Compounds and compositions as GPR52 modulators

Abstract

The present disclosure relates to compounds of formula (I) that can modulate the activity of GPR52. The present disclosure further provides a process for preparing compounds of formula (I) and methods for using compounds of formula (I) in the management of diseases or disorders related to the activity of GPR52, including, but not limited to, the treatment of various neurological conditions. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are compounds or pharmaceutically acceptable salts thereof described in the examples below. In some embodiments, the compounds of formula (I) or pharmaceutically acceptable salts thereof are compounds of formula (Ia), formula (Ib), formula (Ic), formula (Id), or formula (Ie), or pharmaceutically acceptable salts of any of the above. JPEG2026508053000178.jpg3144

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 419,384, filed October 26, 2022. The complete disclosure of this application is incorporated herein by reference in its entirety for all purposes. [Background technology]

[0002] background Technical Field The present disclosure relates to compounds of formula (I) that can modulate the activity of GPR52. The present disclosure further provides a process for preparing the compounds of formula (I), and pharmaceutical preparations that include such compounds. The present disclosure further provides methods for using the compounds of formula (I) and compositions in the management of diseases or disorders related to the activity of GPR52, including but not limited to the treatment of various neurological conditions.

[0003] 2. Description of Related Art GPR52 is an orphan GPCR that is highly conserved in vertebrates. The highest expression level in the central nervous system (CNS) is found in the striatum. Significantly lower expression levels are found in other structures in the CNS, including the cortex. Although GPR52 has been characterized, it remains an orphan receptor with no known internal or external ligand. Several surrogate ligands have been reported, including the extracellular loop 2 (ECL2) of GPR52 itself.

[0004] GPR52 is often co-localized with dopamine receptors D1 and D2. GPR52 is almost exclusively co-localized with D2 receptors in the human striatum and with 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 hyperprolactinemia. In contrast, GPR52 modulators can essentially function as D2 antagonists, thus avoiding the side effects associated with D2 antagonists and simultaneously exhibiting antipsychotic efficacy. Therefore, GPR52 modulators can improve the symptoms of various neurological conditions, diseases, and disorders. Therefore, GPR52 is an attractive target for developing novel therapies for the treatment of various neurological and neuropsychiatric diseases and disorders. GPR52 agonists are particularly relevant for the treatment of schizophrenia, where they have the potential to indirectly improve cognitive and negative symptoms by activating D1 signaling, but alleviate positive symptoms by inhibiting D2-mediated signaling in the striatum.

[0005] Despite advances in this field, there remains an unmet medical need for improved GPR52 agonists. As evidenced by the disclosure below, the present compounds, related compositions and methods fulfill these and other needs. Summary of the Invention [Means for solving the problem]

[0006] overview 1. Some embodiments provide a compound of formula I: [ka] [In the formula, R1 is hydrogen and C 1~2 alkyl, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl, R3 is selected from hydrogen and halo; R4 is [ka] (In the formula, When R5 is attached to a carbon atom, it is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, and R5, when attached to a nitrogen atom, is selected from hydrogen, C 1~2 Alkyl and halo substituted C 1~2 alkyl, When R6 is attached to a carbon atom, it can be hydrogen, amino, cyano, or C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, and R6, when attached to a nitrogen atom, is selected from hydrogen, C 1~2 Alkyl and halo substituted C 1~2 alkyl, R7 is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, R8 is selected from hydrogen and halo. is selected from X1 is selected from N and CH; X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl, or R9 and the nitrogen of X1 form a 5-membered unsaturated ring containing up to two nitrogen atoms; X3 is CR 9a Selected from R 9a is selected from hydrogen and methyl], and pharmaceutically acceptable salts or hydrates thereof.

[0007] In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound or a pharmaceutically acceptable salt thereof set forth in the Examples below. In some embodiments, the compound of Formula (I) or a pharmaceutically acceptable salt thereof is a compound of Formula (Ia), Formula (Ib), Formula (Ic), Formula (Id), or Formula (Ie), or a pharmaceutically acceptable salt of any of the foregoing.

[0008] Some embodiments provide pharmaceutical products selected from pharmaceutical compositions, formulations, unit dosage forms, and kits, each comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0009] Some embodiments provide pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0010] Some embodiments provide a method of modulating the activity of GPR52 comprising contacting the receptor with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0011] Some embodiments provide a method of treating a disease or disorder associated with aberrant expression and / or activity of GPR52 in a patient, the method comprising administering to the patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0012] Some embodiments are directed to a method of treating a neurological disorder, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need of such treatment, wherein the neurological disorder is selected from the group consisting of schizophrenia; cognitive impairment; panic disorder; phobic disorder; drug-induced psychotic disorder; delusional psychosis; neuroleptic-induced dyskinesia; Parkinson's disease; drug-induced parkinsonism; extrapyramidal syndrome; Alzheimer's disease; dementia with Lewy bodies; bipolar disorder; attention-deficit / hyperactivity disorder (ADHD); Tourette's syndrome; extrapyramidal or movement disorder; motor dysfunction; hyperkinetic movement disorder; psychotic disorder; catatonia; mood disorder; depressive disorder; anxiety disorder; obsessive-compulsive disorder (OCD); autism spectrum disorder. and / or other conditions associated with schizophrenia, including encephalopathy, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders, neuropsychiatric disorders,

[0013] Some embodiments are directed to a method of ameliorating one or more symptoms of a neurological disorder, comprising administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the neurological disorder is selected from the group consisting of schizophrenia; cognitive impairment; panic disorder; phobic disorder; drug-induced psychotic disorder; delusional psychosis; neuroleptic-induced dyskinesia; Parkinson's disease; drug-induced parkinsonism; extrapyramidal syndrome; Alzheimer's disease; dementia with Lewy bodies; bipolar disorder; attention-deficit / hyperactivity disorder (ADHD); Tourette's syndrome; extrapyramidal or movement disorder; motor dysfunction; hyperkinetic movement disorder; psychotic disorder; catatonia; mood disorder; depressive disorder; anxiety disorder; obsessive-compulsive disorder (OCD). autism spectrum disorder; prolactin-related disorder (e.g., hyperprolactinemia); neurocognitive disorder; trauma or stressor-related disorder (e.g., PTSD); disruptive impulse control or conduct disorder; sleep-wake disorder; substance-related disorder; addictive disorder; behavioral disorder; frontal lobe hypoactivity; abnormalities of the infundibulopituitary, mesolimbic, mesocortical, or nigrostriatal tracts; striatal hypoactivity; cortical dysfunction; neurocognitive dysfunction; agnosia associated with schizophrenia; drug-induced parkinsonism (DIP); dyskinesia; dystonia; chorea; levodopa-induced dyskinesia; cerebral palsy and progressive supranuclear palsy; and Huntington's disease, including chorea associated with Huntington's disease.

[0014] Some embodiments provide a method for manufacturing a medicament for ameliorating one or more symptoms of a neurological disorder, comprising the step of administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the neurological disorder is selected from the group consisting of schizophrenia; cognitive impairment; panic disorder; phobic disorder; drug-induced psychotic disorder; delusional psychosis; neuroleptic-induced dyskinesia; Parkinson's disease; drug-induced parkinsonism; extrapyramidal syndrome; Alzheimer's disease; dementia with Lewy bodies; bipolar disorder; attention-deficit / hyperactivity disorder (ADHD); Tourette's syndrome; extrapyramidal or movement disorder; motor dysfunction; hyperkinetic movement disorder; psychotic disorder; catatonia; mood disorder; depressive disorder; anxiety disorder; obsessive-compulsive disorder. (OCD); autism spectrum disorder; prolactin-related disorder (e.g., hyperprolactinemia); neurocognitive disorder; trauma or stressor-related disorder (e.g., PTSD); disruptive impulse control or conduct disorder; sleep-wake disorder; substance-related disorder; addictive disorder; behavioral disorder; frontal lobe hypoactivity; abnormalities of the infundibulopituitary, mesolimbic, mesocortical, or nigrostriatal tracts; striatal hypoactivity; cortical dysfunction; neurocognitive dysfunction; agnosia associated with schizophrenia; drug-induced parkinsonism (DIP); dyskinesia; dystonia; chorea; levodopa-induced dyskinesia; cerebral palsy and progressive supranuclear palsy; and Huntington's disease, including chorea associated with Huntington's disease. DETAILED DESCRIPTION OF THE INVENTION

[0015] Detailed Description definition For clarity and consistency, the following definitions are used throughout this patent document.

[0016] As used herein, "about" means ±20% of the specified value, and more particularly includes values ​​of ±10%, ±5%, ±2% and ±1% of the specified value.

[0017] As used herein, "administering" refers to providing a compound or other therapy described herein to a subject in a form that can be introduced into the subject's body in a therapeutically useful form and in a therapeutically useful amount, including, but not limited to, oral dosage forms such as tablets, capsules, syrups, suspensions, etc.; injectable dosage forms such as IV, IM, IP, transdermal dosage forms including creams, jellies, powders and patches, buccal dosage forms, inhalation powders, sprays, suspensions, etc.; and rectal suppositories.

[0018] A medical professional can directly provide a compound described herein in the form of a sample to a subject, or can indirectly provide the compound to a subject by providing an oral or written prescription for the compound. Similarly, for example, a subject can independently obtain the compound without the involvement of a medical professional. When a compound is administered to a subject, the body is transformed by the compound in some way. When a compound described herein is provided in combination with one or more other drugs, "administration" is understood to mean that the compound and the other drugs are administered at the same time or at different times. When combined drugs are administered simultaneously, they can be administered together in a single composition, or they can be administered separately. The preferred method of administration can vary depending on various factors, such as the components of the pharmaceutical preparation, the site of the disease, and the severity of the disease.

[0019] The term "ameliorating," in the context of treatment, refers to, but is not limited to, making the symptoms of a disease better, relieving or improving the symptoms, or making the symptoms more tolerable or tolerable.

[0020] The term "composition" refers to a compound or crystalline form thereof, including salts, solvates, and hydrates of a compound described herein, in combination with at least one additional component, such as, but not limited to, compositions obtained / prepared during synthesis, prior to formulation, in-process testing (e.g., samples for TLC, HPLC, NMR), etc.

[0021] The term "compound," as used herein, is intended to include all stereoisomers, geometric isomers, tautomers, and isotopes of the depicted structures. This term is also intended to refer to the compounds described herein, regardless of how they are prepared, for example, by synthesis, via a biological process (e.g., metabolic or enzymatic transformation), or by a combination thereof. All compounds and pharmaceutically acceptable salts thereof may be found together with other substances, such as water and solvents (e.g., hydrates and solvates), or may be isolated. The compounds and salts thereof described herein may occur in various forms when in the solid state, and may take the form of solvates, including hydrates. The compounds may be in any solid-state form, such as polymorphs or solvates; therefore, unless expressly indicated otherwise, references to compounds and salts thereof herein should be understood to encompass any solid-state form of the compound. In some aspects, the compounds described herein or salts thereof are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially isolated from the environment in which it was formed or detected. Partial isolation can include, for example, compositions enriched in the compounds described herein. Substantial isolation can include compositions 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 a salt thereof.

[0022] The term "hydrate," as used herein, 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.

[0023] The terms "in need of treatment" and "in need thereof" are used interchangeably when referring to treatment and refer to a judgment made by a caregiver (e.g., in the case of humans, a doctor, nurse, nurse practitioner, etc.; in the case of animals, including non-human mammals, a veterinarian) that a subject or animal requires or will benefit from treatment. This judgment is within the caregiver's area of ​​expertise, but is made based on a variety of factors, including knowledge that the subject or animal is suffering from or will become ill as a result of a disease, condition, or disorder treatable by the compounds described herein. Thus, the compounds described herein can be used protectively or prophylactically, or the compounds described herein can be used to alleviate, inhibit, or ameliorate a disease, condition, or disorder.

[0024] The term "subject" refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses, primates, and humans. In the context of clinical trials or screening or activity experiments, a subject may be a healthy volunteer or participant who is not suffering from a potential GPR52-mediated disorder or condition, or a volunteer or participant who has been diagnosed with a disorder or condition that requires medical treatment as determined by a medical professional. In contexts unrelated to clinical trials, a subject under the care of a medical professional who has been diagnosed with a disorder or condition is usually referred to as a subject.

[0025] The term "pediatric subject" refers to a subject who is under 21 years of age at the time of diagnosis or treatment. The term "pediatric" can be further divided into various subgroups, including neonates (birth to the first month of life; infants (1 month to 2 years of age); children (2 to 12 years of age); and adolescents (12 to 21 years of age) (up to, but not including, their 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.

[0026] The phrase "pharmaceutically acceptable" refers to compounds (and salts thereof), compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0027] The term "pharmaceutical composition" refers to a specific composition comprising at least one active ingredient, including but not limited to salts, solvates and hydrates of the compounds described herein, whereby the composition is suitable for study in mammals (e.g., but not limited to, humans) for a specific effective outcome.Those skilled in the art will understand and appreciate the appropriate techniques for determining whether an active ingredient has a desired effective outcome based on the needs of the practitioner.

[0028] The terms "prevent," "preventing," and "prevention" refer to the elimination or reduction of the occurrence or onset of one or more symptoms associated with a particular disorder. For example, the terms "prevent," "preventing," and "prevention" can refer to the administration of a therapy based on preventative or prophylactic principles to a subject who may eventually develop at least one symptom of a disorder, but who has not yet done so. Such subjects can be identified based on risk factors known to correlate with the later development of the disease, such as the presence of biomarkers. Alternatively, a prophylactic therapy can be administered as a preventative measure without prior identification of risk factors. A delay in the onset of at least one episode and / or symptom of a disorder can be considered prevention or prophylaxis.

[0029] The term "solvate," as used herein, refers to a solid-state form of a compound described herein or a pharmaceutically acceptable salt thereof that contains a stoichiometric or non-stoichiometric amount of solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0030] The terms "treat", "treating" and "treatment" refer to the medical management of a disease, disorder or condition of a subject (e.g., a subject) (see, e.g., Stedman's Medical Dictionary). In general, an appropriate dose and treatment regimen will provide a sufficient amount of GPR52 agonist to provide a therapeutic benefit. The therapeutic benefit for a subject to whom the GPR52 agonist compounds described herein are administered includes, for example, improved clinical outcomes, where the purpose is to prevent, slow down, or delay (alleviate) undesirable physiological changes associated with the disease, or to prevent, slow down, or delay (alleviate) the spread or severity of such a disease. The efficacy of one or more GPR52 agonists can include advantageous or desired clinical results, including, but not limited to, a reduction, alleviation, or amelioration of symptoms resulting from or associated with the disease being treated; a decrease in the occurrence of symptoms; an improvement in quality of life; a longer disease-free state (i.e., a decrease in the likelihood or propensity of a subject to exhibit symptoms based on the criteria by which a diagnosis of disease is made); a decrease in the extent of disease; a stable (i.e., non-worsening) state of disease; a delay or slowing of disease progression; an improvement or palliation of the disease state; and remission (whether partial or total), whether detectable or undetectable, and / or overall survival.

[0031] The term "therapeutically effective amount" refers to an amount of a compound described herein or a pharmaceutically acceptable salt thereof, or an amount of a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, that elicits the biological or medical response in a tissue, system, animal, or human that is desired by a subject, researcher, veterinarian, physician, or other clinician, or caregiver, and which may include one or more of the following:

[0032] (1) preventing a disorder, e.g., preventing a disease, condition, or disorder in a subject who may be susceptible to the disease, condition, or disorder but who has not yet experienced or exhibited the associated pathology or symptoms; (2) inhibiting a disorder, e.g., inhibiting a disease, condition, or disorder (i.e., halting further development of the pathology and / or symptoms) in a subject experiencing or exhibiting the associated pathology or symptoms; and (3) Ameliorating a disorder, e.g., ameliorating a disease, condition, or disorder (i.e., reversing the pathology and / or symptoms) in a subject experiencing or exhibiting the associated pathology or symptoms.

[0033] As used herein, the term "contact" refers to bringing together the indicated parts in 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) to a subject, such as a human, that has GPR52 protein, and introducing a compound provided herein into a sample that contains, for example, a cell preparation or purified preparation containing GPR52 protein.

[0034] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. All patents, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are multiple definitions for terms herein, the definitions in this section shall prevail unless otherwise stated.

[0035] The term "n-membered" (where n is an integer) typically describes the number of atoms forming a ring in a moiety, where n is the number of atoms forming the ring. For example, piperidinyl is an example of a 6-membered heterocyclyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0036] For compounds of formula (I) and pharmaceutically acceptable salts thereof, where a variable occurs more than once, each variable may be a different moiety independently selected from the group defining that variable. For example, when a structure is depicted having two R groups co-occurring in the same compound, the two R groups may represent different moieties independently selected from the group defined for R.

[0037] Whenever a group is described as "optionally substituted," the group can be unsubstituted or substituted with one or more of the listed substituents. Similarly, when a group is described as "unsubstituted or substituted," if substituted, the substituent(s) can be selected from one or more of the listed substituents. It is to be understood that substitution at a given atom is limited by valence.

[0038] As used herein, "C" refers to a group of integers where "a" and "b" are integers. a ~C b " 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" (inclusive) carbon atoms. Thus, for example, "C1-C4 alkyl" (or C 1~4An alkyl) group refers to all alkyl groups having 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. When "a" and "b" are not designated for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl group, the broadest range described in those definitions should be assumed. In addition to the foregoing, as used in this specification and the appended claims, unless specifically specified to the contrary, the following terms have the meanings indicated.

[0039] The term "amino" refers to the group -NH2.

[0040] The term "alkylamino" refers to a group of the formula -NH(alkyl), where alkyl is as defined herein. Examples of alkylamino groups include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0041] The term "dialkylamino" refers to a group of formula -N(alkyl), where alkyl is as defined herein. Examples of dialkylamino groups include dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, and the like.

[0042] 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 allenyl, vinylmethyl, and ethenyl. In some embodiments, alkenyl groups can be unsubstituted or substituted. In some embodiments, alkenyl groups can have 2 to 6 carbon atoms. The alkenyl group of a compound can be designated as "C2-C6 alkenyl" or similar designations.

[0043] The term "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. Examples of alkynyl include ethynyl and propyl. Alkynyl groups can be unsubstituted or substituted. In some embodiments, alkynyl groups can have from 2 to 6 carbon atoms. The alkenyl group of a compound can be designated as "C2-C6 alkynyl" or similar designations.

[0044] 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, naphthalenyl, and phenanthrenyl. In some embodiments, an aryl group is an aromatic ring system containing 6 or 10 carbon atoms (i.e., C6 or C6). 10 The "aryl" ring may have one or more substituents. When one or more substituents are present on the "aryl" ring, the substituent(s) may be attached at any available ring carbon. In some embodiments, the aryl group may be substituted or unsubstituted.

[0045] The term "alkyl" refers to a straight-chain or branched, fully saturated hydrocarbon radical. An alkyl group can have 1 to 20 carbon atoms (as used herein, whenever an alkyl group appears, 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 can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on, up to and including 20 carbon atoms. In some embodiments, an alkyl group can have 1 to 6 carbons (i.e., "C1-C6 alkyl"). Some embodiments are 1 to 5 carbons (i.e., C1-C5 alkyl), some are 1 to 4 carbons (i.e., C1-C4 alkyl), some are 1 to 3 carbons (i.e., C1-C3 alkyl), and some are 1 or 2 carbons. By way of example only, "C1-C4 alkyl" refers to It indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, tert-pentyl, neopentyl, 1-methylbutyl [i.e., -CH(CH3)CH2CH2CH3], 2-methylbutyl [i.e., -CH2CH(CH3)CH2CH3], n-hexyl, and the like. When one or more substituents are present on an alkyl group, the substituent(s) can be attached at any available carbon atom. In some embodiments, the alkyl group can be substituted or unsubstituted.

[0046] The term "haloalkyl" refers to an alkyl group, as defined herein (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl), in which one or more hydrogen atoms of the alkyl group are replaced with halogen atoms. In some embodiments, the haloalkyl group has 1 to 6 carbons (i.e., "haloC1-C6 alkyl" or "halo-substituted C 1~4The haloC1-C6 alkyl may be fully substituted, in which case it has the formula C n L 2n+1 where 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 may be selected from fluorine, chlorine, bromine, and iodine. In some embodiments, a haloalkyl contains 1 to 5 carbons (i.e., haloC1-C5 alkyl). In some embodiments, a haloalkyl contains 1 to 4 carbons (i.e., haloC1-C4 alkyl). In some embodiments, a haloalkyl contains 1 to 3 carbons (i.e., haloC1-C3 alkyl). In some embodiments, a haloalkyl 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.

[0047] The term "carbonyl" refers to the group -C(=O)-.

[0048] The term "oxo" refers to an ═O substituent.

[0049] The term "cycloalkyl" refers to an all-carbon, fully saturated, monocyclic or polycyclic ring system. In some embodiments, a cycloalkyl is a monocyclic ring containing 3 to 7 carbon atoms (i.e., a "C3-C7 cycloalkyl"). Some embodiments contain 3 to 6 carbons. Some embodiments contain 3 to 5 carbons. Some embodiments contain 5 to 7 carbons. Some embodiments contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. When one or more substituents are present on an alkyl group, the substituent(s) can be attached at any available carbon atom. In some embodiments, a cycloalkyl group can be substituted or unsubstituted.

[0050] The term "cycloalkenyl" refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; however, if more than one double bond is present, it is not possible to form a completely delocalized pi-electron system (i.e., aromatic system) throughout all rings; otherwise, the group is an "aryl" as defined herein. When a ring is composed of two or more rings, they can be fused, bridged, or spiro-linked together. A cycloalkenyl can contain 3 to 12 atoms in the ring, or 3 to 8 atoms in the ring. In some embodiments, a cycloalkenyl group can be unsubstituted or substituted. In some embodiments, a cycloalkenyl group can have 4 to 8 carbon atoms (i.e., a "C4-C8 cycloalkenyl"). An example is cyclohexenyl.

[0051] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system having 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 embodiments are "5-6 membered heteroaryl," which refers to an aromatic ring containing 5-6 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, pyrazinyl, pyridazinyl, triazinyl, furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuryl, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, dibenzo[b,d]furan, dibenzo[b,d]thiophene, phenanthridinyl, benzimidazolyl, pyrrolyl, quinolinyl, isoquinolinyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, and the like. Heteroaryl groups can be substituted or unsubstituted. In some embodiments, heteroaryl groups have 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups can be referred to as "5- to 7-membered heteroaryl," "5- to 10-membered heteroaryl," or similar designations. In some embodiments, heteroaryl is a substituted or unsubstituted 5-, 6-, 7-, 8-, 9-, 10-, or up to 14-membered C1-C6 heteroaryl containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13It can be a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the heteroaryl can be a substituted or unsubstituted 5- or 6-membered C1-C5 monocyclic ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl can be a substituted or unsubstituted 8-, 9-, or 10-membered C5-C9 bicyclic ring system containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl is a substituted or unsubstituted 8-, 9-, or 10-membered C5-C9 heteroaryl. In some embodiments, the 8-, 9-, or 10-membered C5-C9 bicyclic heteroaryl is imidazo[2,1-b]thiazolyl, 1H-indolyl, isoindolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzisoxazolyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, pyrido[3,4-b]pyrazinyl, or pyrido[4,3-d]pyrimidinyl. In some embodiments, the heteroaryl is a substituted or unsubstituted 13- or 14-membered C8-C9 bicyclic heteroaryl containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 13 In some embodiments, heteroaryl can be an azolyl, such as imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,2,4-thiadiazolyl, thiazolyl, isothiazolyl, oxazolyl, or isoxazolyl, each of which may be substituted or unsubstituted. In some embodiments, heteroaryl can be a 5-membered C1-C 13Heteroaryl. In some embodiments, the 5-membered C1-C4 heteroaryl is furanyl, thienyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, triazolyl, or tetrazolyl. In some embodiments, the heteroaryl is a 6-membered C3-C5 heteroaryl. In some embodiments, the 6-membered C3-C5 heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl. In some embodiments, "5- to 10-membered heteroaryl" refers to furanyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, triazinyl, benzofuranyl, 1H-indolyl, benzo[b]thiophenyl, etc. In some embodiments, "5- to 10-membered heteroaryl" refers to pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, etc. In some embodiments, the heteroaryl group may be substituted or unsubstituted.

[0052] Depending on the position of the nitrogen in the pyridine ring relative to the oxygen linker in Formula I, EC 50 varies, for example: [Table 14]

[0053] The term "heterocyclyl" refers to 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, and up to 18-membered monocyclic, bicyclic, and tricyclic ring systems in which carbon atoms, together with 1 to 5 heteroatoms, comprise the ring system, but optionally containing one or more unsaturated bonds positioned such that complete delocalization of the pi-electron system (aromatic system) does not occur in the monocyclic ring or in at least one ring of the bicyclic or tricyclic ring system. Heteroatoms are elements other than carbon, including, but not limited to, oxygen, sulfur, and nitrogen. In some embodiments, a heterocyclyl can be a 3- to 7-membered saturated nonaromatic ring system containing 3 to 7 ring atoms, in which at least one ring atom is a heteroatom. In some embodiments, "3- to 6-membered heterocyclyl" refers to a saturated nonaromatic ring radical containing 3 to 6 ring atoms, in which at least one ring atom is a heteroatom. In some embodiments, "4- to 6-membered heterocyclyl" refers to a saturated non-aromatic ring radical containing 4 to 6 ring atoms, wherein at least one ring atom is a heteroatom. In some embodiments, the one or two heteroatoms in the ring system are independently selected from O (oxygen) and N (nitrogen). In some embodiments, a heterocyclyl that can be substituted on the carbon adjacent to the heteroatom by oxo can contain a carbonyl (C=O) group adjacent to the heteroatom, in which case the substituted ring system is a lactam, lactone, cyclic imide, cyclic thioimide, or cyclic carbamate.Examples of unsubstituted or oxo-substituted "heterocyclyl" groups include, but are not limited to, aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimidyl, succinimidyl, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, and oxazolidinyl. nyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 2-oxopyrrolidinyl, tetrahydropyranyl, 4H-pyranyl, 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, 2-oxa-6-azaspiro[3,3]heptane, and their benzo-fused analogs (e.g., benzimidazolidinonyl, tetrahydroquinolinyl, and 3,4-methylenedioxyphenyl). Heterocyclyl groups can be designated as "3- to 10-membered heterocyclyl" or similar designations. In some embodiments, heterocyclyl is a 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, or up to 13-membered C-C heterocyclyl containing 1-5 heteroatoms selected from nitrogen, oxygen, and sulfur. 12It can be a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the heterocyclyl can be a substituted or unsubstituted 3-, 4-, 5-, 6-, or 7-membered C2-C6 monocyclic ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclyl can be a substituted or unsubstituted 4-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-membered C2-C6 monocyclic ring containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 10 In some embodiments, the heterocyclyl is a substituted or unsubstituted 12- or 13-membered C-C heterocycle containing 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. 12It may be a tricyclic ring system. In some embodiments, the heteroatoms of a 6-membered monocyclic heterocyclyl are selected from 1 to 3 O (oxygen), N (nitrogen), or S (sulfur), and the heteroatoms of a 5-membered monocyclic heterocyclyl are selected from 1 or 2 heteroatoms selected from O (oxygen), N (nitrogen), or S (sulfur). In some embodiments, the heterocyclyl is selected from aziridinyl, azetidinyl, tetrahydrofuranyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,3-oxathianiyl, 1,4-oxathianiyl, 1,3-oxathiolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, 1,4-oxathianiyl, tetrahydro-1,4-thiazol ... Azinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, indolinyl, oxazolinyl, oxazolidinyl, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl, piperazinyl, 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-naphthyridinyl, 1,2,3,4-tetrahydro-2,7-naphthyridinyl, 1,2,3,4-tetrahydro-1,7-naphthyridinyl, 1 , 2,3,4-tetrahydro-1,6-naphthyridinyl, 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[3,4-d]pyrimidinyl, [1,3]dioxolo[4,5-c]pyridinyl, [1,3]dioxolo[4,5-b]pyridinyl, [1,3]dioxolo[4,5-d]pyrimidinyl or 3,4-methylenedioxyphenyl.In some embodiments, the unsubstituted or substituted heterocyclyl can be selected from aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, 2-piperidone, 1,1-dioxidethiomorpholinyl, oxolanyl (tetrahydrofuranyl), and oxanyl (tetrahydropyranyl). When one or more substituents are present on the heterocyclyl group, the substituent(s) can be bonded to any available carbon atom and / or heteroatom. In some embodiments, the heterocyclyl group can be substituted or unsubstituted.

