Compounds and compositions as GPR52 modulators

Abstract

The present disclosure relates to compounds of formula (I) capable of modulating GPR52 activity. The disclosure also provides methods for making compounds of Formula (I) and methods of using compounds of Formula (I) for managing diseases or conditions associated with GPR52 activity, including but not limited to the treatment of various neurological conditions. # imgabs0 #

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 419,384, filed on October 26, 2022. The entire disclosure of this application is incorporated herein by reference in its entirety and for all purposes. Technical field

[0003] The present disclosure relates to compounds of formula (I) capable of modulating GPR52 activity. The present disclosure also provides methods for preparing compounds of formula (I) and pharmaceutical formulations comprising such compounds. The present disclosure also provides methods of using compounds and compositions of formula (I) for managing diseases or disorders associated with the activity of GPR52, including but not limited to treating various neuropathologies. Background art

[0004] GPR52 is a highly conserved orphan GPCR in vertebrates. The highest expression levels within the central nervous system (CNS) are found in the striatum. Lower, but significant, expression levels are found in other structures within the CNS, including in the cortex. Although GPR52 has been characterized, it remains an orphan receptor with no known endogenous ligand. Several alternative ligands have been reported, including extracellular loop 2 (ECL2) of GPR52 itself.

[0005] GPR52 is typically co - localized with dopamine receptors D1 and D2. GPR52 is co - localized almost exclusively with D2 receptors in the human striatum and D1 receptors in the cortex. The efficacy of existing antipsychotic drugs is mediated by D2 antagonist activity, but this activity is accompanied by side effects such as motor symptoms and hyperprolactinemia. In contrast, GPR52 modulators can essentially act as D2 antagonists and thus exhibit antipsychotic efficacy while avoiding D2 antagonist - related side effects. Thus, GPR52 modulators can improve the symptoms of various neuropathologies, diseases, and disorders. Accordingly, GPR52 represents an attractive target for the development of new therapies for treating various neurological and neuropsychiatric diseases and disorders. GPR52 agonists are particularly relevant to the treatment of schizophrenia, in which they have the potential to indirectly improve cognitive and negative symptoms by enhancing D1 signaling but reduce positive symptoms by inhibiting D2 - mediated signaling in the striatum.

[0006] Despite the progress made in the art, the medical need for improved GPR52 agonists remains unmet. As will be apparent from the following disclosure, related compounds, compositions, and methods satisfy these and other needs. Summary of the invention

[0007] 1. Some aspects provide compounds of formula I:

[0008]

[0009] Wherein:

[0010] R1 is selected from hydrogen and C 1-2 alkyl;

[0011] R2 is selected from C 1-2 alkyl, halogen, methyl-amino and halogen-substituted C 1-2 alkyl;

[0012] R3 is selected from hydrogen and halogen;

[0013] R4 is selected from:

[0014]

[0015]

[0016] Wherein:

[0017] When R5 is attached to a carbon atom, R5 is selected from hydrogen, C 1-2 alkyl, halogen and halogen-substituted C 1-2 alkyl; and when R5 is attached to a nitrogen atom, R5 is selected from hydrogen, C 1-2 alkyl and halogen-substituted C 1-2 alkyl;

[0018] When R6 is attached to a carbon atom, R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl, halogen and halogen-substituted C 1-2 alkyl; and when R6 is attached to a nitrogen atom, R6 is selected from hydrogen, C 1-2 alkyl and halogen-substituted C 1-2 alkyl;

[0019] R7 is selected from hydrogen, C 1-2 alkyl, halogen and halogen-substituted C 1-2 alkyl;

[0020] R8 is selected from hydrogen and halogen;

[0021] X1 is selected from N and CH;

[0022] X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, amino-methyl, methyl-amino-methyl, azetidin-2-yl and azetidin-3-yl; or R9 and the nitrogen of X1 form a 5-membered unsaturated ring containing at most two nitrogen atoms;

[0023] X3 is selected from CR 9a ; wherein R 9a is selected from hydrogen and methyl;

[0024] and pharmaceutically acceptable salts or hydrates thereof.

[0025] In some aspects, the compound of formula (I) or a pharmaceutically acceptable salt thereof is a compound described in the following examples or a pharmaceutically acceptable salt thereof. In some aspects, 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.

[0026] Some aspects provide pharmaceutical products selected from the following: pharmaceutical compositions, formulations, unit dosage forms, and kits; each containing the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0027] Some aspects provide a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0028] Some aspects provide a method of modulating the activity of GPR52, which comprises contacting the receptor with the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0029] Some aspects provide a method of treating a disease or disorder in a patient associated with abnormal expression and / or activity of GPR52, which comprises administering to the patient a therapeutically effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0030] Some aspects provide methods of treating a neurological disorder, which include administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the neurological disorder is selected from: schizophrenia; cognitive impairment; panic disorder; phobic disorder; drug-induced psychotic disorder; delusional psychosis; antipsychotic-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 syndrome; extrapyramidal or movement disorder; motor disorder; hyperkinesia; psychotic disorder; catatonia; mood disorder; depressive disorder; anxiety disorder; obsessive-compulsive disorder (OCD); autism spectrum disorder; prolactin-related conditions (e.g., hyperprolactinemia); neurocognitive disorder; trauma- or stress-related disorder (e.g., PTSD); disruptive, impulse control, or conduct disorder; sleep-wake disorder; substance-related disorder; addictive disorder; behavioral disorder; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; reduced striatal activity; cortical dysfunction; neurocognitive dysfunction; cognitive deficits associated with schizophrenia; drug-induced parkinsonism (DIP); dyskinesias; dystonia; chorea; levodopa-induced dyskinesia; cerebral palsy and progressive supranuclear palsy; and Huntington's disease, including chorea associated with Huntington's disease.

[0031] Some aspects provide methods for ameliorating one or more symptoms of a neurological disorder, which include administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the neurological disorder is selected from: schizophrenia; cognitive impairment; panic disorder; phobic disorder; drug-induced psychotic disorder; delusional psychosis; antipsychotic-induced movement disorder; Parkinson's disease; drug-induced parkinsonism; extrapyramidal syndrome; Alzheimer's disease; dementia with Lewy bodies; bipolar disorder; attention deficit / hyperactivity disorder (ADHD); Tourette syndrome; extrapyramidal or movement disorder; movement disorder; hyperkinesia; psychotic disorder; catatonia; mood disorder; depressive disorder; anxiety disorder; obsessive-compulsive disorder (OCD); autism spectrum disorder; prolactin-related conditions (e.g., hyperprolactinemia); neurocognitive disorder; trauma- or stress-related disorder (e.g., PTSD); disruptive, impulse control, or conduct disorder; sleep-wake disorder; substance-related disorder; addictive disorder; behavioral disorder; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction; cognitive deficits associated with schizophrenia; drug-induced parkinsonism (DIP); movement disorder; dystonia; chorea; levodopa-induced movement disorder; cerebral palsy and progressive supranuclear palsy; and Huntington's disease, including chorea associated with Huntington's disease.

[0032] Some aspects provide methods for preparing a medicament for ameliorating one or more symptoms of a neurological disorder, which include administering to an individual in need an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof; wherein the neurological disorder is selected from: schizophrenia; cognitive impairment; panic disorder; phobic disorder; drug-induced psychotic disorder; delusional psychosis; antipsychotic-induced movement disorder; Parkinson's disease; drug-induced parkinsonism; extrapyramidal syndrome; Alzheimer's disease; dementia with Lewy bodies; bipolar disorder; attention deficit / hyperactivity disorder (ADHD); Tourette syndrome; extrapyramidal or movement disorder; movement disorder; hyperkinesia; psychotic disorder; catatonia; mood disorder; depressive disorder; anxiety disorder; obsessive-compulsive disorder (OCD); autism spectrum disorder; prolactin-related conditions (e.g., hyperprolactinemia); neurocognitive disorder; trauma- or stress-related disorder (e.g., PTSD); disruptive, impulse control, or conduct disorder; sleep-wake disorder; substance-related disorder; addictive disorder; behavioral disorder; frontal lobe hypofunction; abnormalities in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways; decreased striatal activity; cortical dysfunction; neurocognitive dysfunction; cognitive deficits associated with schizophrenia; drug-induced parkinsonism (DIP); movement disorder; dystonia; chorea; levodopa-induced movement disorder; cerebral palsy and progressive supranuclear palsy; and Huntington's disease, including chorea associated with Huntington's disease. Detailed implementation mode

[0033] Definitions

[0034] For clarity and consistency, the following definitions will be used in this patent document.

[0035] As used herein, "about" means ±20% of the stated value, and more specifically includes values of ±10%, ±5%, ±2%, and ±1% of the stated value.

[0036] As used herein, "administer" means providing an individual with a compound or other therapy described herein in a form that can be introduced into the body of the individual in a therapeutically useful form and in a therapeutically useful amount, the forms including but not limited to: oral dosage forms such as tablets, capsules, syrups, suspensions, etc.; injectable dosage forms such as IV, IM, IP, etc.; transdermal dosage forms including creams, gels, powders, and patches; buccal dosage forms; inhaled powders, sprays, suspensions, etc.; and rectal suppositories.

[0037] A healthcare practitioner can directly provide an individual with a compound described herein in the form of a sample, or can indirectly provide the compound to the individual by providing an oral or written prescription for the compound. Additionally, for example, an individual can obtain the compound on their own without the involvement of a healthcare practitioner. When a compound is administered to an individual, the body is transformed by the compound in some way. When a compound described herein is provided in combination with one or more other agents, "administer" should be understood to include the compound and the other agents being administered at the same time or at different times. When the combined agents 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 formulation, the site of the disease, and the severity of the disease.

[0038] In the context of treatment, the term "improve" means, but is not limited to, improving the symptoms of a disease, helping or improving the symptoms, or making the symptoms more tolerable or acceptable.

[0039] The term "composition" means a compound or its crystalline form (including but not limited to salts, solvates, and hydrates of the compounds described herein) combined with at least one additional component, such as a composition obtained / prepared during synthesis, pre-formulation, in-process testing (e.g., TLC, HPLC, NMR samples), etc.

[0040] As used herein, the term "compound" means all stereoisomers, geometric isomers, tautomers, and isotopes of the described structure. The term also means the compounds described herein, regardless of how they are prepared, e.g., prepared synthetically, by biological processes (e.g., metabolism or enzymatic conversion), or combinations thereof. All compounds and their pharmaceutically acceptable salts may be found with other substances (such as water and solvents) (e.g., hydrates and solvates) or may be isolated. When in the solid state, the compounds and salts described herein may exist in various forms and may, for example, take the form of solvates (including hydrates). The compounds may be in any solid form, such as polymorphs or solvates, and thus, unless otherwise explicitly indicated, the compounds and salts referred to in this specification should be understood to encompass any solid form of the compounds. In some aspects, the compounds or salts described herein are substantially isolated. "Substantially isolated" means that the compound is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation may include, for example, a composition enriched in the compound described herein. Substantially isolated may include a composition containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound or salt described herein.

[0041] As used herein, the term "hydrate" refers to the compounds or salts described herein that further include a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces.

[0042] The terms "in need of treatment" and "in need" are used interchangeably when referring to treatment and mean the determination by a caregiver (e.g., a physician, nurse, nurse practitioner, etc. in the case of humans; a veterinarian in the case of animals, including non-human mammals) that an individual or animal needs treatment or would benefit from treatment. This determination is made based on various factors within the caregiver's expertise but includes knowledge that the individual or animal is ill or will become ill due to a disease, disorder, or condition treatable by the compounds described herein. Thus, the compounds described herein may be used in a protective or prophylactic manner; or the compounds described herein may be used to alleviate, inhibit, or reduce a disease, condition, or disorder.

[0043] The term "individual" 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 trials, an individual can be a healthy volunteer or healthy participant without a potential GPR52-mediated disorder or condition, or a volunteer or participant who has received a diagnosis of a disorder or condition that requires medical treatment as determined by a healthcare professional. In contexts outside of clinical trials, an individual who has received a diagnosis of a disorder or condition under the care of a healthcare professional is typically described as an individual.

[0044] The term "pediatric individual" refers to an individual who is less than 21 years of age at the time of diagnosis or treatment. The term "pediatric" can also be divided into various subgroups, including: neonates (from birth to the first month of life); infants (1 month to 2 years); children (2 years to 12 years); and adolescents (12 years to 21 years (up to but not including the twenty-second birthday)), see, for example, Berhman et al., Textbook of Pediatrics, 15th ed. Philadelphia: W.B. 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.

[0045] The phrase "pharmaceutically acceptable" refers to a compound (and its salts), composition, and / or dosage form that, within the scope of sound medical judgment, is suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0046] The term "pharmaceutical composition" refers to a specific composition that contains at least one active ingredient; the active ingredient includes, but is not limited to, salts, solvates, and hydrates of the compounds described herein, whereby the ability to study a specific effective outcome of the composition in mammals (such as, but not limited to, humans) can be achieved. One of ordinary skill in the art should understand and be aware of the techniques suitable for determining whether an active ingredient has the desired effective outcome based on the needs of the skilled person.

[0047] The terms “prevention”, “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 “prevention”, “preventing”, and “prevention” can refer to the administration of a therapy to an individual who may ultimately exhibit at least one symptom of a disorder but has not yet done so, on a prophylactic or preventive basis. Such individuals can be identified based on risk factors known to be associated with the subsequent development of the disease, such as the presence of a biomarker. Optionally, a preventive therapy can be administered as a prophylactic measure without prior identification of risk factors. Delaying the onset of at least one episode of a disorder and / or the onset of symptoms can also be considered prevention or prophylaxis.

[0048] As used herein, the term “solvate” refers to a solid form of a compound or a pharmaceutically acceptable salt thereof described herein that includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, the solvate is a hydrate.

[0049] The terms “treat”, “treating”, and “treatment” refer to the medical management of a disease, disorder, or condition in an individual (e.g., a subject) (see, e.g., Stedman’s Medical Dictionary). Typically, an appropriate dosage and treatment regimen provide an amount of a GPR52 agonist sufficient to provide a therapeutic benefit. Therapeutic benefits for an individual to whom a GPR52 agonist compound described herein is administered include, for example, improved clinical outcomes, where the goal is to prevent or slow or delay (mitigate) undesired physiological changes associated with the disease, or to prevent or slow or delay (mitigate) the progression or severity of such disease. The effectiveness of one or more GPR52 agonists can include beneficial or desired clinical outcomes, which include but are not limited to alleviating, reducing, or relieving symptoms caused by or associated with the disease being treated; reducing the incidence of symptoms; improving quality of life; prolonging disease-free status (i.e., reducing the likelihood or propensity for an individual to exhibit symptoms based on a disease diagnosis made); reducing the severity of the disease; stabilizing (i.e., not worsening) the disease state; delaying or slowing disease progression; improving or ameliorating the disease state; and remission (whether partial or complete), whether detectable or not; and / or overall survival.

[0050] The term "therapeutically effective amount" refers to an amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, that elicits a biological or pharmaceutical response in a tissue, system, animal, or human that is sought by an individual, researcher, veterinarian, physician, or other clinician or caregiver, and the response can include one or more of the following:

[0051] (1) Preventing a disorder, e.g., preventing a disease, disorder, or condition in an individual who may be predisposed to the disease, disorder, or condition but has not yet experienced or presented the relevant pathology or symptoms;

[0052] (2) Inhibiting a disorder, e.g., inhibiting a disease, disorder, or condition in an individual who is experiencing or presenting the relevant pathology or symptoms (i.e., preventing further development of the pathology and / or symptoms); and

[0053] (3) Alleviating a disorder, e.g., alleviating a disease, disorder, or condition in an individual who is experiencing or presenting the relevant pathology or symptoms (i.e., reversing the pathology and / or symptoms).

[0054] As used herein, the term "contact" means that the indicated moiety is brought together in an in vitro system or an in vivo system. For example, bringing GPR52 into "contact" with a compound provided herein includes administering a compound provided herein (or a pharmaceutically acceptable salt thereof) to an individual (such as a human) having the GPR52 protein, and, for example, introducing a compound provided herein into a sample containing a cell or a purified preparation containing the GPR52 protein.

[0055] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents, applications, published applications, and other publications are incorporated herein by reference in their entirety. In cases where there are multiple definitions of a term herein, those defined in this section shall control unless otherwise stated.

[0056] The term "n-membered", where n is an integer, generally describes the number of ring-forming atoms in a moiety, where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocyclic ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridinyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl ring.

[0057] For compounds of formula (I) and their pharmaceutically acceptable salts in which a variable appears more than once, each variable can independently be a different moiety selected from the group defining the variable. For example, in the case of describing a structure having two R groups present on the same compound simultaneously, the two R groups can represent different moieties independently selected from the groups defined for R.

[0058] Whenever a group is described as "optionally substituted", the group can be unsubstituted or substituted with one or more of the specified substituents. Similarly, when a group is described as "unsubstituted or substituted", if substituted, the substituents can be selected from one or more of the specified substituents. It should be understood that substitution at a given atom is limited by valence.

[0059] As used herein, "C a -C b " (wherein "a" and "b" are integers) refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, or aryl group. That is, these groups can contain from "a" to "b" (including the end values) carbon atoms. Thus, for example, a "C1-C4 alkyl" (or C 1-4 alkyl) group refers to all alkyl groups having from 1 to 4 carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. If "a" and "b" are not specified for an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl group, the broadest range described in these definitions is considered.

[0060] In addition to the foregoing, as used in the specification and the appended claims, unless otherwise indicated, the following terms have the indicated meanings:

[0061] The term "amino" refers to the group -NH2.

[0062] The term "alkylamino" refers to a group of the formula -NH(alkyl), wherein alkyl is as defined herein. Examples of alkylamino include methylamino, ethylamino, propylamino (e.g., n-propylamino and isopropylamino), and the like.

[0063] The term "dialkylamino" refers to a group of the formula -N(alkyl)2, wherein alkyl is as defined herein. Examples of dialkylamino include dimethylamino, diethylamino, di-n-propylamino, diisopropylamino), and the like.

[0064] The term "alkenyl" refers to an alkyl group containing one or more double bonds in a straight-chain or branched hydrocarbon chain. Examples of alkenyl include allenylyl, vinylmethyl, and vinyl. In some aspects, the alkenyl can be unsubstituted or substituted. In some aspects, the alkenyl can have 2 to 6 carbon atoms. The alkenyl of a compound can be designated as "C2-C6 alkenyl" or a similar name.

[0065] The term "alkynyl" refers to an alkyl group containing one or more triple bonds in a straight-chain or branched hydrocarbon chain. Examples of alkynyl groups include ethynyl and propynyl. The alkynyl group can be unsubstituted or substituted. In some aspects, the alkynyl group can be unsubstituted or substituted. In some aspects, the alkynyl group can have 2 to 6 carbon atoms. The alkenyl group of a compound can be designated as "C2-C6 alkynyl" or a similar name.

[0066] The term "aryl" refers to an aromatic ring system containing 6, 10, or 14 carbon atoms, which can contain a single ring, two fused rings, or three fused rings, such as phenyl, naphthyl, and phenanthryl. In some aspects, the aryl group can have 6 or 10 carbon atoms (i.e., C6 or C 10 aryl). When one or more substituents are present on the "aryl" ring, the substituents can be bonded at any available ring carbon. In some aspects, the aryl group can be substituted or unsubstituted.

[0067] The term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon group. The alkyl group can have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms. In some aspects, the alkyl group can have 1 to 6 carbons (i.e., "C1-C6 alkyl"). Some aspects are 1 to 5 carbons (i.e., C1-C5 alkyl), some aspects are 1 to 4 carbons (i.e., C1-C4 alkyl), some aspects are 1 to 3 carbons (i.e., C1-C3 alkyl), and some aspects are 1 or 2 carbons. By way of example only, "C1-C4 alkyl" means that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-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, etc. When one or more substituents are present on the alkyl group, the substituents can be bonded at any available carbon atom. In some aspects, the alkyl group can be substituted or unsubstituted.

[0068] The term "haloalkyl" refers to an alkyl group as defined herein, wherein one or more hydrogen atoms of the alkyl group have been replaced by halogen atoms (e.g., monohaloalkyl, dihaloalkyl, and trihaloalkyl). In some aspects, the haloalkyl group can have 1 to 6 carbons (i.e., "halo-C1-C6 alkyl" or "halo-C 1-4 alkyl"). The halo-C1-C6 alkyl can be fully substituted, in which case it can be represented by the formula C n L2n+1 where L is a halogen and “n” is 1, 2, 3, 4, 5 or 6. When there is more than one halogen, they may be the same or different and are selected from: fluorine, chlorine, bromine and iodine. In some aspects, the haloalkyl contains 1 to 5 carbons (i.e., halo C1-C5 alkyl). In some aspects, the haloalkyl contains 1 to 4 carbons (i.e., halo C1-C4 alkyl). In some aspects, the haloalkyl contains 1 to 3 carbons (i.e., halo C1-C3 alkyl). In some aspects, the haloalkyl contains 1 or 2 carbons. Examples of haloalkyls include fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 1-fluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 4,4,4-trifluorobutyl, etc.

[0069] The term “carbonyl” refers to the group -C(=O)-.

[0070] The term “oxo” refers to the =O substituent.

[0071] The term “cycloalkyl” refers to all-carbon monocyclic or polycyclic ring systems that are completely saturated. In some aspects, the cycloalkyl is a monocyclic ring containing 3 to 7 carbon atoms (i.e., “C3-C7 cycloalkyl”). Some aspects contain 3 to 6 carbons. Some aspects contain 3 to 5 carbons. Some aspects contain 5 to 7 carbons. Some aspects contain 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. When one or more substituents are present on the alkyl group, the substituents can be bonded at any available carbon atom. In some aspects, the cycloalkyl can be substituted or unsubstituted.

[0072] The term “cycloalkenyl” refers to a monocyclic or polycyclic hydrocarbon ring system containing one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a completely delocalized π-electron system in all rings (i.e., an aromatic system), otherwise the group would be an “aryl” as defined herein. When composed of two or more rings, the rings can be joined together in a fused, bridged or spiro manner. The cycloalkenyl can contain 3 to 12 atoms in the ring or contain 3 to 8 atoms in the ring. In some aspects, the cycloalkenyl can be unsubstituted or substituted. In some aspects, the cycloalkenyl can have 4 to 8 carbon atoms (i.e., “C4-C8 cycloalkenyl”). An example is cyclohexenyl.

[0073] The term "heteroaryl" refers to a monocyclic or fused polycyclic aromatic ring system and has at least one heteroatom in the ring system, i.e., an element other than carbon, including but not limited to nitrogen, oxygen and sulfur. Some aspects are "5-6 membered heteroaryl" and refer to an aromatic ring containing 5 to 6 ring atoms in a single ring and having at least one heteroatom in the ring system. Examples of heteroaryl rings include, but are not limited to, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, furanyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, isoindolyl, oxazolyl, benzofuranyl, 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, quinolyl, isoquinolyl, benzisoxazolyl, imidazo [1,2-b] thiazolyl, etc. Heteroaryl can be substituted or unsubstituted. In some aspects, heteroaryl has 5 to 10 ring members or 5 to 7 ring members. Heteroaryl groups may be designated as "5-7 membered heteroaryl", "5-10 membered heteroaryl" or similar designations. In some aspects, heteroaryl groups may be substituted or unsubstituted C1-C 13 Five-, six-, seven-, eight-, nine-, ten-, up to 14-membered monocyclic, bicyclic or tricyclic systems, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some aspects, heteroaryl can be a substituted or unsubstituted C1-C5 five- or six-membered monocyclic ring, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some aspects, heteroaryl can be a substituted or unsubstituted C5-C9 eight-, nine- or ten-membered bicyclic ring system, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some aspects, heteroaryl is a substituted or unsubstituted C5-C9 eight-, nine- or ten-membered heteroaryl. In some aspects, the C5-C9 eight-membered, nine-membered or ten-membered bicyclic heteroaryl is imidazo[2,1-b]thiazolyl, 1H-indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzisoxazolyl, indazolyl, purinyl, quinolyl, isoquinolyl, quinoxalinyl, pyrido[3,4-b]pyrazinyl or pyrido[4,3-d]pyrimidinyl. In some aspects, the heteroaryl is a substituted or unsubstituted C8-C 13 A 13- or 14-membered tricyclic ring system comprising 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some aspects, the heteroaryl group can be an oxazolyl group such as an imidazolyl group, a pyrazolyl group, a 1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a 1,2,4-thiadiazolyl group, a thiazolyl group, an isothiazolyl group, an oxazolyl group or an isoxazolyl group, each of which can be substituted or unsubstituted. In some aspects, the heteroaryl group is a C1-C 135-membered heteroaryl. In some aspects, the C1-C4 5-membered heteroaryl is furyl, thienyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl, isothiazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl. In some aspects, the heteroaryl is a C3-C5 6-membered heteroaryl. In some aspects, the C3-C5 6-membered heteroaryl is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl. In some aspects, "5-10 membered heteroaryl" means: furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinoxalinyl, triazinyl, benzofuryl, 1H-indolyl, benzo[b]thienyl, etc. In some aspects, "5-10 membered heteroaryl" means: pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, 1H-indolyl, quinoxalinyl, thiadiazolyl, etc. In some aspects, the heteroaryl can be substituted or unsubstituted.

