TW202425979A - Compounds and compositions as gpr52 modulators - Google Patents

Abstract

The present disclosure relates to compounds capable of modulating the activity of GPR52. The present disclosure further provides a process for the preparation of compounds and methods of using compounds in the management of diseases or disorders associated with the activity of GPR52 including, but not limited to, the treatment of various neurological conditions.

Description

Compounds and compositions as GPR52 modulators

The present invention relates to compounds of formula (I) that are capable of modulating GPR52 activity. The present invention further provides a method for preparing compounds of formula (I) and pharmaceutical formulations containing such compounds. The present invention further provides methods of using compounds of formula (I) and compositions to treat diseases or conditions associated with GPR52 activity, including but not limited to treating various neurological conditions.

GPR52 is an orphan GPCR that is highly conserved in vertebrates. The highest expression levels within the central nervous system (CNS) are found in the striatum. Lower significant levels are found in other structures of the CNS, including the cortex. Although GPR52 has been characterized, it remains an orphan receptor with no known endogenous ligands. Several alternative ligands have been reported, including extracellular loop 2 (ECL2) of GPR52 itself.

GPR52 is usually co-localized with dopamine receptors D1 and D2. GPR52 is almost exclusively co-localized with D2 receptors in the human striatum and D1 receptors in the cortex. The efficacy of existing antipsychotic drugs is mediated by D2 antagonist activity, but this activity is accompanied by side effects such as motor symptoms and hyperlactoprotinemia. In contrast, GPR52 modulators can essentially act as D2 antagonists, and thus exhibit antipsychotic efficacy while avoiding the side effects associated with D2 antagonists. Thus, GPR52 modulators can improve the symptoms of various neurological conditions, diseases, and disorders. Therefore, GPR52 represents an attractive target for the development of novel therapies for the treatment of various neurological and neuropsychiatric diseases and disorders. GPR52 agonists are particularly relevant to the treatment of schizophrenia, where they may improve cognition and negative symptoms indirectly by enhancing D1 signaling, but reduce positive symptoms by inhibiting D2-mediated signaling in the striatum.

Despite the progress that has been made in this area, there remains an unmet medical need for improved GPR52 modulators. As will be apparent from the following disclosure, compounds, compositions, and methods related thereto meet these and other needs.

Some aspects provide a compound that modulates GPR52 activity. Some aspects provide an agonist of GPR52 activity. Some aspects provide a compound having formula (I): (I) wherein: R ₁ is selected from hydrogen, piperidinyl, 2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C _{1 - 2} alkyl, azetidinyl, azetidinyl-C _{1 - 2} alkyl, 2-oxaspiro[3.3]hept-6-yl, cyclobutyl, cyclopropyl, (C _{1 - 2} alkyl) _{0 - 2} NC _{1 - 4} alkyl, (C _{1 -} 2 alkyl) _{0 - 2} NC(O)-C _{1 - 4} alkyl, (C _{1 - 2} alkyl) _{0 - 1} OC _{1 - 4} alkyl, 2-azaspiro[3.3]hept-6-yl, C _{1 - 2} alkyl substituted with hydroxyl wherein _the piperidinyl, (2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C _{1 - 2} alkyl, azetidinyl, azetidinyl-C _{1 - 2} alkyl, 2-azaspiro[3.3]hept-6-yl, (2-oxaspiro[3.3]hept-6-yl, cyclobutyl and cyclopropyl may be unsubstituted or substituted with 1 to 2 R groups independently selected from the following: C _{1 - 4} alkyl _, C _{3 - 5} cycloalkyl, hydroxyl, C _{1 - 2} alkyl substituted _by hydroxyl, amino, dimethyl-amino and halogen; R _R2 is _selected from _C1-3 alkyl, halogen _, cyclopropyl, _{methyl-amino and C1-2 alkyl substituted by halogen} ; _R3 is selected from hydrogen and halogen; _R4 is selected from hydrogen, _C1-3 alkyl, _C3-5 cycloalkyl, _{C3-5 heterocycloalkyl} , cyano _, -S(O _{) 0-2C1-2alkyl , halogen ,} -C _{( O} ) _{C1-2alkyl , -S} (O) _{0-2C1-2alkyl , -OC1-2alkyl , C3-5 cycloalkyl} substituted _by halogen _{, C1-3 alkyl substituted by halogen and C1-2alkoxy substituted by halogen ; wherein the C3-5 cycloalkyl and C3-} wherein the _{heterocycloalkyl} group is unsubstituted or substituted with a halogen group; R ₇ is selected from hydrogen, -OC _{1 - 2} alkyl and amine; X ₁ is selected from N and CR ₆ ; wherein R ₆ is selected from hydrogen, a halogen group, -OC _{1 - 2} alkyl and a cyano group; X ₂ is selected from N and CR ₈ ; wherein R ₈ is selected from hydrogen, -OC _{1 - 2} alkyl and a halogen group; X ₃ is selected from N and CR ₅ ; wherein R ₅ is selected from hydrogen, a halogen group, a cyano group, a C _{1 - 2} alkyl group, -OC _{1 - 2} alkyl group, -S(O) _{0 - 2} C _{1 - 2} alkyl group, -N(C _{1 - 2} alkyl) ₂ , a C _{1 - 2} alkyl group substituted with a halogen group, a C _{1 - 2} alkoxy group substituted with a halogen group and -S(O) _{0 - 2} C _{1-2 alkyl} ; or a pharmaceutically acceptable salt _thereof .

In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound from the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound of formula (IA) or formula (IB) or a pharmaceutically acceptable salt of any of the foregoing.

Some aspects provide a pharmaceutical product selected from: a pharmaceutical composition, a formulation, a unit dosage form, and a kit; each of which comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some aspects provide a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

Some aspects provide a method of modulating GPR52 activity comprising contacting the receptor with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some aspects provide a method for treating a disease or condition associated with abnormal expression and/or activity of GPR52 in a patient, comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

Some embodiments provide a method for treating a neurological disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the neurological disorder is selected from the group consisting of: schizophrenia; cognitive impairment; panic disorder; phobia; drug-induced psychosis; delusional psychosis; neuroleptic-induced dyskinesia; Parkinson's disease; drug-induced Parkinson's syndrome; extrapyramidal syndrome; Alzheimer's disease; Lewy body dementia; bipolar disorder; attention deficit/hyperactivity disorder (ADHD); Tourette's syndrome (Tourette's syndrome); extrapyramidal or movement disorders; movement disorders; hyperkinetic movement disorders; psychiatric disorders; catatonic disorders; mood disorders; depression; anxiety disorders; obsessive-compulsive disorder (OCD); autism spectrum disorders; lactoprogesterone-related disorders (e.g., hyperlactoprogesteroneemia); neurocognitive disorders; trauma or stress-related disorders (e.g., PTSD); disruptive impulse Motor control or disruptive behavior disorders; sleep-wake disorders; substance-related disorders; addiction disorders; behavioral disorders; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; reduced striatal activity; cortical dysfunction; neurocognitive dysfunction; cognitive deficits associated with schizophrenia; drug-induced Parkinsonism (DIP); dyskinesia; hypotonia; chorea; levodopa-induced dyskinesia; cerebral palsy and progressive supranuclear palsy; and hangover. Huntington's disease, including chorea related to Huntington's disease.

Some embodiments provide a method for improving one or more symptoms of a neurological disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the neurological disorder is selected from the group consisting of: schizophrenia; cognitive impairment; panic disorder; phobia; drug-induced psychosis; delusional psychosis; neuroleptic-induced Dyskinesia; Parkinson's disease; Drug-induced Parkinson's syndrome; Extrapyramidal syndrome; Alzheimer's disease; Lewy body dementia; Bipolar disorder; Attention deficit/hyperactivity disorder (ADHD); Tourette syndrome; Extrapyramidal or movement disorder; Movement disorders; Hyperkinetic movement disorder; Psychiatric disorders; Stress disorders; Mood disorders; Depression; Anxiety disorders; Obsessive-compulsive disorder (OCD) D); autism spectrum disorder; lactotropin-related disorder (e.g., hyperlactogeninemia); neurocognitive disorder; trauma or stress-related disorder (e.g., PTSD); disruptive impulse control or disruptive behavior disorder; sleep-wake disorder; substance-related disorder; addiction disorder; behavioral disorder; frontal lobe dysfunction; tuberoinfundibulum, mesolimbic, mesocortical, or nigrostriatal pathways Diametric abnormalities; reduced striatal activity; cortical dysfunction; neurocognitive dysfunction; cognitive deficits associated with schizophrenia; drug-induced Parkinson's disease (DIP); dyskinesia; hypotonia; chorea; levodopa-induced dyskinesia; cerebral palsy and progressive supranuclear palsy; and Huntington's disease, including chorea associated with Huntington's disease.

Some embodiments provide a method for preparing a medicament for improving one or more symptoms of a neurological disorder, comprising administering to a subject in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the neurological disorder is selected from the group consisting of: schizophrenia; cognitive impairment; panic disorder; phobia; drug-induced psychosis; delusional psychosis; psychosis Tranquilizer-induced dyskinesia; Parkinson's disease; Drug-induced Parkinson's syndrome; Extrapyramidal syndrome; Alzheimer's disease; Dementia with Lewy bodies; Manic-depressive disorder; Attention-deficit/hyperactivity disorder (ADHD); Tourette syndrome; Extrapyramidal or movement disorder; Movement disorders; Hyperkinetic movement disorder; Psychiatric disorders; Stress disorders; Mood disorders; Depression; Anxiety disorders; Obsessive-compulsive disorders OCD; autism spectrum disorder; lactoprogesterone-related disorder (e.g., hyperlactoprogesterone); neurocognitive disorder; trauma or stress-related disorder (e.g., PTSD); disruptive impulse control or disruptive behavior disorder; sleep-wake disorder; substance-related disorder; addiction disorder; behavioral disorder; frontal lobe dysfunction; tuberoinfundibulum, mesolimbic, midcortical, or substantia nigra striatum Abnormalities in somatic pathways; reduced striatal activity; cortical dysfunction; neurocognitive dysfunction; cognitive deficits associated with schizophrenia; drug-induced Parkinson's disease (DIP); dyskinesia; hypotonia; chorea; levodopa-induced dyskinesia; cerebral palsy and progressive supranuclear palsy; and Huntington's disease, including chorea associated with Huntington's disease.

Cross-reference to related applications This application claims priority to U.S. Provisional Patent Application No. 63/419,399 filed on October 26, 2022 and U.S. Provisional Patent Application No. 63/472,218 filed on June 09, 2023. The entire disclosures of these applications are incorporated herein by reference in their entirety and for all purposes.

DEFINITIONS For clarity and consistency, the following definitions will be used throughout this patent document.

As used herein, "about" means ±20% of the stated value, and more specifically includes values of ±10%, ±5%, ±2%, and ±1% of the stated value.

As used herein, "administering" means providing a compound or other therapy described herein to a subject in a form that can be introduced into the body of the subject in a therapeutically useful form and amount, including but not limited to: oral dosage forms such as tablets, capsules, syrups, suspensions and the like; injectable dosage forms such as IV, IM, IP and the like; transdermal dosage forms including creams, gels, powders and patches; buccal dosage forms; inhalation powders, sprays, suspensions and the like; and rectal suppositories.

A health care physician may provide a compound described herein in the form of a sample directly to an individual or may provide the compound to an individual indirectly by providing an oral or written prescription for the compound. In addition, for example, an individual may obtain the compound on their own without the involvement of a health care physician. When a compound is administered to an individual, the body is transformed to some extent by the compound. When a compound described herein is provided in combination with one or more other agents, "administration" should be understood to include the compound and at least one of the other agents being administered at the same time or at different times. When the combined agents are administered simultaneously, they may be administered together in a single composition, or they may be administered separately. The preferred method of administration may vary depending on various factors, such as the components of the pharmaceutical formulation, the site of the disease, and the severity of the disease.

In the context of treatment, the term "ameliorate" means, but is not limited to, improving disease symptoms, assisting or ameliorating symptoms, or making symptoms more tolerable or acceptable.

The term "composition" refers to a compound or a crystalline form thereof, including but not limited to salts, solvates and hydrates of the compounds described herein, in combination with at least one additional component, such as a composition obtained/prepared during synthesis, preformulation, in-process testing (e.g., TLC, HPLC, NMR samples), and the like.

As used herein, the term "compound" is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structure. The term also means compounds described herein prepared in any manner, such as synthetically, by biological processes (such as metabolism or enzymatic conversion), or a combination thereof. All compounds and their pharmaceutically acceptable salts may exist together with other substances such as water and solvents (such as hydrates and solvates) or may be separated. When in a solid state, the compounds described herein and their salts may exist in various forms and may, for example, be in the form of solvates (including hydrates). The compound may be in any solid state form, such as a polymorph or solvate, so unless otherwise expressly indicated, reference to the compound and its salt in this specification should be understood to cover any solid state form of the compound. In some aspects, the compounds described herein or their salts are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial isolation can include, for example, a composition enriched with the compounds described herein. Substantial isolation can include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein or its salt.

As used herein, the term "hydrate" refers to a compound described herein or a salt thereof that further includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

The term "in need of treatment" and the term "in need of" when referring to treatment are used interchangeably to mean a judgment made by a caregiver (e.g., a physician, nurse, nurse practitioner, etc. in the case of humans; a veterinarian in the case of animals, including non-human mammals) that an individual or animal is in need of treatment or will benefit from treatment. This judgment is based on a variety of factors that are within the caregiver's area of expertise, in addition to the knowledge that the individual or animal is or will become ill due to a disease, condition, or disorder that can be treated by the compounds described herein. Thus, the compounds described herein can be used in a protective or preventative manner; or the compounds described herein can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

The term "subject" refers to any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In the context of clinical trials or screening or activity trials, a subject may be a healthy volunteer or healthy participant who does not have a potential GPR52-mediated disease or condition, or a volunteer or participant who has received a diagnosis of a disease or condition determined by a healthcare professional to require medical treatment. Outside of clinical trials, a subject who has received a diagnosis of a disease or condition under the care of a healthcare professional is generally described as a subject.

The term "pediatric individual" refers to an individual who is younger than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups including: neonates (from birth to the first month of life); infants (1 month to 2 years); children (2 years to 12 years); and adolescents (12 years to 21 years (up to but not including the 22nd birthday)), see, e.g., Berhman et al., Textbook of Pediatrics , 15th ed. Philadelphia: WB Saunders Company, 1996; Rudolph et al., Rudolph 's Pediatrics , 21st ed. New York: McGraw-Hill, 2002; and Avery et al., Pediatric Medicine , 2nd ed. Baltimore: Williams &Wilkins; 1994.

The phrase "pharmaceutically acceptable" refers to compounds (and their salts), compositions and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction or other problems or complications commensurate with a reasonable benefit/risk ratio.

The term "pharmaceutical composition" refers to a specific composition comprising at least one active ingredient; the active ingredient includes but is not limited to salts, solvates and hydrates of the compounds described herein, whereby the composition can be investigated for a specified effective result in a mammal (such as but not limited to humans). A person skilled in the art will generally understand and appreciate the techniques suitable for determining whether an active ingredient has a desired effective result based on the needs of the artisan.

The terms "prevent," "preventing," and "prevention" refer to eliminating or reducing the occurrence or onset of one or more symptoms associated with a particular disease. For example, the terms "prevent," "preventing," and "prevention" may refer to administering a therapy on a prophylactic or preventive basis to an individual who may eventually manifest at least one symptom of a disease, but has not yet done so. Such individuals may be identified based on risk factors known to be associated with subsequent development of the disease, such as the presence of biomarkers. Alternatively, a preventive therapy may be administered as a preventive measure without previously identifying a risk factor. Delaying the onset of at least one episode and/or symptom of a disease may also be considered prevention or treatment.

As used herein, the term "solvolyte" refers to a solid form of a compound described herein or a pharmaceutically acceptable salt thereof that includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

The terms "treat," "treating," and "treatment" refer to the medical management of a disorder, disease, or condition in an individual (e.g., a subject) (see, e.g., Stedman's Medical Dictionary). In general, appropriate dosages and treatment regimens provide an amount of the GPR52 agonist sufficient to provide a therapeutic benefit. Therapeutic benefits to an individual administered a GPR52 agonist compound described herein include, for example, improved clinical outcomes, where the goal is to prevent or slow down or delay (reduce) undesirable physiological changes associated with a disease or to prevent or slow down or delay (reduce) the extension or severity of such a disease. The effects of one or more GPR52 agonists may include beneficial or desired clinical results, including but not limited to eliminating, alleviating or relieving symptoms caused by or associated with the disease to be treated; reducing the incidence of symptoms; improving quality of life; prolonging the disease-free state (i.e., reducing the likelihood or tendency that an individual will present with symptoms based on a disease diagnosis made); reducing the extent of the disease; stabilizing the disease state (i.e., not worsening); delaying or slowing the progression of the disease; improving or relieving the disease; and remission (whether partial or complete), whether detectable or undetectable; and/or overall survival.

The term "therapeutically effective amount" means an amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, that induces a biological or drug response in a tissue, system, animal or human being that is being sought by an individual, researcher, veterinarian, medical practitioner or other clinician or caregiver, which response may include one or more of the following: (1) prevention of a disorder, such as prevention of a disease, condition or disorder in an individual who may be susceptible to the disease, condition or disorder but has not yet experienced or exhibited the associated pathology or symptoms; (2) inhibition of a disorder, such as inhibition of a disease, condition or disorder in an individual who is experiencing or exhibiting the associated pathology or symptoms (i.e., arresting the further development of the pathology and/or symptoms); and (3) Amelioration of symptoms, such as ameliorating a disease, condition or disorder in a subject who is experiencing or exhibiting the relevant pathology or symptoms (i.e., reversing the pathology and/or symptoms).

As used herein, the term "contacting" refers to bringing the indicated moiety into an in vitro system or an in vivo system. For example, "contacting" GPR52 with a compound provided herein includes administering a compound provided herein (or a pharmaceutically acceptable salt thereof) having a GPR52 protein to an individual (such as a human), and, for example, introducing a compound provided herein into a sample containing cells or purified preparations containing a GPR52 protein.

Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention pertains. All patents, applications, published applications, and other publications are incorporated by reference in their entirety. If there are multiple definitions for a term in this document, the definition in this section shall prevail unless otherwise stated.

The term "n-membered" where n is an integer generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocyclic ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl.

For compounds of formula (I) and their pharmaceutically acceptable salts, where a variable appears more than once, each variable may be a different moiety independently selected from the group defining the variable. For example, when describing a structure with two R groups present simultaneously on the same compound, the two R groups may represent different moieties independently selected from the group defining R.

Whenever a group is described as "optionally substituted," that group may be unsubstituted or may be substituted with one or more of the indicated substituents. Likewise, when a group is described as "unsubstituted or substituted," if substituted, the substituent may be selected from one or more of the indicated substituents. It should be understood that substitution at a given atom is limited by valence.

As used herein, " _Ca - _Cb " (wherein "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, or aryl group. That is, these groups can contain from "a" to "b" carbon atoms (inclusive). Thus, for example, " _{C1 - C4} alkyl" (or _C1-4 alkyl) refers to all alkyl groups having ₁ to 4 carbons, _i.e. , _CH3- , _{CH3CH2- , CH3CH2CH2- , ( CH3 ) 2CH- , CH3CH2CH2CH2- ,} CH3CH2CH( _CH3 )-, and ( _CH3 ) _{3C- .} If "a" and "b" are not specified with respect to alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or aryl, the broadest range described in these definitions is adopted.

In addition to the foregoing, unless otherwise specified, the following terms used in this specification and the accompanying patent claims have the indicated meanings:

The term "amino" refers to the group -NH ₂ .

The term "alkylamino" refers to a radical of the formula -NH(alkyl), wherein alkyl is as defined herein. Example alkylaminos include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

The term "dialkylamino" refers to a radical of the formula -N(alkyl) ₂ , wherein alkyl is as defined herein. Example dialkylaminos include dimethylamino, diethylamino, di-n-propylamino, di-isopropylamino) and the like.

The term "alkenyl" refers to an alkyl group containing one or more double bonds in a straight or branched hydrocarbon chain. Examples of alkenyl groups include propadienyl, vinylmethyl, and vinyl. In some aspects, an alkenyl group may be unsubstituted or substituted. In some aspects, an alkenyl group may have 2 to 6 carbon atoms. The alkenyl group of a compound may be designated as " _C2 - _C6 alkenyl" or similar designations.

The term "alkynyl" refers to an alkyl group containing one or more radicals in a straight or branched hydrocarbon chain. Examples of alkynyl groups include ethynyl and propynyl. Alkynyl groups may be unsubstituted or substituted. In some aspects, alkynyl groups may be unsubstituted or substituted. In some aspects, alkynyl groups may have 2 to 6 carbon atoms. The alkenyl group of a compound may be designated as "C ₂ -C ₆ alkynyl" or similar designations.

The term "aryl" refers to an aromatic ring system containing 6, 10 or 14 carbon atoms, which may contain a single ring, two fused rings or three fused rings, such as phenyl, naphthyl and phenanthrenyl. In some aspects, an aryl group may have 6 or 10 carbon atoms (i.e., _C6 or _C10 aryl). When one or more substituents are present on an "aryl" ring, the substituents may be bonded to any available ring carbon. In some aspects, an aryl group may be substituted or unsubstituted.

The term "alkyl" refers to a fully saturated straight or branched chain alkyl group. An alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. In some embodiments, an alkyl group may have 1 to 6 carbons (i.e., C ₁ -C 6 alkyl). Some embodiments are 1 to 5 carbons (i.e., C 1 -C 5 alkyl), some embodiments are 1 to 4 carbons (i.e., C _{1 -C 4 alkyl), some embodiments are 1 to 3 carbons (i.e., C 1} -C 3 alkyl), and some embodiments are 1 or 2 carbons. By way of example only, "C 1 -C ₆ alkyl" may be 1 to 5 carbons (i.e., C 1 -C ₅ alkyl), some embodiments are 1 to 4 carbons (i.e., C ₁ -C ₄ alkyl), some embodiments are 1 to 3 carbons (i.e., C ₁ -C ₃ alkyl), and some embodiments are 1 or 2 carbons. By way of example only, "C ₁ -C " _4- alkyl" indicates that there are one to four carbon atoms in the alkyl chain, that is, the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, dibutyl and tertiary butyl. Examples of alkyl include: methyl, ethyl, n-propyl, isopropyl, n-butyl, dibutyl, isobutyl, tertiary butyl, pentyl, isopentyl, tertiary pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH ₃ )CH ₂ CH ₂ CH ₃ ], 2-methylbutyl [i.e., -CH ₂ CH(CH ₃ )CH ₂ CH ₃ ], n-hexyl and the like. When one or more substituents are present on the alkyl group, the substituents may be bonded at any available carbon atom. In some aspects, the alkyl group may be substituted or unsubstituted.

As defined herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms of the alkyl group have been replaced with a halogen atom (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). In some aspects, the haloalkyl group may have 1 to 6 carbons (i.e., "haloC ₁ -C ₆ alkyl" or "halo-substituted C _{1 -4} alkyl"). The haloC ₁ -C ₆ alkyl group may be fully substituted, in which case it may be represented by the formula C _n L _{2n + 1} , wherein L is a halogen and "n" is 1, 2, 3 _, 4, 5, or 6. When more than one halogen is present, they may be the same or different and are selected from: fluorine, chlorine, bromine, and iodine. In some aspects, the haloalkyl group contains 1 to 5 carbons (i.e., halogenC ₁ -C ₅ alkyl). In some aspects, the haloalkyl group contains 1 to 4 carbons (i.e., halogenated _C1 - _C4 alkyl). In some aspects, the haloalkyl group contains 1 to 3 carbons (i.e., halogenated _C1 - _C3 alkyl). In some aspects, the haloalkyl group contains 1 or 2 carbons. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, and the like.

The term "carbonyl" refers to the group -C(=O)-.

The term "oxo" refers to a =0 substituent.

The term "cycloalkyl" refers to a fully saturated all carbon monocyclic or polycyclic system. In some aspects, a cycloalkyl is a monocyclic ring containing 3 to 7 carbon atoms (i.e., " _C3 - _C7 cycloalkyl"). Some aspects contain 3 to 6 carbons. Some aspects contain 3 to 5 carbons. Some aspects contain 5 to 7 carbons. Some aspects contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When one or more substituents are present on an alkyl group, the substituents may be bonded at any available carbon atom. In some aspects, a cycloalkyl group may be substituted or unsubstituted.

The term "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; but if there is more than one, the double bonds cannot extend through all rings to form a completely delocalized π-electron system (i.e., an aromatic system), otherwise the group will be an "aryl" as defined herein. When composed of two or more rings, the rings may be fused, bridged, or spiro-linked together. A cycloalkenyl group may contain 3 to 12 atoms in the ring or 3 to 8 atoms in the ring. In some embodiments, a cycloalkenyl group may be unsubstituted or substituted. In some embodiments, a cycloalkenyl group may have 4 to 8 carbon atoms (i.e., a "C ₄ -C ₈ cycloalkenyl group"). An example is cyclohexenyl.

The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system and has at least one heteroatom in the ring system, i.e., an element other than carbon, including but not limited to nitrogen, oxygen and sulfur. Some aspects are "5-6 membered heteroaryl" and refer to aromatic rings containing 5 to 6 ring atoms in a single ring and having at least one heteroatom in the ring system. Examples of heteroaryl rings include, but are not limited to, pyridyl, pyrimidinyl, pyrifoinyl, pyrimidinyl, trifoinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuranyl, benzothiophenyl, benzothiazolyl, isozyole, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, dibenzo[b,d]furan, dibenzo[b,d]thiophene, phenanthidinyl, benzimidazolyl, pyrrolyl, quinolyl, isoquinolyl, benzoisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. Heteroaryl groups may be substituted or unsubstituted. In some embodiments, heteroaryl groups have 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may be designated as "5- to 7-membered heteroaryl groups", "5- to 10-membered heteroaryl groups" or similar designations. In some embodiments, heteroaryl groups may be substituted or unsubstituted C ₁ -C ₁₃ 5-, 6-, 7-, 8-, 9-, 10-, up to 14-membered monocyclic, bicyclic or tricyclic ring systems, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, heteroaryl groups may be substituted or unsubstituted C ₁ -C ₅ 5- or 6-membered monocyclic rings, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group is a substituted or unsubstituted C ₅ -C ₉ eight-membered, nine-membered or ten-membered bicyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group is a substituted or unsubstituted C ₅ -C ₉ eight-membered, nine-membered or ten-membered heteroaryl group. In some embodiments, the _C5 - _C9 eight-membered, nine-membered or ten-membered bicyclic heteroaryl is imidazo[2,1-b]thiazolyl, 1H - indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzisoxazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, quinoxalinyl, pyrido[3,4- b ]pyrrolyl or pyrido[4,3- d ]pyrimidinyl. In some embodiments, the heteroaryl is a substituted or unsubstituted _C8 -C13 ₁₃ -membered or 14-membered tricyclic system including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroaryl group may be an oxazolyl group, such as an imidazolyl group, a pyrazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a 1,2,4-thiadiazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group, or an isoxazolyl group, each of which may be substituted or unsubstituted. In some embodiments, the heteroaryl group is a C ₁ -C ₁₃ 5-membered heteroaryl group. In some embodiments, the C ₁ -C ₄ 5-membered heteroaryl group is a furanyl group, a thienyl group, a 1,2,4-thiadiazolyl group, a 1,2,3-thiadiazolyl group, an isothiazolyl group, a thiazolyl group, an imidazolyl group, a pyrazolyl group, an isoxazolyl group, an oxazolyl group, a pyrrolyl group, a triazolyl group, or a tetrazolyl group. In some embodiments, the heteroaryl group is a C ₃ -C ₅ 6-membered heteroaryl group. In some embodiments, the C ₃ -C ₅ 6-membered heteroaryl group is a pyridyl group, a pyrimidyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a pyrimidinyl group, a tririmidinyl group, a benzofuranyl group, a 1H -indolyl group, a benzo[b]thienyl group, and the like. In some embodiments, "5- to 10-membered heteroaryl" refers to: pyrrolyl, pyrimidinyl, pyridinyl, pyrimidinyl, 1H -indolyl, quinolinyl, thiadiazolyl and the like. In some embodiments, the heteroaryl may be substituted or unsubstituted.

The position of the nitrogen in the pyridine ring relative to the oxygen linker in Formula I changes Emax, for example: Compound structure active At 10 μM, Emax is 80% Emax ＜25% at 10 μM

Substitution of the pyridine ring and the amide moiety on the benzene ring of the compound of formula I changes Emax, for example: Compound structure active Emax is 132% Emax is 13.6% Emax is 5%

The term "heterocyclic group" or "heterocycloalkyl" refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic systems, wherein carbon atoms together with 1 to 5 heteroatoms constitute the ring system and optionally contain one or more unsaturated bonds positioned in this way, however, a completely delocalized π-electron system (aromatic system) is not present in a monocyclic ring or in at least one ring of a bicyclic or tricyclic system. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur and nitrogen. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro manner, wherein heteroatoms may be present in non-aromatic or aromatic rings in the ring system. In some embodiments, the heterocyclic group may be a 3- to 7-membered saturated and non-aromatic ring system containing 3 to 7 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "3- to 6-membered heterocyclic group" refers to a saturated and non-aromatic ring group containing 3 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, "4- to 6-membered heterocyclic group" refers to a saturated and non-aromatic ring group containing 4 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, one or two heteroatoms in the ring system are independently selected from: O (oxygen) and N (nitrogen). In some embodiments, the heterocyclic group can include a carbonyl group (C=O) adjacent to the heteroatom, which is substituted with a pendoxy group on the carbon adjacent to the heteroatom, wherein the substituted ring system is a lactam, a lactone, a cycloimide, a cyclothioimide, or a cyclocarbamate. Examples of unsubstituted or substituted "heterocyclic groups" include, but are not limited to, aziridinyl, aziridinyl, tetrahydrofuranyl, 1,3-dioxadienyl, 1,3-dioxadienyl, 1,4-dioxadienyl, 1,2-dioxolanyl, 1,3-dioxadienyl, 1,4-dioxadienyl, 1,3-oxathiacyclohexanyl, 1,4-dioxadienyl, a thiathiazyl group, a 1,3-oxathiacyclopentyl group, a 1,3-dithiacyclopentenyl group, a 1,3-dithiacyclopentyl group, a 1,4-oxathiacyclohexyl group, a tetrahydro-1,4-thiathiazyl group, a 2H-1,2-thiazyl group, a succinimidyl group, a dihydroxypiperidinyl group, a ureido group, an imidazolinyl group, an imidazolidinyl group, an isozolinyl group, an isozolidinyl group, isoindolyl, indolyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, oxazolidinyl, oxazolidinyl, oxathiolanyl, piperidinyl N-oxide, piperidinyl, piperidine, pyrrolidinyl, pyrrolidinone, pyrrolidone, 4-piperidone, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, tetrahydrothiopiperidone The heterocyclic group may be designated as "3- to 10-membered heterocyclic group" or a similar designation. In some embodiments, the heterocyclic group can be a C ₂ -C ₁₂ three-membered, four-membered, five-membered, six-membered, seven-membered, eight-membered, nine-membered, ten-membered, up to 13-membered monocyclic, bicyclic or tricyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclic group can be a substituted or unsubstituted C _{2 -C 6} three-membered, four-membered, five-membered, six-membered or seven-membered monocyclic ring, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclic group can be a substituted or unsubstituted C ₂ -C ₁₀ four-membered, five-membered, six-membered, seven-membered, eight-membered, nine-membered, ten-membered or eleven-membered bicyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heterocyclic group may be a substituted or unsubstituted _C7 - _C12 12-membered or 13-membered tricyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the heteroatoms of the six-membered monocyclic heterocyclic group are selected from one to three O (oxygen), N (nitrogen) or S (sulfur), and the heteroatoms of the five-membered monocyclic heterocyclic group are selected from one or two heteroatoms selected from O (oxygen), N (nitrogen) or S (sulfur). In some embodiments, the heterocyclic group can be aziridinyl, aziridinyl, tetrahydrofuranyl, 1,3-dioxadicyclohexenyl, 1,3-dioxadicyclohexanyl, 1,4-dioxadicyclohexanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,3-oxathiacyclohexanyl, 1,4-oxathiacyclohexanyl, 1,3-oxathiacyclohexanyl, pentanyl, 1,3-dithiacyclopentenyl, 1,3-dithiacyclopentanyl, 1,4-oxathiacyclohexanyl, tetrahydro-1,4-thiathiazolyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolyl, indolyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, oxazolinyl, oxazoli ... yl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,4-diazabicyclo[2.2.2]octane, 1,4-diazabicyclo[3.1.1]heptane, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl , 1,2,3,4-tetrahydro-2,6-oxadyl, 1,2,3,4-tetrahydro-2,7-oxadyl, 1,2,3,4-tetrahydro-1,7-oxadyl, 1,2,3,4-tetrahydro-1,6-oxadyl, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[3,4- d ]pyrimidinyl, [1,3]dioxacyclopenta[4,5-c]pyridinyl, [1,3]dioxacyclopenta[4,5-b]pyridinyl, [1,3]dioxacyclopenta[4,5- d ]pyrimidinyl or 3,4-methylenedioxyphenyl. In some embodiments, the unsubstituted or substituted heterocyclic group can be selected from aziridinyl, aziridinyl, piperidinyl, oxadiazolyl, oxadiazolyl, piperidinyl, pyrrolidinyl, thiooxadiazolyl, 2-piperidonyl, 1,1-dioxothiooxadiazolyl, oxadiazolyl (tetrahydrofuranyl) and oxadiazolyl (tetrahydropyranyl). When one or more substituents are present on the heterocyclic group, the substituents may be bonded at any available carbon atom and/or heteroatom. In some embodiments, the heterocyclic group may be substituted or unsubstituted.