[0054] The term "alkoxy" refers to the formula -OR, where R is alkyl as defined herein. A non-limiting list of alkoxy is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. The alkoxy group of the compound can be represented as "C1-C6 alkoxy" or similar designations. In some embodiments, the alkoxy can be substituted or unsubstituted.

[0055] The term "haloalkoxy" refers to an alkoxy group (e.g., monohaloalkoxy, dihaloalkoxy, and trihaloalkoxy) in which one or more of the hydrogen atoms have been replaced with a halogen. Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some embodiments, a haloalkoxy group can have 1 to 6 carbon atoms. A haloalkoxy group of a compound can be represented as "haloC1-C6alkoxy" or similar designations.

[0056] The term "cyano" refers to the group --CN.

[0057] The term "halogen" or "halo" refers to a fluoro, chloro, bromo, or iodo group. In some embodiments, the halogen or halo is fluoro, chloro, or bromo. In some embodiments, the halogen or halo is fluoro or chloro. In some embodiments, the halogen or halo is fluoro.

[0058] A "C-amido" group is a "-C(=O)N(R A R B ) group, and R A and R B are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl, C6 or C 10 It can be aryl, heteroaryl or heterocyclyl.

[0059] An "N-amido" group is an amide group that is linked to the rest of the molecule through the nitrogen atom. A )-" group, R and R A are independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl, C6 or C 10 It can be aryl, heteroaryl or heterocyclyl.

[0060] The term "hydroxyalkyl" refers to an alkyl group in which one or more of the hydrogen atoms have been replaced with a hydroxy group. In some embodiments, the hydroxyalkyl group can have 1 to 6 carbon atoms (i.e., a "hydroxyC1-C6 alkyl"). Exemplary hydroxyalkyl groups include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl.

[0061] The term "hydroxy" refers to the group --OH.

[0062] The term "nitro" refers to the group --NO.sub.2.

[0063] As used herein, "excipient" refers to a substance added to a composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. to the composition. "Diluent" is a type of excipient and refers to an ingredient in a pharmaceutical composition that has no pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of an active drug whose mass is too small for manufacture and / or administration. A diluent may also be a liquid for dissolving a drug to be administered by injection, ingestion, or inhalation. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic, inert substance or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well known in the pharmaceutical field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. Additionally, 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 contain antioxidants, buffers, bacteriostats, and other common additives as needed. In some embodiments, the diluent may be, but is not limited to, an aqueous buffer solution such as phosphate-buffered saline. The compositions can also be formulated as capsules, granules or tablets, which contain, in addition to the compounds disclosed and described herein, diluents, dispersants and surfactants, binders, and lubricants.Those skilled in the art can further formulate the compounds disclosed and described herein in an appropriate manner and in accordance with accepted practices, such as those disclosed in Remington, supra.

[0064] As used herein, "dose" or "administration" refers to a measured amount of a drug substance taken by a subject at one time. In certain embodiments where the drug substance is neither a free base nor a free acid, the amount is the molar equivalent to the corresponding amount of the free base or free acid.

[0065] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound having an acidic or basic moiety that is biologically or otherwise undesirable for use in pharmaceuticals. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts due to the presence of an acidic or basic moiety (e.g., amino and / or carboxyl groups, or groups similar thereto). Pharmaceutically acceptable acid addition salts can be formed by combining a compound having a basic moiety with inorganic and organic acids. Inorganic acids that can be used to prepare salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids that can be used to prepare 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 inorganic and organic bases. Inorganic bases that can be used to prepare salts include, for example, hydroxides, carbonates, bicarbonates, phosphates, and the like of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, and aluminum. In some embodiments, inorganic base salts are hydroxides, carbonates, bicarbonates, or phosphates of ammonium, potassium, sodium, calcium, and magnesium. Organic bases that can be used to prepare salts include, for example, primary, secondary, and tertiary amines, substituted amines (specifically, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine), including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Generally, such salts can be prepared by reacting the free acid or free base form of these compounds with at least a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two (generally a non-aqueous medium such as ether, ethyl acetate, alcohol (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN)).Lists of suitable salts can be found in WO 87 / 05297 (Johnston et al.), published September 11, 1987; Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418; and J. Pharm. Sci., 66, 2 (1977), each of which is incorporated herein by reference in its entirety. A reference for the preparation and selection of pharmaceutical salts of the present disclosure is PH Stahl & CG Wermuth, Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002, which is incorporated herein by reference in its entirety.

[0066] The compounds described herein can be asymmetric (e.g., possessing one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. In any of the compounds described herein having one or more chiral centers, where the absolute stereochemistry is not explicitly indicated, it is understood that each center may independently be in the (R)-configuration or the (S)-configuration, or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic, diastereomerically pure, diastereomerically enriched, or stereoisomeric mixtures. Preparation of enantiomerically pure or enantiomerically enriched forms can be achieved by resolution of racemic mixtures, by using enantiomerically pure or enantiomerically enriched starting materials, or by stereoselective or stereospecific synthesis. Stereochemical definitions are available in E.L. Eliel, S.H. Wilen & L.N. Mander, Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, NY, 1994, which is incorporated herein by reference in its entirety. In some embodiments, when the compounds described herein are chiral or otherwise contain one or more stereocenters, compounds can be prepared with an enantiomeric or diastereomeric excess of 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%.

[0067] Resolution of racemic mixtures of compounds can be carried out by any of a number of methods known in the art. An exemplary method involves fractional recrystallization using a chiral resolving organic acid with a racemic mixture containing a basic group. Suitable resolving agents for fractional recrystallization are optically active acids, such as tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or the D- and L-forms of various optically active camphorsulfonic acids. Other chiral resolving agents suitable for fractional crystallization include stereomerically pure forms of methylbenzylamine (e.g., S- and R-forms or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like. Similarly, fractional recrystallization using a chiral resolving base can be utilized with a racemic mixture containing a basic group.

[0068] Resolution of racemic mixtures can also be achieved by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). The composition of a suitable elution solvent can be determined by one skilled in the art.

[0069] In some embodiments, compounds described herein can be prepared having an enantiomeric excess of 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%, or an enantiomeric excess within a range defined by any of the above values.

[0070] Additionally, it is understood that when the compounds described herein contain one or more double bonds (e.g., C=C, C=N, etc.) or other centers of geometric asymmetry, and unless otherwise specified, the compounds are understood to include both E and Z geometric isomers (e.g., cis or trans). Cis and trans geometric isomers of the compounds described herein may be isolated as a mixture of isomers or as separated isomers.

[0071] The compounds described herein also include tautomeric forms.Tautomeric forms result from the exchange of a single bond with an adjacent double bond and the simultaneous migration of a proton.Tautomeric forms include prototropic tautomers, which are isomeric protonation states with the same empirical formula and total charge.Examples of prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and ring forms in which protons can occupy two or more positions in heterocyclic systems, 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 may be in equilibrium or may be sterically locked into one form by appropriate substitution.

[0072] The compounds described herein and their pharmaceutically acceptable salts can be found with other substances such as water and solvent, for example, in the form of hydrate or solvate.The compounds described herein and their salts can occur in various forms when in solid state, and can be in the form of solvate, including hydrate.The compounds can be in any solid state form such as crystalline form, amorphous form, solvate form, and unless otherwise clearly indicated, the references herein to compounds and their salts should be understood to be interpreted as relating to any solid state form of the compounds.

[0073] The compounds described herein can be used in a neutral form, such as a free acid form or a free base form. Alternatively, the compounds can be used in the form of a pharmaceutically acceptable salt, such as a pharmaceutically acceptable addition salt of an acid or base.

[0074] In some embodiments, the compounds described herein or salts thereof are substantially isolated. The phrase "substantially isolated" refers to compounds that are at least partially or largely separated from the environment in which they were formed or detected. Partial isolation can include, for example, compositions enriched in the compounds described herein. Major isolation can include compositions containing at least about 50% by weight, at least about 60% by weight, at least about 65% by weight, at least about 70% by weight, at least about 75% by weight, at least about 80% by weight, at least about 85% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds described herein or salts thereof.

[0075] The compounds disclosed and described herein allow atoms at each position of the compound to independently: 1) have an isotopic distribution of chemical elements in amounts proportional to those normally found in nature; or 2) have an isotopic distribution in amounts different from those normally found in nature, unless the context clearly dictates otherwise. A particular chemical element has an atomic number determined by the number of protons in the atom's nucleus. Each atomic number identifies a specific element, but not an isotope; atoms of a given element may have a wide range of neutron numbers. The number of both protons and neutrons in the nucleus is the atom's mass number, and each isotope of a given element has a different mass number. Compounds in which one or more atoms have an isotopic distribution of chemical elements in amounts different from those normally found in nature are generally referred to as isotopically labeled compounds. Each chemical element represented in a compound structure can include any isotopic distribution of that element. For example, in a compound structure, hydrogen atoms may be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom can be present, the hydrogen atom may be present in an amount proportional to that normally found in nature, including, but not limited to, protium ( 1 H) and deuterium ( 2 The compound may be an isotopic distribution of hydrogen, including H). Thus, when a compound is referred to herein, all possible isotopic distributions for each atom are encompassed unless the context clearly dictates otherwise. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As one skilled in the art will recognize, any of the compounds disclosed and described herein may contain radioactive isotopes. Thus, the use of compounds disclosed and described herein is also contemplated, where one or more atoms contain a higher proportion of isotopes than found in nature. 2 H or 3 H, or a higher proportion than found in nature 11 C. 13 C or 14By way of general example and without limitation, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H) and tritium ( 3 H). Carbon isotopes include carbon-11 ( 11 C), carbon-12( 12 C), carbon-13( 13 C) and carbon-14 ( 14 C). The nitrogen isotope is nitrogen-13( 13 N), nitrogen-14( 14 N) and nitrogen-15( 15 N). The isotope of oxygen is oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O) and oxygen-18( 18 O). The isotopes of fluorine include fluorine-17( 17 F), fluorine-18( 18 F) and fluorine-19( 19 The phosphorus isotope is phosphorus-31( 31 P), phosphorus-32( 32 P), phosphorus-33( 33 P), phosphorus-34( 34 P), phosphorus-35( 35 P) and phosphorus-36( 36 P). The sulfur isotopes include sulfur-32 ( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S) and sulfur-38( 38 S). The chlorine isotope is chlorine-35 ( 35 Cl), chlorine-36( 36 Cl) and chlorine-37( 37 The isotope of bromine is bromine-75( 75 Br), Bromine-76( 76 Br), Bromine-77( 77 Br), Bromine-79( 79 Br), Bromine-81(81 Br) and bromine-82( 82 Br). The isotopes of iodine are iodine-123 ( 123 I), iodine-124( 124 I), iodine-125( 125 I), iodine-131( 131 I) and iodine-135( 135 I). In some embodiments, atoms at every position of the compound have an isotopic distribution of each chemical element in an amount proportional to that normally found in nature. In some embodiments, atoms at one position of the compound have an isotopic distribution of chemical elements in an amount different from that normally found in nature (the remaining atoms have an isotopic distribution of chemical elements in an amount proportional to that normally found in nature). In some embodiments, atoms at at least two positions of the compound independently have an isotopic distribution of chemical elements in an amount different from that normally found in nature (the remaining atoms have an isotopic distribution of chemical elements in an amount proportional to that normally found in nature). In some embodiments, atoms at at least three positions of the compound independently have an isotopic distribution of chemical elements in an amount different from that normally found in nature (the remaining atoms have an isotopic distribution of chemical elements in an amount proportional to that normally found in nature). In some embodiments, atoms at at least four positions of the compound independently have isotopic distributions of chemical elements in amounts proportional to those normally found in nature (the remaining atoms have isotopic distributions of chemical elements in amounts proportional to those normally found in nature). In some embodiments, atoms at at least five positions of the compound independently have isotopic distributions of chemical elements in amounts proportional to those normally found in nature (the remaining atoms have isotopic distributions of chemical elements in amounts proportional to those normally found in nature). In some embodiments, atoms at at least six positions of the compound independently have isotopic distributions of chemical elements in amounts proportional to those normally found in nature (the remaining atoms have isotopic distributions of chemical elements in amounts proportional to those normally found in nature).

[0076] Certain compounds, e.g.3 H and 14 Compounds incorporating radioactive isotopes, such as C, are also useful in drug or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. 2 Compounds bearing isotopes such as H may offer certain therapeutic advantages due to 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 routinely practiced in the chemical arts. Methods for measuring such isotopic variations or enrichments, such as mass spectrometry, are readily available, and in the case of radioisotopes, additional methods are available, such as radiation detectors used in conjunction with HPLC or GC.

[0077] 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 certain embodiments, "isotopic variants" of a compound include, but are not limited to, protium ( 1 H), deuterium ( 2 H), tritium ( 3 H), carbon-11( 11 C), carbon-12( 12 C), carbon-13( 13 C), carbon-14( 14 C), nitrogen-13( 13 N), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-14( 14 O), oxygen-15( 15 O), oxygen-16( 16 O), oxygen-17( 17 O), oxygen-18( 18 O), fluorine-17( 17 F), fluorine-18( 18 F), Phosphorus-31( 31 P), phosphorus-32(32 P), phosphorus-33( 33 P), sulfur-32( 32 S), sulfur-33( 33 S), sulfur-34( 34 S), sulfur-35( 35 S), sulfur-36( 36 S), chlorine-35( 35 Cl), chlorine-36( 36 Cl), chlorine-37( 37 Cl), Bromine-79( 79 Br), Bromine-81( 81 Br), iodine-123( 123 I), iodine-125( 125 I), iodine-127( 127 I), iodine-129( 129 I) and iodine-131( 131 In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., is non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains unnatural proportions of one or more isotopes, including, but not limited to, hydrogen ( 1 H), deuterium ( 2 H), carbon-12( 12 C), carbon-13( 13 C), nitrogen-14( 14 N), nitrogen-15( 15 N), oxygen-16( 16 O), oxygen-17( 17 O) and oxygen-18( 18 In certain embodiments, an "isotopic variant" of a compound is an unstable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound described herein contains, but is not limited to, tritium ( 3 H), carbon-11( 11 C), carbon-14( 14 C), nitrogen-13( 13 N), oxygen-14( 14 O) and oxygen-15( 15In the compounds provided herein, for example, any hydrogen may be present as the major isotope. 2 H, or, for example, every carbon may contain 13C as the major isotope, or, for example, every nitrogen may contain 13C as the major isotope. 15 For example, any oxygen can contain N as its major isotope. 18 It is understood that the isotopic variations of a compound may contain unnatural proportions of deuterium ( 2 H).

[0078] 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 will, in certain embodiments, typically have a minimum isotopic enrichment factor at each designated deuterium position that 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).

[0079] Synthetic methods for incorporating radioisotopes into organic compounds are applicable to the compounds described herein and are well known in the art. For example, these synthetic methods for incorporating activity levels of tritium into target molecules are as follows:

[0080] A. Catalytic reduction with tritium gas: This procedure usually results in products of high specific activity and requires halogenated or unsaturated precursors.

[0081] B. Sodium borohydride [ 3 Reduction with [H]: This procedure is rather inexpensive and requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, and esters.

[0082] C. Lithium aluminum hydride [ 3 Reduction with [H]: This procedure yields products with nearly theoretical specific activities. This procedure also requires precursors containing reducible functional groups such as aldehydes, ketones, lactones, and esters.

[0083] D. Tritium Gas Exposure Labeling: This procedure involves exposing precursors containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0084] E. Methyl iodide [ 3 N-methylation using [H]: This procedure converts the appropriate precursor into methyl iodide ( 3 H) to give O-methyl or N-methyl ( 3 H) products. This method generally allows for higher specific activities, e.g., about 70-90 Ci / mmol. Active level of target molecule 125 Synthetic methods for incorporating I include the following:

[0085] A. Sandmeyer Reaction and Similar Reactions: This procedure converts an aryl or heteroaryl amine into a diazonium salt, such as a diazonium tetrafluoroborate salt, followed by the addition of Na 125 Using I 125 to I-labeled compounds. A representative procedure was reported by Zhu, GD. and coworkers in J. Org. Chem., 2002, 67, 943-948.

[0086] B. Phenol ortho 125Iodination: This procedure allows the formation of iodination groups at the ortho position of phenols, as reported by Collier, TL and coworkers in J. Labeled Compd. Radiopharm., 1999, 42, S264-S266. 125 I can be incorporated.

[0087] C. 125 Aryl and heteroaryl bromide exchange with I: This method is generally a two-step process. The first step is the conversion of the aryl or heteroaryl bromide to the corresponding trialkyltin intermediate, for example, using a Pd catalyzed reaction [i.e., Pd(PhP)] in the presence of a trialkyltin halide or hexaalkylditin [e.g., (CH)Sn(CH)], or via an aryl or heteroaryl lithium. A representative procedure was reported by Le Bas, M.-D., and coworkers in J. Labelled Compd. Radiopharm., 2001, 44, S280-S282.

[0088] The radiolabeled form of the compounds described herein can be used in screening assays to identify / evaluate compounds.In general terms, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled form of the compounds disclosed herein to GPR52.The ability of the test compound to compete with the radiolabeled form of the compounds described herein for binding to GPR52 correlates with its binding affinity. Aspects of the Disclosure

[0089] The present disclosure relates to compounds capable of modulating the activity of GPR52. In one aspect of the disclosure, with respect to compounds of formula (I), a compound of formula (Ia): [ka] is.

[0090] In a further embodiment is a compound of Formula (Ia) wherein R2 is selected from methyl, ethyl, methylamino, chloro, and trifluoromethyl.

[0091] In a further embodiment is a compound of Formula (Ia) wherein R3 is selected from hydrogen and halo.

[0092] In a further embodiment is a compound of Formula (Ia) wherein R5 is selected from hydrogen, methyl and ethyl.

[0093] In a further embodiment is a compound of Formula (Ia) wherein R6 is selected from hydrogen, methyl, fluoro, amino, cyano, and trifluoromethyl.

[0094] In a further embodiment, the compound is of Formula (Ia) wherein X 1 is selected from N and CH.

[0095] In a further aspect, X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl, and compounds of formula (Ia) and pharmaceutically acceptable salts thereof.

[0096] In a further aspect, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl, R3 is selected from hydrogen and halo; R5 is hydrogen and C 1~2 alkyl, R6 is hydrogen, amino, cyano, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, X1 is selected from N and CH; X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; Compounds of formula (Ia) or pharmaceutically acceptable salt forms and pharmaceutically acceptable salts thereof:

[0097] In a further aspect, R2 is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R3 is selected from hydrogen and halo; R5 is selected from hydrogen, methyl and ethyl; R6 is selected from hydrogen, methyl, fluoro, amino, cyano and trifluoromethyl; X1 is selected from N and CH; X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; Compounds of formula (Ia) and pharmaceutically acceptable salts thereof:

[0098] In a further aspect, R2 is selected from methyl, ethyl and trifluoromethyl; R3 is selected from hydrogen and fluoro; X1 is selected from N and CH; Compounds of Formula (Ia) and pharmaceutically acceptable salts thereof, wherein X2 is CR9 and R9 is selected from hydrogen and amino.

[0099] In a further aspect, the following: [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0100] In another aspect of the disclosure, with respect to compounds of formula (I), a compound of formula (Ib): [ka] is.

[0101] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl.

[0102] In a further aspect of the disclosure, R5 is hydrogen, C 1~2 Alkyl and halo substituted C 1~2 alkyl.

[0103] In a further aspect of the disclosure, R6 is hydrogen, amino, cyano, halo, C 1~2 Alkyl and halo substituted C 1~2 alkyl.

[0104] In a further aspect of the disclosure, R7 is hydrogen, C 1~2 The compound of formula Ib is selected from alkyl and halo.

[0105] In a further aspect of the disclosure, R 9a is selected from hydrogen and methyl.

[0106] In a further embodiment of the disclosure are compounds of formula Ib, wherein X 1 is selected from N and CH.

[0107] In a further aspect of the disclosure, X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl, and compounds of formula Ib and pharmaceutically acceptable salts thereof.

[0108] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl, R5 is hydrogen, C 1~2Alkyl and halo substituted C 1~2 alkyl, R6 is hydrogen, amino, cyano, halo, C 1~2 Alkyl and halo substituted C 1~2 alkyl, R7 is hydrogen, C 1~2 selected from alkyl and halo; R 9a is selected from hydrogen and methyl; X1 is selected from N and CH; X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; Compounds of formula Ib and pharmaceutically acceptable salts thereof:

[0109] In a further aspect of the disclosure, R2 is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R5 is selected from hydrogen, methyl, ethyl and trifluoromethyl; R6 is selected from hydrogen, methyl, amino, cyano, fluoro and trifluoromethyl; R7 is selected from hydrogen, methyl and fluoro; R 9a is selected from hydrogen and methyl; X1 is selected from N and CH; Compounds of formula (Ib) and pharmaceutically acceptable salts thereof, wherein X2 is selected from N and CR8, and R8 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl.

[0110] In a further aspect of the present disclosure, there are compounds of formula (Ib) and pharmaceutically acceptable salts thereof, wherein X2 is CR8 and R8 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl.

[0111] In a further aspect of the present disclosure, [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0112] In a further aspect of the disclosure, there is provided a compound of formula (Ic) or a pharmaceutically acceptable salt thereof: [ka] is.

[0113] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl.

[0114] In a further aspect of the disclosure, R5 is hydrogen, C 1~2 Alkyl and halo substituted C 1~2 alkyl.

[0115] In a further aspect of the disclosure, R6 is selected from the group consisting of hydrogen and C 1~2 alkyl.

[0116] In a further embodiment of the disclosure are compounds of formula (Ic) wherein X 1 is selected from N and CH.

[0117] In a further embodiment of the disclosure are compounds of formula (Ic) where X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl.

[0118] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl, R5 is hydrogen, C 1~2 Alkyl and halo substituted C 1~2 alkyl, R6 is hydrogen and C 1~2 alkyl, X1 is selected from N and CH; Compounds of formula (Ic) and pharmaceutically acceptable salts thereof, wherein X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl.

[0119] In a further aspect of the disclosure, R2 is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R5 is selected from hydrogen, fluoro, methyl, ethyl and trifluoromethyl; R6 is selected from hydrogen, methyl, amino, cyano and trifluoromethyl; X1 is selected from N and CH; Compounds of formula (Ic) and pharmaceutically acceptable salts thereof, wherein X2 is selected from N and CR8, and R8 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl.

[0120] In a further aspect of the disclosure, R2 is selected from methyl and ethyl; X1 is N, Compounds of formula (Ic) and pharmaceutically acceptable salts thereof, wherein X2 is CR9 and R9 is selected from hydrogen and amino.

[0121] In a further aspect of the present disclosure, [ka] or a pharmaceutically acceptable salt thereof.

[0122] In another embodiment of the disclosure, there is provided a compound of formula (Id) or a pharmaceutically acceptable salt thereof: [ka] is.

[0123] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl.

[0124] In a further aspect of the disclosure, R5 is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl.

[0125] In a further aspect of the disclosure, R6 is selected from the group consisting of hydrogen and C 1~2 alkyl.

[0126] In a further aspect of the disclosure, R7 is hydrogen, C 1~2 The compound of formula (Id) is selected from alkyl and halo.

[0127] In a further embodiment of the disclosure are compounds of formula (Id) wherein X 1 is selected from N and CH.

[0128] In a further embodiment of the disclosure are compounds of formula (Id) where X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl.

[0129] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C1~2 alkyl, R5 is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, R6 is hydrogen and C 1~2 alkyl, R7 is hydrogen, C 1~2 selected from alkyl and halo; X1 is selected from N and CH; Compounds of formula (Id) and pharmaceutically acceptable salts thereof, wherein X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl.

[0130] In a further aspect of the disclosure, R2 is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R5 is selected from hydrogen, fluoro, methyl and ethyl; R6 is selected from hydrogen, methyl, amino, cyano and trifluoromethyl; R7 is hydrogen, C 1~2 selected from alkyl and halo; X1 is selected from N and CH; Compounds of formula (Id) and pharmaceutically acceptable salts thereof, wherein X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl.

[0131] In a further embodiment of the disclosure are compounds of formula (Id) and pharmaceutically acceptable salts thereof, wherein R2 is selected from methyl, ethyl and chloro, X1 is N and X2 is CH.

[0132] In a further aspect of the present disclosure, [ka] or a pharmaceutically acceptable salt thereof.

[0133] In another embodiment of the present disclosure, a compound of formula (Ie): [ka] or a pharmaceutically acceptable salt thereof.

