WO2025165967A2 - Agonistes inverses de gpr6 - Google Patents

Agonistes inverses de gpr6

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Publication number
WO2025165967A2
WO2025165967A2 PCT/US2025/013748 US2025013748W WO2025165967A2 WO 2025165967 A2 WO2025165967 A2 WO 2025165967A2 US 2025013748 W US2025013748 W US 2025013748W WO 2025165967 A2 WO2025165967 A2 WO 2025165967A2
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WIPO (PCT)
Prior art keywords
compound
alkyl
alkylene
formula
ring
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Pending
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PCT/US2025/013748
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WO2025165967A3 (fr
Inventor
Michael Wood
Vinod F. Patel
Mark Sylvester
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MapLight Therapeutics Inc
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MapLight Therapeutics Inc
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Publication of WO2025165967A2 publication Critical patent/WO2025165967A2/fr
Publication of WO2025165967A3 publication Critical patent/WO2025165967A3/fr
Pending legal-status Critical Current
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • the orphan G- protein coupled receptor GPR6 is densely expressed in medium spiny neurons (MSNs) which constitute 95% of the neurons in the mammalian striatum (Kreitzer 2011). GPR6 is expressed in both of the major subtypes (i.e., direct-pathway and indirect-pathway) of MSNs and it is believed to modulate reactivity of the striatum to incoming stimuli.
  • MSNs medium spiny neurons
  • GPR6 is a member of a receptor family that includes orphan receptors GPR3 & GPR12. All three members exhibit high constitutive activity as evidenced by the production of cyclic AMP (cAMP) upon overexpression. Reversal of constitutive GPR6 activity in the human striatum may treat deficits in reward, learning and motor control. There is a need for novel GPR6 inverse agonists.
  • the present disclosure is directed to compounds that are inverse agonists of the G protein-coupled receptor 6 (GPR6) as well as pharmaceutical compositions and uses thereof in treating a disease or disorder that is treatable by administration of a GPR6 inverse agonist.
  • GPR6 G protein-coupled receptor 6
  • the present disclosure provides compound of Formula (I), (la), lb), (Ic) or (Id), or a pharmaceutically acceptable salt thereof, wherein the definitions of J, L, X, E, M 1 , M 2 , ring Z, ring Q, R 1 , R 2 , R 3 , n, m and p are defined herein: Formula (I),
  • the term "about” when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value).
  • “about 50” can mean 45 to 55
  • "about 25,000” can mean 22,500 to 27,500, etc., unless the context of the disclosure indicates otherwise, or is inconsistent with such an interpretation.
  • “about 50” means a range extending to less than half the interval(s) between the preceding and subsequent values, e.g., more than 49.5 to less than 50.5.
  • the phrases “less than about” a value or “greater than about” a value should be understood in view of the definition of the term “about” provided herein.
  • the term “about” when preceding a series of numerical values or a range of values refers, respectively to all values in the series, or the endpoints of the range.
  • administer refers to administering a compound or pharmaceutically acceptable salt of the compound or a composition or formulation comprising the compound or pharmaceutically acceptable salt of the compound to a patient.
  • salts includes both acid and base addition salts.
  • Pharmaceutically acceptable salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
  • Base addition salts include but are not limited to, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris-(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, triethylamine, dibenzylamine, ephenamine, dehydroabietylamine, N-ethylpiperidine, benzylamine, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, ethylamine, basic amino acids, e.
  • lysine and arginine di cyclohexylamine and the like examples include metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like.
  • metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like.
  • ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like.
  • organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like.
  • treating refers to improving at least one symptom of the patient's disorder. Treating can be improving, or at least partially ameliorating a disorder or an associated symptom of a disorder.
  • an effective amount and “therapeutically effective amount” are used interchangeably in this disclosure and refer to an amount of a compound, or a salt thereof, (or pharmaceutical composition containing the compound or salt) that, when administered to a patient, is capable of performing the intended result.
  • the “effective amount” will vary depending on the active ingredient, the state, disorder, or condition to be treated and its severity, and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
  • carrier or “vehicle” as used interchangeably herein encompasses carriers, excipients, adjuvants, and diluents or a combination of any of the foregoing, meaning a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material involved in carrying or transporting a pharmaceutical agent from one organ, or portion of the body, to another organ or portion of the body.
  • the carrier includes nanoparticles of organic and inorganic nature.
  • C 1 -C 6 alkyl is intended to encompass Ci, C2, C3, C4, C5, C 6 , C 1-6 , Ci-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3.5, C3-4, C4-6, C4-5, and C 5.6 alkyl.
  • Alkyl or “alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a C 1 -C 6 alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl.
  • a C1-C5 alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl).
  • a C 1 -C 6 alkyl includes all moieties described above for C1-C5 alkyls but also includes C 6 alkyls.
