Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
  • C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
  • C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr

Definitions

• GPR139 is an orphan G-protein coupled receptor. GPR139 may be coupled with Gs, Gq and Gi signaling and appears to be constitutively active when recombinantly expressed in mammalian cells. GPR139 is abundantly expressed in the CNS (central nervous system) and to a lesser extent in the pancreas and pituitary and at low levels in other peripheral tissue.
• GPR139 is highly conserved among different species. For example, human, mouse, and rat GPR139 protein sequences share greater than 94% identity at the amino acid level. The predominant expression in the brain and high degree of sequence homology across different species, suggests that GPR139 has an important role in physiology.
• GPR139 has its strongest expression in the medial habenular nucleus of mice.
• the habenula receives inputs from the basal ganglia and the limbic system and sends outputs to midbrain and forebrain structures which contain dopaminergic and serotoneigic neurons.
• Habenular nuclei are involved in pain processing, reproductive behavior, nutrition, sleep-wake cycles, stress responses, and learning.
• modulators of GPR139 are expected to be useful for treating schizophrenia and other CNS disorders such as depression.
• the compounds of the disclosure are metabolites of a GPR139 agonist and may be useful for the treatment of a disease, disorder, or condition associated with GPR139, including uses as biomarkers.
• each R 1 is independently chosen from -OH, -OSO 3 H, -O-glucuronide, -SH, a -S(O)C 1 -C 6 alkyl group, a -S(O)2C 1 -C 6 alkyl group, a -SC 1 -C 6 alkyl group, a -SC 1 -C 6 alkyl-NHC(O)C 1 -C 6 alkyl group, an amino acid, and a peptide, wherein each hydrogen atom in a C 1 -C 6 alkyl group is optionally replaced by OH, oxo, -CO 2 H, -O-glucuronide, -NH 2 , a -NHC(O)C 1 -C 6 alkyl group, or a-N(H)C 1 -C 6 alkyl-CO 2 H group;
• R 2 is H, -OH, or -O-glucuronide
• R 3 is C 1 -C 6 alkyl optionally substituted with -OH, oxo, -O-glucuronide, -NH 2 , -NHC(O)C 1 -C 6 alkyl, or -NHCH 2 COOH; each R 4 is independently -OH or -O-glucuronide; n is 1-4; and m is 0-4; provided that:
• R 2 is not H, and/or
• the disclosure relates to a compound of formula II or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 are independently chosen from C 1 -C 6 alkyl, -NH-C 1 -C 6 alkyl, -NH-aryl, and -NH-heteroaryl groups, wherein each hydrogen atom in a C 1 -C 6 alkyl group is optionally replaced by -OH, oxo, or -CO 2 H.
• the disclosure relates to a compound of formula ⁇ II or a pharmaceutically acceptable salt thereof, wherein R 7 is a C 1 -C 6 alkyl group and each hydrogen atom in the C 1 -C 6 alkyl group is optionally replaced by -OH, oxo, -CO 2 H, or -NH 2 .
• the disclosure relates to a compound selected from:
• Another aspect of the disclosure provides a compound or pharmaceutically acceptable salt as defined in the preceding paragraphs, for use in treating a disease, disorder, or condition selected from schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, pain, and fibromyalgia.
• a disease, disorder, or condition selected from schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, pain, and fibromyalgia.
• a further aspect of the disclosure provides a method of treating a disease, disorder, or condition associated with GPR139 in a subject, the method comprising administering an effective amount of a compound or pharmaceutically acceptable salt as defined in the preceding paragraphs.
• An additional aspect of the disclosure provides a method of treating a disease, disorder, or condition in a subject, the method comprising administering an effective amount of a compound or pharmaceutically acceptable salt as defined in the preceding paragraphs, wherein the disease, disorder, or condition is selected from schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, pain, and fibromyalgia.
• Another aspect of the disclosure provides a use of a compound or pharmaceutically acceptable salt as defined in the preceding paragraphs, for the manufacture of a medicament for the treatment of a disease, disorder, or condition associated with GPR139.
• a further aspect of the disclosure provides a combination comprising a compound or pharmaceutically acceptable salt as defined in the preceding paragraphs, and at least one additional pharmacologically active agent.