[0134] In a further aspect of the disclosure, R is selected from the group consisting of hydrogen and C 1~2 alkyl.

[0135] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl.

[0136] In a further aspect of the disclosure, R4 is: [ka] is a compound of formula (Ie) selected from:

[0137] In a further aspect of the disclosure, R5 is selected from the group consisting of hydrogen and C 1~2 alkyl.

[0138] In a further aspect of the disclosure, R6 is hydrogen, amino, cyano, C 1~2 Alkyl and halo substituted C 1~2 alkyl.

[0139] In a further aspect of the disclosure, R7 is hydrogen, C 1~2 The compound of formula (Ie) is selected from alkyl and halo.

[0140] In a further embodiment of the disclosure are compounds of formula (Ie) wherein X 1 is selected from N and CH.

[0141] In a further embodiment of the present disclosure, X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl, or R9 and the nitrogen of X1 form a 5-membered unsaturated ring containing up to two nitrogen atoms, compounds of formula (Ie).

[0142] In a further aspect of the present disclosure R1 is hydrogen and C 1~2 alkyl, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl, R4, [ka] is selected from R5 is hydrogen and C 1~2 alkyl, R6 is hydrogen, amino, cyano, C 1~2 Alkyl and halo substituted C 1~2 alkyl, R7 is hydrogen, C 1~2 selected from alkyl and halo; X1 is selected from N and CH; Compounds of formula (Ie) and pharmaceutically acceptable salts thereof, wherein X2 is selected from N and CR9, and R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl, or R9 and the nitrogen of X1 form a 5-membered unsaturated ring containing up to two nitrogen atoms.

[0143] In a further aspect of the disclosure, R1 is selected from hydrogen, methyl and ethyl; R2 is selected from methyl and ethyl; R4, [ka] is selected from R5 is methyl; R6, when attached to a carbon atom, is selected from hydrogen, methyl and trifluoromethyl; R7 is hydrogen; X1 is selected from N and CH; Compounds of formula (Ie) and pharmaceutically acceptable salts thereof, wherein X2 is CR9 and R9 is hydrogen.

[0144] In a further aspect of the present disclosure, [ka] or a pharmaceutically acceptable salt thereof.

[0145] In another aspect of the present disclosure, the formula If: [ka] or a pharmaceutically acceptable salt thereof.

[0146] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl.

[0147] In a further aspect of the disclosure, R4 is one of the following: [ka] is a compound of formula (If) selected from

[0148] In a further aspect of the disclosure, R5 is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl.

[0149] In a further aspect of the disclosure, R6 is hydrogen, amino, cyano, C 1~2Alkyl, halo and halo-substituted C 1~2 alkyl.

[0150] In a further aspect of the disclosure, R7 is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl.

[0151] In a further embodiment of the disclosure is a compound of formula (If) wherein R8 is selected from hydrogen and halo.

[0152] In a further aspect of the disclosure, R2 is C 1~2 Alkyl, halo, methylamino and halo substituted C 1~2 alkyl, R4, [ka] is selected from

[0153] R5 is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, R6 is hydrogen, amino, cyano, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, R7 is hydrogen, C 1~2 Alkyl, halo and halo-substituted C 1~2 alkyl, Compounds of formula (If) and pharmaceutically acceptable salts thereof, wherein R8 is selected from hydrogen and halo.

[0154] In a further aspect of the disclosure, R2 is selected from methyl, ethyl, chloro, fluoro, and trifluoromethyl, and R4 is [ka] is selected from R5, when attached to a carbon atom, is selected from hydrogen, fluoro, chloro and methyl; R6 is selected from hydrogen and fluoro; R7 is selected from hydrogen, fluoro, chloro and trifluoromethyl; Compounds of formula (If) and pharmaceutically acceptable salts thereof, wherein R8 is selected from hydrogen and fluoro.

[0155] In a further aspect of the present disclosure, [ka] [ka] [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0156] In a further aspect of the disclosure, [ka] [ka] or a pharmaceutically acceptable salt thereof.

[0157] Pharmaceutical Compositions, Formulations and Dosage Forms

[0158] The disclosure 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.

[0159] The present disclosure also provides pharmaceutical compositions comprising any of the compounds described herein (e.g., compounds of Formula (I), including the specific compounds described herein) or a pharmaceutically acceptable salt thereof, and an excipient, such as a pharmaceutically acceptable excipient. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable, non-toxic, inert substance or ingredient that does not interfere with the activity of the drug substance. An excipient can 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 field and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate-buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.

[0160] Another aspect of the disclosure, with respect to compounds of Formula I, is a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, and one or more excipients.

[0161] For the composition formulated as liquid solution, acceptable carrier and / or diluent include physiological saline and sterilized water, and may contain antioxidant, buffer, bacteriostatic agent and other common additives as necessary.The composition can also be formulated as pills, capsules, granules or tablets, which contain GPR52 agonist as well as diluent, dispersant and surfactant, binder and lubricant.Those skilled in the art can further formulate GPR52 agonist in suitable manner and in accordance with accepted practice such as disclosed in Remington above.

[0162] The method of administration preferably includes the systemic administration of the GPR52 agonist described herein in the form of pharmaceutical compositions discussed above.As used herein, systemic administration includes oral and parenteral methods of administration.For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules, as well as liquids, syrups, suspensions and emulsions.These compositions may also contain flavoring agents, preservatives, suspending agents, thickening agents and emulsifying agents, and other pharmaceutically acceptable additives.For parenteral administration, the compound described herein (or its pharmaceutically acceptable salt) can be prepared in an injectable aqueous solution, which may contain, in addition to the GPR52 agonist, buffers, antioxidants, bacteriostatic agents and other additives commonly used in such solutions.

[0163] Pharmaceutical preparations for oral administration can be obtained by any suitable method, usually by uniformly mixing the compound with a liquid or finely divided solid carrier, or both, in the required proportions, then processing the mixture after adding suitable auxiliaries, if necessary, and, if desired, forming the resulting mixture into the desired shape to obtain tablets or dragee cores.

[0164] Ordinary excipients such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants and disintegrants can be used in tablets and capsules for oral administration.Liquid preparations for oral administration can be in the form of solution, emulsion, aqueous or oily suspension and syrup.Alternatively, oral preparations can be in the form of dry powder, which can be reconstituted with water or other suitable liquid vehicle before use.Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring and coloring agents can be added to liquid preparations.Non-oral dosage forms can be prepared by dissolving the compound described herein in a suitable liquid vehicle, and filtration sterilizing the solution before lyophilization, or simply filling into suitable vials or ampoules and sealing them.

[0165] Some embodiments provide methods for preparing a pharmaceutical composition, comprising mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0166] When preparing a pharmaceutical composition containing a compound of formula (I) or a pharmaceutically acceptable salt thereof, the drug substance is usually mixed (i.e., blended) with an excipient, diluted by an excipient, or enclosed within such a carrier, for example, in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, the excipient can be a solid, semi-solid, or liquid substance that serves as a vehicle, carrier, or medium for the drug substance. Thus, the composition can be in the form of a tablet, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), ointment, soft and hard gelatin capsule, suppository, sterile solution for injection, and sterile-packaged powder.

[0167] When preparing pharmaceutical compositions in solid form, such as powders, tablets, capsules, cachets, suppositories, and dispersible granules, excipients can be one or more substances that can also serve as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials.Similarly, solid form preparations intended to be converted into liquid form preparations for oral administration immediately before use are also included.Such liquid forms include solutions, suspensions, and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0168] For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously within the wax by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby solidify.

[0169] Formulations suitable for vaginal administration may be supplied as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0170] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution. Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile fixed oils are commonly used as solvents or suspending media. For this purpose, any non-irritating fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0171] The pharmaceutical compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the pharmaceutical compositions may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g., sterile, pyrogen-free water, before use.

[0172] The pharmaceutical compositions may be formulated as aqueous solutions, hydroalcoholic solutions, solid suspensions, emulsions, liposomal suspensions, or lyophilized powders for reconstitution. These pharmaceutical compositions may be administered directly or as a mixture for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, irrigation, 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 improve solubility, and the resulting composition is subjected to a suitable sterilization procedure known in the art, such as sterile filtration. In some embodiments, the pH of the aqueous solution is about 2.0 to about 4.0. In some embodiments, the pH of the aqueous solution is about 2.5 to about 3.5.

[0173] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the active ingredient in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.

[0174] Aqueous suspensions suitable for oral use can be made by dispersing finely divided drug substance in water containing a viscous substance such as a natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agent.

[0175] For topical administration to the epidermis, the compound described herein or its pharmaceutically acceptable salt can be formulated as gel, ointment, cream or lotion, or as transdermal patch.Similarly, the formulation suitable for topical administration in the oral cavity includes: lozenges, which contain active ingredient in a flavored base, usually sucrose and acacia or tragacanth; pastilles, which contain active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes, which contain active ingredient in a suitable liquid carrier.Ointments and creams can be formulated, for example, with aqueous or oily bases, and suitable thickeners and / or gelling agents are added.Lotions can be formulated with aqueous or oily bases, and generally also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or coloring agents.In some embodiments, topical preparations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white petrolatum, etc. The carrier composition of creams can be based on water combined with glycerol and one or more other components, for example, glycerin monostearate, PEG-glycerin monostearate, and cetylstearyl alcohol. Gels can be suitably formulated using isopropyl alcohol and water combined with other components such as, for example, glycerol, hydroxyethylcellulose, etc.

[0176] Solution or suspension can be directly applied to nasal cavity by conventional means, for example, using dropper, pipette or spray.Preparation can be provided in single dose form or multiple dose form.In the latter case of dropper or pipette, this can be achieved by subject administering appropriate predetermined amount of solution or suspension.In the case of spray, this can be achieved by, for example, metering atomizing spray pump.

[0177] Administration to the respiratory tract can also be achieved by aerosol preparations provided in pressurized packs containing suitable propellants.When the compounds described herein or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them, are administered as aerosols, for example, as nasal aerosols, or by inhalation, this can be done, for example, using a spray, nebulizer, pump nebulizer, inhalation device, metered dose inhaler, or dry powder inhaler.The pharmaceutical forms for administering the compounds described herein (or pharmaceutically acceptable salts thereof) as aerosols can be prepared by processes well known to those skilled in the art.When preparing them, for example, solutions or dispersions of the compounds described herein (or pharmaceutically acceptable salts thereof) in water, water / alcohol mixtures, or suitable saline solutions can be used, using conventional additives, such as benzyl alcohol or other suitable preservatives, absorption enhancers for improving bioavailability, solubilizers, dispersants, etc., and where appropriate, conventional propellants include, for example, CFCs such as carbon dioxide, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane. The aerosol may conveniently also contain a surfactant such as lecithin. The dosage of drug may be controlled by providing a metered valve.

[0178] Alternatively, the pharmaceutical composition can be provided in the form of a dry powder of the compound, for example, a powder mix, in a suitable powder base such as lactose, starch, starch derivatives (such as hydroxypropylmethylcellulose) and polyvinylpyrrolidone (PVP).Advantageously, the powder carrier forms a gel in the nasal cavity.The powder composition can be provided in a unit dose form, for example, in capsules or cartridges of, for example, gelatin, or in a blister pack, so that the powder can be administered by an inhaler.

[0179] The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered in a rapidly dissolving or slow-release composition, in which case the composition comprises a biodegradable rapidly dissolving or slow-release carrier (e.g., a polymeric carrier, etc.). Rapidly dissolving or slow-release carriers are well known in the art and are used to form complexes that entangle the compound of formula (I) or a pharmaceutically acceptable salt thereof, which decompose / dissolve either rapidly or slowly in a suitable environment (e.g., aqueous, acidic, basic, etc.).

[0180] The pharmaceutical preparation is preferably in unit dosage form.In this form, the preparation is subdivided into unit doses containing appropriate amounts of active pharmaceutical ingredients.The unit dosage form can be a packaged preparation, and the package contains individual amounts of preparations such as tablets, capsules and powders packaged in vials or ampoules.Similarly, the unit dosage form can be a capsule, tablet, cachet or lozenge itself, or any appropriate number of these in packaged form.In some embodiments, the pharmaceutical preparation is a tablet or capsule for oral administration.In some embodiments, the pharmaceutical preparation is a liquid formulated for intravenous administration.

[0181] The compositions may 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 a physically discrete unit of formulation suitable as a unitary dosage for human subjects and other mammals, each unit containing a predetermined quantity of drug substance calculated to produce the desired therapeutic effect, in association with suitable excipients as described herein.

[0182] The compositions described herein can be formulated to provide immediate and / or time-modified (also called sustained, extended, controlled, or slow) release of the active ingredient after administration to a subject using procedures known in the art. For example, tablets containing a compound of Formula (I) or a pharmaceutically acceptable salt thereof may be coated or otherwise compounded to provide a dosage form offering the advantage of extended action. For example, a tablet may comprise an inner and outer component, the latter component wrapped around the former. The two components may be separated by an enteric layer, which serves to resist disintegration in the stomach and to allow the inner component to pass intact into the duodenum or to delay its release. A variety of materials can be used for such enteric layers or coatings, including several polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0183] Liquid forms containing the drug substance may be incorporated for oral or injectable administration and 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 vehicles.

[0184] The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques or sterile filtered. Aqueous solutions can be packaged for immediate use or lyophilized, and the lyophilized preparations are combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations is usually between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It is understood that the use of certain of the above-mentioned excipients may result in the formation of pharmaceutically acceptable salts.

[0185] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions can contain suitable excipients as described herein. In some embodiments, the compositions are administered orally or via the nasal respiratory route for local or systemic effect. The compositions can be nebulized by using an inert gas. Nebulized solutions can be inhaled directly from the nebulizing device, or the nebulizing device can be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or intranasally from a device that delivers the formulation in an appropriate manner.

[0186] The compositions may be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active pharmaceutical ingredient, if desired. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied by a notice attached to the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, which notice reflects the approval by the agency of the drug form for human or veterinary administration. Such notice may, for example, be the labeling approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions that can include the compounds described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for the treatment of an indicated condition.

[0187] When preparing solid compositions such as tablets, the drug substance can be mixed with excipients to form a solid preformulated composition containing a homogeneous mixture of the components. When describing such a preformulated composition as homogeneous, the drug substance is usually dispersed evenly throughout the composition, so that the composition can be readily divided into equally effective unit dosage forms such as tablets and capsules.

[0188] Usually, kits are provided that contain one or more unit doses of the compound described herein in oral or injection doses.Such kits can include the container that contains the unit dose, the package insert information that describes the use of the drug in treating the target pathology and the accompanying benefits, and optionally, the appliance or device that delivers the composition.

[0189] The compound described herein or its pharmaceutically acceptable salt can be effective in a wide range of dosages, and generally be administered in a therapeutically effective amount.However, it is understood that the amount of compound actually administered will usually be determined by a physician according to the relevant circumstances, including the condition to be treated, the route of administration selected, the actual compound to be administered, the age, weight and response of individual subject, the severity of the condition of subject, etc.

[0190] The amount of compound or composition administered to a subject will also vary depending on what is being administered, the purpose of administration, such as prophylaxis or treatment, the condition of the subject, the method of administration, etc. In therapeutic applications, compositions can be administered to a subject 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 dose will depend on the disease state being treated, as well as factors such as the severity of the disease, the age, weight, and general condition of the subject, and the judgment of the attending clinician.

[0191] Desired dose can be conveniently provided as a single dose or as a divided dose, which is administered at appropriate intervals, for example, as two, three, four or more divided doses per day.Divided doses themselves, for example, can be further divided into several separate loosely spaced administrations.Daily dose can be divided into several divided doses, for example, two, three or four divided doses, especially when relatively large amounts are deemed appropriate for administration.In appropriate cases, depending on individual behavior, it may be necessary to deviate upward or downward from the indicated daily dose.

[0192] It will be apparent to one of skill in the art that the dosage forms described herein may comprise a compound described herein or a pharmaceutically acceptable salt thereof.

[0193] Some embodiments include the use of at least one compound or a pharmaceutically acceptable salt thereof disclosed and described herein, 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 impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder (OCD), autism spectrum disorder, and the like. agnosia associated with schizophrenia, Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, including chorea associated with Huntington's disease.

[0194] Some embodiments include the use of at least one compound or a pharmaceutically acceptable salt thereof disclosed and described herein, or a pharmaceutical composition disclosed and described herein, in the manufacture of a medicament for ameliorating one or more symptoms of a neurological disorder, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder (OCD), autism spectrum disorder, prolactin-related disorder (e.g., hyperprolactinemia), neurocognitive disorder, trauma or stressor-related disorder (e.g., PTSD); disruptive impulse control or conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypoactivity, abnormalities of the infundibulopituitary, mesolimbic, mesocortical or nigrostriatal tract, striatal hypoactivity, cortical dysfunction, neurocognitive dysfunction and agnosia associated with schizophrenia; Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, including chorea associated with Huntington's disease.

[0195] Some embodiments provide the use of at least one compound 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).

[0196] Some embodiments provide for the use of at least one compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed and described herein, as monotherapy or as add-on therapy to standard treatment with an antipsychotic, for treating cognitive impairment associated with schizophrenia (CIAS).

[0197] Some embodiments provide for the use of at least one compound or a pharmaceutically acceptable salt thereof disclosed and described herein, or a pharmaceutical composition disclosed and described herein, as monotherapy or as add-on therapy to standard treatment with antipsychotic medications for the treatment of negative symptoms of schizophrenia, impulsive or obsessive-compulsive disorders, non-motor symptoms of Parkinson's disease, autism spectrum disorders, other CNS disorders with associated cognitive dysfunction (e.g., Huntington's disease, multiple sclerosis, etc.).

[0198] Some embodiments provide for the use of at least one compound or a pharmaceutically acceptable salt thereof disclosed and described herein, or a pharmaceutical composition disclosed and described herein, as a monotherapy or as an add-on therapy to standard of care for treating a psychiatric disorder (positive symptoms). Pharmacology and Usefulness

[0199] 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 within the third cytoplasmic loop and / or the carboxy terminus. GPCRs are important components of numerous cell-signaling pathways. GPCRs couple to various enzymes, ion channels, and transporters. Different G protein subunits can stimulate effectors to modulate various downstream functions in cells.

[0200] Ligand binding induces a conformational change in GPCRs that allows them to function as guanine nucleotide exchange factors (GEFs). GPCRs can then activate associated G proteins by exchanging G protein-bound GDP for GTP. This GTP, together with the α subunit of the G protein, then dissociates from the β and γ subunits to further modulate intracellular signaling pathways.

[0201] GPR52 is a highly conserved GPCR in vertebrates with over 90% amino acid sequence identity.The highest expression level in the central nervous system (CNS) is found in the striatum.A lower significant expression level is found in other structures in the CNS, including the cortex.The tissue distribution of GPR52 does not have significant differences between humans, rats and mice, suggesting that there is a common function of GPR52 regardless of species.

[0202] In the rat brain, GPR52 is expressed in various neuronal regions, including the medial prefrontal cortex, basolateral amygdala, and habenula, which are responsible for the manifestations of psychiatric disorders. Furthermore, GPR52 knockout and transgenic mice exhibited psychosis-related and antipsychotic-like behaviors, respectively (Hidetoshi Komatsu, et al., February 2014, Volume 9, Issue 2, PLOSONE, e90134).

[0203] Although GPR52 has been characterized, it remains an orphan receptor, i.e., it has no known internal or external ligand. Several surrogate ligands have been reported, including GPR52's own extracellular loop 2 (ECL2) (Pingyuan Wang, et al., J. Med. Chem., 2020, 63, 13951-72). GPR52 is often co-localized with dopamine receptors (D1 and D2) (see PLOSOne, Vol. 9, No. 2, e90134). GPR52 is almost exclusively co-localized with D2 receptors in the human striatum and with D1 receptors in the cortex. The efficacy of existing antipsychotic drugs is mediated by D2 antagonist activity, which manifests with side effects such as motor symptoms and hyperprolactinemia. Antipsychotic drugs are also associated with serious side effects, including weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperglycemia, insulin resistance, extrapyramidal pathway symptoms, and tardive dyskinesia.In contrast, GPR52 modulators can essentially function as D2 antagonists, thus avoiding the side effects associated with D2 antagonists and simultaneously exhibiting antipsychotic efficacy.Therefore, GPR52 modulators can improve various neurological conditions, diseases, and disorders, and are targeted for treating various nervous system diseases, including but not limited to, psychotic disorders, apathy, anxiety, anxiety / tension associated with psychoneurosis, acute mania, agitation, mania in bipolar disorder, dysthymia, dyspepsia, and drug-related addiction (cocaine, amphetamine, etc.).

[0204] GPR52 co-localizes with D1 receptors in the medial prefrontal cortex but with D2 receptors in the basal ganglia, suggesting that GPR52 may be involved in dopaminergic transmission in D1 receptor-expressing neurons in the cortex and in D2 receptor-expressing neurons in the striatum (Hidetoshi Komatsu, et al., February 2014, Volume 9, Issue 2, PLOSONE, e90134).

[0205] Hypofrontal cortex activity, which is a decrease in blood flow to the prefrontal cortex, is a symptom of several neurological conditions, including cognitive and negative symptoms associated with schizophrenia, attention-deficit / hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and hypofrontal lobe activity associated with substance abuse. Therefore, improving prefrontal cortex function by GPR52 modulators is useful for treating symptoms associated with hypofrontal lobe activity.

[0206] In one aspect of the disclosure is a method of treating a disease or disorder associated with hypofrontal lobe activity, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0207] In a further aspect of the present disclosure, the disease or disorder associated with frontal lobe hypoactivity is selected from cognitive and negative symptoms associated with schizophrenia, attention-deficit / hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and frontal lobe hypoactivity associated with substance abuse.

[0208] In a further aspect, negative symptoms associated with schizophrenia that interfere with typical human emotions, behaviors, and abilities are selected from: decreased speech, odd emotional reactions to situations, lack of emotion or expression, loss of interest or excitement in life, social isolation, difficulty experiencing pleasure, difficulty initiating or continuing projects, and difficulty completing normal daily activities.

[0209] Furthermore, with regard to GPR52 agonists functionally similar to D1 agonists, GPR52 agonists have the potential to be useful in treating disorders treatable by D1 agonists, including, but not limited to, drug-related addictions (e.g., cocaine addiction), hypertension, restless legs syndrome, Parkinson's disease, and depression. Furthermore, based on expression patterns and functional coupling, GPR52 agonists are useful in treating agnosia associated with schizophrenia, schizoaffective disorder, schizophreniform and schizotypal disorders, treatment-resistant schizophrenia, attenuated psychotic syndromes and autism spectrum disorders, 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.

[0210] The striatum is involved in the control of movement, including, but not limited to, hyperkinetic movement disorders characterized by excessive and abnormal involuntary movements (known as hyperkinesis). Examples of hyperkinetic movement disorders include tremor, dystonia, chorea, ballismus, athetosis, tics / Tourette's syndrome, Huntington's disease, myoclonus and startle syndrome, stereotypies, and akathisia. Hyperkinesis is associated with dysfunction of inhibitory D2-expressing neurons in this pathway. This dysfunction results in the inability to inhibit movement, leading to tics, chorea, crying, tremors, and other hyperkinetic symptoms. For example, early hyperkinetic movement symptoms in Huntington's disease are the result of selective damage to the indirect D2-containing pathway. Furthermore, D2 receptor binding in the striatum is associated with the severity of symptoms in Tourette's syndrome. Modulation of GPR52 activity can activate the indirect striatal pathway, resulting in greater inhibitory control of movement and resolution of hyperkinetic symptoms.

[0211] In one aspect of the disclosure is a method of treating hyperkinetic movement disorder, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0212] In a further aspect of the disclosure, the hyperkinetic movement disorder is selected from tremor, dystonia, chorea, ballismus, athetosis, tics / Tourette's syndrome, Huntington's disease, myoclonus and startle syndrome, stereotypies, and akathisia.

[0213] Huntington's disease is primarily caused by the cytotoxicity of mutant HTT proteins with polyglutamine repeat expansions. Reducing soluble mutant HTT may alleviate its downstream toxicity, potentially providing a treatment for Huntington's disease. Knocking out GPR52 significantly reduces mutant HTT levels in the striatum and rescues Huntington's disease-associated behavioral phenotypes in knock-in Huntington's disease mouse models. Furthermore, GPR52 antagonists reduce mutant HTT levels and rescue Huntington's disease-associated phenotypes in cell and mouse models (Haikun Song, et al., June 2018, Brain, Vol. 141, Issue 6, P. 1782-98).

[0214] In one aspect of the disclosure is a method of treating Huntington's disease, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0215] Schizophrenia is a complex neuropsychiatric disorder affecting approximately 0.3% of the population. It is a severe, chronic, and disabling mental disorder. Core clinical features of schizophrenia include positive, negative, and cognitive symptoms. Cognitive impairment associated with schizophrenia (CIAS) is highly 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 demonstrated significant efficacy against negative and cognitive symptoms. Selective GPR52 agonists have demonstrated therapeutic properties for the treatment of positive and cognitive symptoms of schizophrenia (Keiji Nishiyama, et al., J. Pharm. Exp. Ther., November 2017, 363(2) 253-64).

[0216] A major unmet clinical need in schizophrenia is the treatment of negative and cognitive symptoms, as currently approved antipsychotic medications provide little improvement. In particular, agnosia in patients with schizophrenia is recognized as a core part of the disorder and is thought to have a significant impact on patients' recovery and reintegration into society.

[0217] In one aspect of the disclosure is a method of treating schizophrenia, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0218] Another aspect of the disclosure is a method of treating CIAS, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0219] Psychotic symptoms of schizophrenia are caused by the hyperactivity of presynaptic dopamine in the striatum. The clinical efficacy of existing antipsychotic drugs for treating psychotic symptoms depends on the blockade of D2 receptors. All known effective antipsychotic drugs for treating psychosis are either antagonists or partial agonists at dopamine D2 receptors. Although these antipsychotic drugs can treat the positive (or psychotic) symptoms of schizophrenia, they do not 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. Furthermore, because the mechanism of action of GPR52 agonists is unique to known D2 receptor-related antipsychotic drugs, GPR52 agonists are expected to enhance the antipsychotic efficacy of known neuroleptic drugs. This not only improves antipsychotic efficacy, but can also be used to reduce the dose of antipsychotics, thereby reducing the side effects associated with antipsychotics.Improvement of serum prolactin level is one of the prominent side effect profiles of known D2 receptor antagonist antipsychotics, while GPR52 agonists have been demonstrated to reduce serum prolactin level; therefore, the simultaneous application of GPR52 agonists and D2 receptor antagonist antipsychotics can normalize serum prolactin level, thereby reducing the side effects associated with D2 receptor antagonist antipsychotics.In addition, GPR52 agonists should treat the psychotic symptoms associated with various neuropathological symptoms, including schizoaffective disorder, schizotypal disorder, schizophreniform disorder, treatment-resistant schizophrenia, drug-induced psychotic disorder, bipolar disorder, autism spectrum disorder and attenuated psychosis syndrome.