[0074] The position of the nitrogen in the pyridine ring relative to the oxygen linker in Formula I changes the EC 50 , for example:

[0075]

[0076] The term "heterocyclic group" refers to a three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic system, in which carbon atoms together with 1 to 5 heteroatoms form the ring system and optionally contain one or more unsaturated bonds positioned in such a way that, however, a completely delocalized π-electron system (aromatic system) does not exist in the monocyclic ring or at least one of the rings in the bicyclic or tricyclic system. Heteroatoms are elements other than carbon, including but not limited to oxygen, sulfur, and nitrogen. In some aspects, the heterocyclic group can be a 3-7 membered saturated non-aromatic ring system containing 3 to 7 ring atoms, where at least one ring atom is a heteroatom. In some aspects, "3-6 membered heterocyclic group" refers to a saturated non-aromatic ring group containing 3 to 6 ring atoms, where at least one ring atom is a heteroatom. In some aspects, "4-6 membered heterocyclic group" refers to a saturated non-aromatic ring group containing 4 to 6 ring atoms, where at least one ring atom is a heteroatom. In some aspects, one or two heteroatoms in the ring system are independently selected from: O (oxygen) and N (nitrogen). In some aspects, the heterocyclic group can include a carbonyl (C=O) group adjacent to a heteroatom, which can be substituted by oxo on the carbon adjacent to the heteroatom, where the substituted ring system is an lactam, lactone, cyclic imide, cyclic thioimide, or cyclic carbamate. Examples of unsubstituted or oxo-substituted "heterocyclic group" include but are not limited to aziridinyl, azetidinyl, tetrahydrofuryl, 1,3-dioxolenyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-oxathianyl, 1,4-oxathiazinyl, 1,3-oxathiolanyl, 1,3-dithioleneyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, 2H-1,2-oxazinyl, maleimido, succinimido, dioxopiperazinyl, hydantoinyl, imidazolinyl, imidazolidinyl, isoxazolinyl, isoxazolidinyl, isoindolinyl, dihydroindolyl, oxazolinyl, oxazolidinyl, oxazolidinone, thiazolinyl, thiazolidinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, pyrrolidinone, pyrrolidinedione, 4-piperidinone, 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., benzimidazolidinone, tetrahydroquinolinyl, and 3,4-methylenedioxyphenyl). The heterocyclic group can be designated as "3-10 membered heterocyclic group" or a similar name. In some aspects, the heterocyclic group can be C2-C 12Tertiary, quaternary, quinary, senary, septenary, octal, nonary, decal, up to 13-membered monocyclic, bicyclic or tricyclic systems, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some aspects, the heterocyclic group may be a substituted or unsubstituted C2-C6 tertiary, quaternary, quinary, senary or septenary monocyclic ring, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some aspects, the heterocyclic group may be a substituted or unsubstituted C2-C 10 Quaternary, quinary, senary, septenary, octal, nonary, decal or undecal membered bicyclic systems, including 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur. In some aspects, the heterocyclic group may be a substituted or unsubstituted C7-C 12A 12- or 13-membered tricyclic system, including 1 to 5 heteroatoms selected from nitrogen, oxygen, and sulfur. In some aspects, the heteroatoms of the six-membered monocyclic heterocyclic group are selected from one to three of O (oxygen), N (nitrogen), or S (sulfur), and the heteroatoms of the five-membered monocyclic heterocyclic group are selected from one or two heteroatoms of O (oxygen), N (nitrogen), or S (sulfur). In some aspects, the heterocyclic group can be aziridinyl, azetidinyl, tetrahydrofuryl, 1,3-dioxolenyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-dioxolanyl, 1,3-dioxolanyl, 1,3-oxathianyl, 1,4-oxathianyl, 1,3-oxathiolanyl, 1,3-dithioleneyl, 1,3-dithiolanyl, 1,4-oxathianyl, tetrahydro-1,4-thiazinyl, 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]dioxolano[4,5-c]pyridinyl, [1,3]dioxolano[4,5-b]pyridinyl, [1,3]dioxolano[4,5-d]pyrimidinyl, or 3,4-methylenedioxyphenyl. In some aspects, the unsubstituted or substituted heterocyclic group can be selected from aziridinyl, azetidinyl, piperidinyl, morpholinyl, oxetanyl, piperazinyl, pyrrolidinyl, thiomorpholinyl, 2-piperidinonyl, 1,1-dioxothiomorpholinyl, oxolanyl (tetrahydrofuryl), and oxanyl (tetrahydropyranyl). When one or more substituents are present on the heterocyclic group, the substituents can be bonded at any available carbon atom and / or heteroatom. In some aspects, the heterocyclic group can be substituted or unsubstituted.

[0077] The term "alkoxy" refers to the formula -OR, where R is an alkyl group as defined herein. A non-limiting list of alkoxy groups is methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. The alkoxy group of a compound can be designated as "C1-C6 alkoxy" or a similar name. In some aspects, the alkoxy group can be substituted or unsubstituted.

[0078] The term "haloalkoxy" refers to an alkoxy group in which one or more hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy, and tri-haloalkoxy). Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, and 2-fluoroisobutoxy. In some aspects, the haloalkoxy may have 1 to 6 carbon atoms. The haloalkoxy of a compound may be designated as "halo C1-C6 alkoxy" or a similar name.

[0079] The term "cyano" refers to the group -CN.

[0080] The term "halogen" or "halo" refers to a fluorine, chlorine, bromine, or iodine group. In some aspects, the halogen or halo is fluorine, chlorine, or bromine. In some aspects, the halogen or halo is fluorine or chlorine. In some aspects, the halogen or halo is fluorine.

[0081] The "C-acylamino" group refers to the group "—C(═O)N(R A R B )" that is attached to the remainder of the molecule via a carbon atom, and wherein R A and R B can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl, C6 or C 10 aryl, heteroaryl, or heterocyclic group.

[0082] The "N-acylamino" group refers to the group "RC(═O)N(R A )—" that is attached to the remainder of the molecule via a nitrogen atom, and wherein R and R A can independently be hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C5-C8 cycloalkenyl, C6 or C 10 aryl, heteroaryl, or heterocyclic group.

[0083] The term "hydroxyalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a hydroxy group. In some aspects, the hydroxyalkyl may have 1 to 6 carbon atoms (i.e., "hydroxy C1-C6 alkyl"). Exemplary hydroxyalkyls include, but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2-dihydroxyethyl.

[0084] The term "hydroxy" refers to the -OH group.

[0085] The term "nitro" refers to the -NO2 group.

[0086] As used herein, "excipient" refers to a substance added to a composition to provide (but not limited to) volume, consistency, stability, binding ability, lubricity, disintegrating ability, etc. to the composition. A "diluent" is a type of excipient and refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent can be used to increase the volume of an active drug, the mass of which is too small for manufacture and / or administration. It can also be a liquid in which a drug to be administered by injection, ingestion, or inhalation is dissolved. A pharmaceutically acceptable excipient is a physiologically and pharmaceutically suitable non-toxic and inactive material or ingredient that does not interfere with the activity of the drug substance. Pharmaceutically acceptable excipients are well-known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)). Preservatives, stabilizers, dyes, buffers, etc. can be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents can also be used. For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostatic agents, and other commonly used additives. In some aspects, the diluent can be a buffered aqueous solution, such as but not limited to phosphate buffered saline. The composition can also be formulated into capsules, granules, or tablets, which contain, in addition to the compounds disclosed and described herein, diluents, dispersing agents and surfactants, binders, and lubricants. Those skilled in the art can further formulate the compounds disclosed and described herein in a suitable manner and according to recognized practices (such as those disclosed in Remington above).

[0087] As used herein, "dose" or "dosage" refers to the measured amount of a drug substance taken by an individual in a single administration. In some aspects in which the drug substance is not a free base or free acid, the amount is equivalent to the molar equivalent of the corresponding amount of the free base or free acid.

[0088] As used herein, "pharmaceutically acceptable salts" refers to salts of compounds having acidic or basic moieties which are biologically and otherwise suitable for use in pharmaceuticals. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of acidic or basic moieties (e.g., amino and / or carboxyl or similar groups). Pharmaceutically acceptable acid addition salts can be formed by combining a compound having a basic moiety with inorganic and organic acids. Inorganic acids which can be used to prepare salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids which 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 which can be used to prepare salts include, for example, hydroxides, carbonates, bicarbonates, phosphates of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, manganese, aluminum, and the like. In some aspects, the inorganic base salts are hydroxides, carbonates, bicarbonates or phosphates of ammonium, potassium, sodium, calcium and magnesium. Organic bases which can be used to prepare salts include, for example, primary, secondary and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, basic ion exchange resins, and the like, particularly, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. Generally, such salts can be prepared by reacting the free acid or free base forms 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 both; generally, a non-aqueous medium, such as diethyl ether, ethyl acetate, an alcohol (e.g., methanol, ethanol, isopropanol or butanol), or acetonitrile (ACN) is preferred. A list of suitable salts is found in WO87 / 05297; published September 11, 1987 by Johnston et al.; Remington’s Pharmaceutical Sciences, 17th Edition, Mack Publishing Company, Easton, Pa., 1985, page 1418; and J. Pharm. Sci., 66, 2 (1977); each of which is incorporated herein by reference in its entirety. The reference for the preparation and selection of pharmaceutical salts for the present invention is P.H. Stahl & C.G. Wermuth, Handbook of Pharmaceutical Salts, Verlag Helvetica Chimica Acta, Zurich, 2002, which is incorporated herein by reference in its entirety.

[0089] The compounds described herein can be asymmetric (e.g., having one or more stereocenters). Unless otherwise stated, all stereoisomers, such as enantiomers and diastereomers are contemplated. It is understood that in any compound described herein having one or more chiral centers, if the absolute stereochemistry is not explicitly indicated, each center can independently be of the (R)-configuration or (S)-configuration or a mixture thereof. Thus, the compounds provided herein can be enantiomerically pure, enantiomerically enriched, racemic mixtures, diastereomerically pure, diastereomerically enriched or stereoisomeric mixtures. The preparation of enantiomerically pure or enantiomerically enriched forms can be achieved by resolution of racemic mixtures or by using enantiomerically pure or enriched starting materials or by stereoselective or stereospecific synthesis. Stereochemical definitions can be found 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 aspects, when the compounds described herein are chiral or otherwise include one or more stereocenters, the compounds can be prepared with an enantiomeric excess or diastereomeric excess of greater than about 75%, greater than about 80%, greater than about 85%, greater than about 90%, greater than about 95%, greater than about 99% or greater than about 99%.

[0090] Resolution of racemic mixtures of the compounds can be carried out by any of a variety of methods known in the art. Exemplary methods include fractional crystallization using a chiral resolving organic acid with a racemic compound containing a basic group. Resolving agents suitable for the fractional crystallization method are, for example, optically active acids such as D- and L-forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or various optically active camphorsulfonic acids. Other chiral resolving agents suitable for the fractional crystallization method include stereoisomerically pure forms of methylbenzylamine (e.g., S- and R-forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, etc. Similarly, fractional crystallization using a chiral resolving base can be used with a racemic compound containing an acidic group.

[0091] Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoyl phenylglycine). Suitable elution solvent compositions can be determined by those skilled in the art.

[0092] In some aspects, the compounds described herein can be prepared to have 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 the range defined by any of the foregoing numbers.

[0093] In addition, it should be 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 stated, it is understood that the compounds include both E and Z geometric isomers (e.g., cis or trans). The cis and trans geometric isomers of the compounds described herein can be separated into mixtures of isomers or into isolated isomer forms.

[0094] The compounds described herein also include tautomeric forms. Tautomeric forms are generated by the exchange of a single bond with an adjacent double bond and the accompanying proton migration. Tautomeric forms include proton transfer tautomers, which are in isomeric protonated states having the same empirical formula and total charge. Exemplary proton transfer tautomers include keto - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and cyclic forms in which the proton can occupy two or more positions of a heterocyclic system, such as 1H - imidazole and 3H - imidazole, 1H - 1,2,4 - triazole, 2H - 1,2,4 - triazole, and 4H - 1,2,4 - triazole, 1H - isoindole and 2H - isoindole, and 1H - pyrazole and 2H - pyrazole. Tautomeric forms can be in equilibrium or locked in one form spatially by appropriate substitution.

[0095] The compounds described herein and their pharmaceutically acceptable salts can exist together with other substances (such as water and solvents) in the form of, for example, hydrates or solvates. When in the solid state, the compounds and their salts described herein can exist in various forms and can be, for example, in the form of solvates (including hydrates). The compounds can be in any solid form, such as crystalline form, amorphous form, solvated form, etc., and unless otherwise explicitly stated, references to the compounds and their salts in the specification should be understood to cover any solid form of the compounds.

[0096] The compounds described herein can be used in the neutral form, such as in the free acid or free base form. Optionally, the compounds can be used in the form of pharmaceutically acceptable salts, such as pharmaceutically acceptable acid addition salts or base addition salts.

[0097] In some aspects, the compounds or salts thereof described herein are substantially isolated. The phrase "substantially isolated" refers to a compound that is at least partially or substantially separated from the environment in which it is formed or detected. Partial separation can include, for example, a composition enriched in the compound described herein. Substantially isolated can include a composition containing at least about 50%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 97% or at least about 99% by weight of the compound or salt thereof described herein.

[0098] The compounds disclosed and described herein allow the atoms at each position of the compound to independently have: 1) an isotopic distribution of proportional amounts typically present in nature for a chemical element, or 2) an isotopic distribution different from the proportional amounts typically present in nature, unless the context clearly dictates otherwise. A particular chemical element has an atomic number defined by the number of protons in the atomic nucleus. Each atomic number defines a particular element, not an isotope; the atoms of a given element can have a wide range in the number of neutrons. The number of both protons and neutrons in the atomic nucleus is the mass number, and each isotope of a given element has a different mass number. A compound in which one or more atoms have an isotopic distribution of a chemical element different from the proportional amounts typically present in nature is generally referred to as an isotopically labeled compound. Each chemical element as represented in the compound structure can include any isotopic distribution of the element. For example, in the compound structure, a hydrogen atom can 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 can be an isotopic distribution of hydrogen, including but not limited to protium ( 1 H) and deuterium ( 2 H). Thus, unless the context clearly dictates otherwise, the compounds mentioned herein encompass all potential isotopic distributions of each atom. Examples of isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine. As would be understood by one of ordinary skill in the art, any of the compounds disclosed and described herein can include radioactive isotopes. Thus, also encompassed are the uses of the compounds disclosed and described herein in which one or more atoms have an isotopic distribution different from the amounts present in nature, such as having a greater proportion of 2 H or 3 H, or a greater proportion of 11 C, 13 C or 14 C. As a general example, but not limited to, isotopes of hydrogen include protium ( 1 H), deuterium ( 2 H) and tritium ( 3H). Isotopes of carbon include carbon-11 ( 11 C), carbon-12 ( 12 C), carbon-13 ( 13 C), and carbon-14 ( 14 C). Isotopes of nitrogen include nitrogen-13 ( 13 N), nitrogen-14 ( 14 N), and nitrogen-15 ( 15 N). Isotopes of oxygen include oxygen-14 ( 14 O), oxygen-15 ( 15 O), oxygen-16 ( 16 O), oxygen-17 ( 17 O), and oxygen-18 ( 18 O). Isotopes of fluorine include fluorine-17 ( 17 F), fluorine-18 ( 18 F), and fluorine-19 ( 19 F). Isotopes of phosphorus include 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). Isotopes of sulfur 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). Isotopes of chlorine include chlorine-35 ( 35 Cl), chlorine-36 ( 36 Cl), and chlorine-37 ( 37 Cl). Isotopes of bromine include 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). Isotopes of iodine include iodine-123 ( 123 I), iodine-124 ( 124 I), iodine-125 ( 125 I), iodine-131 ( 131 I), and iodine-135 ( 135I). In some aspects, the atoms at each position of the compound have an isotopic distribution of the proportional amounts typically found in nature for each chemical element. In some aspects, the atoms at one position of the compound have an isotopic distribution of a chemical element that is different from the proportional amount typically found in nature (the remaining atoms having an isotopic distribution of the proportional amount typically found in nature for the chemical element). In some aspects, the atoms at at least two positions of the compound independently have an isotopic distribution of a chemical element that is different from the proportional amount typically found in nature (the remaining atoms having an isotopic distribution of the proportional amount typically found in nature for the chemical element). In some aspects, the atoms at at least three positions of the compound independently have an isotopic distribution of a chemical element that is different from the proportional amount typically found in nature (the remaining atoms having an isotopic distribution of the proportional amount typically found in nature for the chemical element). In some aspects, the atoms at at least four positions of the compound independently have an isotopic distribution of a chemical element that is different from the proportional amount typically found in nature (the remaining atoms having an isotopic distribution of the proportional amount typically found in nature for the chemical element). In some aspects, the atoms at at least five positions of the compound independently have an isotopic distribution of a chemical element that is different from the proportional amount typically found in nature (the remaining atoms having an isotopic distribution of the proportional amount typically found in nature for the chemical element). In some aspects, the atoms at at least six positions of the compound independently have an isotopic distribution of a chemical element that is different from the proportional amount typically found in nature (the remaining atoms having an isotopic distribution of the proportional amount typically found in nature for the chemical element).

[0099] Certain compounds, such as those incorporating radioactive isotopes such as 3H and 14 C, can also be used for drug or substrate tissue distribution assays. Tritium ( 3 H) and carbon-14 ( 14 C) isotopes are particularly preferred because of their ease of preparation and detectability. Compounds having a greater proportional amount of an isotope than is typically found in nature (such as deuterium ( 2 H)) may have certain therapeutic advantages due to greater metabolic stability (such as increased in vivo half-life or reduced dose requirements). Isotopically labeled compounds can generally be prepared by procedures routinely practiced in the field of chemistry. Methods for readily obtaining measurements of such isotopic perturbation or enrichment, such as mass spectrometry, are available, and for isotopes that are radioactive isotopes, additional methods, such as radioactive detectors used in conjunction with HPLC or GC, are available.

[0100] As used herein, "isotope variant" means a compound that contains a non-natural proportion of isotopes at one or more of the atoms that make up such compound. In certain aspects, an "isotope variant" of a compound contains a non-natural proportion of one or more isotopes, including but 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 I). In some aspects, the "isotope variant" of the compound is in a stable form, i.e., non-radioactive. In some aspects, the "isotope variant" of the compound contains a non-natural proportion of one or more isotopes, including but not limited to protium ( 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 ( 18O). In some aspects, the "isotope variants" of the compounds are in an unstable form, i.e., radioactive. In some aspects, the "isotope variants" of the compounds described herein contain non-natural proportions of one or more isotopes, including but 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 ( 15 O). It should be understood that in the compounds provided herein, by way of example, any hydrogen can include 2 H as the major isotope form, or by way of example, any carbon includes 13 C as the major isotope form, or by way of example, any nitrogen can include 15 N as the major isotope form, and by way of example, any oxygen can include 18 O as the major isotope form. In some aspects, the "isotope variants" of the compounds contain non-natural proportions of deuterium ( 2 H).

[0101] Regarding the compounds provided herein, when a particular atomic position is designated as having deuterium or "D" or "d", it should be understood that the abundance of deuterium at that position is significantly greater than the natural abundance of deuterium, which is approximately 0.015%. In some aspects, the positions designated as having deuterium typically have a minimum isotope enrichment factor of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium position.

[0102] Synthetic methods for incorporating radioactive isotopes into organic compounds are applicable to the compounds described herein and are well known in the art. These synthetic methods, for example, incorporate tritium at the activity level into the target molecule as follows:

[0103] A. Catalytic reduction with tritium gas: This method generally produces a high specific activity product and requires a halogenated or unsaturated precursor.

[0104] B. Reduction with sodium borohydride 3 H]: This method is quite inexpensive and requires a precursor containing a reducible functional group (such as aldehyde, ketone, lactone, ester, etc.).

[0105] C. Reduction with lithium aluminum hydride 3H] Reduction: This method provides a product at nearly theoretical specific activity. It also requires a precursor containing reducible functional groups such as aldehyde, ketone, lactone, ester, etc.

[0106] D. Tritium gas exposure labeling: This method involves exposing a precursor containing exchangeable protons to tritium gas in the presence of a suitable catalyst.

[0107] E. N-methylation using methyl iodide 3 H]: This method is commonly used to prepare O-methyl or N-methyl ( 3 H) products by treating a suitable precursor with high specific activity methyl iodide ( 3 H). This method generally allows for higher specific activity, such as about 70 - 90 Ci / mmol.

[0108] Synthetic methods for incorporating 125 I at the active level into target molecules include:

[0109] A. Sandmeyer et al. reactions: This method converts arylamines or heteroarylamines into diazonium salts such as diazonium tetrafluoroborates and then uses Na 125 I to convert them into 125 I-labeled compounds. Representative methods were reported by Zhu, G-D. and colleagues in J. Org. Chem., 2002, 67, 943 - 948.

[0110] B. Ortho- 125 iodination of phenol: This method allows for the incorporation of 125 I at the ortho position of phenol, as reported by Collier, T.L. and colleagues in J. Labelled Compd. Radiopharm., 1999, 42, S264 - S266.

[0111] C. Aryland heteroaryl bromide exchange with 125 I: This method is generally a two-step process. The first step is to convert an aryl or heteroaryl bromide into the corresponding trialkyltin intermediate using, for example, Pd-catalyzed reactants [Pd(Ph3P)4] or via aryl or heteroaryllithium in the presence of a trialkyltin halide or hexalkyl distannane [e.g., (CH3)3SnSn(CH3)3]. Representative methods were reported by Le Bas, M.-D. and colleagues in J. Labelled Compd. Radiopharm., 2001, 44, S280 - S282.

[0112] The radiolabeled forms of the compounds described herein can be used in screening assays to identify / evaluate compounds. Generally, a newly synthesized or identified compound (i.e., the test compound) can be evaluated for its 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 is related to its binding affinity.

[0113] Aspects of the present disclosure

[0114] This disclosure relates to compounds capable of modulating GPR52 activity. In one aspect of this disclosure, with respect to the compounds of formula (I), they are compounds of formula (Ia):

[0115]

[0116] In another aspect, they are compounds of formula (Ia) wherein R2 is selected from methyl, ethyl, methyl-amino, chloro, and trifluoro-methyl.

[0117] In another aspect, they are compounds of formula (Ia) wherein R3 is selected from hydrogen and halogen.

[0118] In another aspect, they are compounds of formula (Ia) wherein R5 is selected from hydrogen, methyl, and ethyl.

[0119] In another aspect, they are compounds of formula (Ia) wherein R6 is selected from hydrogen, methyl, fluoro, amino, cyano, and trifluoromethyl.

[0120] In another aspect, they are compounds of formula (Ia) wherein X1 is selected from N and CH.

[0121] In another aspect, they are compounds of formula (Ia) wherein X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, amino-methyl, methyl-amino-methyl, azetidin-2-yl, and azetidin-3-yl;

[0122] and their pharmaceutically acceptable salts.

[0123] In another aspect, they are compounds of formula (Ia) or in the form of a pharmaceutically acceptable salt, wherein:

[0124] R2 is selected from C 1-2 alkyl, halogen, methyl-amino, and halogen-substituted C 1-2 alkyl;

[0125] R3 is selected from hydrogen and halogen;

[0126] R5 is selected from hydrogen and C 1-2 alkyl;

[0127] R6 is selected from hydrogen, amino, cyano, C 1-2Alkyl, halogen and halogen-substituted C 1-2 alkyl;

[0128] X1 is selected from N and CH; and

[0129] X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, amino-methyl, methyl-amino-methyl, azetidin-2-yl and azetidin-3-yl;

[0130] and pharmaceutically acceptable salts thereof.

[0131] In another aspect, there is provided a compound of formula (Ia), wherein:

[0132] R2 is selected from methyl, ethyl, methyl-amino, chloro and trifluoro-methyl;

[0133] R3 is selected from hydrogen and halogen;

[0134] R5 is selected from hydrogen, methyl and ethyl;

[0135] R6 is selected from hydrogen, methyl, fluoro, amino, cyano and trifluoromethyl;

[0136] X1 is selected from N and CH;

[0137] X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, amino-methyl, methyl-amino-methyl, azetidin-2-yl and azetidin-3-yl;

[0138] and pharmaceutically acceptable salts thereof.

[0139] In another aspect, there is provided a compound of formula (Ia), wherein:

[0140] R2 is selected from methyl, ethyl and trifluoromethyl;

[0141] R3 is selected from hydrogen and fluoro;

[0142] X1 is selected from N and CH; and

[0143] X2 is CR9; wherein R9 is selected from hydrogen and amino;

[0144] and pharmaceutically acceptable salts thereof.

[0145] In another aspect, there is provided a compound of formula (Ia) or a pharmaceutically acceptable salt thereof, selected from the following compounds or pharmaceutically acceptable salts thereof:

[0146]

[0147]

[0148] In another aspect of the present disclosure, with respect to the compound of formula (I), there is provided a compound of formula (Ib):

[0149]

[0150] In another aspect of the present disclosure is a compound of formula Ib, wherein R2 is selected from C 1-2 alkyl, halogen, methyl-amino, and halogen-substituted C 1-2 alkyl.

[0151] In another aspect of the present disclosure is a compound of formula Ib, wherein R5 is selected from hydrogen, C 1-2 alkyl, and halogen-substituted C 1-2 alkyl.

[0152] In another aspect of the present disclosure is a compound of formula Ib, wherein R6 is selected from hydrogen, amino, cyano, halogen, C 1-2 alkyl, and halogen-substituted C 1-2 alkyl.

[0153] In another aspect of the present disclosure is a compound of formula Ib, wherein R7 is selected from hydrogen, C 1-2 alkyl, and halogen.

[0154] In another aspect of the present disclosure is a compound of formula Ib, wherein R 9a is selected from hydrogen and methyl.