• Another aspect of the disclosure provides a metabolite of a GPR193 agonist for use as a biomarker.
• An additional aspect of the disclosure provides a process for making a metabolite of a GPR139 agonist and/or an intermediate thereof.
• C 1-6 alkyl refers to a straight or branched alkyl chain of one to six carbon atoms.
• halogen and “halo” refer to chloro, fluoro, bromo, or iodo.
• oxo represents a carbonyl oxygen.
• a cyclopentyl substituted with oxo is cyclopentanone.
• the term “pharmaceutically acceptable salt” refers to a salt of a pharmaceutically acceptable organic acid or base or an inorganic acid or base, and includes those described in Journal of Pharmaceutical Science, 66, 2-19 (1977).
• a non-limiting example is a hydrochloride salt.
• amino refers to -NH 2 .
• hydroxy or “hydroxyl” refers to -OH.
• glucuronide refers to the a and ⁇ isomers of which is sometimes called glucuronic acid.
• aryl refers to an all-carbon monocyclic or fused-ring polycyclic groups of 6 to 12 carbon atoms having a completely conjugated pi-electron system.
• aryl may be of limited size such as C 6 -C 10 aryl.
• Illustrative aryl groups include, but are not limited to, phenyl, naphthylenyl, and anthracenyl.
• the aryl group may be unsubstituted, or substituted, as described for alkyl or as described in the various embodiments provided herein.
• heteroaryl refers to a monocyclic or fused ring group of 5 to 12 ring atoms containing one, two, three or four ring heteroatoms selected from nitrogen, oxygen, and sulfur, the remaining ring atoms being carbon atoms, and also having a completely conjugated pi-electron system. It will be understood that, in some embodiments, heteroaryl may be of limited size such as 3- to 7-membered heteroaryl, 5- to 7-membered heteroaryl, and the like. Heteroaryl may be unsubstituted, or substituted as described for alkyl or as described in the various embodiments provided herein.
• heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, purinyl, tetrazolyl, triazinyl, pyrazinyl, tetrazinyl, quinazolinyl, quinoxalinyl, thienyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzoxazolyl, benzthiazolyl, benzisoxazolyl, benzisothiazolyl and carbazoloyl, and the like.
• Illustrative examples of heteroaryl groups shown in graphical representations include the following entities, in the form of properly bonded
• each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bicyclic heteroaryl groups is independently optionally substituted by C 1 -C 6 alkyl means that an alkyl may be but need not be present on any of the C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3-to 7-membered heterocycloalkyl, C 6 -C 10 aryl, or mono- or bi
• the term “independently” means that the subsequently described event or circumstance is to be read on its own relative to other similar events or circumstances.
• the use of “independently optionally” means that each instance of a hydrogen atom on the group may be substituted by another group, where the groups replacing each of the hydrogen atoms may be the same or different.
• the use of “independently” means that each of the groups can be selected from the set of possibilities separate from any other group, and the groups selected in the circumstance may be the same or different.
• agonist refers to both full agonists and partial agonists and other agonists.
• the term “pharmaceutically acceptable excipient” refers to those typically used in preparing pharmaceutical compositions and should be pharmaceutically pure and non-toxic in the amounts used. They generally are a solid, semi-solid, or liquid material which in the aggregate can serve as a vehicle or medium for the active ingredient.
• compositions include diluents, vehicles, carriers, ointment bases, binders, disintegrates, lubricants, glidants, sweetening agents, flavoring agents, gel bases, sustained release matrices, stabilizing agents, preservatives, solvents, suspending agents, buffers, emulsifiers, dyes, propellants, coating agents, and others.
• substantially enantiomerically pure refers to greater than 90% enantiomeric purity for a given stereocenter.
• substantially enantiomerically pure refers to greater than 80% ee (enantiomeric excess).
• stereoisomers may be substantially enantiomerically pure, or for example, may have greater than 97% enantiomeric purity, or for example, may have greater than 99% enantiomeric purity at the stereocenter.
• Compounds of the disclosure also include all isotopic variations, in which at least one atom is replaced by an atom having the same atomic number, but an atomic mass different from the atomic mass most commonly found in nature.