[0220] In one aspect of the disclosure is a method of treating a neuropathological indication, comprising administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0221] In a further aspect, the neuropathological indication is selected from schizoaffective disorder, schizotypal disorder, schizophreniform disorder, treatment-resistant schizophrenia, drug-induced psychotic disorder, bipolar disorder, autism spectrum disorder and attenuated psychotic syndrome.

[0222] In one aspect of the disclosure is a method of 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.

[0223] In a further aspect, the psychotic 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.

[0224] The present disclosure further provides a method of treating a nervous system disease in a subject in need thereof, the method comprising administering to the subject 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 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) and a pharmaceutically acceptable excipient. The present disclosure 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) to treat a nervous system disease in a subject in need thereof. The present disclosure also provides the manufacture of a medicament disclosed and described herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) to treat a nervous system disease in a subject in need thereof.

[0225] In some embodiments, the subject has previously been diagnosed with a neuropathy. In some embodiments, the subject currently has a neuropathy. In some embodiments, the subject is suspected of having a neuropathy. In some embodiments, the subject has previously been treated with one or more therapeutic agents approved for the treatment of a neuropathy.

[0226] In some embodiments, the neurological disorder is schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder (OCD), autism spectrum disorder, prolactin-related disorder (e.g., hyperprolactinemia), neurocognitive disorder, extrapyramidal syndrome, trauma- or stressor-related disorders (e.g., PTSD); disruptive impulse control or conduct disorders, sleep-wake disorders, substance-related disorders, addictive disorders, behavioral disorders, frontal lobe hypoactivity, abnormalities of the infundibulopituitary, mesolimbic, mesocortical, or nigrostriatal tracts, striatal hypoactivity, cortical dysfunction, neurocognitive dysfunction, and agnosia associated with schizophrenia; Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy, progressive supranuclear palsy, Huntington's disease, and chorea associated with Huntington's disease.

[0227] In some embodiments, the neurological disorder is selected from schizophrenia, cognitive impairment, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, attention deficit / hyperactivity disorder (ADHD), Tourette's syndrome, catatonia, mood disorder, obsessive-compulsive disorder (OCD), hyperprolactinemia, PTSD, frontal lobe hypoactivity, Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy, progressive supranuclear palsy, Huntington's disease, and chorea associated with Huntington's disease.

[0228] In some embodiments, the neurological disorder is selected from schizophrenia. In some embodiments, the neurological disorder is a cognitive disorder. In some embodiments, the neurological disorder is a panic disorder. In some embodiments, the neurological disorder is a phobic disorder. In some embodiments, the neurological disorder is a drug-induced psychotic disorder. In some embodiments, the neurological disorder is a delusional psychosis. In some embodiments, the neurological disorder is neuroleptic-induced dyskinesia. In some embodiments, the neurological disorder is Parkinson's disease. In some embodiments, the neurological disorder is a drug-induced parkinsonism. In some embodiments, the neurological disorder is an extrapyramidal syndrome. In some embodiments, the neurological disorder is Alzheimer's disease. In some embodiments, the neurological disorder is dementia with Lewy bodies. In some embodiments, the neurological disorder is a bipolar disorder. In some embodiments, the neurological disorder is attention deficit / hyperactivity disorder (ADHD). In some embodiments, the neurological disorder is Tourette's syndrome. In some embodiments, the neurological disorder is an extrapyramidal or movement disorder. In some embodiments, the neurological disorder is a motor dysfunction disorder. In some embodiments, the neurological disorder is a hyperkinetic movement disorder. In some embodiments, the neurological disorder is a psychotic disorder. In some embodiments, the neurological disorder is catatonia. In some embodiments, the neurological disorder is a mood disorder. In some embodiments, the neurological disorder is a depressive disorder. In some embodiments, the neurological disorder is an anxiety disorder. In some embodiments, the neurological disorder is obsessive-compulsive disorder (OCD). In some embodiments, the neurological disorder is an autism spectrum disorder. In some embodiments, the neurological disorder is a prolactin-related disorder. In some embodiments, the neurological disorder is hyperprolactinemia. In some embodiments, the neurological disorder is a neurocognitive disorder. In some embodiments, the neurological disorder is a trauma or stressor-related disorder. In some embodiments, the neurological disorder is PTSD. In some embodiments, the neurological disorder is impulse-control. In some embodiments, the neurological disorder is a conduct disorder. In some embodiments, 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 addictive disorder. In some aspects, the neurological disorder is a behavioral disorder. In some aspects, the neurological disorder is frontal lobe hypoactivity. In some aspects, the neurological disorder comprises an abnormality in the infundibulopituitary tract.In some aspects, the neurological disorder comprises abnormalities in the mesolimbic pathway. In some aspects, the neurological disorder comprises striatal hypoactivity. In some aspects, the neurological disorder is cortical dysfunction. In some aspects, the neurological disorder is neurocognitive dysfunction and agnosia associated with schizophrenia or Parkinson's disease. In some aspects, the neurological disorder is drug-induced parkinsonism. In some aspects, the neurological disorder is dyskinesia. In some aspects, the neurological disorder is dystonia. In some aspects, the neurological disorder is chorea. In some aspects, the neurological disorder is levodopa-induced dyskinesia. In some aspects, the neurological disorder is cerebral palsy. In some aspects, the neurological disorder is progressive supranuclear palsy. In some aspects, the neurological disorder is Huntington's disease. In some aspects, the neurological disorder is chorea associated with Huntington's disease.

[0229] In some embodiments, the panic disorder comprises a panic attack. In some embodiments, the phobic disorder is situation-related (e.g., social phobia). In some embodiments, the phobic disorder is object-related (e.g., spider phobia). In some embodiments, the extrapyramidal syndrome comprises persistent spasms or muscle contractions, motor restlessness, muscle rigidity, slow muscle responses, tremors, or irregular, jerky movements. In some embodiments, the extrapyramidal or movement disorder is tardive dyskinesia, acute dystonic reactions, akathisia, or pseudoparkinsonism. In some embodiments, the motor dysfunction disorder is developmental coordination disorder, stereotypic movement disorder, or Tourette's syndrome. In some embodiments, the hyperkinetic movement disorder comprises athetosis, ballismus, chorea, dystonia, myoclonus, restless leg syndrome, stereotypies, tics, or tremors. In some embodiments, the psychotic disorder is schizophrenia, schizophreniform disorder, delusional disorder, or chronic hallucinatory psychosis. In some embodiments, the mood disorder is major depression or bipolar disorder. In some embodiments, the depressive disorder is major depression, atypical depression, melancholic depression, catatonic major depression, postpartum depression, seasonal affective disorder, or bipolar disorder. In some embodiments, the anxiety disorder is generalized anxiety disorder, posttraumatic stress disorder, obsessive-compulsive disorder, phobic disorder, or panic disorder. In some embodiments, the autism spectrum disorder is autism or Asperger's syndrome. In some embodiments, the neurocognitive disorder is severe neurocognitive disorder or mild neurocognitive disorder. In some embodiments, the disruptive, impulse control, or conduct disorder is attention deficit disorder, attention deficit hyperactivity disorder, oppositional defiant disorder, sexual compulsive disorder, internet addiction, pyromania, intermittent explosive disorder, compulsive shopping, or kleptomania. In some embodiments, the sleep-wake disorder is insomnia, narcolepsy or night terrors. In some embodiments, the substance-related disorder is alcoholism, opioid addiction, prescription drug addiction and / or illicit drug addiction. In some embodiments, the addictive disorder comprises substance addiction (e.g., alcoholism) or experiential addiction (e.g., gambling addiction). In some embodiments, the behavioral disorder is attention deficit disorder, attention deficit hyperactivity disorder or oppositional defiant disorder.

[0230] It is understood in the art that some of the syndromes and conditions described herein may have overlapping symptoms, and / or some of the specific disorders described herein may be classified into more than one category of disorders described herein. For example, tardive dyskinesia can be classified as at least an extrapyramidal or movement disorder, a hyperkinetic movement disorder, a movement dysfunction disorder, or an extrapyramidal syndrome.

[0231] Some embodiments provide a method for modulating GPR52 in a cell, comprising contacting the cell with a compound of formula (I) or a pharmaceutically acceptable salt thereof. Without wishing to be bound by any theory, the compound and receptor can be contacted for a sufficient time and under appropriate conditions to allow interaction between the cell and the compound.

[0232] In some aspects, the contacting is in vitro. In some aspects, the contacting is in vivo. In some aspects, the contacting is in vivo, wherein the method comprises administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof to a subject having cells with GPR52 activity.

[0233] In certain embodiments, the cells are present in a subject in need of treatment with a compound disclosed herein. In certain embodiments, the cells are derived from a subject in need of treatment with a compound disclosed herein. In some embodiments, the subject has a nervous system disease, condition, or disorder. In some embodiments, the subject is at risk of developing a nervous system disease, condition, or disorder. In some embodiments, the subject has previously been diagnosed with a nervous system disease, condition, or disorder. In some embodiments, the subject is currently receiving treatment for a nervous system disease, condition, or disorder. In some embodiments, the subject is suffering from a nervous system disease, condition, or disorder. In some embodiments, the subject is suspected of having a nervous system disease, condition, or disorder. In some embodiments, the nervous system disease, condition, or disorder is Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, attention deficit / hyperactivity disorder (ADHD), Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder (OCD), autism spectrum disorder, prolactin-related disorder (e.g., hyperprolactinemia), neurocognitive disorder, trauma or stressor-related disorder (e.g., PTSD); disruptive impulse control disorder These disorders include control or conduct disorders, sleep-wake disorders, substance-related disorders, addictive disorders, behavioral disorders, frontal lobe hypoactivity, abnormalities of the infundibulopituitary, mesolimbic, mesocortical or nigrostriatal tracts, striatal hypoactivity, cortical dysfunction, neurocognitive dysfunction and agnosia associated with schizophrenia, Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, in particular chorea associated with Huntington's disease.

[0234] The cardiac potassium channel hERG (human ether-a-go-go related gene) regulates the rapid delayed rectifier current (I ) in human ventricles. KrInhibition of IKr is the most common cause of noncardiac drug-induced prolongation of the cardiac action potential (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 causes a prolongation of the QT interval and is associated with torsades de pointes (Brown, AM, and Rampe, D., (2000), "Drug-induced long QT syndrome: is HERG the root of all evil?", Pharmaceutical News, 7, 15-20). The compound of formula I was evaluated for its in vitro effect on hERG channel current (the rapidly activating delayed rectifier cardiac potassium current, I Kr(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, Volume 58, Issue 1, April 2003, Pages 32-45). See the Examples below under "Activity of compounds of Formula I on hERG."

[0235] Animal models can be used to model cognitive impairment in schizophrenia. Administration of the glutamate / NMDA antagonist phencyclidine (PCP) provides a model of schizophrenia capable of inducing both the negative and positive symptoms associated with amphetamine psychosis (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 credibility in that there is evidence of abnormalities in the glutamatergic system in the brain in schizophrenia. Such changes include deficits in cortico-striatal innervation that may contribute to, if not underlie, the cognitive impairment 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, 22 August 1997, pages 13-16. Furthermore, some PCP-induced behaviors are reversed by certain atypical antipsychotics but not by typical antipsychotics (Geyer, MA, et al., "Startle response models of sensorimotor gating and habituation deficits in schizophrenia," Brain Research Bulletin, Vol. 25, Issue 3, September 1990, pp. 485-498). This suggests a potential correlation with the effects on negative and cognitive symptoms, which do not respond as effectively to typical antipsychotics.

[0236] Certain preclinical studies have enabled the observation of relatively mild agnosia in rats, resembling dementia in subjects with a range of CNS disorders. These cognitive deficits include visual memory deficits that can be measured by cognitive tasks such as the Novel Object Recognition (NOR) paradigm. Recognition memory tasks allow the comparison of presented stimuli with previously stored information. The NOR test in rats, based on differential exploration of familiar and novel objects, was described by Ennaceur and Delacour ("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 behavioral association paradigm that measures episodic memory based on the spontaneous exploratory behavior of 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 (one familiar from the first trial and one novel object). Object recognition in rats can be measured as the difference in time spent exploring the familiar and novel objects. Rats have been shown to spend more time exploring the novel object. It has been found that rats can distinguish between familiar and novel objects when the intertrial interval is between 3 minutes and 1-3 hours, but not when it exceeds 24 hours; however, this effect may depend on the rat's sex (Sutcliffe et al., "Influence of gender on working and spatial memory in the novel object recognition task in the rat", Behavioral Brain Research, 2007 Feb12;177(1):117-25).The duration of each trial is also important, as the preference for the novel object only lasts for the first 3 minutes, after which the preference declines as both objects become familiar and are explored equally.

[0237] Effects of PCP. Subchronic (sc) treatment with PCP produces neuropathological changes associated with schizophrenia. This regimen produces selective deficits in reversal learning and novel object recognition in operant reversal learning tests. (scPCP)-induced deficits are robust and long-lasting in female rats, and this dosing regimen also produces reduced social behavior in female hooded-Lister rats. PCP-induced object recognition deficits are accompanied by a lack of dopamine release in the prefrontal cortex and hippocampus, and this effect can be attenuated by dopamine D1 receptor activation (Abdul-Monim, et al., "Subchronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat", Psychopharmacology, 2007 (March), 21(2):198-205; and Snigdha, et al., "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, et al., "The effect of atypical and classical antipsychotics on subchronic "PCP-induced cognitive deficits in a reversal-learning paradigm", Behavioral BrainResearch, 169 (2006), 263-273; Abdul-Monim, et al., "Sub-chronicpsychotomimetic phencyclidine induces deficits in reversal learning andalterations in parvalbumin-immunoreactive expression in the rat",Psychopharmacology, 2007 (March), 21(2):198-205; McLean, et al., "D1-likereceptor activation improves PCP-induced cognitive deficits in animal models:Implications for mechanisms of improved cognitive function inschizophrenia", Vol.19, Issue 6, June 2009, Pages 440-450;およびIdris, etal., "Sertindole improves sub-chronic PCP-induced reversal learning andepisodic memory deficits in rodents: involvement of 5-HT6and 5-HT. 2A receptor mechanisms", Psychopharmacology, 208 (23), 2010; Grayson, et al.,"Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitivedeficit in the novel object recognition task in the rat", Behavioral BrainResearch, Vol.184, Issue 1, 2007; Snigdha, et al., "Improvement ofphencyclidine-induced social behavior deficits in rats: Involvement of 5-HT 1A", Behavioral Brain Research, Vol.191, Issue 1, 2008, P26-31).

[0238] Behavioral tests and methods (NOR and social interaction paradigms) are presented in the Examples below. Combination medicines

[0239] It will be further understood that certain features of the present disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the present disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. [Example]

[0240] Detailed compound synthesis methods are described in the examples presented herein. Those skilled in the art of chemistry can prepare compounds of Formula (I) and related formulae (including the specific compounds described herein) by these or similar methods or other methods practiced by those skilled in the art. Generally, the starting components are commercially available chemicals and can be obtained from commercial suppliers, or can be prepared according to organic synthesis techniques known to those skilled in the art, starting from commercially available chemicals and / or compounds described in the chemical literature. The compounds described herein are named in accordance with MarvinSketch 18.24.0 or ChemDraw Professional 20.1.1.125 or later versions. In certain instances, when generic names are used, it is understood that these generic names are recognized by those skilled in the art.

[0241] "Commercial Chemicals" means Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI (including Sigma Chemical and Fluka)), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire UK), BDH Inc. (Toronto, Canada), Bionet (Cornwall, UK), 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 UK), Lancaster Synthesis(Windham NH), Maybridge Chemical Co.Ltd.(Cornwall UK), 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 Products, Inc. (New Brunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (Rockville MD), and Wako Chemicals USA, Inc. (Richmond VA).

[0242] Methods known to those skilled in the art can be identified from various reference books and databases.Suitable reference books and articles that describe the synthesis of the reagents useful for preparing the compounds of the present disclosure or provide the references to the articles that describe 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. Further suitable references and articles detailing the synthesis of reagents useful in the preparation of the compounds of the present disclosure or providing references to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second, Revised and Enlarged Edition (1994) John Wiley & Sons ISBN: 3527-29074-5; Hoffman, RV Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, RCComprehensiveOrganic 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. (editor) Modern Carbonyl Chemistry, (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., Patai’s 1992 Guide to the Chemistry ofFunctional Groups, (1992) Interscience ISBN: 0-471-93022-9; Quin, L.D. et al. AGuide to Organophosphorus Chemistry, (2000) Wiley-Interscience, ISBN:0-471-31824-8; Solomons, T. W. G. Organic Chemistry, 7th Edition (2000) JohnWiley & Sons, ISBN: 0-471-19095-0; Stowell, J.C., 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, in hardcover volumes (86) and electronic volumes (26).

[0243] Specific reactants and similar reactants can also be identified from the index of known chemicals prepared by the Chemical Abstract Service of the American Chemical Society, available in most public and university libraries, as well as from online databases (further details can be contacted from the American Chemical Society, Washington, DC). Known chemicals not commercially available in the catalog can be prepared by custom chemical synthesis houses according to known methods, and many of the standard chemical supply houses (e.g., those listed above) offer custom synthesis services.

[0244] The term "reducing agent" refers to a compound that provides a hydride at an electrophilic position of a reactant compound, such as an unsaturated carbon (e.g., the carbon of a carbonyl moiety), such as converting a ketone-containing reactant compound to an alcohol product compound or converting an ester-containing reactant compound to an alcohol product compound. The reducing agent can be a hydride reducing agent. Exemplary hydride reducing agents include, but are not limited to, diborane, borane (e.g., borane tetrahydrofuran complex), 9-borabicyclo[3.3.1]nonane, lithium aluminum hydride, diisobutylaluminum hydride, lithium diisobutyl-tert-butoxyaluminum hydride, lithium tri-tert-butoxyaluminum hydride, lithium tris[(3-ethyl-3-pentyl)oxy]aluminum hydride, sodium bis(2-methoxyethoxy)aluminum dihydride, sodium aluminum hydride, calcium borohydride, lithium borohydride, magnesium borohydride, potassium borohydride, tetrabutylammonium borohydride, and boron hydride. Examples of suitable cations include tetraethylammonium, tetramethylammonium borohydride, bis(triphenylphosphine)copper(I) borohydride, lithium 9-borabicyclo[3.3.1]nonanehydride, sodium triacetoxyborohydride, potassium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tricyamylborohydride, lithium triethylborohydride, potassium triethylborohydride, sodium triethylborohydride, potassium triphenylborohydride, lithium dimethylaminoborohydride, lithium pyrrolidinoborohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, and sodium borohydride.

[0245] The term "halogenating agent" refers to a compound that donates a halogen atom to a reactant compound, such as converting an alcohol reactant compound to an alkyl halide product compound. Examples of halogenating agents include, but are not limited to, thionyl chloride, oxalyl 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.

[0246] 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, oxalyl chloride, phosphorus oxychloride, Vilsmeier reagent, propylphosphonic anhydride, ethylmethylphosphinic anhydride (EMPA), AcO, 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-triazine (CDMT), 4-(4,6-dimethoxy-1,3,5-triazin-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-di methylaminopropyl)-N'-ethylcarbodiimide (EDC), 1,3-di-p-tolylcarbodiimide, benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yloxytrispyrrolizinophosphonium hexafluorophosphate (PyBOP), 6-chlorobenzotriazol-1-yloxytrispyrrolizinophosphonium hexafluorophosphate (PyClock), ( 7-Azabenzotriazol-1-yloxy)trispyrrolizinophosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethylideneaminooxytrispyrrolizinophosphonium hexafluorophosphate (PyOxim), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate (COMU), 3-(diethoxyphosphoryloxy)-1,2,3-Benzo[d]triazin-4(3H)-one (DEPBT), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), O-(2-oxo-1(2H)pyridyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(N-succinic acid) Examples of such compounds include 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HSTU), 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium hexafluorophosphate (HCTU), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

[0247] The term "base" refers to a compound that is an electron pair donor in an acid-base reaction.

[0248] The base can be an inorganic base or an organic base.

[0249] The term "organic base" refers to a base containing at least one C-H bond (e.g., an amine base). In some embodiments, the amino group 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-methylmorpholine, 4-ethylmorpholine, 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 embodiments, the amine base can contain one alkali metal or alkaline earth metal. Examples of amine bases containing one 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, lithium 2,2,6,6-tetramethylpiperidide, etc. In some embodiments, the organic base can be a metal alkoxide base. Examples of metal alkoxide bases include, but are not limited to, barium tert-butoxide, lithium tert-amoxide, lithium tert-butoxide, lithium ethoxide, lithium isopropoxide, lithium methoxide, magnesium di-tert-butoxide, magnesium ethoxide, magnesium methoxide, potassium tert-butoxide, potassium ethoxide, potassium methoxide, potassium tert-pentoxide, sodium tert-butoxide, sodium ethoxide, sodium methoxide, sodium tert-pentoxide, etc. In some embodiments, the organic base can be an organometallic base (e.g., an organolithium base or an organomagnesium base).Examples of organolithium bases include, but are not limited to, n-butyllithium, sec-butyllithium, tert-butyllithium, ethyllithium, hexyllithium, isobutyllithium, isopropyllithium, methyllithium, hexyllithium, phenyllithium, etc. Examples of organomagnesium bases 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, sec-butylmagnesium chloride, tert-butylmagnesium 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, etc.

[0250] The term "inorganic base" refers to a base that does not contain any C-H bonds and that contains at least one alkali metal or alkaline earth metal. Examples of inorganic bases include, but are not limited to, sodium hydride, potassium hydride, lithium hydride, calcium hydride, 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, etc.

[0251] The term "acid" refers to a compound that is an electron pair acceptor in an acid-base reaction.

[0252] The acid can be an inorganic acid or an organic acid.

[0253] The term "inorganic acid" refers to an acid that does not contain a carbon bond. Inorganic acids can be strong or weak. Examples of inorganic acids include, but are not limited to, sulfamic acid, hydrochloric acid, hydroiodic acid, hydrobromic acid, perchloric acid, sulfuric acid, nitric acid, boric acid, fluorophosphoric acid, phosphoric acid, and the like.

[0254] The term "organic acid" refers to an acid containing at least one C-H, C-F, 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, etc. General reaction scheme

[0255] The present disclosure also includes processes for preparing compounds of formula (I). In the reactions described, if a reactive functional group (e.g., a hydroxy, amino, imino, thio, or carboxy group) is desired in the final product, it may be necessary to protect the reactive functional group to avoid undesired participation of the reactive functional group in the reaction. Conventional protecting groups can be used in accordance with standard practice, see, for example, TW Greene and PGM Wuts in "Protective Groups in Organic Chemistry", John Wiley and Sons, 1991.

[0256] Compounds of formula (I) can be prepared by proceeding as shown in Reaction Scheme 1 below: Reaction Scheme 1 [ka] wherein R1, R2, R3, R4, X1, X2, and X3 are as defined in the Summary of the Disclosure above. Compounds of Formula I can be synthesized by coupling compounds of Formula (2) and Formula (3) in the presence of a suitable solvent (e.g., DCM, DCE, NMP, DMF, EtOAc, toluene, dioxane, ethanol, water, etc.), optionally a suitable base (e.g., DIEA, TEA, etc.), and a suitable coupling agent (e.g., EDC / HOBt, HATU, HBTU, HCTU, etc.). The reaction proceeds at a temperature of about 0°C to about 80°C and can take up to about 24 hours to complete. See the specific examples below.

[0257] Compounds of formula (I) can be prepared by proceeding as shown in Reaction Scheme 2 below: Reaction Scheme 2 [ka] wherein R, R, R, R, X, X, and X are as defined in the Summary of the Disclosure above, and Z is a suitable leaving group such as halogen (e.g., chloro). Compounds of Formula I can be synthesized by coupling compounds of Formula (4) and Formula (5) in the presence of a suitable solvent (e.g., toluene, dioxane, ethanol, DMF, EtOAc, etc.), a suitable base (e.g., sodium carbonate, sodium hydroxide, potassium carbonate, sodium t-butoxide, potassium t-butoxide, etc.), and a suitable coupling agent (e.g., tetrakistriphenylphosphine 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], etc.). The reaction proceeds at a temperature of about 50° C. to about 120° C. and can take up to about 24 hours to complete. See the specific examples below.

[0258] Compounds of formula (I) can be prepared by proceeding as shown in Reaction Scheme 3 below: Reaction Scheme 3 [ka] wherein R1, R2, R3, R4, X1, X2, and X3 are as defined in the Summary of the Disclosure above, and Q is chloro, fluoro, or bromo. Compounds of Formula I can be synthesized by combining compounds of Formula (6) and Formula (7) in the presence of a suitable solvent (e.g., DMF, NMP, THF, dioxane, DMA, EtOH, MeOH, IPA, BuOH, etc.) and a suitable base (e.g., potassium carbonate, sodium carbonate, cesium carbonate, NaH, etc.). The reaction proceeds at a temperature of about 20°C to about 100°C and can take up to about 24 hours to complete. See the specific examples below. Further Processes for Making the Compounds of the Disclosure

[0259] The compounds of the present disclosure can 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 present disclosure can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base.

[0260] The compounds of Formula I can also be modified by adding appropriate functional groups to enhance selective biological properties. Such types of 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, testes), improve bioavailability, improve solubility to allow parenteral administration (e.g., injection, infusion), modify metabolism, and / or modify excretion rate. Examples of such types of modifications include, but are not limited to, esterification (e.g., esterification with polyethylene glycol), derivatization with pivaloyloxy or fatty acid substituents, conversion to carbamate, hydroxylation of the aromatic ring, and heteroatom substitution in the aromatic ring.

[0261] Whenever a compound of formula I, and / or its N-oxides, tautomers and / or (preferably pharmaceutically acceptable) salts is referred to, this includes such modified formulae, but preferably the molecule of formula I, its N-oxides, its tautomers and / or its salts are intended.

