H NMR (300 MHz, CDCl3-d) 7.47 (dd, J = 7.8 and 7.9 Hz, 1H), 7.17 (dd, J = 0.4 and 7.5 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.73 (dd, J = 0.6 and 8.2 Hz, 1H), 6.61 (dd, J = 2.4 and 8.2 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 4.18 (t, J = 5.3 Hz, 2H), 2.77 (t, J = 6.5 Hz, 2H), 2.06 - 1.95 (m, 2H).

[0277] <Example 64> (5R)-3-(6-Chroman-7-yloxy-2-pyridyl)-5-ethyl-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 6-38 (82 mg, 0.27 mmol) and Intermediate 2-1 (38 mg, 0.27 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, the title compound was obtained as a white solid (38 mg, 39% yield). 1 1H NMR (300 MHz, DMSO-d6) 8.49 (bs, 1H), 7.96 (dd, J = 7.7 and 8.1 Hz, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 8.3 Hz, 1H), 6.61 (dd, J = 2.4 and 8.3 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 4.11 (t, J = 5.1 Hz, 2H), 2.70 (t, J = 6.3 Hz, 2H), 2.00 - 1.85 (m, 2H), 1.78 - 1.52 (m, 2H), 1.34 (s, 3H), 0.81 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 368.33

[0278] <Synthesis of Example 65> Intermediate 6-39: 2-Bromo-6-(3,4-dimethylphenoxy)pyridine

Chem.

[0279] <Example 65> (5R)-3-[6-(3,4-Dimethylphenoxy)-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chem.

[0280] <Synthesis of Example 66> Intermediate 6-40: 2-Bromo-6-[(2,2-difluoro-1,3-benzodioxol-5-yl)oxy]pyridine

Chem.

[0281] <Example 66> (5R)-3-[6-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chem.

[0282] <Synthesis of Example 67> Intermediate 6-41: 2-Bromo-6-(2,3-dihydrobenzofuran-6-yloxy)pyridine

Chemical Structure

[0283] <Example 67> (5R)-3-[6-(2,3-Dihydrobenzofuran-6-yloxy)-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chemical Structure

[0284] <Synthesis of Example 69> Intermediate 6 - 43: 2 - Bromo - 6 - indan - 4 - yloxy - pyridine [Chemical Structure] Using indan - 4 - ol (200 mg, 1.49 mmol), following basically the procedure described for Intermediate 6 - 31, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:dichloromethane from 100:0 to 40:60, the title compound was obtained as a white solid (247 mg, 57% yield). ESIMS m / z [M+H] + 290.17

[0285] <Example 69> (5R)-5 - Ethyl - 3 - (6 - indan - 4 - yloxy - 2 - pyridyl)-5 - methyl - imidazolidine - 2,4 - dione [Chemical Structure] Using intermediate 6-43 (245 mg, 0.84 mmol) and intermediate 2-1 (132 mg, 0.93 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100 and freeze-drying using water and methanol, the title compound was obtained as a white solid (208 mg, yield 70%). 1 H NMR (300 MHz, DMSO-d6) 8.46 (bs, 1H), 7.96 (apparent t, J = 7.9 Hz, 1H), 7.20 - 7.06 (m, 3H), 6.98 - 6.86 (m, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.63 (t, J = 7.4 Hz, 2H), 1.95 (quintet, J = 7.4 Hz, 2H), 1.76 - 1.52 (m, 2H), 1.31 (s, 3H), 0.76 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 352.33

[0286] <Synthesis of Example 70> Intermediate 6-44: 2-Bromo-6-(3,5-dimethoxyphenoxy)pyridine

Chemical Structure

[0287] <Example 70> (5R)-3-[6-(3,5-Dimethoxyphenoxy)-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione

Chemical Structure

[0288] <Synthesis of Example 71> Intermediate 6-45: 2-Bromo-6-(3,5-dimethoxy-4-methylphenoxy)pyridine [Chemical formula] Using 3,5-dimethoxy-4-methylphenol (200 mg, 1.19 mmol), following basically the procedure described for intermediate 6-31, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 90:10, the title compound was obtained as a white solid (252 mg, yield 58%). ESIMS m / z [M+H] + 323.9