  • a C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and C 1 -C 6 alkyls, but also includes C7, C8, C9 and C10 alkyls.
  • a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls.
  • Non-limiting examples of C1-C12 alkyl include methyl, ethyl, n-propyl, z-propyl, sec-propyl, n-butyl, z-butyl, sec-butyl, t-butyl, n-pentyl, /-amyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl, n-undecyl, and n-dodecyl.
  • an alkyl group can be optionally substituted.
  • Alkylene or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
  • C1-C12 alkylene include methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to a radical group (e.g., those described herein) through a single bond.
  • the points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
  • alkenyl or “alkenyl group” refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
  • a C2-C5 alkenyl includes C5 alkenyls, C4 alkenyls, C3 alkenyls, and C2 alkenyls.
  • a C2-C6 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C 6 alkenyls.
  • a C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C7, C8, C9 and C10 alkenyls.
  • a C2-C12 alkenyl includes all the foregoing moieties, but also includes C11 and C12 alkenyls.
  • Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (allyl), iso-propenyl, 2-methyl-l -propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1- pentenyl, 2-pentenyl, 3 -pentenyl, 4-pentenyl, 1 -hexenyl, 2-hexenyl, 3 -hexenyl, 4-hexenyl, 5- hexenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1-octenyl, 2- octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3- non
  • alkenylene or “alkenylene chain” refers to an unsaturated, straight or branched divalent hydrocarbon chain radical having one or more olefins and from two to twelve carbon atoms.
  • C2-C12 alkenylene include ethenylene, propenylene, //-butenylene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to a radical group (e.g., those described herein) through a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.
  • Alkynyl or “alkynyl group” refers to a straight or branched hydrocarbon chain having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl
  • an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl
  • an alkynyl group comprising up to 6 carbon atoms is a C2-C6 alkynyl
  • an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl.
  • a C2-C5 alkynyl includes C5 alkynyls, C4 alkynyls, C3 alkynyls, and C2 alkynyls.
  • a C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes C 6 alkynyls.
  • a C2-C10 alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes C7, C8, C9 and C10 alkynyls.
  • a C2-C12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls.
  • Non-limiting examples of C2-C12 alkenyl include ethynyl, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
  • Alkynylene or “alkynylene chain” refers to an unsaturated, straight or branched divalent hydrocarbon chain radical having one or more alkynes and from two to twelve carbon atoms.
  • C2-C12 alkynylene include ethynylene, propynylene, n-butynylene, and the like.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to a radical group (e.g., those described herein) through a single bond.
  • the points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through any two carbons within the chain having a suitable valency.
  • alkynylene chain can be optionally substituted.
  • Alkoxy refers to a group of the formula -OR a where R a is an alkyl, alkenyl or alknyl as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
  • Aryl refers to a hydrocarbon ring system comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring, and which is attached to the rest of the molecule by a single bond.
  • the aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryls include, but are not limited to, aryls derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically in the specification, the “aryl” can be optionally substituted.
  • Aralkyl or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and R c is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
  • Carbocyclyl refers to a rings structure, wherein the atoms which form the ring are each carbon, and which is attached to the rest of the molecule by a single bond.
  • Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring.
  • Carbocyclic rings include aryls and cycloalkyl, cycloalkenyl, and cycloalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon consisting solely of carbon and hydrogen atoms, which can include fused, bridged, or spirocyclic ring systems, having from three to twenty carbon atoms (e.g., having from three to ten carbon atoms) and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Polycyclic cycloalkyls include, for example, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
  • Cycloalkenyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkenyls include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cycloctenyl, and the like.
  • Polycyclic cycloalkenyls include, for example, bicyclo[2.2.1]hept-2-enyl and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
  • Cycloalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkynyl include, for example, cycloheptynyl, cyclooctynyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkynyl group can be optionally substituted.
  • Haloalkyl refers to an alkyl, as defined above, that is substituted by one or more halo radicals, e.g. trifluoromethyl, difluoromethyl, tri chloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloalkyl group can be optionally substituted.
  • Heterocyclyl refers to a saturated, unsaturated, non-aromatic 3- to 20-membered ring which consists of two to nineteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and which is attached to the rest of the molecule by a single bond.
  • Heterocyclyl or heterocyclic rings include heterocyclylalkyls, heterocyclylalkenyls, and hetercyclylalkynyls.
  • the heterocyclyl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, bridged, or spirocyclic ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl can be optionally oxidized; the nitrogen atom can be optionally quatemized; and the heterocyclyl can be partially or fully saturated.
  • heterocyclyl examples include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorph
  • Heterocyclylene refers to a divalent saturated, unsaturated, non-aromatic 3- to 20- membered ring which consists of two to nineteen carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and which is attached to the rest of the molecule by two bonds.