[0262] Alternatively, salt forms of the compounds of the present disclosure can be prepared using salts of starting materials or intermediates.In view of the close relationship between the new compounds of formula I in free form and their salt forms (including salts that can be used as intermediates (for example, in purifying or identifying new compounds)), any reference to the compounds of formula I hereinbefore and hereafter should be understood to refer to the compounds in free form, and / or to one or more of their salts, and, where appropriate and convenient, to one or more solvates, such as hydrates.

[0263] Salts are formed from compounds of formula I having a basic nitrogen atom, for example, as acid addition salts, preferably with organic or inorganic acids, especially as pharmaceutically acceptable salts. Suitable inorganic acids are, for example, halogen acids such as hydrochloric acid, sulfuric acid, or phosphoric acid. Suitable organic acids are, for example, carboxylic acids, phosphonic acids, sulfonic acids, or sulfamic acids, such as acetic acid, propionic acid, octanoic acid, decanoic acid, dodecanoic acid, glycolic acid, lactic acid, fumaric acid, succinic acid, malonic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartaric acid, citric acid, amino acids (such as glutamic acid or aspartic acid), maleic acid, hydroxymaleic acid, methylmaleic acid, cyclohexanecarboxylic acid, adamantanecarboxylic acid, benzoic acid, salicylic acid, 4-aminosalicylic ... The preferred organic protic acids are licylic acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methane 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- or 3-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methyl- or N-ethylsulfamic acid, or other organic protic acids (such as ascorbic acid).

[0264] 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 are used (if applicable in the form of pharmaceutical preparations), and these are therefore preferred.

[0265] The free acid form or free base form of the compound of the present disclosure can be prepared from the corresponding base addition salt form or acid addition salt form.For example, the compound of the present disclosure in the form of an acid addition salt can be converted into the corresponding free base by treating with a suitable base (for example, ammonium hydroxide solution, sodium hydroxide, etc.).The compound of the present disclosure in the form of a base addition salt can be converted into the corresponding free acid by treating with a suitable acid (for example, hydrochloric acid, etc.).

[0266] The non-oxidized forms of the compounds of the present disclosure can be prepared from the oxides of the compounds of the present disclosure by treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide, etc.) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0-80°C.

[0267] Prodrug derivatives of the compounds of the present disclosure can be prepared by methods 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, suitable prodrugs can be prepared by reacting an underivatized compound of the present disclosure with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, paranitrophenyl carbonate, or the like).

[0268] Protected derivatives of the compounds of the present disclosure can be made by means known to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation and removal of protecting groups can be found in TW Greene, "Protecting Groups in Organic Chemistry," 3 rd edition, John Wiley and Sons, Inc., 1999.

[0269] The compounds of the present disclosure can be conveniently prepared, or formed during the process of the present disclosure, as solvates (e.g., hydrates). Hydrates of the compounds of the present disclosure can be conveniently prepared by recrystallization from an aqueous / organic solvent mixture using organic solvents such as dioxin, tetrahydrofuran, or methanol.

[0270] The compounds of the present disclosure 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 diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. While resolution of enantiomers can be carried out using covalent diastereomeric derivatives of the compounds of the present disclosure, separable complexes (e.g., crystalline diastereomeric salts) are preferred. Diastereomers have different physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily separated by exploiting these differences. Diastereomers can be separated by chromatography or, preferably, by separation / resolution techniques based on differences in solubility. The optically pure enantiomers are then recovered along with the resolving agent by any practical means that would not result in racemization. A more detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixtures can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981.

[0271] In summary, compounds of formula I are as follows: (a) the process of Reaction Scheme I, II, or III, and (b) optionally converting a compound of the present disclosure into a pharmaceutically acceptable salt; (c) optionally converting a salt form of a compound of the present disclosure into a non-salt form; (d) optionally converting the non-oxidized form of a compound of the present disclosure into a pharmaceutically acceptable N-oxide; (e) optionally converting an N-oxide form of a compound of the present disclosure into its non-oxidized form; (f) optionally resolving the individual isomers of the compounds of the present disclosure from the mixture of isomers; (g) optionally converting an underivatized compound of the present disclosure into a pharmaceutically acceptable prodrug derivative; and (h) optionally converting a prodrug derivative of a compound of the disclosure into its underivatized form; It can be made by a process including:

[0272] Unless the preparation of a starting material is specifically described, the compound is known or can be prepared analogously to methods known in the art or as disclosed in the Examples hereinafter.

[0273] Those of skill in the art will recognize that the above transformations are only representative of methods for the preparation of the compounds of the present disclosure, and that other well-known methods can similarly be used.

[0274] The following examples are included to demonstrate aspects of the present disclosure. However, those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific aspects that are disclosed and still achieve a like or similar result without departing from the spirit and scope of the disclosure.

[0275] This specification contains a number of abbreviations, the definitions of which are listed in the table below. [Table 15-1] [Table 15-2]

[0276] Analytical HPLC analysis was performed using a UV detector (Dionex TM UVD170u UV / VIS detector), Corona array detector (Thermo TM Veo TM RS) and mass spectrometer (Dionex MSQ Plus TMPurification by reversed-phase preparative HPLC was performed on a Phenomenex LCMS system with a C18 Kinetix 5μ 100A 150 x 21.2 mm column using an ACN / water gradient containing 0.05% TFA. All final compounds were analyzed by analytical HPLC, and peaks were monitored for purity at 210, 254, and 280 nM. 1 H was recorded in an appropriate NMR solvent such as DMSO-d6 on a Bruker 400 MHz spectrometer equipped with a broadband NMR probe. 1 H chemical signals are given in parts per million (ppm) with the residual solvent signal used as reference. Chemical shifts are expressed in ppm (δ) and coupling constants (J) are reported in hertz (Hz). Reactions are carried out under an atmosphere of dry nitrogen unless otherwise stated.

[0277] In addition, the following LCMS method was used: 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 (containing 0.025% TFA) in water (containing 0.025% TFA) for 6 seconds, then increase to 90% acetonitrile over 1.5 minutes. Increase to 99% acetonitrile over 6 seconds, then hold at 99% acetonitrile for 12 seconds. Return to 10% acetonitrile over 6 seconds, 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 (containing 0.025% TFA) in water (containing 0.025% TFA) for 6 seconds, then increase to 90% acetonitrile over 6.5 minutes. Increase to 99% acetonitrile over 6 seconds, then hold at 99% acetonitrile for 12 seconds. Return to 10% acetonitrile over 6 seconds, hold at 10% for 30 seconds. LCMS method 2A: Platform: Thermo Vanquish UHPLC equipped 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 (containing 0.025% TFA) in water (containing 0.025% TFA) for 6 seconds, then increase to 90% acetonitrile over 1.35 minutes. Increase to 99% acetonitrile over 6 seconds, then hold at 99% acetonitrile for 9 seconds. Return to 10% acetonitrile over 6 seconds, hold at 10% for 12 seconds. LCMS method 2B: Platform: Thermo Vanquish UHPLC equipped 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: 1.0 mL / min, 5% acetonitrile (containing 0.025% TFA) in water (containing 0.025% TFA) for 6 seconds, then ramp to 90% acetonitrile over 6.35 minutes. Ramp to 99% acetonitrile over 6 seconds, then hold at 99% acetonitrile for 9 seconds. Ramp back to 5% acetonitrile over 6 seconds, hold at 5% for 12 seconds. LCMS method 3A: Platform: Thermo Vanquish UHPLC equipped 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, 2% acetonitrile (containing 0.025% TFA) in water (containing 0.025% TFA) for 42 seconds, then ramp to 90% acetonitrile over 2.8 minutes, ramp to 99% acetonitrile over 6 seconds, ramp back to 2% acetonitrile over 6 seconds, hold at 2% for 9 seconds.

[0278] The examples illustrate, but are not limited to, the synthesis of compounds of formula (I). Intermediate Example 1 1,3-Dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol [ka] Synthesis of 1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol: [ka] Step A: 6-Bromo-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (10.0 g, 44.23 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (16.85 g, 66.35 mmol), Pd(dppf)Cl*CHCl (3.61 g, 4.42 mmol), and potassium acetate (13.02 g, 132.7 mmol) were suspended in degassed dioxane. The mixture was heated at 100 °C under argon for 2 h. After cooling to room temperature, the mixture was diluted with ethyl acetate / hexane, filtered through a pad of silica, and concentrated in vacuo. The residue was used in the next step without purification.

[0279] Step B: 1,3-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-b]pyridine (10.78 g, 39.46 mmol) was dissolved in THF / HO (3 / 1) and cooled on ice, followed by addition of NaBO 3· 4H2O (17.0 g, 110.49 mmol) was added and stirred overnight. Na2SO3 solution was added and the organic layer was separated. The water was extracted with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, and the solvent was evaporated. The residue was purified by FC (ISCO® Interchim; 220 g SiO2, 0-95% methanol in acetonitrile / methanol, flow rate = 80 mL / min, Rt = 20-55 min) to give 1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol (3.0 g, 18.38 mmol, 46.6% yield). LC / MS [M+H] 164.0. The following intermediate examples in Table 1 were made following the procedures in Intermediate Example 1 using the appropriate starting materials. [Table 1-1] [Table 1-2]

[0280] Intermediate Example 2 1-Methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-ol [ka] Synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-ol: [ka]

[0281] Step A: Hydrazine hydrate (18.77 g, 375.01 mmol) was added to 1-(5-bromo-2-fluoropyridin-3-yl)-2,2,2-trifluoroethan-1-one (5.1 g, 18.75 mmol) in ethanol (50 mL), and the mixture was heated to reflux overnight. The cooled reaction mixture was evaporated to give a solid. Water (100 mL) was added, and the mixture was filtered to give 5-bromo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (4.4 g, 80.0% purity, 13.23 mmol, 70.6% yield) as a solid.

[0282] Step B: A solution of 5-bromo-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (2.4 g, 9.02 mmol) in DMF (30 mL) was cooled to 0 °C, and sodium hydride (281.51 mg, 11.73 mmol) was added. The reaction mixture was stirred at 0 °C for 30 minutes, and iodomethane (2.69 g, 18.95 mmol, 1.18 mL, 2.1 equiv.) was added. The reaction mixture was stirred at 0 °C for 10 minutes and at room temperature for 16 hours. The reaction mixture was quenched with ice / water and diluted with ethyl acetate (50 mL). The organic layer was separated. The aqueous layer was extracted again with ethyl acetate (2 × 50 mL). The ethyl acetate layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography to give 5-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (1.5 g, 5.36 mmol, 59.4% yield).

[0283] Step C: 5-Bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (2.0 g, 7.14 mmol), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (2.72 g, 10.71 mmol), potassium acetate (2.1 g, 21.42 mmol), and Pd(dppf)Cl*CHCl (583.19 mg, 714.13 μmol) were suspended in dry dioxane. The mixture was degassed and heated under argon at 100 °C for 1 h. After cooling to room temperature, the mixture was filtered through silica gel and concentrated in vacuo to give 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (4.45 g, 35.0% purity, 4.76 mmol, 66.7% yield), which was used in the next step without purification.

[0284] Step D: 1-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridine (4.45 g, 13.6 mmol) was dissolved in THF / HO (150 / 50 ml) and treated with NaBO 3· 4H2O (2.05 g, 13.33 mmol) was added in small portions at 15-20 °C, and the resulting mixture was stirred at room temperature for 16 h. After adding aqueous Na2SO3, the mixture was extracted with ethyl acetate (150 ml × 3). The combined extracts were washed with saturated NaCl solution and dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure, and the crude product was purified by column chromatography to give 1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-ol (530.0 mg, 2.44 mmol, 51.3% yield). 1 H NMR (400 MHz,DMSO-d, 27℃): δ = 10.25 (br s, 1H), 8.38 (d, J = 2.1 Hz, 1H), 7.40-7.45 (m,1H), 4.12 ppm (s, 3H). Intermediate Example 3 1-Methyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol [ka] Synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol: [ka]

[0285] Step A: A solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (8.0 g, 40.4 mmol), iodine (20.1 g, 79.18 mmol), and sodium hydroxide (6.06 g, 151.5 mmol) in DMF (80 mL) was stirred at room temperature for 12 hours. The reaction was quenched by diluting with a saturated solution of sodium bisulfite (350 mL), and a precipitate formed. The precipitate was filtered off under vacuum and washed with water (3 × 100 mL). The solid was dried in a vacuum oven at 30 °C overnight to give an orange solid (8.12 g).

[0286] Step B: 6-Bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine (8.1 g, 25.01 mmol) and iodomethane (7.1 g, 50.01 mmol, 3.11 ml, 2.0 equiv.) were suspended in dry DMF (100 mL), and then cesium carbonate (24.44 g, 75.02 mmol) was added at 20 °C. The reaction mixture was stirred at room temperature overnight. The resulting solution was concentrated under reduced pressure. The residue was taken up in 500 mL of water, and the solid was filtered off, washed three times with water, and dried in air at 50 °C. The product, 6-bromo-3-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine (3.5 g, 10.36 mmol, 41.4% yield), was obtained as a brown solid after FC purification. LC / MS [M+H] 337.8.

[0287] Step C: 6-Bromo-3-iodo-1-methyl-1H-pyrazolo[4,3-b]pyridine (9.1 g, 26.93 mmol), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (25.87 g, 134.64 mmol), and copper(I) iodide (25.64 g, 134.64 mmol) were combined in dimethylformamide (100 mL), and the reaction mixture was stirred at 80° C. for 12 hours. The mixture was then concentrated in vacuo and the residue was purified by FC (Companion combiflash®; 80 g SiO, 0-95% MeCN in CHCl / MeCN, flow rate = 60 mL / min, Rf = 3-4 CV) to give 6-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (3.2 g, 95.0% purity, 10.86 mmol, 40.3% yield). LC / MS [M+H] 280.0.

[0288] Step D: To a solution of 6-bromo-1-methyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (2.5 g, 8.93 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.4 g, 13.39 mmol) in 1,4-dioxane (100 mL) was added potassium acetate (1.75 g, 17.85 mmol). The resulting mixture was degassed and flushed with nitrogen three times. Next, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (728.98 mg, 892.67 μmol) was added, and the reaction mixture was stirred under a nitrogen atmosphere at 110 °C overnight, then cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc (500 mL), filtered through a Celite pad, and washed with brine (3 × 300 mL). The separated organic phase was dried over anhydrous NaSO and concentrated in vacuo. 1-Methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (5.7 g, 35.0% purity, 6.1 mmol, 68.3% yield) was used in the next step without further purification. LC / MS [M+H] 246.0.

[0289] Step E: A solution of crude 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (5.7 g, 17.42 mmol) in THF-HO (50 mL + 25 mL) was treated with NaBO 3·4H2O (2.63 g, 17.07 mmol) was added. The mixture was stirred at room temperature overnight. THF was removed under reduced pressure, and the residue was stirred with saturated NH4Cl (25 mL) and methylene chloride (150 mL). The organic layer was separated, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Interchim; 40 g SiO2, 0-95% MeCN in CHCl3 / MeCN, flow rate = 40 mL / min, Rf = 4-6 CV) to give 1-methyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol (710.0 mg, 95.0% purity, 3.11 mmol, 50.9% yield). LC / MS [M+H] 218.0.

[0290] The following intermediate examples in Table 2 were made following the procedure in Intermediate Example 3 using the appropriate starting materials. [Table 2]

[0291] Intermediate Example 4 tert-Butyl (6-chloro-4-fluoropyridin-2-yl)carbamate [ka] Synthesis of tert-butyl (6-chloro-4-fluoropyridin-2-yl)carbamate: [ka]

[0292] Step A: A suspension of 2,6-dichloro-4-nitropyridine (15.0 g, 77.73 mmol), tert-butyl carbamate (5.46 g, 46.63 mmol), tris((1E,4E)-1,5-diphenylpenta-1,4-dien-3-one)dipalladium (3.56 g, 3.89 mmol), Xantphos (4.5 g, 7.77 mmol), and cesium carbonate (37.99 g, 116.59 mmol) in degassed dioxane was stirred at 80° C. overnight under argon. The mixture was cooled to room temperature and then diluted with EtOAc and water. The organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by FC to give tert-butyl N-(6-chloro-4-nitropyridin-2-yl)carbamate (10.0 g, 36.54 mmol, 47% yield).

[0293] Step B: To a stirred solution of tert-butyl N-(6-chloro-4-nitropyridin-2-yl)carbamate (10.0 g, 36.54 mmol) in anhydrous THF (200 mL) cooled to 10 °C, tetrabutylammonium fluoride (76.73 ml, 1 M solution, 76.73 mmol, 2.1 equiv.) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was diluted with EtOAc and water, and the organic layer was separated, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by FC to give tert-butyl N-(6-chloro-4-fluoropyridin-2-yl)carbamate (4.7 g, 19.05 mmol, 52.1% yield). LC / MS [M+H] 191.2. Intermediate Example 5 Di-tert-butyl (4-chloro-6-fluoropyridin-2-yl)iminodicarbonate [ka] Synthesis of di-tert-butyl (4-chloro-6-fluoropyridin-2-yl)iminodicarbonate: [ka]

[0294] To a solution of 4-chloro-6-fluoropyridin-2-amine (5.0 g, 34.1 mmol) in THF was added a 1 M solution of lithium(1+) bis(trimethylsilyl)azanide (6.28 g, 37.5 mmol, 37.5 mL, 1.1 equiv.) in THF at −78° C., and the mixture was stirred for 1 hour. Next, a solution of di-tert-butyl dicarbonate (17.1 g, 78.4 mmol) in THF was added dropwise at −78° C. The reaction was stirred at −78° C. for 1 hour and then at room temperature overnight. After this time, NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was dried, and the solvent was evaporated. The crude product was purified by column chromatography to give tert-butyl N-[(tert-butoxy)carbonyl]-N-(4-chloro-6-fluoropyridin-2-yl)carbamate (7.71 g, 22.2 mmol, 65% yield). Intermediate Example 6 6-((2-chloropyridin-4-yl)oxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine [ka] Synthesis of 6-((2-chloropyridin-4-yl)oxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine [ka]

[0295] 1,3-Dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol (10 g) and 2-chloro-4-fluoropyridine (8.06 g) were dissolved in DMF (50 mL), and then powdered K2CO3 (6.47 g) was added. The mixture was heated to 75°C overnight with stirring. The reaction was cooled, and then approximately 70 mL of water was slowly added to the reaction mixture with stirring. The mixture was then allowed to stand for 2 hours. The solid was collected by filtration and dried on the filter by suction. 14.25 g of product was recovered as a brown solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d, 27℃): δ = 8.40 (d, J = 2.2 Hz,1H), 8.33 (d, J = 5.7 Hz, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 2.2 Hz,1H), 7.08 (dd, J = 5.7, 2.2 Hz, 1H), 3.97 (s, 3H), 2.53 ppm (s, 3H).LCMS Method 1A: Retention time = 1.75 min, m / z(M+H+) = 274.93 actual mass, accurate mass 274.06. The following intermediate examples in Table 3 were made following the procedure in Intermediate Example 6 using the appropriate starting materials. [Table 3-1] [Table 3-2]

[0296] Intermediate Example 7 6-((2-chloropyridin-4-yl)oxy)-1-methyl-1H-indazole [ka]

[0297] Synthesis of 6-((2-chloropyridin-4-yl)oxy)-1-methyl-1H-indazole: [ka]

[0298] 1-Methyl-1H-indazol-6-ol (0.444 g, 3.00 mmol, 1.2 equiv.) was stirred with 60% w / v NaH (1.2 equiv.; alternatively, KCO can be used, 1-1.5 equiv.) in dry DMF (2.5 mL, 1 M) at 0 °C for 30 min, followed by the addition of 2-chloro-4-fluoropyridine (0.330 g, 2.50 mmol, 1.0 equiv., 1 mL in DMF for transfer). The resulting mixture was allowed to warm to room temperature over 30 min and stirred at 80 °C overnight (15-18 h). The reaction was cooled to room temperature. The reaction was quenched with HO (2 mL) and extracted with EtOAc (4x). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification was achieved by automated Combiflash column chromatography on a 12 g column of silica gel with a gradient elution of 0-60% EtOAc / hexanes to give the title compound as a white solid (562.3 mg, 2.16 mmol, 87% yield).

[0299] The following intermediate examples in Table 4 were made following the procedure in Intermediate Example 3 using the appropriate starting materials. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4]

[0300] Intermediate Example 8 tert-Butyl (6-chloro-4-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)pyridin-2-yl)carbamate [ka]

[0301] Synthesis of tert-butyl (6-chloro-4-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)pyridin-2-yl)carbamate: [ka]

[0302] 1,3-Dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ol (0.3 g) was stirred with 60% w / v NaH (1.2 equivalents) in dry DMF (2.5 ml) at 0° C. for 30 minutes, followed by the addition of tert-butyl (6-chloro-4-fluoropyridin-2-yl)carbamate (0.454 g). The resulting mixture was warmed to room temperature over 30 minutes and stirred at 90° C. for 4 hours. The reaction was cooled to room temperature. The reaction was quenched with HO (2 mL) and extracted with EtOAc (4×). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification was carried out by automated Combiflash® column chromatography on silica gel with a gradient elution of EtOAc / hexanes. The title compound was obtained as a white foam. LCMS method 2A: retention time = 1.43 min, m / z (M+H+) = 390.16 actual mass, accurate mass 389.12.

[0303] The following intermediate examples in Table 5 were made following the procedure in Intermediate Example 8 using the appropriate starting materials. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4]

[0304] Intermediate Example 9 6-(3-Bromophenoxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine [ka]

[0305] Synthesis of 6-(3-bromophenoxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine: [ka]

[0306] In a glass vial equipped with a stir bar, 1,3-dibromobenzene (1 mmol) in NMP (10 mL) was treated with 1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol (0.95 mmol), followed by CuO (15 mol%) and CsCO (1 mmol). The reaction mixture in the sealed vial was heated at 210 °C for 5 min and then to 195 °C for an additional 30 min. After completion of the reaction, the mixture was cooled to room temperature, filtered through a Celite plug, and washed with EtOAc. The organic layer was diluted with an additional 100 mL of EtOAc and extracted twice with 200 mL of water. The combined organic layers were washed with brine. The crude material was purified by silica chromatography with an EtOAc / hexane gradient (up to 60% EtOAc) to give 6-(3-bromophenoxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine as a colorless semi-solid. LCMS Method 1A: Retention time = 2.00 min, m / z (M+H+, Br isotope effect) = 319.90 observed mass, exact mass 317.02. The following intermediate examples in Table 6 were made following the procedure in Intermediate Example 9 using the appropriate starting materials. [Table 6]

[0307] Intermediate Example 10 2-Ethyl-4-(4-fluoropyridin-2-yl)benzamide [ka]

[0308] Synthesis of 2-ethyl-4-(4-fluoropyridin-2-yl)benzamide: [ka]

[0309] To a round-bottom flask were added 2-chloro-4-fluoropyridine (0.48 g, 1 equiv.), 2-ethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1 equiv.), and tetrakis(triphenylphosphine)palladium(0) (0.05 equiv.), followed by 1,4-dioxane (10 mL) and Na2CO3 (2N, 1 equiv.). The reaction mixture was degassed by bubbling N2 through it for 15 minutes, then heated to 90 °C and stirred overnight. The mixture was then cooled to room temperature, and the solvent was removed under reduced pressure. The crude reaction mixture was redissolved in DCM / MeOH (4:1) (500 mL) and washed with water (2 × 150 mL). The organic layer was dried over Na2SO4, filtered, and 50 g of silica was added to the crude product, followed by concentration under reduced pressure. The silica loaded crude was purified by silica gel column chromatography using a gradient of 1% to 10% DCM / MeOH over 30 minutes to elute the product, which was obtained after drying as a solid. LCMS Method 2A: Retention time = 0.802 minutes, m / z (M+H+) = 245.15 observed mass, exact mass 244.10. The following intermediate examples in Table 7 were made following the procedure in Intermediate Example 10 using the appropriate starting materials. [Table 7-1] [Table 7-2] [Table 7-3]

[0310] Intermediate Example 11 3'-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1'-biphenyl]-4-carboxylic acid [ka]

[0311] Synthesis of 3'-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1'-biphenyl]-4-carboxylic acid [ka]

[0312] Step 1: (Suzuki coupling) In a vial, 6-(3-bromophenoxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (1 mmol) was treated with methyl 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (1 mmol), Pd(PPh) (5 mol%), and 2 M aqueous KCO (0.25 mL) in 1,4-dioxane (1 mL). The resulting mixture was heated to 95 °C and cooled to room temperature. The crude material was filtered through a plug of Celite and purified by silica gel column chromatography with an EtOAc / hexane gradient (up to 100% EtOAc) to give methyl 3′-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1′-biphenyl]-4-carboxylate as a colorless thick oil.

[0313] Step 2: (Saponified) Methyl 3'-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1'-biphenyl]-4-carboxylate (1 mmol) was dissolved in THF:methanol (3:1) (2 mL) and treated with 2 M aqueous LiOH (0.5 mL). The reaction mixture was stirred at room temperature overnight. The mixture was treated with an aqueous solution of 2 N HCl to adjust the pH to approximately 1. The acidified mixture was diluted with EtOAc (10 mL) and extracted twice with water (10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2CO3, and concentrated in vacuo to give 3'-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1'-biphenyl]-4-carboxylic acid as a white solid. The following examples in Table 8 were made following the procedures in Example 9 using the appropriate starting materials. [Table 8]

[0314] Intermediate Example 12 3-((2-chloropyridin-4-yl)oxy)-6,6-difluoro-5,6,7,8-tetrahydroquinoline [ka]

[0315] Synthesis of 3-((2-chloropyridin-4-yl)oxy)-6,6-difluoro-5,6,7,8-tetrahydroquinoline: [ka]

[0316] To a mixture of prop-2-yn-1-amine (4.11 g, 74.56 mmol, 4.78 mL) in isopropanol (i-PrOH, 40 mL) was added a solution of copper chloride (CuCl, 501.22 mg, 3.73 mmol) and 4,4-difluorocyclohexan-1-one (5 g, 37.28 mmol) in isopropanol (i-PrOH, 20 mL) at 85 °C. The mixture was stirred at 85 °C for 12 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 10) to give 6,6-difluoro-5,6,7,8-tetrahydroquinoline (2.5 g, 39.64% yield) as a red oil. 1 H NMR: 400 MHz, CDCl3δ = 2.34 (tt, J=13.55, 6.96Hz, 2H), 3.19 (t, J=7.00 Hz, 2H), 3.28 (t, J=14.45 Hz, 2H), 7.12(dd, J=7.69, 4.82 Hz, 1H), 7.40 (d, J=7.63 Hz, 1H), 8.45 (d, J=4.50Hz, 1H).

