Gpr6 inverse agonists

Abstract

Provided herein, is a compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein J, L, X, E, M1, M2, ring Z, ring Q, R1, R2, R3, n, m and p are defined herein as well as compositions and methods of use thereof.

Description

GPR6 INVERSE AGONISTSCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of priority to U.S. Provisional Application No. 63 / 548,898, filed February 2, 2024, which is hereby incorporated by reference in its entirety for all purposes.BACKGROUND

[0002] The role of the striatum in controlling motor function (Prager 2019) and in modulating reward (Baez-Mendoza 2013) has been recognized for years. Recently, there is a greater appreciation for the role of the striatum in learning as well (Graybiel 2015). 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. 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.SUMMARY OF THE DISCLOSURE

[0003] 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.

[0004] In one aspect, 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, M1, M2, ring Z, ring Q, R1, R2, R3, n, m and p are defined herein:Formula (I),DETAILED DESCRIPTION

[0005] Throughout this disclosure, various patents, patent applications and publications are referenced. The disclosures of these patents, patent applications and publications in their entireties are incorporated into this disclosure by reference for all purposes in order to more fully describe the state of the art as known to those skilled therein as of the date of this disclosure. This disclosure will govern in the instance that there is any inconsistency between the patents, patent applications and publications cited and this disclosure.Definitions

[0006] For convenience, certain terms employed in the specification, examples and claims are collected here. Unless defined otherwise, all technical and scientific terms used in this disclosure have the same meanings as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[0007] The term "about" when immediately preceding a numerical value means a range (e.g., plus or minus 10% of that value). For example, "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. For example, in a list of numerical values such as "about 49, about 50, about 55, ... ", "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. Furthermore, 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. Similarly, the term "about" when preceding a series of numerical values or a range of values (e.g., "about 10, 20, 30" or "about 10-30") refers, respectively to all values in the series, or the endpoints of the range.

[0008] The terms "administer," "administering" or "administration" as used herein refer 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.

[0009] The term “pharmaceutically acceptable 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. g., lysine and arginine di cyclohexylamine and the like. Examples of metal salts include lithium, sodium, potassium, magnesium, calcium salts and the like. Examples of ammonium and alkylated ammonium salts include ammonium, methylammonium, dimethylammonium, trimethylammonium, ethylammonium, hydroxyethylammonium, diethylammonium, butylammonium, tetramethylammonium salts and the like. Examples of organic bases include lysine, arginine, guanidine, diethanolamine, choline and the like. Those skilled in the art will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.

[0010] The term "treating" as used herein with regard to a patient, 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.

[0011] The terms "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.

[0012] The term "therapeutically 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.

[0013] The term “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. In addition to the adjuvants, excipients and diluents known to one skilled in the art, the carrier includes nanoparticles of organic and inorganic nature.

[0014] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-C6alkyl” is intended to encompass Ci, C2, C3, C4, C5, C6, C1-6, 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 C5.6alkyl.

[0015] “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 C1-C6alkyl 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 C1-C6alkyl includes all moieties described above for C1-C5 alkyls but also includes C6alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and C1-C6alkyls, but also includes C7, C8, C9 and C10 alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11and 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. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0016] “Alkylene” or “alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of 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.

[0017] “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 and 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 C6alkenyls. 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. Similarly, 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- nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, 1 -decenyl, 2-decenyl, 3- decenyl, 4-decenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1-undecenyl, 2- undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1 -dodecenyl, 2-dodecenyl, 3 -dodecenyl, 4-dodecenyl, 5- dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11-dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.

[0018] “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. Non-limiting examples of 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.

[0019] “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 and 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 C6alkynyls. 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. Similarly, 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.

[0020] “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. Non-limiting examples of 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. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.

[0021] “Alkoxy” refers to a group of the formula -ORawhere Rais 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.

[0022] “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. For purposes of this disclosure, 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.

[0023] “Aralkyl” or “arylalkyl” refers to a radical of the formula -Rb-Rc where Rb is an alkylene group as defined above and Rcis 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.

[0024] “Carbocyclyl,” “carbocyclic ring” or “carbocycle” 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.

[0025] “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.

[0026] “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.

[0027] “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.