[0155] In another aspect of the present disclosure is a compound of formula Ib, wherein X1 is selected from N and CH.

[0156] In another aspect of the present disclosure is a compound of formula Ib, wherein X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl;

[0157] and pharmaceutically acceptable salts thereof.

[0158] In another aspect of the present disclosure is a compound of formula Ib, wherein:

[0159] R2 is selected from C 1-2 alkyl, halogen, methyl-amino, and halogen-substituted C 1-2 alkyl;

[0160] R5 is selected from hydrogen, C 1-2 alkyl, and halogen-substituted C 1-2 alkyl;

[0161] R6 is selected from hydrogen, amino, cyano, halogen, C 1-2 alkyl, and halogen-substituted C 1-2 alkyl;

[0162] R7 is selected from hydrogen, C 1-2 alkyl, and halogen;

[0163] R 9a is selected from hydrogen and methyl;

[0164] X1 is selected from N and CH;

[0165] X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, amino-methyl, methyl-amino-methyl, azetidin-2-yl and azetidin-3-yl;

[0166] and pharmaceutically acceptable salts thereof.

[0167] In another aspect of the present disclosure is a compound of formula (Ib), wherein:

[0168] R2 is selected from methyl, ethyl, methyl-amino, chloro and trifluoro-methyl;

[0169] R5 is selected from hydrogen, methyl, ethyl and trifluoromethyl;

[0170] R6 is selected from hydrogen, methyl, amino, cyano, fluoro and trifluoromethyl;

[0171] R7 is selected from hydrogen, methyl and fluoro;

[0172] R 9a is selected from hydrogen and methyl;

[0173] X1 is selected from N and CH;

[0174] X2 is selected from N and CR8; wherein R8 is selected from hydrogen, amino, amino-methyl, methyl-amino-methyl, azetidin-2-yl and azetidin-3-yl;

[0175] and pharmaceutically acceptable salts thereof.

[0176] In another aspect of the present disclosure is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, wherein: X2 is CR8; wherein R8 is selected from hydrogen, amino, amino-methyl, methyl-amino-methyl, azetidin-2-yl and azetidin-3-yl;

[0177] and pharmaceutically acceptable salts thereof.

[0178] In another aspect of the present disclosure is a compound of formula (Ib) or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0179]

[0180]

[0181]

[0182] In another aspect of the present disclosure is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof:

[0183]

[0184] In another aspect of the present disclosure is a compound of formula (Ic), wherein R2 is selected from C 1-2 alkyl, halogen, methyl - amino and halogen - substituted C 1-2 alkyl.

[0185] In another aspect of the present disclosure is a compound of formula (Ic), wherein R5 is selected from hydrogen, C 1-2 alkyl and halogen - substituted C 1-2 alkyl.

[0186] In another aspect of the present disclosure is a compound of formula (Ic), wherein R6 is selected from hydrogen and C 1-2 alkyl.

[0187] In another aspect of the present disclosure is a compound of formula (Ic), wherein X1 is selected from N and CH.

[0188] In another aspect of the present disclosure is a compound of formula (Ic), wherein X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, amino - methyl, methyl - amino - methyl, azetidin - 2 - yl and azetidin - 3 - yl.

[0189] In another aspect of the present disclosure is a compound of formula (Ic), wherein:

[0190] R2 is selected from C 1-2 alkyl, halogen, methyl - amino and halogen - substituted C 1-2 alkyl;

[0191] R5 is selected from hydrogen, C 1-2 alkyl and halogen - substituted C 1-2 alkyl;

[0192] R6 is selected from hydrogen and C 1-2 alkyl;

[0193] X1 is selected from N and CH;

[0194] X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, amino - methyl, methyl - amino - methyl, azetidin - 2 - yl and azetidin - 3 - yl;

[0195] and pharmaceutically acceptable salts thereof.

[0196] In another aspect of the present disclosure is a compound of formula (Ic), wherein:

[0197] R2 is selected from methyl, ethyl, methyl - amino, chlorine and trifluoro - methyl;

[0198] R5 is selected from hydrogen, fluorine, methyl, ethyl and trifluoromethyl;

[0199] R6 is selected from hydrogen, methyl, amino, cyano and trifluoromethyl;

[0200] X1 is selected from N and CH;

[0201] X2 is selected from N and CR8; wherein R8 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin - 2 - yl and azetidin - 3 - yl; and pharmaceutically acceptable salts thereof.

[0202] In another aspect of the present disclosure is a compound of formula (Ic), wherein:

[0203] R2 is selected from methyl and ethyl;

[0204] X1 is N;

[0205] X2 is CR9; wherein R9 is selected from hydrogen and amino;

[0206] and pharmaceutically acceptable salts thereof.

[0207] In another aspect of the present disclosure is a compound of formula (Ic) or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0208]

[0209] In another aspect of the present disclosure is a compound of formula (Id) or a pharmaceutically acceptable salt thereof:

[0210]

[0211] In another aspect of the present disclosure is a compound of formula (Id), wherein:

[0212] R2 is selected from C 1-2 alkyl, halogen, methyl - amino and halogen - substituted C 1-2 alkyl.

[0213] In another aspect of the present disclosure is a compound of formula (Id), wherein R5 is selected from hydrogen, C 1-2 alkyl, halogen and halogen - substituted C 1-2 alkyl.

[0214] In another aspect of the present disclosure is a compound of formula (Id), wherein R6 is selected from hydrogen and C 1-2 alkyl.

[0215] In another aspect of the present disclosure is a compound of formula (Id), wherein R7 is selected from hydrogen, C 1-2 alkyl, and halogen.

[0216] In another aspect of the present disclosure is a compound of formula (Id), wherein X1 is selected from N and CH.

[0217] In another aspect of the present disclosure is a compound of formula (Id), wherein X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl.

[0218] In another aspect of the present disclosure is a compound of formula (Id), wherein:

[0219] R2 is selected from C 1-2 alkyl, halogen, methylamino, and halogen-substituted C 1-2 alkyl;

[0220] R5 is selected from hydrogen, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl;

[0221] R6 is selected from hydrogen and C 1-2 alkyl;

[0222] R7 is selected from hydrogen, C 1-2 alkyl, and halogen;

[0223] X1 is selected from N and CH;

[0224] X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl;

[0225] and pharmaceutically acceptable salts thereof.

[0226] In another aspect of the present disclosure is a compound of formula (Id), wherein:

[0227] R2 is selected from methyl, ethyl, methylamino, chloro, and trifluoromethyl;

[0228] R5 is selected from hydrogen, fluoro, methyl, and ethyl;

[0229] R6 is selected from hydrogen, methyl, amino, cyano, and trifluoromethyl;

[0230] R7 is selected from hydrogen, C 1-2 alkyl, and halogen;

[0231] X1 is selected from N and CH;

[0232] X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl;

[0233] and pharmaceutically acceptable salts thereof.

[0234] In another aspect of the present disclosure is a compound of formula (Id), wherein R2 is selected from methyl, ethyl and chlorine; X1 is N; X2 is CH;

[0235] and pharmaceutically acceptable salts thereof.

[0236] In another aspect of the present disclosure is a compound of formula (Id) or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0237]

[0238] In another aspect of the present disclosure is a compound of formula (Ie) or a pharmaceutically acceptable salt thereof:

[0239]

[0240] In another aspect of the present disclosure is a compound of formula (Ie), wherein R1 is selected from hydrogen and C 1-2 alkyl.

[0241] In another aspect of the present disclosure is a compound of formula (Ie), wherein R2 is selected from C 1-2 alkyl, halogen, methylamino and halogen-substituted C 1-2 alkyl.

[0242] In another aspect of the present disclosure is a compound of formula (Ie), wherein R4 is selected from:

[0243]

[0244] In another aspect of the present disclosure is a compound of formula (Ie), wherein R5 is selected from hydrogen and C 1-2 alkyl.

[0245] In another aspect of the present disclosure is a compound of formula (Ie), wherein R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl and halogen-substituted C 1-2 alkyl.

[0246] In another aspect of the present disclosure is a compound of formula (Ie), wherein R7 is selected from hydrogen, C 1-2 alkyl and halogen.

[0247] In another aspect of the present disclosure is a compound of formula (Ie), wherein X1 is selected from N and CH.

[0248] In another aspect of the present disclosure is a compound of formula (Ie), wherein X2 is selected from N and CR9; wherein 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 at most two nitrogen atoms.

[0249] In another aspect of the present disclosure is a compound of formula (Ie), wherein:

[0250] R1 is selected from hydrogen and C 1-2 alkyl;

[0251] R2 is selected from C 1-2 alkyl, halogen, methylamino and halogen-substituted C 1-2 alkyl;

[0252] R4 is selected from:

[0253]

[0254] R5 is selected from hydrogen and C 1-2 alkyl;

[0255] R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl and halogen-substituted C 1-2 alkyl;

[0256] R7 is selected from hydrogen, C 1-2 alkyl and halogen;

[0257] X1 is selected from N and CH;

[0258] X2 is selected from N and CR9; wherein 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 at most two nitrogen atoms;

[0259] and pharmaceutically acceptable salts thereof.

[0260] In another aspect of the present disclosure is a compound of formula (Ie), wherein:

[0261] R1 is selected from hydrogen, methyl and ethyl;

[0262] R2 is selected from methyl and ethyl;

[0263] R4 is selected from:

[0264]

[0265] R5 is methyl;

[0266] When R6 is attached to a carbon atom, R6 is selected from hydrogen, methyl and trifluoromethyl;

[0267] R7 is hydrogen;

[0268] X1 is selected from N and CH;

[0269] X2 is CR9; wherein R9 is hydrogen;

[0270] and pharmaceutically acceptable salts thereof.

[0271] In another aspect of the present disclosure is a compound of formula (Ie) or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0272]

[0273]

[0274] In another aspect of the present disclosure is a compound of formula (If) or a pharmaceutically acceptable salt thereof:

[0275]

[0276] In another aspect of the present disclosure is a compound of formula (If), wherein R2 is selected from C 1-2 alkyl, halogen, methyl - amino and halogen - substituted C 1-2 alkyl.

[0277] In another aspect of the present disclosure is a compound of formula (If), wherein R4 is selected from:

[0278]

[0279] In another aspect of the present disclosure is a compound of formula (If), wherein R5 is selected from hydrogen, C 1-2 alkyl, halogen and halogen - substituted C 1-2 alkyl.

[0280] In another aspect of the present disclosure is a compound of formula (If), wherein R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl, halogen and halogen - substituted C 1-2 alkyl.

[0281] In another aspect of the present disclosure is a compound of formula (If), wherein R7 is selected from hydrogen, C 1-2 alkyl, halogen and halogen - substituted C 1-2 alkyl.

[0282] In another aspect of the present disclosure is a compound of formula (If), wherein R8 is selected from hydrogen and halogen.

[0283] In another aspect of the present disclosure is a compound of formula (If), wherein:

[0284] R2 is selected from C 1-2 alkyl, halogen, methyl - amino and halogen - substituted C 1-2 alkyl;

[0285] R4 is selected from:

[0286]

[0287] R5 is selected from hydrogen, C 1-2 alkyl, halogen and halogen - substituted C 1-2 alkyl;

[0288] R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl, halogen and halogen - substituted C 1-2 alkyl;

[0289] R7 is selected from hydrogen, C 1-2 alkyl, halogen and halogen - substituted C 1-2 alkyl;

[0290] R8 is selected from hydrogen and halogen;

[0291] and pharmaceutically acceptable salts thereof.

[0292] In another aspect of the present disclosure is a compound of formula (If), wherein R2 is selected from methyl, ethyl, chlorine, fluorine and trifluoromethyl; R4 is selected from:

[0293]

[0294] When R5 is attached to a carbon atom, R5 is selected from hydrogen, fluorine, chlorine and methyl;

[0295] R6 is selected from hydrogen and fluorine;

[0296] R7 is selected from hydrogen, fluorine, chlorine and trifluoromethyl;

[0297] R8 is selected from hydrogen and fluorine;

[0298] and pharmaceutically acceptable salts thereof.

[0299] In another aspect of the present disclosure is a compound of formula (If) or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0300]

[0301]

[0302]

[0303]

[0304] In another aspect of the present disclosure is a compound or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

[0305]

[0306]

[0307]

[0308] Pharmaceutical compositions, formulations, and dosage forms

[0309] The present disclosure also provides pharmaceutical products such as pharmaceutical compositions, formulations, unit dosage forms, and kits; each containing a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0310] The present disclosure also provides a pharmaceutical composition comprising any of the compounds described herein (e.g., a compound 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 and inactive material or ingredient that does not interfere with the activity of the drug substance; the excipient may also be referred to as a carrier. The formulation methods and excipients described herein are exemplary and in no way limiting. Pharmaceutically acceptable excipients are well known in the pharmaceutical art and are described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Edition, 2006 and Remington: The Science and Practice of Pharmacy (Gennaro, 21st Edition Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, etc. may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used.

[0311] In another aspect of the present disclosure, with respect to the compound of formula I, is a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof and one or more excipients.

[0312] For compositions formulated as liquid solutions, acceptable carriers and / or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostatic agents, and other common additives. The compositions may also be formulated as pills, capsules, granules, or tablets, which, in addition to containing the GPR52 agonist, also contain diluents, dispersants, and surfactants, binders, and lubricants. Those skilled in the art can also formulate the GPR52 agonist in a suitable manner and according to recognized practice, such as in Remington as disclosed above.

[0313] Methods of administration include systemic administration of the GPR52 agonist described herein, preferably in the form of the pharmaceutical compositions discussed above. Systemic administration as used herein 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 include flavoring agents, preservatives, suspending agents, thickening agents, and emulsifying agents, as well as other pharmaceutically acceptable additives. For parenteral administration, the compounds (or their pharmaceutically acceptable salts) described herein may be prepared in aqueous injection solutions, which, in addition to the GPR52 agonist, may also contain buffers, antioxidants, bacteriostatic agents, and other additives commonly used in such solutions.

[0314] 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 desired proportions, and, if necessary, treating the mixture after adding suitable adjuvants, and, if necessary, shaping the resulting mixture into the desired form to obtain tablets or pill cores.

[0315] Conventional excipients, such as binders, fillers, adjuvants, carriers, acceptable wetting agents, tableting lubricants, and disintegrants, can be used for tablets and capsules for oral administration. Liquid preparations for oral administration can be in the form of solutions, emulsions, aqueous or oily suspensions, and syrups. Optionally, the oral preparations can be in dry powder form, which can be reconstituted with water or another suitable liquid vehicle before use. Additional additives, such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives, and flavoring agents, as well as coloring agents, can be added to the liquid preparations. Parenteral dosage forms can be prepared by dissolving the compounds described herein in a suitable liquid vehicle and filtering and sterilizing the solution before lyophilization, or simply filling and sealing appropriate vials or ampoules.

[0316] Some aspects provide methods for preparing pharmaceutical compositions, which include the step of mixing a compound of formula (I) or its pharmaceutically acceptable salt with a pharmaceutically acceptable carrier.

[0317] In the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, the drug substance is usually admixed with excipients (i.e., mixed), diluted with excipients or enclosed within a carrier in the form of, for example, a capsule, sachet, paper or other container. When an excipient is used as a diluent, it can be a solid, semi-solid or liquid material which acts as a vehicle, carrier or medium for the drug substance. Thus, the compositions can be in the form of tablets, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.

[0318] For the preparation of solid forms of pharmaceutical compositions, such as powders, tablets, capsules, cachets, suppositories and dispersible granules, the excipient can be one or more substances which can also function as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrants or encapsulating materials. Also included are solid form preparations which are converted immediately before use into preparations in liquid form for oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the drug substance, these preparations may also contain coloring agents, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickening agents, solubilizing agents and the like.

[0319] To prepare suppositories, first melt a low melting point wax, such as a mixture of fatty acid glycerides or cocoa butter, and disperse the drug substance uniformly therein by stirring. Then pour the molten homogeneous mixture into a suitable size mold and allow it to cool and thus solidify.

[0320] Preparations suitable for vaginal administration may be presented as vaginal suppositories, tampons, creams, gels, pastes, foams or sprays which, in addition to the drug substance, also contain suitable carriers known in the art.

[0321] Liquid form preparations include solutions, suspensions and emulsions, such as water or water-propylene glycol solutions. For example, parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol. Injectable preparations (e.g., 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 a non-toxic parenterally acceptable diluent or solvent. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used, including synthetic mono- or di-glycerides of fatty acids. In addition, fatty acids such as oleic acid can be used in the preparation of injectable preparations.

[0322] The pharmaceutical composition can take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and can contain formulating agents such as suspending, stabilizing and / or dispersing agents. Optionally, the pharmaceutical composition can be in powder form, obtained by aseptic isolation of sterile solids or by lyophilization from solution, for reconstitution before use with a suitable vehicle such as sterile pyrogen-free water.

[0323] The pharmaceutical composition can be formulated as an aqueous solution, a water-alcohol solution, a solid suspension, an emulsion, a liposome suspension or a lyophilized powder for reconstitution. Such pharmaceutical composition can be administered directly or as a mixture for further dilution / reconstitution. Routes of administration include intravenous bolus, intravenous infusion, perfusion and drip. Suitable solvents include water, alcohol, PEG, propylene glycol and lipids; pH adjustment using an acid (e.g., HCl or citric acid) can be used to increase solubility and subject the resulting composition to suitable sterilization procedures known in the art such as sterile filtration. In some aspects, the pH of the aqueous solution is from about 2.0 to about 4.0. In some aspects, the pH of the aqueous solution is from about 2.5 to about 3.5.

[0324] Aqueous preparations suitable for oral use can be prepared by dissolving or suspending the pharmaceutical substance in water and adding suitable coloring, flavoring, stabilizing and thickening agents as required.

[0325] Aqueous suspensions suitable for oral use can be prepared by dispersing the finely powdered pharmaceutical substance in water together with a viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose or other well-known suspending agents.

[0326] For topical application to the epidermis, the compounds or their pharmaceutically acceptable salts described herein can be formulated as gels, ointments, creams or lotions, or as transdermal patches. In addition, formulations suitable for topical application in the mouth include lozenges containing the drug substance in a flavored matrix (usually sucrose and gum arabic or tragacanth); lozenges containing the drug substance in an inert matrix such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes containing the drug substance in a suitable liquid carrier. Ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents. Lotions can be formulated with an aqueous or oily base and usually also contain one or more emulsifiers, stabilizers, dispersants, suspending agents, thickeners or colorants. In some aspects, topical formulations can contain one or more conventional carriers. In some aspects, ointments can contain water and one or more hydrophobic carriers selected from, for example, liquid paraffin, polyoxyethylene alkyl ethers, propylene glycol, white petrolatum, etc. The carrier composition of creams can be based on a combination of water with glycerol and one or more other components (e.g., glyceryl monostearate, PEG-glyceryl monostearate and cetearyl alcohol). Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as glycerol, hydroxyethyl cellulose, etc.

[0327] Solutions or suspensions can be applied directly to the nasal cavity by conventional means, for example using a dropper, pipette or spray. Formulations can be provided in single-dose or multi-dose forms. In the latter case of a dropper or pipette, this can be achieved by administering to the individual an appropriate predetermined volume of the solution or suspension. In the case of a spray, this can be achieved, for example, by a metered atomizing spray pump.

[0328] Administration to the respiratory tract can also be achieved by providing an aerosol formulation with a suitable propellant in a pressurized package. If the compounds or their pharmaceutically acceptable salts described herein or pharmaceutical compositions containing them are administered as an aerosol, for example as a nasal aerosol or by an inhaler, this can be carried out, for example, using a nebulizer, atomizer, pump atomizer, inhalation device, metered-dose inhaler or dry powder inhaler. Pharmaceutical forms for administering the compounds (or their pharmaceutically acceptable salts) described herein as an aerosol can be prepared by methods well known to those skilled in the art. For their preparation, for example, conventional additives can be used, such as benzyl alcohol or other suitable preservatives, absorption enhancers for increasing bioavailability, solubilizers, dispersants and other additives (if suitable), and conventional propellants, for example including carbon dioxide, CFCs such as dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane; etc. using a solution or dispersion of the compounds (or their pharmaceutically acceptable salts) described herein in water, a water / alcohol mixture or a suitable saline solution. Aerosols can also suitably contain a surfactant such as lecithin. The dose of the drug can be controlled by providing a metering valve.

[0329] Optionally, the pharmaceutical composition can be provided in dry powder form, for example, a powder mixture of the compound in a suitable powder matrix such as lactose, starch, starch derivatives such as hydroxypropyl methylcellulose and polyvinylpyrrolidone (PVP). Suitably, the powder carrier will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form, for example, in a capsule or cartridge of gelatin, or in a blister pack, and the powder can be administered from the blister pack via an inhaler.

[0330] The compound of formula (I) or a pharmaceutically acceptable salt thereof can also be administered via a rapidly dissolving or sustained release composition, wherein the composition comprises a biodegradable rapidly dissolving or sustained release carrier such as a polymeric carrier, etc. Rapidly dissolving or sustained release carriers are well known in the art and are used to form complexes in which the compound of formula (I) or a pharmaceutically acceptable salt thereof is entrapped and which degrade / dissolve rapidly or slowly in a suitable environment (e.g., aqueous, acidic, basic, etc.).

[0331] The pharmaceutical preparation is preferably in unit dosage form. In this form, the preparation is subdivided into unit doses containing a suitable quantity of the pharmaceutical substance. The unit dosage form can be an encapsulated preparation containing discrete quantities of the preparation, such as encapsulated tablets, capsules, and powders in vials or ampoules. In addition, the unit dosage form can be the capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these dosage forms in encapsulated form. In some aspects, the pharmaceutical preparation is a tablet or capsule for oral administration. In some aspects, the pharmaceutical preparation is a liquid formulated for intravenous administration.

[0332] The composition can be formulated in unit dosage form, each dose containing the pharmaceutical substance or an equivalent mass of the pharmaceutical substance. The term "unit dosage form" refers to a physically discrete unit suitable as a unit dose for human individuals and other mammals, each unit containing a predetermined quantity of the pharmaceutical substance calculated to produce the desired therapeutic effect, together with the suitable excipients as described herein.

[0333] The compositions described herein can be formulated by processes known in the art to provide immediate and / or timed release (also referred to as extended release, sustained release, controlled release, or slow release) of a pharmaceutical substance upon administration to an individual. For example, tablets comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof can be coated or otherwise compounded to provide a dosage form having the advantage of an extended effect. For example, a tablet can contain an inner dose and an outer dose component, the latter being in the form of an envelope that coats the former. The two components can be separated by an enteric layer that is resistant to disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be released slowly. 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.

[0334] It can be incorporated into a liquid form comprising a pharmaceutical substance for oral or parenteral administration, including aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and emulsions flavored with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, and similar excipients.

[0335] The pharmaceutical compositions described herein can be sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions can be encapsulated for use as such or lyophilized, and the lyophilized preparation is combined with a sterile aqueous vehicle prior to administration. The pH of the compound preparation is generally from 3 to 11, more preferably from 5 to 9, and most preferably from 7 to 8. It should be understood that the use of certain of the foregoing excipients can result in the formation of pharmaceutically acceptable salts.

[0336] Compositions for inhalation or insufflation include solutions and suspensions, and powders, in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions can contain suitable excipients as described herein. In some aspects, the composition is administered by the oral or nasal respiratory route for local or systemic effect. The composition can be atomized by the use of an inert gas. The atomized solution can be inhaled directly from the atomizing device, or the atomizing device can be connected to a face mask adapter or an intermittent positive pressure breathing machine. The solution, suspension, or powder composition can be administered orally or nasally from a device that delivers the preparation in a suitable manner.

[0337] If desired, the composition can be present in a packaging or dispenser device, which can contain one or more unit dosage forms containing the pharmaceutical substance. The packaging can include, for example, a metal or plastic foil, such as a blister pack. The packaging or dispenser device can be accompanied by instructions for administration. The packaging or dispenser can also be accompanied by precautions associated with the container in the form required by a government agency that regulates the manufacture, use, or sale of the drug, and the precautions reflect the approval of the drug form for human or veterinary administration by that agency. Such precautions can be, for example, the label of a prescription drug approved by the U.S. Food and Drug Administration, or an approved product insert. A composition can also be prepared that includes the compounds described herein formulated in a compatible pharmaceutical carrier, placed in a suitable container, and labeled for the treatment of the designated condition.

[0338] For preparing solid compositions, such as tablets, the pharmaceutical substance can be mixed with excipients to form a solid preformulated composition that contains a homogeneous mixture of the components. When referring to these preformulated compositions as homogeneous, the pharmaceutical substance is generally uniformly dispersed throughout the composition such that the composition can be readily subdivided into equal effective unit dosage forms, such as tablets and capsules.

[0339] A kit is provided that includes one or more of the compounds described herein in a unit dose, typically an oral or injectable dose. Such a kit can include a container containing the unit dose, an information insert that describes the use and attendant benefits of the drug in treating relevant pathological conditions, and optionally an instrument or device for delivering the composition.

[0340] The compounds described herein or their pharmaceutically acceptable salts can be effective over a wide range of doses and are generally administered in a therapeutically effective amount. However, it should be understood that the amount of the compound actually administered will generally be determined by the physician based on relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound being administered, the age, weight, and response of the individual, the severity of the individual's symptoms, etc.

[0341] The amount of the compound or composition administered to an individual will also vary depending on the drug being administered, the purpose of administration (such as prophylaxis or treatment), the condition of the individual, the mode of administration, etc. In therapeutic applications, the composition can be administered to an individual already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms and / or pathology of the disease and its complications. The therapeutically effective dose will depend on the disease condition being treated and the judgment of the attending clinician based on factors such as the severity of the disease, the age, weight, and general condition of the individual.