[0289] <Example 71> (5R)-3-[6-(3,5-Dimethoxy-4-methylphenoxy)-2-pyridyl]-5-ethyl-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 6-45 (252 mg, 0.78 mmol) and Intermediate 2-1 (142 mg, 0.78 mmol), following basically the procedure described in Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50, the title compound was obtained as a white solid (75 mg, 24% yield). 1 H NMR (300 MHz, DMSO-d6) δ 8.53 (bs, 1H), 7.99 (dd, J = 7.8 and 8.0 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.52 (s, 2H), 3.74 (s, 6H), 1.97 (s, 3H), 1.80 - 1.56 (m, 2H), 1.36 (s, 3H), 0.83 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 386.33

[0290] <Synthesis of Example 72> <Example 72> (5S)-5-Ethyl-3-[6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-5-methyl-imidazolidine-2,4-dione [Chemical formula] Using Intermediate 6-32 (200 mg, 0.68 mmol) and Intermediate 2-7 (146 mg, 0.68 mmol), following basically the procedure described in Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 0:100, Sephadex column (eluent DCM / MeOH, 75 / 25) and freeze drying using water and acetonitrile, the title compound was obtained as a white foam (108 mg, 44% yield). 11H NMR (300 MHz, DMSO-d6) δ 8.49 (bs, 1H), 7.97 (dd, J = 7.8 and 8.0 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 6.82 (d, J = 2.2 Hz, 1H), 6.63 (dd, J = 2.2 and 8.0 Hz, 1H), 3.74 (s, 3H), 2.11 (s, 3H), 1.80 - 1.55 (m, 2H), 1.33 (s, 3H), 0.80 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 356.42.

[0291] <Synthesis of Example 73> <Example 73> 3-[6-(3-Methoxy-4-methyl-phenoxy)-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione [Chemical formula] Using intermediate 6-32 (570 mg, 1.94 mmol), following basically the procedure described for Example 2, silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50 and purification by lyophilization using water and methanol, the title compound was obtained as a white foam (394 mg, 58% yield). 1 1H NMR (300 MHz, DMSO-d6) δ 8.50 (bs, 1H), 7.99 (dd, J = 7.7 and 8.1 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.83 (d, J = 2.3 Hz, 1H), 6.64 (dd, J = 2.3 and 8.1 Hz, 1H), 3.76 (s, 3H), 2.13 (s, 3H), 1.37 (s, 6H). ESIMS m / z [M+H] + 342.42.

[0292] <Synthesis of Example 74> <Example 74> 7-[6-(3-Methoxy-4-methyl-phenoxy)-2-pyridyl]-5,7-diazaspiro[3.4]octane-6,8-dione

Chemical formula

[0293] <Synthesis of Example 75> <Example 75> 3-[6-(3-Methoxy-4-methyl-phenoxy)-2-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical formula

[0294] <Synthesis of Example 76> <Example 76> 3-[6-(3-Methoxy-4-methyl-phenoxy)-2-pyridyl]-1,3-diazaspiro[4.4]nonane-2,4-dione

Chemical Structure

[0295] <Synthesis of Example 77> Intermediate 6 - 46: 4 - [(6 - Bromo - 2 - pyridyl)oxy]-2 - isopropyl - benzonitrile

Chem.

[0296] <Example 77> 4 - [[6 - (4,4 - Dimethyl - 2,5 - dioxo - imidazolidin - 1 - yl)-2 - pyridyl]oxy]-2 - isopropyl - benzonitrile

Chem.

[0297] <Synthesis of Example 78> Intermediate 7-1: 6-Bromo-3-fluoro-2-(3-methoxy-4-methyl-phenoxy)pyridine

Chemical Structure

[0298] <Example 78> 3-[5-Fluoro-6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical Structure

[0299] <Synthesis of Example 79> Intermediate 7-2: 6-Bromo-3-fluoro-2-indan-5-yloxy-pyridine

Chemical formula

[0300] <Example 79> 3-(5-Fluoro-6-indan-5-yloxy-2-pyridyl)-5,5-dimethyl-imidazolidine-2,4-dione

Chemical formula

[0301] <Synthesis of Example 80> Intermediate 7-3: 6-Bromo-3-fluoro-2-(4-fluoro-3-methoxy-phenoxy)pyridine

Chemical formula

[0302] <Example 80> 3-[5-Fluoro-6-(4-fluoro-3-methoxy-phenoxy)-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical formula

[0303] <Synthesis of Example 81> Intermediate 7-4: 2-(Benzofuran-6-yloxy)-6-bromo-3-fluoro-pyridine