[0028] “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.

[0029] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” 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. Unless stated otherwise specifically in the specification, 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. Examples of such heterocyclyl 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-thiomorpholinyl, and1.1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.

[0030] “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. Unless stated otherwise specifically in the specification, 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. Examples of such 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, and1.1-dioxo-thiomorpholinylene. Unless stated otherwise specifically in the specification, a heterocyclylene group can be optionally substituted.

[0031] “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. For purposes of this disclosure, 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, imidazolyl, indazolyl,indolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2 oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1 oxidopyrimidinyl, 1- oxidopyrazinyl, 1-oxidopyridazinyl, 1 phenyl 1H pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.

[0032] “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. For purposes of this disclosure, 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, cinnolinylene, dibenzofuranyl ene, dibenzothiophene, furanylene, furanonylene, isothiazolyl ene, imidazolylene, indazolylene, indolylene, indazolylene, isoindolylene, indolinylene, isoindolinylene, isoquinolylene, indolizinylene, isoxazolyl ene, naphthyridinylene, oxadi azolyl ene, 2-oxoazepinylene, oxazolylene, oxiranylene, 1- oxidopyridinylene, 1-oxidopyrimidinylene, 1-oxidopyrazinylene, 1-oxidopyridazinylene, 1 -phenyl- IH-pyrrolylene, phenazinyl ene, phenothiazinylene, phenoxazinylene, phthalazinylene, pteridinylene, purinylene, pyrrolylene, pyrazolylene, pyridinylene, pyrazinylene, pyrimidinylene, pyridazinylene, quinazolinylene, quinoxalinylene, quinolinylene, quinuclidinylene, isoquinolinylene, tetrahydroquinolinylene, thiazolylene, thiadi azolyl ene, triazolylene, tetrazolyl ene, triazinylene, and thiophene (e.g., thienylene). Unless stated otherwise specifically in the specification, a heteroarylene group can be optionally substituted.

[0033] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Re where Rb is an alkylene, alkenylene, or alkynylene group as defined above and Reis a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocyclylalkyl group can be optionally substituted.

[0034] The term “substituted” used herein 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, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups. “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. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced with -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh,-NRgC(=O)ORh, -NRgSO2Rh, -OC(=O)NRgRh, -ORg, -SRg, -SORg, -SO2Rg, -OSO2Rg, -SO2O Rg, =NSO2Rg, and -SO2NRgRh. “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, -C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg,-CH2SO2NRgRh. In the foregoing, Rgand 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. In some embodiments, “substituted” further means any alkyl, cycloalkyl or heterocyclylalkyl in which one or more hydrogen atomsis replaced by an isotope e.g., deuterium. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.

[0035] 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. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). 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.

[0036] As used herein, the symbol “” (hereinafter can be referred to as “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. For example, “” indicates that the chemical entity “XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound CH3-R3, wherein R3is H or “” infers that when R3is “XY”, the point of attachment bond is the same bond as the bond by which R3is depicted as being bonded to CH3.Compounds

[0037] 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.

[0038] In some aspects, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof:whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X; provided that when L is CH2, then J is notX is C, CRbor N;™ represents a single bond or a double bond; each of M1and M2is independently C, CRc, N, or NRd, wherein at least one of M1and M2is N or NRd;Ring Q is 5-6 membered heterocyclylene, or 5-6 membered heteroarylene;Ring Z is 5-6 membered heterocyclylene, or 5-6 membered heteroarylene, wherein Ring Z comprises at least one nitrogen atom; each of R1, R2and R3is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -0-, -S-, -S(=0)-, or -S(=0)2-; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3 or 4; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; provided that when m is 1 and R2is OCH3, then J is notwhen n is i and R1is C(=O)NReRf, then J is notwhen X is C(=0), then J is not

[0039] In some aspects, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof:whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X;X is C, CRbor N;= represents a single bond or a double bond; each of M1and M2is independently C, CRc, N, or NRd, wherein at least one of M1and M2is N or NRd;Ring Q is 5-6 membered heterocyclylene or 5-6 membered heteroarylene;Ring Z is 5-6 membered heterocyclylene or 5-6 membered heteroarylene, wherein Ring Z comprises at least one nitrogen atom;each of R1, R2and R3 is each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -0-, -S-, -S(=0)-, or -S(=0)2-; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3 or 4; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; provided that the compound of formula (I) is not any one of the following compounds