[0342] The required dose can conveniently be presented as a single dose or as divided doses administered at appropriate intervals (e.g., as two, three, four or more sub-doses per day). The sub-doses themselves can be further divided, for example, into multiple discrete spaced administrations. The daily dose can be divided into several, e.g., two, three or four parts for administration, especially when a relatively large amount of administration is considered appropriate. If appropriate, depending on individual behavior, it may be necessary to deviate upwards or downwards from the indicated daily dose.

[0343] It will be apparent to those skilled in the art that the dosage forms described herein may contain the compounds described herein or pharmaceutically acceptable salts thereof.

[0344] Some aspects provide the use of at least one compound or a pharmaceutically acceptable salt thereof as disclosed and described herein or a pharmaceutical composition as disclosed and described herein in the manufacture of a medicament for the treatment of a neurological disorder, wherein the neurological disorder is selected from schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, antipsychotic-induced movement disorder, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, Lewy body dementia, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorders, movement diseases, hyperkinesia, psychotic disorders, catatonia, mood disorders, depressive disorders, anxiety disorders, obsessive-compulsive disorder (OCD), autism spectrum disorder, prolactin-related conditions (e.g., hyperprolactinemia), neurocognitive disorders, trauma- or stress-related disorders (e.g., PTSD), disruptive, impulse control or conduct disorders, sleep-wake disorders, substance-related disorders, addictive disorders, behavioral disorders, frontal lobe hypofunction, abnormalities in the tuberoinfundibular, mesolimbic, mesocortical or nigrostriatal pathways, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia; Parkinson's disease, drug-induced parkinsonism, movement disorders, dystonia, chorea, levodopa-induced movement disorder, cerebral palsy and progressive supranuclear palsy, and Huntington's disease, including chorea associated with Huntington's disease.

[0345] Some aspects provide for the use of at least one compound or a pharmaceutically acceptable salt thereof as disclosed and described herein, or a pharmaceutical composition as disclosed and described herein, in the manufacture of a medicament for improving one or more symptoms of a neurological disorder selected from schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, antipsychotic-induced movement disorder, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorder, movement disorder, hyperkinesia, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder (OCD), autism spectrum disorder, prolactin-related conditions (e.g., hyperprolactinemia), neurocognitive disorder, trauma- or stress-related disorder (e.g., PTSD), disruptive, impulse control, or conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypofunction, abnormalities in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways, decreased striatal activity, cortical dysfunction, neurocognitive dysfunction, and cognitive deficits associated with schizophrenia; Parkinson's disease, drug-induced parkinsonism, movement disorder, dystonia, chorea, levodopa-induced movement disorder, cerebral palsy, and progressive supranuclear palsy, and Huntington's disease, including chorea associated with Huntington's disease.

[0346] Some aspects provide for the use of at least one compound or a pharmaceutically acceptable salt thereof as disclosed and described herein, or a pharmaceutical composition as 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).

[0347] Some aspects provide for the use of at least one compound or a pharmaceutically acceptable salt thereof as disclosed and described herein, or a pharmaceutical composition as disclosed and described herein, as a monotherapy or as an adjunctive therapy to standard of care in combination with an antipsychotic for treating cognitive impairment associated with schizophrenia (CIAS).

[0348] Some aspects provide for the use of at least one compound or a pharmaceutically acceptable salt thereof as disclosed and described herein, or a pharmaceutical composition as disclosed and described herein, as a monotherapy or as an adjunctive therapy to standard of care in combination with an antipsychotic for treating the following disorders: negative symptoms of schizophrenia, impulse or compulsive disorder, non-motor symptoms of Parkinson's disease, autism spectrum disorder, and other CNS conditions associated with cognitive dysfunction (such as Huntington's disease, multiple sclerosis, etc.).

[0349] Some aspects provide for the use of at least one compound or a pharmaceutically acceptable salt thereof as disclosed and described herein, or a pharmaceutical composition as disclosed and described herein, as a monotherapy or as an adjunctive therapy to standard of care for treating psychosis (positive symptoms).

[0350] Pharmacology and utility

[0351] G-protein coupled receptors (GPCRs) have seven conserved transmembrane domains linked by 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 carboxyl terminus. GPCRs are key components of many cellular signaling pathways. GPCRs are coupled to various enzymes, ion channels, and transporters. Different G-protein subunits can stimulate effectors to regulate various downstream functions in cells.

[0352] Ligand binding induces a conformational change in the GPCR such that the GPCR acts as a guanine nucleotide exchange factor (GEF). The GPCR can then activate the associated G protein by exchanging GDP bound to the G protein for GTP. This GTP, together with the α subunit of the G protein, then dissociates from the β and γ subunits to further regulate intracellular signaling pathways.

[0353] GPR52 is a GPCR that is highly conserved in vertebrates, with more than 90% amino acid sequence identity. The highest expression levels within the central nervous system (CNS) are found in the striatum. Lower but significant expression levels are found in other structures within the CNS, including in the cortex. The tissue distribution of GPR52 does not differ significantly between humans, rats, and mice, indicating that GPR52 has a common function independent of species.

[0354] In the rat brain, GPR52 is expressed in neurons in various regions, including the medial prefrontal cortex, basolateral amygdala, and habenula nucleus, which are responsible for the clinical manifestations of mental disorders. In addition, GPR52 knockout and transgenic mice exhibit psychotic-related and antipsychotic-like behaviors, respectively (Hidetoshi Komatsu et al., February 2014, Volume 9, Issue 2, PLOS ONE, e90134).

[0355] Although GPR52 has been characterized, it remains an orphan receptor, i.e., it does not have a known endogenous ligand. Several alternative ligands have been reported, including extracellular loop 2 (ECL2) of GPR52 itself (Pingyuan Wang et al., J. Med. Chem., 2020, 63, 13951 - 72). GPR52 is commonly co - localized with dopamine receptors (D1 and D2). (See PLOS One, Volume 9, Issue 2, e90134). GPR52 is almost exclusively co - localized with D2 receptors in the human striatum and D1 receptors in the cortex. The efficacy of existing antipsychotic drugs is mediated by D2 antagonist activity, but this activity is accompanied by side effects such as movement symptoms and hyperprolactinemia. Antipsychotic drugs are also associated with a significant side effect profile, including weight gain, metabolic syndrome, diabetes, hyperlipidemia, hyperglycemia, insulin resistance, extrapyramidal symptoms, and tardive dyskinesia. In contrast, GPR52 modulators can essentially act as D2 antagonists and thus exhibit antipsychotic efficacy while avoiding D2 antagonist - related side effects. Accordingly, GPR52 modulators can improve the symptoms of various neurological conditions, diseases, and disorders and represent a target for treating various neurological diseases, including but not limited to psychotic disorders, dissociation, anxiety, anxiety / tension related to psychoneurosis, acute mania, agitation, mania in bipolar disorder, dysthymia, dyspepsia, and drug - related addictions such as cocaine, amphetamines, etc.

[0356] GPR52 is co - localized 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 D2 receptor - expressing neurons in the striatum (Hidetoshi Komatsu et al., February 2014, Volume 9, Issue 2, PLOS ONE, e90134).

[0357] Hypofrontality, i.e., reduced blood flow in 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 hypofrontality associated with substance abuse. Thus, increasing the function in the prefrontal cortex with a GPR52 modulator could be used to treat symptoms associated with hypofrontality.

[0358] In one aspect of the present disclosure is a method of treating a disease or disorder associated with hypofrontality, which comprises administering to a patient in need an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0359] In another aspect of the present disclosure, the frontal lobe hypofunction-related diseases or disorders are selected from the cognitive and negative symptoms associated with schizophrenia, attention deficit / hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder, and frontal lobe hypofunction associated with substance abuse.

[0360] In another aspect, the negative symptoms associated with schizophrenia (interrupting typical emotions, behaviors, and abilities of a person) are selected from reduced speech, strange emotional responses to situations, lack of emotion or expression, loss of interest or excitement in life, social isolation, difficulty experiencing pleasure, difficulty starting or sticking to plans, and difficulty performing normal daily activities.

[0361] Furthermore, with regard to GPR52 agonists that are functionally similar to D1 agonists, GPR52 agonists have the potential to treat conditions 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. In addition, based on their expression patterns and functional coupling, GPR52 agonists can be used to treat cognitive deficits associated with schizophrenia, schizoaffective disorder, schizophreniform and schizotypal disorders, treatment-resistant schizophrenia, minor 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.

[0362] The striatum is involved in the control of movement, including but not limited to hyperkinesias characterized by excessive abnormal involuntary movements (referred to as hyperkinesia). Examples of hyperkinesias include tremors, dystonia, chorea, ballismus, athetosis, tic disorders / Tourette syndrome, Huntington's disease, myoclonus, and startle syndromes, stereotypies, and akathisia. Hyperkinesia is associated with dysfunction of the inhibitory, D2-expressing neurons of this pathway. This dysfunction results in an inability to inhibit movement, leading to tic disorders, chorea, vocalizations, tremors, and other hyperkinetic symptoms. For example, the early hyperkinetic motor symptoms in Huntington's disease are the result of selective damage to the indirect D2-containing pathway. In addition, D2 receptor binding in the striatum is associated with the severity of Tourette syndrome symptoms. Regulation of GPR52 activity can activate the indirect striatal pathway, thereby exerting more inhibitory control over movement and resolution of hyperkinetic symptoms.

[0363] In one aspect of the present disclosure is a method of treating hyperkinesia, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0364] In another aspect of the present disclosure, hyperkinetic disorders are selected from tremors, dystonia, chorea, ballismus, athetosis, tic disorders / Tourette syndrome, Huntington's disease, myoclonus and startle syndrome, stereotypies, and akathisia.

[0365] Huntington's disease is mainly caused by the cytotoxicity of mutant HTT proteins with expanded polyglutamine repeat tracts. Reducing soluble mutant HTT can reduce its downstream toxicity and provide potential treatment for Huntington's disease. Gene knockout of GPR52 significantly reduces mutant HTT levels in the striatum and rescues Huntington's disease-related behavioral phenotypes in a gene-embedded Huntington's disease mouse model. In addition, GPR52 antagonists reduce mutant HTT levels and rescue Huntington's disease-related phenotypes in cellular and mouse models (Haikun Song et al., June 2018, Brain, Vol. 141, No. 6, pp. 1782-98).

[0366] One aspect of the present disclosure is a method for treating Huntington's disease, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0367] Schizophrenia is a complex neuropsychiatric disorder that affects approximately 0.3% of the population. It is a severe, chronic, and disabling mental disorder. The core clinical features of schizophrenia include positive, negative, and cognitive symptoms. Cognitive impairment associated with schizophrenia (CIAS) is highly detrimental to functional ability, and the severity of CIAS is the most accurate predictor of patient outcomes. Antipsychotic drugs can reduce the severity of positive symptoms via dopamine D2 receptor antagonism, but have not demonstrated significant efficacy for negative and cognitive symptoms. Selective GPR52 agonists show therapeutic properties for treating the positive and cognitive symptoms of schizophrenia (Keiji Nishiyama et al., J. Pharm. Exp. Ther., September 2017, 363(2) 253-64).

[0368] The main clinically unmet need in schizophrenia is the treatment of negative and cognitive symptoms, as currently approved antipsychotics provide little improvement. Notably, cognitive deficits in schizophrenia patients are considered a core part of the disorder and are thought to have a significant impact on the patient's recovery and reintegration into society.

[0369] One aspect of the present disclosure is a method for treating schizophrenia, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0370] In another aspect of the present disclosure is a method for treating CIAS, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0371] The psychotic symptoms of schizophrenia are caused by overactive presynaptic dopamine activity in the striatum. The clinical efficacy of existing antipsychotic drugs used to treat psychotic symptoms relies on the blockade of D2 receptors. All known antipsychotic drugs with therapeutic psychosis efficacy are antagonists or partial agonists of the dopamine D2 receptor. 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 the dopamine D2 receptor, GPR52 agonists should treat the psychotic symptoms associated with schizophrenia. Additionally, since the mechanism of action of GPR52 agonists is unique to known D2 receptor-related antipsychotic drugs, it is expected that GPR52 agonists increase the antipsychotic efficacy of known neuroleptics. This would not only improve the efficacy of antipsychotic drugs but also be used to reduce the dose of antipsychotic drugs, thereby reducing their associated side effects. Elevated serum prolactin levels are one of the prominent side effect characteristics of known D2 receptor antagonist antipsychotics, and GPR52 agonists have been shown to reduce serum prolactin levels. Therefore, the co-administration of GPR52 agonists and D2 receptor antagonist antipsychotics can normalize serum prolactin levels, thereby reducing the side effects associated with D2 receptor antagonist antipsychotics. In addition, GPR52 agonists should treat the psychotic symptoms associated with various psychiatric indications, including schizoaffective disorder, schizotypal disorder, schizophreniform disorder, treatment-resistant schizophrenia, drug-induced psychotic disorder, bipolar disorder, autism spectrum disorder, and brief psychotic syndrome.

[0372] In one aspect of the present disclosure is a method of treating a psychiatric indication, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0373] In another aspect, the psychiatric indication is selected from schizoaffective disorder, schizotypal disorder, schizophreniform disorder, treatment-resistant schizophrenia, drug-induced psychotic disorder, bipolar disorder, autism spectrum disorder, and brief psychotic syndrome.

[0374] In one aspect of the present disclosure is a method of treating psychosis and neuropsychiatric symptoms associated with various neurodegenerative indications of the nervous system, which comprises administering to a patient in need thereof an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0375] In another aspect, the psychosis and neuropsychiatric symptoms associated with various neurodegenerative indications of the nervous system are selected from Parkinson's disease, Alzheimer's disease, frontotemporal dementia, vascular cognitive impairment, and dementia with Lewy bodies.

[0376] The present disclosure also provides methods for treating a neurological disorder in an individual in need thereof, the methods comprising administering to the individual a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as disclosed and described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof as disclosed and described herein (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 or a pharmaceutically acceptable salt thereof as disclosed and described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for treating a neurological disorder in an individual in need thereof. The present disclosure also provides the preparation of a medicament or a pharmaceutically acceptable salt thereof as disclosed and described herein (e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof) for treating a neurological disorder in an individual in need thereof.

[0377] In some aspects, the individual has previously been diagnosed with a neurological disorder. In some aspects, the individual currently has a neurological disorder. In some aspects, the individual is suspected of having a neurological disorder. In some aspects, the individual has previously been treated with one or more therapeutics approved for treating neurological disorders.

[0378] In some aspects, the neurological disorder is selected from schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, antipsychotic-induced movement disorder, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorder, movement disorder, hyperkinesia, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder (OCD), autism spectrum disorder, prolactin-related conditions (e.g., hyperprolactinemia), neurocognitive disorder, trauma- or stress-related disorder (e.g., PTSD), disruptive, impulse control, or conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypofunction, abnormalities in the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways, decreased striatal activity, cortical dysfunction, neurocognitive dysfunction, and cognitive deficits associated with schizophrenia; Parkinson's disease, drug-induced parkinsonism, movement disorder, dystonia, chorea, levodopa-induced movement disorder, cerebral palsy, progressive supranuclear palsy, Huntington's disease, and chorea associated with Huntington's disease.

[0379] In some aspects, the neurological disorder is selected from schizophrenia, cognitive impairment, drug-induced psychotic disorder, delusional psychosis, antipsychotic-induced movement disorder, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, attention deficit / hyperactivity disorder (ADHD), Tourette syndrome, catatonia, mood disorder, obsessive-compulsive disorder (OCD), hyperprolactinemia, PTSD, frontal lobe hypofunction, Parkinson's disease, drug-induced Parkinson's syndrome, movement disorder, dystonia, chorea, levodopa-induced movement disorder, cerebral palsy, progressive supranuclear palsy, Huntington's disease, and chorea associated with Huntington's disease.

[0380] In some aspects, the neurological disorder is a neurological disorder selected from schizophrenia. In some aspects, the neurological disorder is a cognitive impairment. In some aspects, the neurological disorder is a panic disorder. In some aspects, the neurological disorder is a phobic disorder. In some aspects, the neurological disorder is a drug-induced psychotic disorder. In some aspects, the neurological disorder is a delusional psychosis. In some aspects, the neurological disorder is an antipsychotic-induced movement disorder. In some aspects, the neurological disorder is Parkinson's disease. In some aspects, the neurological disorder is a drug-induced parkinsonism. In some aspects, the neurological disorder is an extrapyramidal syndrome. In some aspects, the neurological disorder is Alzheimer's disease. In some aspects, the neurological disorder is Lewy body dementia. In some aspects, the neurological disorder is bipolar disorder. In some aspects, the neurological disorder is attention deficit / hyperactivity disorder (ADHD). In some aspects, the neurological disorder is Tourette syndrome. In some aspects, the neurological disorder is an extrapyramidal or movement disorder. In some aspects, the neurological disorder is a movement disorder. In some aspects, the neurological disorder is hyperkinesia. In some aspects, the neurological disorder is a psychotic disorder. In some aspects, the neurological disorder is catatonia. In some aspects, the neurological disorder is a mood disorder. In some aspects, the neurological disorder is a depressive disorder. In some aspects, the neurological disorder is an anxiety disorder. In some aspects, the neurological disorder is obsessive-compulsive disorder (OCD). In some aspects, the neurological disorder is an autism spectrum disorder. In some aspects, the neurological disorder is a prolactin-related condition. In some aspects, the neurological disorder is hyperprolactinemia. In some aspects, the neurological disorder is a neurocognitive disorder. In some aspects, the neurological disorder is a trauma- or stress-related disorder. In some aspects, the neurological disorder is PTSD. In some aspects, the neurological disorder is impulse control. In some aspects, the neurological disorder is or a conduct disorder. In some aspects, the neurological disorder is a sleep-wake disorder. In some aspects, the neurological disorder is a substance-related disorder. In some aspects, the neurological disorder is an addictive disorder. In some aspects, the neurological disorder is a behavioral disorder. In some aspects, the neurological disorder is frontal lobe hypofunction. In some aspects, the neurological disorder includes an abnormality in the tuberoinfundibular pathway. In some aspects, the neurological disorder includes an abnormality in the mesolimbic pathway. In some aspects, the neurological disorder includes reduced striatal activity. In some aspects, the neurological disorder is a cortical dysfunction. In some aspects, the neurological disorder is a neurocognitive dysfunction and a cognitive deficit associated with schizophrenia. In some aspects, the neurological disorder is a drug-induced parkinsonism. In some aspects, the neurological disorder is a movement disorder. In some aspects, the neurological disorder is dystonia. In some aspects, the neurological disorder is chorea. In some aspects, the neurological disorder is a levodopa-induced movement disorder. 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 and chorea associated with Huntington's disease.

[0381] In some aspects, panic disorder includes panic attacks. In some aspects, phobic disorder is related to situations (e.g., social phobia). In some aspects, phobic disorder is related to objects (e.g., arachnophobia). In some aspects, extrapyramidal syndrome includes persistent spasms or muscle contractions, motor restlessness, muscle rigidity, slowed muscle response, tremors or irregular jerky movements. In some aspects, extrapyramidal or movement disorders are tardive dyskinesia, acute dystonic reaction, akathisia or pseudoparkinsonism. In some aspects, movement disorders are developmental coordination disorder, stereotyped movement disorder or Tourette syndrome. In some aspects, hyperkinesia includes athetosis, ballismus, chorea, dystonia, myoclonus, restless legs syndrome, stereotypic movement disorder, tics or tremors. In some aspects, mental disorders are schizophrenia, schizophreniform disorder, delusional disorder or chronic hallucinatory psychosis. In some aspects, mood disorders are major depressive disorder or bipolar depression. In some aspects, depression is major depressive disorder, atypical depression, melancholic depression, catatonic major depression, postpartum depression, seasonal affective disorder or double depression. In some aspects, anxiety disorders are generalized anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder, phobic disorder or panic disorder. In some aspects, autism spectrum disorder is autism or Asperger syndrome. In some aspects, neurocognitive disorders are major neurocognitive disorder or mild neurocognitive disorder. In some aspects, disruptive, impulse-control or conduct disorders are attention deficit disorder, attention deficit hyperactivity disorder, oppositional defiant disorder, sexual compulsion, Internet addiction, pyromania, intermittent explosive disorder, compulsive shopping or kleptomania. In some aspects, sleep-wake disorders are insomnia, narcolepsy or night terrors. In some aspects, substance-related disorders are alcoholism, opioid addiction, prescription drug addiction and / or illegal drug addiction. In some aspects, addictive disorders include substance addiction (e.g., alcoholism) or experiential addiction (e.g., gambling addiction). In some aspects, conduct disorders are attention deficit disorder, attention deficit hyperactivity disorder or oppositional defiant disorder.

[0382] It should be understood in the art that some of the syndromes and symptoms described herein can have overlapping symptoms, and / or some of the specific disorders described herein can belong to multiple categories of the disorders described herein. For example, tardive dyskinesia can be classified at least as an extrapyramidal or movement disorder, hyperkinesia, movement disorder or extrapyramidal syndrome.

[0383] Some aspects provide methods for modulating GPR52 in cells, which include contacting the cells with a compound of formula (I) or a pharmaceutically acceptable salt thereof. Without being bound by any theory, the compound and the receptor can be contacted for a sufficient time under suitable conditions that permit interaction between the cells and the compound.

[0384] In some aspects, the contact is in vitro. In some aspects, the contact is in vivo. In some aspects, the contact is in vivo, wherein the method comprises administering to an individual having cells with GPR52 activity a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0385] In certain aspects, the cells are in an individual in need of treatment with a compound disclosed herein. In certain aspects, the cells are from an individual in need of treatment with a compound disclosed herein. In some aspects, the individual has a neurological disease, condition, or disorder. In some aspects, the individual is at risk of developing a neurological disease, condition, or disorder. In some aspects, the individual has previously been diagnosed with a neurological disease, condition, or disorder. In some aspects, the individual is currently receiving treatment for a neurological disease, condition, or disorder. In some aspects, the individual has a neurological disease, condition, or disorder. In some aspects, the individual is suspected of having a neurological disease, condition, or disorder. In some aspects, the neurological disease, condition, or disorder is Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, attention deficit / hyperactivity disorder (ADHD), Tourette syndrome, extrapyramidal or movement disorders, movement diseases, hyperkinesias, psychotic disorders, catatonia, mood disorders, depressive disorders, anxiety disorders, obsessive-compulsive disorder (OCD), autism spectrum disorder, prolactin-related disorders (e.g., hyperprolactinemia), neurocognitive disorders, trauma- or stress-related disorders (e.g., PTSD); disruptive, impulse control, or conduct disorders, sleep-wake disorders, substance-related disorders, addictive disorders, behavioral disorders, frontal lobe hypofunction, abnormalities of the tuberoinfundibular, mesolimbic, mesocortical, or nigrostriatal pathways, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction, and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced parkinsonism, movement disorders, dystonia, chorea, levodopa-induced dyskinesia, cerebral palsy, and progressive supranuclear palsy, and Huntington's disease, particularly chorea associated with Huntington's disease.

[0386] The cardiac potassium channel hERG (human ether-a-go-go related gene) is responsible for the rapid delayed rectifier current (IKr) in the human ventricle. Inhibition of IKr is the most common cause of drug-induced prolongation of the cardiac action potential by non-cardiac drugs (Brown, A.M. 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, Y.G. and Camm, A.J. (1999), “Arrhythmogenic mechanisms of non-sedating antihistamines”, Clin Exp. Allergy, 29 Suppl 3, 174-181). The increased action potential duration results in prolongation of the QT interval and is associated with torsade de pointes (Brown, A.M. and Rampe, D., (2000), “Drug-induced long QT syndrome: is HERG the root of all evil?”, Pharmaceutical News, 7, 15-20). Evaluate the in vitro effects of Formula I compounds on hERG channel current (a surrogate for IKr, i.e., rapidly activating delayed rectifier cardiac potassium current) (Redfern, W.S. et al., “Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development”, Cardiovascular Research, Vol. 58, No. 1, April 2003, pp. 32–45). See the “Activity of Formula I Compounds on hERG” examples below.

[0387] Animal models can be used to model the cognitive impairments in schizophrenia. Administration of the glutamate / NMDA antagonist phencyclidine (PCP) provides a model of schizophrenia that induces both 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 validity because there is evidence of abnormalities in the glutamatergic system in the brains of schizophrenics; such changes include deficits in corticostriatal innervation which, even if not the basis of the cognitive dysfunction of the disease, can contribute to it (Aparicio-Legarza et al., “Deficits of 3 H]d-aspartate binding to glutamate uptake sites in striatal and accumbens tissue in patients with schizophrenia”, Neuroscience Letters, August 22, 1997, pp. 13-16). In addition, some of the PCP-induced behaviors are reversed by certain atypical but not typical antipsychotics (Geyer, M.A. et al., “Startle response models of sensorimotor gating and habituation deficits in schizophrenia”, Brain Research Bulletin, Vol. 25, No. 3, September 1990, 485-498). This suggests a potential relevance to the effects on negative and cognitive symptoms that are less responsive to typical antipsychotics.