  • the heterocyclylene radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, spiro, or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclylene radicals include, but are not limited to, dioxolanylene, decahydroisoquinolylene, imidazolinylene, imidazolidinylene, isothiazolidinylene, isoxazolidinylene, morpholinylene, octahydroindolylene, octahydroisoindolylene, 2-oxopiperazinylene, 2-oxopiperidinylene, 2-oxopyrrolidinylene, oxazolidinylene, piperidinylene, piperazinylene, 4-piperidonylene, pyrrolidinylene, pyrazolidinylene, quinuclidinylene, thiazolidinylene, tetrahydrofurylene, trithianylene, tetrahydropyranylene, thiomorpholinylene, thiamorpholinylene, 1-oxo-thiomorpholinylene, and
  • 1.1-dioxo-thiomorpholinylene Unless stated otherwise specifically in the specification, a heterocyclylene group can be optionally substituted.
  • Heteroaryl refers to a 5- to 20-membered ring system comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, at least one aromatic ring, including compounds with aromatic resonance structures (e.g., 2-pyridone), and which is attached to the rest of the molecule by a single bond.
  • the heteroaryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atom can be optionally quaternized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzooxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4 benzodi oxanyl, benzonaphthofuranyl, benzoxazolyl, benzodi oxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2 a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazoly
  • Heteroarylene refers to a divalent 5- to 20-membered ring system radical comprising hydrogen atoms, one to nineteen carbon atoms, one to six heteroatoms selected from nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroarylene radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused, or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized.
  • Examples include, but are not limited to, azepinylene, acridinylene, benzimidazolylene, benzothiazolylene, benzindolylene, benzodi oxolylene, benzofuranyl ene, benzooxazolylene, benzothiazolylene, benzothiadiazolylene, benzo[b][l,4]dioxepinylene, 1,4-benzodioxanylene, benzonaphthofuranylene, benzoxazolylene, benzodi oxolylene, benzodioxinylene, benzopyranyl ene, benzopyranonylene, benzofuranyl ene, benzofuranonylene, benzothienyl ene (divalent benzothiophene radical), benzotriazolylene, benzo[4,6]imidazo[l,2-a]pyridinylene, carb azolyl ene, cin
  • Heterocyclylalkyl refers to a radical of the formula -Rb-Re where Rb is an alkylene, alkenylene, or alkynylene group as defined above and R e is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.
  • substituted means any of the groups described herein (e.g., alkyl, alkenyl, alkynyl, alkoxy, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, haloalkyl, heterocyclyl, and/or heteroaryl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and I; an oxygen atom in groups such as hydroxyl groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfonyl groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamine
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles.
  • R g and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, N- heterocyclyl, heterocyclylalkyl, heteroaryl, /f-heteroaryl and/or heteroarylalkyl.
  • “Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, /f-heterocyclyl, heterocyclylalkyl, heteroaryl, /'/-heteroaryl and/or heteroarylalkyl group.
  • substituted further means any alkyl, cycloalkyl or heterocyclylalkyl in which one or more hydrogen atoms is replaced by an isotope e.g., deuterium.
  • each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the disclosure.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond.
  • the present disclosure provides compounds that are inverse agonists of the G protein- coupled receptor 6 (GPR6) as well as pharmaceutical compositions thereof and uses thereof in treating various diseases and disorders.
  • GPR6 G protein- coupled receptor 6
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein J is aryl substituted with 1-4 R a , or heteroaryl substituted with 1-4 R a ,
  • X is C, CR b or N
  • TM represents a single bond or a double bond; each of M 1 and M 2 is independently C, CR c , N, or NR d , wherein at least one of M 1 and M 2 is N or NR d ;
  • Ring Q is 5-6 membered heterocyclylene, or 5-6 membered heteroarylene
  • the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein
  • J is aryl substituted with 1-4 R a , or heteroaryl substituted with 1-4 R a ,
  • X is C, CR b or N
  • each of M 1 and M 2 is independently C, CR c , N, or NR d , wherein at least one of M 1 and M 2 is N or NR d ;
  • Ring Q is 5-6 membered heterocyclylene or 5-6 membered heteroarylene
  • the compound disclosed herein is a compound of formula (la),
  • J is aryl substituted with 1-4 R a , or heteroaryl substituted with 1-4 R a ,
  • X is C, CR b or N
  • the compound disclosed herein is a compound of formula (la): Formula (la), wherein
  • J is aryl substituted with 1-4 R a , or heteroaryl substituted with 1-4 R a ,
  • X is C, CR b or N
  • the compound disclosed herein is a compound of formula (lb): Formula (lb), wherein
  • J is aryl substituted with 1-4 R a , or heteroaryl substituted with 1-4 R a ,
  • X is C, CR b or N
  • the compound disclosed herein is a compound of formula (Ic): Formula (Ic),
  • J is aryl substituted with 1-4 R a , or heteroaryl substituted with 1-4 R a ,
  • X is C, CR b or N
  • the compound disclosed herein is a compound of formula (Id): Formula (Id), wherein
  • J is aryl substituted with 1-4 R a , or heteroaryl substituted with 1-4 R a ,
  • X is C, CR b or N
  • R b is absent, H, OH, Ci-3alkyl or halogen.