[0040] In some embodiments, the compound disclosed herein is a compound of formula (la),(lb), (Ic) or (Id),Formula (la),Formula (lb),Formula (Ic) orFormula (Id), whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X;X is C, CRbor N;= represents a single bond or a double bond;each of R1is each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -O-, -S-, -S(=O)-, or -S(=O)2-; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0041] In some embodiments, the compound disclosed herein is a compound of formula (la):Formula (la), whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X;X is C, CRbor N;= represents a single bond or a double bond; each of R1is each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -O-, -S-, -S(=O)-, or -S(=O)2-; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0042] In some embodiments, the compound disclosed herein is a compound of formula (lb):Formula (lb), whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X;X is C, CRbor N;= represents a single bond or a double bond; each of R1is each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=O)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -O-, -S-, -S(=O)-, or -S(=O)2-; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0043] In some embodiments, the compound disclosed herein is a compound of formula (Ic):Formula (Ic),J is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X;X is C, CRbor N;= represents a single bond or a double bond;each of R1is each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -0-, -S-, -S(=0)-, or -S(=O)2-; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0044] In some embodiments, the compound disclosed herein is a compound of formula (Id):Formula (Id), whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X;X is C, CRbor N;= represents a single bond or a double bond; each of R1is each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -0-, -S-, -S(=0)-, or -S(=0)2-; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.

[0045] In some embodiments, the compound disclosed herein is not any one of the following

[0046] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), L is selected from a bond, C1-6alkylene, C1-6alkenylene, -N(Rd)-, -O-, -S-, -S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -C(=0)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X.

[0047] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), Rbis absent, H, OH, Ci-3alkyl or halogen.

[0048] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), L is a bond, -CH2-, -C(=O)-, CH, -CH(CH3)-, -CHF-, -CF2-, -CH(OH)-, -C(CH3)(OH)-, -O-, -S(=O)2-, *-CH2O-, *-C(=O)OCH2- orwherein * represents the point of attachment to X.

[0049] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), L is -CH2-, - C(=O)- or -S(=O)2-.

[0050] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), L is -C(=O)-

[0051] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), L is -CH2-.

[0052] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), L is -S(=O)2-.

[0053] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), = represents a single bond.X and R3

[0054] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), X is N, CH or C.

[0055] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), X is N or CH, and = represents a single bond.

[0056] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), X is N, and ™ represents a single bond.

[0057] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), X is CH, and = represents a single bond.

[0058] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), p is 0.

[0059] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), p is 1 and R3is =0.

[0060] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id),J

[0061] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), J is aryl substituted with 1-4 Ra.

[0062] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), J is phenyl substituted with 1-4 Ra.

[0063] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), Rais H, halogen, C1-6alkyl, C1-6alkoxy or CN. c) or (Id), J is, wherein Rais C 1-3 alkyl, halogen, C1-3 alkoxy or CN.

[0065] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), J is

[0066] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id),ISwherein p is 0, 1 or 2, andRais Ci-3 alkyl, halogen, C1-3 alkoxy or CN.

[0067] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id),halogen, C1-3 alkoxy or CN.

[0068] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id),wherein p is 0, 1 or 2, and Rais C1-3 alkyl, halogen, C1-3 alkoxy or CN.

[0069] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id),, wherein p is 0, 1 or 2, and Rais C1-3 alkyl, halogen, C1-3 alkoxy or CN.

[0070] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id),is, wherein p is 0, 1 or 2, and Rais C1-3 alkyl, halogen, C1-3 alkoxy or CN.

[0071] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), J is heteroaryl optionally substituted with 1-4 Ra.

[0072] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), Rais H, halogen or =0.

[0073] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), J is

[0074] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), E is NRd

[0075] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), E is NH, NCH3orNC(=O)CH3. ,

[0076] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), E is NH. Ring Q, M1, M2, R1and n

[0077] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), one of M1and M2is N, and the other one of M1and M2is C.

[0078] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), is M2is N, and M1is C.