Chemical Structure

[0304] <Example 81> 3-[6-(Benzofuran-6-yloxy)-5-fluoro-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical Structure

[0305] <Synthesis of Example 82> Intermediate 7-5: 6-Bromo-3-fluoro-2-(4-chloro-3-methoxy-phenoxy)pyridine

Chemical Structure

[0306] <Example 82> 3-[5-Fluoro-6-(4-chloro-3-methoxy-phenoxy)-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical formula

[0307] <Synthesis of Example 83> Intermediate 7-6: 6-Bromo-3-fluoro-2-(3-fluoro-4-methyl-phenoxy)pyridine

Chemical formula

[0308] <Example 83> 3-[5-Fluoro-6-(3-fluoro-4-methyl-phenoxy)-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chem.

[0309] <Synthesis of Example 84> Intermediate 7-7: 6-Bromo-2-[(2,2-difluoro-1,3-benzodioxol-5-yl)oxy]-3-fluoro-pyridine

Chem.

[0310] <Example 84> 3-[6-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-5-fluoro-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chem.

[0311] <Synthesis of Example 85> Intermediate 7-8: 6-Bromo-3-fluoro-2-[3-methoxy-4-(trifluoromethyl)-phenoxy]pyridine

Chem.

[0312] <Example 85> 3-[5-Fluoro-6-[3-methoxy-4-(trifluoromethyl)-phenoxy]-2-pyridyl]-5,5-dimethyl-imidazolidine-2,4-dione

Chemical Structure

[0313] <Synthesis of Example 86> <Example 86> 7-[5-Fluoro-6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-5,7-diazaspiro[3.4]octane-6,8-dione

Chemical Structure

[0314] <Synthesis of Example 87> <Example 87> 3-[5-Fluoro-6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical Structure

[0315] <Synthesis of Example 88> <Example 88> 3-[5-Fluoro-6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-1,3-diazaspiro[4.4]nonane-2,4-dione

Chemical formula

[0316] <Synthesis of Example 89> <Example 89> (5R)-5-Ethyl-3-[5-fluoro-6-(3-methoxy-4-methyl-phenoxy)-2-pyridyl]-5-methyl-imidazolidine-2,4-dione [Chemical Formula] Using Intermediate 7-1 (115 mg, 0.37 mmol) and Intermediate 2-1 (52 mg, 0.37 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 40:60, the title compound was obtained as a white foam (63 mg, 44% yield). 1 H NMR (300 MHz, DMSO-d6) 8.52 (bs, 1H), 8.05 (dd, J = 8.3 and 8.4 Hz, 1H), 7.24 (dd, J = 2.8 and 8.3 Hz, 1H), 7.12 (d, J = 8.1 Hz, 1H), 6.87 (d, J = 2.3 Hz, 1H), 6.66 (dd, J = 2.3 and 8.1 Hz, 1H), 3.76 (s, 3H), 2.12 (s, 3H), 1.80 - 1.50 (m, 2H), 1.33 (s, 3H), 0.78 (t, J = 7.4 Hz, 3H). ESIMS m / z [M+H] + 374.0

[0317] <Synthesis of Example 90> Intermediate 8-1: 3-Fluoro-4-iodo-2-(3-methoxy-4-methyl-phenoxy)pyridine [Chemical Formula] Using 2,3-difluoro-4-iodopyridine (400 mg, 1.66 mmol), following basically the procedure described for Intermediate 1-2, after stirring at 50 °C for 18 h, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:dichloromethane from 100:0 to 50:50, the title compound was obtained as a white solid (510 mg, 86% yield). 1 H NMR (300 MHz, CDCl3-d) 7.57 (d, J = 5.3 Hz, 1H), 7.36 - 7.29 (m, 1H), 7.17 - 7.10 (m, 1H), 6.67 - 6.61 (m, 1H), 3.80 (s, 3H), 2.20 (s, 3H).