[0317] To a mixture of 6,6-difluoro-5,6,7,8-tetrahydroquinoline (2.5 g, 14.78 mmol) in tetrahydrofuran (THF, 25 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (4.13 g, 16.26 mmol), [Ir(COD)(OMe)] (293.87 mg, 443.34 μmol), and 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (237.98 mg, 886.68 μmol). The mixture was stirred at 70° C. under a nitrogen atmosphere for 12 hours. The reaction was quenched with water (200 mL), and the aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was triturated with methyl tert-butyl ether (10 mL) for 1 hour. After filtration, the filter cake was dried to give 6,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydroquinoline (2 g, 45.86% yield) as a black solid. 1 H NMR: 400 MHz,MeOD, δ = 1.34 (s, 12H), 2.37 (td, J=13.35, 6.69 Hz,2H), 3.15 (t, J=7.00 Hz, 2H), 3.33-3.39 (m, 2H), 7.91 (s, 1H), 8.58 (s,1H).

[0318] To a mixture of 6,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydroquinoline (2 g, 6.78 mmol) in tetrahydrofuran (20 mL) and water (5 mL) was added NaBO 3·4H2O (3.13 g, 20.33 mmol) was added. The mixture was stirred at 20 °C for 2 hours. The reaction mixture was diluted with water (100 mL) and acidified with 1 M hydrochloric acid to pH = 7. The aqueous layer was extracted with ethyl acetate (2 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was triturated with methyl tert-butyl ether (5 mL) for 1 hour, filtered, and the filter cake was dried to give 6,6-difluoro-5,6,7,8-tetrahydroquinolin-3-ol (921 mg, 73.03% yield, 99.5% purity) as a white solid. Without acidifying the reaction mixture, 6-fluoro-7,8-dihydroquinolin-3-ol (189 mg, 17.4% yield, 93% purity) was obtained as a yellow solid.

[0319] In the case of 6,6-difluoro-5,6,7,8-tetrahydroquinolin-3-ol, 1 H NMR: 400 MHz, DMSO-d6,δ = 2.28 (tt, J=14.01, 7.00 Hz, 2H), 2.90 (t, J=7.00Hz, 2H), 3.27 (br t, J=15.01 Hz, 2H), 6.91 (d, J=2.63 Hz, 1H),7.96 (d, J=2.75 Hz, 1H), 9.75 (s, 1H).LCMS(ESI+):m / z186.1(M+H) + Retention time: 1.305 min. LC / MS (gradient: 0% B for 0.40 min, 0–60% B from 0.4–3.0 min, 60–100% B from 3.0–4.0 min, then 100–0% B over 0.01 min. Flow rate: 1.0 mL / min). Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 2.1 × 50 mm, 5 μm column. Detection was by diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 100–1000.

[0320] In the case of 6-fluoro-7,8-dihydroquinolin-3-ol, 1 H NMR: 400 MHz, DMSO-d6,δ = 2.65 (td, J=8.54, 3.44 Hz, 2H), 2.97 (td, J=8.63,2.50 Hz, 2H), 6.14 (d, J=13.01 Hz, 1H), 6.84 (d, J=2.63 Hz, 1H),7.76 (d, J=2.63 Hz, 1H), 9.62 (s, 1H).LCMS(ESI+):m / z166.2(M+H) + Retention time: 1.328 min. LC / MS (gradient: 0% B for 0.40 min, 0–60% B from 0.4–3.0 min, 60–100% B from 3.0–4.0 min, then 100–0% B over 0.01 min. Flow rate: 1.0 mL / min). Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 2.1 × 50 mm, 5 μm column. Detection was by diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 100–1000.

[0321] To a mixture of 6,6-difluoro-5,6,7,8-tetrahydroquinolin-3-ol (400 mg, 2.16 mmol) in dimethylformamide (4 mL) was added 2-chloro-4-fluoropyridine (568.28 mg, 4.32 mmol) and cesium carbonate (CsCO, 914.98 mg, 2.81 mmol). The mixture was stirred at 20 °C for 4 hours. The reaction was quenched with water (80 mL), the aqueous layer was extracted with ethyl acetate (2 × 30 mL), and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (petroleum ether / ethyl acetate=1 / 1) to give 3-((2-chloropyridin-4-yl)oxy)-6,6-difluoro-5,6,7,8-tetrahydroquinoline (303 mg, 47.13% yield, 99.7% purity) as a white solid.1 H NMR: 400 MHz,MeOD, δ = 2.39 (tt, J=13.57, 6.94 Hz, 2H), 3.17 (t, J=7.00Hz, 2H), 3.38 (t, J=14.45 Hz, 2H), 6.97 (dd, J=5.75, 2.25 Hz,1H), 7.04 (d, J=2.25 Hz, 1H), 7.50 (d, J=2.38 Hz, 1H), 8.26 (d, J=5.88Hz, 1H), 8.29 (d, J=2.63 Hz, 1H).LCMS(ESI+):m / z297.1(M+H) + , retention time: 1.865 min. LC / MS (gradient: 5% B for 0.40 min, 5–95% B from 0.40–3.00 min, hold at 95% B for 1.00 min, then change from 95–5% B over 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). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, with positive electrospray ionization. MS range was 100–1000. Intermediate Example 13 3-((2-chloropyridin-4-yl)oxy)-6,8-difluoroquinoline [ka]

[0322] Synthesis of 3-((2-chloropyridin-4-yl)oxy)-6,8-difluoroquinoline: [ka]

[0323] To a mixture of 5,7-difluoro-1H-indole (2.2 g, 14.37 mmol) and benzyl(triethyl)ammonium chloride (163.62 mg, 718.35 μmol) in toluene (2 mL) was added bromoform (3.63 g, 14.37 mmol) and the temperature was warmed to 40 °C. A solution of sodium hydroxide (4.31 g, 107.75 mmol) in water (12 mL) was added dropwise over 0.25 h, resulting in the formation of a dark mass. The reaction mixture was stirred at 40 °C for 16 h as a biphasic mixture. An additional vial was prepared as above, and both mixtures were combined for workup. The reaction was quenched with water (300 mL), the aqueous phase was extracted with ethyl acetate (3 × 100 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=5 / 1) to give 3-bromo-6,8-difluoroquinoline (900 mg, 12.83% yield) as a white solid. 1 H NMR: 400 MHz, CDCl3, δ = 7.20-7.24 (m, 1H), 7.27-7.30(m, 1H), 8.32 (s, 1H), 8.92 (d, J =1.88 Hz, 1H).

[0324] To a mixture of 3-bromo-6,8-difluoroquinoline (900 mg, 3.69 mmol) in 1,4-dioxane (10 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (BPD, 1.40 g, 5.53 mmol), potassium acetate (KOAc, 1.09 g, 11.06 mmol), and Pd(dppf)Cl (301.18 mg, 368.80 μmol). The mixture was stirred at 100° C. under a nitrogen atmosphere for 12 hours. The reaction was quenched with water (100 mL), the aqueous layer extracted with ethyl acetate (2 × 30 mL), the organic layer dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give 6,8-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2 g, crude) as a black oil. The crude product was used directly in the next step without purification. LC / MS description: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 2.0 mL / min, using an elution gradient from 10% to 100% (solvent B) over 0.5 min, held at 100% for 0.4 min; Column: Halo C18, 3.0 × 30 mm, 5 μm; Wavelength: UV 220 nm and 254 nm, Column temperature: 40 °C; MS ionization: ESI.

[0325] To a mixture of 6,8-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (2.150 g, 7.39 mmol) in tetrahydrofuran (16 mL) and water (4 mL) was added NaBO 3·4H2O (4.55 g, 29.54 mmol) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (100 mL), the aqueous layer was extracted with ethyl acetate (2 × 30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give 6,8-difluoroquinolin-3-ol (700 mg, 52.06% yield) as a white solid. 1 H NMR: 400 MHz,DMSO-d6, δ = 7.36-7.45 (m, 1H), 7.46-7.52 (m, 1H), 7.55 (dd, J=2.25, 1.63 Hz, 1H), 8.57 (d, J =2.63 Hz, 1H), 10.75 (br s, 1H).LCMS(ESI+):m / z182.1(M+H) + , retention time: 2.554 min. LC / MS (gradient: 0% B for 0.40 min, 0–30% B from 0.4–3.0 min, 30–100% B from 3.0–4.0 min, then 100–0% B over 0.01 min. Flow rate: 1.0 mL / min). Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Luna C18 50 × 2.0 mm column (5 μm particles). Detection was by diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 100–1000.

[0326] To a mixture of 6,8-difluoroquinolin-3-ol (200 mg, 1.10 mmol) in dimethylformamide (2 mL) was added 2-chloro-4-fluoropyridine (290.46 mg, 2.21 mmol) and cesium carbonate (467.67 mg, 1.44 mmol). The mixture was stirred at 110° C. for 2 hours. The reaction was quenched with water (30 mL), and the aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue that was purified by preparative TLC (petroleum ether / ethyl acetate=2 / 1) to give 3-((2-chloropyridin-4-yl)oxy)-6,8-difluoroquinoline (243 mg, 74.75% yield) as a white solid. 1 H NMR: 400 MHz,DMSO-d6, δ = 7.14-7.26 (m, 1H), 7.35 (d, J=1.38 Hz,1H), 7.67 (br d, J=9.13 Hz, 1H), 7.70-7.81 (m, 1H), 8.29 (br s, 1H),8.39 (d, J=5.63 Hz, 1H), 8.91 (d, J=1.88 Hz, 1H).LCMS(ESI+):m / z293.1(M+H) + , retention time: 2.096 min. LC / MS (gradient: 5% B for 0.40 min, 5–95% B from 0.40–3.00 min, hold at 95% B for 1.00 min, then change from 95–5% B over 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). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, with positive electrospray ionization. The MS range was 100–1000. Intermediate Example 14 3-Methyl-1-(trifluoromethyl)-1H-indazol-5-ol [ka]

[0327] Synthesis of 3-methyl-1-(trifluoromethyl)-1H-indazol-5-ol: [ka]

[0328] A solution of 5-bromo-3-methyl-1H-indazole (50 mg, 236.90 μmol), 1,1,3,3-tetramethylguanidine (109.14 mg, 947.61 μmol, 119.15 μL), and CsCO (192.97 mg, 592.25 μmol) in trifluoro(iodo)methane (556.94 mg, 710.70 μmol) (25% dimethylformamide solution) was stirred under nitrogen at 80° C. for 12 hours. 29 additional vials were prepared as described above. The reaction mixtures were combined and purified. The reaction was quenched by adding water (30 mL) and then extracted with ethyl acetate (3×8 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=1 / 0 to 6 / 1) to give 5-bromo-3-methyl-1-(trifluoromethyl)-1H-indazole (270 mg, yield 12.57%) as a yellow solid. 1 H NMR: 400 MHz, CD3OD, δ = 1.79(s, 3H), 7.91 (dd, J=8.25, 1.63 Hz, 1H), 7.98 (s, 1H), 8.14 (d, J=8.38Hz, 1H)

[0329] A solution of 5-bromo-3-methyl-1-(trifluoromethyl)-1H-indazole (140 mg, 501.69 μmol), BPD (254.80 mg, 1.00 mmol), potassium acetate (98.47 mg, 1.00 mmol), and Pd(dppf)Cl (36.71 mg, 50.17 μmol) in dioxane (1.4 mL) was degassed and then heated to 80° C. under nitrogen for 12 hours. Two additional vials were prepared as above (totaling 270 mg of 5-bromo-3-methyl-1-(trifluoromethyl)-1H-indazole). The reaction mixture was concentrated to give the crude product (151.92 mg), which was used in the next step without further purification. The crude product (163 mg) was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indazole (71 mg, yield 41.31%) as a yellow solid. 1 H NMR: 400 MHz, CDCl3, δ = 1.38(s, 12H), 1.79 (s, 3H), 8.04 (s, 1H), 8.08 (d, J=7.75 Hz, 1H), 8.14-8.21(m, 1H).LCMS(ESI+):m / z327.3(M+H) + , retention time: 2.693 minutes, m / z245.1 (M-83+H) + , retention time: 1.666 min. LC / MS (gradient: 5% B for 0.40 min, 5–95% B from 0.40–3.00 min, hold at 95% B for 1.00 min, then 95–5% B over 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). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, with positive electrospray ionization. MS range was 100–1000.

[0330] To a stirred mixture of 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indazole (128.55 mg, 394.18 μmol, 1 equiv.) in tetrahydrofuran (2 mL) and water (0.4 mL) was added NaBO 3· 4HO (181.87 mg, 1.18 mmol, 3 equiv.) was added. The mixture was stirred at 20 °C for 2 h. The reactions were combined to give a total of 151.92 mg of crude 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indazole. Water (2 mL) was added, followed by extraction with ethyl acetate (3 × 5 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to give 3-methyl-1-(trifluoromethyl)-1H-indazol-5-ol (70 mg, 60.61% yield) as a white solid. 1 H NMR: 400 MHz, CD3OD, δ = 1.71(s, 3H), 6.95-7.14 (m, 2H), 8.00 (d, J=8.26 Hz, 1H).LCMS(ESI+):m / z217.2(M+H) + , retention time: 1.705 min. LC / MS (gradient: 5% B for 0.40 min, 5–95% B from 0.40–3.00 min, held at 95% B for 1.00 min, then 95–5% B for 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). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, with positive electrospray ionization. MS range was 100–1000. Intermediate Example 15 3-Methyl-1-(trifluoromethyl)-1H-indazol-6-ol [ka]

[0331] Synthesis of 3-methyl-1-(trifluoromethyl)-1H-indazol-6-ol: [ka]

[0332] A mixture of 6-bromo-3-methyl-1H-indazole (3.1 g, 14.69 mmol) and potassium tert-butoxide (3.30 g, 29.38 mmol) in tetrahydrofuran (124 mL) was stirred under nitrogen at 20° C. for 30 minutes. Methanedithione (4.47 g, 58.75 mmol) was added at 20° C., and the reaction was stirred at 20° C. for 2 hours. Iodomethane (8.34 g, 58.75 mmol) was added at 20° C., and the mixture was stirred at 20° C. for 1 hour. An additional vial was prepared as above (total of 4.3 g of 6-bromo-3-methyl-1H-indazole). The reaction was quenched by adding water (400 mL) and extracted with ethyl acetate (3×50 mL). The combined organic phase was concentrated, filtered, and the filter cake was dried to give methyl 6-bromo-3-methyl-1H-indazole-1-carbodithioate (3.9 g, 70.07% yield) as a yellow solid. 1 H NMR: 400 MHz, DMSO-d6, δ= 2.57 (br s, 3H), 2.63 (br s, 3H), 7.69 (br d, J=7.63 Hz, 1H), 7.90 (brd, J=8.00 Hz, 1H), 9.26 (br s, 1H).LCMS(ESI+): m / z301.0 and 303.0(M+H) +, Retention time: 0.697 min. Description: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 2.0 ml / min, using an elution gradient of 10% to 100% (solvent B) over 0.5 min, held at 100% for 0.4 min; Column: Halo C18, 3.0 x 30 mm, 5 µm; Wavelength: UV 220 nm and 254 nm. Column temperature: 40 °C; MS ionization: ESI.

[0333] To a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (1.14 g, 3.98 mmol) in dichloromethane (16 mL) was added pyridine-HF complex (2.63 g, 26.56 mmol, 2.39 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes. To the solution was added dropwise a solution of methyl 6-bromo-3-methyl-1H-indazole-1-carbodithioate (400 mg, 1.33 mmol) in dichloromethane (8 mL) at 0° C. The reaction was stirred at 0° C. for 2 hours. Eight additional vials were prepared as above (total of 3.4 g of methyl 6-bromo-3-methyl-1H-indazole-1-carbodithioate). The mixture was combined and concentrated. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=8 / 1) to give 6-bromo-3-methyl-1-(trifluoromethyl)-1H-indazole (500 mg, 15.22% yield) as a white solid. 1 H NMR: 400 MHz, CDCl3, δ = 2.59(s, 3H), 7.46 (dd, J=8.51, 1.50 Hz, 1H), 7.55-7.59 (m, 1H), 7.83 (s, 1H).LCMS(ESI+): m / z279.1 and 281.1(M+H) +, Retention time: 0.608 min. Description: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 2.0 ml / min, using an elution gradient of 10% to 100% (solvent B) over 0.5 min, held at 100% for 0.4 min; Column: Halo C18, 3.0 x 30 mm, 5 μm; Wavelength: UV 220 nm and 254 nm; Column temperature: 40 °C; MS ionization: ESI.

[0334] A mixture of 6-bromo-3-methyl-1-(trifluoromethyl)-1H-indazole (420 mg, 1.51 mmol), BPD (764.39 mg, 3.01 mmol), potassium acetate (295.42 mg, 3.01 mmol), and Pd(dppf)Cl (110.13 mg, 150.51 μmol) in dioxane (4.2 mL) was degassed and then heated to 80° C. under N for 12 h. An additional vial was prepared as above (total of 500 mg of 6-bromo-3-methyl-1-(trifluoromethyl)-1H-indazole). The reaction mixture was concentrated. 338 mg of crude product was used in the next step without further purification. 245 mg of the crude product was purified by preparative TLC (petroleum ether / ethyl acetate=10 / 1) to give 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indazole (201 mg, 79.53% yield) as a white solid. 1 H NMR: 400 MHz, CDCl 3, δ = 1.39(s, 12H), 2.62 (s, 3H), 7.67-7.72 (m, 1H), 7.73-7.78 (m, 1H), 8.10 (s, 1H).LCMS(ESI+):m / z327.2(M+H) + , retention time: 2.850 minutes, m / z245.2 (M-83+H) +Retention time: 1.736 min. LCMS: (Gradient: 5% B for 0.40 min, 5-95% B from 0.40 to 3.00 min, hold at 95% B for 1.00 min, then 95-5% B over 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 x 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, with positive electrospray ionization. MS range was 100-1000.

[0335] To a stirred mixture of 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indazole (245 mg, 751.25 μmol) in tetrahydrofuran (5 mL) and water (1 mL) was added NaBO 3· 4HO (346.76 mg, 2.25 mmol) was added. The mixture was stirred at 20 °C for 2 hours. The reaction was filtered and concentrated in vacuo. The crude products were combined (338.49 mg total of 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-indazole) and purified by preparative TLC (petroleum ether / ethyl acetate = 4 / 1) to give 3-methyl-1-(trifluoromethyl)-1H-indazol-6-ol (177 mg, 75.82% yield) as a white solid. 1 H NMR: 400 MHz, DMSO-d 6, δ = 2.47 (s, 3H), 6.89 (dd, J=8.69, 1.94 Hz, 1H), 6.94(d, J=1.38 Hz, 1H), 7.68 (d, J=8.63 Hz, 1H), 10.30 (s, 1H).LCMS(ESI+):m / z217.2(M+H) +Retention time: 1.824 min. LCMS: (Gradient: 5% B for 0.40 min, 5-95% B from 0.40 to 3.00 min, hold at 95% B for 1.00 min, then 95-5% B for 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 x 2.1 mm column (5 μm particles). Detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection, with positive electrospray ionization. MS range was 100-1000. Intermediate Example 16 3-Methyl-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol [ka]

[0336] Synthesis of 3-methyl-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol: [ka]

[0337] To a solution of 5-bromo-3-fluoropicolinonitrile (10 g, 49.75 mmol) in tetrahydrofuran (250 mL) under a nitrogen atmosphere was added methylmagnesium chloride (13.27 mL, 3 M, 39.80 mmol) dropwise over 15 minutes at 0°C. The mixture was stirred at 0°C for 15 minutes. The reaction mixture was added to a stirred solution of HCl (500 mL, 3 M, 1.5 mol) at 0°C. The mixture was stirred at 20°C for 15 hours. The solution was then reverse quenched by adding saturated aqueous sodium carbonate (500 mL) at 0°C. The aqueous layer was extracted with ethyl acetate (2 x 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated to give the crude product, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate=6 / 1) to give 1-(5-bromo-3-fluoropyridin-2-yl)ethan-1-one (6 g, yield 55.31%, purity 99%) as a yellow solid. 1 H NMR: 400 MHz,MeOD, δ = 2.64 (d, J=0.88 Hz, 3H), 8.06 (dd, J=10.26,1.75 Hz, 1H), 8.62 (s, 1H).

[0338] To a solution of 1-(5-bromo-3-fluoropyridin-2-yl)ethan-1-one (4 g, 18.35 mmol) in ethylene glycol (40 mL) was added hydrazine hydrate (NH2NH2·HO, 40.00 mL, 808.12 mmol, 98% purity) at 20 °C. The reaction mixture was stirred at 100 °C for 12 h. The reaction was quenched with saturated aqueous ammonium chloride (300 mL), and the aqueous layer was extracted with ethyl acetate (2 × 150 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to give 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine (2 g, 50.38% yield, 98% purity) as a yellow solid. 1H NMR: 400 MHz, MeOD, δ = 2.59 (s, 3H), 8.16 (d, J=1.75 Hz, 1H), 8.51(d, J=1.88 Hz, 1H).

[0339] To a solution of 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine (2.8 g, 13.20 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (792.20 mg, 19.81 mmol, 60% purity) at 0° C. The mixture was stirred at 20° C. for 1 hour. Methanedithione (2.01 g, 26.41 mmol) was added dropwise at 0° C., and the resulting mixture was stirred at 20° C. for 16 hours. The mixture was again cooled to 0° C., and iodomethane (2.25 g, 15.85 mmol) was added dropwise to the solution. The resulting mixture was stirred at 20° C. for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride (150 mL), the aqueous layer was extracted with ethyl acetate (3 × 50 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue that was triturated with ethyl acetate (10 mL) and acetonitrile (2 mL) for 1 hour. After filtration, the filter cake was dried to give methyl 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine-1-carbodithioate (2 g, 48.11% yield, 96% purity) as a yellow solid. 1 H NMR: 400 MHz, DMSO-d 6, δ = 2.60(s, 3H), 2.66 (s, 3H), 8.87 (d, J=2.00 Hz, 1H), 9.44 (d, J=2.00Hz, 1H).

[0340] To a solution of 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (5.45 g, 19.06 mmol) in dichloromethane (80 mL) was added pyridine hydrogen fluoride (17.17 mL, 190.59 mmol) at −78° C. The mixture was stirred at −78° C. for 10 minutes. To the solution was added dropwise a solution of methyl 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine-1-carbodithioate (2 g, 6.35 mmol) in dichloromethane (40 mL) at −78° C. After the addition, the resulting mixture was stirred at −15° C. for 20 minutes. The reaction was quenched with saturated aqueous sodium bicarbonate (200 mL), and the aqueous layer was extracted with dichloromethane (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO, petroleum ether / ethyl acetate=6 / 1) to give 6-bromo-3-methyl-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (600 mg, yield 30.35%, purity 90%) as a white solid. 1 H NMR: 400 MHz, MeOD, δ = 2.63 (s, 3H), 8.40 (s, 1H), 8.78 (d, J=1.75Hz, 1H).

[0341] To a mixture of 6-bromo-3-methyl-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (600 mg, 1.93 mmol) in 1,4-dioxane (6 mL) was added 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (BPD 734.49 mg, 2.89 mmol), potassium acetate (KOAc 567.72 mg, 5.78 mmol), and Pd(dppf)Cl CHCl (157.47 mg, 192.83 μmol). The mixture was stirred at 100 °C under a nitrogen atmosphere for 12 h. The reaction was quenched with water (50 mL), the aqueous layer was extracted with ethyl acetate (2 × 20 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (1.1 g, crude) as a black oil, which was used directly in the next step without purification. LC / MS: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 2.0 mL / min, using an elution gradient of 10% to 100% (solvent B) over 0.5 min, held at 100% for 0.4 min; Column: Halo C18, 3.0 x 30 mm, 5 um; Wavelength: UV 220 nm and 254 nm, Column temperature: 40 °C; MS ionization: ESI.

[0342] To a mixture of 3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (1.1 g, 1.68 mmol, 50% purity) in tetrahydrofuran (8.8 mL) and water (2.2 mL) was added NaBO 3·4H2O (1.03 g, 6.73 mmol) was added. The mixture was stirred at 25 °C for 2 hours. The reaction was quenched with water (50 mL), and the aqueous layer was extracted with ethyl acetate (2 × 20 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give 3-methyl-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol (215 mg, 58.71% yield, 99.7% purity) as a white solid. 1 H NMR: 400 MHz, MeOD , δ = 2.56(s, 3H), 7.27-7.36 (m, 1H), 8.28 (d, J=2.25 Hz, 1H).LCMS(ESI+):m / z218.1(M+H) + , retention time: 2.086 min. LC / MS (gradient: 0% B for 0.40 min, 0–60% B from 0.4–3.0 min, 60–100% B from 3.0–4.0 min, then 100–0% B over 0.01 min. Flow rate: 1.0 mL / min). Mobile phase A was 0.04% trifluoroacetic acid in water, and mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 2.1 × 50 mm, 5 μm column. Detection was by diode array (DAD) and evaporative light scattering (ELSD). MS mode was positive electrospray ionization. MS range was 100–1000. Intermediate Example 17 3-Fluoro-1-methyl-1H-indazol-6-ol [ka]

[0343] Synthesis of 3-fluoro-1-methyl-1H-indazol-6-ol: [ka]

[0344] To a solution of 6-bromo-1-methyl-1H-indazole (7.3 g, 34.59 mmol, 1 equiv) in ACN (110 mL) was added Selectfluor (15.93 g, 44.96 mmol, 1.3 equiv). The mixture was stirred at 90° C. for 16 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was purified by preparative HPLC (HCl) to give 6-bromo-3-fluoro-1-methyl-1H-indazole (1.9 g, 22.78% yield, 95% purity) as a yellow solid. LCMS (ESI+): m / z 227.97, (M+H) + , Retention time: 0.499 min. Description: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 2.0 ml / min, using an elution gradient of 10% to 100% (solvent B) over 0.5 min, held at 100% for 0.4 min; Column: Halo C18, 3.0 x 30 mm, 5 um; Wavelength: UV 220 nm and 254 nm, Column temperature: 40 °C; MS ionization: ESI. 1 H NMR: 400 MHz,MeOD, δ = 3.88-3.90 (m, 3H), 7.27 (dd, J=8.69,1.44 Hz, 1H), 7.54 (d, J=8.76 Hz, 1H), 7.75 (t, J=1.38 Hz, 1H).