• the terms “the compounds of the disclosure” and “a compound of the disclosure” and the like include the embodiment of formula I, formula II, formula II ⁇ , and the other more particular embodiments encompassed by formulae I, II, and ⁇ II described herein, each of the exemplified compounds described herein, and a pharmaceutically acceptable salt of each of these embodiments. It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
• Metabolites of Compound A may be generated by administering Compound A to a subject. Fluid or tissue may then be collected and analyzed for metabolites.
• the fluid is whole blood, urine, bile, urine, or any other fluid suitable for analyzing metabolites.
• the tissue is liver tissue, kidney tissue, or any other suitable tissue for analyzing metabolites.
• Illustrative subjects include humans and non-human animals, for example, mammals, such as monkeys, mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like.
• the subject is a human.
• the subject is a non-human mammal, such as a mouse, rat, dog, or any other animal suitable for testing.
• the metabolites are generated in vitro. In some embodiments, metabolites are generated using hepatocytes.
• Some embodiments include a compound of formula I or a pharmaceutically acceptable salt thereof.
• each R 1 is independently chosen from -OH, -OSO 3 H, -O- glucuronide, -SH, a -S(O)C 1 -C 6 alkyl group, a -S(O) 2 C 1 -C 6 alkyl group, a -SC 1 -C 6 alkyl group, a -SC 1 -C 6 alkyl-NHC(O)C 1 -C 6 alkyl group, an amino acid, and a peptide.
• each hydrogen atom in a C 1 -C 6 alkyl group is optionally replaced by OH, oxo, - CO 2 H, -O-glucuronide, -NH 2 , a -NHC(O)C 1 -C 6 alkyl group, or a -N(H)C 1 -C 6 alkyl-COzH group.
• R 1 is at C-1. In some embodiments, R 1 is at C-2. In some embodiments, R 1 is at C-3. In some embodiments, R 1 is at C-4.
• n is 2 or 3
• the R l s may be at any combination of C-1, C-2, C-3, and C-4.
• R 1 is an amino acid.
• Illustrative amino acids include natural amino acids, unnatural amino acids, and derivatives thereof.
• the amino acid when R 1 is an amino acid, the amino acid is attached through the side chain of the amino acid.
• the amino acid if the amino acid is cysteine, the amino acid may be attached to the compound of formula I through the side chain thiol of cysteine.
• the amino acid is N- terminally acetylated.
• R 1 is a peptide. In some embodiments, the peptide is 2-6 residues in length. In some embodiments, the peptide is 2 residues in length. In some embodiments, the peptide is 3 residues in length. In some embodiments, the peptide comprises a cysteine. In some embodiments, when R 1 is a peptide, the peptide may be attached through the side chain of the amino acid of the peptide. As an example, if the peptide includes a cysteine, the peptide can be attached to the compound of formula I through the side chain thiol of the cysteine. In some embodiments, the peptide is N-terminally acetylated. [0050] In some embodiments, R 2 is H, -OH, or -O-glucuronide. In some embodiments, R 2 is H. In some embodiments, R 2 is -OH or -O-glucuronide.
• R 3 is a C 1 -C 6 alkyl group optionally replaced by -OH, oxo, -O-glucuronide, -NH 2 , a -NHC(O)C 1 -C 6 alkyl group, or -NHCH 2 COOH.
• R 3 is an optionally substituted methyl, ethyl, propyl, butyl, pentyl, or hexyl group.
• R 3 is methyl.
• R 3 is substituted with -OH, oxo, -O- glucuronide, -NH 2 , an -NHC(O)C 1 -C 6 alkyl group, or -NHCH 2 COOH.
• R 4 is -OH or -O-glucuronide.
• R 4 is at C-5. In some embodiments, R 4 is at C-6. In some embodiments, R 4 is at C-7. In some embodiments, R 4 is at C-8. Illustratively, when m is 2 or 3, the R 4 S may be at any combination of C-5, C-6, C-7, and C-8.
• n is an integer from 0 to 4. In some embodiments, n is 1, 2, 3, or 4. In some embodiments, n is 0. In some embodiments, n is 1.