  • L is -CH 2 -.
  • L is -
  • X is N, CH or C.
  • J is aryl substituted with 1-4 R a .
  • J is phenyl substituted with 1-4 R a .
  • R a is H, halogen, C 1-6 alkyl, C 1-6 alkoxy or CN.
  • J is , wherein R a is C 1-3 alkyl, halogen, C1-3 alkoxy or CN.
  • J is [0066] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), IS wherein p is 0, 1 or 2, and
  • R a is Ci-3 alkyl, halogen, C1-3 alkoxy or CN.
  • compound of formula (I), (la), (lb), (Ic) or (Id) is , wherein p is 0, 1 or 2, and R a is C1-3 alkyl, halogen, C1-3 alkoxy or CN.
  • J is heteroaryl optionally substituted with 1-4 R a .
  • J is
  • E is NR d
  • E is NH. Ring Q, M 1 , M 2 , R 1 and n
  • one of M 1 and M 2 is N, and the other one of M 1 and M 2 is C.
  • M 1 is N
  • M 2 is C
  • Ring Q is 5-membered heteroarylene.
  • Ring Q is
  • n 1
  • R 1 is C 1-6 alkyl optionally substituted with OH or alkoxy, haloalkyl, cycloalkyl or C 1-6 alkenyl.
  • R 1 is C 1-6 alkyl optionally substituted with OH, haloalkyl, cycloalkyl or C 1-6 alkenyl.
  • R 1 is C 1-6 alkyl, haloalkyl or cycloalkyl.
  • R 1 is CH3, CH2CH3, isopropyl, cyclopropyl,
  • R 1 is CH3, CH2CH3, isopropyl, cyclopropyl or CF3.
  • R 1 is isopropyl.
  • n is i and R 1 is isopropyl.
  • Ring Z is 6-membered heterocyclylene or 6-membered heteroarylene.
  • Ring Z is 6-membered heteroarylene.
  • Ring Z is pyridylene or pyrazinylene.
  • NA means the concat optical rotation data for this compound is not available or not applicable.
  • the concat optical rotation data are obtained through the procedure included in example 3.
  • a pharmaceutical composition for providing inverse agonism of the GPR6 receptor in a subject.
  • a pharmaceutical composition comprises one or more compounds of the present disclosure (e.g., a compound of Formula (I), (la), (lb), (Ic), (Id) or Table 1) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprises a therapeutically effective amounts of one or more compounds of the present disclosure (e.g., a compound of Formula (I), (la), (lb), (Ic), (Id) or Table 1) or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising one or more compounds of the present disclosure (e.g., a compound of Formula (I), (la), (lb), (Ic), (Id) or Table 1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or adjuvant is provided.
  • the pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes.
  • a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, and the like.
  • the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectally in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters.
  • the compounds of the present disclosure are administered in a therapeutically effective amount.
  • the amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • the compounds of the present disclosure find use in any number of methods.
  • the compounds are useful in methods for modulating a G protein-coupled receptor, e.g., G protein-coupled receptor 6 (GPR6).
  • G protein-coupled receptor 6 G protein-coupled receptor 6
  • the present disclosure provides the use of any one of the foregoing compounds of Formula (I), (la), (lb), (Ic), (Id) or Table 1 or a pharmaceutically acceptable salt thereof, for modulating G protein-coupled receptor, (e.g., GPR6) activity.
  • G protein-coupled receptor e.g., GPR6 activity is in a mammalian cell.
  • Modulating G protein-coupled receptor, (e.g., GPR6) activity can be in a subject in need thereof (e.g., a mammalian subject, such as a human) and for treatment of any of the described conditions or diseases.
  • the G protein-coupled receptor, (e.g., GPR6) activity is binding.
  • the G protein-coupled receptor, (e.g., GPR6) activity is inverse agonism of GPR6.
  • the present disclosure provides methods of treating a disease or disorder that is treatable by administration of an G protein-coupled receptor, (e.g., GPR6) inverse agonist, the method comprising administering a therapeutically effective amount of one or more compounds of the present disclosure (e.g., Formula (I), (la), (lb), (Ic), (Id) or Table 1).
  • the compounds of the present disclosure are used for treating a variety of disorders associated with G protein-coupled receptors, including one or more of the following conditions or diseases: Parkinson's disease, dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety, and depression.
  • the present disclosure provides methods of treating Parkinson’s disease comprising administering a therapeutically effective amount of one or more compound of Formula (I), (la), (lb), (Ic), (Id).