[0079] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), M1is N, and M2is C.

[0080] In some embodiments of compound of formula (I), Ring Q is 5-membered heteroarylene.

[0081] In some embodiments of compound of formula (I), Ring Q is

[0082] In some embodiments of compound of formula (I),has the structure of

[0083] In some embodiments of compound of formula (I),has the structure of

[0084] In some embodiments of compound of formula (I) or any one of the foregoing embodiments, n is 1.

[0085] In some embodiments of compound of formula (I),has the structure of ents of compound of formula (I),has the structure of

[0087] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id) or any of the foregoing embodiments, R1is C1-6alkyl optionally substituted with OH or alkoxy, haloalkyl, cycloalkyl or C1-6alkenyl.

[0088] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id) or any of the foregoing embodiments, R1is C1-6alkyl optionally substituted with OH, haloalkyl, cycloalkyl or C1-6alkenyl.

[0089] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id) or any of the foregoing embodiments, R1is C1-6alkyl, haloalkyl or cycloalkyl.

[0090] In some embodiments of compound of formula ( Id), or any of the foregoing embodiments, R1is CH3, CH2CH3, isopropyl,cyclopropyl,

[0091] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), or any of the foregoing embodiments, R1is CH3, CH2CH3, isopropyl, cyclopropyl or CF3.

[0092] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), or any of the foregoing embodiments, R1is isopropyl.

[0093] In some embodiments of compound of formula (I), (la), (lb), (Ic) or (Id), or any of the foregoing embodiments, n is i and R1is isopropyl.Ring Z, R2and m

[0094] In some embodiments of compound of formula (I), Ring Z is 6-membered heterocyclylene or 6-membered heteroarylene.

[0095] In some embodiments of compound of formula (I), Ring Z is 6-membered heteroarylene.

[0096] In some embodiments of compound of formula (I), Ring Z is pyridylene or pyrazinylene.

[0097] In some embodiments of compound of formula (I), Ring

[0098] In some embodiments of compound of formula (I), Ring

[0099] In some embodiments of compound of formula (I), Ring

[0100] In some embodiments of compound of formula (I),has the

[0101] In some embodiments of compound of formula (I),has the structure

[0102] In some embodiments of compound of formula (I), or any of the foregoing embodiments, m is 0.

[0103] In embodiments, provided herein is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof.Table 1. Compounds[1]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.Compositions

[0104] The present disclosure provides pharmaceutical compositions for providing inverse agonism of the GPR6 receptor in a subject. In embodiments, 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.

[0105] In embodiments of the present disclosure, 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.

[0106] In embodiments, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0107] In embodiments of the present disclosure, 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. In some embodiments, a pharmaceutical composition comprising one or more compounds disclosed herein, or a pharmaceutically acceptable salt thereof, further comprise a pharmaceutically acceptable carrier. In some embodiments, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and / or diluent. In some embodiments, suitablepharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. In some embodiments, 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.

[0108] For the purposes of this disclosure, 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. The term 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.

[0109] Generally, 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.Methods of Treatment

[0110] The compounds of the present disclosure find use in any number of methods. For example, in some embodiments the compounds are useful in methods for modulating a G protein-coupled receptor, e.g., G protein-coupled receptor 6 (GPR6). Accordingly, in embodiments, 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. For example, in embodiments modulating 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.[oni] In some embodiments, the G protein-coupled receptor, (e.g., GPR6) activity is binding. In embodiments, the G protein-coupled receptor, (e.g., GPR6) activity is inverse agonism of GPR6.

[0112] In embodiments, 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).

[0113] In embodiments, 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. In embodiments, 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). In embodiments, 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.

[0114] In embodiments, 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.

[0115] In embodiments the compounds of the present disclosure are administered in combination with one or more other compounds used for treating dyskinesia.Jn embodiments, 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._In embodiments, the one or more other compounds used for treating dyskinesia are an NMDA antagonist. In embodiments, the NMDA antagonist is amantadine.Jn embodiments, the one or more other compounds used for treating dyskinesia are a VMAT2 inhibitor. In embodiments, the VMAT2 inhibitor is deutetrabenazine and / or valbenazine.