The term "alkoxy" refers to the formula -OR, where R is an alkyl group as defined herein. A non-limiting list of alkoxy groups is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, di-butoxy, and tert-butoxy. The alkoxy group of a compound may be designated as "C ₁ -C ₆ alkoxy" or similar designations. In some aspects, the alkoxy group may be substituted or unsubstituted.

The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some aspects, the haloalkoxy group may have 1 to 6 carbon atoms. The halogen alkoxy group of a compound may be designated as "halogen C ₁ -C ₆ alkoxy" or similar designations.

The term "cyano" refers to the group -CN.

The term "halogen" or "halogen group" refers to fluorine, chlorine, bromine or iodine. In some aspects, the halogen or halogen group is fluorine, chlorine or bromine. In some aspects, the halogen or halogen group is fluorine or chlorine. In some aspects, the halogen or halogen group is fluorine.

“C-amido” refers to “—C( ^═O )N( ^RARB )” which is attached to the rest of the molecule via a carbon atom, and wherein ^RA and ^RB may independently be hydrogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C3 - _C7 cycloalkyl, _C5 - _C8 cycloalkenyl, _C6 or _C10 aryl, heteroaryl or heterocyclic.

“N-amido” refers to “RC(═O)N( ^RA )-” which is linked to the rest of the molecule via a nitrogen atom, and wherein R and ^RA may independently be hydrogen, _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C2 - _C6 alkynyl, _C3 - _C7 cycloalkyl, _C5 - _C8 cycloalkenyl, _C6 or _C10 aryl, heteroaryl or heterocyclic.

The term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxyl group. In some aspects, the hydroxyalkyl group can have 1 to 6 carbon atoms (i.e., " _hydroxyC1 - _C6 alkyl"). Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl.

The term "hydroxy" refers to an -OH group.

The term "nitro" refers to the _-NO2 group.

As used herein, "excipient" refers to a substance added to a composition to provide, without limitation, bulk, consistency, stability, binding ability, lubricity, disintegration ability, etc. to the composition. "Diluent" is a type of excipient and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be medically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug that is too small in mass to manufacture and/or administer. It may also be a liquid used to dissolve a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable nontoxic and inactive material or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients : A Comprehensive Guide to Uses , Properties , and Safety , 5th edition, 2006 and Remington : The Science and Practice of Pharmacy (Gennaro, 21st edition Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and antioxidants, buffers, antibacterial agents and other common additives may be included as appropriate. In some aspects, the diluent may be a buffered aqueous solution, such as, but not limited to, phosphate buffered saline. The composition may also be formulated as a capsule, granule, or tablet, which contains, in addition to the compounds disclosed and described herein, a diluent, a dispersant, and a surfactant, a binder, and a lubricant. Those skilled in the art may further formulate the compounds disclosed and described herein in an appropriate manner and according to recognized practices, such as those disclosed in Remington above.

As used herein, "dose" or "dosage" refers to the amount of a drug substance taken by a subject at one time. In certain aspects where the drug substance is not a free base or free acid, the amount is the molar concentration equivalent to the corresponding amount of the free base or free acid.

As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound having an acidic or basic moiety that is suitable for use in medicine, biologically or otherwise. In many cases, the compounds disclosed herein are capable of forming acid salts and/or base salts by virtue of the presence of an acidic or basic moiety (e.g., an amine group and/or a carboxyl group or a group similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining a compound having a basic moiety with an inorganic acid and an organic acid. Inorganic acids useful for preparing salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids useful for preparing salts include, for example, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and the like. Pharmaceutically acceptable base addition salts can be formed by combining a compound having an acidic moiety with an inorganic base and an organic base. Inorganic bases that can be used to prepare the salts include, for example, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, calcium hydroxide, magnesium hydroxide, iron hydroxide, zinc hydroxide, manganese hydroxide, aluminum hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, ammonium carbonate, calcium carbonate, magnesium carbonate, iron carbonate, zinc carbonate, manganese carbonate, , aluminum carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate, iron bicarbonate, zinc bicarbonate, manganese bicarbonate, aluminum bicarbonate, sodium phosphate, potassium phosphate, lithium phosphate, ammonium phosphate, calcium phosphate, magnesium phosphate, iron phosphate, zinc phosphate, manganese phosphate, aluminum phosphate, and the like. In some aspects, the inorganic base salt is ammonium hydroxide, potassium hydroxide, sodium hydroxide, calcium hydroxide and magnesium hydroxide, ammonium carbonate, potassium carbonate, sodium carbonate, calcium carbonate and magnesium carbonate, ammonium bicarbonate, potassium bicarbonate, sodium bicarbonate, calcium bicarbonate and magnesium bicarbonate, or ammonium phosphate, potassium phosphate, sodium phosphate, calcium phosphate and magnesium phosphate. Organic bases that can be used to prepare salts include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins and the like, in particular, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine and ethanolamine. Generally, such salts can be prepared by reacting the free acid or base form of these compounds with at least a stoichiometric amount of the appropriate base or acid in water or in an organic solvent or in a mixture of the two; generally, in a non-aqueous medium such as ether, ethyl acetate, an alcohol (e.g., methanol, ethanol, isopropanol or butanol) or acetonitrile (ACN ) . Lists of suitable salts are found in WO 87/05297; Johnston et al., published September 11, 1987; Remington's Pharmaceutical Sciences, 17th edition, Mack Publishing Company, Easton, Pa., 1985, page 1418; and J. Pharm . Sci . , 66, 2 (1977); each of which is incorporated herein by reference in its entirety. The reference for the preparation and selection of the pharmaceutical salts of the present invention is PH Stahl & CG Wermuth, Handbook of Pharmaceutical Salts , Verlag Helvetica Chimica Acta, Zurich, 2002, which is incorporated herein by reference in its entirety.

The compounds described herein may be asymmetric (e.g., have one or more stereocenters). Unless otherwise indicated, all stereoisomers, both mirror image and non-mirror image, are intended to be encompassed. It should be understood that in any compound described herein having one or more chiral centers, if the absolute stereochemistry is not explicitly indicated, each center may independently be in the (R)-configuration or the (S)-configuration or a mixture thereof. Thus, the compounds provided herein may be mirror image pure, mirror image enriched, a racemic mixture, non-mirror image pure, non-mirror image enriched, or a stereoisomeric mixture. The preparation of imagerically pure or imagerically enriched forms can be achieved by resolution of racemic mixtures or by using imagerically pure or enriched starting materials or by stereoselective or stereospecific synthesis. Stereochemical definitions can be found in EL Eliel, SH Wilen & LN Mander, Stereochemistry of Organic Compounds , John Wiley & Sons, Inc., New York, NY, 1994, which is incorporated herein by reference in its entirety. In some aspects, when a compound described herein is chiral or otherwise includes one or more stereocenters, the compound can be prepared with greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, or greater than about 99% excess of the mirror image isomer or non-mirror image isomer.

Resolution of a racemic mixture of compounds can be performed by any of a number of methods known in the art. An example method includes fractional recrystallization of the racemic compound using a chiral resolving organic acid and a base-containing racemic compound. Resolving agents suitable for fractional recrystallization methods are, for example, optically active acids such as tartaric acid in its D and L forms, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids. Other chiral resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of toluidine (e.g., S and R forms, or non-image-wise isomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Similarly, fractional recrystallization using chiral resolving bases can be used with racemic compounds containing alkaline groups.

Resolution of the racemic mixture can also be carried out by elution on a column packed with an optically active analytical reagent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent compositions can be determined by one skilled in the art.

In some aspects, the compounds described herein can be prepared with at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 99%, or at least about 99.9% mirror image isomer excess, or a mirror image isomer excess within a range defined by any of the foregoing numbers.

Additionally, it is understood that when the compounds described herein contain one or more double bonds (e.g., C=C, C=N, and the like) or other centers of geometric asymmetry, and unless otherwise specified, it is understood that the compounds include both E and Z geometric isomers (e.g., cis or trans). The cis and trans geometric isomers of the compounds described herein can be isolated as a mixture of isomers or in separated isomeric forms.

The compounds described herein also include tautomeric forms. Tautomeric forms result from the exchange of a single bond for an adjacent double bond and concomitant proton migration. Tautomeric forms include proton-shift tautomers in isomeric protonation states having the same empirical formula and total charge. Example proton-shift tautomers include keto-enol pairs, amide-imidic acid pairs, lactamide-lactimide pairs, enamine-imine pairs, and cyclic forms in which protons can occupy two or more positions of a heterocyclic system, such as 1H -imidazole and 3H -imidazole, 1H -1,2,4-triazole, 2H -1,2,4-triazole and 4H -1,2,4-triazole, 1H -isoindole and 2H -isoindole, and 1H -pyrazole and 2H -pyrazole. Tautomeric forms can be in equilibrium or stereotactically locked into one form by appropriate substitution.

The compounds described herein and their pharmaceutically acceptable salts may exist in the form of, for example, hydrates or solvates together with other substances, such as water and solvents. When in a solid state, the compounds described herein and their salts may exist in various forms and may, for example, take the form of solvates (including hydrates). The compound may be in any solid form, such as a crystalline form, an amorphous form, a solvated form, etc., and unless otherwise expressly indicated, the reference to the compound and its salt in this specification should be understood as indicating any solid form of the compound.

The compounds described herein can be used in neutral form, such as free acid or free base form. Alternatively, the compounds can be used in the form of a pharmaceutically acceptable salt, such as a pharmaceutically acceptable acid addition salt or base addition salt.

In some aspects, the compounds described herein or their salts are substantially isolated. The phrase "substantially isolated" refers to a compound that is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched with the compounds described herein. Substantial separation can include a composition containing at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of a compound described herein or their salts.

Unless the context clearly dictates otherwise, the compounds disclosed and described herein allow for atoms at each position of the compound to independently have: 1) an isotopic distribution in the proportions of chemical elements that usually occur in nature, or 2) an isotopic distribution that is different from the proportions that usually occur in nature. The atomic number of a particular chemical element is defined by the number of protons in the nucleus. Each atomic number identifies a particular element rather than an isotope; atoms of a given element can have a wide range of neutron numbers. The number of protons and neutrons in the nucleus is the mass number of the atom, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have an isotopic distribution of a chemical element that is different from the proportions that usually occur in nature are generally referred to as isotopically labeled compounds. Each chemical element represented in a compound structure may include any isotopic distribution of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom may be an isotopic distribution of hydrogen, including but not limited to protium ( ^1H ) and deuterium ( ^2H ) in proportions and amounts different from those normally present in nature. Therefore, unless the context clearly dictates otherwise, references to compounds herein encompass all potential isotopic distributions of each atom. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As will be appreciated by those skilled in the art, any of the compounds disclosed and described herein may include radioactive isotopes. Thus, the compounds disclosed and described herein are also contemplated for use in which one or more atoms have an isotopic distribution different from that normally found in nature, such as having a greater proportion of ² H or ³ H than occurs in nature, or a greater proportion of ¹¹ C, ¹³ C, or ¹⁴ C than occurs in nature. By way of general example and without limitation, isotopes of hydrogen include protium ( ¹ H), deuterium ( ² H), and tritium ( ³ H). Isotopes of carbon include carbon-11 ( ¹¹ C), carbon-12 ( ¹² C), carbon-13 ( ¹³ C), and carbon-14 ( ¹⁴ C). Isotopes of nitrogen include nitrogen-13 ( ¹³ N), nitrogen-14 ( ¹⁴ N), and nitrogen-15 ( ¹⁵ N). Isotopes of oxygen include oxygen-14 ( ^14O ), oxygen-15 ( ^15O ), oxygen-16 ( ^16O ), oxygen-17 ( ^17O ) and oxygen-18 ( ^18O ). Isotopes of fluorine include fluorine-17 ( ^17F ), fluorine-18 ( ^18F ) and fluorine-19 ( ^19F ). Isotopes of phosphorus include phosphorus-31 ( ^31P ), phosphorus-32 ( ^32P ), phosphorus-33 ( ^33P ), phosphorus-34 ( ^34P ), phosphorus-35 ( ^35P ) and phosphorus-36 ( ^36P ). Isotopes of sulfur include sulfur-32 ( ^32S ), sulfur-33 ( ^33S ), sulfur-34 ( ^34S ), sulfur-35 ( ^35S ), sulfur-36 ( ^36S ) and sulfur-38 ( ^38S ). Isotopes of chlorine include chlorine-35 ( ^35Cl ), chlorine-36 ( ^36Cl ) and chlorine-37 ( ^37Cl ). Isotopes of bromine include bromine-75 ( ^75Br ), bromine-76 ( ^76Br ), bromine-77 ( ^77Br ), bromine-79 ( ^79Br ), bromine-81 ( ^81Br ) and bromine-82 ( ^82Br ). Isotopes of iodine include iodine-123 ( ^123I ), iodine-124 ( ^124I ), iodine-125 ( ^125I ), iodine-131 ( ^131I ) and iodine-135 ( ^135I ). In some embodiments, the atoms at each position of the compound have an isotopic distribution in the proportions of the amounts of each chemical element that are normally present in nature. In some aspects, atoms in one position of a compound have an isotopic distribution of a chemical element that is different from the ratios that are usually found in nature (the remaining atoms have the isotopic distribution of the chemical element in the ratios that are usually found in nature). In some aspects, atoms in at least two positions of a compound independently have an isotopic distribution of a chemical element in the ratios that are usually found in nature (the remaining atoms have the isotopic distribution of the chemical element in the ratios that are usually found in nature). In some aspects, atoms in at least three positions of a compound independently have an isotopic distribution of a chemical element in the ratios that are different from the ratios that are usually found in nature (the remaining atoms have the isotopic distribution of the chemical element in the ratios that are usually found in nature). In some embodiments, the atoms in at least four positions of the compound independently have an isotopic distribution of a chemical element that is different from the ratios that are usually found in nature (the remaining atoms have the isotopic distribution of the chemical element in the ratios that are usually found in nature). In some embodiments, the atoms in at least five positions of the compound independently have an isotopic distribution of a chemical element that is different from the ratios that are usually found in nature (the remaining atoms have the isotopic distribution of the chemical element in the ratios that are usually found in nature). In some embodiments, the atoms in at least six positions of the compound independently have an isotopic distribution of a chemical element that is different from the ratios that are usually found in nature (the remaining atoms have the isotopic distribution of the chemical element in the ratios that are usually found in nature).

Certain compounds, for example those incorporating radioactive isotopes such as ³ H and ¹⁴ C, are also useful in drug or substrate tissue distribution analysis. Tritium ( ³ H) and carbon-14 ( ¹⁴ C) isotopes are particularly preferred because of their ease of preparation and detectability. Compounds having isotopes such as deuterium ( ² H) in amounts greater than the proportion normally found in nature may offer certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds can generally be prepared by carrying out procedures conventionally practiced in chemical techniques. Such isotopic perturbations or enrichments can be readily measured using methods such as mass spectrometry, and for isotopes that are radioactive, other methods may be used such as radioactive detectors coupled to HPLC or GC.

As used herein, "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. In some aspects, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including but not limited to protium ( ^1H ), deuterium ( ^2H ), tritium ( ^3H ), carbon-11 ( ^11C ), carbon-12 ( ^12C ), carbon-13 ( ^13C ), carbon-14 ( ^14C ), nitrogen-13 ( ^13N ), nitrogen-14 ( ^14N ), nitrogen-15 ( ^15N ), oxygen-14 ( ^14O ), oxygen-15 ( ^15O ), oxygen-16 ( ^16O ), oxygen-17 ( ^17O ), oxygen-18 ( ^18O ), fluorine-17 ( ^17F ), fluorine-18 ( ^18F ), phosphorus-31 ( ^31P ), phosphorus-32 ( ^32P ), phosphorus-33 ( ^33P ), sulfur-32 ( ^32S ), sulfur-33 ( ^33S ), The invention relates to iodine-131 ( ¹³¹ I), iodine-132 ( ¹³² I), iodine-133 ( ¹³³ I), iodine-134 (135 S), iodine-135 ( ¹³⁶ S), iodine-137 (131 I), iodine-138 ( ¹³⁸ I), iodine-139 ( ¹⁴¹ I), iodine-142 (142 I), iodine-143 (143 I), iodine-144 ( ¹⁴⁴ I), iodine-145 (145 I), iodine-146 ( ¹⁴⁷ I), iodine-147 (147 I), iodine-148 (149 I), iodine-149 ( ¹⁵² I), iodine-150 (153 I), iodine-151 (153 I), iodine-152 ( ¹⁵³ I), iodine-153 (153 I), iodine-154 (154 I), iodine-155 ( ¹⁵⁵ I), iodine-156 (156 I), iodine-157 (157 I), iodine-158 (158 I), iodine-159 ( ¹⁵⁹ I), and iodine-151 ( ¹⁵¹ I). In certain embodiments, an “isotopic variant” of a compound is in a stable form, i.e., non-radioactive. In some aspects, an "isotopic variant" of a compound contains one or more isotopes in unnatural proportions, including but not limited to hydrogen ( ^1H ), deuterium ( ^2H ), carbon-12 ( ^12C ), carbon-13 ( ^13C ), nitrogen-14 ( ^14N ), nitrogen-15 ( ^15N ), oxygen-16 ( ^16O ), oxygen-17 ( ^17O ), and oxygen-18 ( ^18O ). In some aspects, an "isotopic variant" of a compound is in an unstable form, i.e., radioactive. In some aspects, an "isotopic variant" of a compound described herein contains one or more isotopes in unnatural proportions, including but not limited to tritium ( ^3H ), carbon-11 ( ^11C ), carbon-14 ( ^14C ), nitrogen-13 ( ^13N ), oxygen-14 ( ^14O ), and oxygen-15 ( ^15O ). It is understood that in the compounds provided herein, as an example, any hydrogen can include ² H as the predominant isotopic form, or as an example, any carbon can include ¹³ C as the predominant isotopic form, or as an example, any nitrogen can include ¹⁵ N as the predominant isotopic form, and as an example, any oxygen can include ¹⁸ O as the predominant isotopic form. In certain aspects, an "isotopic variant" of a compound contains unnatural proportions of deuterium ( ² H).

With respect to the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d," it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. Positions designated as having deuterium typically have a minimum isotopic enrichment factor, which in certain aspects is at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds described herein and are well known in the art. Such synthetic methods (e.g., incorporating active levels of tritium into target molecules) are as follows: A. Catalytic reduction by tritium gas: This procedure generally produces highly radioactive products and requires halogenated or unsaturated precursors. B. Reduction by sodium borohydride [ ^3H ]: This procedure is relatively inexpensive and requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, and the like. C. Reduction by lithium aluminum hydride [ ^3H ]: This procedure provides products at nearly theoretical radioactive levels. It also requires precursors containing reducible functional groups, such as aldehydes, ketones, lactones, esters, and the like. D. Tritium exposure labeling: This procedure involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst. E. N -methylation using iodomethane [ ^3H ]: This procedure is commonly used to prepare O-methyl or N-methyl ( ^3H ) products by treating the appropriate precursor with high radioactivity concentrations of iodomethane ( ^3H ). This method generally allows for relatively high radioactivity concentrations, such as about 70 to 90 Ci/mmol.

Synthetic methods for incorporating active levels of ¹²⁵ I into target molecules include: A. Sandmeyer and analogous reactions: This procedure converts an aryl amine or heteroaryl amine to a diazonium salt, such as diazonium tetrafluoroborate, and subsequently converts to the ¹²⁵ I-labeled compound using Na ¹²⁵ I. A representative procedure was reported by Zhu, GD. and co-workers in J . Org . Chem . , 2002, 67, 943-948. B. Ortho- ¹²⁵ iodination of phenols: This procedure allows for the incorporation of ¹²⁵ I at an ortho position of phenol as reported by Collier, TL and co-workers in J . Labelled Compd . Radiopharm . , 1999, 42, S264-S266. C. Exchange of aryl and heteroaryl bromides with ¹²⁵ I: This method is generally a two-step process. The first step is to convert the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate using, for example, a Pd-catalyzed reactant [i.e., Pd(Ph ₃ P) ₄ ] or via an aryl or heteroaryl lithium in the presence of a trialkyltin halide or hexaalkylditin [e.g., (CH ₃ ) ₃ SnSn(CH ₃ ) ₃ ]. A representative procedure was reported by Le Bas, M.-D. and co-workers in J . Labelled Compd . Radiopharm . , 2001, 44, S280-S282.

Radiolabeled forms of the compounds described herein can be used in screening assays to identify/evaluate compounds. Generally, a newly synthesized or identified compound (i.e., a test compound) can be evaluated for its ability to reduce binding of a radiolabeled form of a compound disclosed herein to GPR52. The ability of a test compound to compete with a radiolabeled form of a compound described herein for binding to GPR52 is related to its binding affinity.

Aspects The present invention relates to compounds capable of regulating GPR52 activity. In one aspect of the present invention, the compound of formula (I) is a compound of formula (Ia): (Ia) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2 _- methyl- ₂ -azetidin-6-yl; _R2 is selected from _C1-3 alkyl, cyclopropyl and halogen; _R3 is selected from fluorine and hydrogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl, 1-fluorocyclopropyl and 3-fluorooxycyclobutane-3-yl; _R5 is selected from hydrogen, cyano, halogen, dimethyl- _amino , methoxy, ethoxy, _{trifluoromethyl} , -S(O) _0-2C1-2alkyl , _{trifluoromethoxy ,} -N( _C1-2alkyl ) ₂ and _{C1-2alkyl ; R6} is selected _from hydrogen _, halogen _{, cyano and -OC1-} or _a pharmaceutically acceptable salt thereof.

In another embodiment, _R is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azaspiro[3.3]hept-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azaspiro[3.3]hept-6-yl.

In another aspect, R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl.

In another aspect, R ₃ is selected from fluorine and hydrogen.

In another aspect, _R is selected from hydrogen, methyl, difluoromethyl, chloro, fluoro, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl and 1-fluorocyclopropyl.

In another aspect, R ₅ is selected from hydrogen, chloro, fluoro, methyl-thio, cyano, methyl, dimethyl-amino, trifluoromethyl, trifluoromethoxy, ethoxy and methoxy.

In another aspect, R ₆ is selected from hydrogen, fluorine, chlorine, cyano and methoxy.

In another embodiment, _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azetidin-6-yl; _R2 is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl; _R3 is selected from fluoro and hydrogen; R _R4 is selected from hydrogen, methyl, difluoromethyl, chlorine, fluorine, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl, 1-fluorocyclopropyl and 3-fluorooxycyclobutane-3-yl; _R5 is selected from hydrogen, chlorine, fluorine, methyl-sulfenyl, cyano, methyl, dimethyl-amino, trifluoromethyl, trifluoromethoxy, ethoxy and methoxy; _R6 is selected from hydrogen, fluorine, chlorine, cyano and methoxy; or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is selected from the following compounds or their pharmaceutically acceptable salts: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and .

In another embodiment, the compound is of formula Ib: (Ib) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2 _- methyl- ₂ -azetidin-6-yl; _R2 is selected from _C1-3 alkyl, cyclopropyl and halogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop- ₂ -yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl and _{1-fluorocyclopropyl; R5 is selected from hydrogen, halogen, cyano, -OC1-2 alkyl, C1-2 alkyl substituted with halogen and -S(O)0-2C1-2 alkyl ; R6 is selected from hydrogen , halogen and} cyano; _R7 is selected from hydrogen and _-OC1-2 alkyl; _{R8 is} selected from hydrogen _{, -OC1-2} alkyl and _halogen ; or _a pharmaceutically acceptable _{salt thereof} .

In another embodiment, _R is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azaspiro[3.3]hept-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azaspiro[3.3]hept-6-yl.

In another aspect, R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl.

In another aspect, _R is selected from hydrogen, methyl, difluoromethyl, chloro, fluoro, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl and 1-fluorocyclopropyl.

In another aspect, R ₅ is selected from hydrogen, fluorine, chlorine, ethoxy, trifluoromethyl, methyl-thio and cyano.

In another embodiment, R ₆ is selected from hydrogen, chlorine, fluorine and cyano.

In another aspect, R ₇ is selected from hydrogen and methoxy.

In another embodiment, R ₈ is selected from hydrogen, methoxy and fluorine; or a pharmaceutically acceptable salt thereof.

In another embodiment, R ₁ is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azetidin-6-yl; R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl; R _R4 is selected from hydrogen, methyl, difluoromethyl, chlorine, fluorine, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl and 1-fluorocyclopropyl; _R5 is selected from hydrogen, fluorine, chlorine, methoxy, ethoxy, trifluoromethyl, methyl-sulfanyl and cyano; _R6 is selected from hydrogen, chlorine, fluorine and cyano; _R7 is selected from hydrogen and methoxy; _R8 is selected from hydrogen, methoxy and fluorine; or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is selected from the following compounds or their pharmaceutically acceptable salts: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and .

In another embodiment, the compound of formula Ic is: (Ic) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and _{2 -} methyl-2-azetidin-6-yl; _R2 is selected from _C1-3 alkyl, halogen, cyclopropyl, _{methyl-amino and C1-2 alkyl} substituted _with halogen; _R3 is selected from fluorine and hydrogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl and 1 _{- fluorocyclopropyl} ; _R6 is selected from hydrogen and _-OC1-2 alkyl; _R8 is selected from hydrogen, _halogen and _-OC1-2 alkyl; or a pharmaceutically acceptable _salt thereof.

In another embodiment, _R is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azaspiro[3.3]hept-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azaspiro[3.3]hept-6-yl.

In another aspect, R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl.

In another aspect, R ₃ is selected from fluorine and hydrogen.

In another embodiment, R ₄ is chloro.

In another aspect, R ₆ is selected from hydrogen and methoxy.

In another embodiment, R ₈ is selected from hydrogen, halogen and methoxy; or a pharmaceutically acceptable salt thereof.

In another embodiment, R ₁ is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azetidin-6-yl; R ₂ is selected from chlorine, methyl, ethyl, cyclopropyl and isopropyl; R ₃ is selected from fluorine and hydrogen; R ₄ is chlorine; R ₆ is selected from hydrogen and methoxy; R ₈ is selected from hydrogen, halogen and methoxy; or a pharmaceutically acceptable salt thereof.

In another embodiment, the compound is selected from the following compounds or their pharmaceutically acceptable salts: .

In another embodiment, the compound is of formula II: (II) wherein: R ₁ is selected from hydrogen, piperidinyl, (2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C _{1 - 2} alkyl, azetidinyl, azetidinyl-C _{1 - 2} alkyl, (2-oxaspiro[3.3]hept-6-yl, cyclobutyl, cyclopropyl and (C _{1 - 2} alkyl) _{0 - 2} NC _{1 - 4} alkyl, (C _{1 - 2} alkyl) _{0 - 2} NC(O)-C _{1 - 4} alkyl, (C _{1 - 2} alkyl) _{0 - 1} OC _{1 -} 4 alkyl wherein _the piperidinyl, (2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C 1 _- 2 alkyl, azetidinyl, azetidinyl-C ₁ - ₂ alkyl, 2-azaspiro[3.3]hept-6-yl, (2-oxaspiro[3.3]hept-6-yl, cyclobutyl and cyclopropyl are unsubstituted or substituted with 1 _{to 2 R groups independently selected from the group consisting of C 1 - 4 alkyl , C 3 - 5 cycloalkyl} , hydroxyl _, C _{1 - 5} substituted with hydroxyl; _R2 is selected from _C1-3 alkyl, halogen, cyclopropyl _{, methyl} -amino and _C1-2 alkyl substituted by halogen; _R3 is selected from hydrogen and _halogen ; _R4 is selected from hydrogen, methyl, halogen, cyano _, difluoromethyl, _2,2,2 -trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl and _{1 -} fluorocyclopropyl; _X1 is selected from N and _CR6 ; wherein _R6 is selected from hydrogen, _-OC1-2 alkyl and cyano; _X2 is selected from N and _CR8 ; wherein R _X8 is selected from _hydrogen , _{-OC1-2 alkyl} and halogen; _X3 is selected from N _{and CR5} ; wherein _R5 is selected _from hydrogen _, halogen _, cyano _{, C1-2} alkyl, _-OC1-2 alkyl, -N _{(C1-2 alkyl} ) ₂ , _C1-2 alkyl substituted with _halogen and -S( _{O ) 0-2C1-2 alkyl ;} and pharmaceutically acceptable _{salts thereof} .

In another embodiment, the compound of formula IIa: (IIa) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and _{2 -} methyl-2-azetidin-6-yl; _R2 is selected from _C1-3 alkyl, halogen, cyclopropyl, _{methyl-amino and C1-2 alkyl} substituted _with halogen; _R3 is selected from fluorine and hydrogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl and _{1 -} fluorocyclopropyl; _R5 is selected from hydrogen, trifluoromethoxy and _C1-2 alkyl; _R6 is selected from hydrogen and _{-OC1-2 alkyl ;} and pharmaceutically acceptable salts thereof.

In another embodiment, _R is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azaspiro[3.3]hept-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azaspiro[3.3]hept-6-yl.

In another aspect, R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl.

In another aspect, R ₃ is selected from fluorine and hydrogen.

In another aspect, _R is selected from hydrogen, methyl, difluoromethyl, chloro, fluoro, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl and 1-fluorocyclopropyl.

In another aspect, R ₆ is selected from hydrogen and methoxy.

In another embodiment, _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl and 2-methyl-2-azetidin-6-yl; _R2 is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl; _R3 is selected from fluoro and hydrogen; R _R4 is selected from hydrogen, methyl, difluoromethyl, chlorine, fluorine, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl and 1-fluorocyclopropyl; _R6 is selected from hydrogen and methoxy; and pharmaceutically acceptable salts thereof.

In another embodiment, the compound is selected from the following compounds or their pharmaceutically acceptable salts: ; ;and . Pharmaceutical Compositions, Formulations and Dosage Forms The present invention further provides pharmaceutical products, such as pharmaceutical compositions, formulations, unit dosage forms and kits; each comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

The present invention also provides pharmaceutical compositions comprising any compound described herein (e.g., a compound of formula (I), including specific compounds described herein) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance; an excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients : A Comprehensive Guide to Uses , Properties , and Safety , 5th edition, 2006 and Remington : The Science and Practice of Pharmacy (Gennaro, 21st edition Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.

For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may include antioxidants, buffers, antibacterial agents and other common additives as appropriate. The composition may also be formulated as pills, capsules, granules or tablets, which contain diluents, dispersants and surfactants, binders and lubricants in addition to the GPR52 agonist. Those skilled in the art may further formulate the GPR52 agonist in an appropriate manner and according to recognized practices, such as those disclosed in Remington above.

Administration methods include systemic administration of the GPR52 agonists described herein, preferably in the form of pharmaceutical compositions as discussed above. As used herein, systemic administration includes oral and parenteral administration methods. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions. Such compositions may also include flavoring agents, preservatives, suspending agents, thickeners and emulsifiers, and other pharmaceutically acceptable additives. For parenteral administration, the compounds described herein (or their pharmaceutically acceptable salts) can be prepared in aqueous injection solutions which, in addition to the GPR52 agonist, may also contain buffers, antioxidants, antibacterial agents and other additives commonly used in such solutions.