  • the present disclosure provides methods of treating Parkinson’s disease comprising administering a therapeutically effective amount of one or more compound described in Table 1.
  • the compounds of the present disclosure are administered in combination with one or more other compounds used for treating a variety of disorders associated with G protein-coupled receptors, including one or more of the following conditions or diseases: Parkinson's disease, dyskinesia, Huntington's disease, drug addiction, eating disorders, cognitive disorders, schizophrenia, bipolar disorder, epilepsy, Alzheimer's disease, anxiety, and depression.
  • the compounds of the present disclosure are administered in combination with one or more other compounds used for treating dyskinesia.
  • the one or more other compounds used for treating dyskinesia are an N-methyl-D-aspartate (NMDA) antagonist and/or vesicular monoamine transporter 2 (VMAT2) inhibitor.
  • NMDA N-methyl-D-aspartate
  • VMAT2 vesicular monoamine transporter 2
  • the one or more other compounds used for treating dyskinesia are an NMDA antagonist.
  • the NMDA antagonist is amantadine.
  • the one or more other compounds used for treating dyskinesia are a VMAT2 inhibitor.
  • the VMAT2 inhibitor is deutetrabenazine and/or valbenazine.
  • the compounds of the present disclosure are administered in combination with one or more other compounds used for treating depression.
  • the one or more other compounds used for treating depression are an antidepressant, atypical antidepressant, atypical antipsychotic, monoamine oxidase inhibitor (MAOI), N-methyl-D- aspartate (NMDA) antagonist, neuroactive steroid gamma-aminobutryic acid (GABA)-A receptor positive modulator, selective serotonin reuptake inhibitor (SSRI), and/or serotoninnorepinephrine reuptake inhibitor (SNRI).
  • the one or more other compounds used for treating depression are an antidepressant.
  • the antidepressant is amoxapine, amitriptyline, desipramine, doxepin, imipramine, lithium carbonate, maprotiline, mirtazapine, nortriptyline, protriptyline, and/or trimipramine.
  • the one or more other compounds used for treating depression are an atypical antidepressant.
  • the atypical antidepressant is bupropion, nefazodone and/or trazodone.
  • the one or more other compounds used for treating depression are an atypical antipsychotic.
  • the atypical antipsychotic is lumateperone, brexpiprazole, quetiapine, and/or olanzapine.
  • the one or more other compounds used for treating depression are a MAOI.
  • the MAOI is isocarboxazid, phenelzine, selegiline, and/or tranylcypromine.
  • the one or more other compounds used for treating depression are an NMDA antagonist.
  • the NMDA antagonist is esketamine.
  • the one or more other compounds used for treating depression are a neuroactive steroid GAB A-A receptor positive modulator.
  • the neuroactive steroid GAB A- A receptor positive modulator is brexanolone.
  • the one or more other compounds used for treating depression are an SSRI.
  • the SSRI is citalopram, escitalopram, fluoxetine, paroxetine, sertraline, vilazodone, and/or vortioxetine.
  • the one or more other compounds used for treating depression are an SNRI.
  • the SNRI is desvenlafaxine, duloxetine, levomilnacipran, and/or venlafaxine.
  • the compounds of the present disclosure are administered in combination with one or more other compounds used for treating anxiety.
  • the one or more other compounds used for treating anxiety are an antidepressant, anxiolytic, anticonvulsant, noradrenergic agent, and/or atypical antipsychotic.
  • the one or more other compounds used for treating anxiety are an antidepressant.
  • the antidepressant is amitriptyline, bupropion, citalopram, clomiprimine, desipramine, duloxetine, doxepin, escitalopram, isocarboxid, fluvoxamine, fluoxetine, imipramine, maprotiline, mirtazapine, nortriptyline, paroxetine, phenelzine, protriptyline, sertraline, tranylcypromine, trazodone, trimipramine, and/or venlafaxine.
  • the one or more other compounds used for treating anxiety are an anxiolytic.
  • the anxiolytic is alprazolam, buspirone, chlordiazepoxide, clonazepam, clorazepate, diazepam, hydroxyzine, flurazepam, lorazepam, oxazepam, triazolam, and/or temazepam.
  • the one or more other compounds used for treating anxiety are an anticonvulsant.
  • the anticonvulsant is tiagabine, gabapentin, valproate, lamotrigine, and/or topiramate.
  • the one or more other compounds used for treating anxiety are a noradrenergic agent.
  • the noradrenergic agent is propranolol, atenolol, prazosin, prazosin, clonidine, and/or guanfacine.
  • the one or more other compounds used for treating anxiety are an atypical antipsychotic.
  • the atypical antipsychotic is aripiprazole, ziprasidone, risperidone, quetiapine, and/or olanzapine.
  • the compounds of the present disclosure are administered in combination with one or more other compounds used for treating Parkinson’s disease.