[0388] Some preclinical tests allow relatively subtle cognitive deficits to be observed in rats that are similar to the cognitive symptoms in individuals with a range of CNS disorders. These cognitive impairments include visual memory deficits, which can be measured by recognition tasks such as the novel object recognition (NOR) paradigm. Recognition memory tasks allow a comparison between the presented stimuli and previously stored information. The NOR test in rats described by Enn & Delacour is based on the differential exploration of familiar and new objects (“A new one-trial test for neurobiological studies of memory in rats: I. Behavioral data”, Behavioral Brain Research, 31(1), 47–59, 1988). The NOR test is a non-rewarded, behaviorally relevant paradigm based on the spontaneous exploratory behavior of rats that measures episodic memory. Each session consists of two trials. In the first trial, the rat is exposed to two identical objects in an open field. During the second trial, the rat is exposed to two different objects, one a familiar object from the first trial and the other a novel object. Object recognition in rats can be measured by the difference in the time spent exploring the familiar and new objects. It has been shown that rats spend more time exploring the novel object. It has been found that rats are able to discriminate between familiar and novel objects when the inter-trial interval is between 3 minutes and 1–3 hours, but are unable to distinguish when the inter-trial interval is greater than 24 hours, although this effect may be gender-related in rats (Sutcliffe et al., “Influence of gender on working and spatial memory in the novel object recognition task in the rat”, Behavioral Brain Research, 2007 Feb 12;177(1):117-25). The duration of each trial is also important, as the preference for the novel object only lasts for the first 3 minutes, after which the preference decreases as the two objects become familiar and are explored equally.

[0389] Effects of PCP. Sub-chronic (sc) treatment with PCP produces neuropathological changes associated with schizophrenia. This protocol produces selective deficits in reversal learning in the operant reversal learning test and in novel object recognition. The deficits induced by (scPCP) are strong and persistent in female rats, and this dosing protocol also produces a reduction in social behavior in female hooded-Lister rats. The 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., “Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat”, Psychopharmacology, 2007 (March), 21(2):198-205; 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 sub-chronic PCP-induced cognitive deficits in a reversal-learning paradigm”, Behavioral Brain Research, 169(2006), 263-273;Abdul-Monim et al., "Sub-chronic psychotomimetic phencyclidine induces deficits in reversal learning and alterations in parvalbumin-immunoreactive expression in the rat", Psychopharmacology, 2007 (March), 21(2):198-205; McLean et al., "D1-like receptor activation improves PCP-induced cognitive deficits in animal models: Implications for mechanisms of improved cognitive function in schizophrenia", Vol. 19, No. 6, June 2009, pp. 440-450; and Idris et al., "Sertindole improves sub-chronic PCP-induced reversal learning and episodic memory deficits in rodents: involvement of 5-HT6 and 5-HT2A receptor mechanisms", Psychopharmacology, 208(23), 2010; Grayson et al., "Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat", Behavioral Brain Research, Vol. 184, No. 1, 2007; Snigdha, et al., "Improvement of phencyclidine-induced social behavior deficits in rats: Involvement of 5-HT1A receptors", Behavioral Brain Research, Vol. 191, No. 1, 2008, pp. 26-31).;

[0390] The following examples provide behavioral tests and methods (NOR and social interaction paradigms).

[0391] Drug combinations

[0392] It should also be understood that, for clarity, certain features of the present disclosure described in the context of separate aspects may also be provided in combination in a single aspect. Conversely, for brevity, the various features of the present disclosure described in the context of a single aspect may also be provided separately or in any suitable sub-combination.

[0393] Examples

[0394] Detailed methods for the synthesis of compounds are described in the examples provided herein. A person of ordinary skill in the art of chemistry will be able to prepare the compounds of formula (I) and related formulas by these methods or similar methods or other methods practiced by those skilled in the art, including the specific compounds described herein. Generally, the starting components are commercially available chemicals and can be obtained from commercial sources or can be prepared starting from commercially available chemicals and / or from compounds described in the chemical literature according to organic synthesis techniques known to those skilled in the art. The compounds described herein are named according to MarvinSketch 18.24.0 or ChemDraw Professional 20.1.1.125 or later versions. In certain cases, when common names are used, it should be understood that these common names will be recognized by those skilled in the art.

[0395] "Commercially available chemicals" can be obtained from standard commercial sources, including Acros Organics (Pittsburgh PA), Aldrich Chemical (Milwaukee WI, including Sigma Chemical and Fluka), Apin Chemicals Ltd. (Milton Park UK), Avocado Research (Lancashire U.K.), BDH Inc. (Toronto, Canada), Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester PA), Crescent Chemical Co. (Hauppauge NY), Eastman Organic Chemicals, Eastman Kodak Company (Rochester NY), Fisher Scientific Co. (Pittsburgh PA), Fisons Chemicals (Leicestershire UK), Frontier Scientific (Logan UT), ICN Biomedicals, Inc. (Costa Mesa CA), KeyOrganics (Cornwall U.K.), Lancaster Synthesis (Windham NH), Maybridge ChemicalCo.Ltd. (Cornwall U.K.), Parish Chemical Co. (Orem UT), Pfaltz & Bauer, Inc. (Waterbury CN), Polyorganix (Houston TX), Pierce Chemical Co. (Rockford IL), Riedel de Haen AG (Hanover, Germany), Spectrum Quality Product, Inc. (NewBrunswick, NJ), TCI America (Portland OR), Trans World Chemicals, Inc. (RockvilleMD), and Wako Chemicals USA, Inc. (Richmond VA).

[0396] Methods known to those of ordinary skill in the art can be identified through various reference books and databases. Suitable reference books and papers that detail the synthesis of reactants useful for preparing the compounds of the present disclosure or provide a suitable reference to articles describing the preparation include, for example, Synthetic Organic Chemistry, John Wiley & Sons, Inc., New York; S.R. Sandler et al., Organic Functional Group Preparations, 2nd Edition, Academic Press, New York, 1983; H.O. House, Modern Synthetic Reactions, 2nd Edition, W.A. Benjamin, Inc. Menlo Park, Calif. 1972; T.L. 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. Other suitable reference books and papers that detail the synthesis of reactants useful for preparing the compounds of the present disclosure or provide a reference to articles describing the preparation include, for example, Fuhrhop, J. and Penzlin G. Organic Synthesis: Concepts, Methods, Starting Materials, Second Revised Edition (1994) John Wiley & Sons ISBN: 3 527-29074-5; Hoffman, R.V. Organic Chemistry, An Intermediate Text (1996) Oxford University Press, ISBN 0-19-509618-5; Larock, R.C. Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (1999) Wiley-VCH, ISBN: 0-471-19031-4; March, J. Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 4th Edition (1992) John Wiley & Sons, ISBN: 0-471-60180-2; Otera, J.(Editor) Modern Carbonyl Chemistry, (2000) Wiley-VCH, ISBN: 3-527-29871-1; Patai, S., Patai's 1992 Guide to the Chemistry of Functional Groups, (1992) Interscience ISBN: 0-471-93022-9; Quin, L.D. et al. A Guide to Organophosphorus Chemistry, (2000) Wiley-Interscience, ISBN: 0-471-31824-8; Solomons, T.W.G. Organic Chemistry, 7th Edition (2000) John Wiley & 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, hardcover volumes (86) and electronic volumes (26).

[0397] Specific and similar reactants can also be identified by indexes of known chemical substances prepared by the Chemical Abstract Service of the American Chemical Society (which are available in most public and university libraries) and by online databases (more details can be obtained by contacting the American Chemical Society, Washington, D.C.). Chemicals that are known but not cataloged can be prepared by custom chemical synthesis facilities according to known methods, and many of the standard chemical supply facilities (such as those listed above) offer custom synthesis services.

[0398] The term "reducing agent" refers to a compound that donates a hydride to an electrophilic position of a reactant compound, such as unsaturated carbon (e.g., the carbon of a carbonyl moiety), such as converting a reactant compound containing a ketone into an alcohol product compound or converting a reactant compound containing an ester into an alcohol product compound. The reducing agent can be a hydride reducing agent. Example 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, diisobutyl-tert-butoxyaluminum lithium, lithium tris(tert-butoxy)aluminum 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, tetraethylammonium borohydride, tetramethylammonium borohydride, copper(I) bis(triphenylphosphine) borohydride, lithium 9-borabicyclo[3.3.1]nonane hydride, sodium triacetoxyborohydride, potassium tri-sec-butylborohydride, sodium tri-sec-butylborohydride, potassium tripentylborohydride, lithium triethylborohydride, potassium triethylborohydride, sodium triethylborohydride, potassium triphenylborohydride, lithium dimethylaminoborohydride, lithium pyrrolidinylborohydride, sodium cyanoborohydride, sodium trimethoxyborohydride, sodium borohydride, etc.

[0399] The term "halogenating agent" refers to a compound that donates a halogen atom to a reactant compound, such as converting an alcohol reactant compound into an alkyl halide product compound. Examples of halogenating agents include, but are not limited to, thionyl chloride, oxalyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, methanesulfonyl chloride and NaI, p-toluenesulfonyl chloride and NaI, phosphorus tribromide, triphenylphosphine dibromide, phosphorus pentabromide or thionyl bromide, etc.

[0400] The term "amide coupling agent" refers to a compound that promotes the formation of an amide bond, where carboxylic acid activation is required to facilitate coupling with an amine. Examples of amide coupling agents include, but are not limited to, thionyl chloride, oxalyl chloride, phosphoryl chloride, Vilsmeier reagent, propylphosphonic anhydride, ethylmethylphosphinic anhydride (EMPA), Ac2O, 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-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC), 1,3-di-p-tolylcarbodiimide, benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyBOP), 6-chloro-benzotriazol-1-yloxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyClock), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), 1-cyano-2-ethoxy-2-oxoethylideneaminooxy-tris-pyrrolidinophosphonium hexafluorophosphate (PyOxim), 1-[(1-(cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpholino)]uronium hexafluorophosphate (COMU), 3-(diethoxy-phosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU), O-(2-oxo-1(2H)pyridinyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium tetrafluoroborate (TBTU), N,N,N',N'-tetramethyl-O-(N-succinimidyl)uronium hexafluorophosphate (HSTU), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), 2-(6-chloro-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylammonium hexafluorophosphate (HCTU), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU).

[0401] The term "base" refers to a compound that is an electron pair donor in an acid-base reaction.

[0402] A base can be an inorganic base or an organic base.

[0403] The term "organic base" refers to a base that contains at least one C-H bond (such as an amine base). In some aspects, the amine base can be a primary amine, secondary amine, 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-dimethylpyridine, 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, etc. In some aspects, the amine base can include an alkali metal or an alkaline earth metal. Examples of amine bases including an alkali metal include, but are not limited to, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, lithium dicyclohexylamide, lithium dimethylamide, lithium diethylamide, lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidide, etc. In some aspects, the organic base can be a metal alkoxide. Examples of metal alkoxides include, but are not limited to, barium tert-butoxide, lithium tert-pentoxide, lithium tert-butoxide, lithium ethoxide, lithium isopropoxide, lithium methoxide, magnesium bis(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 aspects, 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.

[0404] The term "inorganic base" refers to a base that does not include at least one C-H bond and includes at least one alkali metal or 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.

[0405] The term "acid" refers to a compound that is an electron pair acceptor in an acid-base reaction.

[0406] An acid can be an inorganic acid or an organic acid.

[0407] The term "inorganic acid" refers to an acid that does not contain a carbon bond. An inorganic acid can be a strong acid or a weak acid. 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, etc.

[0408] The term "organic acid" refers to an acid that includes at least one C-H bond, C-F bond, or C-C bond. Examples of organic acids include, but are not limited to, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, difluoroacetic acid, ethanesulfonic acid, formic acid, fumaric acid, gallic acid, glycolic acid, lactic acid, maleic acid, malonic acid, methanesulfonic acid, nitrilotriacetic acid, oxalic acid, phthalic acid, propionic acid, salicylic acid, succinic acid, 5-sulfosalicylic acid, L-(+)-tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc.

[0409] General reaction schemes

[0410] The present disclosure also includes a method for preparing a compound of formula (I). In the described reaction, it may be necessary to protect reactive functional groups, such as hydroxyl, amino, imino, thio, or carboxyl groups, where these are required in the final product, to avoid their unnecessary participation in the reaction. Conventional protecting groups can be used according to standard practice, for example, see "Protective Groups in Organic Chemistry" by T.W. Greene and P.G.M. Wuts, John Wiley and Sons, 1991.

[0411] The compound of formula (I) can be prepared by the following reaction scheme 1:

[0412] Reaction Scheme 1

[0413]

[0414] wherein R1, R2, R3, R4, X1, X2 and X3 are as defined in the above Summary of the Invention. The compound of formula I can be synthesized by combining the compound of formula (2) and the compound of formula (3) in the presence of a suitable solvent (such as DCM, DCE, NMP, DMF, EtOAc, toluene, dioxane, ethanol, water, etc.), an optional suitable base (such as DIEA, TEA, etc.) and a suitable coupling agent (such as EDC / HOBt, HATU, HBTU, HCTU, etc.). The reaction is carried out 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.

[0415] The compound of formula (I) can be prepared by the following Reaction Scheme 2:

[0416] Reaction Scheme 2

[0417]

[0418] wherein R1, R2, R3, R4, X1, X2 and X3 are as defined in the above Summary of the Invention, and Z is a suitable leaving group such as a halogen (such as chlorine, etc.). The compound of formula I can be prepared by using a suitable solvent (such as toluene, dioxane, ethanol, DMF, EtOAc, etc.), a suitable base (such as sodium carbonate, sodium hydroxide, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, etc.) and a suitable coupling agent (such as tetrakis(triphenylphosphine)palladium(0) [CAS: 14221-01-3], X-phos-Pd-G2 [CAS: 1310584-14-5], X-phos-Pd-G3 [CAS: 1445085-55-1], X-phos Pd-G4 [CAS: 1599466-81-5, etc.]. The reaction is carried out 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.

[0419] The compound of formula (I) can be prepared by the following Reaction Scheme 3:

[0420] Reaction Scheme 3

[0421]

[0422] Wherein R1, R2, R3, R4, X1, X2 and X3 are as defined in the above Summary of the Invention, and Q is chlorine, fluorine or bromine. The compound of formula I can be synthesized by combining the compound of formula (6) and the compound of formula (7) in the presence of a suitable solvent (such as DMF, NMP, THF, dioxane, DMA, EtOH, MeOH, IPA, BuOH, etc.) and a suitable base (such as potassium carbonate, sodium carbonate, cesium carbonate, NaH, etc.). The reaction is carried out 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. Additional methods for preparing the compounds of the present disclosure

[0423] 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. Optionally, the 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.

[0424] The compound of formula I can also be modified by attaching appropriate functional groups to enhance its selective biological properties. This type of modification is known in the art and includes those that increase penetration into a given biological system (such as blood, lymphatic system, central nervous system, testis), increase bioavailability, increase solubility to allow parenteral administration (such as injection, infusion), alter metabolism and / or alter the secretion rate. Examples of this type of modification include, but are not limited to, esterification (such as esterification with polyethylene glycol), derivatization with pivaloyloxy or fatty acid substituents, conversion to carbamate, hydroxylation of aromatic rings and substitution of heteroatoms in aromatic rings.

[0425] Whenever reference is made to a compound of formula I and / or its N-oxides, tautomers and / or (preferably pharmaceutically acceptable) salts, this includes such modified forms, and preferably refers to the molecule of formula I, its N-oxides, its tautomers and / or its salts.

[0426] Optionally, salts of the compounds of the present disclosure can be prepared using salts of the starting materials or intermediates. In view of the close relationship between the new compound of formula I in free form and its salt forms (including those salts that can be used as intermediates, such as in the purification or identification of new compounds), any reference to the compound or the compound of formula I above and below should be understood to refer to the compound in free form and / or, where appropriate and advantageous, also to one or more of its salts, and one or more solvates, such as hydrates.

[0427] Preferably, it forms a salt, such as an acid addition salt, especially a pharmaceutically acceptable salt, with an organic acid or an inorganic acid from the compound of formula I having a basic nitrogen atom. Suitable inorganic acids are, for example, hydrohalic 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 acid, phthalic acid, phenylacetic acid, mandelic acid, cinnamic acid, methanesulfonic acid or ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid, benzenesulfonic acid, 4-toluenesulfonic acid, 2-naphthalenesulfonic acid, 1,5-naphthalenedisulfonic acid, 2- or 3-methylbenzenesulfonic acid, methylsulfuric acid, ethylsulfuric acid, dodecylsulfuric acid, N-cyclohexylsulfamic acid, N-methylsulfamic acid or N-ethylsulfamic acid, or other organic protonic acids, such as ascorbic acid.

[0428] For separation or purification purposes, pharmaceutically unacceptable salts, such as picrates or perchlorates, can also be used. For therapeutic use, only pharmaceutically acceptable salts or free compounds (when applied in the form of a pharmaceutical preparation) are used, and thus these are preferred.

[0429] The free acid or free base form of the compounds of the present disclosure can be prepared from the corresponding base addition salts or acid addition salts, respectively. For example, a compound of the present disclosure in acid addition salt form can be converted into the corresponding free base by treatment with a suitable base (such as an ammonium hydroxide solution, sodium hydroxide, etc.). A compound of the present disclosure in base addition salt form can be converted into the corresponding free acid by treatment with a suitable acid (such as hydrochloric acid, etc.).

[0430] The compounds of the present disclosure in non-oxidized form can be prepared from the oxides of the compounds of the present disclosure by treatment with a reducing agent (such as sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide, etc.) in a suitable inert organic solvent (such as acetonitrile, ethanol, aqueous dioxane, etc.) at 0 to 80 °C.

[0431] Prodrug derivatives of the compounds of the present disclosure can be prepared by methods known to those of ordinary skill in the art (e.g., for other details, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, suitable prodrugs can be prepared by reacting the non-derivatized compounds of the present disclosure with suitable carbamoylating reagents (e.g., 1,1-acyloxyalkylcarbamoyl chlorides, p-nitrophenyl carbonates, etc.).

[0432] Protected derivatives of the compounds of the present disclosure can be prepared by methods known to those of ordinary skill in the art. A detailed description of the techniques applicable to the generation and removal of protecting groups can be found in T.W. Greene, "Protecting Groups in Organic Chemistry", 3rd Edition, John Wiley and Sons, Inc., 1999.

[0433] The compounds of the present disclosure can be conveniently prepared or formed as solvates (e.g., hydrates) during the methods of the present disclosure. Hydrates of the compounds of the present disclosure can be conveniently prepared by recrystallization from a water / organic solvent mixture using an organic solvent such as dioxene, tetrahydrofuran or methanol.

[0434] 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 diastereomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. Although covalent diastereomeric derivatives of the compounds of the present disclosure can be used for the resolution of enantiomers, dissociable complexes are preferred (e.g., crystalline diastereomeric salts). Diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and can be readily separated by taking advantage of these differences. Diastereomers can be separated by chromatography or preferably by separation / splitting techniques based on differences in solubility. The optically pure enantiomers, as well as the resolving agent, are then recovered by any practical method that does not cause racemization. A more detailed description of the techniques applicable to the resolution of the stereoisomers of a compound from its racemic mixture can be found in Jean Jacques, Andre Collet, Samuel H. Wilen, "Enantiomers, Racemates and Resolutions", John Wiley and Sons, Inc., 1981.

[0435] In summary, the compounds of formula I can be prepared by a method comprising the following steps:

[0436] (a) A method of Reaction Scheme I, II or III; and

[0437] (b) Optionally converting a compound of the present disclosure into a pharmaceutically acceptable salt;

[0438] (c) Optionally converting a salt form of a compound of the present disclosure into a non-salt form;

[0439] (d) Optionally converting an unoxidized form of a compound of the present disclosure into a pharmaceutically acceptable N-oxide;

[0440] (e) Optionally converting an N-oxide form of a compound of the present disclosure into its unoxidized form;

[0441] (f) Optionally resolving individual isomers of a compound of the present disclosure from a mixture of isomers;

[0442] (g) Optionally converting an underivatized compound of the present disclosure into a pharmaceutically acceptable prodrug derivative; and

[0443] (h) Optionally converting a prodrug derivative of a compound of the present disclosure into its underivatized form.

[0444] In the case where the production of the starting materials is not specifically described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the examples below.

[0445] Those skilled in the art should understand that the above conversions only represent methods for preparing the compounds of the present disclosure, and other well-known methods can be used similarly.

[0446] The following examples are included to illustrate aspects of the present disclosure. However, in view of the present disclosure, those skilled in the art should understand that many changes can be made to the specific aspects disclosed without departing from the spirit and scope of the disclosure, and still obtain the same or similar results.

[0447] This specification includes many abbreviations, the definitions of which are listed in the following table:

[0448]

[0449]

[0450] Analytical HPLC analysis was performed on an LC-MS system equipped with a UV detector (DionexTM UVD 170u UV / VIS detector), a corona array detector (ThermoTM VeoTM RS), and a mass spectrometer (Dionex MSQ PlusTM). Reverse-phase preparative HPLC purification was carried out on a Phenomenex LCMS system C18 Kinetix 5μ 100A 150X21.2 mm column using an ACN / water gradient containing 0.05% TFA. All final compounds were analyzed by analytical HPLC, and the peaks of purity were monitored at 210, 254, and 280 nM. 1 H 1 H chemical signals were given in parts per million (ppm), with the residual solvent signal used as a reference. Chemical shifts were expressed in ppm (δ), and coupling constants (J) were reported in hertz (Hz). Unless otherwise stated, reactions were carried out under a dry nitrogen atmosphere.

[0451] In addition, the following LCMS methods were used:

[0452] LCMS method 1A:

[0453] Platform: Agilent 1260 UPLC with a Thermo MSQ mass detector and an Agilent DAD (220 and 254 nm);

[0454] HPLC column: Waters XBridge BEH C18, 2.5 μM, 50×3.0 mm XP;

[0455] HPLC gradient: 1.5 mL / min, 10% acetonitrile (containing 0.025% TFA) / water (containing 0.025% TFA) for 6 seconds, then increased to 90% acetonitrile in 1.5 minutes. Increased to 99% acetonitrile in 6 seconds, then held at 99% acetonitrile for 12 seconds. Returned to 10% acetonitrile in 6 seconds and held at 10% for 30 seconds.

[0456] LCMS method 1B:

[0457] Platform: Agilent 1260 UPLC with a Thermo MSQ mass detector and an Agilent DAD (220 and 254 nm);

[0458] HPLC column: Waters XBridge BEH C18, 2.5 μM, 50x 3.0 mm XP;

[0459] HPLC gradient: 1.5 mL / min, 10% acetonitrile (containing 0.025% TFA) / water (containing 0.025% TFA) for 6 seconds, then increased to 90% acetonitrile in 6.5 minutes. Increased to 99% acetonitrile in 6 seconds, then held at 99% acetonitrile for 12 seconds. Returned to 10% acetonitrile in 6 seconds and held at 10% for 30 seconds.

[0460] LCMS method 2A:

[0461] Platform: Thermo Vanquish UHPLC with Thermo ISQEC mass detector, Thermo DAD (212, 220, 254 and 270 nm) and Thermo charged aerosol detector;

[0462] HPLC column: Waters ACQUITY UPLC BEH C18, 1.7 μM, 50 x 2.1 mm;

[0463] HPLC gradient: 1.1 mL / min, 10% acetonitrile (containing 0.025% TFA) / water (containing 0.025% TFA) for 6 seconds, then increased to 90% acetonitrile in 1.35 minutes. Increased to 99% acetonitrile in 6 seconds, then held at 99% acetonitrile for 9 seconds. Returned to 10% acetonitrile in 6 seconds and held at 10% for 12 seconds.

[0464] LCMS method 2B:

[0465] Platform: Thermo Vanquish UHPLC with Thermo ISQEC mass detector, Thermo DAD (212, 220, 254 and 270 nm) and Thermo charged aerosol detector;

[0466] HPLC column: Waters ACQUITY UPLC BEH C18, 1.7 μM, 50 x 2.1 mm;

[0467] HPLC gradient: 1.0 mL / min, 5% acetonitrile (containing 0.025% TFA) / water (containing 0.025% TFA) for 6 seconds, then increased to 90% acetonitrile in 6.35 minutes. Increased to 99% acetonitrile in 6 seconds, then held at 99% acetonitrile for 9 seconds. Returned to 5% acetonitrile in 6 seconds and held at 5% for 12 seconds.

[0468] LCMS method 3A:

[0469] Platform: Thermo Vanquish UHPLC with Thermo ISQ EC mass detector, Thermo DAD (212, 220, 254 and 270 nm), and Thermo electrical aerosol detector;

[0470] HPLC column: Waters ACQUITY UPLC BEH C18, 1.7 μM, 50 x 2.1 mm;

[0471] HPLC gradient: 1.1 mL / min, 2% acetonitrile (containing 0.025% TFA) / water (containing 0.025% TFA) for 42 seconds, then increased to 90% acetonitrile in 2.8 minutes. Increased to 99% acetonitrile in 6 seconds. Returned to 2% acetonitrile in 6 seconds and held at 2% for 9 seconds.

[0472] The examples illustrate but are not limited to the synthesis of compounds of formula (I).

[0473] Intermediate Example 1

[0474] 1,3-Dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol

[0475]

[0476] Synthesis of 1,3 - dimethyl - 1H - pyrazolo[4,3 - b]pyridin - 6 - ol:

[0477]

[0478] Step A: Suspend 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)Cl2·CH2Cl2 (3.61 g, 4.42 mmol), and potassium acetate (13.02 g, 132.7 mmol) in degassed dioxane. Heat the mixture at 100 °C for 2 h under argon. After cooling to room temperature, dilute the mixture with ethyl acetate / hexane, filter through a silica pad, and concentrate in vacuo. The residue is used in the next step without purification.