[0318] <Example 90> 3-[3-Fluoro-2-(3-methoxy-4-methyl-phenoxy)-4-pyridyl]-1,3-diazaspiro[4.4]nonane-2,4-dione [Chemical formula] Using Intermediate 8-1 (200 mg, 0.56 mmol) and 1,3-diazaspiro[4.4]nonane-2,4-dione (95 mg, 0.61 mmol), following basically the procedure described for Example 2, after purification by silica gel flash chromatography eluting with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50, the title compound was obtained as a colorless oil (8 mg, 3% yield). 1 H NMR (300 MHz, DMSO-d6) 9.03 (bs, 1H), 8.00 (d, J = 5.3 Hz, 1H), 7.25 (dd, J = 4.6 and 5.1 Hz, 1H), 7.15 (d, J = 8.1 Hz, 1H), 6.83 (d, J = 2.1 Hz, 1H), 6.66 (dd, J = 2.1 and 8.0 Hz, 1H), 3.74 (s, 3H), 2.12 (s, 3H), 2.12 - 2.00 (m, 2H), 1.96 - 1.66 (m, 6H). ESIMS m / z [M+H] + 386.25

[0319] <Synthesis of Example 91> <Example 91> 3-[3-Fluoro-2-(3-methoxy-4-methyl-phenoxy)-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione

Chemical formula

[0320] <Synthesis of Example 92> Intermediate 8-2: 2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-3-fluoro-4-iodo-pyridine

Chemical formula

[0321] <Example 92> 3-[2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-3-fluoro-4-pyridyl]-1,3-diazaspiro[4.4]nonane-2,4-dione

Chemical Structure

[0322] <Synthesis of Example 93> <Example 93> 3-[2-[(2,2-Difluoro-1,3-benzodioxol-5-yl)oxy]-3-fluoro-4-pyridyl]-1,3-diazaspiro[4.5]decane-2,4-dione [Chemical Structure] Using Intermediate 8-2 (300 mg, 0.76 mmol) and 1,3-diazaspiro[4.5]decane-2,4-dione (140 mg, 0.84 mmol), following basically the procedure described for Example 2, eluting first with a gradient of cyclohexane:ethyl acetate from 100:0 to 50:50 and second with a gradient of cyclohexane:dichloromethane from 100:0 to 0:100, after two purifications by silica gel flash chromatography, the title compound was obtained as a white foam (15 mg, 4% yield). 1 1H NMR (300 MHz, DMSO-d6) 9.25 (broad singlet, 1H), 8.00 (doublet, J = 5.3 Hz, 1H), 7.53 (doublet, J = 2.1 Hz, 1H), 7.46 (doublet, J = 8.7 Hz, 1H), 7.29 (triplet, J = 4.8 Hz, 1H), 7.10 (doublet of doublets, J = 2.1 and 8.7 Hz, 1H), 1.86 - 1.47 (multiplet, 9H), 1.42 - 1.28 (multiplet, 1H). ESIMS m / z [M+H] + 436.25.

[0323] Cell biology protocols and data Cell lines hKv3.1, hKv3.2, hKv3.3, and hKv3.4 were stably expressed in CHO-K1 (Chinese hamster ovary) cells and maintained under constant antibiotic selection. For in vitro assays, the cells were maintained in appropriate growth medium at 37 °C and 5% CO2 in a humidified incubator.

[0324] Electrophysiology CHO / Kv3.x cell preparation hKv3.X-expressing cells were seeded into a T-25 flask at 37 °C for 3 - 4 days (without selection antibiotics) before use and grown to 80% confluence. The cells were washed twice with PBS (calcium- and magnesium-free), detached by treatment with 2 - 3 ml of Accutase® at 37 °C for 5 minutes. The cells were collected, the flask was washed with CHO-SFM II medium (Life Technologies Gibco), centrifuged at approximately 110 × g for 2 minutes, and resuspended to obtain a single-cell suspension of approximately 2 - 3×10 6 cells / ml.

[0325] Solution and compound preparation The intracellular solution contained (in mM) KCl 50, NaCl 10, KF 60, EGTA 20, HEPES 10, was adjusted to pH 7.2 with KOH, and the molar osmolarity was adjusted to 285 mOsmol. The seal enhancer was purchased from Nanion (80 mM NaCl, 3 mM KCl, 10 mM MgCl2, 35 mM CaCl2, 10 mM HEPES, pH 7.4, 298 mOsmol. The extracellular solution contained (in mM) NaCl 140, KCl 4, CaCl2 2, MgCl2 1, HEPES 10, glucose 5, was adjusted to pH 7.4 and a molar osmolarity of 298 mOsmol.