  • the one or more other compounds used for treating Parkinson’s disease are an adenosine A2A (A2A) antagonist, anticholinergic, dopamine (DOPA) agonist, DOPA decarboxylase inhibitor, DOPA precursor, catechol -O-methyl transferase (COMT) inhibitor, monoamine Oxidase Type B (MAO-B) inhibitor, and/or N-methyl-D-aspartate (NMDA) antagonist.
  • the one or more other compounds used for treating Parkinson’s disease are an A2A antagonist.
  • the A2A antagonist is istradefylline.
  • the one or more other compounds used for treating Parkinson’s disease are an anticholinergic. In embodiments, the anticholinergic is trihexyphenidyl and/or benztropine. In embodiments, the one or more other compounds used for treating Parkinson’s disease are a DOPA agonist. In embodiments, the DOPA agonist is pramipexole, ropinirole, apomorphine, and/or rotigotine. In embodiments, the one or more other compounds used for treating Parkinson’s disease are a DOPA decarboxylase inhibitor. In embodiments, the DOPA decarboxylase inhibitor is carbidopa. In embodiments, the one or more other compounds used for treating Parkinson’s disease are a DOPA precursor.
  • the DOPA precursor is levodopa.
  • the one or more other compounds used for treating Parkinson’s disease are a COMT inhibitor.
  • the COMT inhibitor is entacapone, opicapone, and/or tolcapone.
  • the one or more other compounds used for treating Parkinson’s disease are a MAO-B inhibitor.
  • the MAO-B inhibitor is selegiline, safinamide, and/or rasagiline.
  • the one or more other compounds used for treating Parkinson’s disease are an NMBA antagonist.
  • the NMDA antagonist is amantadine.
  • Preparation of compounds can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene and Wuts, Protective Groups in Organic Synthesis, 44th. Ed., Wiley & Sons, 2006, as well as in Jerry March, Advanced Organic Chemistry, 4 th edition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.
  • the compounds of the present disclosure can be prepared using, for example, methods described in Scheme 1, Scheme 2, Scheme 3, Scheme 4 or Scheme 5.
  • Table 2 provides characterization data (e.g., NMR and Mass Spectrometry) for example compounds of the present disclosure.
  • the GPR6 IC50 data was obtained using the procedure as described in Example 2.
  • Step E General procedure for reductive amination:
  • CHO cells stably expressing GPR6 receptors were dissociated from cell culture flasks and incubated for 2h at 37°C in a 10 cm dish in a humidified incubator. Cells were dissociated, counted to have le6 cells/mL (4.5e6 cells needed/384-well plate), washed once in starved media, than in D-PBS and finally suspended in assay buffer (Krebs-Ringer Bicarbonate Buffer with 1800 mg/L glucose, without calcium chloride and sodium bicarbonate (Sigma) in the presence of 0.1 % BSA and 150 pM of Ro 20-1724 Phosphodiesterase inhibitor).
  • assay buffer Karls-Ringer Bicarbonate Buffer with 1800 mg/L glucose, without calcium chloride and sodium bicarbonate (Sigma) in the presence of 0.1 % BSA and 150 pM of Ro 20-1724 Phosphodiesterase inhibitor.
  • LANCE® Ultra cAMP assay Perkin Elmer
  • TR-FRET fluorescence resonance energy transfer
  • WI Tin-halogen lamp
  • Step -a 2-(2-isopropyl-lH-imidazol-l-yl)-3-nitropyridine (4-2):
  • Step-b 2-(2-isopropyl-lH-imidazol-l-yl)pyridin-3-amine (4-3):
  • Step-c benzyl 9-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[3,2-e]pyrazine-6,4'- piperidinej-l '-carboxylate (compound 282):
  • Step-d 9-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[3,2-e]pyrazine-6,4'-piperidine] (4-5):
  • Step-e 1 '-(2,4-difluorobenzyl)-9-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[3,2- e]pyrazine-6, 4 '-piperidine] (4-118-11):
  • Step-f 1 '-(2,4-difluorobenzyl)-9-isopropyl-5-methyl-5H-spiro[imidazo[l,5- a]pyrido[3,2-e]pyrazine-6,4'-piperidine] (compound 214):
  • Step -a 2-(2-isopropyl-lH-imidazol-l-yl)-3-nitropyridine (5-2):
  • Step-b 2-(2-isopropyl-lH-imidazol-l-yl)pyridin-3-anune ( 5-120-24):
  • Step-c 4-(benzyloxy)-9 '-isopropyl-5 'H-spiro[cyclohexane-1, 6 '-imidazo[l, 5- a]pyrido[3, 2-e]pyrazine] (5-120-26):
  • Step-d 9 '-isopropyl-5 'H-spiro[cyclohexane-l, 6 '-imiddzo[l, 5-a]pyrido[3,2- e]pyrazin]-4-ol (5-120-27):
  • Step-e 9 '-isopropyl- 5 'H-spiro[cyclohexane-l, 6 '-imidazo[l, 5-a]pyrido[3, 2- e]pyr azin] -4-yl methanesulfonate (5-120-28):
  • Step-f 4-(2,4-difluorophenoxy)-9 '-isopropyl-5 'H-spiro[cyclohexane-l, 6 '- imidazo[l,5-a]pyrido[3,2-e]pyrazine] (5-120-11):
  • Step-g Chiral separation of Comp-120-11 to get compound 148 and 149:
  • Step -a 5-fluoro-2-methoxypyridine 1-oxide (6-146-20):
  • Step-b 5-fluoro-2-methoxy-4-nitropyridine (6-146-21):
  • Step-c 5-(2-isopropyl-lH-inudazol-l-yl)-2-methoxy-4-nitropyridine (6-146-16):
  • reaction mixture was concentrated then diluted with water and basify with aq ISfeCCL soln and extracted with EtOAc (100 mL) and water, layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure, obtained crude was purified by silica-gel column chromatography (60-120) using 20-30% Ethyl acetate in Hexane as eluent to afford the product 6-146-17 (1.7 g) as yellow semi solid.