[0479] Step B: Dissolve 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) in THF / H2O (3 / 1), and cool with ice. Then add NaBO3·4H2O (17.0 g, 110.49 mmol), and stir overnight. After that, add Na2S2O3 and separate the organic layer. Extract the water with EtOAc, wash the combined organic layers with brine, dry over Na2SO4 and evaporate. Subject the residue to FC ( Interchim; 220 g SiO2, acetonitrile / methanol, methanol from 0 - 95%, flow rate = 80 mL / min, Rt = 20 - 55 min) to obtain 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.

[0480] Following the procedure in Intermediate Example 1, prepare the following Intermediate Examples in Table 1 using the appropriate starting materials:

[0481] Table 1

[0482]

[0483]

[0484] Intermediate Example 2

[0485] 1-Methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-ol

[0486]

[0487] Synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-ol:

[0488]

[0489] Step A: Add hydrazine hydrate (18.77 g, 375.01 mmol) 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 heat the mixture to reflux overnight. Evaporate the cooled reaction mixture to obtain a solid. Add water (100 ml), and filter the mixture to obtain 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.

[0490] 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 min and iodomethane (2.69 g, 18.95 mmol, 1.18 ml, 2.1 eq) was added. The reaction mixture was stirred at 0 °C for 10 min and then at room temperature for 16 h. 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).

[0491] 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), Pd(dppf)Cl2·CH2Cl2 (583.19 mg, 714.13 μmol) were suspended in anhydrous dioxane. The mixture was degassed and heated at 100 °C for 1 h under argon. 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 without purification in the next step.

[0492] Step D: Dissolve 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) in THF / H2O (150 / 50 ml), add NaBO3·4H2O (2.05 g, 13.33 mmol) portionwise at 15 - 20 °C, and stir the resulting mixture at room temperature for 16 h. After adding an aqueous solution of Na2S2O3, extract the mixture with ethyl acetate (150 ml × 3). Combine the extracts, wash with saturated NaCl solution, dry over anhydrous sodium sulfate, then remove the solvent under reduced pressure, and purify the crude product by column chromatography to obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-5-ol (530.0 mg, 2.44 mmol, 51.3% yield). 1 1H NMR (400 MHz, DMSO-d6, 27 °C): 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).

[0493] Intermediate Example 3

[0494] 1-Methyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol

[0495]

[0496] Synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol:

[0497]

[0498] Step A: Stir 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) at room temperature for 12 h. Quench the reaction by diluting with a saturated solution of sodium bisulfite (350 mL) and form a precipitate. Filter the precipitate under vacuum and wash with water (3 × 100 mL). Dry the solid in a vacuum oven at 30 °C overnight to obtain an orange solid (8.12 g).

[0499] Step B: 6-Bromo-3-iodo-1H-pyrazolo[4,3-b]pyridine (8.1 g, 25.01 mmol) and methyl iodide (7.1 g, 50.01 mmol, 3.11 ml, 2.0 equiv) were suspended in anhydrous DMF (100 mL), and then cesium carbonate (24.44 g, 75.02 mmol) was added at 20 °C. The reaction mixture was stirred overnight at room temperature. The resulting solution was concentrated under reduced pressure. The residue was dissolved in 500 mL of water, the solid was filtered off, washed 3 times with water, and dried in air at 50 °C. After purification by FC, 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. LC / MS [M+H] 337.8.

[0500] 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). The reaction mixture was stirred at 80 °C for 12 h. The mixture was then concentrated in vacuo, and the residue was purified by FC (Companion combiflash; 80 g SiO2, CHCl3 / MeCN, MeCN from 0 - 95%, 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.

[0501] Step D: Potassium acetate (1.75 g, 17.85 mmol) was added 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). The resulting mixture was degassed and purged with nitrogen three times. Then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (728.98 mg, 892.67 μmol) was added, and the reaction mixture was stirred overnight at 110 °C under a nitrogen atmosphere, then cooled to room temperature and concentrated in vacuo. The residue was diluted with EtOAc (500 mL), filtered through a pad of Celite and washed with brine (3 X 300 mL). The separated organic phase was dried over anhydrous Na2SO4 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.

[0502] Step E: NaBO3·4H2O (2.63 g, 17.07 mmol) was added to 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-H2O (50 + 25 mL). The mixture was stirred overnight at room temperature. THF was removed under reduced pressure, and the residue was stirred with saturated NH4Cl (25 mL) and dichloromethane (150 mL). The organic layer was separated, dried over Na2SO4 and concentrated. The residue was purified by column chromatography (Interchim; 40 g SiO2, CHCl3 / MeCN, MeCN from 0 - 95%, 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.

[0503] The following Intermediate Examples in Table 2 were prepared using appropriate starting materials according to the procedure in Intermediate Example 3:

[0504] Table 2

[0505]

[0506] Intermediate Example 4

[0507] tert-Butyl (6-chloro-4-fluoropyridin-2-yl)carbamate

[0508]

[0509] (Synthesis of tert-Butyl (6-chloro-4-fluoropyridin-2-yl)carbamate):

[0510]

[0511] Step A: 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) were stirred in a degassed dioxane suspension under argon at 80 °C overnight. After cooling to r.t., the mixture was 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).

[0512] 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 was added dropwise tetrabutylammonium fluoride (76.73 ml of 1 M solution, 76.73 mmol, 2.1 equiv). 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, 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.

[0513] Intermediate Example 5

[0514] Di-tert-butyl (4-chloro-6-fluoropyridin-2-yl)iminodicarbonate

[0515]

[0516] (Synthesis of Di-tert-butyl (4-chloro-6-fluoropyridin-2-yl)iminodicarbonate):

[0517]

[0518] At -78 °C, a solution of lithium bis(trimethylsilyl)amide (1+) (6.28 g, 37.5 mmol, 37.5 mL, 1.1 eq) in THF was added to a solution of 4-chloro-6-fluoropyridin-2-amine (5.0 g, 34.1 mmol) in THF, and the mixture was stirred for 1 h. Then, a solution of di-tert-butyl dicarbonate (17.1 g, 78.4 mmol) in THF was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 1 h and then stirred overnight at r.t. Then, NH4Cl was added, and the mixture was extracted with EtOAc. The organic layer was dried and 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).

[0519] Intermediate Example 6

[0520] 6-((2-Chloropyridin-4-yl)oxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine

[0521]

[0522] Synthesis of 6-((2-chloropyridin-4-yl)oxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine

[0523]

[0524] 1,3-Dimethyl-1H-pyrazolo[4,3-b]pyridin-6-ol (10 g) and 2-chloro-4-fluoropyridine (8.06 g) were dissolved in 50 mL of DMF, and then powdered K2CO3 (6.47 g) was added. The mixture was heated to 75 °C with stirring overnight. The reaction was cooled, and then approximately 70 mL of water was slowly added to the reaction mixture with stirring. Then, the mixture was allowed to stand for 2 h. The solid was collected by filtration and dried by suction on the filter. 14.25 g of the product as a brown solid was recovered and used without further purification. 1H NMR (400 MHz, DMSO-d, 27 °C): 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: r.t. = 1.75 min, m / z (M+H+) = 274.93 observed mass, exact mass 274.06.

[0525] Following the procedure in Intermediate Example 6, the following Intermediate Examples in Table 3 were prepared using appropriate starting materials:

[0526] Table 3

[0527]

[0528]

[0529] Intermediate Example 7

[0530] 6-((2-Chloropyridin-4-yl)oxy)-1-methyl-1H-indazole

[0531]

[0532] Synthesis of 6-((2-chloropyridin-4-yl)oxy)-1-methyl-1H-indazole

[0533]

[0534] 1-Methyl-1H-indazol-6-ol (0.444 g, 3.00 mmol, 1.2 eq) was stirred with 60% w / v NaH (1.2 eq; alternatively, 1 - 1.5 eq of K2CO3 can be used) in dry DMF (2.5 ml, 1 M) at 0 °C for 30 minutes, then 2-chloro-4-fluoropyridine (0.330 g, 2.50 mmoles, 1.0 eq, 1 mL, for transfer in DMF) was added. The resulting mixture was warmed to room temperature over 30 minutes and stirred at 80 °C overnight (15 - 18 hours). The reaction was cooled to room temperature. The reaction mixture was quenched with H2O (2 mL) and extracted with EtOAc (4x). The organic layer was dried over sodium sulfate, filtered, and concentrated. Purification was performed by automated Combiflash column chromatography on a 12 g silica gel column with a 0 - 60% EtOAc / hexane gradient elution. The title compound was obtained as a white solid (562.3 mg, 2.16 mmol, 87% yield).

[0535] Following the procedure in Intermediate Example 3, the following Intermediate Examples in Table 4 were prepared using appropriate starting materials:

[0536] Table 4

[0537]

[0538]

[0539]

[0540]

[0541] Intermediate Example 8

[0542] (6-Chloro-4-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)pyridin-2-yl)carbamic acid tert-butyl ester

[0543]

[0544] (Synthesis of tert-Butyl (6-chloro-4-((1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl)oxy)pyridin-2-yl)carbamate):

[0545]

[0546] 1,3-Dimethyl-1H-pyrazolo[3,4-b]pyridin-5-ol (0.3 g) was stirred with 60% w / v NaH (1.2 equiv) 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 mixture was quenched with H2O (2 mL) and extracted with EtOAc (4x). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Purification was carried out by automated Combiflash column chromatography on a silica gel column with a gradient elution of EtOAc / hexanes. The title compound was obtained as a white foam. LCMS Method 2A: r.t. = 1.43 min, m / z (M+H+) = 390.16 observed mass, exact mass 389.12.

[0547] Following the procedure in Intermediate Example 8, the following intermediate examples in Table 5 were prepared using the appropriate starting materials:

[0548] Table 5

[0549]

[0550]

[0551]

[0552] Intermediate Example 9

[0553] 6-(3-Bromophenoxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine

[0554]

[0555] Synthesis of 6-(3-Bromophenoxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine:

[0556]

[0557] In a glass vial equipped with a magnetic 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), then with Cu2O (15 mol%) and Cs2CO3 (1 mmol). The reaction mixture in the sealed vial was heated at 210 °C for 5 min and then at 195 °C for an additional 30 min. After completion of the reaction, the mixture was cooled to room temperature and 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 gel chromatography using an EtOAc / hexane gradient up to 60% EtOAc to afford 6-(3-bromophenoxy)-1,3-dimethyl-1H-pyrazolo[4,3-b]pyridine as a colorless semi-solid. LCMS Method 1A: r.t. = 2.00 min, m / z (M+H+, Br isotope effect) = 319.90 observed mass, exact mass 317.02.

[0558] Following the procedure in Intermediate Example 9, the following Intermediate Examples in Table 6 were prepared using appropriate starting materials:

[0559] Table 6

[0560]

[0561] Intermediate Example 10

[0562] 2-Ethyl-4-(4-fluoropyridin-2-yl)benzamide

[0563]

[0564] Synthesis of 2-ethyl-4-(4-fluoropyridin-2-yl)benzamide:

[0565]

[0566] 2-Chloro-4-fluoropyridine (0.48 g, 1 eq), 2-ethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1 eq), and tetrakis(triphenylphosphine)palladium(0) (0.05 eq) were added to a round-bottom flask, followed by 1,4-dioxane (10 mL) and Na2CO3 (2 N, 1 eq). The reaction mixture was degassed with bubbling N2 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 500 mL of DCM / MeOH (4:1) 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, which was then concentrated under reduced pressure. The silica-loaded crude product was purified by silica column chromatography using a 1% to 10% gradient of DCM / MeOH over 30 minutes to elute the product obtained as a solid after drying. LCMS method 2A: r.t. = 0.802 min, m / z (M+H+) = 245.15 observed mass, exact mass 244.10.

[0567] Following the procedure in Intermediate Example 10, the following Intermediate Examples in Table 7 were prepared using appropriate starting materials:

[0568] Table 7

[0569]

[0570]

[0571]

[0572] Intermediate Example 11

[0573] 3'-((1,3-Dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1'-biphenyl]-4- carboxylic acid

[0574]

[0575] Synthesis of 3'-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1'-biphenyl]-4-carboxylic acid

[0576]

[0577] 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(PPh3)4 (5 mol %), and 2 M aqueous K2CO3 solution (0.25 mL) in 1,4-dioxane (1 mL). The resulting mixture was heated to 95 °C and cooled to room temperature. The crude product was filtered through a Celite plug and purified by silica gel column chromatography using an EtOAC / hexane gradient up to 100% EtOAc to afford methyl 3'-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)-3-ethyl-[1,1'-biphenyl]-4-carboxylate as a colorless viscous oil.

[0578] Step 2: (Saponification) 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 solution (0.5 mL). The reaction mixture was stirred overnight at rt. The mixture was treated with 2 N aqueous HCl solution to adjust the pH to ~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 afford 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.

[0579] The following examples in Table 8 were prepared using appropriate starting materials according to the procedure in Example 9:

[0580] Table 8

[0581]

[0582]

[0583] Intermediate Example 12

[0584] 3-((2-Chloropyridin-4-yl)oxy)-6,6-difluoro-5,6,7,8-tetrahydroquinoline

[0585]

[0586] Synthesis of 3-((2-chloropyridin-4-yl)oxy)-6,6-difluoro-5,6,7,8-tetrahydroquinoline:

[0587]

[0588] At 85 °C, a solution of copper(II) chloride (CuCl2, 501.22 mg, 3.73 mmol) and 4,4-difluorocyclohexan-1-one (5 g, 37.28 mmol) in isopropyl alcohol (i-PrOH, 20 mL) was added to a mixture of prop-2-yn-1-amine (4.11 g, 74.56 mmol, 4.78 mL) in isopropyl alcohol (i-PrOH, 40 mL). 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, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 10) to afford 6,6-difluoro-5,6,7,8-tetrahydroquinoline (2.5 g, yield 39.64%) as a red oil. 1H NMR: 400 MHz, CDCl3 δ = 2.34 (tt, J = 13.55, 6.96 Hz, 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 = 4.50 Hz, 1H).

[0589] 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)]2 (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 for 12 h under a nitrogen atmosphere. 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, which was triturated with methyl tert-butyl ether (10 mL) for 1 h. After filtration, the cake was dried to afford 6,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6,7,8-tetrahydroquinoline (2 g, yield 45.86%) as a black solid. 11H 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).

[0590] 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 NaBO3·4H2O (3.13 g, 20.33 mmol). The mixture was stirred at 20 °C for 2 h. The reaction mixture was diluted with water (100 mL) and acidified to pH = 7 with 1 M acid. The aqueous layer was extracted with ethyl acetate (2 × 100 mL), and 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 h, filtered and the cake was dried to give 6,6 - difluoro - 5,6,7,8 - tetrahydroquinolin - 3 - ol (921 mg, yield 73.03%, purity 99.5%) as a white solid. Without acidifying the reaction mixture, 6 - fluoro - 7,8 - dihydroquinolin - 3 - ol (189 mg, yield 17.4%, purity 93%) was obtained as a yellow solid.

[0591] For 6,6 - difluoro - 5,6,7,8 - tetrahydroquinolin - 3 - ol, 1 1H NMR: 400 MHz, DMSO - d6, δ = 2.28 (tt, J = 14.01, 7.00 Hz, 2H), 2.90 (t, J = 7.00 Hz, 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 / z 186.1 (M + H)+, Rt: 1.305 min. LC / MS (gradient: 0% B at 0.40 min and 0 - 60% B from 0.4 - 3.0 min, 60 - 100% B from 3.0 - 4.0 min, then 100 - 0% B in 0.01 min, flow rate 1.0 mL / min. Mobile phase A is an aqueous solution of 0.04% trifluoroacetic acid, and mobile phase B is an acetonitrile solution of 0.02% trifluoroacetic acid. The column used for chromatography is Kinetex C18 2.1 * 50 mm, 5 μm. The detection methods are diode array (DAD) and evaporative light scattering detection (ELSD). The MS mode is positive electrospray ionization. The MS range is 100 - 1000.

[0592] For 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 / z 166.2 (M+H)+, Rt: 1.328 min. LC / MS (Gradient: 0% B in 0.40 min and 0 - 60% B in 0.4 - 3.0 min, 60 - 100% B in 3.0 - 4.0 min, then 100 - 0% B in 0.01 min, flow rate 1.0 mL / min. Mobile phase A is an aqueous solution of 0.04% trifluoroacetic acid, and mobile phase B is an acetonitrile solution of 0.02% trifluoroacetic acid. The column used for chromatography is Kinetex C18 2.1*50 mm, 5um. The detection methods are diode array (DAD) and evaporative light scattering detection (ELSD). The MS mode is positive electrospray ionization. The MS range is 100 - 1000.

[0593] 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 (Cs2CO3, 914.98 mg, 2.81 mmol). The mixture was stirred at 20 °C for 4 h. The reaction was quenched with water (80 mL), the aqueous layer was extracted with ethyl acetate (2×30 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 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, yield 47.13%, purity 99.7%), as a white solid. 11H NMR: 400 MHz, MeOD, δ = 2.39 (tt, J = 13.57, 6.94 Hz, 2H), 3.17 (t, J = 7.00 Hz, 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 = 5.88 Hz, 1H), 8.29 (d, J = 2.63 Hz, 1H). LCMS (ESI+): m / z 297.1 (M+H)+, Rt: 1.865 min. LC / MS (Gradient: 5% B in 0.40 min and 5 - 95% B from 0.40 - 3.00 min, hold at 95% B for 1.00 min, then 95 - 5% B in 0.01 min, flow rate 1.0 mL / min. Mobile phase A is aqueous solution of 0.037% trifluoroacetic acid, mobile phase B is acetonitrile solution of 0.018% trifluoroacetic acid. Column used for chromatography is Kinetex C18 50*2.1 mm column (5 μm particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. MS range is 100 - 1000.

[0594] Intermediate Example 13

[0595] 3-((2-Chloropyridin-4-yl)oxy)-6,8-difluoroquinoline

[0596]

[0597] Synthesis of 3 - ((2 - chloropyridin - 4 - yl)oxy)-6,8 - difluoroquinoline:

[0598]

[0599] 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 such that a dark color formed. The reaction was stirred as a biphasic mixture at 40 °C for 16 h. An additional vial was set up as described above, and the two 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, yield 12.83%) as a white solid. 1 1H 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).

[0600] 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)Cl2 (301.18 mg, 368.80 μmol). Under a nitrogen atmosphere, the mixture was stirred at 100 °C for 12 h. The reaction was quenched with water (100 mL), the aqueous layer was extracted with ethyl acetate (2 × 30 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was 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), using an elution gradient of 10% - 100% (solvent B) over 0.5 min and held at 100% for 0.4 min at a flow rate of 2.0 mL / min; Column: Halo C18, 3.0*30 mm, 5 μm; Wavelength: UV 220 nm & 254 nm Column temperature: 40 °C; MS ionization: ESI.

[0601] 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 NaBO3·4H2O (4.55 g, 29.54 mmol). The mixture was stirred at 25 °C for 2 h. 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-difluoro-3-ol (700 mg, yield 52.06%) as a white solid. 1 1H 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 / z 182.1 (M+H)+, Rt: 2.554 min. LC / MS (gradient was 0% B at 0.40 min and 0 - 30% B from 0.4 - 3.0 min, 30 - 100% B from 3.0 - 4.0 min, then 100 - 0% B in 0.01 min, flow rate was 1.0 mL / min. Mobile phase A was an aqueous solution of 0.04% trifluoroacetic acid and mobile phase B was an acetonitrile solution of 0.02% trifluoroacetic acid. The column used for chromatography was a Luna C18 50*2.0 mm column (5 μm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection. The MS mode was positive electrospray ionization. The MS range was 100 - 1000. 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 h. The reaction was quenched with water (30 mL), the aqueous layer was extracted with ethyl acetate (2 × 10 mL), the organic layer was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a residue, which was purified by preparative TLC (petroleum ether / ethyl acetate = 2 / 1) to give 3-((2-chloropyridin-4-yl)oxy)-6,8-difluoroquinoline (243 mg, yield 74.75%) as a white solid. 11H 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 / z 293.1 (M+H) + , Rt: 2.096 min. LC / MS (Gradient: 5% B in 0.40 min and 5 - 95% B from 0.40 - 3.00 min, hold at 95% B for 1.00 min, then 95 - 5% B in 0.01 min, flow rate 1.0 mL / min. Mobile phase A is aqueous solution of 0.037% trifluoroacetic acid, mobile phase B is acetonitrile solution of 0.018% trifluoroacetic acid. Column for chromatography is Kinetex C18 50*2.1 mm column (5um particles). Detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. MS range is 100 - 1000.

[0602] Intermediate Example 14

[0603] 3-Methyl-1-(trifluoromethyl)-1H-indazol-5-ol

[0604]

[0605] Synthesis of 3 - methyl - 1 - (trifluoromethyl) - 1H - indazol - 5 - ol:

[0606]

[0607] At 80 °C under nitrogen, 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 Cs2CO3 (192.97 mg, 592.25 μmol) in trifluoro(iodo)methane (556.94 mg, 710.70 μmol) (25% dimethylformamide solution) was stirred for 12 h. Twenty - nine additional vials were set up as described above. The reaction mixtures were combined and purified. The reaction was quenched by adding water (30 mL), then extracted with ethyl acetate (3 × 8 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 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. 11H 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 = 8.38 Hz, 1H)

[0608] 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)Cl2 (36.71 mg, 50.17 μmol) in dioxane (1.4 mL) were degassed and then heated at 80 °C under nitrogen for 12 h. Another two vials were set up as described above (resulting in a total of 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 1H 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 / z 327.3 (M + H)+, Rt: 2.693 min, m / z 245.1 (M - 83 + H)+, Rt: 1.666 min. LC / MS (gradient: 5% B in 0.40 min and 5 - 95% B in 0.40 - 3.00 min, hold at 95% B for 1.00 min, then 95 - 5% B in 0.01 min, flow rate 1.0 ml / min. Mobile phase A is an aqueous solution of 0.037% trifluoroacetic acid, and mobile phase B is an acetonitrile solution of 0.018% trifluoroacetic acid. The column used for chromatography is a Kinetex C18 50*2.1 mm column (5 μm particles). The detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. MS range is 100 - 1000.

[0609] NaBO3.4H2O (181.87 mg, 1.18 mmol, 3 equiv) was added 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). The mixture was stirred at 20 °C for 2 h. The reaction was 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, and then the mixture was extracted with ethyl acetate (3 × 5 mL). The combined organic phases were dried over anhydrous Na2SO4, 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, yield 60.61%) as a white solid. 1 1H 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 / z 217.2 (M+H)+, Rt: 1.705 min. LC / MS (gradient was 5% B in 0.40 min and 5 - 95% B in 0.40 - 3.00 min, held at 95% B for 1.00 min, then 95 - 5% B in 0.01 min, flow rate was 1.0 ml / min. Mobile phase A was an aqueous solution of 0.037% trifluoroacetic acid, and mobile phase B was an acetonitrile solution of 0.018% trifluoroacetic acid. The column used for chromatography was a Kinetex C18 50*2.1 mm column (5um particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization. The MS range was 100 - 1000.

[0610] Intermediate Example 15

[0611] 3-Methyl-1-(trifluoromethyl)-1H-indazol-6-ol

[0612]

[0613] Synthesis of 3-methyl-1-(trifluoromethyl)-1H-indazol-6-ol:

[0614]

[0615] Under nitrogen at 20 °C, 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 for 30 minutes. Methanedithione (4.47 g, 58.75 mmol) was added at 20 °C and the reaction mixture 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 h. Additional vials were set up as described above (total of 4.3 g of 6-bromo-3-methyl-1H-indazole). The reaction was quenched by the addition of water (400 mL) and the mixture was extracted with ethyl acetate (3 × 50 mL). The combined organic phases were concentrated, filtered, and the filter cake was dried to give 6-bromo-3-methyl-1H-indazole-1-carbodithioic acid methyl ester (3.9 g, yield 70.07%), as a yellow solid. 1H 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 (br d, J = 8.00 Hz, 1H), 9.26 (br s, 1H). LCMS (ESI+): m / z 301.0 & 303.0 (M+H)+, Rt: 0.697 min. Description: Mobile phase: 0.04% TFA / water (solvent A) and 0.02% TFA / acetonitrile (solvent B), elution gradient 10% - 100% (solvent B) in 0.5 minutes and held at 100% for 0.4 minutes at a flow rate of 2.0 ml / min; Column: Halo C18, 3.0*30 mm, 5um; Wavelength: UV 220 nm & 254 nm. Column temperature: 40 °C; MS ionization: ESI.

[0616] To a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (1.14 g, 3.98 mmol) in dichloromethane (16 mL) at 0 °C was added pyridine-HF complex (2.63 g, 26.56 mmol, 2.39 mL). The mixture was stirred at 0 °C for 10 min. At 0 °C, a solution of 6-bromo-3-methyl-1H-indazole-1-carbodithioic acid methyl ester (400 mg, 1.33 mmol) in dichloromethane (8 mL) was added dropwise to the above solution. The reaction was stirred at 0 °C for 2 h. Eight additional vials were set up as described above (total of 3.4 g of 6-bromo-3-methyl-1H-indazole-1-carbodithioic acid methyl ester). The mixtures were 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, yield 15.22%), as a white solid. 11H 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 / z 279.1 & 281.1 (M + H)+, Rt: 0.608 min. Description: Mobile phase: 0.04% TFA / water (solvent A) and 0.02% TFA / acetonitrile (solvent B), using an elution gradient of 10% - 100% (solvent B) within 0.5 min and maintaining at 100% for 0.4 min at a flow rate of 2.0 ml / min; Column: Halo C18, 3.0 * 30 mm, 5 μm; Wavelength: UV 220 nm & 254 nm; Column temperature: 40 °C; MS ionization: ESI.