Pharmaceutical preparations for oral administration can be obtained by any suitable method, generally by uniformly mixing the compound with a liquid or finely powdered solid carrier or both in the desired proportion, and then processing the mixture after adding suitable auxiliaries if necessary, and, if necessary, forming the resulting mixture into the desired shape to obtain tablets or dragee cores.

In tablets and capsules for oral administration, conventional formulations such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants and disintegrants may be used. Liquid formulations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups. Alternatively, oral formulations may be in the form of dry powders, which may be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavoring agents and coloring agents may be added to the liquid formulations. Parenteral dosage forms may be prepared by dissolving a compound described herein in a suitable liquid vehicle and filter sterilizing the solution prior to lyophilization or simply filling and sealing an appropriate vial or ampoule.

Some aspects provide a method for preparing a pharmaceutical composition, comprising the step of admixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In the manufacture of pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, the drug substance is usually mixed (i.e., admixed) with an excipient, diluted by the excipient or enclosed in such a carrier in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it may be a solid, semisolid or liquid material which serves as a vehicle, carrier or medium for the drug substance. Thus, the compositions may be in the form of tablets, powders, buccal tablets, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (either in a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

For the preparation of solid form pharmaceutical compositions, such as powders, tablets, capsules, cachets, suppositories and dispersible granules, the excipient may be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating materials. Also included are solid form preparations intended to be converted into liquid form preparations for oral administration immediately prior to use. Such liquid forms include solutions, suspensions and emulsions. In addition to the drug substance, these preparations may also contain colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers and the like.

To prepare suppositories, a low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the drug substance is uniformly dispersed therein by stirring. The molten homogeneous mixture is then poured into a mold of suitable size, allowed to cool, and thereby solidified.

Formulations suitable for vaginal administration may be delivered as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the drug substance, such carriers as are known in the art to be appropriate.

Liquid form preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in polyethylene glycol aqueous solutions. Suitable dispersants or wetting agents and suspending agents can be used according to known techniques to prepare injectable preparations, such as sterile injectable aqueous or oily suspensions. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenteral acceptable diluents or solvents. Among acceptable vehicles and solvents, those that can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile non-volatile oils are commonly used as solvents or suspending media. For this purpose any bland, fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

The pharmaceutical composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain formulating agents such as suspending agents, stabilizers and/or dispersing agents. Alternatively, the pharmaceutical composition may be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization from a solution, and reconstituted with a suitable vehicle (e.g., sterile, pyrogen-free water) before use.

The pharmaceutical composition can be formulated as an aqueous solution, a water-alcohol solution, a solid suspension, an emulsion, a liposome suspension, or a lyophilized powder for reconstitution. Such pharmaceutical compositions can be administered directly or as an admixture for further dilution/reconstitution. Routes of administration include intravenous bolus, intravenous infusion, perfusion, and infusion. Suitable solvents include water, alcohol, PEG, propylene glycol, and lipids; pH adjustment using an acid (e.g., HCl or citric acid) can be used to increase solubility and the resulting composition is subjected to suitable sterilization procedures known in the art, such as sterile filtration. In some aspects, the pH of the aqueous solution is about 2.0 to about 4.0. In some aspects, the pH of the aqueous solution is about 2.5 to about 3.5.

Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the drug substance in water and adding suitable colorants, flavorings, stabilizers and thickening agents as required.

Aqueous suspensions suitable for oral use may be prepared by dispersing the finely powdered drug substance in water together with a viscous material such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agents.

For topical administration to the epidermis, the compounds described herein or their pharmaceutically acceptable salts may be formulated as gels, ointments, creams or lotions or transdermal patches. In addition, suitable formulations for topical administration in the mouth include lozenges comprising the drug substance in a flavored base (usually sucrose and acacia or tragacanth); tablets comprising the drug substance in an inert base (such as gelatin and glycerin or sucrose and acacia); and mouthwashes comprising the drug substance in a suitable liquid carrier. Ointments and creams may be formulated, for example, with an aqueous or oily base with the addition of a suitable thickener and/or gelling agent. Lotions can be formulated with aqueous or oily bases and will typically also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents. In some aspects, topical formulations may contain one or more conventional carriers. In some aspects, ointments may contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum and the like. The carrier composition of a cream may be based on a combination of water with glycerol and one or more other components, such as glyceryl monostearate, PEG-glyceryl monostearate and cetearyl alcohol. Gels may be formulated using isopropyl alcohol and water, appropriately combined with other ingredients such as glycerin, hydroxyethyl cellulose and the like.

The solution or suspension can be applied directly to the nasal cavity by known means, for example, with a dropper, pipette or sprayer. The formulation can be provided in a single dose or multiple doses. In the case of a dropper or pipette, this can be achieved by administering an appropriate predetermined volume of the solution or suspension to the subject. In the case of a sprayer, this can be achieved, for example, by a metered atomizing spray pump.

Administration to the respiratory tract can also be achieved by aerosol formulations provided in pressurized packages with a suitable propellant. If the compounds described herein or their pharmaceutically acceptable salts or pharmaceutical compositions comprising them are administered by aerosol (e.g., nasal aerosol) or by inhalation, this can be performed, for example, using a nebulizer, atomizer, pump nebulizer, inhalation device, metered inhaler or dry powder inhaler. Pharmaceutical forms for administration of the compounds described herein (or their pharmaceutically acceptable salts) as aerosols can be prepared by processes well known to those skilled in the art. For its preparation, for example, solutions or dispersions of the compounds described herein (or their pharmaceutically acceptable salts) in water, water/alcohol mixtures or suitable saline solutions may be used, using customary additives such as benzyl alcohol or other suitable preservatives, absorption enhancers for increasing bioavailability, solubilizers, dispersants and other additives, and, where appropriate, customary propellants, including, for example, carbon dioxide; CFCs such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; and the like. Aerosols may also conveniently contain surfactants such as lecithin. The dosage of the drug may be controlled by providing a metering valve.

Alternatively, the pharmaceutical composition may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives, such as hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). Conveniently, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example in gelatin capsules or cartridges, or in blister packs, wherein the powder can be administered by inhaler.

The compound of formula (I) or its pharmaceutically acceptable salt can also be administered via a fast dissolving or slow releasing composition, wherein the composition includes a biodegradable fast dissolving or slow releasing carrier (such as a polymer carrier and the like). Fast dissolving or slow releasing carriers are well known in the art and are used to form a complex in which the compound of formula (I) or its pharmaceutically acceptable salt is captured and degrades/dissolves rapidly or slowly in a suitable environment (e.g., aqueous, acidic, alkaline, etc.).

The pharmaceutical preparation is preferably in unit dosage form. In such forms, the preparation is subdivided into unit doses containing an appropriate amount of the drug substance. The unit dosage form may be a packaged preparation containing discrete amounts of the preparation, such as packaged tablets, capsules, and vials or ampoules of powder. In addition, the unit dosage form may be a capsule, tablet, cachet, or buccal tablet itself, or it may be any of these unit dosage forms in packaged form in an appropriate number. In some aspects, the pharmaceutical preparation is a tablet or capsule for oral administration. In some aspects, the pharmaceutical preparation is a liquid formulated for intravenous administration.

The composition can be formulated in unit dosage form, each dosage containing the drug substance or an equivalent mass of the drug substance. The term "unit dosage form" refers to physically discrete units of formulation suitable for use as unit dosages in human subjects and other mammals, each unit containing a predetermined amount of the drug substance calculated to produce the desired therapeutic effect in combination with a suitable formulation as described herein.

The compositions described herein may be formulated to provide immediate and/or timed release (also referred to as extended release, sustained release, controlled release, or slow release) of the drug substance after administration to a subject by procedures known in the art. For example, tablets comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof may be coated or otherwise compounded to provide a dosage form having a prolonged effect advantage. For example, a tablet may comprise an inner dose and an outer dose component, the latter being in the form of a coating that coats the former. The two components may be separated by an enteric layer that serves to prevent disintegration in the stomach and allow the inner component to pass intact into the duodenum or to be released later. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as insect glue, cetyl alcohol, and cellulose acetate.

Liquid forms containing the drug substance which may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions and flavored emulsions containing edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, and similar excipients.

The pharmaceutical compositions described herein can be sterilized by known sterilization techniques, or can be aseptically filtered. The aqueous solution can be packaged for use as is, or lyophilized, and the lyophilized preparation is combined with a sterile aqueous carrier before administration. The pH of the compound preparation is usually between 3 and 11, more preferably 5 to 9, and most preferably 7 to 8. It should be understood that the use of some of the aforementioned excipients can form a pharmaceutically acceptable salt.

Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable excipients as described herein. In some embodiments, the composition is administered by the oral or nasal respiratory route for local or systemic effect. The composition may be aerosolized by the use of an inert gas. The aerosolized solution may be inhaled directly from the aerosolizing device, or the aerosolizing device may be attached to a mask holder or an intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

If necessary, the composition may be delivered in a package or dispenser device that may contain one or more unit dosage forms containing the drug substance. The package may, for example, comprise metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration. The package or dispenser may also be accompanied by a note associated with the container in a form specified by a governmental agency that regulates the manufacture, use, or sale of pharmaceuticals, which note reflects the agency's approval of the drug form for human or veterinary administration. Such notes may, for example, be a prescription drug label approved by the U.S. Food and Drug Administration, or an approved product instruction sheet. Compositions that may include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of the indicated condition.

To prepare solid compositions such as tablets, the drug substance may be mixed with a molding agent to form a solid preformulation composition containing a uniform mixture of the components. When referring to these preformulation compositions as homogeneous, the drug substance is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms, such as tablets and capsules.

Kits are provided having unit doses of one or more of the compounds described herein, usually in the form of oral or injectable doses. Such kits may include a container containing the unit dose, an informative package insert describing the use and concomitant benefits of the drug in treating the pathological condition of interest, and, if appropriate, an implement or device for delivering the composition.

The compounds described herein or their pharmaceutically acceptable salts are effective over a wide dosage range and are generally administered in a therapeutically effective amount. However, it should be understood that the actual amount of compound administered will generally be determined by a physician based on relevant circumstances, including the condition to be treated, the selected route of administration, the actual compound administered, the age, weight and response of the individual, the severity of the individual's symptoms, and the like.

The amount of the compound or composition administered to an individual will also vary depending on what is being administered, the purpose of administration (e.g., prophylaxis or treatment), the state of the individual, the mode of administration, and the like. In therapeutic applications, the composition can be administered to an individual already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms and/or pathology of the disease and its complications. The therapeutically effective amount will depend on the disease condition being treated, as well as on the judgment of the attending clinician depending on factors such as the severity of the disease, the age, weight and general condition of the individual, and the like.

The required dose is preferably presented as a single dose or as divided doses (e.g., two, three, four or more sub-doses per day) to be administered at appropriate time intervals. The sub-doses themselves may be further divided, for example, into a number of discrete administrations at loose intervals. The daily dose may be divided into several portions (e.g., two, three or four portions) for administration, especially when administration of relatively large amounts is considered appropriate. Where appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the indicated daily dose.

It will be apparent to those skilled in the art that the dosage forms described herein may comprise a compound described herein or a pharmaceutically acceptable salt thereof.

Some aspects provide the use of at least one compound disclosed and described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed and described herein in the manufacture of a medicament for treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive disorders, panic disorder, phobia, drug-induced psychosis, delusional psychosis, Neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorder, movement disorders, hyperkinetic movement disorder, mental illness, tension disorder, mood disorders, depression, anxiety disorder, obsessive-compulsive disorder (OCD) , autism spectrum disorder, lactotropin-related disorder (e.g., hyperlactogeninemia), neurocognitive disorder, trauma or stress-related disorder (e.g., PTSD), disruptive impulse control or disruptive behavior disorder, sleep-wake disorder, substance-related disorder, addiction, behavioral disorder, frontal lobe dysfunction, tuberoinfundibulum, mesolimbic, mesocortical, or nigrostriatal pathways Abnormalities, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, including chorea associated with Huntington's disease.

Some aspects provide the use of at least one compound disclosed and described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed and described herein in the manufacture of a medicament for improving one or more symptoms of a neurological disorder, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive disorders, panic disorder, phobia, drug-induced psychosis, delusions, Sexual Psychosis, Neuroleptic-Induced Dyskinesia, Parkinson's Disease, Drug-Induced Parkinson's Syndrome, Extrapyramidal Syndrome, Alzheimer's Disease, Dementia with Lewy Bodies, Manic Depression, ADHD, Tourette Syndrome, Extrapyramidal or Movement Disorder, Movement Disorder, Hyperkinetic Movement Disorder, Psychosis, Tension Disorder, Mood Disorder, Depression, Anxiety Disorder, Obsessive-Compulsive Disorder (O CD), autism spectrum disorder, lactotropin-related disorder (e.g., hyperlactogeninemia), neurocognitive disorder, trauma or stress-related disorder (e.g., PTSD), disruptive impulse control or disruptive behavior disorder, sleep-wake disorder, substance-related disorder, addiction, behavioral disorder, frontal lobe dysfunction, tuberoinfundibulum, mesolimbic, midcortical, or nigrostriatal pathways Pathological abnormalities, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, including chorea associated with Huntington's disease.

Some aspects provide use of at least one compound disclosed and described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition disclosed and described herein in the manufacture of a medicament for treating a neurological disorder, wherein the neurological disorder is schizophrenia or cognitive impairment associated with schizophrenia (CIAS).

Some aspects provide for the use of at least one compound disclosed and described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed and described herein as a stand-alone therapy or as an additional therapy to the standard of care for the treatment of cognitive impairment associated with schizophrenia (CIAS) with an antipsychotic agent.

Some aspects provide the use of at least one compound disclosed and described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed and described herein as an independent therapy or an additional therapy to the standard of care for the treatment of the following diseases with antipsychotic drugs: negative symptoms of schizophrenia, impulsive or obsessive-compulsive disorders, non-motor symptoms of Parkinson's disease, autism spectrum disorders, and other CNS disorders associated with cognitive dysfunction (such as Huntington's disease, multiple sclerosis, etc.).

Some aspects provide for the use of at least one compound disclosed and described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed and described herein, as a standalone therapy or as an additional therapy to the standard of care for the treatment of psychosis (positive symptoms).

Pharmacology and Utility G protein-coupled receptors (GPCRs) have seven conserved transmembrane domains connected to at least eight cytoplasmic loops. The transmembrane regions are designated TM1, TM2, TM3, TM4, TM5, TM6, and TM7. Most GPCRs contain potential phosphorylation sites in the third cytoplasmic loop and/or the carboxyl terminus. GPCRs are key components of many cellular signaling pathways. GPCRs couple to a variety of enzymes, ion channels, and transporters. Different G protein subunits can stimulate effectors to regulate a variety of downstream functions in the cell.

Ligand binding causes a conformational change in the GPCR, allowing the GPCR to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate the associated G protein by exchanging the GDP bound to the G protein for GTP. This GTP, along with the α subunit of the G protein, then dissociates from the β and γ subunits to further regulate intracellular signaling pathways.

GPR52 is a highly conserved GPCR in vertebrates, with over 90% amino acid sequence identity. The highest expression within the central nervous system (CNS) is found in the striatum. Lower significant expression levels are found in other structures in the CNS, including the cortex. GPR52 tissue distribution does not differ significantly between humans, rats, and mice, suggesting that GPR52 has common functions that are species independent.

In the rat brain, GPR52 is expressed in neurons in various regions, including the medial prefrontal cortex, basal amygdala, and cortical nucleus, which are responsible for the clinical features of psychiatric disorders. In addition, GPR52 knockout and transgenic mice exhibit psychosis-related and antipsychotic-like behaviors, respectively (Hidetoshi Komatsu et al., February 2014, Vol. 9, No. 2, PLOS ONE, e90134).

Although GPR52 has been characterized, it is still an orphan receptor, meaning that it has no known endogenous ligand. Several alternative ligands have been reported, including the extracellular loop 2 (ECL2) of GPR52 itself (Pingyuan Wang et al., J. Med. Chem., 2020, 63, 13951-72). GPR52 normally coexists with dopamine receptors (D1 and D2). (See PLOS One, Vol. 9, No. 2, e90134). GPR52 coexists almost exclusively with D2 receptors in human striatum and D1 receptors in cortex. The efficacy of existing antipsychotics is mediated by D2 antagonist activity, but this activity is accompanied by side effects such as motor symptoms and hyperlactoprotinemia. Antipsychotic drugs are also associated with significant side effects, including weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperglycemia, insulin resistance, extrapyramidal symptoms, and delayed dyskinesia. In contrast, GPR52 modulators may essentially act as D2 antagonists and thus exhibit antipsychotic efficacy while avoiding the side effects associated with D2 antagonists. Thus, GPR52 modulators may improve symptoms of a variety of neurological conditions, diseases and disorders and represent targets for the treatment of a variety of neurological disorders, including but not limited to psychosis, dissociation, anxiety, anxiety/tension associated with psychosis, acute mania, agitation, mania in bipolar disorder, hypodepression, dyspepsia, and drug-related addictions such as cocaine, amphetamines, or the like.

GPR52 colocalizes with D1 receptors in the medial prefrontal cortex but with D2 receptors in the basal ganglia, suggesting that GPR52 may be involved in dopamine-induced transmission in neurons expressing D1 receptors in the cortex and D2 receptors in the striatum (Hidetoshi Komatsu et al., February 2014, Vol. 9, No. 2, PLOS ONE, e90134).

Frontal hypofunction, i.e., decreased blood flow in the prefrontal cortex, is a symptom of several neurological conditions, including cognitive and negative symptoms associated with frontal hypofunction in schizophrenia, attention deficit/hyperactivity disorder (ADHD), bipolar disorder, major depression, and substance abuse-related frontal hypofunction. Therefore, enhancing the function of the prefrontal cortex with GPR52 modulators would be useful in treating symptoms associated with frontal hypofunction.

In one embodiment of the present invention is a method for treating diseases or conditions related to frontal lobe dysfunction, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect of the present invention, the frontal lobe dysfunction-related disease or disorder is selected from schizophrenia, attention deficit/hyperactivity disorder (ADHD), bipolar disorder, major depression, and frontal lobe dysfunction-related cognitive and negative symptoms associated with substance abuse.

In another aspect, negative symptoms associated with schizophrenia disrupt a person's typical emotions, behaviors, and abilities and are selected from decreased speech, odd emotional responses to situations, lack of emotion or expression, loss of interest or excitement in life, social isolation, difficulty experiencing pleasure, difficulty starting or completing plans, and difficulty completing normal daily activities.

In addition, with respect to GPR52 agonists that are functionally similar to D1 agonists, GPR52 agonists may be useful for treating conditions that can be treated by D1 agonists, including but not limited to drug-related addictions (e.g., cocaine addiction), hypertension, restless legs syndrome, Parkinson's disease, and depression. In addition, based on its expression pattern and functional coupling, GPR52 agonists can be used to treat cognitive deficits associated with schizophrenia, schizoaffective disorder, schizophrenia-like and schizophrenia-like disorders, refractory schizophrenia, attenuated psychotic syndrome and autistic spectrum disorder, bipolar disorder, Alzheimer's disease, Parkinson's disease, frontotemporal dementia (Pick's disease), Lewy body dementia, vascular dementia, post-stroke dementia and Creutzfeldt-Jakob disease.

The striatum is involved in motor control, including but not limited to hyperkinetic movement disorders characterized by excessive abnormal involuntary movements (called hyperactivity). Examples of hyperkinetic movement disorders include tremor, hypotonia, chorea, ballism, athetosis, tics/Tourette's syndrome, Huntington's disease, myoclonus and startle syndrome, dyskinesia Movement and akathisia. ADHD is associated with dysfunction of the inhibitory, D2-expressing neurons of this pathway. This dysfunction results in an inability to inhibit movement, resulting in tics, chorea, vocalizations, tremors, and other hyperkinetic symptoms. For example, the early hyperkinetic movement symptoms of Huntington's disease are the result of selective damage to the D2-containing indirect pathway. In addition, D2 receptor binding in the striatum is associated with the severity of Tourette syndrome symptoms. Modulating GPR52 activity activates the indirect striatal pathway, thereby exerting more inhibitory control over movement and resolving hyperactive symptoms.

In one aspect of the present invention is a method for treating hyperkinetic movement disorder, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect of the invention, the hyperkinetic movement disorder is selected from the group consisting of tremor, hypotonia, chorea, throwing disorder, athetosis, tics/Tourette's syndrome, Huntington's disease, myogram Syndrome and startle syndrome, printing behavior and akathisia.

Huntington's disease is primarily caused by the cytotoxicity of mutant HTT proteins with expanded polyglutamine repeats. Reducing soluble mutant HTT can reduce its downstream toxicity and provide a potential treatment for Huntington's disease. Genetic knockout of GPR52 significantly reduced mutant HTT levels in the striatum and rescued Huntington's disease-associated behavioral phenotypes in the genetically inserted Huntington's disease mouse model. In addition, GPR52 antagonists reduced mutant HTT levels and rescued Huntington's disease-associated phenotypes in cells and mouse models (Haikun Song et al., June 2018, Brain, Vol. 141, No. 6, pp. 1782-98).

In one aspect of the present invention is a method for treating Huntington's disease, comprising administering an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

Schizophrenia is a complex neuropsychiatric disorder that affects approximately 0.3% of the population. It is a severe, chronic, and disabling mental disorder. The core clinical features of schizophrenia include positive, negative, and cognitive symptoms. Cognitive impairment associated with schizophrenia (CIAS) is extremely detrimental to functional ability, and the severity of CIAS is the most accurate predictor of patient outcome. Antipsychotic drugs can reduce the severity of positive symptoms through dopamine D2 receptor antagonism, but have not been shown to have significant efficacy on negative and cognitive symptoms. Selective GPR52 agonists show therapeutic properties for the treatment of positive and cognitive symptoms of schizophrenia (Keiji Nishiyama et al., J. Pharm. Exp. Ther., Nov 2017, 363 (2) 253-64).

The major unmet clinical need in schizophrenia is the treatment of negative and cognitive symptoms, as currently approved antipsychotics offer little improvement. Notably, cognitive deficits in schizophrenia patients are considered a core part of the disorder and are thought to have a significant impact on the patient's recovery and social reintegration.

In one aspect of the present invention is a method for treating schizophrenia, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect of the present invention is a method for treating CIAS, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

The psychotic symptoms of schizophrenia result from excessive presynaptic dopamine activity in the striatum. The clinical efficacy of existing antipsychotics for treating psychotic symptoms depends on the blockade of D2 receptors. All known antipsychotics effective for treating psychosis are antagonists or partial agonists of dopamine D2 receptors. Although these antipsychotics can treat the positive (or psychotic) symptoms of schizophrenia, they cannot treat other aspects of schizophrenia, such as negative symptoms or cognitive impairment. Based on the co-expression of GPR52 and dopamine D2 receptors, GPR52 agonists should treat psychotic symptoms associated with schizophrenia. In addition, since the mechanism of action of GPR52 agonists is unique to known D2 receptor-related antipsychotics, it is expected that GPR52 agonists will enhance the antipsychotic efficacy of known neuroleptics. This will not only improve the antipsychotic efficacy, but can also be used to reduce the dosage of antipsychotics, thereby reducing their associated side effects. Elevated serum lactoprogesterone levels are one of the significant side effect profiles of known D2 receptor antagonist antipsychotics, and GPR52 agonists have been shown to reduce serum lactoprogesterone levels. Therefore, co-administration of GPR52 agonists and D2 receptor antagonist antipsychotics can normalize serum lactoprogesterone levels, thereby reducing the side effects associated with D2 receptor antagonist antipsychotics. Additionally, GPR52 agonists should treat psychotic symptoms associated with a variety of psychiatric indications, including schizoaffective disorder, schizophrenia, schizophrenia-like disorders, refractory schizophrenia, drug-induced psychosis, bipolar disorder, autistic spectrum disorder, and attenuated psychotic syndromes.

In one aspect of the present invention is a method for treating psychiatric disorders, comprising administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a patient in need thereof.

In another aspect, the psychiatric disorder is selected from schizoaffective disorder, schizophrenia, schizophrenia-like disorder, refractory schizophrenia, drug-induced psychosis, bipolar disorder, autistic spectrum disorder, and hypopsychotic syndrome.

In one aspect of the present invention is a method for treating psychotic and neuropsychiatric symptoms associated with various neurodegenerative indications, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect, the psychotic illness and neuropsychiatric symptoms associated with various neurodegenerative indications are selected from Parkinson's disease, Alzheimer's disease, frontotemporal dementia, vascular cognitive impairment, and dementia with Lewy bodies.

The present invention further provides a method for treating a neurological disease in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of a compound disclosed and described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition and a pharmaceutically acceptable formulation comprising a compound disclosed and described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof). The present invention also provides the use of a compound disclosed and described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for treating a neurological disease in an individual in need thereof. The present invention also provides the preparation of a medicament disclosed and described herein or a pharmaceutically acceptable salt thereof (eg, a compound of formula (I) or a pharmaceutically acceptable salt thereof) for treating a neurological disease in a subject in need thereof.

In some aspects, the individual has been previously diagnosed with a neurological disorder. In some aspects, the individual currently has a neurological disorder. In some aspects, the individual is suspected of having a neurological disorder. In some aspects, the individual has previously been treated with one or more therapeutic agents approved for the treatment of a neurological disorder.

In some aspects, the neurological disorder is selected from schizophrenia, cognitive disorders, panic disorder, phobia, drug-induced psychosis, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extra-conical syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extra-conical or movement disorders, movement disorders, hyperkinetic movement disorders, psychotic disorders, tension disorders, mood disorders, depression, anxiety disorders, obsessive-compulsive disorder (OCD), autism spectrum disorders, lactoprogesterone-related disorders (e.g., hyperlactoprogesteroneemia), neurocognitive disorders, Trauma or stress-related disorders (such as PTSD), disruptive impulse control or disruptive behavior disorders, sleep-wake disorders, substance-related disorders, addictions, behavioral disorders, frontal hypofunction, tuberoinfundibular, mesolimbic, mesocortical or nigrostriatal pathway abnormalities, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy, progressive Supranuclear palsy, Huntington's disease, and chorea related to Huntington's disease.

In some embodiments, the neurological disorder is selected from schizophrenia, cognitive impairment, drug-induced psychosis, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, attention deficit/hyperactivity disorder (ADHD), Tourette's Syndrome, catatonia, mood disorders, obsessive-compulsive disorder (OCD), hyperlactotropinemia, PTSD, frontal lobe hypofunction, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy, progressive supranuclear palsy, Huntington's disease and chorea related to Huntington's disease.

In some aspects, the neurological disorder is a neurological disorder selected from schizophrenia. In some aspects, the neurological disorder is a cognitive disorder. In some aspects, the neurological disorder is panic disorder. In some aspects, the neurological disorder is phobia. In some aspects, the neurological disorder is a drug-induced psychotic disorder. In some aspects, the neurological disorder is delusional psychosis. In some aspects, the neurological disorder is neuroleptic-induced dyskinesia. In some aspects, the neurological disorder is Parkinson's disease. In some aspects, the neurological disorder is drug-induced Parkinson's syndrome. In some aspects, the neurological disorder is extrapyramidal syndrome. In some aspects, the neurological disorder is Alzheimer's disease. In some aspects, the neurological disorder is dementia with Lewy bodies. In some aspects, the neurological disorder is bipolar disorder. In some aspects, the neurological disorder is attention deficit/hyperactivity disorder (ADHD). In some aspects, the neurological disorder is Tourette syndrome. In some aspects, the neurological disorder is extrapyramidal or movement disorder. In some aspects, the neurological disorder is movement disorder. In some aspects, the neurological disorder is hyperkinetic movement disorder. In some aspects, the neurological disorder is a psychiatric disorder. In some aspects, the neurological disorder is tension disorder. In some aspects, the neurological disorder is a mood disorder. In some aspects, the neurological disorder is depression. In some aspects, the neurological disorder is anxiety disorder. In some aspects, the neurological disorder is obsessive-compulsive disorder (OCD). In some aspects, the neurological disorder is autism spectrum disorder. In some aspects, the neurological disorder is a lactoprogesterone-related disorder. In some aspects, the neurological disorder is hyperprolactinemia. In some aspects, the neurological disorder is a neurocognitive disorder. In some aspects, the neurological disorder is a trauma or stress-related disorder. In some aspects, the neurological disorder is PTSD. In some aspects, the neurological disorder is impulse control. In some aspects, the neurological disorder may be a disruptive behavior disorder. In some aspects, the neurological disorder is a sleep-wake disorder. In some aspects, the neurological disorder is a substance-related disorder. In some aspects, the neurological disorder is an addiction. In some aspects, the neurological disorder is a behavioral disorder. In some aspects, the neurological disorder is frontal lobe dysfunction. In some aspects, the neurological disorder comprises tuberoinfundibulum pathway abnormalities. In some aspects, the neurological disorder comprises midbrain limbic pathway abnormalities. In some forms, neurological disorders include decreased striatal activity. In some forms, the neurological condition is cortical dysfunction. In some aspects, the neurological disorder is neurocognitive dysfunction and cognitive deficits associated with schizophrenia or Parkinson's disease. In some aspects, the neurological disorder is drug-induced Parkinson's disease. In some forms, neurological symptoms include difficulty moving. In some forms, neuropathy is a lack of muscle tone. In some forms, the neurological condition is chorea. In some forms, the neurological disorder is levodopa-induced dyskinesia. In some forms, the neurological disorder is cerebral palsy. In some forms, the neurological disorder is progressive supranuclear palsy. In some forms, the neurological disorder is Huntington's disease. In some aspects, the neurological disorder is chorea associated with Huntington's disease.

In some forms, panic disorder involves panic attacks. In some forms, phobias are situational (e.g., social phobia). In some forms, the phobia is object-related (such as arachnophobia). In some forms, extrapyramidal syndrome includes persistent spasms or muscle contractions, restless movements, muscle stiffness, slowed muscle reflexes, tremors, or erratic jerky movements. In some forms, the extrapyramidal or dyskinesia is tardive dyskinesia, acute dystonic reaction, akathisia, or pseudo-Parkinsonism. In some forms, the movement disorder is developmental coordination disorder, stereotyped movement disorder, or Tourette syndrome. In some forms, hyperkinetic dyskinesias include athetosis, twitching, chorea, hypotonia, myoclonus, restless legs syndrome, stereopathy, tics, or tremors. In some aspects, the psychotic disorder is schizophrenia, schizophrenia-like disorder, delusional disorder, or chronic hallucinatory psychosis. In some forms, the mood disorder is major depressive disorder or bipolar depression. In some forms, the depression is major depressive disorder, major depressive disorder, melancholic depression, catatonic major depression, postpartum depression, seasonal affective disorder, or bipolar disorder. In some aspects, the anxiety disorder is generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, phobia, or panic disorder. In some aspects, the autism spectrum disorder is autism or Asperger's syndrome ( Asperger syndrome). In some aspects, the neurocognitive disorder is a major neurocognitive disorder or a mild neurocognitive disorder. In some aspects, the disruptive impulse control or disruptive behavior disorder is attention deficit disorder, attention deficit hyperactivity disorder, obsessive-compulsive disorder, oppositional defiant disorder, obsessive-compulsive disorder, sexual compulsion, Internet addiction, pyromania, rage disorder, compulsive shopping, or kleptomania. In some aspects, sleep-wake disorder Insomnia, narcolepsy, or night terrors. In some aspects, the substance-related disorder is alcoholism, opioid addiction, prescription drug addiction, and/or illegal drug addiction. In some aspects, the addiction disorder comprises substance addiction (e.g., alcoholism) or experience addiction. In some embodiments, the behavioral disorder is attention deficit disorder, attention deficit hyperactivity disorder, or oppositional defiant disorder.

It is understood in the art that some of the syndromes and symptoms described herein may have overlapping symptoms, and/or some of the specific conditions described herein may belong to multiple categories of conditions described herein. For example, delayed dyskinesia may be classified as at least extrapyramidal or movement disorder, hyperkinetic movement disorder, movement disorder, or extrapyramidal syndrome.

Some aspects provide a method of modulating GPR52 in a cell, comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. Without being bound by any theory, the compound can contact the receptor for a time sufficient to allow interaction between the cell and the compound and under appropriate conditions to allow interaction between the cell and the compound.