[0116] In embodiments the compounds of the present disclosure are administered in combination with one or more other compounds used for treating depression. In embodiments, 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)-Areceptor positive modulator, selective serotonin reuptake inhibitor (SSRI), and / or serotoninnorepinephrine reuptake inhibitor (SNRI). In embodiments, the one or more other compounds used for treating depression are an antidepressant. In embodiments, the antidepressant is amoxapine, amitriptyline, desipramine, doxepin, imipramine, lithium carbonate, maprotiline, mirtazapine, nortriptyline, protriptyline, and / or trimipramine. In embodiments, the one or more other compounds used for treating depression are an atypical antidepressant. In embodiments, the atypical antidepressant is bupropion, nefazodone and / or trazodone. In embodiments, the one or more other compounds used for treating depression are an atypical antipsychotic. In embodiments, the atypical antipsychotic is lumateperone, brexpiprazole, quetiapine, and / or olanzapine. In embodiments, the one or more other compounds used for treating depression are a MAOI. In embodiments, the MAOI is isocarboxazid, phenelzine, selegiline, and / or tranylcypromine. In embodiments, the one or more other compounds used for treating depression are an NMDA antagonist. In embodiments, the NMDA antagonist is esketamine. In embodiments, the one or more other compounds used for treating depression are a neuroactive steroid GAB A-A receptor positive modulator. In embodiments, the neuroactive steroid GAB A- A receptor positive modulator is brexanolone. In embodiments, the one or more other compounds used for treating depression are an SSRI. In embodiments, the SSRI is citalopram, escitalopram, fluoxetine, paroxetine, sertraline, vilazodone, and / or vortioxetine. In embodiments, the one or more other compounds used for treating depression are an SNRI. In embodiments, the SNRI is desvenlafaxine, duloxetine, levomilnacipran, and / or venlafaxine.

[0117] In embodiments the compounds of the present disclosure are administered in combination with one or more other compounds used for treating anxiety. In embodiments the one or more other compounds used for treating anxiety are an antidepressant, anxiolytic, anticonvulsant, noradrenergic agent, and / or atypical antipsychotic. In embodiments, the one or more other compounds used for treating anxiety are an antidepressant. In embodiments, 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. In embodiments, the one or more other compounds used for treating anxiety are an anxiolytic. In embodiments, the anxiolytic is alprazolam, buspirone, chlordiazepoxide, clonazepam, clorazepate, diazepam, hydroxyzine, flurazepam, lorazepam, oxazepam, triazolam, and / or temazepam. In embodiments, the one or more other compounds used for treating anxiety are an anticonvulsant. In embodiments, theanticonvulsant is tiagabine, gabapentin, valproate, lamotrigine, and / or topiramate. In embodiments, the one or more other compounds used for treating anxiety are a noradrenergic agent. In embodiments, the noradrenergic agent is propranolol, atenolol, prazosin, prazosin, clonidine, and / or guanfacine. In embodiments, the one or more other compounds used for treating anxiety are an atypical antipsychotic. In embodiments, the atypical antipsychotic is aripiprazole, ziprasidone, risperidone, quetiapine, and / or olanzapine.

[0118] In embodiments the compounds of the present disclosure are administered in combination with one or more other compounds used for treating Parkinson’s disease. In embodiments, 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. In embodiments, the one or more other compounds used for treating Parkinson’s disease are an A2A antagonist. In embodiments, the A2A antagonist is istradefylline. In embodiments, 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. In embodiments, the DOPA precursor is levodopa. In embodiments, the one or more other compounds used for treating Parkinson’s disease are a COMT inhibitor. In embodiments, the COMT inhibitor is entacapone, opicapone, and / or tolcapone. In embodiments, the one or more other compounds used for treating Parkinson’s disease are a MAO-B inhibitor. In embodiments, the MAO-B inhibitor is selegiline, safinamide, and / or rasagiline. In embodiments, the one or more other compounds used for treating Parkinson’s disease are an NMBA antagonist. In embodiments, the NMDA antagonist is amantadine.EXAMPLES

[0119] The disclosure now being generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration ofcertain aspects and embodiments of the present disclosure and are not intended to limit the invention.