[0326] All compounds were first tested at 10 μM with a final DMSO concentration of 0.33%. The compounds were dissolved in dimethyl sulfoxide (DMSO) at a stock concentration of 30 mM. The compounds were further diluted 1:10 to obtain a stock concentration of 3 mM in DMSO. The final assay solution was diluted 1:300 into the external solution to obtain a final concentration of 10 μM. As a DMSO control buffer, 30 μL of DMSO was added to 10 mL of buffer.

[0327] The following voltage protocol was used to evaluate different hKv3.X channels.

[0328] Patchliner protocol All electrophysiological recordings were performed at ambient temperature (21 - 23 °C) in the whole-cell configuration using an automated patch clamp (Patchliner, Nanion Technologies GmbH).

[0329] The cell membrane potential was held at -80 mV and currents were evoked by voltage steps from -60 to +60 mV in 10 mV increments (duration 1000 ms). This was done first with vehicle (0.33% DMSO) and then with 10 μM compound after a 3-minute incubation. Data were taken from 4 cells per assay.

[0330] Data analysis To remove inappropriate cells from the analysis, recordings were analyzed and selected using the peak current amplitude (above 100 pA at a voltage step of -10 mV) in the absence of compound. The peak current amplitude was measured and recorded for each voltage step, and the data were normalized to the maximum current at +60 mV. The normalized Kv3.x current after compound addition was then compared to the current recorded before compound addition (vehicle control). Positive modulation was determined as enhancement (%) = [current (compound) / current (vehicle)] * 100 - 100 at a voltage step of -10 mV. Enhancement (%) ≥ 50% was considered acceptable. Furthermore, the voltage change of the IV curve at V 1 / 2 was measured. V above -5 mV 1 / 2was considered acceptable. The IV curves were plotted using GraphPad Prism (software version 6.0) and fitted to the Boltzmann equation. Here, V 1 / 2 is the voltage at half-maximal activation.

[0331] Electrophysiological data [Table 1] JPEG2025091422000212.jpg234159JPEG2025091422000213.jpg255152JPEG2025091422000214.jpg255153JPEG2025091422000215.jpg252159JPEG2025091422000216.jpg255153JPEG2025091422000217.jpg184159

Claims

1. 1. A method of treating cognitive dysfunction and negative symptoms associated with a CNS disorder in which fast-spiking PV+ interneurons and circuitry involved in the generation of cortical gamma oscillations are disrupted in a patient in need thereof, comprising administering to said patient a compound represented by formula (I): 【Chemistry 1】 [In the formula, X １ , X ２ , X ３ or X ４ is N, and the others are independently CH, CF, or CCF ３ , CCl, CCH ３ or COCF ３ Selected from: R １ is phenyl, CN, F, OCF ３ , C １ ~C ３ Alkoxy or C １ ~C ５ is alkyl; R ２ is H, C １ ~C ５ Alkyl or C １ ~C ５ is alkoxy; R ３ is H or CH ３ or R １ and R ２ taken together represent an optionally substituted 5- or 6-membered O-containing heterocyclylene, an optionally substituted 5- or 6-membered O-containing heteroarylene, or an optionally substituted 5- or 6-membered arylene; and R ４ and R ５ are independently H or C １ ~C ４ alkyl, or R ４ and R ５ taken together represent an optionally substituted 4- to 7-membered cycloalkylene or an optionally substituted 5- to 7-membered heterocyclene. or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and stereoisomers thereof, comprising administering to said patient an effective amount of said compound of formula (I) or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and stereoisomers thereof.

2. Formula (I'): 【Chemistry 2】 [In the formula, X １ , X ２ , X ３ or X ４ is N, and the others are independently CH, CF, or CCF ３ , C.C.H. ３ or COCF ３ Selected from: R １ is phenyl, CN, F, OCF ３ , C １ ~C ３ Alkoxy or C １ ~C ５ is alkyl; R ２ is H, C １ ~C ５ Alkyl or C １ ~C ５ is alkoxy; R ３ is H or CH ３ or R １ and R ２ taken together represent an optionally substituted 5- or 6-membered O-containing heterocyclylene, an optionally substituted 5- or 6-membered O-containing heteroarylene, or an optionally substituted 5- or 6-membered arylene; and R ４ and R ５ are independently H or C １ ~C ４ alkyl, or R ４ and R ５ taken together represent an optionally substituted 4- to 7-membered cycloalkylene or an optionally substituted 5- to 7-membered heterocyclene. or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and stereoisomers thereof.