In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering to a subject having cells with GPR52 activity a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

In some aspects, the cell is in an individual in need of treatment with a compound disclosed herein. In some aspects, the cell is from an individual in need of treatment with a compound disclosed herein. In some aspects, the individual has a neurological disease, condition, or disorder. In some aspects, the individual is at risk of developing a neurological disease, condition, or disorder. In some aspects, the individual has previously been diagnosed with a neurological disease, condition, or disorder. In some aspects, the individual is currently being treated for a neurological disease, condition, or disorder. In some aspects, the individual has a neurological disease, condition, or disorder. In some aspects, the individual is suspected of having a neurological disease, condition, or disorder. In some embodiments, the neurological disease, condition or disorder is Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, attention deficit/hyperactivity disorder (ADHD), Tourette syndrome, extrapyramidal or movement disorders, movement disorders, hyperkinetic movement disorders, psychiatric disorders, tension disorders, mood disorders, depression, anxiety disorders, obsessive-compulsive disorder (OCD), autism spectrum disorders, lactoprogesterone-related disorders (e.g., hyperlactogenetic disorders), neurocognitive disorders, trauma or stress-related disorders (e.g., PTSD), disruptive impulse control, or disruptive behavior. disorders, sleep-wake disorders, substance-related disorders, addiction, behavioral disorders, frontal hypofunction, tuberoinfundibular, mesolimbic, mesocortical or nigrostriatal pathway abnormalities, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, especially with Huntington's disease Chorea associated with the disease.

The cardiac potassium channel hERG (human ether-a-go-go-related gene) is responsible for the rapid delayed rectifier current ( I _Kr ) in the human ventricle. Inhibition of IKr is the most common cause of prolongation of cardiac action potentials by non-cardiac drugs (Brown, AM and Rampe, D., (2000), “Drug-induced long QT syndrome: is HERG the root of all evil?”, Pharmaceutical News, 7, 15-20; Weirich, J. and Antoni, H., (1998), “Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs”, Basic Res. Cardiol., 93 Suppl 1, 125-132; Yap, YG and Camm, AJ (1999), “Arrhythmogenic mechanisms of non-sedating antihistamines”, Clin Exp. Allergy, 29 Suppl 3, 174-181). Increased action potential duration leads to QT interval prolongation and is associated with polymorphic ventricular tachycardia (Brown, AM and Rampe, D., (2000), "Drug-induced long QT syndrome: is HERG the root of all evil?", Pharmaceutical News, 7, 15-20). The in vitro effects of compounds of formula I on hERG channel currents (a surrogate of I _Kr , i.e., the rapidly activated delayed rectifier cardiac potassium current) were evaluated (Redfern, WS et al., "Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development", Cardiovascular Research , Vol. 58, No. 1, April 2003, pp. 32-45). See the examples below under "Activity of compounds of Formula I against hERG".

Animal models can be used to model the cognitive disturbances of schizophrenia. Administration of the glutamine/NMDA antagonist phencyclidine (PCP) provides a model of schizophrenia that can induce negative symptoms associated with amphetamine psychosis as well as positive symptoms (Jentsch and Roth, "The neuropsychopharmacology of phencyclidine: from NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia", Neuropsychopharmacology, March 1999, 20(3), 201-225). This approach has pathological validity because there is evidence that glutamate systems in the brain of patients with schizophrenia are abnormal; such changes include defects in cortical-striatal innervation that may contribute to, if not underlie, the cognitive dysfunction of the disease (Aparicio-Legarza et al., "Deficits of [ ³ H]D-aspartate binding to glutamate uptake sites in striatal and accumbens tissue in patients with schizophrenia," Neuroscience Letters, August 22, 1997, pp. 13-16). Additionally, some PCP-induced behaviors are reversed by some nontypical antipsychotics (Geyer, MA et al., "Startle response models of sensorimotor gating and habituation deficits in schizophrenia", Brain Research Bulletin, Vol. 25, No. 3, September 1990, 485-498). This suggests a potential relevance to the effects of negative and cognitive symptoms that are less responsive to typical antipsychotics.

Certain preclinical tests have revealed relatively subtle cognitive deficits in rats that resemble cognitive symptoms seen in individuals with a range of CNS disorders. These cognitive impairments include visual memory deficits, which can be measured using recognition tasks such as the novel object recognition (NOR) paradigm. Recognition memory tasks allow for comparisons between presented stimuli and previously stored information. Ennaceur and Delacour described the NOR test in rats, which is based on the exploration of differences between familiar and novel objects (“A new one-trial test for neurobiological studies of memory in rats: I. Behavioral data”, Behavioral Brain Research , 31 ( 1), 47-59, 1988). The NOR test is a non-rewarding, behavior-related paradigm for measuring episodic memory, based on spontaneous exploratory behavior in rats. Each session consists of two trials. In the first trial, rats are exposed to two identical objects in an open field. During the second trial, rats are exposed to two different objects, a familiar object from the first trial and a novel object. Object recognition in rats can be measured by the difference in time spent exploring familiar and novel objects. Rats have been shown to spend more time exploring novel objects. Rats have been found to be able to discriminate between familiar and novel objects when the inter-trial interval is between 3 minutes and 1 to 3 hours, but not when the inter-trial interval is greater than 24 hours, although this effect may be gender-dependent (Sutcliffe et al., "Influence of gender on working and spatial memory in the novel object recognition task in the rat", Behavioral Brain Research, 2007 Feb 12; 177(1): 117-25). The duration of each trial is also important, as the preference for the novel object lasts only for the first 3 minutes, after which the preference diminishes as the two objects become familiar and are explored equally.

Effects of PCP. Subchronic (sc) treatment with PCP produces neuropathological changes associated with schizophrenia. This regimen produces selective deficits in reversal learning in both the operant reversal learning test and novel object recognition. The (scPCP)-induced deficits are robust and persistent in female rats, and this dosing regimen also reduces social behavior in female hooded Lister rats. PCP-induced object recognition deficits are accompanied by deficiencies in dopamine release in the prefrontal cortex and hippocampus, and this effect can be attenuated by activation of dopamine D1 receptors. (Abdul-Monim等人, 「Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat」, Psychopharmacology, 2007 (3月), 21(2):198-205；及Snigdha等人, 「PCP-Induced Disruption in Cognitive Performance is Gender-Specific and Associated with A Reduction in Brain-Derived Neurotrophic Factor (BDNF) in Specific Regions of the Female rat Brain」, J. Mol. Neurosci., 2011, 43:337-345；Abdul-Monim等人, 「The effect of atypical and classical antipsychotics on sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm」, Behavioral Brain Research, 169 (2006), 263-273；Abdul-Monim等人, "Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat", Psychopharmacology, 2007 (March), 21(2):198-205; McLean et al., "D ₁ -like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia", vol. 19, no. 6, June 2009, pp. 440-450; and Idris et al., "Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT ₆ and 5-HT _2A receptor mechanisms", Psychopharmacology, 208 (23), 2010; Grayson et al., "Atypical antipsychotics attenuate a sub-chronic "PCP-induced cognitive deficits in the novel object recognition task in the rat", Behavioral Brain Research, Volume 184, Issue 1, 2007; Snigdha et al., "Improvement of phencyclidine-induced social behavior deficits in rats: Involvement of 5-HT _1A receptors", Behavioral Brain Research, Volume 191, Issue 1, 2008, pp. 26-31).

The following examples provide behavioral tests and methods (NOR and social interaction examples).

It will be further appreciated that certain features of the invention described in the context of separate embodiments for clarity may also be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may also be provided separately or in any suitable sub-combination.

Examples Detailed compound synthesis methods are described in the examples provided herein. A person skilled in the art of chemistry will be able to make compounds of formula (I) and related formulae, including the specific compounds described herein, by these methods or similar methods or other methods practiced by a person skilled in the art. In general, the starting components are commercially available chemicals and can be obtained from commercial sources, or can be made according to organic synthesis techniques known to a person skilled in the art, using commercially available chemicals and/or compounds described in the chemical literature as starting materials. The compounds described herein are named according to MarvinSketch 18.24.0 or ChemDraw Professional 20.1.1.125. In some cases, when common names are used, it should be understood that such common names will be recognized by a person skilled in the art.

"Commercially available chemicals" are available from standard commercial sources, including Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.) , BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co . (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), Key Organics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge Chemical Co. Ltd . (Cornwall U.K.), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (New Brunswick , NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD) and Wako Chemicals USA, Inc. (Richmond VA).

Methods generally known to those skilled in the art can be identified through various reference books and databases. Suitable reference books and papers detailing the synthesis of reactants suitable for preparing the compounds of the present invention or referring to articles describing the preparation include, for example, Synthetic Organic Chemistry , John Wiley & Sons, Inc., New York; SR Sandler et al., Organic Functional Group Preparations , 2nd edition, Academic Press, New York, 1983; HO House, Modern Synthetic Reactions , 2nd edition, WA Benjamin, Inc. Menlo Park, Calif. 1972; TL Gilchrist, Heterocyclic Chemistry , 2nd edition, John Wiley & Sons, New York, 1992; J. March, Advanced Organic Chemistry : Reactions , Mechanisms and Structure , 4th edition, Wiley Interscience, New York, 1992. Additional suitable reference books and articles detailing the synthesis of reactants suitable for preparing the compounds of the present invention or referring to articles describing such preparations include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials , 2nd Revised Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, RV Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RC Comprehensive Organic Transformations: A Guide to Functional Group Preparations , 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure , 4th edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J. (Ed.) Modern Carbonyl Chemistry , (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai , S., Patai's 1992 Guide to the Chemistry of Functional Groups , (1992) Interscience ISBN: 0-471-93022-9; Quin, LD et al. A Guide to Organophosphorus Chemistry , (2000) Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, TWG Organic Chemistry , 7th edition (2000) John Wiley & Sons, ISBN: 0-471-19095-0; Stowell, JC, Intermediate Organic Chemistry , 2nd edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2; Industrial Organic Chemicals: Starting Materials and Intermediates: An Ullmann's Encyclopedia , (1999) John Wiley & Sons, ISBN: 3-527-29645-X, 8 volumes; Organic Reactions , (1942-2019) John Wiley & Sons, over 95 volumes; and Chemistry of Functional Groups , John Wiley & Sons, hardcover volumes (86) and electronic volumes (26).

Specific and similar reactants may also be identified through the Index to Known Chemicals compiled by the Chemical Abstract Service of the American Chemical Society, which is available in most public and university libraries, and through online databases (for more details, contact the American Chemical Society, Washington, D.C.). Chemicals that are known but not listed in commercially available catalogs may be prepared by custom chemical synthesizers according to known methods, many of which provide custom synthesis services.

The term "reducing agent" refers to a compound that donates a hydride to an electrophilic position of a reactant compound, such as an unsaturated carbon (e.g., a carbon of a carbonyl moiety), such as converting a reactant compound containing a ketone into an alcohol product compound or converting a reactant compound containing an ester into an alcohol product compound. The reducing agent may be a hydride reducing agent. Exemplary hydride reducing agents include, but are not limited to, diborane, borane (e.g., borane tetrahydrofuran complex), 9-boranebicyclo[3.3.1]nonane, lithium aluminum hydroxide, diisobutyl aluminum hydroxide, diisobutyl-tert-butoxy lithium aluminum hydroxide, tris-tert-butoxy lithium aluminum hydroxide, tris[(3-ethyl-3-pentyl)oxy] lithium aluminum hydroxide, sodium bis(2-methoxyethoxy)aluminum hydroxide, sodium aluminum hydroxide, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, tetraethylammonium borohydride, tetramethylammonium borohydride, copper(I)bis(triphenylphosphine)borohydride, lithium 9-boranobicyclo[3.3.1]nonanehydride, sodium triacetyloxyborohydride, potassium tri-dibutylborohydride, sodium tri-dibutylborohydride, tripentylpotassium borohydride, lithium triethylborohydride, potassium triethylborohydride, sodium triethylborohydride, potassium triphenylborohydride, lithium dimethylaminoborohydride, lithium pyrrolidinylborohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, sodium borohydride and the like.

The term "halogenating agent" refers to a compound that donates a halogen atom to a reactant compound, such as a compound that converts an alcohol reactant compound into a halogenated product compound. Examples of halogenating agents include, but are not limited to, thionyl chloride, ethylenediyl chloride, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, methanesulfonyl chloride and NaI, p-toluenesulfonyl chloride and NaI, phosphorus tribromide, triphenylphosphine dibromide, phosphorus pentabromide or thionyl bromide and the like.

The term "amide coupling agent" refers to a compound that facilitates the formation of an amide bond, where carboxylic acid activation is required to promote coupling with an amine. Examples of amide coupling agents include, but are not limited to, thionyl chloride, ethylenediamine chloride, phosphorus oxychloride, Vilsmeier reagent, propylphosphonic anhydride, ethylmethylphosphinic anhydride (EMPA), Ac ₂ O, pivaloyl chloride, ethyl chloroformate (ECF), isobutyl chloroformate (IBCF), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), methanesulfonyl chloride (MsCl), p-toluenesulfonyl chloride (TsCl), pentafluorophenyl trifluoroacetate, cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-trioxanthate (CDMT), 4-(4,6-dimethoxy-1,3,5-trioxanthate-2-yl)-4-methylmorpholinium chloride (DMTMM), 1-tert-butyl-3-ethylcarbodiimide, 1,1'-carbonyldiimidazole (CDI), N , N' -dicyclohexylcarbodiimide (DCC), N , N' -diisopropylcarbodiimide (DIC), N -(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), 1,3-di-p-toluenecarbodiimide, benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris(tris-pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris(tris-pyrrolidinyl)phosphonium hexafluorophosphate (PyClock), 7-nitrophenyl hexafluorophosphate 1-(1-(cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-N-oxo-1-yl)-1-pyrrolidinylphosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethyleneaminooxy-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), 1-[(1-(cyano-2-ethoxy-2-oxoethyleneaminooxy)dimethylamino-N-oxo-1-yl)-1-uronium hexafluorophosphate (COMU), 3-(diethoxy-phosphatyloxy)-1,2,3-benzo[d]trioxo-4(3 H )-ketone (DEPBT), O -[(ethoxycarbonyl)cyanomethyleneamino]- N , N , N ', N '-tetramethyluronium tetrafluoroborate (TOTU), O -(2-oxo-1(2H)pyridinyl)- N , N , N ', N '-tetramethyluronium tetrafluoroborate (TPTU), 2-(1 H -benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), N , N , N ', N '-tetramethyl- O -( N -succinimidyl)uronium hexafluorophosphate (HSTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(6-chloro-1 H -benzotriazol-1-yl)-1,1,3,3-tetramethylammonium hexafluorophosphate (HCTU) and 1-[bis(dimethylamino)methylene]-1H - 1,2,3-triazolo[4,5-b]pyridinium 3-oxide (HATU).

The term "base" refers to a compound that acts as an electron pair donor in an acid-base reaction.

The base may be an inorganic base or an organic base.

The term "organic base" refers to a base including at least one CH bond (e.g., an amine base). In some embodiments, the amine base can be a primary, secondary, or tertiary amine. Examples of amine bases include, but are not limited to, methylamine, dimethylamine, diethylamine, diphenylamine, trimethylamine, triethylamine, N , N -diisopropylethylamine, diisopropylamine, piperidine, 2,2,6,6-tetramethylpiperidine, pyridine, 2,6-lutidine, 4-methylphosphine, 4-ethylphosphine, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,8-diazabicyclo[5,4.0]undec-7-ene, 1,8-diazabicyclo[5,4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane, 1,8-bis(dimethylamino)naphthalene, 4-(dimethylamino)pyridine, and the like. In some aspects, the amine base may include an alkali metal or an alkali earth metal. Examples of amine bases including an alkali metal include, but are not limited to, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithium dicyclohexylamide, lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, 2,2,6,6-tetramethylpiperidinium, and the like. In some aspects, the organic base may be a metal alkoxide. Examples of metal alkoxides include, but are not limited to, barium tertiary butoxide, lithium tertiary pentanolate, lithium tertiary butoxide, lithium ethoxide, lithium isopropoxide, lithium methoxide, magnesium di-tertiary butoxide, magnesium ethoxide, magnesium methoxide, potassium tertiary butoxide, potassium ethoxide, potassium methoxide, potassium tertiary pentanolate, sodium tertiary butoxide, sodium ethoxide, sodium methoxide, sodium tertiary pentanolate, and the like. In some aspects, the organic base may be an organic metal base (e.g., an organic lithium base or an organic magnesium base). Examples of the organic lithium base include, but are not limited to, n-butyl lithium, dibutyl lithium, tertiary butyl lithium, ethyl lithium, hexyl lithium, isobutyl lithium, isopropyl lithium, methyl lithium, hexyl lithium, phenyl lithium and the like. Examples of organic magnesium alkalis include, but are not limited to, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium bromide, ethylmagnesium chloride, isopropylmagnesium bromide, isopropylmagnesium chloride, n-propylmagnesium chloride, propylmagnesium chloride, isobutylmagnesium bromide, isobutylmagnesium chloride, butylmagnesium chloride, dibutylmagnesium bromide, tertiarybutylmagnesium chloride, cyclopentylmagnesium bromide, cyclopentylmagnesium chloride, 2-pentylmagnesium bromide, 3-pentylmagnesium bromide, isopentylmagnesium bromide, pentylmagnesium bromide, phenylmagnesium bromide, phenylmagnesium chloride, cyclohexylmagnesium chloride, pentadecylmagnesium bromide, octadecylmagnesium chloride, and the like.

The term "inorganic base" refers to a base that does not include at least one C-H bond and includes at least one alkali metal or alkali earth metal. Examples of inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium carbonate, calcium carbonate, cesium carbonate, lithium carbonate, magnesium carbonate, potassium carbonate, sodium carbonate, cesium bicarbonate, potassium bicarbonate, sodium bicarbonate, barium hydroxide, calcium hydroxide, cesium hydroxide, lithium hydroxide, magnesium hydroxide, potassium hydroxide, sodium hydroxide, and the like.

The term "acid" refers to a compound that acts as an electron pair acceptor in an acid-base reaction.

The acid may be an inorganic acid or an organic acid.

The term "inorganic acid" refers to an acid that does not include a carbon bond. Inorganic acids can be strong or weak. Examples of inorganic acids include, but are not limited to, aminosulfonic acid, hydrochloric acid, hydroiodic acid, hydrobromic acid, perchloric acid, sulfuric acid, nitric acid, boric acid, fluorophosphoric acid, phosphoric acid, and the like.

The term "organic acid" refers to an acid that includes at least one C-H bond, C-F bond, or C-C bond. Examples of organic acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, difluoroacetic acid, ethanesulfonic acid, formic acid, fumaric acid, gallic acid, glycolic acid, lactic acid, maleic acid, malonic acid, methanesulfonic acid, nitrilotriacetic acid, oxalic acid, phthalic acid, propionic acid, salicylic acid, succinic acid, 5-sulfosalicylic acid, L-(+)-tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, and the like.

General Reaction Schemes The present invention also includes processes for compounds of formula (I). In the reactions described, it may be necessary to protect reactive functional groups, such as hydroxyl, amine, imino, thio or carboxyl groups, where these are desired in the final product, to avoid their unwanted participation in the reaction. Conventional protecting groups may be used in accordance with standard practice, for example, see T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

The compound of formula (I) can be prepared by following the reaction scheme 1: wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , X ₁ , X ₂ and X ₃ are as defined in the above invention. The compound of formula I can be synthesized by combining the compound of formula (2) with the compound of formula (3) in the presence of a suitable solvent (such as DCM, DCE, NMP, DMF, EtOAc, toluene, dioxane, ethanol, water and the like), optionally a suitable base (such as DIEA, TEA and the like) and a suitable coupling agent (such as EDC/HOBt, HATU, HBTU, HCTU and the like). The reaction is carried out at a temperature of about 0° C. to about 80° C. and may take up to about 24 hours to complete. See the following specific examples.

The compound of formula (I) can be prepared by following the reaction scheme 2: wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , X ₁ , X ₂ and X ₃ are as defined in the above invention, and Z is a suitable ionizable group, such as a halogen (e.g. chlorine) and the like. The compound of formula (I) can be synthesized by combining a compound of formula (4) with a compound of formula (5) in the presence of a suitable solvent (such as toluene, dioxane, ethanol, DMF, EtOAc and the like), a suitable base (such as sodium carbonate, sodium hydroxide, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide and the like) and a suitable coupling agent (such as tetrakis-triphenylphosphine palladium (0) [CAS: 14221-01-3], X-Phos-Pd-G2 [CAS: 1310584-14-5], X-Phos-Pd-G3 [CAS: 1445085-55-1], X-Phos Pd-G4 [CAS: 1599466-81-5] and the like). The reaction is carried out at a temperature of about 50°C to about 120°C and may take up to about 24 hours to complete. See specific examples below.

The compound of formula (I) can be prepared by following the reaction scheme 3: wherein R ₁ , R ₂ , R ₃ , R ₄ , R ₇ , X ₁ , X ₂ and X ₃ are as defined in the above invention, and Q is chlorine, fluorine or bromine. The compound of formula I can be synthesized by combining the compound of formula (6) with the compound of formula (7) in the presence of a suitable solvent (such as DMF, NMP, THF, dioxane, DMA, EtOH, MeOH, IPA, BuOH and the like) and a suitable base (such as potassium carbonate, sodium carbonate, cesium carbonate, NaH and the like). The reaction is carried out at a temperature of about 20° C. to about 100° C. and may take up to about 24 hours to complete. See the following specific examples.

Additional Processes for Making the Compounds of the Invention The compounds of the invention may be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, pharmaceutically acceptable base addition salts of the compounds of the invention may be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.

The compounds of formula I may also be modified by appending appropriate functional groups to enhance selective biological properties. Such modifications are known in the art and include those that increase penetration into a given biological system (e.g., blood, lymphatic system, central nervous system, testis), increase bioavailability, increase solubility to allow parenteral administration (e.g., injection, infusion), alter metabolism, and/or alter secretion rate. Examples of this type of modification include, but are not limited to, for example, esterification with polyethylene glycol, derivatization with pivaloyloxy or fatty acid substituents, conversion to carbamates, hydroxylation of aromatic rings, and heteroatom substitution in aromatic rings.

Whenever a compound of formula I and/or its N-oxide, tautomer and/or (preferably pharmaceutically acceptable) salt is mentioned, this includes such modified forms and preferably means a molecule of formula I, its N-oxide, its tautomer and/or its salt.

Alternatively, salts of the starting materials or intermediates may be used to prepare the salt forms of the compounds of the invention. In view of the close relationship between the novel compounds of formula I in free form and those in the form of their salts (including those salts which can be used as intermediates, for example, in the purification or identification of the novel compounds), any reference above and below to one or more compounds of formula I should be understood as referring to the compound in free form and/or, where appropriate and expedient, also to one or more salts thereof, and to one or more solvates, such as hydrates.

Preferably, the salt is formed from the compound of formula I having a basic nitrogen atom with an organic or inorganic acid, for example as an acid addition salt, in particular a pharmaceutically acceptable salt. Suitable inorganic acids are, for example, hydrohalides (such as hydrochloric acid), sulfuric acid or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphoric acid, sulfonic acids or sulfamic acids, for example acetic acid, propionic acid, caprylic acid, capric acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, apple acid, tartaric acid, citric acid, amino acids (such as glutamine or aspartic acid), citric acid, hydroxycitric acid, methylcitric acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminohydrogen iodide. Salicylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methanesulfonic acid or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalene-disulfonic acid, 2-methylbenzenesulfonic acid or 3-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylaminesulfonic acid, N-methylaminesulfonic acid or N-ethylaminesulfonic acid, or other organic protonic acids (such as ascorbic acid).

For isolation or purification purposes, it is also possible to use pharmaceutically unacceptable salts, such as picrates or perchlorates. For therapeutic use, only pharmaceutically acceptable salts or free compounds (where appropriate in the form of pharmaceutical preparations) are used and, therefore, these are preferred.

The free acid or free base form of the compound of the present invention can be prepared from the corresponding base addition salt or acid addition salt form, respectively. For example, the compound of the present invention in the form of an acid addition salt can be converted into the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide and the like). The compound of the present invention in the form of a base addition salt can be converted into the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

The compounds of the present invention can be prepared in unoxidized form from oxides of the compounds of the present invention by treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide or the like) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane or the like) at 0 to 80°C.

Prodrug derivatives of the compounds of the present invention can be prepared by methods generally known to those skilled in the art (e.g., see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985 for further details). For example, a suitable prodrug can be prepared by reacting an underivatized compound of the present invention with a suitable aminoformylating agent (e.g., 1,1-acyloxyalkyl chloroformate, p-nitrophenyl carbonate or the like).

Protected derivatives of the compounds of the present invention can be prepared by methods generally known to those skilled in the art. A detailed description of techniques applicable to the generation of protecting groups and their removal can be found in T. W. Greene, "Protecting Groups in Organic Chemistry", 3rd edition, John Wiley and Sons, Inc., 1999.

The compounds of the present invention may be conveniently prepared or formed as solventates (e.g., hydrates) during the process of the present invention. Hydrates of the compounds of the present invention may be conveniently prepared by recrystallization from an aqueous/organic solvent mixture using an organic solvent such as dioxane, tetrahydrofuran, or methanol.

The compounds of the present invention can be prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of non-mirror image isomers, separating the non-mirror image isomers, and recovering the optically pure mirror image isomers. Although mirror image isomers can be resolved using covalent non-mirror image derivatives of the compounds of the present invention, it is preferred to resolve the complex (e.g., crystalline non-mirror image isomer salts). Non-mirror image isomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and can be easily separated by utilizing these differences. Non-mirror isomers can be separated by chromatography or, preferably, by separation/resolution techniques based on differences in solubility. The optically pure mirror isomers are then recovered along with the resolving agent by any practical means that will not produce racemization. A more detailed description of techniques applicable to the resolution of stereoisomers of a compound from its racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley And Sons, Inc., 1981.

In summary, the compound of formula I can be prepared by a process involving: (a) the process of reaction scheme 1, 2 or 3; and (b) converting the compound of the present invention into a pharmaceutically acceptable salt, as appropriate; (c) converting the salt form of the compound of the present invention into a non-salt form, as appropriate; (d) converting the unoxidized form of the compound of the present invention into a pharmaceutically acceptable N-oxide, as appropriate; (e) converting the N-oxide form of the compound of the present invention into its unoxidized form, as appropriate; (f) resolving the individual isomers of the compound of the present invention from an isomeric mixture, as appropriate; (g) converting the underivatized compound of the present invention into a pharmaceutically acceptable prodrug derivative, as appropriate; and (h) converting the prodrug derivative of the compound of the present invention into its underivatized form, as appropriate.

Insofar as the production of the starting materials is not particularly described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the examples below.

Those skilled in the art will appreciate that the above transformations merely represent methods for preparing the compounds of the present invention, and that other well-known methods may be similarly used.

The following examples are included to demonstrate aspects of the invention. However, in light of the present invention, those skilled in the art will appreciate that many changes may be made to the specific aspects disclosed without departing from the spirit and scope of the invention and still obtaining the same or similar results.

This manual contains many abbreviations, which are defined in the following table: Abbreviation Definition ACN or CH ₃ CN Acetonitrile BOC tert-butyloxycarbonyl CDI 1,1'-Carbonyldiimidazole EtOAc Ethyl acetate DBU 1,8-Diazabicyclo[5,4.0]undec-7-ene DCC Dicyclohexylcarbodiimide DCE Ethylene dichloride DCM Dichloromethane or methylene chloride de Excess of non-mirror isomers DIPEA N ,N -Diisopropylethylamine DMSO Dimethyl sulfoxide DMSO- d ₆ Dimethylsulfoxide - d ₆ ee Excessive mirror image isomers FC Rapid chromatography HPLC HPLC KHMDS Potassium bis(trimethylsilyl)amine LCMS Liquid chromatography-mass spectrometry min. minute NH ₄ Cl Ammonium chloride Pd(PPh ₃ ) ₄ Tetrakis(triphenylphosphine)palladium TEA Triethylamine TFA Trifluoroacetate THF Tetrahydrofuran

Analytical HPLC analysis was performed on a LC-MS system with a UV detector (Dionex ^™ UVD 170u UV/VIS detector), a corona array detector (Thermo ^™ Veo ^™ RS) and a mass spectrometer (Dionex MSQ Plus ^™ ). Reverse phase preparative HPLC purification was performed on a Phenomenex LCMS system C18 Kinetix 5μ 100 A 150×21.2 mm column using an ACN/water gradient containing 0.05% TFA. All final compounds were analyzed by analytical HPLC and the peaks for purity were monitored at 210, 254 and 280 nM. ¹ H (referenced to tetramethylsilane (TMS) signal) in a suitable NMR solvent (e.g. DMSO -d ₆ ) was recorded on a Bruker 400 MHz (or Varian 400 MHz) mass spectrometer equipped with an in-house broadband NMR probe. ¹ H chemical signals are given in parts per million (ppm) with the residual solvent signal used as a reference. Chemical shifts are expressed in ppm ( δ ) and coupling constants ( J ) are reported in Hertz (Hz). Reactions were performed under a dry nitrogen atmosphere unless otherwise stated.

HPLC method A: Column: XSelect CSH C18 (150×4.6) mm, 3.5μ; Mobile phase A: 0.1% FA/water:ACN (95:05); Mobile phase B: acetonitrile; Gradient program: T/B%: 0.01/5, 1/5, 8/100, 12/100, 14/5, 18/5; Flow rate: 1.2 mL/min

In addition, the following LCMS method was used: LCMS method A : LCMS XSelect (formic acid); column: XSelect CSH C18 (3.0×50) mm 2.5μ; mobile phase: A: 0.05% formic acid/water:ACN (95:5); B: 0.05% formic acid/ACN; injection volume: 2.0 μL, column oven temperature: 50°C; flow rate: 1.2 mL/min; gradient program: 0% B to 98% B in 2.0 min, hold until 3.0 min, B concentration is 0% at 3.2 min until 4.0 min. LCMS Method 1A : Platform: Agilent 1260 UPLC with Thermo MSQ mass detector and Agilent DAD (220 and 254 nm); HPLC column: Waters XBridge BEH C18, 2.5 µM, 50×3.0 mm XP; HPLC gradient: 1.5 mL/min, 10% acetonitrile (with 0.025% TFA)/water (with 0.025% TFA) for 6 seconds, followed by an increase to 90% acetonitrile in 1.5 minutes. Increase to 99% acetonitrile in 6 seconds, followed by a hold at 99% acetonitrile for 12 seconds. Return to 10% acetonitrile in 6 seconds and hold at 10% for 30 seconds. LCMS Method 1B : Platform: Agilent 1260 UPLC with Thermo MSQ mass detector and Agilent DAD (220 and 254 nm); HPLC column: Waters XBridge BEH C18, 2.5 µM, 50×3.0 mm XP; HPLC gradient: 1.5 mL/min, 10% acetonitrile (with 0.025% TFA)/water (with 0.025% TFA) for 6 seconds, followed by an increase to 90% acetonitrile in 6.5 minutes. Increase to 99% acetonitrile in 6 seconds, followed by a hold at 99% acetonitrile for 12 seconds. Return to 10% acetonitrile in 6 seconds and hold at 10% for 30 seconds. LCMS Method 2A : Platform: Thermo Vanquish UHPLC with Thermo ISQEC mass detector, Thermo DAD (212, 220, 254 and 270 nm) and Thermo Charged Aerosol Detector; HPLC column: Waters ACQUITY UPLC BEH C18, 1.7 µM, 50×2.1 mm; HPLC gradient: 1.1 mL/min, 10% acetonitrile (with 0.025% TFA)/water (with 0.025% TFA) for 6 seconds, followed by an increase to 90% acetonitrile in 1.35 minutes. Increase to 99% acetonitrile in 6 seconds, followed by a hold at 99% acetonitrile for 9 seconds. Return to 10% acetonitrile in 6 seconds and hold at 10% for 12 seconds. LCMS Method 2B : Platform: Thermo Vanquish UHPLC with Thermo ISQEC mass detector, Thermo DAD (212, 220, 254 and 270 nm) and Thermo electrospray detector; HPLC column: Waters ACQUITY UPLC BEH C18, 1.7 µM, 50×2.1 mm; HPLC gradient: 1.0 mL/min, 5% acetonitrile (with 0.025% TFA)/water (with 0.025% TFA) for 6 seconds, followed by an increase to 90% acetonitrile in 6.35 minutes. Increase to 99% acetonitrile in 6 seconds, followed by a hold at 99% acetonitrile for 9 seconds. Return to 5% acetonitrile in 6 seconds and hold at 5% for 12 seconds. LCMS Method 3A : Platform: Thermo Vanquish UHPLC with Thermo ISQEC mass detector, Thermo DAD (212, 220, 254 and 270 nm) and Thermo electrospray detector; HPLC column: Waters ACQUITY UPLC BEH C18, 1.7 µM, 50 x 2.1 mm; HPLC gradient: 1.1 mL/min, 2% acetonitrile (with 0.025% TFA)/water (with 0.025% TFA) for 42 seconds, followed by an increase to 90% acetonitrile in 2.8 minutes. Increase to 99% acetonitrile in 6 seconds. Return to 2% acetonitrile in 6 seconds and hold at 2% for 9 seconds.