[0120] The compounds of the present disclosure can be synthesized using the methods as hereinafter described below, together with synthetic methods known in the art of synthetic organic chemistry or variations thereon as appreciated by those skilled in the art.

[0121] 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, 4thedition, John Wiley & Sons, publisher, New York, 1992 which are incorporated herein by reference in their entirety.

[0122] The compounds of the present disclosure (e.g. Table 1) 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.Table 2. Characterization for compounds of the present disclosure[1]<0.luM = ****>0. luM to <1.0uM = ***>1.0uM to <30uM = **>30uM = * ;NA means the result of this compound is not available.|2|._NA means the result of this compound is not available.Example 1. synthesis of 1 '-(2,4-difluorobenzyl)-9-isopropyl-5H-spiro[imidazo[l,5- a]pyrido[3,2-e]pyrazine-6,4'-piperidine] (compound 273) and relevant compoundsStep A:Compound 1 (24.93 g, 157.24 mmol) and 2-isopropyl-UT-imidazole (34.64 g, 2 eq., 314.49 mmol) were mixed in DMF (32 mL) and the resulting mixture was heated at 110 °C overnight. The reaction mixture was cooled and poured into water (150 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL) and combined organic layers were washed with water (3 x 150 mL), brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc-hexane, 2: 1) to obtain compound 2 (24.82 g, 67.4%)Step B:Compound 2 (24.82 g, 106.89 mmol) was dissolved in a mixture of EtOH (500 mL) and water (250 mL) and iron powder (59.69 g, 10 eq., 1069 mmol) was added followed by the addition of ammonium chloride (97.2 g, 17 eq., 1817 mmol). The resulting mixture was refluxed for 3 h. The reaction mixture was cooled and EtOAc (750 mL) was added. The resulting mixture was filtered through a paper filter and the filtrate was transferred to a separation funnel. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 500 mL). Combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc, Rf= ~0.2) to obtain compound 3 (15 g, 69.4%)Step C:Compound 3 (6.9 g, 34.11 mmol) and benzyl 4-oxopiperidine-l -carboxylate (7.96 g, 1 eq., 34.11 mmol) were dissolved in toluene (310 mL) and trifluoroacetic acid (3.13 mL, 1.2 eq., 40.94 mmol) was added. The resulting solution was refluxed with Dean-Stark trap overnight. The reaction mixture was cooled and poured into an aq. sodium bicarbonate solution (400 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (400 mL). Combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc-hexane 1 : 1) to obtain compound 4, (10.9 g, 76.5%).Step D:To a stirred solution of Compound 4 (4 g 9.58 mmol) in methanol (40 mL) was added 10%Pd / C (50% wet) (400 mg). The reaction mixture was stirred under EE balloon pressure for 16h. After completion of the reaction it was filtered through celite pad and washed with Methanol (50mL). Combined filtrates concentrated under reduced pressure to obtain crude (3 g) as colourless gummy material. To the crude compound added 4N HC1 in Dioxane (10 mL),stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain Compound 5 (As HC1 salt), compound 5 (2.8 g, quantitative) as an off white solid.Step E: General procedure for reductive amination:To a stirred solution of compound 5 (100 mg, 1.42 mmol, 1 eq) in DCE (5 vol) added corresponding aldehyde (2 eq) followed by STAB (5 eq) at room temperature. The reaction mixture was stirred at rt for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction it was diluted with DCM (10 Vol) and washed with sat. NaHCCh solution (2x 5 vol ). Finally, the organic layer was dried over anhydrous ISfeSCU, filtered and concentrated to get crude compound. The crude compound was purified by flash reverse phase column / prep HPLC to obtain product.Following the above procedure below list of compounds were preparedStep F: General procedure for Acid-Amide coupling:To the stirred solution compound 5 (100 mg, 1.42 mmol, 1 eq), corresponding Acid (2 eq) in Ethyl acetate was added TEA (3.0 eq.) followed by T3P (2 eq) at room temperature. The resulting reaction mixture was stirred at RT for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction, it was diluted with sat. NaHCCh and extracted with EtOAc. Finally, the organic layer was dried over anhydrous ISfeSCU, filtered and evaporated to get crude compound. The crude compound was purified by flash reverse phase column / prep HPLC to obtain product.Following the above procedure below list of compounds were preparedLCMS-Conditions :Prep-HPLC Conditions:Example 2. GPR6 Antagonist Functional cAMP Assay

[0123] 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 starvedmedia, 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).