• m is an integer from 0 to 4. In some embodiments, m is 1, 2, 3, or 4.
• n 0
• m 1
• n 1
• R 2 is not H, R 3 is substituted, or a combination thereof.
• n 0 and m is 0, then R 2 is not H or R 3 is substituted, or a combination thereof.
• Some embodiments include a compound of formula II or a pharmaceutically acceptable salt thereof.
• R 5 and R 6 are independently chosen from C 1 -C 6 alkyl, -NH- C 1 -C 6 alkyl, -NH-aryl, and -NH-heteroaryl group, wherein each hydrogen atom in a C 1 -C 6 alkyl group is optionally replaced by -OH, oxo, or -CO 2 H.
• R 5 is methyl
• R 6 is a -NH-C 1 -C 6 alkyl group, wherein each hydrogen atom in the C 1 -C 6 alkyl group is optionally replaced by -OH, oxo, or -CO 2 H.
• R 6 is -NH-ethyl.
• at least one hydrogen atom in ethyl is substituted with - OH, oxo, or -CO 2 H.
• R 6 is -NH(1,2,3-oxadiazole).
• Some embodiments include a compound of formula ⁇ II or a pharmaceutically acceptable salt thereof.
• R 7 is a C 1 -C 6 alkyl group, wherein each hydrogen atom in the C 1 -C 6 alkyl group is optionally replaced by -OH, oxo, -CO 2 H, or -NHz.
• R 7 is ethyl, wherein at least one hydrogen atom in ethyl is replaced by -OH, oxo, -CO 2 H, or - NHz.
• the compounds of the disclosure can be administered alone or in the form of a pharmaceutical composition.
• a compound of the disclosure is administered in the form of a pharmaceutical composition, that is, in admixture with at least one pharmaceutically acceptable excipient.
• the proportion and nature of any pharmaceutically acceptable excipient(s) are determined by the properties of the selected compound of the disclosure, the chosen route of administration, and standard pharmaceutical practice.
• the present disclosure provides a pharmaceutical composition
• a pharmaceutical composition comprising: a compound or pharmaceutically acceptable salt disclosed herein; and at least one pharmaceutically acceptable excipient.
• a compound or pharmaceutically acceptable salt thereof of the disclosure can be administered in any form and route which makes the compound bioavailable.
• the compounds and pharmaceutically acceptable salts of the disclosure can be administered by a variety of routes, including orally, for example, using tablets and capsules.
• the compounds of the disclosure can also be administered by parenteral routes, for example, by inhalation, subcutaneously, intramuscularly, intravenously, intraarterially, transdermally, intranasally, rectally, vaginally, ocularly, topically, sublingually, and buccally, intraperitoneally, intraadiposally, intrathecally and via local delivery for example by catheter or stent.
• compositions of the disclosure may be administered to the patient, for example, in the form of tablets, capsules, cachets, papers, lozenges, wafers, elixirs, ointments, transdermal patches, aerosols, inhalants, suppositories, solutions, and suspensions.
• the pharmaceutical compositions of the present disclosure may be prepared in a manner well known in the pharmaceutical art and include at least one of the compounds disclosed herein as the active ingredient.
• the amount of a compound of the disclosure may vary depending upon its particular form and, in some embodiments, may be between 1% to about 50% of the weight of the unit dose form.
• the present pharmaceutical compositions are formulated in a unit dose form, each dose containing from about 0.5 mg to about 100 mg of a compound or pharmaceutically acceptable salt thereof of the disclosure.
• unit dose form refers to a physically discrete unit containing a predetermined quantity of active ingredient, in association with a suitable pharmaceutical excipient, by which one or more is used throughout the dosing regimen to produce the desired therapeutic effect.
• One or more “unit dose form” may be taken to affect the treatment dosage, typically on a daily schedule.
• the pharmaceutical composition is a pharmaceutical composition adapted for oral administration, such as a tablet or a capsule or a liquid formulation, for example, a solution or suspension, adapted for oral administration.
• the pharmaceutical composition is a liquid formulation adapted for parenteral administration.