The examples illustrate but are not limited to the synthesis of compounds of formula (I).

Intermediate Example 1 4 -(( 2 - chloropyridin - 4 - yl ) oxy ) -2 - fluorobenzonitrile Synthesis of 4-((2-chloropyridin-4-yl)oxy)-2-fluorobenzonitrile

NaH (44 mg, 1.1 mmol, 1.1 eq, 60% dispersion in mineral oil) was slowly added to a solution of 2-fluoro-4-hydroxybenzonitrile (151 mg, 1.1 mmol, 1.1 eq) in anhydrous DMF (660 µL, 1.5 M) at 0 °C. The mixture was allowed to warm to room temperature and stirred for 20 min. 4-Fluoro-2-chloropyridine (131 mg, 1 mmol, 1 eq.) was added to the reaction mixture. The reaction mixture was stirred at 100 °C. After 18 h, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (ISCO 24 g, 0 to 30% EtOAc/hexanes) to give 4-[(2-chloropyridin-4-yl)oxy]-2-fluorobenzonitrile (71 mg, 28%) as a white solid. 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.40 (d, J = 5.7 Hz, 1H), 8.06 (t, J = 8.1 Hz, 1H), 7.57 (dd, J = 10.6, 2.3 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.27 (dd, J = 8.7, 2.2 Hz, 1H), 7.18 ppm (dd, J = 5.7, 2.3 Hz, 1H). LCMS method 1A: r.t. = 1.83 min, m/z (M+H+) = 248.9 observed mass, exact mass 248.01.

According to the procedure in Intermediate Example 1, the following intermediate examples in Table 1 were prepared using appropriate starting materials: Table 1 5-((2-chloropyridin-4-yl)oxy)-2-fluorobenzonitrile LCMS Method 1A: rt = 1.88 min, m/z (M+H+) = 248.96 observed mass, exact mass 248.01 2-Chloro-4-((5-methoxypyridin-3-yl)oxy)pyridine 1H NMR (400 MHz, DMSO-d, 27 °C): δ = 8.27 to 8.36 (m, 2H), 8.13 (br s, 1H), 7.42 (m, 1H), 7.13 (s, 1H), 7.03 (m, 1H), 3.84 ppm (s, 1H) LCMS Method 2A: rt = 0.931 min, m/z (M+H+) = 237.08 observed mass, exact mass 236.04. 2-Chloro-4-(4-(trifluoromethyl)phenoxy)pyridine 1H NMR (400 MHz, DMSO-d, 27 °C): δ = 8.36 (d, J = 5.7 Hz, 1H), 7.84 to 7.91 (m, J = 8.6 Hz, 2H), 7.42 to 7.48 (m, J = 8.4 Hz, 2H), 7.20 (d, J = 2.0 Hz, 1H), 7.07 ppm (dd, J = 5.7, 2.1 Hz, 1H) LCMS Method 1A: rt = 2.17 min, m/z (M+H+) = 273.88 observed mass, exact mass 273.02 2-Chloro-4-((5-chloropyridin-3-yl)oxy)pyridine LCMS Method 1A: rt = 1.79 min, m/z (M+H+) = 240.87 observed mass, exact mass 239.98 3-Chloro-5-((2-chloropyridin-4-yl)oxy)-2-methylpyridine LCMS Method 1A: rt = 1.92 min, m/z (M+H+) = 254.89 observed mass, exact mass 254.00 5-Chloro-3-((2-chloropyridin-4-yl)oxy)-2-fluoropyridine LCMS Method 1A: rt = 1.95 min, m/z (M+H+) = 258.90 observed mass, exact mass 257.97 4-Chloro-6-(4-ethoxy-3-fluorophenoxy)pyridin-2-amine (starting from 4,6-dichloropyridin-2-amine and 4-ethoxy-3-fluorophenol) LCMS method 2A: rt = 1.17 min, m/z (M+H+) = 283.06 observed mass, exact mass 282.06 3-Chloro-5-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridine LCMS Method 3A: rt = 1.87 min, m/z (M+H+) = 274.9 observed mass, exact mass 274.01 3-Chloro-5-((5-(1,1-difluoroethyl)pyridin-3-yl)oxy)pyridine LCMS Method 3A: rt = 1.77 min, m/z (M+H+) = 271.01 observed mass, exact mass 270.04.

Intermediate Example 2 Methyl 2 - methyl - 4- ( 4- ( 4- ( trifluoromethyl ) phenoxy ) pyridin - 2 - yl ) benzoate Synthesis of methyl 2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzoate

A solution of methyl 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.800 mmol, 1.0 equiv), 2-chloro-4-(4-(trifluoromethyl)phenoxy)pyridine (0.241 g, 0.880 mmol, 1.1 equiv), tetrakis-triphenylphosphine Pd(0) (46.2 mg, 0.0400 mmol, 5 mol%) and sodium carbonate (0.8 mL, 1 M aqueous solution, 2.0 equiv) in degassed dioxane (0.15 M, 5.3 mL) was heated at 85 °C for 5 h. The reaction mixture was concentrated and loaded directly onto silica gel. Purify on a 12 g silica gel column using a gradient of 0 to 40% EtOAc/hexanes over 20 min. The title compound (191.6 mg, 0.493 mmol, 62% yield) was obtained as an oil. LCMS Method 2A: r.t. = 1.36 min, m/z (M+H+) = 388.12 observed mass, exact mass 387.11.

Intermediate Example 3 2 - Methyl - 4- ( 4- ( 4- ( trifluoromethyl ) phenoxy ) pyridin - 2 - yl ) benzoic acid Synthesis of 2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzoic acid

A solution of methyl 2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzoate (123 mg, 0.318 mmol, 1.0 equiv.) in NaOH (2 M, 1.6 mL, 10 equiv.):methanol (0.2 mL, 0.1 M) was stirred at 40 °C overnight. Methanol was added until the solution became homogeneous under heating. The next day, the reaction was complete. Methanol was removed under reduced pressure. 1 M HCl (3.0 mL) was added to the aqueous solution until the pH became acidic. The desired product was precipitated from acidic water. The sample was filtered and the white precipitate was collected (washed with hexanes). The title compound (0.1049 g, 0.281 mmol, 88% yield) was obtained as a white solid. LCMS Method 2A: r.t. = 1.17 min, m/z (M+H+) = 374.08 observed mass, exact mass 373.09.

Intermediate Example 4 4-(4- fluoropyridin -2- yl )-2- methylbenzamide Synthesis of 4-(4-fluoropyridin-2-yl)-2-methylbenzamide

In a 100 mL RB flask, Pd(PPh ₃ ) ₄ (2.88 g, 2.5 mmol, 5 mol%) was added to a solution of 2-chloro-4-fluoropyridine (6.58 g, 50 mmol) and 2-methyl-4-(tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)benzamide (15.67 g, 60 mmol, 1.2 eq) in toluene/ethanol/saturated aqueous Na ₂ CO ₃ (2/2/1, 500 mL, 0.1 M). The reaction was heated at 80 °C. After 18 h, the reaction was cooled to rt and diluted with water (300 mL). The solution was extracted with EtOAc (3×400 mL) and the organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with dichloromethane (150 mL) and filtered. The filter cake was washed with dichloromethane (50 mL). The dark brown filtrate was concentrated in vacuo, and the dark brown solid was triturated again with dichloromethane (about 50 mL) and filtered. The filter cake was washed with dichloromethane (about 30 mL). The solids were combined and triturated with dichloromethane (100 mL), filtered, and dried under high vacuum to give 4-(4-fluoropyridin-2-yl)-2-methylbenzamide (8.36 g, 72%) as an off-white solid which was used without further purification. 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.71 (dd, J = 9.1, 5.6 Hz, 1H), 8.02 (s, 1H), 7.93 to 8.00 (m, 2H), 7.79 (m, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.42 (br s, 1H), 7.32 (ddd, J = 8.5, 5.8, 2.3 Hz, 1H), 2.44 to 2.48 ppm (s, 3H). LCMS method 1A: rt = 1.42 min, m/z (M+H+) = 230.99 observed mass, exact mass 230.09.

Intermediate Example 5 2 - Chloro - 4 -(( 6- ( trifluoromethoxy ) pyridin - 3 - yl ) oxy ) pyridine Synthesis of 2-chloro-4-((6-(trifluoromethoxy)pyridin-3-yl)oxy)pyridine:

Step 1: Synthesis of 2-chloro-4-[(6-methoxy-3-pyridinyl)oxy]pyridine (1): To a stirred solution of 2-chloro-4-fluoropyridine (3 g x 2, 22.807 mmol) in DMSO (5 mL, 70 mmol) was added potassium carbonate (2.5 equiv., 57.017 mmol), 5-hydroxy-2-methoxypyridine (1.5 equiv., 34.210 mmol) at room temperature and the reaction mixture was stirred at 80 °C for 4 h. The progress of the reaction was monitored by TLC. After the starting material was consumed, the reaction mixture was diluted with water and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate, filtered and evaporated in vacuo to give the crude compound. The crude compound was purified by FCC. The compound was eluted with 12% EtOAc/heptane to give 2-chloro-4-((6-methoxypyridin-3-yl)oxy)pyridine (3.5 g, 64% yield) as a brown solid. 1H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.24 (d, J = 6.0 Hz, 1H), 8.00 (d, J = 2.8 Hz, 1H), 7.35 (dd, J = 9.0 Hz, 2.8 Hz, 1H), 6.84-6.77 (m, 3H), 3.97 (s, 3H). LC-MS (Method A) = 238.0 [M+H]; RT: 1.90 min.

Step 2: Synthesis of 5-[(2-chloro-4-pyridinyl)oxy]pyridin-2-ol (2): To a stirred solution of 2-chloro-4-((6-methoxypyridin-3-yl)oxy)pyridine (5 g, 21.128 mmol, 100 mass %) in ACN (50 mL) was added KI (2.5 equiv., 52.821 mmol) dropwise at room temperature followed by trimethylsilyl chloride (TMSCl) (2.5 equiv., 52.821 mmol) while stirring at 80 °C for 16 h. After completion of the starting material (monitored by TLC and LCMS), the reaction mixture was quenched with water (5.0 mL) and extracted with EtOAc (2 x 5.0 mL). The combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated under reduced pressure. The crude residue was purified by combi-flash column chromatography using silica gel mesh (100-200) eluting with 100% EtOAc/heptane to afford 5-[(2-chloro-4-pyridyl)oxy]pyridin-2-ol (2.5 g, 11 mmol, 52% yield) as a brown solid. LC-MS (Method A) = 223.1 [M+H]; RT: 0.93 min.

Step 3: Synthesis of 2-chloro-4-[[6-(trifluoromethoxy)-3-pyridinyl]oxy]pyridine (NA026): To a stirred solution of 5-[(2-chloro-4-pyridinyl)oxy]pyridin-2-ol (1.00 g, 4.49 mmol) in nitromethane (5 mL) was added 1-trifluoromethyl-1,2-benzoiodinecyclopentan-3(1H)-one (0.3 equiv., 1.35 mmol) at 0 °C. The resulting reaction mixture was stirred at 120 °C for 2 h at MW. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was evaporated under reduced pressure to obtain the crude compound. The crude compound was first partially purified by combi-flash eluting with 0 to 20% EtOAc/heptane to give a mixture of compounds with 79% LCMS, 45% HPLC purity. This mixture was further purified by preparative HPLC (obtained by combi flash purification) to give pure 2-chloro-4-[[6-(trifluoromethoxy)-3-pyridinyl]oxy]pyridine (30.00 mg, 2.30% yield) as a white solid. 1H NMR (400 MHz, CDCl ₃ ): δ (ppm) = 8.38 (d, J = 2.8 Hz, 1H), 8.33 (d, J = 6.0 Hz, 1H), 8.00 (dd, J = 8.8 Hz, 2.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.21 to 7.20 (m, 1H), 7.09 to 7.07 (m, 1H). LC-MS (Method A) = 290.9 [M+H]; RT: 6.17 min. HPLC (Method A) = 99.80% at RT; 6.06 min.

Intermediate Example 6 2 - Chloro - 4 -(( 5- ( trifluoromethoxy ) pyridin - 3 - yl ) oxy ) pyridine Synthesis of 2-chloro-4-((5-(trifluoromethoxy)pyridin-3-yl)oxy)pyridine:

Step 1: Synthesis of 3-methyl-1-((methylthio)thiocarbonyl)-1H-benzo[d]imidazol-3-ium iodide: A solution of 1H-benzo[d]imidazole 7 (5.0 g, 42.3 mmol, 1.0 equiv.) in tetrahydrofuran (50 mL, 0.8 M) was added to a stirred suspension of sodium hydride (1.3 g, 1.1 mmol) in tetrahydrofuran (50 mL, 0.8 M). After 5 min, carbon disulfide (3.05 mL, 1.02 mmol) and iodomethane (4 mL, 1.27 mmol) were added to the reaction mixture at room temperature and the reaction mixture was stirred for another 30 min. The reaction mixture was diluted with ice-cold water and extracted with ethyl acetate. The combined organic extracts were concentrated under reduced pressure to give a residue, which was separated by silica gel combi-flash (ethyl acetate/hexane: 30%) to give 1H-benzo[d]imidazole-1-carbodisulfate methyl ester 8 (6.1 g, 69%) as a yellow solid. 1H NMR (CDCl3, 400 MHz): δ 8.90 (s, 1H), 8.53-8.55 (m, 1H), 7.81-7.83 (m, 1H), 7.38-7.44 (m, 2H), 2.85 (s, 3H). LCMS: Rt = 3.36 min, [M+H] = 208.8. The samples were analyzed using the following conditions: Shimadzu Prominence HPLC attached to Applied Biosystems API 2000 mass spectrometer; Column-X bridge C18 (4.6×50 mm, 5µ); column temperature-ambient, mobile phase A: 10 mm ammonium acetate/water, mobile phase B: acetonitrile, flow rate: 1.20 ml/min, analysis time: 5.10 min.

A single-neck-shield flask equipped with a stir bar and a septum was purged with nitrogen. 1H-Benzo[d]imidazol-1-carbodisulfate methyl ester 8 (3.0 g, 14.4 mmol, 1.0 equiv.) in acetonitrile (30 mL, 0.48 M) and excess iodomethane (12 mL) were added. The resulting mixture was heated in an oil bath at 80 °C for 6 h. A bright orange precipitate was produced. The precipitate was filtered, washed with ethyl acetate/hexanes 3:1 (100 mL) and dried under reduced pressure to give 3-methyl-1-((methylthio)thiocarbonyl)-1H-benzo[d]imidazol-3-ium iodide 6 (3.8 g, 75%) as an orange solid. 1H NMR (CDCl3, 400 MHz): δ 11.82 (s, 1H), 8.50 to 8.52 (m, 1H), 7.74 to 7.81 (m, 3H), 4.53 (s, 3H), 2.96 (s, 3H). LCMS: Rt = 2.81 min, [M+NH4] = 241.2. The sample was analyzed using the following conditions: Shimadzu Prominence HPLC attached to Applied Biosystems API 2000 mass spectrometer; Column-X bridge C18 (4.6×50 mm, 5µ); column temperature-ambient, mobile phase A: 10 mm ammonium acetate/water, mobile phase B: acetonitrile, flow rate: 1.20 ml/min, analysis time: 5.10 min.

Preparation of 2-chloro-4-((5-methoxypyridin-3-yl)oxy)pyridine: To a stirred solution of 2-chloro-4-fluoropyridine (1 g, 7.6 mmol, 1.0 equiv.) in DMSO (12 mL, 0.63 M) was added potassium carbonate (2.1 g, 15.2 mmol, 2.0 equiv.) and 5-methoxypyridin-3-ol (1.2 g, 9.16 mmol, 1.2 equiv.) at room temperature, followed by heating at 80 °C for 12 h. Subsequently, the reaction mixture was cooled to room temperature, quenched with ice water and extracted with ethyl acetate, washed with water and brine. The organic layer was dehydrated over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel combi-flash (ethyl acetate/hexane: 20 to 30%) to give the desired compound 2-chloro-4-((5-methoxypyridin-3-yl)oxy)pyridine 3 (1.4 g, 77%) as an off-white solid. ¹ H NMR (DMSO-d6, 400 MHz): δ 8.31 (d, J = 5.8 Hz, 1H), 8.29 (d, J = 2.4 Hz, 1H), 8.13 (d, J = 2.1 Hz, 1H), 7.41 (t, J = 2.2 Hz, 1H), 7.12 (d, J = 2.1 Hz, 1H), 7. 02 (dd, J = 5.8 Hz, J = 2.2 Hz, 1H), 3.85 (s, 3H). LCMS: Rt = 2.88 min, [M+H] = 236.8. The samples were analyzed using the following conditions: Shimadzu Prominence HPLC attached to Applied Biosystems API 2000 mass spectrometer; Column-X bridge C18 (4.6×50 mm, 5µ); column temperature-ambient, mobile phase A: 10 mm ammonium acetate/water, mobile phase B: acetonitrile, flow rate: 1.20 ml/min, analysis time: 5.10 min.

Preparation of 5-((2-chloropyridin-4-yl)oxy)pyridin-3-ol: To a stirred solution of 2-chloro-4-((5-methoxypyridin-3-yl)oxy)pyridine (500 mg, 2.11 mmol, 1.0 equiv.) in toluene (10 mL, 0.21 M) was added aluminum chloride (1.2 g, 8.4 mmol, 4.0 equiv.) at room temperature, followed by reflux at 100 °C for 3 h. The reaction mixture was cooled to room temperature and quenched with a saturated ammonium chloride solution, extracted with ethyl acetate and washed with brine. The organic portion was dried over sodium sulfate and concentrated under reduced pressure to give a crude product, which was purified by silica gel column combi-flash (MeOH/DCM: 2 to 5%) to give 5-((2-chloropyridin-4-yl)oxy)pyridin-3-ol 4 (400 mg, 85%) as an off-white solid. ¹ H NMR (DMSO-d6, 400 MHz): δ 10.43 (s, 1H), 8.31 (d, J = 5.7 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 2.3 Hz, 1H), 7.12 (d, J = 2.2 Hz, 1H), 7.04 (t, J = 2.3 Hz, 1H), 7.01 to 7.02 (m, 1H). LCMS: Rt = 2.59 min, [M+H] = 223.0. The samples were analyzed using the following conditions: Shimadzu Prominence HPLC attached to Applied Biosystems API 2000 mass spectrometer; Column-X bridge C18 (4.6×50 mm, 5µ); column temperature-ambient, mobile phase A: 10 mm ammonium acetate/water, mobile phase B: acetonitrile, flow rate: 1.20 ml/min, analysis time: 5.10 min.

Preparation of S-methyl O-(5-((2-chloropyridin-4-yl)oxy)pyridin-3-yl)carbonodithioate: 3-Methyl-1-((methylthio)thiocarbonyl)-1H-benzo[d]imidazol-3-ium iodide (157 mg, 0.45 mmol, 1.0 equiv.) was added to a stirred solution of 5-((2-chloropyridin-4-yl)oxy)pyridin-3-ol (100 mg, 0.45 mmol, 1.0 equiv.), triethylamine (0.06 mL, 0.49 mmol, 1.1 equiv.) and acetonitrile (3.0 mL, 0.15 M) at 0° C. After stirring at 0° C. for 1 h, the mixture was quenched with saturated aqueous sodium bicarbonate (1 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over _{anhydrous Na2SO4} , filtered and concentrated. The residue was purified by silica gel combi-flash (ethyl acetate/hexane: 20%) to give S-methyl O-(5-((2-chloropyridin-4-yl)oxy)pyridin-3-yl)carbonodithioate (112 mg, 86%) as a yellow viscous gel. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.56 (d, J = 2.3 Hz, 1H), 8.48 (d, J = 2.2 Hz, 1H), 8.35 (d, J = 5.8 Hz, 1H), 7.90 (t, J = 2.3 Hz, 1H), 7.17 (d, J = 2.2 Hz, 1H), 7. 06 (dd, J = 5.7 Hz, J = 2.2 Hz, 1H), 2.72 (s, 3H). LCMS: Rt = 3.35 min, [M+H] = 312.8. The samples were analyzed using the following conditions: Shimadzu Prominence HPLC attached to Applied Biosystems API 2000 mass spectrometer; Column-X bridge C18 (4.6×50 mm, 5µ)/Zorbax Ext (4.6×50 mm, 5µ); column temperature-ambient, mobile phase A: 10 mm ammonium acetate/water, mobile phase B: acetonitrile, flow rate: 1.20 ml/min, analysis time: 5.10 min.

Preparation of 2-chloro-4-((5-(trifluoromethoxy)pyridin-3-yl)oxy)pyridine: Excess HF (45 mL, 197.6 mmol, 80.0 equiv.) in pyridine was added dropwise to a stirred solution of _Br2 -Me2-hydantoin (3.16 g, 11.1 mmol, 4.5 equiv.) in DCM (32 mL, 0.34 M) at -78 °C under an atmosphere of hydrogen. After 30 min, S-methyl O-(5-(( ₂ -chloropyridin-4-yl)oxy)pyridin-3-yl)carbonic acid dithioate (770 mg, 2.47 mmol, 1.0 equiv.) was added in DCM (8 mL, 0.3 M) at the same temperature and stirred at -5 °C for 2 h. The reaction mixture was diluted with 3 mL of diethyl ether and neutralized by cold saturated sodium bicarbonate. Saturated sodium bisulfate solution was added until the red color disappeared. The pH was maintained at 10 to 11 by adding 5 N NaOH solution under ice-cold conditions. The mixture was extracted with diethyl ether (3×50 mL), washed with water and brine. The organic portion was dried over sodium sulfate and concentrated under reduced pressure to obtain a crude product, which was purified by silica gel combi-flash (ethyl acetate/hexane: 15%) to obtain the compound as a yellow liquid with some impurities. The crude product was further purified by preparative HPLC to give 2-chloro-4-((5-(trifluoromethoxy)pyridin-3-yl)oxy)pyridine (200 mg, 29%) as a light yellow liquid. ¹ H NMR (DMSO-d6, 400 MHz) δ 8.64-8.67 (m, 2H), 8.35 (d, J = 5.7 Hz, 1H), 8.04 (s, 1H), 7.26 (d, J = 2.1 Hz, 1H), 7.11 (dd, J = 5.8 Hz, J = 2.2 Hz, 1H). LCMS: Rt = 2.65 min, [M+H] = 291.0. The sample was analyzed using the following conditions: Waters Acquity H Class UPLC attached to a Waters SQD2 mass spectrometer; Column-X bridge C18 (3×50 mm, 3.5µ); column temperature -40°C, mobile phase A: 5 mm ammonium acetate/water, mobile phase B: 5 Mm NH4OAc/ACN:water (90:10), flow rate: 1.20 ml/min, analysis time: 5.10 min. HPLC purity: 98.88%. Reverse phase HPLC was performed on an Agilent 1200 series instrument at a flow rate of 1.0 ml/min, column name Gemini NX C18 (3um, 100×4.6 mm). Two mobile phases were used, i.e., mobile phase A: 0.05% HCOOH/water; mobile phase B: acetonitrile (HPLC grade), and they were used to run gradient conditions, with the mobile phase being 98% [0.05% HCOOH/water] and 0.2% [CH3CN] for 0.01 min, the mobile phase being 98% [0.05% HCOOH]/water] and 0.2% [CH3CN] for 1.0 min, 50% [0.05% HCOOH/water] and 50% [CH3CN] for 5.0 min, 5% [0.05% HCOOH/water] and 95% [CH3CN] for 9.0 min, and this composition was maintained for 12.0 min, and then returned to the initial composition within 12.5 min and maintained for 16.0 min (total run time 16.0 min). Use an injection volume of 0.5 μL.

Intermediate Example 7 5-(1,1 -difluoroethyl ) pyridin -3- ol

To a solution of 1-(5-bromopyridin-3-yl)ethan-1-one (500 mg, 2.50 mmol) in a round vial at 0 °C was added DAST (5 mL). The mixture was stirred at 50 °C for 12 h. Five additional vials were set up as described above. All six reaction mixtures were combined and quenched with saturated aqueous NaHCO ₃ (300 mL), the aqueous layer was extracted with ethyl acetate (3×100 mL), the organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 6/1) to obtain 3-bromo-5-(1,1-difluoroethyl)pyridine (2.5 g, yield 75.08%) as a yellow oil. ¹ H NMR: 400 MHz, CDCl ₃ δ = 1.95 (t, J = 18.20 Hz, 3H), 7.96 (t, J = 2.06 Hz, 1H), 8.64-8.78 (m, 2H).

To a solution of 3-bromo-5-(1,1-difluoroethyl)pyridine (2.5 g, 11.26 mmol) and triisopropyl borate (5.29 g, 28.15 mmol, 6.47 mL) in THF (25 mL) was added n-BuLi (2.5 M, 11.26 mL) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 20 min. The mixture was stirred at 25 °C for 2 h. The reaction was cooled to 0 °C, and H ₂ O ₂ (5.11 g, 45.04 mmol, 4.33 mL, 30% purity) and NaOH (2 M, 5.63 mL) were added. The reaction was stirred at 0 °C for 10 min. The mixture was stirred at 25 °C for 12 h. The mixture was alkalized to pH = 7 with HCl (1 M). The reaction was quenched with a saturated aqueous solution _{of Na2S2O3} (50 mL), and the aqueous layer was extracted with _{ethyl acetate (2×20 mL). The combined organic phases were dried over Na2SO4 , filtered} , and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (FA) to give 5-(1,1-difluoroethyl)pyridin-3-ol (750 mg, yield 41.19%) as a white solid. ^1H NMR: 400 MHz, DMSO _-d6 δ =1.98 (t, J =19.07 Hz, 3H), 7.28 (s, 1H), 8.24 (d, J =1.75 Hz, 2H), 10.32 (s, 1H). LCMS (ESI+): m/z 160.2 (M+H) ⁺ , Rt: 1.110 min. LC/MS (gradient 5% B in 0.40 min and 5 to 95% B in 0.40 to 3.00 min, hold 95% B for 1.00 min, and then 95 to 5% B in 0.01 min, flow rate 1.0 ml/min). Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50×2.1 mm column (5 μm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. The MS range was 100 to 1000.

Intermediate Example 8 2 - Chloro - 4 - ( ( 5- ( 1,1 - difluoroethyl ) pyridin - 3 - yl ) oxy ) pyridine

To a solution of 5-(1,1-difluoroethyl)pyridin-3-ol (54.25 mg, 340.91 μmol) and 2-chloro-4-fluoro-pyridine (49.33 mg, 375.00 μmol) in DCM (1 mL) was added Cs ₂ CO ₃ (144.40 mg, 443.18 μmol). The mixture was stirred at 20 °C for 2 h. Three additional vials were set up as described above. All four mixtures were combined and quenched with saturated aqueous NH ₄ Cl solution (40 mL). The aqueous layer was extracted with H ₂ O (10 mL) and ethyl acetate (3×10 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 1/1) to give 2-chloro-4-((5-(1,1-difluoroethyl)pyridin-3-yl)oxy)pyridine (294 mg, yield 79.66%) as a colorless oil. ¹ H NMR: ET68748-66-P1F, 400 MHz, CDCl ₃ δ = 2.00 (t, J = 18.26 Hz, 3H), 6.83 (dd, J = 5.63, 2.25 Hz, 1H), 6.89 (d, J = 2.13 Hz, 1H), 7.59 (t, J = 2.00 Hz, 1H), 8.33 (d, J = 5.63 Hz, 1H), 8.55 (d, J = 2.50 Hz, 1H), 8.71 (s, 1H). LCMS (ESI+): m/z 271.1 (M+H) ⁺ , Rt: 1.944 min. LC/MS (gradient 5% B in 0.40 min and 5 to 95% B in 0.40 to 3.00 min, hold 95% B for 1.00 min, and then 95 to 5% B in 0.01 min, flow rate 1.0 ml/min). Mobile phase A was 0.037% trifluoroacetic acid in water, and mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was Kinetex C18 50×2.1 mm column (5 um particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. MS range was 100 to 1000.

Intermediate Example 9 5-(2,2 -difluoroethyl ) pyridin -3- ol

To a solution of 3-bromo-5-methoxypyridine (250 mg, 1.33 mmol, 1 eq) in 1,2-dimethoxyethane (5 mL) under an argon atmosphere were added 2 _- bromo-1,1-difluoro-ethane (289.09 mg, 1.99 mmol, 1.5 eq), NiCl2.ethylene glycol dimethyl ether (1.46 mg, 6.65 μmol, 0.005 eq), _Na2CO3 (281.86 mg, 2.66 mmol, 2 eq), dtbbpy (1.78 mg, 6.65 μmol, 0.005 eq), TTMSS (330.63 mg, 1.33 mmol, 410.21 μL, 1 eq), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (14.92 mg, 13.30 μmol, 0.01 eq). The mixture was stirred at 25 °C under a 34 W blue LED for 12 h. Fifteen additional vials were set up as described above. All sixteen reaction mixtures were combined for workup and purification. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 1/0 to 10/1) to give 3-(2,2-difluoroethyl)-5-methoxypyridine (1.15 g, 6.64 mmol, 31.22% yield) as a yellow oil. ¹ H NMR: 400 MHz, MeOD- d ₄ δ = 3.21 (td, J =17.64, 4.25 Hz, 2H), 3.88 (s, 3H), 6.09 (tt, J =56.34, 4.25 Hz, 1H), 7.38 (s, 1H), 8.06 (d, J =1.25 Hz, 1H), 8.17 (d, J =2.75 Hz, 1H).

To a solution of 3-(2,2-difluoroethyl)-5-methoxypyridine (95 mg, 548.63 μmol, 1 eq) in dichloromethane (5 mL) was added BBr ₃ (274.88 mg, 1.10 mmol, 105.72 μL, 2 eq) at 0°C. The mixture was stirred at 20°C for 5 h. BBr ₃ (274.88 mg, 1.10 mmol, 105.72 μL, 2 eq) was then added to the mixture at 0°C. The mixture was stirred at 20°C for 12 h. Nine vials were set up as described above. All ten reaction mixtures were combined for workup and purification. The reaction mixture was filtered and concentrated under reduced pressure to remove dichloromethane. The mixture was poured into water (30 mL). The mixture was basified to pH = 8 by slow addition of NaHCO ₃ , and the aqueous layer was extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with saturated NaCl solution (5 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was purified by preparative HPLC (HCl) to give 5-(2,2-difluoroethyl)pyridin-3-ol (310 mg, 1.58 mmol, 28.83% yield, 99.8% purity, HCl) as a white solid. ¹ H NMR: 400 MHz, MeOD -d ₄ δ = 3.30 (td, J=18.17, 4.19 Hz, 2H), 6.32 (tt, J=56.09, 4.19 Hz, 1H), 7.56 (br s, 1H), 8.19 (s, 1H), 8.24 (d, J=2.50 Hz, 1H), 10. 91 to 11.19 (m, 1H). LCMS (ESI+): m/z 160.1 [M+H] ⁺ , Rt: 0.462 min.