[0124] Cells in suspension from above were plated in 384-well white Optiplate (PerkinElmer) at 10,000 cells / well / lOpl, briefly centrifuged prior direct addition of compounds (50 nL / well) in 10 mM DMSO using a Tecan D300e Digital Dispenser, final DMSO in each well was normalized to 0.1%. Cells were incubated in the presence of compounds for 45min at 37°C in a humidified incubator.

[0125] To measure cAMP levels, LANCE® Ultra cAMP assay (Perkin Elmer), a homogeneous time-resolved fluorescence resonance energy transfer (TR-FRET) immunoassay was used following manufacturer’s recommendations. Plates were shaken for Ih at room temperature before reading on a Tecan InfiniteF200Pro multi-mode plate reader using standard FRET settings (Excitation 340 nm, Emission at 615 nm). FRET values were reported as readings obtained at 665 nm. Data were normalized to DMSO (0.1%) and reference compounds (100%) and fit to a 4-parameter logistical fit to generate antagonist IC50s.

[0126] The GPR6 antagonist functional cAMP assay data are included in table 2.Example 3. Specific optical rotation (SOR) Method of analysis (Mo A)Reagents: MethanolEquipment: SOR, Jasco P2000Instrument parameters:Light source: WI (Tungsten-halogen lamp)Wavelength: 589 nmPath length: 10 mmTemperature: 25 °CNumber of Scans: 5Sample Preparation:Weigh 5 mg of the sample and dissolved it in 1 mL of diluent (methanol).Procedure:Measure the specific optical rotation of the sample in a Polarimeter at 25 ± 0.5°C.Conduct the blank with diluent, feed the rotation of the blank and sample concentration on Polarimeter. Calculate the specific optical rotation of the sample on as is basis using the formulagiven below. The average result from the five scans will be considered for the calculation of SOR.Optical rotationSpecific optical rotationPath length x Concentration of sampleThe data are included in table 1.Example 4. Synthesis of compound 282 and compound 214

[0127] General Scheme 1:General Scheme 1. - 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,rt; f)HCHO, formic acid, 100°C.

[0128] Step -a: 2-(2-isopropyl-lH-imidazol-l-yl)-3-nitropyridine (4-2):

[0129] Compound 4-1 (24.93 g, 157.24 mmol) and 2-isopropyl-1H-imidazole (34.64 g, 2 eq., 314.49 mmol) were mixed in DMF (32 mL) and the resulting mixture was heated at 110 °C overnight. The reaction mixture was cooled and poured into water (150 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL) and combined organic layers were washed with water (3 x 150 mL), brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc-hexane, 2: 1) to obtain compound 4-2 (24.82 g)

[0130] Step-b: 2-(2-isopropyl-lH-imidazol-l-yl)pyridin-3-amine (4-3):

[0131] Compound 4-2 (24.82 g, 106.89 mmol) was dissolved in a mixture of EtOH (500 mL) and water (250 mL) and iron powder (59.69 g, 10 eq., 1069 mmol) was added followed by the addition of ammonium chloride (97.2 g, 17 eq., 1817 mmol). The resulting mixture was refluxed for 3 h. The reaction mixture was cooled and EtOAc (750 mL) was added. Theresulting mixture was filtered and the filtrate was transferred to a separation funnel. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 500 mL). Combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc, Rf= ~0.2) to obtain compound 4-3 (15 g).

[0132] Step-c: benzyl 9-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[3,2-e]pyrazine-6,4'- piperidinej-l '-carboxylate (compound 282):

[0133] Compound 4-3 (6.9 g, 34.11 mmol) and benzyl 4-oxopiperidine-l -carboxylate (7.96 g, 1 eq., 34.11 mmol) were dissolved in toluene (310 mL) and trifluoroacetic acid (3.13 mL, 1.2 eq., 40.94 mmol) was added. The resulting solution was refluxed with a Dean- Stark trap overnight. The reaction mixture was cooled and poured into an aq. sodium bicarbonate solution (400 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (400 mL). Combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc- hexane 1 :1) to obtain compound 282 (10.9 g).