• the disclosure provides a method of treating a disease, disorder, or condition associated with GPR139, comprising: administering to a patient in need thereof an effective amount of a compound or pharmaceutically acceptable salt disclosed herein.
• a compound or pharmaceutically acceptable salt of the disclosure is provided for use as a medicament.
• the disclosure also provides uses of a compound or pharmaceutically acceptable salt disclosed herein, including a use for the manufacture of a medicament, to treat a disease, disorder, or condition associated with GPR139 described herein.
• the compounds of the disclosure are GPR139 agonists for treating a variety of subjects (e.g., humans, non-human mammals and non-mammals). In some embodiments, the subject is a human.
• condition relate to any unhealthy or abnormal state.
• the compounds of the disclosure are metabolites of GPR139 agonists and may be useful for treating a variety of conditions.
• disease, disorder, or condition associated with GPR139 includes conditions, disorders, and diseases in which an agonist of GPR139 may provide a therapeutic benefit, such as CNS disorders, disorders of the pancreas, such as pancreatitis, phenylketonuria, and pituitary disorders.
• the term “disease, disorder, or condition associated with GPR139” includes, but is not limited to, CNS disorders such as schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, including mild cognitive impairment, Alzheimer's Disease, disorders affecting short term memory, disorders affecting long term memoiy, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, including generalized anxiety disorder and social anxiety disorder, pain, fibromyalgia, and other disorders mentioned herein, among others.
• CNS disorders such as schizophrenia, autism spectrum disorder, sleep disorders, depression, bipolar disorder, cognitive impairment, including mild cognitive impairment, Alzheimer's Disease, disorders affecting short term memory, disorders affecting long term memoiy, attention deficit hyperactivity disorder, post-traumatic stress disorder, substance abuse, drug addiction, eating disorders, obsessive compulsive disorder, anxiety disorders, including generalized anxiety disorder and social anxiety disorder, pain, fibromyalgia, and other disorders mentioned herein, among others
• Schizophrenia is a chronic, severe, and disabling disorder characterized, in part, by negative symptoms, such as blunted affect, deficits in social functioning, anhedonia, avolition and poverty of speech, and by cognitive impairment associated with schizophrenia (CIAS), such as impairment in attention, working memory, executive function and social cognition.
• schizophrenia is a group of developmental disabilities that can cause significant social, communication and behavioral challenges (repetitive and stereotyped behavior). Because of the pro-social effects expected from GPR139 agonists, the present compounds may treat schizophrenia and autism spectrum disorder.
• the term “disease, disorder, or condition associated with GPR139” includes schizophrenia.
• the term “disease, disorder, or condition associated with GPR139” includes autism spectrum disorder.
• the term “disease, disorder, or condition associated with GPR139” includes addiction.
• addiction includes addiction to nicotine, alcohol, and/or cocaine.
• the term “disease, disorder, or condition associated with GPR139” includes attention deficit hyperactivity disorder.
• disease, disorder, or condition associated with GPR139 includes bipolar disorder.
• disease, disorder, or condition associated with GPR139 includes depression, such as major depressive disorder.
• the terms “treat,” “treatment,” and “treating” include improvement of the conditions described herein.
• the terms “treat,” “treatment,” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition.
• the terms “treat,” “treatment,” and “treating” are intended to include therapeutic treatment of such disorders.
• the terms “treat,” “treatment,” and “treating” are intended to include prophylactic treatment of such disorders.
• the terms “patient” and “subject” include humans and non-human animals, for example, mammals, such as mice, rats, guinea pigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. The term also includes birds, fish, reptiles, amphibians, and the like.
• the patient is a human.
• the patient is a non- human mammal, such as a mouse, rat, or dog.
• the term “effective amounf ’ refers to the amount of compound of the disclosure which treats, upon single or multiple dose administration, a patient suffering from the mentioned condition.
• An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances.
• an effective amount of the present disclosure, the treatment dosage is in the range of 1 mg to 100 mg. Specific amounts can be determined by the skilled person. Although these dosages are based on an average human subject having a mass of about 60 kg to about 70 kg, a physician will be able to determine the appropriate dose for a patient having a mass that falls outside of this weight range.