Intermediate Example 10 2 - Chloro - 4 - ( ( 5- ( 2,2 - difluoroethyl ) pyridin - 3 - yl ) oxy ) pyridine

To a solution of 5-bromopyridin-3-ol (1 g, 5.75 mmol, 1 eq) in N,N-dimethylformamide (20 mL) was added 2-chloro-4-fluoro-pyridine (755.97 mg, 5.75 mmol, 1 eq) and Cs ₂ CO ₃ (2.43 g, 7.47 mmol, 1.3 eq). The mixture was stirred at 20° C. for 2 h. The mixture was poured into water (200 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL), the combined organic layers were washed with saturated NaCl solution (3×50 mL), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give 4-((5-bromopyridin-3-yl)oxy)-2-chloropyridine (1.14 g, 3.99 mmol, 69.47% yield) as an orange solid. ¹ H NMR: 400 MHz, MeOD- d ₄ δ = 7.01 (dd, J=5.75, 2.25 Hz, 1H), 7.12 (d, J=2.25 Hz, 1H), 7.98 (t, J=2.13 Hz, 1H), 8.30 (d, J=5.88 Hz, 1H), 8.47 (d, J=2.38 Hz , 1H), 8.64 (d, J=1.88 Hz, 1H).

To a solution of 4-((5-bromopyridin-3-yl)oxy)-2-chloropyridine (500 mg, 1.75 mmol, 1 eq) in 1,2-dimethoxyethane (10 mL) under an argon atmosphere were added 2-bromo-1,1-difluoro-ethane (2.54 g, 17.51 mmol, 10 eq), NiCl ₂ .ethylene glycol dimethyl ether (1.92 mg, 8.76 μmol, 0.005 eq), Na ₂ CO ₃ (371.21 mg, 3.50 mmol, 2 eq), dtbbpy (2.35 mg, 8.76 μmol, 0.005 eq), TTMSS (435.44 mg, 1.75 mmol, 540.25 μL, 1 eq), Ir[dF(CF ₃ )ppy] ₂ (dtbpy)(PF ₆ ) (19.65 mg, 17.51 μmol, 0.01 eq). The mixture was stirred at 25 °C under a 34 W blue LED for 24 h. Another vial was set up as described above. The two reaction mixtures were combined for workup and purification. The mixture was poured into water (100 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), the combined organic layers were washed with a saturated NaCl solution (2×30 mL), the combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated to give a residue. The residue was purified by preparative HPLC (HCl) to give 2-chloro-4-((5-(2,2-difluoroethyl)pyridin-3-yl)oxy)pyridine (275 mg, 1.02 mmol, 58.02 % yield) as a yellow oil. ¹ H NMR: 400 MHz, DMSO- d ₆ δ = 3.32 (td, J=18.10, 4.06 Hz, 2H), 6.34 (tt, J=56.17, 4.11 Hz, 1H), 7.04 (dd, J=5.69, 2.19 Hz, 1H), 7.15 (d, J=2.00 Hz, 1H), 7 .77 (br s, 1H), 8.35 (d, J=5.75 Hz, 1H), 8.52 (br d, J=2.88 Hz, 2H). LCMS (ESI+): m/z 271.1 [M+H] ⁺ , Rt: 1.701 min.

Intermediate Example 11 2 - Chloro - 4 - ( ( 5- ( 2,2 - difluoropropyl ) pyridin - 3 - yl ) oxy ) pyridine

To _a solution of 3,5-dibromopyridine (20 g, 84.43 mmol, 1 eq ) in toluene (200 mL) was added isopropenyl acetate (9.30 g, 92.87 mmol, 10.11 mL, 1.1 eq ), tributyl(methoxy)tinane (34.64 g, 107.88 mmol, 31.07 mL, 1.28 eq ), _Pd2 (dba) ₃ (1.55 g, 1.69 mmol, 0.02 eq ) and 2-(2-diphenylphosphinophenyl)-N,N-dimethyl-aniline (644.09 mg, 1.69 mmol, 0.02 eq ) under N2. The mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to 25 °C and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether:ethyl acetate = 1/0 to 1/1) to give 1-(5-bromopyridin-3-yl)propan-2-one (7 g, 32.70 mmol, 38.73% yield) as a yellow oil. ¹ H NMR: 400 MHz, DMSO- d ₆ δ = 2.20 (s, 3H), 3.89 (s, 2H), 7.88 (t, J = 2.00 Hz, 1H), 8.36 (d, J = 1.63 Hz, 1H), 8.58 (d, J = 2.25 Hz, 1H).

A mixture of 1-(5-bromopyridin-3-yl)propan-2-one (5 g, 23.36 mmol, 1 eq ) in DAST (48.80 g, 302.75 mmol, 40 mL, 12.96 eq ) was stirred at 25 °C for 12 h. The mixture was basified to pH = 9 by slow addition of 2 N _{Na2CO3 ,} the aqueous layer was extracted with DCM (3×100 mL), the combined organic layers were washed with brine (2×200 mL), the combined organic layers were dried over _{anhydrous Na2SO4} , filtered and concentrated in vacuo. The residue was purified by preparative HPLC (neutral) to give 3-bromo-5-(2,2-difluoropropyl)pyridine (2.5 g, 10.59 mmol, 41.67% yield) as a yellow oil. ¹ H NMR: 400 MHz, DMSO- d ₆ δ = 1.62 (t, J = 18.26 Hz, 3H), 3.14 (t, J = 15.57 Hz, 2H), 7.81 (s, 1H), 8.44 (d, J = 1.25 Hz, 1H), 8.64 (d, J = 2.13 Hz, 1H).

To a solution of 3-bromo-5-(2,2-difluoropropyl)pyridine (2.5 g, 10.59 mmol, 1 eq ) and triisopropyl borate (4.98 g, 26.48 mmol, 6.09 mL, 2.5 eq ) in THF (25 mL) was added n-BuLi (2.5 M, 10.59 mL, 2.5 eq ) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 30 min. The mixture was then stirred at 25 °C for 2 h. The reaction was cooled to 0 °C and H ₂ O ₂ (5.67 g, 50.06 mmol, 4.81 mL, 30% purity, 4.73 eq ) and NaOH (2 M, 5.30 mL, 1 eq ) were added. The reaction was stirred at 0 °C for 12 min. The mixture was stirred at 25 °C for 12 h. The pH of the mixture was adjusted to about 7 with HCl (1 M). The reaction was then quenched with a _saturated aqueous solution of _Na2SO3 (200 mL), the aqueous layer _was extracted with ethyl acetate (2 x 40 mL), the organic layer was dried over _Na2SO4 , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral) to give 5-(2,2-difluoropropyl)pyridin-3-ol (300 mg, 1.73 mmol, 34.08% yield, 90% purity) as a white solid. ¹ H NMR: 400 MHz, CDCl ₃ δ = 1.60 (t, J =18.26 Hz, 3H), 3.14 (t, J =15.51 Hz, 2H), 7.28 (s, 1H), 8.02 (d, J =1.25 Hz, 1H), 8.23 (d, J =2.63 Hz, 1H).

To a solution of 5-(2,2-difluoropropyl)pyridin-3-ol (300 mg, 1.73 mmol, 1 eq ) in DCM (3 mL) was added _Cs2CO3 ( _733.83 mg, 2.25 mmol, 1.3 eq ) and 2-chloro-4-fluoro-pyridine (227.89 mg, 1.73 mmol, 1 eq ). The mixture was stirred at 25 °C for 4 h. The reaction was poured into water (30 mL). The mixture was extracted with ethyl acetate (3 x 8 mL). The combined organic layers were washed with _brine and dried over _Na2SO4 . The organic layer was concentrated under high vacuum. The residue was purified by preparative HPLC (neutral) to give 2-chloro-4-((5-(2,2-difluoropropyl)-pyridin-3-yl)oxy)pyridine (254 mg, 889.53 μmol, 51.34% yield, 99.7% purity) as a colorless oil. ¹ H NMR: 400 MHz, CDCl ₃ δ = 1.65 (t, J = 18.20 Hz, 3H), 3.21 (t, J = 15.76 Hz, 2H), 6.82 (dd, J = 5.69, 2.06 Hz, 1H), 6.88 (d, J = 2.13 Hz, 1H), 7.42 (s, 1H), 8.30 (d, J = 5.75 Hz, 1H), 8.41-8.50 (m, 2H). LCMS (ESI+): m/z 285.2 [M+H] ⁺ , Rt: 1.866 min.

Intermediate Example 12 5- ( 1 - Fluorocyclopropyl ) pyridin - 3 - ol

To a solution of 3-(benzyloxy)-5-bromopyridine (5 g, 18.93 mmol) in ethylene glycol dimethyl ether (50 mL) and water (10 mL) was added 4,4,5,5-tetramethyl-2-ethylene-1,3,2-dioxaborolane cyclopentane (4.37 g, 28.40 mmol, 4.82 mL), sodium carbonate (3.14 g, 37.86 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.31 g, 1.14 mmol). The reaction mixture was stirred at 85 °C under nitrogen for 16 h. Three additional vials were set up as described above. All four reaction mixtures were combined and cooled to 20 °C, followed by quenching the combined mixture by the addition of water (300 mL). The mixture was extracted with ethyl acetate (3×200 mL). The combined organic phases were washed with brine (300 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to obtain 3-(benzyloxy)-5-vinylpyridine (12 g, yield 67.51%) as a yellow oil. ¹ H NMR: 400 MHz, CDCl ₃ δ= 5.14 (s, 2H), 5.40 (d, J =11.01 Hz, 1H), 5.82 (d, J =17.51 Hz, 1H), 6.70 (dd, J =17.64, 11.01 Hz, 1H), 7.31 to 7.50 (m, 6H), 8.27 (dd, J =9.44, 2.19 Hz, 2H).

To a solution of 3-(benzyloxy)-5-vinylpyridine (4 g, 18.93 mmol) in dichloromethane (40 mL) at 0°C was added a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (8.12 g, 28.40 mmol) in dichloromethane (40 mL), the reaction mixture was stirred at 0°C for 30 min, then triethylamine trihydrofluoride (4.58 g, 28.40 mmol, 4.63 mL) was added to the mixture. The reaction mixture was stirred at 0°C for 30 min. Two additional vials were set up as described above. All three reaction mixtures were combined and warmed to 20°C. The mixture was quenched with a saturated solution of sodium bicarbonate (100 mL) and extracted with dichloromethane (3 x 80 mL). The combined organic phases were washed with brine (150 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to obtain 3-(benzyloxy)-5-(2-bromo-1-fluoroethyl)pyridine (10 g, yield 56.76%) as a yellow oil. ¹ H NMR: 400 MHz, CDCl ₃ δ = 3.56 to 3.78 (m, 2H), 5.15 (s, 2H), 5.62 (dd, J =6.88, 4.75 Hz, 1H), 5.74 (dd, J =6.69, 4.94 Hz, 1H), 7.30 (t, J =2.06 Hz, 1H), 7.34 to 7 .49 (m, 5H), 8.23 (s, 1H), 8.41 (d, J =2.63 Hz, 1H).

To a solution of 3-(benzyloxy)-5-(2-bromo-1-fluoroethyl)pyridine (5 g, 16.12 mmol) in tetrahydrofuran (50 mL) at -20 °C was added potassium tri-butoxide (1 M, 32.24 mL, 32.24 mmol) dropwise and the reaction mixture was stirred at 0 °C for 1 h. An additional vial was set up as described above. The two reaction mixtures were combined and quenched with saturated citric acid solution (80 mL). The mixture was extracted with ethyl acetate (3 x 50 mL) and the combined organic phases were washed with brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to obtain 3-(benzyloxy)-5-(1-fluorovinyl)pyridine (6.5 g, yield 83.54%) as a brown solid. ¹ H NMR: 400 MHz, CDCl ₃ δ= 4.85 (d, J =3.88 Hz, 1H), 4.89 (d, J =3.88 Hz, 1H), 4.94 (d, J =3.88 Hz, 1H), 5.03 (s, 2H), 5.07 (d, J =3.88 Hz, 1H), 7.22 to 7.39 (m, 6H), 8.26 (d, J =2.75 Hz, 1H), 8.34 (d, J =1.00 Hz, 1H).

To a solution of 3-(benzyloxy)-5-(1-fluorovinyl)pyridine (100 mg, 436.21 μmol) in dimethylsulfoxide (8 mL) was added 2,4,5,6-tetra(carbazol-9-yl)benzene-1,3-dicarbonitrile (34.41 mg, 43.62 μmol) and triethylammonium bis(catecholyl)iodomethylsilicate (318.65 mg, 654.31 μmol). The resulting solution was degassed (vacuum/refilled with nitrogen) and placed under two blue LED lights (Kessil, H150 Growlights, 32 W, 420 to 500 nm ahead). The reaction mixture was stirred at 50 °C for 18 h. Fourteen additional vials were set up as described above. All fifteen reaction mixtures were combined and quenched by adding water (200 mL) and extracted with ethyl acetate (3×150 mL). The combined organic phases were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC (neutral conditions) to give 3-(benzyloxy)-5-(1-fluorocyclopropyl)pyridine (330 mg, 20.73% yield) as a yellow oil. ¹ H NMR: 400 MHz, CDCl ₃ δ= 1.11 to 1.22 (m, 2H), 1.61 to 1.76 (m, 2H), 5.20 (s, 2H), 7.28 to 7.43 (m, 5H), 7.68 (t, J =1.90 Hz, 1H), 8.18 (d, J =1.22 Hz, 1H), 8.44 (d, J =2.57 Hz, 1H).

To a mixture of Pd/C (72.18 mg, 67.82 μmol, 10% purity) in methanol (8 mL) was added 3-(benzyloxy)-5-(1-fluorocyclopropyl)pyridine (165 mg, 678.24 μmol) and the reaction mixture was stirred under hydrogen (15 psi) at 25 °C for 3 h. An additional vial was set up as described above. The two reaction mixtures were combined and filtered through a pad of celite and the filtrate was concentrated under reduced pressure to give 5-(1-fluorocyclopropyl)pyridin-3-ol (170 mg, 72.74% yield, 85% purity) as a white solid. LCMS (ESI+): m/z 154.2 (M+H) ⁺ , Rt: 0.122 min. Description: Mobile phase: 0.04% TFA/water (solvent A) and 0.02% TFA/acetonitrile (solvent B), using a gradient of 10% to 100% (solvent B) in 0.5 min and maintaining 100% for 0.4 min at a flow rate of 2.0 mL/min; Column: Halo C18, 3.0×30 mm, 5 um; Wavelength: UV 220 nm and 254 nm. Column temperature: 40°C; MS ionization: ES.

Intermediate Example 13 2 - Chloro - 4 -(( 5- ( 1 - fluorocyclopropyl ) pyridin - 3 - yl ) oxy ) pyridine

To a solution of 5-(1-fluorocyclopropyl)pyridin-3-ol (170 mg, 943.50 μmol) and 2-chloro-4-fluoro-pyridine (248.21 mg, 1.89 mmol) in dimethylformamide (6 mL) was added cesium carbonate (491.86 mg, 1.51 mmol). The reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was quenched by the addition of water (10 mL) and extracted with ethyl acetate (3 x 5 mL). The combined organic phases were washed with brine (10 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate-residue was concentrated under reduced pressure and purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 5/1) to give 2-chloro-4-((5-(1-fluorocyclopropyl)pyridin-3-yl)oxy)pyridine (180 mg, yield 70.64%) as a white solid. ¹ H NMR: 400 MHz, CDCl ₃ δ= 1.13 to 1.22 (m, 2H), 1.60 to 1.70 (m, 2H), 6.83 (dd, J =5.63, 2.25 Hz, 1H), 6.88 (d, J =2.25 Hz, 1H), 7.41 (t, J =2.19 Hz, 1H), 8.30 (d , J =5.75 Hz, 1H), 8.36 (d, J =1.38 Hz, 1H), 8.39 (d, J =2.63 Hz, 1H). LCMS (ESI+): m/z 265.0 (M+H) ⁺ , Rt: 2.743 min.

The gradient was 5% B in 0.40 min and 5 to 95% B in 0.40 to 3.40 min, holding 95% B for 0.45 min, and then 95 to 5% B in 0.01 min, with a flow rate of 0.8 ml/min. Mobile phase A was H ₂ O + 10 mM NH ₄ HCO ₃ , and mobile phase B was acetonitrile. The column used for chromatography was an Xbridge C18 2.1×50 mm column (5 μm particles). The detection method was diode array (DAD) and evaporative light scattering (ELSD) detection. The MS mode was positive electrospray ionization. The MS range was 100 to 1000.

Intermediate Example 14 5- ( 2 - fluoropropan - 2 - yl ) pyridin - 3 - ol

To a solution of 2- ( 5 - bromopyridin - 3 - yl ) propan - 2 - ol (4.5 g, 20.83 mmol) in dichloromethane (50 mL) was added bis(2-methoxyethyl)aminosulfide trifluoride (BAST, 9.22 g, 41.65 mmol, 9.12 mL) in dichloromethane (10 mL) dropwise at -78 °C. After the addition, the mixture was stirred at -40 °C for 4 h. The combined reaction mixture was quenched by additional water (500 mL) at 0 °C and extracted with ethyl acetate (3 x 40 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate = 100/1 to 1/1) to give 3-bromo-5-(2-fluoropropan-2-yl)pyridine (2.7 g, yield 49.45%) as a colorless oil. ¹ H NMR: 400 MHz, CDCl ₃ δ = 1.69 (s, 3H), 1.74 (s, 3H), 7.88 (t, J = 2.06 Hz, 1H), 8.54 (d, J = 1.63 Hz, 1H), 8.62 (d, J = 2.13 Hz, 1H).

To a solution of 3-bromo-5-(2-fluoropropan-2-yl)pyridine (2.7 g, 12.26 mmol) in _1,4 -dioxane (30 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (BPD, 4.67 g, 18.39 mmol), potassium acetate (KOAc, 3.61 g, 36.77 mmol) and Pd(dppf) _Cl2 (1.00 g, 1.23 mmol) under N2. The mixture was stirred at 100 °C for 12 h. The crude reaction mixture was concentrated in vacuo to give (5-(2-fluoropropan-2-yl)pyridin-3-yl) Acid (2.7 g, yield 72.22%). LCMS (ESI+): m/z 184.0 (M+H) ⁺ , Rt: 0.153 min. Description: Mobile phase: 0.04% TFA/water (solvent A) and 0.02% TFA/acetonitrile (solvent B), using a gradient of 10% to 100% (solvent B) in 0.5 min and maintaining 100% for 0.4 min at a flow rate of 2.0 ml/min; column: Halo C18, 3.0×30 mm, 5 um; wavelength: UV 220 nm and 254 nm; column temperature: 40°C; MS ionization: ESI.

To (5-(2-fluoropropan-2-yl)pyridin-3-yl) To a solution of 1H 2 O (2.7 g, 8.85 mmol) in tetrahydrofuran (24 mL) was added NaBO ₃ :4H ₂ O (5.45 g, 35.41 mmol, 6.81 mL) and water (6 mL). The mixture was stirred at 25 °C for 2 h. The reaction mixture was diluted with 300 mL of water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (dichloromethane/methanol = 100/1 to 10/1) and preparative HPLC (HCl) to give 5-(2-fluoropropan-2-yl)pyridin-3-ol (630 mg, yield 7.46%, purity 97.3%) as a white solid. Column: Phenomenex luna C18 100×40mm×5 μm; mobile phase: [H ₂ O (0.04% HCl)-ACN]; gradient: 1% to 20% B in 8.0 min.

¹ H NMR: 400 MHz, CDCl ₃ δ = 1.69 (s, 3H), 1.74 (s, 3H), 7.34 (t, J = 2.19 Hz, 1H), 8.16 (d, J = 1.50 Hz, 1H), 8.23 (d, J = 2.50 Hz, 1H). LCMS (ESI+): m/z 156.1 (M+H) ⁺ , Rt: 2.045 min. LC/MS (gradient: 0% B in 0.00 min and 0 to 60% B in 0.00 to 4.00 min, hold 60% B for 2.00 min, and then 60 to 0% B in 0.01 min, flow rate 0.8 ml/min). Mobile phase A is H ₂ O + 10 mM NH ₄ HCO ₃ , mobile phase B is acetonitrile. The column used for the analysis was an XBridge C18 2.1×50 mm column (5 um particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection. The MS mode was positive electrospray ionization. The MS range was 100 to 1000.

Intermediate Example 15 2 - Chloro - 4 -(( 5- ( 2 - fluoropropyl - 2 - yl ) pyridin - 3 - yl ) oxy ) pyridine

To a solution of 5-(2-fluoropropan-2-yl)pyridin-3-ol (190 mg, 1.19 mmol) in N,N-dimethylformamide (2 mL) was added Cs ₂ CO ₃ (465.82 mg, 1.43 mmol) and 2-chloro-4-fluoro-pyridine (313.42 mg, 2.38 mmol). The mixture was stirred at 20 °C for 2 h. The mixture from ET73527-93 (a total of 240 mg of 5-(2-fluoropropan-2-yl)pyridin-3-ol) was combined for work-up. The reaction mixture was quenched to pH = 6 by the addition of a saturated solution of citric acid at 0 °C and subsequently diluted with water (50 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a residue which was purified by preparative TLC (SiO ₂ , petroleum ether/ethyl acetate = 1/1) to give 2-chloro-4-((5-(2-fluoropropan-2-yl)pyridin-3-yl)oxy)pyridine (244 mg, 75.87% yield, 98.8% purity) as a yellow oil. ¹ H NMR: 400 MHz, CDCl ₃ δ = 1.73 (s, 3H), 1.78 (s, 3H), 6.82 (dd, J =5.69, 2.19 Hz, 1H), 6.88 (d, J =2.25 Hz, 1H), 7.51 (t, J =2.25 Hz, 1H), 8.31 (d, J =5.75 Hz, 1H), 8.41 (d, J =2.50 Hz, 1H), 8.56 (d, J =0.88 Hz, 1H). LCMS (ESI+): m/z 267.1 (M+H) ⁺ , Rt: 1.927 min. LC/MS (gradient 5% B in 0.40 min and 5 to 95% B in 0.40 to 3.00 min, hold 95% B for 1.00 min, and then 95 to 5% B in 0.01 min, flow rate 1.0 ml/min). Mobile phase A was 0.037% trifluoroacetic acid in water, mobile phase B was 0.018% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 50×2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. MS range was 100 to 1000.

Intermediate Example 16 5 - Chloro - 6 - ethoxypyridin - 3 - ol

To a solution of 5-bromo-3-chloro-2-fluoropyridine (4 g, 19.01 mmol) in ethanol (40 mL) was added sodium ethoxide (3.88 g, 57.03 mmol) and the mixture was stirred at 80 °C for 2 h. The mixture was concentrated. H ₂ O (200 mL) was added to the residue and the aqueous phase was extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 5-bromo-3-chloro-2-ethoxypyridine (4 g, 80.08% yield, 90% purity) as a red solid. The crude product was used in the next step without further purification. ¹ H NMR: 400 MHz, CDCl ₃ δ= 1.43 (t, J =7.07 Hz, 3H), 4.43 (q, J =7.00 Hz, 2H), 7.75 (d, J =2.25 Hz, 1H), 8.08 (d, J =2.25 Hz, 1H).

To a solution of 5-bromo-3-chloro-2-ethoxypyridine (4 g, 15.22 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan-2-yl (5.80 g, 22.83 mmol) in dioxane (40 mL) were added potassium acetate (4.48 g, 45.67 mmol) and Pd(dppf) _{Cl2 - CH2Cl2} (1.24 g, 1.52 mmol), and the mixture was stirred at 100 °C for 12 h. The mixture was filtered and the filtrate was concentrated to give 3-chloro-2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyridine (4 g, crude product) as a black solid. The crude product was used in the next step without further purification. LCMS (ESI+): m/z 284.0 (M+H) ⁺ , Rt: 0.661 min. Description: Mobile phase: 0.04% TFA/water (solvent A) and 0.02% TFA/acetonitrile (solvent B), using a gradient of 10% to 100% (solvent B) in 0.5 min and maintaining 100% for 0.4 min at a flow rate of 2.0 ml/min; Column: Halo C18, 3.0×30 mm, 5 um; Wavelength: UV 220 nm and 254 nm; Column temperature: 40°C; MS ionization: ESI.

To a solution of 3-chloro-2-ethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)pyridine (4 g, 12.70 mmol) in tetrahydrofuran (32 mL) and H ₂ O (8 mL) was added NaBO ₃ .4H ₂ O (7.81 g, 50.78 mmol), and the mixture was stirred at 25° C. for 2 h. The reaction was quenched with water (400 mL), the aqueous layer was extracted with ethyl acetate (2×100 mL), the organic layer was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral conditions) to give 5-chloro-6-ethoxypyridin-3-ol (1.55 g, yield 61.80%, purity 99.3%) as a gray solid. ¹ H NMR: 400 MHz, CDCl ₃ δ = 1.42 (t, J =7.07 Hz, 3H), 4.38 (q, J =7.05 Hz, 2H), 4.89 (br s, 1H), 7.29 (d, J =2.63 Hz, 1H), 7.69 (d, J =2.75 Hz, 1H). LCMS (ESI+): m/z 174.0 (M+H) ⁺ , Rt: 2.365 min. LC/MS (gradient 5% B in 0.40 min and 5 to 95% B in 0.40 to 3.40 min, hold 95% B for 0.45 min, and then 95 to 5% B in 0.01 min, flow rate 0.8 ml/min). Mobile phase A was H ₂ O + 10 mM NH ₄ HCO ₃ , mobile phase B was acetonitrile. The column used for chromatography was Xbridge-C18 2.1×50 mm column (5 μm particles). The detection method was diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. The MS range was 100 to 1000.

Intermediate Example 17 5- ( Difluoromethyl ) -6 - methoxypyridin - 3 - ol

To a solution of 5-bromo-3-(difluoromethyl)-2-methoxypyridine (1 g, 4.20 mmol, 1 eq ) and triisopropyl borate (1.98 g, 10.50 mmol, 2.41 mL, 2.5 eq ) in THF (10 mL) was added n-BuLi (2.5 M, 4.20 mL, 2.5 eq ) at -78 °C under nitrogen. The mixture was stirred at -78 °C for 30 min. The mixture was then stirred at 25 °C for 2 h. The reaction was cooled to 0 °C and _H2O2 (4.43 g, 39.08 mmol, 3.75 mL, 30% purity, 9.30 eq ) and _NaOH (2 M, 2.10 mL, 1 eq ) were added. The reaction was stirred at 0 °C for 12 min. The mixture was stirred at 25 °C for 2 h. The pH of the mixture was adjusted to about 7 with HCl (1 M). The reaction was then quenched with a _saturated aqueous solution of _Na2S2O3 (50 mL), the aqueous layer was extracted with _ethyl acetate (2 x 10 mL), the organic layer _was dried over _Na2SO4 , filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral) to give 5-(difluoromethyl)-6-methoxypyridin-3-ol (500 mg, 2.85 mmol, 67.89% yield, 99.9% purity) as a white solid. ¹ H NMR: 400 MHz, DMSO- d ₆ δ = 3.84 (s, 3H), 6.99 (t, J =54.78 Hz, 1H), 7.35 (d, J =2.88 Hz, 1H), 7.83 to 7.88 (m, 1H), 9.68 (br s, 1H). LCMS (ESI+): m/z 176.1 [M+H] ⁺ , Rt: 1.531 min.

Intermediate Example 18 2 - Ethyl - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolatocyclopentan - 2 - yl ) benzamide ​ ​ ​ ​ ​ ​ ​ Synthesis of 2 - ethyl - 4- ( 4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolatocyclopentan - 2 - yl ) benzamide : ​ ​ ​ ​ ​ ​ ​

4-Bromo-2-ethylbenzoic acid (0.750 g) was dissolved in _SOCl2 (2 mL) and heated to 45 °C overnight. Toluene (5 mL) was added and the solvent was dried completely. DCM (5 mL) was added and the reaction vial was cooled to 0 °C in an ice bath. _NH4OH was added slowly while stirring until no more precipitate formed. The solid was filtered, the mother liquor was separated, and the aqueous layer was washed with DCM. The organic layer was dried, filtered, and concentrated under vacuum. The combined solids gave 4-bromo-2-ethylbenzamide (750 mg; 100% yield) as a white powder.

4-Bromo-2-ethylbenzamide (0.6 g), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolato-2-yl)-1,3,2-dioxaborolato-2-yl (0.73 g), Pd(dppf)Cl ₂ .CH ₂ Cl ₂ (0.04 eq) and KOAc (3 eq) were dissolved in 10 mL of N ₂ flushed dioxane. The reaction was heated to 95 °C overnight. The reaction was diluted with EtOAc and the solid was filtered. The product was concentrated under high vacuum and purified by column chromatography (0 to 60% hexanes/EtOAc) to afford 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)benzamide (500 mg; 69% yield) as a white powder.

Example 1 4-(4-(4 -cyano -3- fluorophenoxy ) pyridin -2- yl )-2- methylbenzamide Synthesis of 4-(4-(4-cyano-3-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide

In a 0.5 to 2 mL conical microwave vial, Pd(PPh ₃ ) ₄ (approximately 4 mg) was added to a solution of 4-[(2-chloropyridin-4-yl)oxy]-2-fluorobenzonitrile (20 mg, 0.08 mmol) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)benzamide (0.096 mmol, 1.2 eq) in toluene/ethanol/saturated Na ₂ CO ₃ (2/2/1, 1 mL, 0.08 M). The vial was sealed and the solution was placed in an 80 °C oil bath. After 2 h, the reaction was cooled to rt and diluted with water (2 mL). The solution was extracted with EtOAc (3 x 2 mL) and the organics _were dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was dissolved in methanol/dichloromethane (1 mL, 9:1) and purified by preparative HPLC. LCMS Method 3A: rt = 2.13 min, m/z (M+H+) = 347.9 observed mass, exact mass 347.1.

Example 2 4-(4-(3- cyclopropyl -4- fluorophenoxy ) pyridin -2- yl )-2- methylbenzamide Synthesis of 4-(4-(3-cyclopropyl-4-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide

In a 4 mL vial, potassium carbonate (2 eq) was added to a solution of 4-(4-fluoropyridin-2-yl)-2-methylbenzamide (10 mg) and 3-cyclopropyl-4-fluorophenol (1.4 eq) in anhydrous DMF (0.5 mL) at r.t., and the reaction mixture was heated to 90 °C for 6 h. The solution was cooled to rt, then filtered through a PTFE filter, diluted with methanol and purified by HPLC to give 4-[4-(3-cyclopropyl-4-fluorophenoxy)pyridin-2-yl]-2-methylbenzamide. LCMS Method 3A: r.t. = 2.09 min, m/z (M+H+) = 363.2 observed mass, exact mass 362.1.

Example 3 N- ( 2- ( dimethylamino ) ethyl ) -2 - methyl - 4- ( 4- ( 4- ( trifluoromethyl ) phenoxy ) pyridin - 2 - yl ) benzamide Synthesis of N-(2-(dimethylamino)ethyl)-2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzamide

A solution of 2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzoic acid (7.5 mg, 0.02 mmol, 1.0 eq) and HATU (1.2 eq) in DCM (0.1 M) was stirred for 10 min. To this solution was added (2-aminoethyl)dimethylamine (2 eq) and DIPEA (2 eq). The reaction mixture was stirred at room temperature overnight (18 h). The reaction mixture was then diluted with methanol, filtered and purified by HPLC to give N-(2-(dimethylamino)ethyl)-2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)-pyridin-2-yl)benzamide. LCMS Method 3A: r.t. = 1.26 min, m/z (M+H+) = 444.2 observed mass, exact mass 443.2.