[0345] A solution of 6-bromo-3-fluoro-1-methyl-1H-indazole (1.9 g, 7.88 mmol, 1 equiv.) in 1,4-dioxane (20 mL) was treated with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.00 g, 11.82 mmol, 1.5 equiv.), potassium acetate (2.32 g, 23.64 mmol, 3 equiv.) and cyclopentyl(diphenyl)Pd(dppf)2Cl under N2. 2·CHCl (643.54 mg, 788.04 μmol, 0.1 equiv) was added. The mixture was stirred at 100° C. for 12 h. The reaction mixture was quenched with water (2 mL) at 20° C. and then extracted with ethyl acetate (3×1 mL). The combined organic layers were filtered and concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=2 / 1) to give 3-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.4 g, 45.04% yield, 70% purity) as a yellow solid. LCMS (ESI+): m / z 276.14, (M+H) + , Retention time: 0.596 min. Description: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 2.0 ml / min, using an elution gradient of 10% to 100% (solvent B) over 0.5 min, held at 100% for 0.4 min; Column: Halo C18, 3.0 x 30 mm, 5 um; Wavelength: UV 220 nm and 254 nm, Column temperature: 40 °C; MS ionization: ESI. 1 H NMR: 400 MHz,MeOD, δ = 1.39 (s, 12H), 3.96 (d, J=0.63Hz, 3H), 7.55 (d, J=8.25 Hz, 1H), 7.65 (d, J=8.13 Hz, 1H), 7.82(s, 1H).

[0346] To a solution of 3-fluoro-1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.7 g, 4.31 mmol, 1 equiv.) in THF (17 mL) and HO (4.3 mL) was added NaBO 3·4H2O (2.65 g, 17.24 mmol, 3.32 mL, 4 equiv) was added. The mixture was stirred at 25 °C for 16 h. The reaction was quenched with 1 M HCl (500 mL), the aqueous layer was extracted with ethyl acetate (3 x 200 mL), the organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure to give a residue. The reaction mixture was purified by preparative HPLC (NH4HCO3) to give 3-fluoro-1-methyl-1H-indazol-6-ol (0.5049 g, 70.51% yield) as a white solid. LCMS (ESI+): m / z 166.05, (M+H) + , retention time: 1.449 min. Description: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 1.0 ml / min, using an elution gradient of 5% to 95% (solvent B) over 3.0 min, held at 95% for 1.0 min; 1 H NMR:ET68711-172-P1A1, 400 MHz, MeOD, δ = 3.76 (d,J=0.88 Hz, 3H), 6.67 (t, J=2.00 Hz, 1H), 6.71 (dd, J=8.76,1.88 Hz, 1H), 7.42 (d, J=8.76 Hz, 1H). Intermediate Example 18 3-Fluoro-1-methyl-1H-indazol-5-ol [ka]

[0347] Synthesis of 3-fluoro-1-methyl-1H-indazol-5-ol: [ka]

[0348] To a solution of 5-bromo-1-methyl-1H-indazole (5 g, 23.69 mmol, 1 equiv.) in ACN (50 mL) was added Selectfluor (16.78 g, 47.38 mmol, 2 equiv.) and HOAc (0.1 mL). The mixture was stirred at 80 °C for 14 h. Water (100 mL) was added to the reaction. The mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine and dried over NaSO. The organic layers were concentrated under high vacuum. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to afford 5-bromo-3-fluoro-1-methyl-1H-indazole (2.5 g, 5.46 mmol, 23.04% yield, 50% purity) as a yellow oil. LCMS(ESI+):m / z229.0 / 231.0[M+H] + Retention time: 0.530 minutes.

[0349] To a solution of 5-bromo-3-fluoro-1-methyl-1H-indazole (1 g, 4.37 mmol, 1 equiv.) and triisopropyl borate (821.09 mg, 4.37 mmol, 1.00 mL, 1 equiv.) in THF (10 mL) was added n-BuLi (2.5 M, 4.37 mL, 2.5 equiv.) under nitrogen at −78° C. The mixture was stirred at −78° C. for 30 minutes. The mixture was then stirred at 25° C. for 2 hours. The reaction was cooled to 0° C., and HO (1.83 g, 16.15 mmol, 1.55 mL, 30% purity, 3.7 equiv.) and NaOH (2 M, 2.18 mL, 1 equiv.) were added. The reaction was stirred at 0° C. for 12 minutes. The mixture was stirred at 25° C. for 12 hours. The pH of the mixture was adjusted to approximately 7 with HCl (1 M). The reaction was then quenched with saturated aqueous NaSO (30 mL), the aqueous layer extracted with ethyl acetate (2 x 40 mL), the organic layer dried over NaSO, filtered, and the filtrate concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl conditions) to give 3-fluoro-1-methyl-1H-indazol-5-ol (216 mg, 1.27 mmol, 11.62% yield, 97.6% purity) as a yellow solid. LCMS (ESI+): m / z 167.2 [M+H]+ Retention time: 1.351 minutes. 1 HNMR: 400 MHz, CDCl3, δ = 3.89 (d, J=1.13 Hz, 3H), 4.69-4.82 (m, 1H),6.98 (d, J=2.25 Hz, 1H), 7.05 (dd, J=9.07, 2.31 Hz, 1H), 7.20 (dd, J=9.01, 2.13Hz, 1H). Intermediate Example 19 3-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol [ka]

[0350] Synthesis of 3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol: [ka]

[0351] 3-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol was prepared following a procedure similar to that of Intermediate Example 18 using the appropriate starting materials. LCMS (ESI+): m / z 168.2 [M+H] + Retention time: 1.074 minutes. 1 HNMR: 400 MHz, CD3OD, δ = 3.91 (s, 3H), 7.47-7.48 (m, 1H), 8.30 (d,J=2.40 Hz, 1H). Intermediate Example 20 3-Fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-ol [ka]

[0352] Synthesis of 3-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-ol: [ka]

[0353] To a solution of 5-bromo-1-methyl-1H-pyrazolo[3,4-b]pyridine (4.3 g, 20.23 mmol) in acetonitrile (50 mL) and acetic acid (5 mL) was added Selectfluor (3.04 g, 60.84 mmol). The mixture was stirred at 80 °C for 12 h. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 0 to 90 / 10) to give 5-bromo-3-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine (2.4 g, 51.45% yield) as a white solid. 1 H NMR: 400 MHz, CDCl3, δ = 3.94(d, J=1.00 Hz, 3H), 8.05-8.09 (m, 1H), 8.50 (d, J=2.13 Hz, 1H).

[0354] A solution of 5-bromo-3-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridine (100 mg, 434.71 μmol) in 1,4-dioxane (1 mL) was treated with potassium acetate (127.99 mg, 1.30 mmol) and Pd(dppf)2Cl under nitrogen. 2·CHCl (35.50 mg, 43.47 μmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (165.58 mg, 652.07 μmol) were added. The mixture was stirred at 100° C. for 12 hours. The reaction mixture was quenched at 0° C. by the addition of sodium hydroxide (3×2 mL), then diluted with water (3×2 mL) and extracted with dichloromethane (3×2 mL). The combined organic layers were washed with sodium bicarbonate (3×2 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO, petroleum ether / ethyl acetate=4:1) to afford 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (54 mg, 44.83% yield) as a white solid. 1 H NMR: 400 MHz,CDCl3, δ = 1.30 (s, 12H), 3.96 (d, J=0.63 Hz, 3H),8.40 (s, 1H), 8.81 (d, J=1.50 Hz, 1H).LCMS(ESI+):m / z278.1(M+H) + , retention time: 0.565 min. (The column used for chromatography was a HALO AQ-C18 2.1 x 30 mm (2.7 µm particles). The detection method was diode array (DAD). The MS mode was positive electrospray ionization. The MS range was 100-1000. Mobile phase A was 0.037% TFA in water, and mobile phase B was 0.018% TFA in HPLC-grade acetonitrile. The gradient was 5-95% B in 2.20 min, 5% B for 0.01 min, 5-95% B (0.01-1.00 min), 95-100% B (1.00-1.80 min), 5% B for 1.81 min, held at 5% B for 0.40 min. The flow rate was 1.0 mL / min.

[0355] To a solution of 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (1.0 g, 3.61 mmol, 1 equiv.) in tetrahydrofuran (10 mL) and water (2.5 mL) was added NaBO 3· 4HO (2.22 g, 14.44 mmol, 2.78 mL, 4 equiv.) was added. The mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water (2 × 30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic layers were washed with brine (30 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / ethyl acetate = 100 / 0 to 85 / 15) to give 3-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-ol (1.6 g, 28.52% yield) as a white solid. 1 H NMR: 400 MHz,DMSO-d6, δ = 3.90 (s, 3H), 7.39 (d, J=1.88 Hz, 1H),8.30 (d, J=2.50 Hz, 1H), 9.97 (s, 1H).LCMS(ESI+):m / z399.1(M+H) + , Retention time: 0.543 min. Description: Mobile phase: 0.04% TFA in water (solvent A) and 0.02% TFA in acetonitrile (solvent B) at a flow rate of 2.0 ml / min, using an elution gradient of 10% to 100% (solvent B) over 0.5 min, held at 100% for 0.4 min; Column: Halo C18, 3.0 x 30 mm, 5 um; Wavelength: UV 220 nm and 254 nm, Column temperature: 40 °C; MS ionization: ESI. Intermediate Example 21 2-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0356] Synthesis of 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide: [ka]

[0357] 4-Bromo-2-ethylbenzoic acid (0.750 g) was dissolved in SOCl2 (2 mL) and stirred overnight at 45°C. o The mixture was heated to 0°C. Toluene (5 mL) was added and the solvent evaporated. 5 mL of DCM (5 mL) was added and the reaction vial was cooled to 0°C in an ice bath. NH4OH was added slowly 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.

[0358] 4-Bromo-2-ethylbenzamide (0.6 g), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (0.73 g), Pd(dppf)Cl 2· CHCl (0.04 equiv.) and KOAc (3 equiv.) were dissolved in dioxane (10 mL) under a rapid N flush. 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 (0-60% hexanes / EtOAc) to give 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide as a white powder (500 mg; 69% yield). Example 1 4-(4-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide [ka]

[0359] Synthesis of 4-(4-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide: [ka]

[0360] 6-((2-chloropyridin-4-yl)oxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (24.1 g), 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (24.2 g), and tetrakis(triphenylphosphine)palladium(0) (4 mol%, 4.06 g) were combined in a 1 L flask, then 44 mL of 2 M Na2CO3 was added, followed by 110 mL of dioxane. The reaction was degassed by bubbling N2 through it and heated to 80 °C for 20 h. The reaction was then cooled to approximately 60 °C, then filtered, and the aqueous suspension was washed with hot dioxane. Approximately 120 g of silica gel was then added to the crude mixture, and the material was rotary evaporated to dryness and loaded onto two 330 g ISCO silica gel cartridges. The material was purified by column chromatography eluting with a hexane / acetone gradient. The material was redissolved in MeOH, and the solid was reloaded onto a second column with MeOH / DCM to remove additional impurities. Pure fractions were then dried, and the solid material was recrystallized from MeOH to yield 15.503 g of an off-white powder. To remove palladium residues, the material was redissolved in 150 mL of EtOAc, 2 mL of diethylenetriamine was added, and the solution was washed with 350 mL of water. This process was repeated three times. The organic phase was washed with water, then brine, and dried over MgSO4. To further reduce Pd levels, the remaining solid was dissolved in 80 mL of warm DMF and diluted to 2 L with EtOAc. To this was added 20 mL of diethylenetriamine, and then the solution was washed with 120 mL of water. This washing with diethylenetriamine was repeated two more times, and then the organic phase was finally washed once with 120 mL of water and 120 mL of brine, dried over MgSO4, filtered, and the solvent evaporated to approximately 50 mL of suspension. To this mixture was added 50 mL of diethyl ether. The solid was collected by filtration and washed with additional ether. The solid was dried on the filter by suction and then dried under vacuum at 65°C overnight. This resulted in 14.96 g of a white solid.Pd レベルは, 3ppm ICP-MS によりmeasurement. 1H NMR (400 MHz, DMSO-d, 27℃): δ = 8.59 (d, J = 5.6 Hz,1H), 8.42 (d, J = 2.3 Hz, 1H), 8.04 (d, J = 2.3 Hz, 1H), 7.99 (d, J = 1.6 Hz,1H), 7.89 (dd, J = 8.0, 1.8 Hz, 1H), 7.78 (s, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.41 (d, J = 7.9 Hz, 2H), 6.96 (dd, J = 5.6, 2.3 Hz, 1H), 3.97 (s, 3H), 2.82(q, J = 7.5 Hz, 2H), 2.52-2.55 (m, 3H), 1.07-1.23 (t, J = 7.5 Hz, 3H). LCMS method 3A: holding time = 1.7 min, m / z(M+H+) = 388.1 measured mass, precision mass 387.17.

[0361] Alternatively, 6-((2-chloropyridin-4-yl)oxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine (48 g), 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (48 g), and tetrakis(triphenylphosphine)palladium(0) (1.5 mol%, 3.0 g) were combined in 1-butanol (480 mL) in a 1 L flask, followed by the addition of sodium tert-butoxide (18.5 g). The reaction was degassed by bubbling N through the mixture and then heated at 95° C. for 20 hours. The reaction was cooled to 50° C., quenched with 0.5 M HCl (480 mL), and stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with 0.5 M HCl (480 mL and 240 mL). The combined aqueous layers were washed with methyl tert-butyl ether (240 mL). The aqueous phase was placed in a 2 L flask and the pH was adjusted to 11-13 using 10 N NaOH (approximately 70 mL). The slurry was stirred for 2 h. The solid was collected by filtration and washed with HO (240 mL) and hexanes (240 mL). The solid was dried under vacuum at 55 °C overnight to give 59.5 g (88% isolated yield) as an off-white solid. Pd level was determined by ICP-MS at 20 ppm. NMR is consistent. LCMS method: retention time = 6.7 min, m / z (M+H+) = 388.1 observed mass, exact mass 387.17. Example 2 2-Ethyl-4-{4-[(1-methyl-1H-indazol-6-yl)oxy]pyridin-2-yl}benzamide [ka]

[0362] Synthesis of 2-ethyl-4-(4-((1-methyl-1H-indazol-6-yl)oxy)pyridin-2-yl)benzamide [ka]

[0363] 6-((2-chloropyridin-4-yl)oxy)-1-methyl-1H-indazole (20 g) was added to dioxane (230 mL) and N was bubbled through the suspension for 30 min. 2-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22.25 g) was added, followed by tetrakis(triphenylphosphine)palladium(0) (0.04 equiv.), and the reaction was heated under N to 85 °C for 8 h in a round-bottom flask equipped with a condenser. Once complete, the reaction was filtered while still hot through a pad of Celite. Upon cooling, 30 mL of brine was added, the mixture was shaken, and the aqueous portion was discarded. The organic layer was concentrated and then purified by chromatography on silica gel (2 x 220 g silica gel ISCO columns) eluting with acetone / hexanes. Pure fractions were concentrated under reduced pressure to approximately 75 mL. The mixture was allowed to stand overnight, after which the solid precipitate was collected by filtration. The solid was redissolved in 50 mL of warm DMF and diluted to 2 L with EtOAc. 20 mL of liquid tris-amine was added, followed by 500 mL of water. The mixture was shaken vigorously, and the aqueous layer was discarded. This was repeated three times, followed by washing with brine (300 mL). The solution was concentrated under vacuum to approximately 75 mL, forming a suspension. After storing at room temperature overnight, the precipitate was collected by filtration to give 20.53 g of a white solid.1H NMR (400 MHz, DMSO-d, 27℃): δ = 8.56 (d, J = 5.6 Hz,1H), 8.11 (d, J = 0.7 Hz, 1H), 7.98 (d, J = 1.7 Hz, 1H), 7.83- 7.91 (m, 2H),7.79 (br s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 7.55-7.60 (m, 1H), 7.36-7.46 (m,2H), 7.01 (dd, J = 8.6, 2.0 Hz, 1H), 6.87 (dd, J = 5.6, 2.3 Hz, 1H), 4.03 (s,3H), 2.82 (q, J = 7.5 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H).LCMS Method 2A: Retention time = 1.83 min, m / z(M+H+) = 373.20 actual mass, exact mass 372.16. Example 3 4-(4-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide [ka]

[0364] Synthesis of 4-(4-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide: [ka]

[0365] To a solution of 1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol (1.58 g, 9.77 mmol, 1.4 equiv.) in anhydrous DMF (10 mL) in a 20 mL microwave vial, NaH (0.416 g, 10.4 mmol, 1.6 equiv., 60% dispersion in mineral oil) was added at room temperature. The mixture was stirred for 20 minutes. 2-Ethyl-4-(4-fluoropyridin-2-yl)benzamide (1.50 g, 6.51 mmol, 1 equiv.) was added to the reaction mixture, and the reaction mixture was heated to 90 °C in a heating block. After 5 hours, the brown solution was cooled to room temperature and then added dropwise to water (approximately 5 mL) with stirring over 15 minutes. The precipitated solid was filtered off, triturated with EtO (20 mL), and filtered. The solid was triturated with dichloromethane (approximately 10 mL), sonicated for approximately 3 minutes, and filtered. The filtrate was filtered through a larger 0.45 μm HPLC filter, concentrated under vacuum to approximately 6 mL, and purified by flash column chromatography (ISCO 40 g, 0-100% ethyl acetate / hexanes); the product was approximately 90-95% pure. The solid was dissolved in approximately 2 mL of DMSO and purified by reverse-phase column chromatography (ISCO 30 g, 10-60% acetonitrile / water) to afford 4-(4-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide as a white solid. Example 4 4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide [ka]

[0366] Synthesis of 4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide. [ka]

[0367] To a solution of 1,3-dimethyl-1H-indazol-6-ol (1.48 g, 9.11 mmol, 1.4 equiv.) in anhydrous DMF (10 mL) in a 20 mL microwave vial, NaH (0.416 g, 10.4 mmol, 1.6 equiv., 60% dispersion in mineral oil) was added at room temperature. The mixture was stirred for 20 minutes. 4-(4-fluoropyridin-2-yl)-2-methylbenzamide (1.50 g, 6.51 mmol, 1 equiv.) was added, and the reaction mixture was heated to 90 °C in a heating block. After 6 hours, the brown solution was cooled to room temperature, then added dropwise to water (approximately 5 mL) and stirred for 15 minutes. The precipitated solid was filtered off, triturated with EtO (20 mL), and filtered. The solid was triturated with dichloromethane (approximately 10 mL), sonicated for approximately 3 minutes, and filtered. The filtrate was filtered through a larger 0.45 μm HPLC filter, concentrated under vacuum to approximately 6 mL, and purified by flash column chromatography (ISCO 40 g, 0-100% ethyl acetate / hexanes); the product was approximately 90-95% pure. The solid was then dissolved in approximately 2 mL of DMSO and purified by reverse-phase column chromatography (ISCO 30 g, 10-60% acetonitrile / water) to give 4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide as a white solid.1H NMR (400 MHz, DMSO-d, 27℃): δ = 8.55 (d, J = 5.6 Hz,1H), 7.94 (s, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H),7.76 (br s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.40 (br s, 1H), 6.96 (dd, J = 8.6, 2.0 Hz, 1H), 6.86 (dd, J =5.6, 2.3 Hz, 1H), 3.93 (s, 3H), 2.48-2.50 (overlapped with solvent DMSO peak,3H), 2.45 (br s, 3H).LCMS method 1A: retention time = 1.38 min, m / z(M+H+) = 373.20 measured mass, accurate mass 372.16. The following examples in Table 9 were made following the procedures of the above examples using the appropriate starting materials. [Table 9-1] [Table 9-2]

[0368] Example 12 2-methyl-4-(4-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)benzamide [ka]

[0369] Synthesis of 2-methyl-4-(4-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)benzamide [ka]

[0370] 2-Chloro-4-({1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl}oxy)pyridine (8 mg) and 2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (10 mg) were dissolved in 350 μL of dioxane, followed by 150 μL of 2 M aqueous NaCO solution, followed by X-Phos Pd-G catalyst (1.5 mg). The reaction was sealed in a small glass vial and heated to 95° C. overnight. After adding 500 μL of cold DMF, the reaction was filtered, and the mixture was purified by HPLC to give 2-methyl-4-(4-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)benzamide. The catalyst X-Phos Pd-G3 was replaced with tetrakis(triphenylphosphine)palladium(0) (0.02-0.1 equiv.) in dioxane with aqueous sodium carbonate. The catalyst was replaced with EtOH / toluene with aqueous sodium carbonate. LCMS Method 3A: Retention time = 0.73 min, m / z (M+H+) = 360.2 observed mass, exact mass 359.14. The following examples in Table 10 were made following the procedure in Example 3 using the appropriate starting materials. [Table 10]

[0371] Example 15 4-(2-amino-6-((2-methyl-2H-indazol-5-yl)oxy)pyridin-4-yl)-2-methylbenzamide [ka]

[0372] Synthesis of 4-(2-amino-6-((2-methyl-2H-indazol-5-yl)oxy)pyridin-4-yl)-2-methylbenzamide [ka]

[0373] To 10% w / v Na2CO3 (2 equiv.) and dioxane (1 ml) was added tert-butyl (4-chloro-6-((2-methyl-2H-indazol-5-yl)oxy)pyridin-2-yl)carbamate (27 mg, 1 equiv.), 2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1 equiv.), and Pd(PPh3)4 (5 mol%). The reaction was purged with N2 and heated at 90 °C overnight. After cooling, the reaction was treated with EtOAc, water was added, and the organic layer was separated. The crude product was dried under vacuum and then resuspended in MeCN:TFA (1 ml, 1:1) and stirred at 45 °C for 4 h. The reaction was neutralized with 10% Na2CO3 solution, extracted with EtOAc, and the crude material was purified by chromatography on silica gel (0–15% MeOH in DCM). LCMS method 3A: retention time = 0.85 min, m / z (M+H+) = 374.2 actual mass, accurate mass 373.15. The following examples in Table 11 were made following the procedures in Example 4 using the appropriate starting materials. [Table 11-1] [Table 11-2] [Table 11-3]

[0374] Example 25 4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide [ka]

[0375] Synthesis of 4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide [ka]

[0376] 6-[(2-chloropyridin-4-yl)oxy]-1,3-dimethyl-1H-indazole (26.8 g), 2-methyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (26.9 g), and tetrakis(triphenylphosphine)palladium(0) (0.05 equivalents) were transferred to a round-bottom flask, followed by the addition of 1,4-dioxane and NaCO (2N, 1 equivalent). The reaction mixture was degassed for 15 minutes and then heated to 90° C. The reaction mixture was stirred at 90° C. overnight.

[0377] After completion of the reaction, the mixture was cooled to room temperature. The residual solvent was removed under reduced pressure. The crude product was redissolved in DCM / MeOH (4:1) (500 mL) and washed with water (150 mL × 2). The organic solvent was dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. Silica (50 g) was added to the crude product, and the silica-loaded crude product was purified by silica column chromatography using DCM / MeOH (gradient of 1% to 10% over 30 minutes).

[0378] After purification, the purified products were collected, combined, and concentrated to give a pale yellow solid, which was thoroughly washed with EtOAc until all colored impurities were removed to give 4-{4-[(1,3-dimethyl-1H-indazol-6-yl)oxy]pyridin-2-yl}-2-methylbenzamide (26.7 g, 73%) as a white solid.

[0379] The white solid was redissolved in DCM / MeOH (4:1) (1 L), and trisamine (50 mL) and 500 mL of water were added. This mixture was washed, and the organic layer was separated. The washing procedure was repeated three times to remove all traces of Pd contamination. After the trisamine wash was complete, the organic layer was dried over anhydrous Na2SO4 and concentrated to give the final product. The white product was dried under high vacuum at 40 °C overnight. 1H NMR (400 MHz, DMSO-d, 27℃): δ = 8.55 (d, J = 5.6 Hz,1H), 7.94 (s, 1H), 7.86 (dd, J = 8.0, 1.4 Hz, 1H), 7.81 (d, J = 8.7 Hz, 1H),7.76 (br s, 1H), 7.61 (d, J = 2.3 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H), 7.45 (d, J= 7.9 Hz, 1H), 7.40 (br s, 1H), 6.96 (dd, J = 8.6, 2.0 Hz, 1H), 6.86 (dd, J =5.6, 2.3 Hz, 1H), 3.93 (s, 3H), 2.48-2.50 (overlapped with solvent DMSO peak,3H), 2.45 (br s, 3H).LCMS method 3A: retention time = 1.01 min, m / z(M+H+) = 373.2 measured mass, accurate mass 372.16. Example 26 2-Ethyl-4-(7-((1-methyl-1H-indazol-6-yl)oxy)imidazo[1,2-a]pyridin-5-yl)benzamide [ka]

[0380] Synthesis of 2-ethyl-4-(7-((1-methyl-1H-indazol-6-yl)oxy)imidazo[1,2-a]pyridin-5-yl)benzamide [ka]

[0381] 4-(6-amino-4-((1-methyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide (50 mg) was dissolved in MeOH (0.5 mL), chloroacetaldehyde (50 wt% in water, 200 μL) was added, followed by 10 mg of solid NaHCO, and the mixture was heated at 80° C. in a sealed vial for 4 h. The reaction was concentrated, and the crude product was purified by chromatography on silica gel eluting with DCM / methanol. After drying, the product was recrystallized from MeOH / EtOAc / ether to give 2-ethyl-4-(7-((1-methyl-1H-indazol-6-yl)oxy)imidazo[1,2-a]pyridin-5-yl)benzamide as a white solid (25 mg). LCMS method 2A: retention time = 0.8 min, m / z (M+H+) = 412.2 actual mass, accurate mass 411.17. The following examples in Table 12 were made following the procedures of the above examples using the appropriate starting materials. [Table 12-1] [Table 12-2] [Table 12-3] [Table 12-4] [Table 12-5] [Table 12-6] [Table 12-7] [Table 12-8] [Table 12-9] Table 12-10 Table 12-11 Table 12-12 Table 12-13 Table 12-14 Table 12-15 Table 12-16 Table 12-17 Table 12-18 Table 12-19 Table 12-20 Table 12-21 Table 12-22 Table 12-23 Table 12-24 Table 12-25

[0382] Example A GPR52 activity

[0383] The ability of the compound of formula I to modulate GPR52 activity was evaluated. HTRF cAMP assay was performed using a commercially available assay kit (cAMP Gs HiRange HTRF®, CisBio). Controls and compounds were dissolved in DMSO, and 62.5 nanoliters of diluted compound was transferred to a 384-well NBS assay plate by acoustic dispensing or precision small-volume dispensing. Compounds were further diluted to 1x by adding 20,000 cells per well. Flp-In cells stably expressing recombinant human GPR52 were used. TM -CHO cells were used in the assay.