• the compounds of the disclosure may be combined with one or more other pharmacologically active compounds or therapies for the treatment of one or more disorders, diseases or conditions for which GPR139 is indicated may be administered simultaneously, sequentially or separately in combination with one or more compounds or therapies for treating a particular disease, disorder, or condition associated with GPR139.
• a compound or pharmaceutically acceptable salt of the disclosure may be administered in combination with one or more sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, cyclopyrrolones, imidazopyri dines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, mGlu2/3 agonists, 5HT-2 antagonists, PDE10 antagonists, GlyTl inhibitors, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, busprione, butabarbital, butalbital, cap
• a compound or pharmaceutically acceptable salt of the disclosure may be administered in combination with an anti-depressant or anti-anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical anti-depressants, benzodiazepines, 5-HTA agonists or antagonists, especially 5-HTA partial agonists, and corticotropin releasing factor (CRF) antagonists.
• norepinephrine reuptake inhibitors including tertiary amine tricyclics and secondary amine tri
• Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide, venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazopam, chlorazepate, diazopam, halazepam, lorazepam, oxazopam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and the like.
• a compound or pharmaceutically acceptable salt of the disclosure may be administered in combination with one or more anti-Alzheimer's agents, beta-secretase inhibitors, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, NSAID's including ibuprofen, vitamin E, anti-amyloid antibodies, also sedatives, hypnotics, anxiolytics, antipsychotics, antianxiety agents, and tranquilizers, and such other medications as are used in the treatment of Alzheimer's disease or mild cognitive impairment.
• the activity of compounds as GPR139 agonists and metabolites of GPR103 agonists may be determined by a variety of methods, including in vitro and in vivo methods.
• Example chemical entities useful in methods of the description will now be described by reference to illustrative synthetic schemes for their general preparation below and the specific examples that follow.
• Artisans will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product.
• it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent.
• the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups.
• Rat plasma samples were obtained from a study in which male and female Sprague Dawley rats were administered repeat 3-mg/kg oral doses of Compound A QD for 14 days.
• Whole blood was obtained from rats at selected time points on Day 14 (predose and 0.5, 1, 2, 4, 8, and 24 hours postdose) and processed into plasma for analysis.
• Plasma from 3 animals/sex/time point were pooled (30 ⁇ L each), combined with 360 ⁇ L of ice cold ACN and mixed to precipitate proteins. Samples were centrifuged, and the supernatants were taken and dried down under a stream of nitrogen. Each sample was reconstituted with 100 ⁇ L of 5% ACN, and 10 ⁇ L was analyzed by LC/MS/MS for profiling and metabolite identification.
• Dog plasma samples were obtained from a study in which male and female beagle dogs were administered repeat 30-mg/kg oral doses of Compound A QD for 14 days.
• Whole blood was obtained from dogs at selected time points on Day 14 (predose and 0.5, 1, 2, 4, 8, and 24 hours postdose) and processed into plasma for analysis.
• Plasma from 2 animals/sex/time point were pooled (50 ⁇ L each), combined with 400 ⁇ L of ice cold ACN and mixed to precipitate proteins. Samples were centrifuged, and the supernatants were taken and dried down under a stream of nitrogen. Each sample was reconstituted with 100 ⁇ L of 5% ACN, and 10 ⁇ L was analyzed by LC/MS/MS for profiling and metabolite identification.
• Dog urine, bile, and liver and kidney tissue samples were obtained from a study in which male and female beagle dogs were administered repeat 60-mg/kg oral doses of Compound A QD for 13 weeks.
• Urine and bile were centrifuged and supernatant was analyzed by LC/MS/MS without further processing or dilution.
• Kidney and centrilobular, midzonal, and periportal liver tissue samples were diluted 3-fold with saline solution and homogenized. Homogenized samples were crashed with 4 volumes of ACN, vortexed, and centrifuged at 15,000 ⁇ g for 10 minutes. The resulting supernatant was reconstituted with 100 ⁇ L of 5% ACN, and 10 ⁇ L was analyzed by LC/MS/MS for profiling and metabolite identification.
• Cynomolgus monkey plasma and urine samples were obtained from a study in which animals were administered a single 200 mg/kg oral dose of Compound A.