According to the procedures described in the above examples, the following examples in Table 2a were prepared using appropriate starting materials: Table 2a Example 4 4-(4-(3-cyclopropyl-4-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.09 min, m/z (M+H+, Br isotope effect) = 363.2 observed mass, exact mass 362.14 Example 5 4-(4-(4-chloro-3-cyanophenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.92 min, m/z (M+H+, Br isotope effect) = 364.2 observed mass, exact mass 363.08 Example 6 4-(4-(3-cyano-5-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.83 min, m/z (M+H+, Br isotope effect) = 348.2 observed mass, exact mass 347.11 Example 7 2-Methyl-4-(4-(3-(methylsulfonyl)phenoxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.53 min, m/z (M+H+, Br isotope effect) = 383.2 observed mass, exact mass 382.1 Example 8 4-(2-amino-6-(4-ethoxy-3-fluorophenoxy)pyridin-4-yl)-2-methylbenzamide LCMS method 3A: rt = 1.35 min, m/z (M+H+, Br isotope effect) = 382.2 observed mass, exact mass 381.15 Example 9 N-(2-(Dimethylamino)ethyl)-2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.26 min, m/z (M+H+, Br isotope effect) = 444.2 observed mass, exact mass 443.18 Example 10 N-(2-Methoxyethyl)-2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.47 min, m/z (M+H+, Br isotope effect) = 431.2 observed mass, exact mass 430.15 Example 11 N-(2-amino-2-oxoethyl)-2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.24 min, m/z (M+H+, Br isotope effect) = 430.2 observed mass, exact mass 429.13 Example 12 N-(2-Hydroxyethyl)-2-methyl-4-(4-(4-(trifluoromethyl)phenoxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.27 min, m/z (M+H+, Br isotope effect) = 417.2 observed mass, exact mass 416.13 Example 13 4-(4-(3-Acetylphenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.85 min, m/z (M+H+, Br isotope effect) = 346.9 observed mass, exact mass 346.13 Example 14 2-Methyl-4-(4-(4-(methylthio)phenoxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 2.16 min, m/z (M+H+, Br isotope effect) = 350.9 observed mass, exact mass 350.11 Example 15 4-(4-(4-Cyano-3-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.13 min, m/z (M+H+, Br isotope effect) = 347.9 observed mass, exact mass 347.11 Example 16 4-(4-(3-cyano-4-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.77 min, m/z (M+H+, Br isotope effect) = 348.2 observed mass, exact mass 347.11 Example 17 4-(4-(4-cyano-3-methoxyphenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.03 min, m/z (M+H+, Br isotope effect) = 359.9 observed mass, exact mass 359.13 Example 18 4-(6-Methoxy-4-(3-(methylsulfonyl)benzyl)pyridin-2-yl)-2-methylbenzamide LCMS Method 3A: rt = 2.49 min, m/z (M+H+, Br isotope effect) = 410.9 observed mass, exact mass 410.13 Example 19 4-(4-(4-cyano-2,3-difluorophenoxy)pyridin-2-yl)-2-methylbenzamide Example 20 4-(4-(3-cyano-5-methoxyphenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.85 min, m/z (M+H+, Br isotope effect) = 360.2 observed mass, exact mass 359.13 Example 21 4-(4-(4-cyano-3-(trifluoromethyl)phenoxy)pyridin-2-yl)-2-methylbenzamide Example 22 4-(4-(4-cyano-2-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide Example 23 4-(4-(2-chloro-4-cyanophenoxy)pyridin-2-yl)-2-methylbenzamide Example 24 4-(4-(4-cyano-3,5-difluorophenoxy)pyridin-2-yl)-2-methylbenzamide Example 25 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(2-azaspiro[3.3]hept-6-yl)benzamide 1H NMR (400 MHz, DMSO-d, 27 °C): δ = 8.57 to 8.64 (m, 3H), 8.51 to 8.57 (m, 2H), 7.98 to 8.02 (m, 2H), 7.94 (br d, J = 7.9 Hz, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.40 (d, J = 8.1 Hz, 1H), 7.01 (dd, J = 5.6, 2.3 Hz, 1H), 4.13 to 4.37 (m, 1H), 4.04 (br s, 2H), 3.92 (br s, 2H), 2.54 to 2.67 (m, 2H), 2.39 (s, 3H), 2.16 to 2.36 (m, 2H). LCMS method 3A: rt = 1.67 min, m/z (M+H+) = 435.20 observed mass, exact mass 434.15 Example 26 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.69 min, m/z (M+H+, Br isotope effect) = 449.2 observed mass, exact mass 448.17 Example 27 4-(4-((5-chloro-6-methylpyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.76 min, m/z (M+H+, Br isotope effect) = 449.2 observed mass, exact mass 448.17 Example 28 4-(4-((5-chloro-6-methylpyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.78 min, m/z (M+H+, Br isotope effect) = 463.2 observed mass, exact mass 462.18 Example 29 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.78 min, m/z (M+H+, Br isotope effect) = 463.3 observed mass, exact mass 462.18 Example 30 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.87 min, m/z (M+H+, Br isotope effect) = 479.2 observed mass, exact mass 478.18 Example 31 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.85 min, m/z (M+H+, Br isotope effect) = 465.2 observed mass, exact mass 464.16 Example 32 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.76 min, m/z (M+H+, Br isotope effect) = 449.2 observed mass, exact mass 448.17 Example 33 4-(4-((5-chloro-6-methylpyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.85 min, m/z (M+H+, Br isotope effect) = 477.3 observed mass, exact mass 476.2 Example 34 4-(4-((5-chloro-6-methylpyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.84 min, m/z (M+H+, Br isotope effect) = 463.3 observed mass, exact mass 462.18 Example 35 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.95 min, m/z (M+H+, Br isotope effect) = 493.3 observed mass, exact mass 492.19 Example 36 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(2-azaspiro[3.3]hept-6-yl)benzamide LCMS method 3A: rt = 1.94 min, m/z (M+H+, Br isotope effect) = 479.3 observed mass, exact mass 478.18 Example 37 4-(4-(4-Cyano-3-methylphenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.9 min, m/z (M+H+, Br isotope effect) = 344.2 observed mass, exact mass 343.13 Example 38 4-(4-(3-chloro-4-cyanophenoxy)pyridin-2-yl)-2-methylbenzamide Example 39 4-(4-(4-chloro-2-cyanophenoxy)pyridin-2-yl)-2-methylbenzamide Example 40 4-(4-(3-cyanophenoxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.71 min, m/z (M+H+, Br isotope effect) = 330.2 observed mass, exact mass 329.12 Example 41 4-(4-(4-Cyanophenoxy)pyridin-2-yl)-2-methylbenzamide

Example 42 4- ( 4 -(( 5- ( difluoromethyl ) pyridin - 3 - yl ) oxy ) pyridin - 2 - yl ) -2 - ethylbenzamide

In a 100 mL RB flask, Pd(PPh ₃ ) ₄ (2.88 g, 2.5 mmol, 5 mol%) was added to a solution of 2-chloro-4-fluoropyridine (6.58 g, 50 mmol) and 2-ethyl-4-(tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)benzamide (16.2 g, 60 mmol, 1.2 eq) in toluene/ethanol/saturated aqueous Na ₂ CO ₃ (2/2/1, 500 mL, 0.1 M). The reaction was heated at 80 °C. After 18 h, the reaction was cooled to rt and diluted with water (300 mL). The solution was extracted with EtOAc (3×400 mL) and the organics were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was triturated with dichloromethane (150 mL) and filtered. The filter cake was washed with dichloromethane (50 mL). The dark brown filtrate was concentrated in vacuo, and the dark brown solid was triturated again with dichloromethane (about 50 mL) and filtered. The filter cake was washed with dichloromethane (about 30 mL). The solids were combined and triturated with dichloromethane (100 mL), filtered, and dried under high vacuum to give 4-(4-fluoropyridin-2-yl)-2-ethylbenzamide (8.36 g, 72%) as an off-white solid which was used without further purification.

In a 4 mL vial, potassium carbonate (2 eq) was added to a solution of 4-(4-fluoropyridin-2-yl)-2-ethylbenzamide (10 mg) and 5-(difluoromethyl)pyridin-3-ol (1.4 eq) in anhydrous DMF (0.5 mL) at r.t. and the reaction mixture was heated to 90 °C for 6 h. The solution was cooled to rt, then filtered through a PTFE filter, diluted with methanol and purified by HPLC to give 4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide. 1H NMR (400 MHz, DMSO-d, 27℃): δ = 8.74 (m, 2H), 8.62 (d, J = 5.5 Hz, 1H), 7.99 (d, J = 1.47 Hz, 1H), 7.91 (m, 2H), 7.79 (s, 1H), 7.74 (d, J = 2.32, 1H), 7.42 (m , 2H), 7.32 to 7.07 (t, J = 57.3 Hz, 1H), 6.99 (dd, J = 5.62, 2.32 Hz, 1H), 2.82 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.5 Hz, 3H). LCMS Method 1A: r.t. = 1.85 min, m/z (M+H+) = 369.13 observed mass, exact mass 370.25.

Alternatively, 4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide can be synthesized as follows:

In a flask, chloro-pyridine (21.6 g), =C1-Butanol (220 mL) was added with 1-butylene oxide (24.3 g) and sodium tert-butoxide (8.9 g) and the reaction was purged/degassed with vacuum/bubbling _N2 (3 times). Tetrakis(triphenylphosphine)palladium(0) (1.5 mol%, 1.5 g) (480 mL) was added to the mixture and the purging/degassing process was repeated. The reaction was heated at 95 °C for 20 h. The reaction was cooled to 50 °C and quenched with 0.5 M HCl (430 mL) and stirred for 30 min. The layers were separated and the aqueous layer was extracted with 0.5 M HCl (220 mL). The combined aqueous solutions were washed with methyl tert-butyl ether (100 mL). The aqueous phase was placed in a 2 L flask and the pH was adjusted to 11-13 using 10 N NaOH (approximately 30 mL). The slurry was stirred for 2 h. The solid was collected by filtration, washed with H ₂ O (2×100 mL) and methyl tert-butyl ether (100 mL). The solid was dried under vacuum at 55° C. overnight to yield 18.5 g (60% isolated yield) of a brown solid. The Pd content was measured by ICP-MS to be 20 ppm.

If the Pd content is above the acceptable range, an additional step is added. The final product is treated with N-acetyl-L-(+)-cysteine. 4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide is dissolved in dichloromethane (5 V) and 1 M N-acetyl-L-(+)-cysteine in H ₂ O (2 to 3 V) is added. The mixture is stirred at 40 °C for 18 h. The solution is cooled to room temperature and the layers are separated. The organic layer is washed with H ₂ O (2 V) and separated into layers. A sample of the organics is removed and evaporated to dryness to determine the palladium content. If the palladium is within acceptable limits, the material is recrystallized.

NMR was consistent with LCMS method: r.t = 6.7 min, m/z (M+H+) = 370.25 observed mass, accurate mass 369.37.

According to the procedures described in the above examples, the following examples in Table 2b were prepared using appropriate starting materials: Table 2b Example 43 4-(4-((5-(2,2-difluoroethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.60 (d, J = 5.6 Hz, 1H), 8.46 to 8.52 (m, 2H), 7.94 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.76 (br s, 1H), 7.71 (s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.39 (br s, 1H), 6.93 (dd, J = 5.6, 2.3 Hz, 1H), 6.17 to 6.51 (m, 1H), 3.26 to 3.37 (m, 2H), 2.44 (s, 3H). LCMS Method 1A: rt = 1.48 min, m/z (M+H+) = 370.20 observed mass, exact mass 369.13 Example 44 2-Ethyl-4-(4-((5-(2,2,2-trifluoroethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.97 min, m/z (M+H+, Br isotope effect) = 402.2 observed mass, exact mass 401.14 Example 45 4-(4-((5-(1,1-difluoroethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 2.02 min, m/z (M+H+, Br isotope effect) = 384.2 observed mass, exact mass 383.14. Example 46 4-(4-((5-(2,2-difluoropropyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.60 (d, J = 5.6 Hz, 1H), 8.51 (d, J = 2.7 Hz, 1H), 8.45 (s, 1H), 7.95 (s, 1H), 7.88 (dd, J = 7.9, 1.6 Hz, 1H), 7.79 (br s, 1H), 7.64 (d, J = 2.3 Hz, 2H), 7.36 to 7.47 (m, 2H), 6.94 (dd, J = 5.6, 2.3 Hz, 1H), 3.33 to 3.40 (m, 2H), 2.81 (q, J = 7.5 Hz, 2H), 1.62 (t, J = 18.8 Hz, 3H), 1.19 ppm (t, J = 7.5 Hz, 3H). LCMS method 1A: rt = 1.64 min, m/z (M+H+) = 398.11 observed mass, exact mass 397.16. Example 47 2-Ethyl-4-(4-((5-(1-fluorocyclopropyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 1A: rt = 1.52 min, m/z (M+H+, Br isotope effect) = 378.2 observed mass, exact mass 377.15 Example 48 4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.79 min, m/z (M+H+, Br isotope effect) = 356 observed mass, exact mass 355.11 Example 49 2-Methyl-4-(4-((5-(2,2,2-trifluoroethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.88 min, m/z (M+H+, Br isotope effect) = 388.2 observed mass, exact mass 387.12 Example 50 2-Ethyl-4-(4-((5-(trifluoromethoxy)pyridin-3-yl)oxy)pyridin-2-yl)benzamide 1H NMR (400 MHz, DMSO-d, 27°C): δ = 8.62 to 8.67 (m, 3H), 7.97 to 8.01 (m, 2H), 7.91 (dd, J = 7.9, 1.7 Hz, 1H), 7.79 (br s, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.39 to 7.45 (m, 2H), 7.03 (dd, J = 5.6, 2.3 Hz, 1H), 2.82 (q, J = 7.5 Hz, 2H), 1.15 to 1.25 ppm (m, 3H). LCMS Method 3A: rt = 2.11 min, m/z (M+H+) = 404.20 observed mass, exact mass 403.11. Example 51 2-Ethyl-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 1A: rt = 1.53 min, m/z (M+H+, Br isotope effect) = 388.2 observed mass, exact mass 387.12 Example 52 4-(4-((5-(1,1-difluoroethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.75 (s, 1H), 8.70 (d, J = 2.4 Hz, 1H), 8.61 (d, J = 5.5 Hz, 1H), 7.89 to 7.99 (m, 3H), 7.76 (br s, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.40 (br s, 1H), 6.96 (dd, J = 5.6, 2.3 Hz, 1H), 2.42 to 2.47 (m, 3H), 2.06 ppm (t, J = 19.2 Hz, 3H). LCMS method 3A: rt = 1.91 min, m/z (M+H+) = 370.20 observed mass, exact mass 369.13 Example 53 2-Chloro-4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.88 min, m/z (M+H+, Br isotope effect) = 376 observed mass, exact mass 375.06 Example 54 4-(4-((5-(difluoromethoxy)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide 1H NMR (400 MHz, DMSO-d, 27°C): δ = 8.62 (d, J = 5.6 Hz, 1H), 8.47 (dd, J = 5.0, 2.3 Hz, 2H), 7.99 (s, 1H), 7.90 (dd, J = 8.0, 1.4 Hz, 1H), 7.79 (br s, 1H), 7.68 to 7.74 (m, 2H), 7.19 to 7.58 (m, 3H), 6.99 (dd, J = 5.6, 2.3 Hz, 1H), 2.82 (q, J = 7.5 Hz, 2H), 1.20 ppm (t, J = 7.5 Hz, 3H). LCMS Method 1A: rt = 1.51 min, m/z (M+H+) = 386.20 observed mass, exact mass 385.12. Example 55 2-Methyl-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.87 min, m/z (M+H+, Br isotope effect) = 374.2 observed mass, exact mass 373.1 Example 56 2-Ethyl-4-(4-((6-(trifluoromethoxy)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 2.16 min, m/z (M+H+, Br isotope effect) = 404.2 observed mass, exact mass 403.11 Example 57 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 1.98 min, m/z (M+H+, Br isotope effect) = 354 observed mass, exact mass 353.09 Example 58 4-(4-((5-(1-fluorocyclopropyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS Method 1A: rt = 1.47 min, m/z (M+H+, Br isotope effect) = 364.2 observed mass, exact mass 363.14 Example 59 4-(4-((5-(2,2-difluoroethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.60 (d, J = 5.6 Hz, 1H), 8.46 to 8.52 (m, 2H), 7.94 (s, 1H), 7.89 (d, J = 8.2 Hz, 1H), 7.76 (br s, 1H), 7.71 (s, 1H), 7.64 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.39 (br s, 1H), 6.93 (dd, J = 5.6, 2.3 Hz, 1H), 6.17 to 6.51 (m, 1H), 3.26 to 3.37 (m, 2H), 2.81 (q, J = 7.5 Hz, 2H), 1.20 ppm (t, J = 7.5 Hz, 3H). LCMS Method 1A: rt = 1.54 min, m/z (M+H+) = 384.23 observed mass, exact mass 383.14 Example 60 4-(4-((5-(2,2-difluoropropyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS Method 1A: rt = 1.73 min, m/z (M+H+, Br isotope effect) = 384.2 observed mass, exact mass 383.14 Example 61 2-Methyl-4-(4-((5-(trifluoromethoxy)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 2.05 min, m/z (M+H+, Br isotope effect) = 390.2 observed mass, exact mass 389.1 Example 62 2-Chloro-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 2.22 min, m/z (M+H+, Br isotope effect) = 394.1 observed mass, exact mass 393.05 Example 63 2-Ethyl-4-(4-((5-(2-fluoropropan-2-yl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 1.92 min, m/z (M+H+, Br isotope effect) = 380.1 observed mass, exact mass 379.17 Example 64 2-Methyl-4-(4-((6-(trifluoromethoxy)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS Method 3A: rt = 2.06 min, m/z (M+H+, Br isotope effect) = 390.2 observed mass, exact mass 389.1 Example 65 4-(4-((5-Methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 0.75 min, m/z (M+H+) = 336.20 observed mass, exact mass 335.13. Example 66 2-Ethyl-4-(4-((5-fluoropyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.68 min, m/z (M+H+) = 338.20 observed mass, exact mass 337.12. Example 67 4-(4-((5-cyanopyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 0.78 min, m/z (M+H+) = 331.20 observed mass, exact mass 330.11. Example 68 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.61 (d, J = 5.6 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.01 (t, J = 2.1 Hz, 1H), 7.97 (s, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.76 (br s, 1H), 7.72 (d, J = 2.3 Hz, 1H), 7.46 (d, J = 8.1 Hz, 1H), 7.40 (br s, 1H), 7.00 (dd, J = 5.6, 2.3 Hz, 1H), 2.42 to 2.47 ppm (m, 3H). LCMS Method 1A: rt = 1.46 min, m/z (M+H+) = 340.10 observed mass, exact mass 339.08. Example 69 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.61 (d, J = 5.6 Hz, 1H), 8.59 (d, J = 2.0 Hz, 1H), 8.55 (d, J = 2.3 Hz, 1H), 8.00 (s, 1H), 8.00 (d, J = 3.9 Hz, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.79 (br s, 1H), 7.73 (d, J = 2.1 Hz, 1H), 7.36 to 7.47 (m, 2H), 7.00 (dd, J = 5.6, 2.3 Hz, 1H), 2.82 (q, J = 7.5 Hz, 2H), 1.20 ppm (t, J = 7.5 Hz, 3H). LCMS method 3A: rt = 1.98 min, m/z (M+H+) = 354.0 observed mass, exact mass 353.09. Example 70 4-(4-((5-chloro-6-methylpyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.85 min, m/z (M+H+) = 354.0 observed mass, exact mass 353.09. Example 71 4-(4-((5-chloro-6-methylpyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 1.95 min, m/z (M+H+) = 368.10 observed mass, exact mass 367.11 Example 72 4-(4-((6-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.76 min, m/z (M+H+) = 336.20 observed mass, exact mass 335.13 Example 73 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.06 min, m/z (M+H+) = 370.10 observed mass, exact mass 369.09 Example 74 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 2.17 min, m/z (M+H+) = 384.20 observed mass, exact mass 383.10 Example 75 2-Ethyl-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.98 min, m/z (M+H+) = 388.20 observed mass, exact mass 387.12 Example 76 2-Methyl-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.88 min, m/z (M+H+) = 374.20 observed mass, exact mass 373.10 Example 77 2-Ethyl-4-(4-((2-methoxypyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.86 min, m/z (M+H+) = 350.10 observed mass, exact mass 349.14 Example 78 2-Ethyl-4-(4-((2-fluoro-5-methoxypyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.94 min, m/z (M+H+) = 368.20 observed mass, exact mass 367.13 Example 79 4-(4-((5,6-dimethoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 1.9 min, m/z (M+H+) = 380.10 observed mass, exact mass 379.15 Example 80 4-(4-((6-(dimethylamino)pyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 1.57 min, m/z (M+H+) = 363.10 observed mass, exact mass 362.17 Example 81 2-Ethyl-4-(4-((5-fluoropyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.68 min, m/z (M+H+) = 338.20 observed mass, exact mass 337.12 Example 82 2-Chloro-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 2.22 min, m/z (M+H+) = 394.10 observed mass, exact mass 393.05 Example 83 2-Methyl-4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.15 min, m/z (M+H+) = 374.10 observed mass, exact mass 373.10 Example 84 4-(4-((5-chloro-6-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 2.15 min, m/z (M+H+) = 384.20 observed mass, exact mass 383.10 Example 85 4-(4-((5-chloro-6-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.05 min, m/z (M+H+) = 370.20 observed mass, exact mass 369.09 Example 86 2-Ethyl-4-(4-((6-methoxypyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.87 min, m/z (M+H+) = 350.20 observed mass, exact mass 349.14 Example 87 2-Ethyl-4-(4-((2-methoxypyridin-4-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.97 min, m/z (M+H+) = 350.10 observed mass, exact mass 349.14 Example 88 2-Chloro-4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 2.08 min, m/z (M+H+) = 360.10 observed mass, exact mass 359.02 Example 89 4-(4-((6-methoxy-5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.19 min, m/z (M+H+) = 404.20 observed mass, exact mass 403.11 Example 90 2-Ethyl-4-(4-((6-methoxy-5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 2.28 min, m/z (M+H+) = 418.20 observed mass, exact mass 417.13 Example 91 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(1-methylpiperidin-4-yl)benzamide LCMS method 3A: rt = 1.76 min, m/z (M+H+) = 451.10 observed mass, exact mass 450.18 Example 92 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(1-methylpiperidin-4-yl)benzamide LCMS method 3A: rt = 1.85 min, m/z (M+H+) = 467.20 observed mass, exact mass 466.18 Example 93 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(1-methylazinylcyclobutane-3-yl)benzamide LCMS method 3A: rt = 1.86 min, m/z (M+H+) = 439.20 observed mass, exact mass 438.14 Example 94 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(1-methylazolobutan-3-yl)benzamide LCMS method 3A: rt = 1.78 min, m/z (M+H+) = 423.20 observed mass, exact mass 422.15 Example 95 4-(4-((5-chloro-6-methylpyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(1-methylazolobutyl-3-yl)benzamide LCMS method 3A: rt = 1.85 min, m/z (M+H+) = 437.30 observed mass, exact mass 436.17 Example 96 4-(4-((5-chloro-2-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(1-methylazolobutan-3-yl)benzamide LCMS method 3A: rt = 1.96 min, m/z (M+H+) = 453.20 observed mass, exact mass 452.16 Example 97 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-methyl-N-(1-methylpiperidin-4-yl)benzamide LCMS method 3A: rt = 1.64 min, m/z (M+H+) = 437.10 observed mass, exact mass 436.16 Example 98 N-(Azocyclobutane-3-yl)-4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 1.73 min, m/z (M+H+) = 409.20 observed mass, exact mass 408.13 Example 99 4-(4-((5-chloropyridin-3-yl)oxy)pyridin-2-yl)-2-ethyl-N-(piperidin-4-yl)benzamide LCMS method 3A: rt = 1.75 min, m/z (M+H+) = 437.20 observed mass, exact mass 436.17 Example 100 2-Ethyl-N-(1-methylazin-3-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.99 min, m/z (M+H+) = 457.20 observed mass, exact mass 456.18 Example 101 2-Ethyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 2.00 min, m/z (M+H+) = 497.30 observed mass, exact mass 496.20 Example 102 2-Ethyl-N-(1-methylpiperidin-4-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.96 min, m/z (M+H+) = 485.30 observed mass, exact mass 484.21 Example 103 2-Methyl-N-(2-methyl-2-azaspiro[3.3]hept-6-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.91 min, m/z (M+H+) = 483.30 observed mass, exact mass 482.19 Example 104 2-Methyl-N-(1-methylpiperidin-4-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.88 min, m/z (M+H+) = 471.30 observed mass, exact mass 470.19 Example 105 2-Ethyl-N-(2-azaspiro[3.3]hept-6-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.96 min, m/z (M+H+) = 483.30 observed mass, exact mass 482.19 Example 106 2-Methyl-N-(1-methylazin-3-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.90 min, m/z (M+H+) = 443.20 observed mass, exact mass 442.16 Example 107 N-(Azocyclobutane-3-yl)-2-ethyl-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.97 min, m/z (M+H+) = 443.20 observed mass, exact mass 442.16 Example 108 2-Ethyl-N-(piperidin-4-yl)-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.96 min, m/z (M+H+) = 471.20 observed mass, exact mass 470.19 Example 109 4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-2-isopropylbenzamide LCMS method 3A: rt = 1.92 min, m/z (M+H+) = 384.30 observed mass, exact mass 383.14 Example 110 2-Cyclopropyl-4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.81 min, m/z (M+H+) = 382.00 observed mass, exact mass 381.13 Example 111 2-Cyclopropyl-4-(4-((5-(1,1-difluoroethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 1.97 min, m/z (M+H+) = 396.00 observed mass, exact mass 395.14 Example 112 2-Cyclopropyl-4-(4-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 2.03 min, m/z (M+H+) = 400.00 observed mass, exact mass 399.12 Example 113 2-Cyclopropyl-4-(4-((5-(trifluoromethoxy)pyridin-3-yl)oxy)pyridin-2-yl)benzamide LCMS method 3A: rt = 2.08 min, m/z (M+H+) = 416.00 observed mass, exact mass 415.11 Example 114 4-(4-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)-5-fluoro-2-methylbenzamide LCMS method 3A: rt = 1.81 min, m/z (M+H+) = 374.00 observed mass, exact mass 373.10 Example 115 4-(4-((5-(2-fluoropropan-2-yl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 1.84 min, m/z (M+H+) = 366.00 observed mass, exact mass 365.15 Example 116 4-(4-((5-(difluoromethyl)-6-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.01 min, m/z (M+H+) = 386.00 observed mass, exact mass 385.12 Example 117 4-(4-((5-(difluoromethyl)-6-methoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 2.10 min, m/z (M+H+) = 400.00 observed mass, exact mass 399.14 Example 118 4-(4-((5-(difluoromethoxy)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide 1H NMR (400 MHz, DMSO-d, 27°C): δ = 8.62 (d, J = 5.6 Hz, 1H), 8.47 (dd, J = 5.0, 2.3 Hz, 2H), 7.99 (s, 1H), 7.90 (dd, J = 8.0, 1.4 Hz, 1H), 7.79 (br s, 1H), 7.68 to 7.74 (m, 2H), 7.19 to 7.58 (m, 3H), 6.99 (dd, J = 5.6, 2.3 Hz, 1H), 2.82 (m, 2H), 2.44 ppm (s, 3H). LCMS Method 1A: rt = 1.44 min, m/z (M+H+) = 372.18 observed mass, exact mass 371.11 Example 119 4-(4-((5-chloro-6-ethoxypyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide LCMS method 3A: rt = 2.17 min, m/z (M+H+) = 384.00 observed mass, exact mass 383.10 Example 120 4-(4-((5-chloro-6-ethoxypyridin-3-yl)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS method 3A: rt = 2.26 min, m/z (M+H+) = 398.20 observed mass, exact mass 397.12

Example 121 4- ( 5 -(( 5- ( difluoromethyl ) pyridin - 3 - yl ) oxy ) pyridin - 3 - yl ) -2 - ethylbenzamide Synthesis of 4-(5-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)-2-ethylbenzamide:

In a glass bottle with a stir bar, 3-bromo-5-chlorobenzene (1 mmol) in NMP (10 ml) was treated with 5-(difluoromethyl)pyridin-3-ol (0.95 mmol) followed by Cu ₂ O (15 mol%) and Cs ₂ CO ₃ (1 mmol). The reaction mixture in a sealed vial was heated at 210 °C for 5 min and then at 195 °C for another 30 min. After the reaction was complete, the mixture was cooled to room temperature and filtered through a plug of celite and washed with EtOAc. The organic layer was diluted with another 100 mL of EtOAc and extracted twice with 200 mL of water. The organic layers were combined and washed with brine. The crude material was purified by silica gel chromatography with an EtOAc/hexanes gradient up to 60% EtOAc to afford 3-chloro-5-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridine as a colorless oil. LCMS Method 1A: rt = 1.67 min, m/z (M+H+) = 257.0 observed mass, exact mass 256.02

In a 0.5 to 2 mL conical microwave vial, Pd(PPh ₃ ) ₄ (5 mol %) was added to a solution of 3-chloro-5-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridine (1 mmol), K ₂ CO ₃ (1.3 eq), and 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolatocyclopentan-2-yl)benzamide (1.2 eq) in 1,4-dioxane/H 2 O (10:1, 1 ml). The vial was sealed and the solution was placed in an 80 °C oil bath overnight. Upon completion, the reaction was cooled to room temperature and diluted with water (2 mL). The solution was extracted with EtOAc (3 x 2 mL) and the organics _were dried over _Na2SO4 , filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give 4-(5-((5-(difluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)-2-ethylbenzamide as a white powder. LCMS Method 3A: rt = 2.03 min, m/z (M+H+) = 369.13 observed mass, exact mass 370.30.

According to the procedures described in the above examples, the following examples in Table 2c were prepared using appropriate starting materials: Table 2c Example 122 2-Ethyl-4-(5-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)benzamide LCMS Method 3A: rt = 1.63 min, m/z (M+H+) = 388.1 observed mass, exact mass 387.12 Example 123 4-(5-((5-(1,1-difluoroethyl)pyridin-3-yl)oxy)pyridin-3-yl)-2-ethylbenzamide LCMS method 3A: rt = 1.55 min, m/z (M+H+) = 384.1 observed mass, exact mass 383.14 Example 124 2-Ethyl-4-(4-((5-(3-fluorocyclobutane-3-yl)pyridin-3-yl)oxy)pyridin-2-yl)benzamide 1H NMR (400 MHz, DMSO-d, 27 ° C): δ = 8.74 (s, 1H), 8.62 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.88 to 7.94 (m, 2H), 7.79 (br s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.36 to 7.47 (m, 2H), 6.97 (dd, J = 5.6, 2.3 Hz, 1H), 4.94 to 5.08 (m, 4H), 2.82 (q, J = 7.5 Hz, 2H), 1.20 ppm (t, J = 7.5 Hz, 3H). LCMS Method 1A: rt = 1.51 min, m/z (M+H+) = 394.25 observed mass, exact mass 393.15 Example 125 4-(4-((5-(3-fluorocyclobutane-3-yl)pyridin-3-yl)oxy)pyridin-2-yl)-2-methylbenzamide 1H NMR (400 MHz, DMSO-d, 27° C.): δ = 8.74 (s, 1H), 8.62 (d, J = 2.6 Hz, 1H), 8.60 (d, J = 5.6 Hz, 1H), 7.99 (s, 1H), 7.88 to 7.94 (m, 2H), 7.79 (br s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.36 to 7.47 (m, 2H), 6.97 (dd, J = 5.6, 2.3 Hz, 1H), 4.94 to 5.08 (m, 4H), 2.44 (s, 3H). LCMS Method 1A: rt = 1.42 min, m/z (M+H+) = 380.22 observed mass, exact mass 379.13 Example 126 4-(4-(4-Fluoro-3-methoxyphenoxy)pyridin-2-yl)-2-methylbenzamide 1H NMR (400 MHz, DMSO-d, 27°C): δ = 8.62 to 8.68 (m, 1H), 7.92 to 7.97 (m, 1H), 7.83 to 7.91 (m, 2H), 7.79 to 7.83 (m, 1H), 7.48 to 7.57 (m, 2H), 7.32 to 7.45 (m, 1H), 7.17 to 7.25 (m, 1H), 7.11 to 7.16 (m, 1H), 6.85 to 6.91 (m, 1H), 3.85 (s, 3H), 2.44 to 2.48 (m, 3H). LCMS method 3A: rt = 1.81 min, m/z (M+H+) = 353.20 observed mass, exact mass 352.12 Example 127 4-(4-(4-Ethoxy-3-fluorophenoxy)pyridin-2-yl)-2-methylbenzamide 1H NMR (400 MHz, DMSO-d, 27°C): δ = 8.63 (d, J = 6.2 Hz, 1H), 7.93 (s, 1H), 7.82 to 7.90 (m, 2H), 7.75 (d, J = 4.6 Hz, 1H), 7.44 to 7.58 (m, 2H), 7.26 to 7.38 (m, 2H), 7.05 to 7.13 (m, 2H), 4.15 (q, J = 6.9 Hz, 2H), 2.44 to 2.47 (m, 3H), 1.37 (t, J = 7.0 Hz, 3H). LCMS method 3A: rt = 1.3 min, m/z (M+H+) = 367.20 observed mass, exact mass 366.14 Example 128 4-(4-((5-(Difluoromethyl-d)pyridin-3-yl-4-d)oxy)pyridin-2-yl)-2-ethylbenzamide LCMS Method 3A: rt = 1.82 min, m/z (M+H+) = 372.17 observed mass, exact mass 371.14.