3. R １ But, CN, F, OCF ３ , C １ ~C ３ Alkoxy or C １ ~C ５ The compound of formula (I') according to claim 2, which is alkyl.

4. R ２ But, C １ ~C ５ Alkyl or C １ ~C ５ is alkoxy, or R １ and R ２ taken together represent an optionally substituted 5-membered O-containing heterocyclyl; A compound of formula (I') according to claim 2 or 3.

5. Formula (I'a), (I'b), (I'c), or (Id') 【Chemistry 3】 [In the formula, R １ ~R ５ is as defined in claim 2, and R ６ is independent, OF ３ , C.F. ３ , F, or CH ３ and n is 0, 1, or 2. The compound of formula (I') according to claim 2, which is a compound of the formula:

6. Compounds of formula (I'a) to (I'd) [wherein R ４ and R ５ and taken together represent an optionally substituted 4- to 7-membered cycloalkylene or an optionally substituted 5- to 7-membered heterocyclene.

7. Formula (I'a) [wherein, R １ ~R ５ is as defined in claim 2, and R ６ is independent, OF ３ , C.F. ３ , F, or CH ３ and n is 0, 1, or 2.

8. Formula (I'a) 【Chemistry 4】 [In the formula, R １ ~R ６ and n is as defined in claim 5.

6. The compound of formula (I') according to claim 5, which is a compound of the formula:

9. Formula (I″a) 【Chemistry 5】 [In the formula, R １ ~R ６ is as defined in claim 2.

9. The compound of formula (I') according to claim 8, which is a compound of the formula:

10. Formula (I”b) 【Chemistry 6】 [In the formula, R １ ~R ５ is as defined in claim 2.

10. The compound of formula (I') according to claim 9, which is a compound of the formula:

11. basis 【Chemistry 7】 but, 【Chemistry 8】 11. The compound according to any one of claims 2 to 10, selected from:

12. R ４ and R ５ The foundation comes together, 【Chemistry 9】 is selected from R ７ and R ８ are independent, H, F, CH ３ and C.F. ３ 12. The compound according to any one of claims 2 to 11, selected from:

13. and (b) a compound of formula (I) in the manufacture of a medicament for the treatment of cognitive dysfunction and negative symptoms associated with CNS disorders in which the circuitry involved in fast-spiking PV+ interneurons and the generation of cortical gamma oscillations is disrupted. 【Chemistry 10】 [In the formula, X １ , X ２ , X ３ or X ４ is N, and the others are independently CH, CF, or CCF ３ , CCl, CCH ３ or COCF ３ Selected from: R １ is phenyl, CN, F, OCF ３ , C １ ~C ３ Alkoxy or C １ ~C ５ is alkyl; R ２ is H, C １ ~C ５ Alkyl or C １ ~C ５ is alkoxy; R ３ is H or CH ３ or R １ and R ２ taken together represent an optionally substituted 5- or 6-membered O-containing heterocyclylene, an optionally substituted 5- or 6-membered O-containing heteroarylene, or an optionally substituted 5- or 6-membered arylene; and R ４ and R ５ are independently H or C １ ~C ４ alkyl, or R ４ and R ５ taken together represent an optionally substituted 4- to 7-membered cycloalkylene or an optionally substituted 5- to 7-membered heterocyclene. or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and stereoisomers thereof.

14. 2. Therapeutic compositions comprising a compound of formula (I): 【Chemistry 11】 [In the formula, X １ , X ２ , X ３ or X ４ is N, and the others are independently CH, CF, or CCF ３ , CCl, CCH ３ or COCF ３ Selected from: R １ is phenyl, CN, F, OCF ３ , C １ ~C ３ Alkoxy or C １ ~C ５ is alkyl; R ２ is H, C １ ~C ５ Alkyl or C １ ~C ５ is alkoxy; R ３ is H or CH ３ or R １ and R ２ taken together represent an optionally substituted 5- or 6-membered O-containing heterocyclylene, an optionally substituted 5- or 6-membered O-containing heteroarylene, or an optionally substituted 5- or 6-membered arylene; and R ４ and R ５ are independently H or C １ ~C ４ alkyl, or R ４ and R ５ taken together represent an optionally substituted 4- to 7-membered cycloalkylene or an optionally substituted 5- to 7-membered heterocyclene. or a pharma- ceutically acceptable salt, solvate or prodrug thereof, and stereoisomers thereof.

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