• Plasma samples from each monkey was pooled using Hamilton’s method using the area under the plasma concentration-time curve from time 0 to 24 hours. Proteins were precipitated with 3 volumes of ACN and mixed thoroughly. The samples were vortexed and centrifuged. The supernatant was removed, dried under a stream of nitrogen, and reconstituted with 80/20 water/ACN (v/v) for analysis by LC/MS/MS for profiling and metabolite identification.
• Urine was pooled across subjects (1000 ⁇ L each, 6 subjects) from 0 to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to72 hours postdose and centrifuged at 4000 x g for 10 minutes to remove any pellet. Predose and placebo urine samples were also pooled by combining equivalent volumes (1,000 ⁇ L) and processed in the same manner. Samples were then analyzed by LC/MS/MS for profiling and metabolite and identification.
• Plasma samples from 6 subjects were pooled using Hamilton’s method using the area under the plasma concentration-time curve from time 0 to 48 hours for each subject, and further pooled across the subjects (250 ⁇ L each) to generate a single plasma pool.
• equal volumes (250 ⁇ L) of predose plasma were pooled, as well as equal volumes (625 ⁇ L) of plasma were pooled from 2 subjects who received placebo.
• Proteins were precipitated with 3 volumes of ACN and mixed thoroughly. The samples were centrifuged and supernatant was removed. The pellets were resuspended with 2 mL of 80/20 ACN/water (volume-over-volume [v/v]), mixed, and centrifuged. Supernatants were combined, dried under a stream of nitrogen, and reconstituted with 80/20 water/ ACN (v/v) with 0.1% formic acid (FA) for analysis by LC/MS/MS for profiling and metabolite identification.
• ACN volume-over-volume
• Urine was pooled across subjects (1000 ⁇ L each, 6 subjects) from 0 to 6, 6 to 12, 12 to 24, 24 to 48, and 48 to72 hours postdose and centrifuged at 4000 x g for 10 minutes to remove any pellet. Predose and placebo urine samples were also pooled by combining equivalent volumes (1000 ⁇ L) and processed in the same manner. Samples were then analyzed by LC/MS/MS for profiling and metabolite identification.
• the hepatocyte incubations consisted of (final concentrations): 10-pM Compound A, 1x10 6 cells/mL hepatocytes (Life Technologies [Grand Island, NY, USA]; Sprague Dawley rat, lot RS688, 3 male donors; beagle dog, lot DB295, 1 male donor; cynomolgus monkey, lot CY359, 1 male donor; and human, lot HUE115, 5 male and 5 female donors), 0.1% DMSO, and KHB at pH 7.4 made up to a final volume of 100 ⁇ L. Hepatocytes were thawed, processed, and prepared according to the protocol recommended by the vendor. A 96-well plate was used for this study.
• the reaction was initiated by adding Compound A to hepatocytes in the plate. Plates were incubated at 37 °C for 0 and 120 minutes. The reactions were terminated by adding equal volume of ice cold ACN. Precipitated protein was removed by centrifugation (5,000 lpm for 10 minutes at room temperature) and the supernatant was analyzed by LC/MS/MS.
• HepatoPac application and maintenance media were prepared per instructions from the vendor. HepatoPac cells pre-plated in 24-well plates were received from the vendor and a full medium change was performed with the species-specific maintenance medium. Rat wells and associated stromal and blank wells were filled with 300 ⁇ L of maintenance media and multi- species wells and associated stromal and blank wells were filled with 400 ⁇ L of maintenance media. Plates were incubated at 37 °C in a 10% CO 2 atmosphere with >95% humidity for 48 hours.
• the fortified media was capped and stored at 37 °C in a water bath until use.
• the maintenance media was withdrawn from all plates replaced with the species- specific application media.
• the application media was withdrawn a second time and replaced with species-specific application media (300 ⁇ L for rat HepatoPac, stromal, and blank wells and 400 ⁇ L for multi -species HepatoPac, stromal, and blank wells).
• Cells were stored in the incubator until dosing.
• media in all wells were removed and replaced with fresh application media at half the final dosing volume (150 ⁇ L for rat, stromal, and blank wells and 200 ⁇ L for multi-species, stromal, and blank wells).