  • Step-e benzyl l-isopropyl-7-methoxy-5H-spiro[imidazole[l,5-a] pyrido[4,3-e] pyr azine-4, 4' -piperidine] -1 '-carboxylate (6-146-18):
  • Step-f 1 '-(2,4-difluorobenzyl)-l-isopropyl-7-methoxy-5H-spiro[imidazo[l,5-a] pyrido[4,3-e] pyrazine-4,4'-piperidine] (compound 121):
  • Step-g l '-(2,4-difluorobenzyl)-l-isopropyl-5H-spiro[imidazo[l,5-a] pyrido[4,3-e] pyrazine-4,4'-piperidin]-7(8H)-one (compound 122).
  • Step -a 3-(2-isopropyl-lH-imidazol-l-yl)-2-nitropyridine 1-2):
  • Step-b 3-(2-isopropyl-lH-imidazol-l-yl)pyridin-2-amine (1-3):
  • Step-c benzyl l-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[2,3-e]pyrazine-4,4'- piperidinej-l '-carboxylate 1-4):
  • Step-e 1 '-(2,4-difluorobenzyl)-l-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[2,3- e]pyrazine-4,4'-piperidine] (compound 139):
  • Scheme 8-2 [0190] Scheme 8-2. - Conditions: a) 2-isopropyl-1H-imidazole, DMF, 110°C, 16h; b) Fe powder, NH4C1, EtOH, Reflux; c) TFA, Toluene, reflux; d) 10%Pd/C, MeOH; e) STAB, DCE, [0191] Scheme 8-3. - Conditions: a) 2-isopropyl-U/-imidazole, DMF, 110°C, 16h; b) Fe powder, NH4C1, EtOH, Reflux; c) TFA, Toluene, reflux; d) 10%Pd/C, MeOH; e) STAB, DCE,
  • Step-b 8-((2,4-difluorophenyl) sulfonyl)-!, 4-dioxaspiro [4.5] decane (Comp-174-4- 3)
  • Step-c 4-((2,4-difluorophenyl) sulfonyl) cyclohexan-l-one (Comp-174-4-4)
  • Step-d 4-((2,4-difluorophenyl) sulfonyl)-9'-isopropyl-5'H-spiro[cyclohexane-l,6'- imidazo[l,5-a] pyrido[3,2-e] pyrazine] (174-4a/4b)
  • Peak-2 compound 295: 63 mg
  • Step-a 5-fluoro-l-((4-oxocyclohexyl) methyl) pyridin-2(lH)-one (Comp-174-5-3)
  • 5-fluoropyridin-2(lH)-one (174-5-1) 500 mg, 1.0 e q
  • 4-(bromomethyl) cyclohexan-l-one (174-5-2) 1.0 eq
  • TBAB 0.1
  • K2CO3 2.0eq
  • Step-b 5-fluoro-l-((9'-isopropyl-5'H-spiro[cyclohexane-l,6'-imidazo[l,5-a] pyrido[3,2-e] pyrazin]-4-yl) methyl) pyridin-2(lH)-one (Comp-174-5)
  • Step -a 4-(((4-fluoropyridin-2-yl) oxy) methyl) cyclohexan-l-one (Comp-174-6- 2A):
  • Step-b 4-(((4-fluoropyridin-2-yl) oxy) methyl)-9'-isopropyl-5'H- spiro[cyclohexane-l,6'-imidazo[l,5-a] pyrido[3,2-e] pyrazine] (Comp-174-6)
  • Peak-1 (compound 109): 2.2 mg.
  • Example 12 Synthesis of compound 104 and 105 [0229] s Conditions: a) PTSA, HC(OCH3)3, MeOH, 70°C, 16hrs. b). NaH, DMF, rt, 2h c) THF, Aq.HCl, rt, 3h; d) TFA, Toluene, Reflux, 16h; e). Chiral separation.