[0384] Cells were harvested using a cell stripper and resuspended in stimulation buffer. After 30 minutes of incubation at room temperature, detection reagent was added to each well. The plate was then incubated for an additional 30 minutes at room temperature. cAMP produced by the cells during the initial incubation period competes with d2-labeled cAMP for binding to the europium cryptate-labeled anti-cAMP monoclonal antibody. The measured signal is inversely proportional to the concentration of cAMP produced by the cells, and this signal was quantified using a PHERAstar® multimode plate reader.

[0385] Dose-response curves were generated from converted HTRF counts based on a cAMP reference curve and then normalized to the positive control. A nonlinear regression curve-fitting program was used to calculate the EC 50 Table 13 shows the mean EC 50Values ​​(n=1-15) are presented, where A is <25 nM, B is 25-100 nM, C is 101-1000 nM, and D is >1000 nM but less than 2000 nM. Emax (Table 13) is the maximum amount of cAMP (nM) produced by incubating cells with 10 μM or 31.6 μM of test compound. Compounds are defined by the upper plateau of a 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, Volume 25, Issue 12, June 2017, pages 3098-3115) and expressed as a percentage of the Emax of the reference compound. For example, Example 1 had a mean ECmax of 270 nM (n=12). 50 and 106% Emax, and Example 4 had a mean EC of 83 nM (n=9). 50 and 106% Emax, and Example 25 had an EC of 83 nM (n=9). 50 and has an Emax of 103%. [Table 13-1] [Table 13-2] [Table 13-3]

[0386] Example B Selectivity Panel

[0387] The selectivity of compounds of Formula I was evaluated using the BioPrint® CEREP panel (Eurofins) of 130+ binding, enzyme, and uptake assays. Compounds of Formula I were tested at a single concentration (10 μM). Compound binding was calculated as the percentage inhibition of the binding of radiolabeled ligands specific to each target. The enzyme inhibitory activity of compounds was calculated as the percentage inhibition of the activity of the control enzyme.

[0388] Results showing greater than 50% inhibition or stimulation were considered to indicate significant efficacy of compounds of formula I. Compounds of formula I demonstrate a highly distinct profile and are highly selective. Example C Induction of compounds when incubated with the PXR nuclear receptor

[0389] A reporter gene assay was used to assess in vitro induction of drugs that metabolize enzymes or transporters via activation of the pregnane X receptor (PXR). An expression vector containing full-length human PXR and an appropriate enhancer, coupled to a promoter 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 in duplicate wells with either a single concentration (10 μM) or six different concentrations of a compound of Formula I and returned to the incubator for an additional 24 hours. At the end of the incubation period, the number of viable cells per well was determined using Promega's Cell Titer Fluor cytotoxicity assay. Following cytotoxicity assessment, Promega's ONE-Glo was added to the same wells to assess reporter gene activity. Rifampicin was used as a positive control and tested in the same manner as the test compounds; at a single concentration (10 mM) or six different concentrations. Data reported were obtained as the mean fold receptor activation (n=2) relative to vehicle-treated cells at 10 mM or each of the six doses, and were normalized to the number of viable cells / well and expressed as a percentage of the response obtained with rifampicin at the 10 μM dose. Example D Stability of the compound of formula I in mammalian liver microsomes

[0390] The stability of the compound of Formula I in mammalian liver microsomes was evaluated. The compound of Formula I (0.5 μM) was incubated with pooled, mixed-gender 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 were relative to a final incubation volume of 125 μL. Incubations were performed in a water bath at 37°C for 0, 5, 10, 20, 40, and 60 minutes and terminated by rapid mixing with 150 μL of ice-cold acetonitrile containing an internal standard. The precipitated protein was removed by centrifugation prior to LC-MS / MS analysis. Aliquots of the resulting supernatant fractions were analyzed for the disappearance of the parent compound by LC-MS / MS monitoring. The resulting peak area ratio versus time data was fitted to a nonlinear regression using XLfit Scientific curve-fitting software (IDBS Ltd., Surrey, UK), and the half-life was calculated from the slope. Pharmacokinetic parameters were predicted using the method described by Obach et al. (J. Pharmacol. Exp. Ther. 1997; 283: 46.58). Briefly, intrinsic clearance values ​​were calculated from in vitro half-life data and then scaled to represent the predicted clearance in whole animals (humans). Additional values ​​calculated included predicted extraction rates and predicted maximum bioavailability. For example, O-linkers have superior metabolic stability compared to methyl or -CHO- linkers, as shown by the following comparison: [Table 16-1] [Table 16-2]

[0391] Example E Permeability of compounds of formula I in MDR1-MDCK cells

[0392] The permeability of compounds of formula I in MDR1-MDCK cells was evaluated and determined. The apparent permeability (P app ) and efflux rates were generated. Cells were grown as monolayers on microporous membranes in 24-well assay plates. Each compound was evaluated at a single concentration equivalent to 5 μM. The assay buffer consisted of Hanks' balanced salt solution (Mediatech, Inc., Corning) (pH 7.4) containing 10 mM HEPES and 15 mM glucose. Test articles were diluted in the assay buffer and then administered to the apical chamber of the cell monolayer plate to determine apical-to-basolateral (A to B) permeability. Basolateral-to-apical (B to A) permeability was determined by adding the administration solution to the basolateral chamber. Test article-administered cell monolayers were incubated for 1 hour at 37°C and 5% CO2 in a humidified incubator. At 1 hour, samples were taken from both the donor and receiver chambers and then prepared for LC-MS / MS analysis using electrospray ionization. Triplicate measurements of A to B and B to A permeability were collected for each compound. The excretion rate was calculated using the following formula: P app B>A / P app A>B. Controls were included to ensure cell monolayer integrity (1 μM atenolol) and activity of the MDR1 protein (digoxin). Example F Effect of Compounds of Formula I on hERG Channel Currents

[0393] The in vitro effects of compounds of Formula I 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 the cloned hERG potassium channel, encoded by the KCNH2 gene. The hERG potassium channel is a channel that expresses endogenous I Kr The gene was expressed in gene-deficient Chinese hamster ovary (CHO) cells.

[0394] Stock solutions of the positive control articles were prepared in DMSO and stored at room temperature. Control 1, dofetilide (Sigma; catalog number PZ0016), has a molecular weight of 441.56. Control 2, verapamil (Tocris; catalog number 0654), has a molecular weight of 491.07. Both controls 1 and 2 are stored at room temperature. The CHO / hERG cell line was derived from the Cricetulus griseus organism: tissue (ovary; transfected with ion channel cDNA); type (epithelial); age / stage (fetal); strain source (ATCC, Manassas, VA); and substrain source (Charles River Laboratories).

[0395] CHO cells were stably transfected with hERG cDNA. Stable transfectants were maintained in culture medium with appropriate selection pressure and antibiotics. All experiments were performed at room temperature. Each cell was treated as its own control. Complete blocking was achieved by adding 20 μM verapamil. Two groups (test article-treated and positive control-treated) were tested.

[0396] Automated patch clamp procedure. For hERG testing, a 384-well-based automated patch clamp system, SyncroPatch384PE (Nanion Technologies), equipped with PatchControl software (data acquisition) and DataControl software (data analysis) was used. Recordings were performed at room temperature (22°C) on a planar NPC-384 multihole chip with medium resistance and four holes per well. Recordings were performed in whole-cell patch mode. The internal solution consisted of 10 mM EGTA, 10 mM HEPES, 10 mM KCl, 10 mM NaCl, and 110 mM KF, pH 7.2, mOsm = 285. The external solution consisted of 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. Compounds of Formula I were dissolved in 100% DMSO. On the day of the experiment, serial dilutions of DMSO were prepared manually. The pre-diluted compounds of formula I were further diluted in the external solution with a dilution factor of 1:500 (0.2% DMSO by volume). A single application of the compound of formula I was used at concentrations across the chip. Each well received one compound concentration, followed by a fully blocking dose of verapamil to assess leak current. Various concentrations of each compound were sprayed across the chip to generate individual dose-response relationships.

[0397] hERG current onset and blockade were measured using a stimulation voltage pattern consisting of a 500 ms prepulse to -40 mV (leak subtraction), a 2 s activation pulse to +40 mV, followed by a 2 s test pulse to -40 mV, and then a 2 s test pulse to -40 mV. This pulse pattern was repeated continuously with a 6 s interval from a holding potential of -80 mV. Peak tail currents were calculated from the current amplitude evoked by the -40 mV prepulse and subtracted from the total membrane current recordings. For quality control, small hyperpolarizing voltage steps from -80 to -90 mV were performed during the holding potential to calculate resistance according to Ohm's law.

[0398] Data acquisition and analysis were performed using Nanion Data Control software. Steady state was defined by limiting the rate of change with time (linear time dependence). The steady state before and after application of the test article was used to calculate the percentage of current inhibited at each concentration.

[0399] The compound of formula I is evaluated for its ability to alleviate the deficits in cognitive and negative symptoms of schizophrenia.Animals exposed to repeated administration of PCP show deficits in cognition (measured by NOR) and sociality (measured by social interaction).These deficits are considered to be related to the cognitive and negative symptoms of schizophrenia, respectively.To clarify, animals are administered PCP twice a day for 7 days, and then after a washout period of at least 1 week, administered the compound of formula 1 once a day for 6 days, and then administered one more time, after which NOR (no PCP is administered at this time) is tested, and the next day, administered the compound of formula I (no PCP is administered at this time) and social interaction is tested.The experiment is described in detail in the following examples. Example G Novel Object Recognition (NOR)

[0400] The compounds of formula I were evaluated using the following subchronic phencyclidine (scPCP) protocol. The NOR test was performed as previously described in detail (Grayson, et al., "Atypical antipsychotics attenuate a subchronic PCP-induced cognitive deficit in the novel object recognition task in the rat," Behavioral Brain Research, Vol. 184, Issue 1, 2007; Snigdha et al., "Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), α5-Hydroxytryptamine 2A "Receptor Inverse Agonist", Journal of Pharmacology and Experimental Therapeutics, February 2010, 332 (2) 622-631).

[0401] Before testing, all animals were habituated to an empty test box. Habituation consisted of placing all rats from one cage together in an empty test arena for 20 minutes on the day before testing. Rats (scPCP and vehicle-treated) were given two 3-minute trials in their home cages, separated by a 60-minute interval. In the first trial (acquisition), animals were placed in the test box and allowed to explore two identical objects (A1 and A2). In the second trial (memorization), animals were placed in the test box containing one familiar object (to avoid olfactory traces) and one novel object replicated from the acquisition phase. Compounds of formula I or vehicle were administered once daily for 6 days, before NOR and 120 minutes before acquisition. Behavior was filmed and scored by an experienced experimenter blinded to the treatment groups. Total object exploration time (defined as the time the animal spent licking, smelling, or touching the object, but not the time spent standing or sitting on it, or leaning on it) was recorded for each familiar and novel object in the acquisition and retention trials. Locomotor activity (defined as movement, measured by the number of lines crossed in both trials) and a discrimination index (defined as the difference between the time spent exploring the novel and familiar object divided by the total time spent exploring both objects) were also calculated.

[0402] All data were expressed as mean ± sem (standard error of the mean). Exploration time data from NOR during the acquisition and retention phases were analyzed separately by two-way analysis of variance (ANOVA) with factors drug and exploration time for the two objects (two identical objects during acquisition, and novel and familiar objects during retention). Locomotor activity data (total number of line crossings) and DI were analyzed by one-way ANOVA. Time spent exploring the objects was analyzed by paired Student's t-test. Post-hoc analysis was performed after significant one-way ANOVA with Dunnett's t-test (for locomotor activity and DI). Example H social interaction

[0403] To assess the social withdrawal aspect of the negative symptoms of schizophrenia with subchronic administration of PCP, the following social interaction test is used to evaluate compounds of Formula I.

[0404] One day after assessment in the NOR, rats were assessed for social interactions using the same arena. Pairs of weight-matched (15-20 g) unfamiliar rats receiving either untreated ("conspecific" rats) or different treatments (PCP and vehicle; "test" rats or PCP + Formula I compound; "test" rats) were placed together in the test arena for 10 minutes, and behavioral assessments were performed as described below. Formula I compound or vehicle was administered for 7 days prior to SI and 120 minutes prior to interaction assessment.

[0405] An inanimate object, such as an unopened beverage can, was also placed in the center of the arena to measure any differences in the interaction between the test animal and the unknown animal on the opposite side of the unknown object. After each 10-minute trial, the object and arena were cleaned with 10% alcohol to remove any traces of olfactory cues. All trials were conducted under standard room illumination (70 cd / m 2 ) was carried out.

[0406] Immediately after SI study, brains and blood (n=12 per treatment group) were collected. Trunk blood was collected in Li heparin-coated tubes on ice before centrifugation. Blood was centrifuged at 7,000 RPM for 10 minutes 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 cortices were excised, collected in vials, and stored at -80°C. Behavior was video recorded for subsequent blind scoring. A behavioral scoring software program (Hindsight, Scientific programming services) was used to score the following parameters (a) to (e): (a) Investigative sniffing behavior: sniffing the snout of a conspecific or any part of its body, including the anogenital region; (b) Following - rats follow conspecific, i.e., vehicle-treated rats of the same species, around the arena; (c) avoidance—actively turning away when approached by a conspecific; (d) object exploration—exploring an object placed in the center of the arena; (e) Locomotor activity was recorded by counting the total number of areas (i.e., lines) crossed by the test rat.

[0407] All data are expressed as mean ± sem. Data were analyzed by ANOVA followed by Dunnett's post-hoc test where appropriate. Statistical significance was considered when P < 0.05. All analyses were performed with the SPSS statistical package (IBM).

[0408] The specification, including the examples, is intended to be illustrative only, and it will be apparent to those skilled in the art that various modifications and variations can be made to this application without departing from the scope or spirit of the disclosure, as defined by the appended claims. Each reference is incorporated herein by reference in its entirety, including all patents, patent applications, and publications cited in this application.

Claims

1. Compounds of Formula I: 【Chemistry 90】 and pharmaceutically acceptable salts thereof, wherein R １ is hydrogen and C １～２ alkyl, R ２ is C １～２ Alkyl, halo, methylamino and halo-substituted C １～２ alkyl, R ３ is selected from hydrogen and halo; R ４ teeth, 【Chemistry 91】 【Chemistry 92】 (where, R ５ When bonded to a carbon atom, it is hydrogen, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, and R ５ When bonded to a nitrogen atom, １～２ Alkyl and halo substituted C １～２ alkyl, R ６ When attached to a carbon atom, it is hydrogen, amino, cyano, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, and R ６ When bonded to a nitrogen atom, １～２ Alkyl and halo substituted C １～２ alkyl, R ７ is hydrogen, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, R ８ is selected from hydrogen and halo is selected from X １ is selected from N and CH; X ２ is N and CR ９ and R ９ is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl, or R ９ and X １ the nitrogens form a 5-membered unsaturated ring containing up to two nitrogen atoms, X ３ is CR ９ａ and R ９ａ is selected from hydrogen and methyl; Compounds and pharmaceutically acceptable salts thereof.

2. Formula Ia: 【Chemistry 93】 2. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein: R ２ is C １～２ Alkyl, halo, methylamino and halo-substituted C １～２ alkyl, R ３ is selected from hydrogen and halo; R ５ is hydrogen and C １～２ alkyl, R ６ is hydrogen, amino, cyano, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, X １ is selected from N and CH; X ２ is N and CR ９ and R ９ is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; Compounds and pharmaceutically acceptable salts thereof.

3. R ２ is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R ３ is selected from hydrogen and halo; R ５ is selected from hydrogen, methyl and ethyl; R ６ is selected from hydrogen, methyl, fluoro, amino, cyano, and trifluoromethyl; X １ is selected from N and CH; X ２ However, N and CR ９ and R ９ 3. The compound of claim 2, wherein is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl, and pharmaceutically acceptable salts thereof.

4. R ２ is selected from methyl, ethyl and trifluoromethyl; R ３ is selected from hydrogen and fluoro; X １ is selected from N and CH; X ２ But, CR ９ and R ９ 4. The compound of claim 3, wherein is selected from hydrogen and amino, and pharmaceutically acceptable salts thereof. 【Request Item 5】 【Chemistry 94】 【Chemical 95】 5. The compound of claim 4, selected from: or a pharmaceutically acceptable salt thereof.

6. Formula Ib: 【Chemistry 96】 2. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein: R ２ is C １～２ Alkyl, halo, methylamino and halo-substituted C １～２ alkyl, R ５ is hydrogen, C １～２ Alkyl and halo substituted C １～２ alkyl, R ６ is hydrogen, amino, cyano, halo, C １～２ Alkyl and halo substituted C １～２ alkyl, R ７ is hydrogen, C １～２ selected from alkyl and halo; R ９ａ is selected from hydrogen and methyl; X １ is selected from N and CH; X ２ is N and CR ９ and R ９ is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; Compounds and pharmaceutically acceptable salts thereof.

7. R ２ is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R ５ is selected from hydrogen, methyl, ethyl and trifluoromethyl; R ６ is selected from hydrogen, methyl, amino, cyano, fluoro and trifluoromethyl; R ７ is selected from hydrogen, methyl and fluoro; R ９ａ is selected from hydrogen and methyl; X １ is selected from N and CH; X ２ However, N and CR ８ and R ８ 7. The compound of claim 6, wherein is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl, and pharmaceutically acceptable salts thereof.

8. X ２ But, CR ８ and R ８ 8. The compound of claim 7, wherein is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl, and pharmaceutically acceptable salts thereof. 【Request Item 9】 【Chemistry 97】 【Chem.98】 【Chem.99】 9. The compound of claim 8, selected from:

10. Formula Ic: 【Chemistry 100】 2. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein: R ２ is C １～２ Alkyl, halo, methylamino and halo-substituted C １～２ alkyl, R ５ is hydrogen, C １～２ Alkyl and halo substituted C １～２ alkyl, R ６ is hydrogen and C １～２ alkyl, X １ is selected from N and CH; X ２ is N and CR ９ and R ９ is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; Compounds and pharmaceutically acceptable salts thereof.

11. R ２ is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R ５ is selected from hydrogen, fluoro, methyl, ethyl and trifluoromethyl; R ６ is selected from hydrogen, methyl, amino, cyano and trifluoromethyl; X １ is selected from N and CH; X ２ However, N and CR ８ and R ８ 11. The compound of claim 10, wherein is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl, and pharmaceutically acceptable salts thereof.

12. R ２ is selected from methyl and ethyl; X １ is N, X ２ But, CR ９ and R ９ 12. The compound of claim 11, and pharmaceutically acceptable salts thereof, wherein is selected from hydrogen and amino. 【Request Item 13】 【Chemistry 101】 13. The compound of claim 12, selected from: or a pharmaceutically acceptable salt thereof.

14. Formula Id: 【Chemical Engineering 102】 2. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein: R ２ is C １～２ Alkyl, halo, methylamino and halo-substituted C １～２ alkyl, R ５ is hydrogen, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, R ６ is hydrogen and C １～２ alkyl, R ７ is hydrogen, C １～２ selected from alkyl and halo; X １ is selected from N and CH; X ２ is N and CR ９ and R ９ is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; Compounds and pharmaceutically acceptable salts thereof.

15. R ２ is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R ５ is selected from hydrogen, fluoro, methyl and ethyl; R ６ is selected from hydrogen, methyl, amino, cyano and trifluoromethyl; R ７ But hydrogen, C １～２ selected from alkyl and halo; X １ is selected from N and CH; X ２ However, N and CR ９ and R ９ 15. The compound of claim 14, wherein is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl, and pharmaceutically acceptable salts thereof.

16. R ２ is selected from methyl, ethyl and chloro; X １ is N and X ２ and pharmaceutically acceptable salts thereof. 【Request Item 17】 【Chemistry 103】 【Chemical 104】 17. The compound of claim 16, selected from: or a pharmaceutically acceptable salt thereof.

18. Formula Ie: 【Chemistry 105】 2. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein: R １ is hydrogen and C １～２ alkyl, R ２ is C １～２ Alkyl, halo, methylamino and halo-substituted C １～２ alkyl, R ４ teeth, 【Chemistry 106】 is selected from R ５ is hydrogen and C １～２ alkyl, R ６ is hydrogen, amino, cyano, C １～２ Alkyl and halo substituted C １～２ alkyl, R ７ is hydrogen, C １～２ selected from alkyl and halo; X １ is selected from N and CH; X ２ is N and CR ９ and R ９ is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl, or R ９ and X １ the nitrogens form a 5-membered unsaturated ring containing up to two nitrogen atoms, Compounds and pharmaceutically acceptable salts thereof.

19. R １ is selected from hydrogen, methyl and ethyl; R ２ is selected from methyl and ethyl; R ４ but, 【Chemistry 107】 is selected from R ５ is methyl, R ６ when attached to a carbon atom is selected from hydrogen, methyl and trifluoromethyl; R ７ is hydrogen, X １ is selected from N and CH; X ２ But, CR ９ and R ９ 19. The compound of claim 18, and pharmaceutically acceptable salts thereof, wherein is hydrogen. 【Request Item 20】 【Chemistry 108】 【Chemistry 109】 20. The compound of claim 19, selected from: or a pharmaceutically acceptable salt thereof.

21. Formula If: 【Chemical 110】 2. The compound of claim 1 and pharmaceutically acceptable salts thereof, wherein: R ２ is C １～２ Alkyl, halo, methylamino and halo-substituted C １～２ alkyl, R ４ teeth, 【Chemistry 111】 is selected from R ５ is hydrogen, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, R ６ is hydrogen, amino, cyano, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, R ７ is hydrogen, C １～２ Alkyl, halo and halo-substituted C １～２ alkyl, R ８ is selected from hydrogen and halo; Compounds and pharmaceutically acceptable salts thereof.

22. R ２ is selected from methyl, ethyl, chloro, fluoro and trifluoromethyl; R ４ but, 【Chemistry 112】 (R ５ is selected from hydrogen, fluoro, chloro and methyl when attached to a carbon atom; R ６ is selected from hydrogen and fluoro; R ７ is selected from hydrogen, fluoro, chloro and trifluoromethyl; R ８ is selected from hydrogen and fluoro 22. The compound of claim 21 selected from: and pharmaceutically acceptable salts thereof. 【Request Item 23】 【Chemistry 113】 【Chemical 114】 【Chemical 115】 【Chemistry 116】 23. The compound of claim 22, selected from: 【Request Item 24】 【Chemistry 117】 【Chemistry 118】 【Chemical 119】 2. The compound of claim 1 selected from: or a pharmaceutically acceptable salt thereof.

25. A pharmaceutical composition comprising a compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, and one or more excipients.

26. 26. A method of treating a neurological disorder, comprising administering an effective amount of at least one compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 25, to a subject in need of such treatment, wherein the neurological disorder is selected from the group consisting of schizophrenia, negative symptoms associated with schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder. the disorder is selected from the group consisting of: obsessive-compulsive disorder, autism spectrum disorder, prolactin-related disorder, hyperprolactinemia, neurocognitive disorder, trauma or stressor-related disorder, post-traumatic stress disorder, disruptive impulse control disorder, disruptive conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypoactivity, abnormalities of the infundibulopituitary tract, mesolimbic tract, mesocortical tract or nigrostriatal tract, striatal hypoactivity, cortical dysfunction, agnosia associated with neurocognitive dysfunction and schizophrenia, Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, Huntington's disease, and chorea associated with Huntington's disease.

27. 27. The method of claim 26, wherein the neurological disorder is selected from schizophrenia, cognitive impairment associated with schizophrenia (CIAS), and vascular cognitive impairment.

28. 28. The method of claim 27, wherein the schizophrenia is selected from negative symptoms associated with schizophrenia, psychotic symptoms of schizophrenia, schizoaffective disorder, schizotypal disorder, schizophreniform disorder, treatment-resistant schizophrenia and attenuated psychotic syndrome.

29. 26. A method for ameliorating one or more symptoms of a neurological disorder, comprising the step of administering an effective amount of at least one compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 25, to a subject in need thereof, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, prolactin-related disorder, hyperprolactinemia, neurocognitive disorder, trauma or stressor-related disorder, post-traumatic stress disorder, disruptive impulse control disorder, disruptive conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypoactivity, abnormalities of the infundibulopituitary, mesolimbic, mesocortical or nigrostriatal tracts, striatal hypoactivity, cortical dysfunction, agnosia associated with neurocognitive dysfunction and schizophrenia, Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, and chorea associated with Huntington's disease.

30. 26. A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 25, for use in the treatment of a neurological disorder, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, prolactin-related disorder, hyperprolactinemia, psychiatric disorders, and the like. A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical product selected from the group consisting of neurocognitive disorders, trauma or stressor-related disorders, post-traumatic stress disorder, disruptive impulse control disorders, disruptive conduct disorders, sleep-wake disorders, substance-related disorders, addictive disorders, behavioral disorders, frontal lobe hypoactivity, abnormalities of the infundibulopituitary tract, mesolimbic tract, mesocortical tract, or nigrostriatal tract, striatal hypoactivity, cortical dysfunction, agnosia associated with neurocognitive dysfunction and schizophrenia, Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, and chorea associated with Huntington's disease.

31. 26. A method for manufacturing a medicament for treating a neurological disorder, wherein the neurological disorder is selected from the group consisting of schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, neuroleptic-induced dyskinesia, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette's syndrome, extrapyramidal or movement disorder, motor dysfunction disorder, hyperkinetic movement disorder, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, prostatitis, rheumatoid arthr ... the condition is selected from the group consisting of: prolactin-related disorders, hyperprolactinemia, neurocognitive disorders, trauma or stressor-related disorders, post-traumatic stress disorder, disruptive impulse control disorders, disruptive conduct disorders, sleep-wake disorders, substance-related disorders, addictive disorders, behavioral disorders, frontal lobe hypoactivity, abnormalities of the infundibulopituitary, mesolimbic, mesocortical or nigrostriatal tracts, striatal hypoactivity, cortical dysfunction, agnosia associated with neurocognitive dysfunction and schizophrenia, Parkinson's disease, drug-induced parkinsonism, dyskinesia, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy and progressive supranuclear palsy, and Huntington's disease and chorea associated with Huntington's disease.

32. A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, or a pharmaceutical product according to claim 25, for use as a medicament.

Images