[0617] 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)Cl2 (110.13 mg, 150.51 μmol) in dioxane (4.2 mL) was degassed and then heated at 80 °C under N2 for 12 h. Set up another additional vial as described above (a total of 500 mg of 6 - bromo - 3 - methyl - 1 - (trifluoromethyl) - 1H - indazole). Concentrate the reaction mixture. 338 mg of the crude product was used for 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, yield 79.53%), as a white solid. 11H NMR: 400 MHz, CDCl3, 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 / z 327.2 (M + H)+, Rt: 2.850 min, m / z 245.2 (M - 83 + H)+, Rt: 1.736 min. LCMS: (Gradient was 5% B in 0.40 min and 5 - 95% B in 0.40 - 3.00 min, held at 95% B for 1.00 min, then 95 - 5% B in 0.01 min, flow rate was 1.0 ml / min. Mobile phase A was an aqueous solution of 0.037% trifluoroacetic acid and mobile phase B was an acetonitrile solution of 0.018% trifluoroacetic acid. The column used for chromatography was a Kinetex C18 50*2.1 mm column (5 μm particles). The detection methods were diode array (DAD) and evaporative light scattering (ELSD) detection and positive electrospray ionization, MS range was 100 - 1000.)

[0618] NaBO3·4H2O (346.76 mg, 2.25 mmol) was added 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). The mixture was stirred at 20 °C for 2 h. The reaction was filtered and concentrated in vacuo. The combined crude product (3 - methyl - 6 - (4,4,5,5 - tetramethyl - 1,3,2 - dioxaborolan - 2 - yl) - 1 - (trifluoromethyl) - 1H - indazole, total 338.49 mg) was purified by preparative TLC (petroleum ether / ethyl acetate = 4 / 1) to give 3 - methyl - 1 - (trifluoromethyl) - 1H - indazol - 6 - ol (177 mg, yield 75.82%) as a white solid. 11H NMR: 400 MHz, DMSO-d6, 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 / z 217.2 (M+H)+, Rt: 1.824 min. LCMS: (Gradient is 5% B in 0.40 min and 5 - 95% B in 0.40 - 3.00 min, hold at 95% B for 1.00 min, then 95 - 5% B in 0.01 min, flow rate is 1.0 ml / min. Mobile phase A is an aqueous solution of 0.037% trifluoroacetic acid, and mobile phase B is an acetonitrile solution of 0.018% trifluoroacetic acid. The column used for chromatography is a Kinetex C18 50*2.1 mm column (5um particles). The detection methods are diode array (DAD) and evaporative light scattering (ELSD) detection as well as positive electrospray ionization, and the MS range is 100 - 1000.)

[0619] Intermediate Example 16

[0620] 3-Methyl-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol

[0621]

[0622] Synthesis of 3-methyl-1-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridin-6-ol:

[0623]

[0624] At 0 °C under a nitrogen atmosphere, methylmagnesium chloride (13.27 mL, 3 M, 39.80 mmol) was added dropwise to a solution of 5-bromo-3-fluoropyridinecarbonitrile (10 g, 49.75 mmol) in tetrahydrofuran (250 mL) over 15 minutes. The mixture was stirred at 0 °C for 15 min. 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 h. Then the solution was quenched by adding it to saturated aqueous sodium carbonate solution (500 mL) at 0 °C. The aqueous layer was extracted with ethyl acetate (2 × 500 mL). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by column chromatography (SiO2, 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. 11H 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).

[0625] At 20 °C, hydrazine hydrate (NH2NH2·H2O, 40.00 mL, 808.12 mmol, 98% purity) was added to a solution of 1-(5-bromo-3-fluoropyridin-2-yl)ethan-1-one (4 g, 18.35 mmol) in ethylene glycol (40 mL). The reaction mixture was stirred at 100 °C for 12 h. The reaction was quenched with saturated aqueous ammonium chloride solution (300 mL), the aqueous layer was extracted with ethyl acetate (2 × 150 mL), the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1) to obtain 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine (2 g, yield 50.38%, purity 98%), 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).

[0626] At 0 °C, sodium hydride (792.20 mg, 19.81 mmol, 60% purity) was added to a solution of 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine (2.8 g, 13.20 mmol) in tetrahydrofuran (30 mL). The mixture was stirred at 20 °C for 1 h. Methanedithione (2.01 g, 26.41 mmol) was added dropwise at 0 °C, and the resulting mixture was stirred at 20 °C for 16 h. The mixture was cooled to 0 °C again, and iodomethane (2.25 g, 15.85 mmol) was added dropwise to the above solution. The resulting mixture was stirred at 20 °C for 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution (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 obtain a residue, which was triturated with ethyl acetate (10 mL) and acetonitrile (2 mL) for 1 h. After filtration, the filter cake was dried to obtain 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine-1-carbodithioic acid methyl ester (2 g, yield 48.11%, purity 96%), as a yellow solid. 1 1H NMR: 400 MHz, DMSO-d6, δ = 2.60 (s, 3H), 2.66 (s, 3H), 8.87 (d, J = 2.00 Hz, 1H), 9.44 (d, J = 2.00 Hz, 1H).

[0627] At -78 °C, hydrofluoropyridine (17.17 mL, 190.59 mmol) was added to a solution of 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (5.45 g, 19.06 mmol) in dichloromethane (80 mL). The mixture was stirred at -78 °C for 10 min. At -78 °C, a solution of 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine-1-carbodithioic acid methyl ester (2 g, 6.35 mmol) in dichloromethane (40 mL) was added dropwise to the above solution. After the addition, the resulting mixture was stirred at -15 °C for 20 min. 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, filtered, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO2, 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 1H NMR: 400 MHz, MeOD, δ = 2.63 (s, 3H), 8.40 (s, 1H), 8.78 (d, J = 1.75 Hz, 1H).

[0628] 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)Cl2·CH2Cl2 (157.47 mg, 192.83 μmol). Under a nitrogen atmosphere, the mixture was stirred at 100 °C 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), using an elution gradient of 10% - 100% (solvent B) in 0.5 min and held at 100% for 0.4 min at a flow rate of 2.0 mL / min; Column: Halo C18, 3.0*30 mm, 5 μm; Wavelength: UV 220 nm & 254 nm Column temperature: 40 °C; MS ionization: ESI.

[0629] 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, purity 50%) in tetrahydrofuran (8.8 mL) and water (2.2 mL) was added NaBO3·4H2O (1.03 g, 6.73 mmol). The mixture was stirred at 25 °C for 2 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 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, yield 58.71%, purity 99.7%), as a white solid. 11H 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 / z 218.1 (M + H)+, Rt: 2.086 min. LC / MS (Gradient: 0% B in 0.40 min and 0 - 60% B in 0.4 - 3.0 min, 60 - 100% B in 3.0 - 4.0 min, then 100 - 0% B in 0.01 min, flow rate 1.0 mL / min. Mobile phase A is an aqueous solution of 0.04% trifluoroacetic acid, and mobile phase B is an acetonitrile solution of 0.02% trifluoroacetic acid. The column used for chromatography is Kinetex C18 2.1 * 50 mm, 5 μm. The detection methods are diode array (DAD) and evaporative light scattering detection (ELSD). MS mode is positive electrospray ionization. MS range is 100 - 1000.

[0630] Intermediate Example 17

[0631] 3-Fluoro-1-methyl-1H-indazol-6-ol

[0632]

[0633] Synthesis of 3 - fluoro - 1 - methyl - 1H - indazol - 6 - ol:

[0634]

[0635] 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 h. 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)+, Rt: 0.499 min. Description: Mobile phase: 0.04% TFA / water (solvent A) and 0.02% TFA / acetonitrile (solvent B), using an elution gradient of 10% - 100% (solvent B) in 0.5 min and held at 100% for 0.4 min at a flow rate of 2.0 ml / min; Column: Halo C18, 3.0 * 30 mm, 5 um; Wavelength: UV 220 nm & 254 nm Column temperature: 40 °C; MS ionization: ESI. 1HNMR: 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).

[0636] Under N2, to 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 added 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)2Cl2·CH2Cl2 (643.54 mg, 788.04 μmol, 0.1 equiv). 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)+, Rt: 0.596 min. Description: Mobile phase: 0.04% TFA / water (solvent A) and 0.02% TFA / acetonitrile (solvent B), using an elution gradient of 10% - 100% (solvent B) in 0.5 min and held at 100% for 0.4 min at a flow rate of 2.0 ml / min; Column: Halo C18, 3.0 * 30 mm, 5 μm; Wavelength: UV 220 nm & 254 nm Column temperature: 40 °C; MS ionization: ESI. 1 H NMR: 400 MHz, MeOD, δ = 1.39 (s, 12H), 3.96 (d, J = 0.63 Hz, 3H), 7.55 (d, J = 8.25 Hz, 1H), 7.65 (d, J = 8.13 Hz, 1H), 7.82 (s, 1H).

[0637] 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 H2O (4.3 mL) was added NaBO3·4H2O (2.65 g, 17.24 mmol, 3.32 mL, 4 equiv). 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 × 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 afford 3-fluoro-1-methyl-1H-indazol-6-ol (0.5049 g, yield 70.51%) as a white solid. LCMS (ESI+): m / z 166.05 (M+H) + , Rt: 1.449 min. Description: Mobile phase: 0.04% TFA / water (solvent A) and 0.02% TFA / acetonitrile (solvent B), using an elution gradient of 5% - 95% (solvent B) over 3.0 min and held at 95% for 1.0 min at a flow rate of 1.0 ml / 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).

[0638] Intermediate Example 18

[0639] 3-Fluoro-1-methyl-1H-indazol-5-ol

[0640]

[0641] Synthesis of 3-fluoro-1-methyl-1H-indazol-5-ol:

[0642]

[0643] To a solution of 5-bromo-1-methyl-1H-indazole (5 g, 23.69 mmol, 1 equiv) in ACN (50 mL) was added a selective fluorinating reagent (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 Na2SO4. The organic layer was concentrated under high vacuum. The residue was purified by column chromatography (SiO2, 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 / z 229.0 / 231.0 [M+H]+ Rt: 0.530 min.

[0644] 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) at -78 °C under nitrogen was added n-BuLi (2.5 M, 4.37 mL, 2.5 equiv). The mixture was stirred at -78 °C for 30 min. Then the mixture was stirred at 25 °C for 2 h. The reaction was cooled to 0 °C and H2O2 (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 mixture was stirred at 0 °C for 12 min. The mixture was stirred at 25 °C for 12 h. The pH of the mixture was adjusted to about 7 with HCl (1 M). Then the reaction was quenched with saturated aqueous Na2S2O3 solution (30 mL), the aqueous layer was extracted with ethyl acetate (2 × 40 mL), the organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl conditions) to afford 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] + Rt: 1.351 min. 1 H NMR: 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, 2.13 Hz, 1H).

[0645] Intermediate Example 19

[0646] 3-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol

[0647]

[0648] Synthesis of 3-fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol:

[0649]

[0650] 3-Fluoro-1-methyl-1H-pyrazolo[4,3-b]pyridin-6-ol was prepared using appropriate starting materials according to a procedure similar to Intermediate Example 18. LCMS (ESI+): m / z 168.2 [M+H] + Rt: 1.074 min. 1 1H NMR: 400 MHz, CD3OD, δ = 3.91 (s, 3H), 7.47 - 7.48 (m, 1H), 8.30 (d, J = 2.40 Hz, 1H).

[0651] Intermediate Example 20

[0652] 3-Fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-ol

[0653]

[0654] Synthesis of 3-fluoro-1-methyl-1H-pyrazolo[3,4-b]pyridin-5-ol:

[0655]

[0656] 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 a selective fluorinating reagent (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 (SiO2, 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, yield 51.45%), as a white solid. 1 1H 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).

[0657] Under nitrogen, potassium acetate (127.99 mg, 1.30 mmol), Pd(dppf)2Cl2·CH2Cl2 (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 to 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). The mixture was stirred at 100 °C for 12 h. The reaction mixture was quenched by adding sodium hydroxide (3 × 2 mL) at 0 °C, 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 (SiO2, petroleum ether / ethyl acetate = 4:1) to give 3-fluoro-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine (54 mg, yield 44.83%) as a white solid. 1H 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 / z 278.1 (M+H)+, Rt: 0.565 min. (The column used for chromatography was HALO AQ-C18 2.1*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 / aqueous solution, and mobile phase B was 0.018% TFA / HPLC grade acetonitrile solution. The gradient was 5 - 95% B in 2.20 min, 5 - 95% B in 0.01 min (0.01 - 1.00 min), 95 - 100% B (1.00 - 1.80 min), 5% B in 1.81 min, and held at 5% B for 0.40 min. The flow rate was 1.0 mL / min.)

[0658] 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 NaBO3·4H2O (2.22 g, 14.44 mmol, 2.78 mL, 4 equiv). The mixture was stirred at 25 °C for 4 h. The reaction mixture was concentrated under reduced pressure, 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 (SiO2, 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, yield 28.52%) 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 / z 399.1 (M + H) + , Rt: 0.543 min. Description: Mobile phase: 0.04% TFA / water (solvent A) and 0.02% TFA / acetonitrile (solvent B), using an elution gradient of 10% - 100% (solvent B) in 0.5 min and maintaining at 100% for 0.4 min at a flow rate of 2.0 ml / min; Column: Halo C18, 3.0 * 30 mm, 5 um; Wavelength: UV 220 nm & 254 nm Column temperature: 40 °C; MS ionization: ESI.

[0659] Intermediate Example 21

[0660] 2-Ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzamide

[0661]

[0662] Synthesis of 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide:

[0663]

[0664] 4-Bromo-2-ethylbenzoic acid (0.750 g) was dissolved in SOCl2 (2 mL) and heated at 45 °C overnight. Toluene (5 mL) was added and the solvent was dried completely. 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 with stirring until no more precipitate was 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 solids were combined to give 4-bromo-2-ethylbenzamide (750 mg; 100% yield) as a white powder.

[0665] 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)Cl2·CH2Cl2 (0.04 equiv), and KOAc (3 equiv) were dissolved in 10 mL of N2-flushed dioxane. The reaction was heated at 95 °C overnight. The reaction mixture was diluted with EtOAc and the solid was filtered. The product was concentrated under high vacuum and purified by column chromatography (0 - 60% hexane / 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).

[0666] Example 1

[0667] 4-(4-((1,3-Dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzene carboxamide

[0668]

[0669] Synthesis of 4-(4-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide:

[0670]

[0671] In a 1 L flask, 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, followed by the addition of 44 mL of 2 M Na2CO3, and then 110 mL of dioxane. The reaction was degassed by bubbling N2, and then heated to 80 °C for 20 h. The reaction was then cooled to about 60 °C, then filtered, and the aqueous suspension was washed with hot dioxane. Then about 120 g of silica gel was added to the crude mixture, the material was rotary evaporated to dryness, and loaded onto a 2 × 330 g ISCO silica gel column. The material was purified by column chromatography eluting with a hexane / acetone gradient. The material was redissolved in MeOH, and the solid was again loaded onto a second column with MeOH / DCM to remove additional impurities. After the pure fraction was completely dried, the solid material was recrystallized from MeOH to give 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. The operation was repeated three times. The organic phase was washed with water, then with brine, dried over MgSO4, and dried completely. To further reduce the Pd content, the remaining solid was dissolved in 80 mL of warm DMF and diluted to 2 L with EtOAc. 20 mL of diethylenetriamine was added thereto, and then the solution was washed with 120 mL of water. The wash with diethylenetriamine was repeated twice more, and then the organic phase was finally washed once with 120 mL of water and 120 mL of brine, dried over MgSO4, filtered and evaporated to about 50 mL of suspension. 50 mL of diethyl ether was added to the mixture. The solid was collected by filtration and washed with more diethyl ether. The solid was dried by suction on the filter, and then dried under vacuum at 65 °C overnight. 14.96 g of a white solid was obtained. The Pd content was measured by ICP-MS to be 3 ppm. 11H NMR (400 MHz, DMSO-d6, 27 °C): 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: r.t. = 1.7 min, m / z (M + H+) = 388.1 observed mass, exact mass 387.17.

[0672] Optionally, in a 1 L flask, 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), and then sodium tert - butoxide (18.5 g) was added. The reaction was degassed with bubbling N2 and then heated at 95 °C for 20 h. The reaction was cooled to 50 °C and 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 solution was 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 (ca. 70 mL). The slurry was stirred for 2 h. The solid was collected by filtration and washed with H2O (240 mL) and hexane (240 mL). The solid was dried in vacuo at 55 °C overnight to give 59.5 g (88% isolated yield) as an off - white solid. The Pd content was measured by ICP - MS to be 20 ppm. NMR was consistent, and LCMS method: Rt = 6.7 min, m / z (M + H+) = 388.1 observed mass, exact mass 387.17.

[0673] Example 2

[0674] 2-Ethyl-4-{4-[(1-methyl-1H-indazol-6-yl)oxy]pyridin-2-yl}benzamide

[0675]

[0676] Synthesis of 2-Ethyl-4-(4-((1-methyl-1H-indazol-6-yl)oxy)pyridin-2-yl)benzamide

[0677]

[0678] Add 6-((2-chloropyridin-4-yl)oxy)-1-methyl-1H-indazole (20 g) to dioxane (230 mL), and bubble N2 through the suspension for 30 minutes. Add 2-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (22.25 g), then add tetrakis(triphenylphosphine)palladium(0) (0.04 equivalent), and heat the reaction in an RB flask equipped with a condenser under N2 at 85 °C for 8 hours. Once completed, filter the reaction while it is hot through a pad of diatomaceous earth. Once cooled, add 30 mL of brine, shake the mixture, and discard the aqueous fraction. Concentrate the organic layer, then purify it by silica gel chromatography (2 x 220 g silica ISCO column), eluting with acetone / hexane. Concentrate the pure fractions under reduced pressure to approximately 75 mL. After allowing the mixture to stand overnight, collect the solid precipitate by filtration. Redissolve this solid in 50 mL of warm DMF and dilute it to 2 L with EtOAc. Add 20 mL of liquid triamine, followed by 500 mL of water. Shake the mixture vigorously and discard the aqueous layer. Repeat the operation three times, then wash with brine (300 mL). Concentrate this solution under vacuum, leaving approximately 75 mL and forming a suspension. After storing overnight at r.t., collect the precipitate by filtration to obtain 20.53 g of a white solid. 1H NMR (400 MHz, DMSO-d, 27 °C): 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: r.t. = 1.83 min, m / z (M+H+) = 373.20 observed mass, exact mass 372.16.

[0679] Example 3

[0680] 4-(4-((1,3-Dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzene carboxamide

[0681]

[0682] Synthesis of 4-(4-((1,3-dimethyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide:

[0683]

[0684] In a 20 mL microwave vial, NaH (0.416 g, 10.4 mmol, 1.6 equiv., 60% dispersion in mineral oil) was added 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) at rt. 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 h, the brown solution was cooled to rt and then added dropwise to water (ca. 5 mL) with stirring for 15 minutes. The caked solid was filtered out and triturated with Et2O (20 mL) and filtered. The solid was triturated with dichloromethane (ca. 10 mL) and sonicated for ca. 3 minutes and filtered. The filtrate was filtered through a large 0.45 μm HPLC filter, concentrated in vacuo to ca. 6 mL and purified by flash column chromatography (ISCO 40 g, 0 - 100% ethyl acetate / hexane), and the product purity was ca. 90 - 95%. The solid was dissolved in ca. 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-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide as a white solid.

[0685] Example 4

[0686] 4-(4-((1,3-Dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide

[0687]

[0688] Synthesis of 4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide.

[0689]

[0690] In a 20 mL microwave vial, NaH (0.416 g, 10.4 mmol, 1.6 equiv., 60% dispersion in mineral oil) was added 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) at rt. The mixture was stirred for 20 min. 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 h, the brown solution was cooled to rt and then added dropwise to water (ca. 5 mL), and stirred for 15 min. The lumpy solid was filtered out and triturated with Et2O (20 mL) and filtered. The solid was triturated with dichloromethane (ca. 10 mL) and sonicated for ca. 3 min and filtered. The filtrate was filtered through a larger 0.45 μm HPLC filter, concentrated in vacuo to ca. 6 mL and purified by flash column chromatography (ISCO 40 g, 0 - 100% ethyl acetate / hexane), and the product purity was ca. 90 - 95%. Thus, the solid was dissolved in ca. 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 °C): 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 (overlapping with DMSO peak, 3H), 2.45 (br s, 3H). LCMS method 1A: r.t. = 1.38 min, m / z (M + H+) = 373.20 observed mass, exact mass 372.16.

[0691] Following the procedure in the above examples, the following examples in Table 9 were prepared using appropriate starting materials:

[0692] Table 9

[0693]

[0694]

[0695] Example 12

[0696] 2-Methyl-4-(4-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)benzamide amine

[0697]

[0698] Synthesis of 2-methyl-4-(4-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)benzamide

[0699]

[0700] Dissolve 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) in 350 μL of dioxane, then add 150 μL of 2M aqueous Na2CO3 solution, and then add X-Phos Pd-G3 catalyst (1.5 mg). Seal the reaction in a small glass vial and heat it at 95 °C overnight. After cooling, add 500 μL of DMF, filter the reaction, and purify the mixture by HPLC to obtain 2-methyl-4-(4-((1-methyl-1H-pyrazolo[4,3-b]pyridin-6-yl)oxy)pyridin-2-yl)benzamide. A substitute for the catalyst X-Phos Pd-G3 catalyst is tetrakis(triphenylphosphine)palladium(0) (0.02 - 0.1 equivalent) in dioxane and aqueous sodium carbonate solution. Substitutes for dioxane and aqueous sodium carbonate solution are EtOH / toluene solvent and aqueous sodium carbonate solution. LCMS method 3A: r.t. = 0.73 min, m / z (M+H+) = 360.2 observed mass, exact mass 359.14.

[0701] According to the procedure in Example 3, the following examples in Table 10 were prepared using appropriate starting materials:

[0702] Table 10

[0703]

[0704] Example 15

[0705] 4-(2-Amino-6-((2-methyl-2H-indazol-5-yl)oxy)pyridin-4-yl)-2-methylbenzamide

[0706]

[0707] Synthesis of 4-(2-amino-6-((2-methyl-2H-indazol-5-yl)oxy)pyridin-4-yl)-2-methylbenzamide

[0708]

[0709] 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 %) were added to 10% w / v Na2CO3 (2 equiv) and dioxane (1 ml). The reaction was purged with N2 and heated at 90 °C overnight. After cooling, the reaction mixture was treated with EtOAc, water was added, and the organic layer was separated. After drying under vacuum, the crude product was 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 product was purified by silica gel chromatography (0-15% MeOH-DCM). LCMS method 3A: r.t. = 0.85 min, m / z (M+H+) = 374.2 observed mass, exact mass 373.15.

[0710] The following examples in Table 11 were prepared using the appropriate starting materials according to the procedure in Example 4:

[0711] Table 11

[0712]

[0713]

[0714]

[0715] Example 25

[0716] 4-(4-((1,3-Dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide

[0717]

[0718] Synthesis of 4-(4-((1,3-dimethyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-methylbenzamide

[0719]

[0720] 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 equiv) were transferred to a round-bottom flask, followed by the addition of 1,4-dioxane and Na2CO3 (2N, 1 equiv). The reaction mixture was degassed for 15 min and then heated to 90 °C. The reaction mixture was stirred at 90 °C overnight.

[0721] After the reaction was completed, the mixture was cooled to room temperature. The residual solvent was removed under reduced pressure. The crude product was redissolved in 500 mL of DCM / MeOH (4:1) and washed with water (150 mL × 2). The organic solvent was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Silica gel (50 g) was added to the crude product, and the crude product loaded with silica gel was purified by silica gel column chromatography using a 1% to 10% gradient of DCM / MeOH within 30 minutes.

[0722] After purification, the purified product was collected, combined, and concentrated to obtain a pale yellow solid. The pale yellow solid was washed thoroughly with EtOAc until all color impurities were removed to obtain 4-{4-[(1,3-dimethyl-1H-indazol-6-yl)oxy]pyridin-2-yl}-2-methylbenzamide (26.7 g, 73%), as a white solid.

[0723] The white solid was redissolved in 1 L of DCM / MeOH (4:1), and tris(hydroxymethyl)aminomethane (Trisamine) (50 mL) and 500 mL of water were added. The mixture was washed, and the organic layer was separated. The washing process was repeated three times to remove all traces of Pd contamination. After completion of the washing with tris(hydroxymethyl)aminomethane, the organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the final product. The white product was dried under high vacuum at 40 °C overnight. 1H NMR (400 MHz, DMSO-d, 27 °C): 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 DMSO peak, 3H), 2.45 (br s, 3H). LCMS method 3A: r.t. = 1.01 min, m / z (M + H+) = 373.2 observed mass, exact mass 372.16.

[0724] Example 26

[0725] 2-Ethyl-4-(7-((1-methyl-1H-indazol-6-yl)oxy)imidazo[1,2-a]pyridin-5-yl)benzamide Amine

[0726]

[0727] Synthesis of 2-Ethyl-4-(7-((1-methyl-1H-indazol-6-yl)oxy)imidazo[1,2-a]pyridin-5-yl)benzamide

[0728]

[0729] Dissolve 4-(6-amino-4-((1-methyl-1H-indazol-6-yl)oxy)pyridin-2-yl)-2-ethylbenzamide (50 mg) in MeOH (0.5 mL), add chloroacetaldehyde (50 wt%, in 200 μL of water), then add 10 mg of solid NaHCO3, and heat the mixture in a sealed vial at 80 °C for 4 h. Concentrate the reaction and purify the crude product by silica gel chromatography, eluting with DCM / methanol. After drying, crystallize the product from MeOH / EtOAc / ether to obtain 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: r.t. = 0.8 min, m / z (M+H+) = 412.2 observed mass, exact mass 411.17.