  • Peak-2 (compound 105): 4.9 mg.
  • Step-c' 1 '-(2,4-difluorobenzyl)-9-isopropyl-5H-spiro [imidazo [1,5-a] pyrido [3,2- e]pyrazine-6,4'-piperidin]-2'-one (174-8):
  • Peak-1 Compound 284): 21.4 mg.
  • Rt @ Chiral HPLC 5.40 min
  • Peak-2 Compound 285): 23.8 mg.
  • Rt @Chiral HPLC 11.25 min
  • Step-g diethyl (2,4-difluorobenzyl) phosphonate (139-1-2):
  • Step -a 9-isopropyl-5H-dispiro[imidazo[l,5-a]pyrido[3,2-e]pyrazine-6,l '- cyclohexane-4',2"-[l,3]dioxolane] (121-22):
  • Step-b 9’-isopropyl-5’H-spiro[cyclohexane-l,6’-imidazo[l,5-a] pyrido[3,2- ejpyr azin] -4-one (121-23):
  • Step-c 4-(2, 4-difluorobenzylidene)-9 '-isopropyl-5 'H-spiro[cyclohexane-l, 6 '- inudazo[l,5-a] pyrido[3,2-e] pyrazine] (MLT-139-03):
  • Step-d Chiral separation of MLT-139-03 to get compound 118 and 117:
  • Peak-1 (compound 118): 29 mg.
  • PEAK-2 (compound 117): 65 mg
  • Step-e 4-(2,4-difluorobenzyl)-9 '-isopropyl-5 'H-spiro[cyclohexane-l, 6 '-imidazo[l, 5- a]pyrido[3,2-e]pyrazine (MLT-139-01 ):
  • Step-b 4-(2, 5-difluorobenzylidene)-9 '-isopropyl-5 'H-spiro[cyclohexane-l, 6 '- imidazo[l,5-a]pyrido[3,2-e]pyrazine] (Comp-166-2):
  • Peak-1 (compound 114) (-) Isomer: 15 mg.
  • PEAK-2 (compound 125) (+) Isomer: 24 mg.
  • Example 16 Synthesis of compound 287 and 283 [0288] S Conditions: a) K2CO3, DMF,120°C; b) Pd(dppfC12). DCM, K2CO3, 1,4- Dioxane/Water, 100°C; c) NH4C1, EtOH/H2O (4: 1), 80°C; d) TFA, Toluene, 100°C; e) Beta- Admix, H2NSO2Me, H2O/t-BuOH (1 : 1), 0°C to rt; f). K2CO3, DMF, 25-30°C.
  • Step -a 2-(2-bromo-lH-inudazol-l-yl)-3-nitro pyridine) (183-1-5):
  • Step-b 2-(2-(2-methylprop-l-en-l-yl)-lH-inndazol-l-yl)-3-nitropyridine (183-1-9):
  • Step-c 2-(2-(2-methylprop-l-en-l-yl)-lH-inudazol-l-yl) pyridin-3-amine (183-1- 10):
  • the crude product was purified by flash reverse phase column (120 g) and eluted with 50-60% Acetonitrile in water as eluent. Evaporated the product fractions to afford the Compound- 183- 1-10 (2.5 g) as brown liquid.
  • Step-d 1 '-(2,5-difluorobenzyl)-9-(2-methylprop-l-en-l-yl)-5H-spiro[imidazo[l,5-a] pyrido [3,2-e] pyrazine-6,4'-piperidine] (compound 283):
  • comp-183-1-10 (2.5 g, 11.6 mmol, 1 eq) in toluene (25 mL) at 25-30°C was added comp-183-1-3 (10 g, 11.6 mmol,l eq), followed by added TFA (0.4 mL,5.8 mmol, 0.5 eq).
  • TFA 0.4 mL,5.8 mmol, 0.5 eq
  • the reaction mixture was heated to 100°C and stirred for 16h. Progress of the reaction was monitored by TLC. After completion the reaction, it was cooled to 25-30°C, evaporated under reduced pressure to get residue. The residue was dissolved in EtOAc (100 mL) and washed with saturated NaHCOs solution (50 mL X 2).
  • Step-e l-(l '-(2,5-difluorobenzyl)-5H-spiro[imidazo[l,5-a] pyrido[3,2-e] pyrazine- 6,4'-piperidin]-9-yl)-2-metbylpropane-l,2-diol (compound 287):

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Abstract

L'invention concerne un composé de formule (I) ou un sel pharmaceutiquement acceptable de celui-ci, J, L, X, E, M1, M2, le cycle Z, le cycle Q, R1, R2, R3, n, m et p étant tels que définis dans la description ainsi que des compositions et des procédés d'utilisation associés.
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