• An equal volume of species- specific 20- ⁇ M dosing solution was applied to each well and gently swirled to initiate the incubation.
• 250 ⁇ L (rat wells) and 350 ⁇ L (multi-species wells) of media were removed from the HepatoPac, stromal and blank wells and quenched with 500 ⁇ L (rat wells) or 700 ⁇ L (multi-species wells) of ice-cold ACN in polypropylene tubes; these were referred to as the primary samples.
• a 250- ⁇ L (rat wells) or 350 ⁇ L (multi-species wells) aliquot of blank application media was added back to each well and all contents were removed and quenched with 600 ⁇ L (rat wells) or 800 ⁇ L (multi species wells) of ice-cold ACN in polypropylene tubes; these were referred to as the wash samples.
• Ice cold ACN 600 ⁇ L for rat wells and 800 ⁇ L for multi-species wells was added back to the wells. Using the edge of a 1,000 ⁇ L pipette tip, the well was scraped thoroughly side to side starting at the top and moving to the bottom. After thorough scraping, all ACN was removed and transferred to polypropylene tubes; these were referred to as the cell lysate samples. After all samples were collected, an aliquot of 300 ⁇ L (rat wells) or 400 ⁇ L (multi-species wells) of application media was returned to the wells to maintain the local humidity for the remaining samples.
• Cell lysate samples were stored frozen at -80 °C for future analysis. Primary and wash samples were gently rotated manually several times to ensure thorough mixing of sample and quench solutions, then centrifuged at 3,000 rpm for 30 minutes in an Allegra® X-14R centrifuge (Beckman Coulter [Brea, CA, USA]). Supernatant (500 ⁇ L for rat samples and 800 ⁇ L for multi species samples) was collected and transferred to fresh polypropylene tubes and stored frozen at -80 °C until analysis. Tubes containing residual quench solution and protein pellet were stored frozen at -80 °C for possible future analysis.
• HPLC analysis was conducted using an Agilent 1290 binary pump (Agilent Technologies, Inc. [Santa Clara, CA, USA]) with a PAL autosampler (Leap Technologies). Separation was achieved on a Kinetex 5- ⁇ m C18 column (2.1 x 150 mm; Phenomenex, Inc [Torrance, CA, USA]) under ambient conditions.
• the HPLC eluent was introduced via electrospray positive ionization directly into an MDS SCIEX TripleTOF 5600 mass spectrometer with a source temperature of 500 °C, IonSpray voltage floating set to 5,000, declustering potential of 80, and MS 2 collision energy set to 20. The samples were analyzed in full scan mode with independent data acquisition triggered product ion scanning and mass defect filtering enabled.
• the reaction mixture was stirred at RT for 1 hour, then water was added and the white solid was filtered.
• the resulting crude material was dissolved in CH 2 C I2 and purified via ISCO automated purification system, eluting with a gradient of 0-20% MeOH in DCM. The collected fractions were combined and solvent was removed via rotary evaporation at 35 °C. The resulting mixture was dried in vacuo to give the title compound as a white solid (454 mg, 65%).
• Step 2 (S)-2-(6-(methylthio)-4-oxobenzo[d] [1,2,3]triazin-3 (4H)-yl)-N-( 1 -(4- (trifluoromethoxy)phenyl)ethyl)acetamide
• Step 1 (S)-2-(6-mercapto-4-oxobenzo[d][1,2,3]triazin-3(4H)-yl)-N-(1-(4- (trifluoromethoxy)phenyl)ethyl)acetamide
• the vial was heated at 90 °C for 1 hour, then poured into 1 M HC1, extracted with EtOAc (2 x 10 mL), washed with water (2 x 20 mL), dried over MgSC>4, filtered and concentrated to yield the title compound as a yellow solid, which was used without further purification.
• Step 2 N-acetyl-S-(4-oxo-3-(2-oxo-2-(((S)-1-(4-(trifluoromethoxy)phenyl)ethyl)amino)ethyl)- 3 ,4-dihydrobenzo[d] [1,2,3]triazin-6-yl)cysteine

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