Example A GPR52 Activity The ability of Formula I compounds to modulate GPR52 activity was assessed. HTRF cAMP assays were performed using a commercially available assay kit (cAMP Gs HiRange HTRF®, CisBio). Controls and compounds were dissolved in DMSO and 62.5 nanoliters of the diluted compound were transferred to a 384-well NBS assay plate by acoustic or precision low volume dispensing. 20,000 cells were added per well and the compound was further diluted to 1-fold. Flp-In™-CHO cells that stably express recombinant human GPR52 were used in the assay.

Cells were harvested with a cell dissociator and resuspended in stimulation buffer. After thirty minutes of incubation at room temperature, the probe was added to each well. The plate was then incubated for another 30 minutes at room temperature. The cAMP produced by the cells during the first incubation period competes with the d2-labeled cAMP for binding to the anti-cAMP monoclonal antibody labeled with cryptate. The measured signal is inversely proportional to the concentration of cAMP produced by the cells, and this signal is quantified using a ^PHERAstar® multi-mode plate reader.

Dose-response curves were generated from HTRF counts transformed based on a cAMP reference curve and then normalized to a positive control. _EC50 values were obtained using a nonlinear regression curve fitting program. Table 3 provides _EC50 values, where A <25 nM; B is 25 to 100 nM; C is 101 to 1000 nM; and D is >1000 nM and less than 2000 nM. Emax (Table 3) is the maximum amount of cAMP (nM) produced by incubating cells with 10 μM or 31.6 μM test compound. The compound was defined by the top plateau region of the sigmoidal curve fit. The curves were then normalized to a reference compound, in this case 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (Tokumaru, K. et al., "Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists", Bioorganic & Medicinal Chemistry, Vol. 25, No. 12, June 2017, pp. 3098-3115), and expressed as a percentage of the Emax of that reference compound. For example, Example 8 had an EC ₅₀ of 19 nM and an Emax of 105%, Example 31 had an EC ₅₀ of 188 nM and an Emax of 102%, Example 35 had an EC ₅₀ of 159 nM and an Emax of 118%, and Example 42 had an EC ₅₀ of 92 nM and an Emax of 132%. Table 3 Examples EC ₅₀ (N=) E _max (%) Examples EC ₅₀ (N=) E _max (%) 1 71 C 83 2 72 C 72 3 B 68 73 C 89 4 C 116 74 D 102 5 C 75 75 C 119 6 C 104 76 C 89 7 C 84 77 D 85 8 A 105 78 D 73 9 B 68 79 C 137 10 B 61 80 C 67 11 C 60 81 D 106 12 C 70 82 C 84 13 D 99 83 D 53 14 C 143 84 C 131 15 D 77 85 C 110 16 D 97 86 C 105 17 D 70 87 D 110 18 D 82 88 C 85 19 89 C 107 20 D 69 90 C 111 twenty one 91 C 86 twenty two 92 C 101 twenty three 93 C 112 twenty four 94 C 124 25 95 C 76 26 C 76 96 C 125 27 97 C 67 28 33 98 B 123 29 41 99 C 99 30 C 101 100 B 130 31 C 102 101 B 120 32 B 116 102 C 86 33 C 75 103 C 65 34 B 72 104 C 78 35 C 118 105 B 104 36 B 106 106 C 92 37 D 84 107 B 138 38 108 C 97 39 109 D 58 40 D 83 110 C 121 41 111 C 100 42 B 132 112 C 91 43 C 114 113 C 112 44 B 116 114 D 88 45 B 132 115 C 93 46 C 129 116 C 102 47 C 126 117 C 121 48 C 129 118 C 109 49 C 104 119 C 96 50 C 144 120 B 136 51 C 127 121 C 128 52 C 127 122 C 143 53 C 105 123 C 147 54 C 135 124 55 C 97 125 56 C 107 126 C 126 57 C 117 127 A 116 58 C 121 128 B 132 59 C 132 60 C 128 61 C 112 62 C 87 63 C 96 64 C 66 65 C 93 66 D 106 67 D 68 68 C 88 69 C 115 70 C 53

Example B Selectivity Panel The selectivity of compounds of Formula I was evaluated using the BioPrint® CEREP panel (Eurofins) containing more than 130 binding, enzyme and uptake assays. Compounds of Formula I were tested at a single concentration (10 μM). Compound binding was calculated as the percent inhibition of binding of the radiolabeled ligand specific for each target. Compound enzyme inhibition was calculated as the percent inhibition of control enzyme activity.

Results showing inhibition or stimulation greater than 50% are considered to represent a significant effect of the compounds of formula I. The compounds of formula I are highly selective, showing a very sharp distribution.

Example C Induction of compounds when incubated with PXR nuclear receptors Induction of drug metabolites or transporters via activation of the pregnane X receptor (PXR) was assessed in vitro using a reporter gene assay. An expression vector containing full-length human PXR and appropriate enhancers and promoters linked to a luciferase reporter gene was integrated into tumor cells. These transfected tumor cells were seeded into 96-well microtiter plates and placed in a tissue culture incubator. After 24 hours, cells were treated with a single concentration (10 μM) or 6 different concentrations of the compound of formula I in duplicate wells, and the cells were returned to the incubator for an additional 24 hours. At the end of the incubation period, the number of viable cells/well was determined using Promega's Cell Titer Fluor cytotoxicity assay. Following the cytotoxicity assessment, Promega's ONE-Glo was added to the same wells and reporter gene activity was assessed. Rifampicin was used as a positive control and was tested in the same manner as the test compounds; either at a single concentration (10 mM) or at six concentrations. The data reported are presented as the mean of the fold receptor activation relative to vehicle-treated cells at 10 mM or each of the six doses (n=2). In addition, the data were normalized to the number of viable cells/well and expressed as a percentage of the response given by rifampicin at a dose of 10 μM.

For example, the oxygen linker region changes Emax and PXR induction relative to the _-CH2O- linker: Compound structure active Emax was 93% and PXR induction was 2.4 times that at 10 μM Emax was 74% and PXR induction was 4.4 times that at 10 μM

Example D Stability of Formula I Compounds in Mammalian Liver Microsomes The stability of Formula I compounds in mammalian liver microsomes was assessed. Formula I compounds (0.5 μM) were incubated with pooled mixed-sex human liver microsomes (HLM) (0.5 mg/mL total protein) at 37° C. in the presence of an NADPH generating system containing 50 mM potassium phosphate buffer, pH 7.4, 3 mM magnesium chloride, 1 mM EDTA, 1 mM NADP, 5 mM glucose-6-phosphate, and 1 unit/mL glucose-6-phosphate dehydrogenase. All concentrations are relative to a final incubation volume of 125 μL. Incubations were performed at 37°C in a water bath for 0, 5, 10, 20, 40 and 60 minutes and terminated by rapid mixing with 150 μL of ice-cold acetonitrile containing internal standard and the precipitated protein removed by centrifugation for subsequent LC-MS/MS analysis. Aliquots of the resulting supernatant fractions were analyzed by LC-MS/MS monitoring the depletion of the parent compound. The resulting peak area ratios versus time data were fit to a nonlinear regression using XLfit scientific curve fitting software (IDBS Ltd., Surrey, UK) and half-lives were calculated from the slopes. Pharmacokinetic parameters were predicted using the method described by Obach et al. ( J. Pharmcol . Exp . Ther . 1997 ; 283: 46.58). Briefly, a value for intrinsic clearance is calculated based on in vitro half-life data and then scaled to represent the expected clearance in whole animals (humans). Additional values calculated include the predicted extraction rate and the predicted maximum bioavailability. For example, an oxygen linker alters metabolic stability relative to a methylene linker as follows: Compound structure Microsomal stability Higher metabolic stability - predicted systemic clearance (Example D above) is 3.1 ml/min/kg Poor metabolic stability - predicted systemic clearance (Example D above) is 15.6 ml/min/kg

Example E Permeability of Formula I Compounds in MDR1 - MDCK Cells Formula I compounds were evaluated to determine their permeability in MDR1-MDCK cells. Apparent permeability (P _app ) and efflux ratios were generated using Madin-Darby canine kidney (MDCK) cells transfected with human multidrug resistance protein 1 (MDR1). Cells were grown as monolayers on microporous membranes in 24-well assay plates. Each compound was evaluated at a single concentration equal to 5 μM. The assay buffer consisted of Hanks' balanced salt solution (Mediatech, Inc., Corning) containing 10 mM HEPES and 15 mM glucose, pH 7.4. The test article was diluted in assay buffer and then dosed into the apical chamber of the cell monolayer to determine the apical to basolateral (A to B) permeability. The basolateral to apical (B to A) permeability was determined by adding the dosing solution to the basolateral chamber. The cell monolayer dosed with the test article was incubated for 1 hour in a humidified incubator at 37°C and 5% _CO2 . Samples were collected from the donor and receiving chambers at 1 hour and subsequently prepared for LC-MS/MS analysis using electrospray ionization. Triplicate measurements of the A to B and B to A permeabilities were collected for each compound. The efflux ratio was calculated using the following formula: P _app B>A/P _app A>B. Controls were included to ensure monolayer integrity (1 µM atenolol) and MDR1 protein activity (digoxin).

Example F Effects of Formula I Compounds on hERG Channel Current The in vitro effects of Formula I compounds on hERG channel current were evaluated. The concentration-response relationship of all compounds on hERG potassium channel current was evaluated at room temperature in stably transfected mammalian cells expressing a selected hERG potassium channel encoded by the KCNH2 gene. The hERG potassium channel was expressed in Chinese Hamster's Ovary (CHO) cells lacking endogenous I _Kr .

Stock solutions of positive controls were prepared in DMSO and stored at room temperature. Control 1, Dofetilide (Sigma; Catalog No. PZ0016) has a molecular weight of 441.56. Control 2, Verapamil (Tocris; Catalog No. 0654) has a molecular weight of 491.07. Both controls 1 and 2 were stored at room temperature. CHO/hERG cell lines were derived from the Gray Hamster organism: tissue (ovary; transfected with ion channel cDNA); morphology (epithelial); age/stage (embryonic); source strain (ATCC, Manassas, VA); and source substrain (Charles River Laboratories).

CHO cells were stably transfected with hERG cDNA. Stable transfections were maintained in medium with appropriate selective pressure and antibiotics. All experiments were performed at room temperature. Each cell served as its own control. Complete blockade was achieved by adding 20 µM verapamil. Two groups were tested: test article treatment and positive control treatment.

Automated patch clamp procedure For all hERG assays, the 384-well based automated patch clamp system SyncroPatch 384PE (Nanion Technologies) with PatchControl software (data acquisition) and DataControl software (data analysis) was used. Recordings were performed at room temperature (22°C) with medium resistance on planar NPC-384 multiwell chips with 4 wells per well. Recordings were performed in whole-cell patch mode. The composition of the internal solution was: 10 mM EGTA, 10 mM HEPES, 10 mM KCl, 10 mM NaCl, and 110 mM KF, pH 7.2, mOsm = 285. The composition of the external solution was: 10 mM HEPES, 80 mM NaCl, 60 mM NMDG, 5 mM glucose, 4 mM KCl, 5 mM _CaCl2 and 1 mM _MgCl2 , pH 7.4, mOsm = 298. The compound of formula I was dissolved in 100% DMSO. On the day of the experiment, a DMSO serial dilution was prepared manually. The pre-diluted compound of formula I was further diluted into the external solution at a dilution factor of 1:500 (0.2% DMSO by volume). A single application of the compound of formula I was performed at the concentration of the entire chip. Each well received a single concentration of compound, followed by complete blockade of verapamil to assess leakage. Different concentrations of each compound were distributed throughout the chip to generate individual dose-response relationships.

The onset and block of hERG currents were measured using a stimulation voltage pattern consisting of a 500 ms prepulse to -40 mV (leak), a 2 s activation pulse to +40 mV, followed by a 2 s test pulse to -40 mV, followed by a 2 s test pulse to -40 mV. The pulse pattern was repeated continuously at 6 s intervals from the clamping potential of -80 mV. The peak-to-tail current was calculated from the current amplitude evoked by the -40 mV prepulse and was subtracted from the total membrane current record. Smaller superpolarization voltage steps from -80 to -90 mV are applied during the clamping potential to calculate the resistance according to Ohm's law for quality control.

Data acquisition and analysis were performed using Nanion Data Control software. Steady state was defined by limiting the constant rate over time (linear time dependence). Steady state before and after application of the test article was used to calculate the percentage of current suppressed at each concentration.

The ability of the compound of formula I to counteract the cognitive deficits and negative symptoms of schizophrenia was assessed. Animals exposed to repeated PCP administration showed cognitive deficits (measured in NOR) and sociability (measured in social interaction). It is believed that these deficiencies are mapped to the cognitive and negative symptoms of schizophrenia, respectively. For clarity, animals were administered PCP for 7 days, 2 times/day, and then after a washout period of at least 1 week, administered once a day with the compound of formula 1 for 6 days, and administered once before testing in NOR (but without PCP inside at this time), and then administered with the compound of formula I the next day (but without PCP inside at this time) and tested in social interaction. The experiment is described in detail in the following examples.

Example G Novel Object Recognition (NOR) Compounds of Formula I were evaluated using the following subchronic phencyclidine (scPCP) protocol. The NOR test was performed as described in detail previously (Grayson et al., "Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat", Behavioral Brain Research, Vol. 184, No. 1, 2007; Snigdha et al., "Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine _2A Receptor Inverse Agonist", Journal of Pharmacology and Experimental Therapeutics, February 2010, 332 (2) 622-631).

Before testing, all animals were accustomed to an empty test box. Habituation consisted of placing all rats from one cage together in an empty test field once for 20 min the day before testing. Rats (treated with scPCP and vehicle) were subjected to two 3 min trials in a cage, 60 min apart. In the first trial (acquisition), animals were placed in a test box and allowed to explore two identical objects (A1 and A2). In the second trial (maintenance), animals were placed in a test box with one repeated familiar object from the acquisition phase (to avoid olfactory traces) and one novel object. Formula I compound or vehicle was administered once a day six days before NOR and 120 minutes before acquisition. Behavior was filmed and scored by a trained experimenter who was blinded to treatment group. In the acquisition and retention trials, total object exploration time (defined as the duration that the animal licked, sniffed, or touched the object, but excluding time spent standing, sitting, or leaning on the object) was recorded for each of the familiar and novel objects; locomotor activity (defined as movement, measured by the number of lines crossed in two trials) and discrimination index (defined as the difference in time spent exploring the novel and familiar objects divided by the total time spent exploring the two objects) were also calculated.

All data are expressed as mean ± s.e.m. (standard error of the mean). The exploration time data of NOR in the acquisition and retention phases were analyzed by two-way analysis of variance (ANOVA), with drug and exploration time of 2 objects (2 identical objects in the acquisition phase and novel and familiar objects in the retention phase) as factors. The locomotor activity data (total number of line crossings) and DI were analyzed by one-way ANOVA. The time spent exploring the objects was analyzed by paired Student's t test. After the one-way ANOVA results were significant, post hoc analysis was performed by Dunnett's t test (for locomotor activity and DI).

Example H Social Interaction The following social interaction test was used to evaluate compounds of Formula I to assess one aspect of the amotivational domain of negative symptoms in schizophrenia, namely social withdrawal using subchronic administration of PCP.

One day after the NOR assessment, the rats were assessed for social interaction using the same arena. Pairs of rats matched in weight (15-20 g) and unfamiliar to each other, either untreated ("same-species" rats) or treated differently (PCP and vehicle; "tested" rats or PCP + Formula I compound; "tested" rats) were placed together in the test arena for 10 min and behavior was assessed as described below. Formula I compound or vehicle was administered seven days before SI and 120 min before interaction assessment.

Inanimate objects, such as unopened drink cans, may also be placed in the center of the arena to measure any differences in the interaction of the test animal with the unfamiliar animal versus the unfamiliar object. After each 10-minute trial, the objects and arena were cleaned with 10% alcohol to remove any traces of olfactory cues. All tests were conducted under standard room lighting levels (70 cd/m ² ).

Immediately after the SI study, brain and blood were collected (n=12 per treatment group). Trunk blood was collected in Li-heparin coated tubes on ice and then centrifuged. Blood was centrifuged at 7000 RPM for 10 min at 4°C. Plasma was then transferred to vials (approximately 400 µl) and immediately stored at -80°C. Whole brains were removed and immediately stored at -80°C. Frontal cortex was dissected and collected in vials and stored at -80°C.

Behavior was recorded on video for subsequent blind scoring. The following parameters (a) to (e) were scored using a behavior scoring software program (Hindsight, Scientific Programming Services): (a) Investigative sniffing behavior: sniffing the snout or body parts including the anal genital area of conspecifics; (b) Following - rats followed conspecifics, i.e., vehicle-treated rats of the same species, around the arena; (c) Avoidance - actively turning away when a conspecific approaches; (d) Object investigation - exploration of an object placed in the center of the arena; (e) Locomotor activity was recorded by counting the total number of sectors (i.e., lines) crossed by the test rat.

All data are expressed as mean ± s.e.m. Data were analyzed by ANOVA followed by Dunnett's post hoc test when appropriate. Statistical significance was assumed when P < 0.05. All analyses were performed in SPSS statistical suite (IBM).

This specification (including examples) is intended to be illustrative only, and it will be apparent to those skilled in the art that various modifications and variations may be made in this application without departing from the scope or spirit of the invention as defined by the attached patent claims. All references cited in this application (including all patents, patent applications, and publications) are incorporated herein by reference in their entirety.

Claims (21)

A compound having formula I: (I) wherein: R ₁ is selected from hydrogen, piperidinyl, 2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C _{1 - 2} alkyl, azetidinyl, azetidinyl-C _{1 - 2} alkyl, 2-oxaspiro[3.3]hept-6-yl, cyclobutyl, cyclopropyl, (C _{1 - 2} alkyl) _{0 - 2} NC _{1 - 4} alkyl, (C _{1 -} 2 alkyl) _{0 - 2} NC(O)-C _{1 - 4} alkyl, (C _{1 - 2} alkyl) _{0 - 1} OC _{1 - 4} alkyl, 2-azaspiro[3.3]hept-6-yl, C _{1 - 2} alkyl substituted with hydroxyl wherein _the piperidinyl, (2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C _{1 - 2} alkyl, azetidinyl, azetidinyl-C _{1 - 2} alkyl, 2-azaspiro[3.3]hept-6-yl, (2-oxaspiro[3.3]hept-6-yl, cyclobutyl and cyclopropyl may be unsubstituted or substituted with 1 to 2 R groups independently selected from the following: C _{1 - 4} alkyl, C _{3 - 5} cycloalkyl, _hydroxyl , C _{1 - 4} substituted with hydroxyl; _R2 is selected _{from C1-3} alkyl, halogen, cyclopropyl _, methyl-amino, and _C1-2 alkyl substituted with halogen; _R3 is selected _from hydrogen and halogen; _R4 is selected from hydrogen, _C1-3 alkyl, _C3-5 cycloalkyl, _C3-5 heterocycloalkyl _{, cyano ,} -S _{( O ) 0-2C1-2alkyl , halogen} , -C( _O ) _{C1-2alkyl , -S} ( _{O ) 0-2C1-2alkyl , -OC1-2alkyl , C3-5 cycloalkyl} substituted _{with halogen , C1-3 alkyl substituted with} halogen, _{and C1-2alkoxy substituted with halogen ; wherein the C3-} wherein R ₇ is selected from hydrogen, -OC _{1 - 2} alkyl and amine; X _{1 is selected from} N and CR ₆ ; wherein R ₆ is selected from hydrogen, halogen, _{-OC 1 - 2} alkyl and cyano; X ₂ is selected from N and CR ₈ ; wherein R ₈ is selected from hydrogen, -OC _{1 -} 2 alkyl and halogen; X ₃ is selected from N and CR ₅ ; wherein R ₅ is selected from hydrogen, halogen, cyano, C _{1 - 2} alkyl, -OC _{1 - 2} alkyl, -S(O) _{0 - 2} C _{1 - 2} alkyl, -N(C _{1 - 2 alkyl} ) ₂ , C _{1 - 2 alkyl substituted with halogen, C 1 - 2 alkyl substituted} with halogen ₂ alkoxy, and -S(O) _{0 - 2} C _{1 - 2} alkyl; or a pharmaceutically acceptable salt thereof. The compound of claim 1, which has formula Ia: (Ia) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, and 2 _- methyl- ₂ -azetidin-6-yl; _R2 is selected from _C1-3 alkyl, cyclopropyl and halogen; _R3 is selected from fluorine and hydrogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl, 1-fluorocyclopropyl, and 3-fluorooxycyclobutane-3 _- yl; _R5 is selected from hydrogen, cyano, halogen, dimethyl- _amino , methoxy, ethoxy, trifluoromethyl, -S(O) _0-2C1-2alkyl , _{trifluoromethoxy ,} -N( _C1-2alkyl ) ₂ , _{and C1-2alkyl} ; _R6 is selected _from hydrogen _, halogen, _{cyano , and -OC1-} or _a pharmaceutically acceptable salt thereof. The compound of claim 2, wherein: R ₁ is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, and 2-methyl-2-azetidin-6-yl; R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl; R ₃ is selected from fluoro and hydrogen; R _R4 is selected from hydrogen, methyl, difluoromethyl, chlorine, fluorine, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl, 1-fluorocyclopropyl, and 3-fluorooxycyclobutane-3-yl; _R5 is selected from hydrogen, chlorine, fluorine, methyl-sulfanyl, cyano, methyl, dimethyl-amino, trifluoromethyl, trifluoromethoxy, ethoxy, and methoxy; _R6 is selected from hydrogen, fluorine, chlorine, cyano, and methoxy; or a pharmaceutically acceptable salt thereof. The compound of claim 3 or a pharmaceutically acceptable salt thereof, which is selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and . The compound of claim 1, which has formula Ib: (Ib) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, _and 2-methyl- ₂ -azetidin-6-yl; _R2 is selected from _C1-3 alkyl, cyclopropyl and halogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl, and _{1 -} fluorocyclopropyl; _R5 is selected from hydrogen, halogen, cyano, _-OC1-2 alkyl, _C1-2 alkyl _substituted with _{halogen ,} and -S( _O ) _0-2C1-2 alkyl; _R6 is selected from hydrogen, halogen, and cyano; _R7 is selected from hydrogen and _-OC1-2 alkyl; _{R8 is} selected from hydrogen _{, -OC1-2} alkyl _, and _halogen ; or _a pharmaceutically acceptable _{salt thereof} . The compound of claim 5, wherein: R ₁ is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, and 2-methyl-2-azetidin-6-yl; R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl; R _R4 is selected from hydrogen, methyl, difluoromethyl, chlorine, fluorine, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl and 1-fluorocyclopropyl; _R5 is selected from hydrogen, fluorine, chlorine, methoxy, ethoxy, trifluoromethyl, methyl-sulfanyl and cyano; _R6 is selected from hydrogen, chlorine, fluorine and cyano; _R7 is selected from hydrogen and methoxy; _R8 is selected from hydrogen, methoxy and fluorine; or a pharmaceutically acceptable salt thereof. The compound of claim 6 or a pharmaceutically acceptable salt thereof, which is selected from: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;and . The compound of claim 1, which has the formula Ic: (Ic) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, and 2 _- methyl- ₂ -azetidin-6-yl; _R2 is selected from _C1-3 alkyl, halogen, cyclopropyl, methyl-amino, _{and C1-2 alkyl} substituted with halogen; _R3 is selected from fluorine and hydrogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl and 1 _{- fluorocyclopropyl} ; _R6 is selected from hydrogen and _-OC1-2 alkyl; _R8 is selected from hydrogen, _halogen and _-OC1-2 alkyl; or a pharmaceutically acceptable _salt thereof. The compound of claim 8, wherein: R ₁ is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, and 2-methyl-2-azetidin-6-yl; R ₂ is selected from chlorine, methyl, ethyl, cyclopropyl and isopropyl; R ₃ is selected from fluorine and hydrogen; R ₄ is chlorine; R ₆ is selected from hydrogen and methoxy; R ₈ is selected from hydrogen, halogen and methoxy; or a pharmaceutically acceptable salt thereof. The compound of claim 9 or a pharmaceutically acceptable salt thereof, which is selected from: . A compound having formula II: (II) wherein: R ₁ is selected from hydrogen, piperidinyl, 2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C _{1 - 2} alkyl, azetidinyl, azetidinyl-C _{1 - 2} alkyl, 2-oxaspiro[3.3]hept-6-yl, cyclobutyl, cyclopropyl, and (C _{1 - 2} alkyl) _{0 - 2} NC _{1 - 4} alkyl, (C _{1 - 2} alkyl) _{0 - 2} NC(O)-C _{1 - 4} alkyl, (C _{1 -} 2 alkyl) _{0 - 1} OC _{1 - 4} alkyl, wherein _the piperidinyl, 2-azabicyclo[2.2.1]hept-5-yl, pyrrolidinyl, pyrrolidinyl-C _{1 - 2} alkyl, pyrazolyl, pyrazolyl-C 1 - 2 alkyl, azetidinyl, azetidinyl-C _{1 - 2} alkyl, 2-azaspiro[3.3]hept-6-yl, 2-oxaspiro[3.3]hept-6-yl, cyclobutyl and _cyclopropyl are unsubstituted or substituted with 1 to 2 R groups independently selected from the group consisting of C _{1 - 4} alkyl, C _{3 - 5} cycloalkyl, hydroxyl, C _{1 - 5} substituted with _{hydroxyl ; R} is selected from C _{1 - 3} alkyl, _halogen , cyclopropyl, methyl-amino, and C _{1 - 2} alkyl substituted with halogen; _R is selected from hydrogen and halogen; R is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl _- sulfonyl, cyclopropyl, and 1-fluorocyclopropyl; _X is selected from N and CR ₆ ; wherein _R is selected from hydrogen, -OC _{1 - 2} alkyl and cyano; _X is selected from N and CR ₈ ; wherein R _X8 is selected from _hydrogen , _{-OC1-2 alkyl} and halogen; _X3 is selected from N _{and CR5} ; wherein _R5 is selected _from hydrogen _, halogen _, cyano _{, C1-2} alkyl, _-OC1-2 alkyl, -N _{(C1-2 alkyl} ) ₂ , _C1-2 alkyl substituted with _halogen and -S( _{O ) 0-2C1-2 alkyl ;} and pharmaceutically acceptable _{salts thereof} . The compound of claim 11 has the formula IIa: (IIa) wherein: _R1 is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, and 2 _- methyl- ₂ -azetidin-6-yl; _R2 is selected from _C1-3 alkyl, halogen, cyclopropyl, methyl-amino, _{and C1-2 alkyl} substituted with halogen; _R3 is selected from fluorine and hydrogen; R _R4 is selected from hydrogen, methyl, halogen, cyano, difluoromethyl, 2,2,2-trifluoroethyl, trifluoromethyl, 2,2-difluoroethyl, methoxy, trifluoromethoxy, difluoromethoxy, 1,1-difluoroethyl, 2,2-difluoropropyl, 2-fluoroprop-2-yl, methyl-carbonyl, methyl-sulfonyl, cyclopropyl and _{1 -} fluorocyclopropyl; _R5 is selected from hydrogen, trifluoromethoxy and _C1-2 alkyl; _R6 is selected from hydrogen and _{-OC1-2 alkyl ;} and pharmaceutically acceptable salts thereof. The compound of claim 12, wherein: R ₁ is selected from hydrogen, piperidin-4-yl, 1-methylpiperidin-4-yl, azetidin-3-yl, 1-methylazetidin-3-yl, 2-azetidin-6-yl, hydroxy-ethyl, amino-carbonyl-methyl, dimethyl-amino-ethyl, methoxy-ethyl, and 2-methyl-2-azetidin-6-yl; R ₂ is selected from chloro, methyl, ethyl, cyclopropyl and isopropyl; R ₃ is selected from fluoro and hydrogen; R _R4 is selected from hydrogen, methyl, difluoromethyl, chlorine, fluorine, cyano, 1,1-difluoroethyl, 2-difluoroethyl, 2,2-difluoropropyl, 2,2-trifluoroethyl, trifluoromethyl, trifluoromethoxy, 2-fluoroprop-2-yl, methoxy, difluoromethoxy, methyl, carbonyl, methyl-sulfonyl, cyclopropyl and 1-fluorocyclopropyl; _R6 is selected from hydrogen and methoxy; and pharmaceutically acceptable salts thereof. The compound of claim 13 or a pharmaceutically acceptable salt thereof, which is selected from: ; ;and . A pharmaceutical composition comprising a compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof and one or more excipients. A method for treating a neurological disorder, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15; wherein the neurological disorder is selected from the group consisting of: schizophrenia, cognitive impairment, panic disorder, phobia, drug-induced psychosis, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, Lewy bodies, Body) dementia, bipolar disorder, ADHD, Tourette's syndrome, pyramidal or movement disorder, motor disorder, hyperkinetic movement disorder, mental illness, tension disorder, mood disorder, depression, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, lactotropin-related disorder, hyperlactogenetic disorder, neurocognitive disorder, trauma or stress-related disorder, post-traumatic stress disorder, disruptive impulse control, disruptive behavior disorder, sleep-wake disorder, substance-related disorder, addiction, behavioral disorder, frontal lobe dysfunction, tuberoinfundibulum, mesolimbic , mesocortical or nigrostriatal pathway abnormalities, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, Huntington's disease, and chorea related to Huntington's disease. The method of claim 16, wherein the neurological disorder is selected from schizophrenia, cognitive impairment associated with schizophrenia (CIAS), and vascular cognitive impairment. The method of claim 17, wherein schizophrenia is selected from negative symptoms associated with schizophrenia, psychotic symptoms of schizophrenia, schizoaffective disorder, schizoaffective disorder, schizophrenia-like disorder, treatment resistant schizophrenia, and attenuated psychotic syndrome. A method for improving one or more symptoms of a neurological disorder, comprising administering to a subject in need thereof an effective amount of at least one compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 15; wherein the neurological disorder is selected from the group consisting of: schizophrenia, cognitive impairment, panic disorder, phobia, drug-induced Psychosis, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorders, movement disorders, hyperkinetic disorders, psychosis, tension disorders, mood disorders, depression, anxiety Anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, lactotropin-related disorder, hyperlactogeninemia, neurocognitive disorder, trauma or stress-related disorder, post-traumatic stress disorder, disruptive impulse control, disruptive behavior disorder, sleep-wake disorder, substance-related disorder, addiction, behavioral disorder, frontal lobe dysfunction, tuberoinfundibulum, mesolimbic, midcortical or nigrostriatal pathways Pathological abnormalities, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, and chorea associated with Huntington's disease. A use of at least one compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical product of claim 15 for treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive impairment, panic disorder, phobia, drug-induced psychosis, delusional psychosis, neuroleptic Induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorder, movement disorders, hyperkinetic movement disorder, mental illness, tension disorder, mood disorders, depression, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorders, lactotropin-related disorders, hyperlactogeninemia, neurocognitive disorders, trauma- or stress-related disorders, post-traumatic stress disorder, disruptive impulse control, disruptive behavior disorders, sleep-wake disorders, substance-related disorders, addictions, behavioral disorders, frontal lobe dysfunction, tuberoinfundibular, mesolimbic, midcortical, or nigrostriatal pathway abnormalities, striatal Decreased physical activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, and chorea associated with Huntington's disease. A method for producing a medicament for treating a neurological disorder comprising at least one compound of any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof or a pharmaceutical product of claim 15, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive impairment, panic disorder, phobia, drug-induced psychosis, delusional psychosis, Neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorders, movement disorders, hyperkinetic movement disorders, mental illness, tension disorders, mood disorders, depression, anxiety disorders, obsessive-compulsive disorder, autism Spectrum disorders, lactotropin-related disorders, hyperlactogeninemia, neurocognitive disorders, trauma or stress-related disorders, post-traumatic stress disorder, disruptive impulse control, disruptive behavior disorders, sleep-wake disorders, substance-related disorders, addictions, behavioral disorders, frontal lobe dysfunction, tuberoinfundibular, mesolimbic, midbrain cortical or substantia nigra striatum pathway abnormalities, striae Decreased cortical activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's disease, dyskinesia, hypotonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, and chorea associated with Huntington's disease.