[0730] Prepare the following examples in Table 12 according to the procedures in the above examples using appropriate starting materials:

[0731] Table 12

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745]

[0746]

[0747]

[0748]

[0749]

[0750]

[0751]

[0752]

[0753]

[0754] Example A GPR52 activity

[0755] Evaluate the ability of the compounds of Formula I to modulate GPR52 activity. The HTRF cAMP assay was performed using a commercially available assay kit (cAMP Gs HiRange CisBio). The controls and compounds were dissolved in DMSO, and 62.5 nanoliters of the diluted compounds were transferred via acoustic or precise low-volume dispensing to a 384-well NBS assay plate. The compounds were further diluted to 1-fold, and 20,000 cells were added to each well. FLP-In TM -CHO cells stably expressing recombinant human GPR52 were used in the assay.

[0756] The cells were harvested with a cell stripper and resuspended in stimulation buffer. After incubation for thirty minutes at room temperature, the detection reagent was added to each well. The plate was then incubated for an additional 30 minutes at room temperature. The cAMP produced by the cells during the first incubation period competes with the d2-labeled cAMP for binding to the anti-cAMP monoclonal antibody labeled with an europium cryptate. The measured signal is inversely proportional to the concentration of cAMP produced by the cells, and the signal was quantified using a multimode plate reader.

[0757] A dose-response curve was generated from the HTRF counts that had been transformed based on a cAMP reference curve and then normalized relative to a positive control. The EC 50 values were obtained using a non-linear regression curve fitting program. Table 13 provides the mean EC 50Values (n=1 to 15), where A<25nM; b is 25-100nM; c is 101-1000nM; and D>1000nM and less than 2000nM. Emax (Table 13) is the maximum amount of cAMP (nM) produced by incubating cells with 10μM or 31.6μM of the test compound. The compound is defined by the top plateau of the sigmoidal curve fit. The curves were then normalized to a control compound, in this case 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (Tokumaru, K. et al., "Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists", Bioorganic & Medicinal Chemistry, Vol. 25, No. 12, June 2017, pp. 3098-3115), and expressed as a percentage of the Emax of the control compound. For example, Example 1 has an average EC of 270 nM (n=12). 50 and 106% of Emax, Example 4 had an average EC of 83 nM (n=9) 50 and an Emax of 106%, Example 25 had an EC of 83 nM (n=9) 50 and 103% Emax.

[0758] Table 13

[0759]

[0760]

[0761]

[0762] Example B

[0763] Selective group

[0764] Use 130+ binding, enzyme and uptake assays The selectivity of compounds of formula I was evaluated by the CEREP group (Eurofins). Compounds of formula I were tested at a single concentration (10 μM). Compound binding was calculated as the percent inhibition of binding of each target-specific radiolabeled ligand. Compound enzyme inhibition effects were calculated as the percent inhibition of control enzyme activity.

[0765] Results showing inhibition or stimulation above 50% are considered to represent a significant effect of the compound of formula I. The compounds of formula I are highly selective and show a very distinct profile.

[0766] Example C

[0767] Compound induced when co-cultured with the PXR nuclear receptor

[0768] In vitro evaluation of the induction of drug-metabolizing enzymes or transporters via activation of the pregnane X receptor (PXR) was performed using a reporter gene assay. An expression vector containing the full-length human PXR and the appropriate enhancer and promoter linked to a luciferase reporter gene was integrated into tumor cells. These transfected tumor cells were seeded onto 96-well microtiter plates and placed in a tissue culture incubator. After 24 hours, the cells were treated in duplicate wells with a single concentration (10 μM) or 6 different concentrations of the compound of formula I and returned to the incubator for an additional 24 hours. At the end of the incubation, the number of viable cells / well was determined using Promega's Cell Titer Fluor cytotoxicity assay. After cytotoxicity evaluation, Promega's ONE-Glo was added to the same wells and reporter gene activity was evaluated. Rifampicin was used as a positive control and was tested in the same manner as the test compounds; single concentration (10 mM) or six concentrations. The data reported are provided as the mean (n = 2) of fold receptor activation relative to vehicle-treated cells at each of 10 mM or 6 doses. Additionally, the data were normalized to the number of viable cells / well and expressed as a percentage of the response given by rifampicin at the 10 μM dose.

[0769] Example D

[0770] Stability of the compound of formula I in mammalian liver microsomes

[0771] Evaluate the stability of the Formula I compounds in mammalian liver microsomes. In the presence of a 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, the Formula I compounds (0.5 μM) were incubated with pooled human liver microsomes (HLM) (0.5 mg / mL total protein) at 37 °C. All concentrations were relative to a final incubation volume of 125 μL. Incubation was carried out at 37 °C in a water bath for 0, 5, 10, 20, 40, and 60 minutes and terminated by rapid mixing with 150 μL of ice-cold acetonitrile containing an internal standard, and the precipitated protein was removed by centrifugation, followed by LC-MS / MS analysis. Aliquots of the resulting supernatant fraction were analyzed by monitoring the consumption of the parent compound by LC-MS / MS. The resulting peak area ratio-time data were fitted to a non-linear 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, the value of the intrinsic clearance was calculated from the in vitro half-life data and then scaled to represent the clearance expected in the whole animal (human). Additional values calculated included the predicted extraction ratio and the predicted maximum bioavailability. For example, the O-linker has better metabolic stability relative to the methyl linker or the -CH2O-linker, as shown by the following comparison:

[0772]

[0773]

[0774] Example E

[0775] Permeability of the compound of formula I in MDR1-MDCK cells

[0776] Evaluate the Formula I compounds to determine their permeability in MDR1-MDCK cells. Madin-Darby canine kidney (MDCK) cells transfected with human multidrug resistance protein 1 (MDR1) were used to generate the apparent permeability (P app) and efflux ratio. Cells were grown as a monolayer on the microporous membrane in a 24-well assay plate. Each compound was evaluated at a single concentration equal to 5 μM. The assay buffer consisted of Hanks' balanced salt solution (Mediatech, Inc., Corning) containing 10 mM HEPES and 15 mM glucose, pH 7.4. The test article was diluted in the assay buffer and then administered to the apical chamber of the cell monolayer plate to determine the apical-to-basolateral (A to B) permeability. The basolateral-to-apical (B to A) permeability was determined by adding the dosing solution to the basolateral chamber. The cell monolayer to which the test article was administered was incubated for 1 hour in a humidified incubator at 37 °C with 5% CO2. Samples were collected from the donor and receptor chambers at 1 hour and then prepared for LC-MS / MS analysis using electrospray ionization. Triplicate measurements of the A to B and B to A permeabilities of each compound were collected. The efflux ratio 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 the activity of the MDR1 protein (digoxin).

[0777] Example F

[0778] Effect of the compound of formula I on hERG channel current

[0779] The in vitro effect of the compounds of Formula I on hERG channel current was evaluated. At room temperature, the concentration-response relationship of all compounds on hERG potassium channel current was evaluated in stably transfected mammalian cells expressing the cloned hERG potassium channel encoded by the KCNH2 gene. The hERG potassium channel was expressed in Chinese hamster ovary (CHO) cells lacking endogenous I Kr .

[0780] A stock solution of the positive control article was 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 Control 1 and Control 2 were stored at room temperature. The CHO / hERG cell line was from the Grey Syrian hamster organism: tissue (ovary; transfected with ion channel cDNA); morphology (epithelial); age / stage (embryonic); source strain (ATCC, Manassas, VA); and source sub-strain (Charles River Laboratories).

[0781] Stably transfect CHO cells with hERG cDNA. Maintain the stable transfectants in a medium with appropriate selection pressure and antibiotics. All experiments are conducted at room temperature. Each cell serves as its own control. Complete blockage is achieved by adding 20 μM verapamil. Two groups are tested: test article treatment and positive control treatment.

[0782] Automated patch clamp procedure. For all hERG tests, use a 384-well based automated patch clamp system SyncroPatch 384PE (Nanion Technologies) with PatchControl software (data acquisition) and DataControl software (data analysis). Recordings are made at room temperature (22 °C) at medium resistance on a planar NPC-384 multi-well wafer with 4 holes per well. Recordings are made in the whole cell patch mode. The composition of the internal solution is: 10 mM EGTA, 10 mM HEPES, 10 mM KCl, 10 mM NaCl, and 110 mM KF, pH 7.2, mOsm = 285. The composition of the external solution is: 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. Dissolve the compound of formula I in 100% DMSO. On the day of the experiment, prepare serial dilutions in DMSO manually. Further dilute the pre-diluted compound of formula I to the external solution (0.2% DMSO by volume) at a dilution factor of 1:500. Use a single application of the compound of formula I at the said concentration to the entire wafer. Each well receives one compound concentration, followed by verapamil for complete blockage to assess leakage. Distribute each compound at different concentrations on the wafer to generate separate dose-response relationships.

[0783] Measure the onset and blockage of hERG current 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 two 2 s test pulses to -40 mV. Repeat the pulse pattern continuously from a holding potential of -80 mV at 6 s intervals. Calculate the peak-tail current from the current amplitude induced by the -40 mV prepulse and subtract the peak-tail current from the total membrane current recording. Implement a small hyperpolarizing voltage step from -80 to -90 mV during the holding potential to calculate the resistance according to Ohm's law for quality control.

[0784] Data acquisition and analysis were performed using Nanion Data Control software. Steady state was defined by a limiting constant rate (linear time dependence) that varied over time. Steady states before and after application of the test article were used to calculate the percentage of current inhibited at each concentration.

[0785] The ability of the compounds of Formula I to counter cognitive deficits and negative symptoms of schizophrenia was evaluated. Animals exposed to repeated PCP administration showed cognitive (measured by NOR) and social (measured by social interaction) deficits. These deficits are thought to map to the cognitive and negative symptoms of schizophrenia, respectively. For clarity, animals were dosed with PCP for 7 days, twice a day, and then, after a washout period of at least 1 week, dosed once a day with a compound of Formula 1 for 6 days, and dosed once more (but without PCP internally at this time) before testing in NOR, and then dosed with a compound of Formula I (but without PCP internally at this time) the next day and tested in social interaction. The experiments are elaborated in detail in the following examples.

[0786] Example G

[0787] Novel object recognition (NOR)

[0788] The compounds of Formula I were evaluated using the following sub-chronic phencyclidine (scPCP) protocol. The NOR test was performed as previously described in detail (Grayson, et al., “Atypical antipsychotics attenuate a sub-chronic PCP-induced cognitive deficit in the novel object recognition task in the rat”, Behavioral Brain Research, Vol. 184, No. 1, 2007; Snigdha et al., “Attenuation of Phencyclidine-Induced Object Recognition Deficits by the Combination of Atypical Antipsychotic Drugs and Pimavanserin (ACP 103), a 5-Hydroxytryptamine 2A Receptor Inverse Agonist”, Journal of Pharmacology and Experimental Therapeutics, February 2010, 332(2)622 - 631).

[0789] Before testing, all animals were habituated to the empty test chamber. Habituation consisted of placing all rats from one cage together in the empty test arena for 20 min on the day before testing. The rats (scPCP and vehicle-treated) were given two 3-min trials in the home cage, separated by 60 min. In the first trial (acquisition), the animals were placed in the test chamber and allowed to explore two identical objects (A1 and A2). In the second trial (retention), the animals were placed in the test chamber with one repeated familiar object from the acquisition phase and one novel object (to avoid olfactory traces). The formula I compound or vehicle was administered once daily for six days before NOR and 120 min before acquisition. Behavior was filmed and scored by a trained experimenter who was unaware of the treatment group. In the acquisition and retention trials, the total object exploration time for each of the familiar and novel objects was recorded (defined as the time the animal spent licking, sniffing, or touching the object, but not including time spent standing or sitting or leaning on the object); locomotor activity (defined as movement, measured by the number of lines crossed in two trials) and discrimination index (defined as the difference in time spent exploring the novel and familiar objects divided by the total time spent exploring both objects) were also calculated.

[0790] All data are expressed as mean ± s.e.m. (standard error of the mean). Exploration time data for NOR in the acquisition and retention phases were analyzed separately by two-factor analysis of variance (ANOVA), with drug and two-object (the two identical objects in the acquisition phase and the novel and familiar objects in the retention phase) exploration times as factors. Locomotor activity data (total number of line crossings) and DI were analyzed by one-factor ANOVA. The time spent exploring the objects was analyzed by paired Student's t-test. Post hoc analysis was performed by Dunnett's t-test (for locomotor activity and DI) after the one-factor ANOVA results were significant.

[0791] Example H

[0792] Social interaction

[0793] The following social interaction test was used to evaluate the formula I compound to assess aspects of the anhedonia domain of negative symptoms in schizophrenia, using sub-chronic administration of PCP for social withdrawal.

[0794] One day after NOR assessment, social interaction of the rats was evaluated using the same arena. Pairs of rats that were weight-matched (15 - 20 g), unfamiliar with each other, untreated (''syngeneic'' rats) or treated differently (PCP and vehicle; ''test'' rats or PCP + formula I compound; ''test'' rats) were placed together in the test arena for 10 min and behavior was evaluated as described below. The formula I compound or vehicle was administered seven days before SI and 120 min before interaction assessment.

[0795] Inanimate objects such as unopened beverage cans can also be placed in the center of the arena to measure any differences in the interactions of the test animals and unfamiliar animals relative to the unfamiliar object. After each 10-minute trial, the object and the arena are cleaned with 10% alcohol to remove any traces of olfactory cues. All tests are conducted at a standard room lighting level (70 cd / m 2 ).

[0796] Brains and blood are collected immediately after the SI study (n = 12 for each treatment group). Trunk blood is collected in Li-heparin-coated tubes on ice and then centrifuged. The blood is centrifuged at 7,000 RPM for 10 min at a temperature of 4 °C. The plasma is then transferred to vials (approx. 400 μl) and immediately stored at -80 °C. The whole brain is removed and immediately stored at -80 °C. The frontal cortex is dissected and collected in vials and stored at -80 °C.

[0797] Behaviors are recorded on video for subsequent blind scoring. The following parameters (a) to (e) are scored using a behavioral scoring software program (Hindsight, Scientific Programming Services):

[0798] Investigative sniffing behavior: Sniffing the muzzle or body parts including the anogenital region of a conspecific;

[0799] Following - A rat follows a conspecific, i.e., a rat of the same species treated with the vehicle, moving around the arena;

[0800] Avoidance - Actively turning away when a conspecific approaches;

[0801] Object investigation - Exploring an object placed in the center of the arena;

[0802] Locomotor activity is recorded by counting the total number of sectors (i.e., lines) traversed by the test rats.

[0803] All data are expressed as mean ± s.e.m. The data are analyzed by ANOVA and then, where appropriate, Dunnett's post hoc test is performed. Statistical significance is considered when P < 0.05. All analyses are performed in the SPSS statistical package (IBM).

[0804] This specification (including the examples) is merely exemplary, and it will be apparent to those skilled in the art that various modifications and variations can be made in the present application without departing from the scope or spirit of the invention as defined by the appended claims. Each reference cited in this application, including all patents, patent applications, and publications, is incorporated herein by reference in its entirety.

Claims

1. Compound of formula (I): Wherein: R1 is selected from hydrogen and C 1-2 alkyl; R2 is selected from C 1-2 alkyl, halogen, methyl-amino and halogen-substituted C 1-2 alkyl; R3 is selected from hydrogen and halogen; R4 is selected from: Wherein: When R5 is attached to a carbon atom, R5 is selected from hydrogen, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl; and when R5 is attached to a nitrogen atom, R5 is selected from hydrogen, C 1-2 alkyl, and halogen-substituted C 1-2 alkyl; When R6 is attached to a carbon atom, R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl; and when R6 is attached to a nitrogen atom, R6 is selected from hydrogen, C 1-2 alkyl, and halogen-substituted C 1-2 alkyl; R7 is selected from hydrogen, C 1-2 alkyl, halogen and halogen-substituted C 1-2 alkyl; R8 is selected from hydrogen and halogen; X1 is selected from N and CH; X2 is selected from N and CR9; wherein 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 at most two nitrogen atoms; X3 is selected from CR 9a ; wherein R 9a is selected from hydrogen and methyl; And its pharmaceutically acceptable salts.

2. The compound according to claim 1, which has the formula Ia: Wherein: R2 is selected from C 1-2 alkyl, halogen, methyl-amino and halogen-substituted C 1-2 alkyl; R3 is selected from hydrogen and halogen; R5 is selected from hydrogen and C 1-2 alkyl; R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl; X1 is selected from N and CH; X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; And its pharmaceutically acceptable salts.

3. The compound according to claim 2, wherein: R2 is selected from methyl, ethyl, methylamino, chloro and trifluoromethyl; R3 is selected from hydrogen and halogen; 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; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; And its pharmaceutically acceptable salts.

4. The compound according to claim 3, wherein: R2 is selected from methyl, ethyl and trifluoromethyl; R3 is selected from hydrogen and fluoro; X1 is selected from N and CH; X2 is CR9; wherein R9 is selected from hydrogen and amino; And its pharmaceutically acceptable salts.

5. The compound according to claim 4, which is selected from the following compounds or its pharmaceutically acceptable salts:

6. The compound according to claim 1, which has the formula Ib: Wherein: R2 is selected from C 1-2 alkyl, halogen, methyl - amino and halogen - substituted C 1-2 alkyl; R5 is selected from hydrogen, C 1-2 alkyl and halogen-substituted C 1-2 alkyl; R6 is selected from hydrogen, amino, cyano, halogen, C 1-2 alkyl, and halogen-substituted C 1-2 alkyl; R7 is selected from hydrogen, C 1-2 alkyl, and halogen; R 9a selected from hydrogen and methyl; X1 is selected from N and CH; X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; And its pharmaceutically acceptable salts.

7. The compound according to claim 6, wherein: 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 selected from hydrogen and methyl; X1 is selected from N and CH; X2 is selected from N and CR8; wherein R8 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; And its pharmaceutically acceptable salts.

8. The compound according to claim 7, wherein X2 is CR8; wherein R8 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl and azetidin-3-yl; and its pharmaceutically acceptable salts.

9. The compound according to claim 8, which is selected from the following compounds or its pharmaceutically acceptable salts:

10. The compound according to claim 1, which has the formula Ic: Wherein: R2 is selected from C 1-2 alkyl, halogen, methyl - amino and halogen - substituted C 1-2 alkyl; R5 is selected from hydrogen, C 1-2 alkyl and halogen-substituted C 1-2 alkyl; R6 is selected from hydrogen and C 1-2 alkyl; X1 is selected from N and CH; X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl; and pharmaceutically acceptable salts thereof.

11. The compound according to claim 10, wherein: 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; X2 is selected from N and CR8; wherein R8 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl; and pharmaceutically acceptable salts thereof.

12. The compound according to claim 11, wherein: R2 is selected from methyl and ethyl; X1 is N; X2 is CR9; wherein R9 is selected from hydrogen and amino; and pharmaceutically acceptable salts thereof.

13. The compound according to claim 12, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

14. The compound according to claim 1, which has the formula Id: wherein: R2 is selected from C 1-2 alkyl, halogen, methyl-amino, and halogen-substituted C 1-2 alkyl; R5 is selected from hydrogen, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl; R6 is selected from hydrogen and C 1-2 alkyl; R7 is selected from hydrogen, C 1-2 alkyl and halogen; X1 is selected from N and CH; X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl; and pharmaceutically acceptable salts thereof.

15. The compound according to claim 14, wherein: 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 selected from hydrogen, C 1-2 alkyl, and halogen; X1 is selected from N and CH; X2 is selected from N and CR9; wherein R9 is selected from hydrogen, amino, aminomethyl, methylaminomethyl, azetidin-2-yl, and azetidin-3-yl; and pharmaceutically acceptable salts thereof.

16. The compound according to claim 15, wherein: R2 is selected from methyl, ethyl, and chloro; X1 is N; X2 is CH; and pharmaceutically acceptable salts thereof.

17. The compound according to claim 16, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

18. The compound according to claim 1, which has the formula Ie: wherein: R1 is selected from hydrogen and C 1-2 alkyl; R2 is selected from C 1-2 alkyl, halogen, methyl-amino and halogen-substituted C 1-2 alkyl; R4 is selected from: R5 is selected from hydrogen and C 1-2 alkyl; R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl and halogen-substituted C 1-2 alkyl; R7 is selected from hydrogen, C 1-2 alkyl, and halogen; X1 is selected from N and CH; X2 is selected from N and CR9; wherein 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 at most two nitrogen atoms; and pharmaceutically acceptable salts thereof.

19. The compound according to claim 18, wherein: R1 is selected from hydrogen, methyl, and ethyl; R2 is selected from methyl and ethyl; R4 is selected from: R5 is methyl; when R6 is connected to a carbon atom, R6 is selected from hydrogen, methyl, and trifluoromethyl; R7 is hydrogen; X1 is selected from N and CH; X2 is CR9; wherein R9 is hydrogen; and pharmaceutically acceptable salts thereof.

20. The compound according to claim 19, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

21. The compound according to claim 1, which has the formula If: wherein: R2 is selected from C 1-2 alkyl, halogen, methyl-amino and halogen-substituted C 1-2 alkyl; R4 is selected from: R5 is selected from hydrogen, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl; R6 is selected from hydrogen, amino, cyano, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl; R7 is selected from hydrogen, C 1-2 alkyl, halogen, and halogen-substituted C 1-2 alkyl; R8 is selected from hydrogen and halogen; and pharmaceutically acceptable salts thereof.

22. The compound according to claim 21, wherein: R2 is selected from methyl, ethyl, chlorine, fluorine and trifluoromethyl; R4 is selected from: When R5 is connected to a carbon atom, R5 is selected from hydrogen, fluorine, chlorine and methyl; R6 is selected from hydrogen and fluorine; R7 is selected from hydrogen, fluorine, chlorine and trifluoromethyl; R8 is selected from hydrogen and fluorine; and pharmaceutically acceptable salts thereof.

23. The compound according to claim 22, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

24. The compound according to claim 1, which is selected from the following compounds or pharmaceutically acceptable salts thereof:

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

26. A method for treating a neurological disorder, which comprises administering to an individual in need 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; wherein the neurological disorder is selected from schizophrenia, negative symptoms associated with schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, antipsychotic-induced movement disorder, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, Lewy body dementia, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorder, movement disease, hyperkinesia, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, prolactin-related disorder, hyperprolactinemia, neurocognitive disorder, trauma- or stress-related disorder, post-traumatic stress disorder, disruptive impulse control, disruptive conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypofunction, abnormality in the tuberoinfundibular, mesolimbic, mesocortical or nigrostriatal pathway, decreased striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficit associated with schizophrenia, Parkinson's disease, drug-induced parkinsonism, movement disorder, dystonia, chorea, levodopa-induced movement disorder, cerebral palsy and progressive supranuclear palsy, Huntington's disease and chorea associated with Huntington's disease.

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

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

29. A method of improving one or more symptoms of a neurological disorder, which comprises administering to an individual in need thereof an effective amount of at least one compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 24 or the pharmaceutical composition according to claim 25; wherein the neurological disorder is selected from schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, antipsychotic-induced movement disorder, Parkinson's disease, drug-induced parkinsonism, extrapyramidal syndrome, Alzheimer's disease, dementia with Lewy bodies, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorder, movement disorder, hyperkinesia, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, prolactin-related disorder, hyperprolactinemia, neurocognitive disorder, trauma- or stress-related disorder, post-traumatic stress disorder, disruptive impulse control, disruptive conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypofunction, abnormalities in the tuberoinfundibular, mesolimbic, mesocortical or nigrostriatal pathways, decreased striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia; Parkinson's disease, drug-induced parkinsonism, movement disorder, dystonia, chorea, levodopa-induced movement disorder, cerebral palsy and progressive supranuclear palsy, and Huntington's disease and chorea associated with Huntington's disease.

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

31. A method of manufacturing a medicament for treating at least one compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof or a pharmaceutical product according to claim 25, wherein the neurological disorder is selected from schizophrenia, cognitive impairment, panic disorder, phobic disorder, drug-induced psychotic disorder, delusional psychosis, antipsychotic-induced movement disorder, Parkinson's disease, drug-induced Parkinson's syndrome, extrapyramidal syndrome, Alzheimer's disease, Lewy body dementia, bipolar disorder, ADHD, Tourette syndrome, extrapyramidal or movement disorder, movement disease, hyperkinesia, psychotic disorder, catatonia, mood disorder, depressive disorder, anxiety disorder, obsessive-compulsive disorder, autism spectrum disorder, prolactin-related disorder, hyperprolactinemia, neurocognitive disorder, trauma- or stress-related disorder, post-traumatic stress disorder, disruptive impulse control, disruptive conduct disorder, sleep-wake disorder, substance-related disorder, addictive disorder, behavioral disorder, frontal lobe hypofunction, abnormalities in the tuberoinfundibular, mesolimbic, mesocortical or nigrostriatal pathways, reduced striatal activity, cortical dysfunction, neurocognitive dysfunction and cognitive deficits associated with schizophrenia, Parkinson's disease, drug-induced Parkinson's syndrome, movement disorder, dystonia, chorea, levodopa-induced movement disorder, 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.

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