[0134] Step-d: 9-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[3,2-e]pyrazine-6,4'-piperidine] (4-5):

[0135] To a stirred solution of Compound 282 (4 g 9.58 mmol) in Methanol (40 mL) was added 10%Pd / C (50% wet) (400 mg). The reaction mixture was stirred under H2 balloon pressure for 16h. After completion of the reaction it was filtered through celite pad and washed with Methanol (50mL). Combined filtrates concentrated under reduced pressure to obtain crude (3 g) as colourless gummy material. To the crude compound added 4N HC1 in Dioxane (10 mL), stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain Compound 5 (As HC1 salt), compound 4-5 (2.8 g, quantitave) as an off white solid.

[0136] 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):

[0137] To a stirred solution of compound 4-5 (100 mg, 1.42 mmol, 1 eq) in dichloro ethane (DCE) (5 vol) added corresponding aldehyde (2 eq) followed by STAB (5 eq) at room temperature. The reaction mixture was stirred at rt for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction it was diluted with DCM (10 Vol) and washed with sat. NaHCCf solution (2x 5 vol). Finally, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to get crude compound. The crude compound was purified by flash reverse phase column / prep HPLC to obtain product.

[0138] 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):

[0139] To the solution of Compound 4-118-11 (120 mg, 0.29 mmol, 1.0 eq) in formic acid (1 mL) at 25-30°C was added formaldehyde (1 mL). The reaction mixture was heated to 100°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion, it was diluted with DCM (20 mL) and washed with water (2 X 10 mL). Finally, the organic layer was dried over anhydrous Na2SO4 filtered and evaporated under reduced pressure to obtain crude (140 mg) as Brown liquid. The crude product was purified by PREP -HPLC. Concentrated the Prep HPLC fractions and further lyophilized to afford the compound 214 (12 mg) as a white solid.

[0140] Preparative HPLC Conditions:LC retention time for compound 214: 1.90 minExample 5. Synthesis of compounds 148 and 149

[0141] General Scheme 1. - Conditions: a) 2-isopropyl-l / Z-imidazole, DMF, 110°C, 16h b) Fe powder, NH4C1, EtOH, reflux; c) TFA, Toluene, reflux; d) 10%Pd / C, MeOH; e) Ms-Cl, TEA, DCM, rt; 1) Cs2CO3, ACN, 80°C; g). Chiral separation.

[0142] Step -a: 2-(2-isopropyl-lH-imidazol-l-yl)-3-nitropyridine (5-2):

[0143] Compound 5-1 (24.93 g, 157.24 mmol) and 2-isopropyl-U / -imidazole (34.64 g, 2 eq., 314.49 mmol) were taken in DMF (32 mL) and the reaction mixture was heated at 110 °Covernight. The reaction mixture was cooled and poured into water (150 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL) and combined organic layers were washed with water (3 x 150 mL), brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc-hexane, 2: 1) to obtain compound 5-2 (24.82 g)

[0144] Step-b: 2-(2-isopropyl-lH-imidazol-l-yl)pyridin-3-anune ( 5-120-24):

[0145] Compound 5-2 (24.82 g, 106.89 mmol) was dissolved in a mixture of EtOH (500 mL) and water (250 mL) and iron powder (59.69 g, 10 eq., 1069 mmol) was added followed by the addition of ammonium chloride (97.2 g, 17 eq., 1817 mmol). The resulting mixture was refluxed for 3 h. The reaction mixture was cooled and EtOAc (750 mL) was added. The resulting mixture was filtered through a paper filter and the filtrate was transferred to a separation funnel. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc, Rf= ~0.2) to obtain compound 5-120-24 (15 g).

[0146] Step-c: 4-(benzyloxy)-9 '-isopropyl-5 'H-spiro[cyclohexane-1, 6 '-imidazo[l, 5- a]pyrido[3, 2-e]pyrazine] (5-120-26):

[0147] Compound 5-120-24 (3 g, 14.83 mmol, leq) and Comp-120-25 (3.02 g, 14.83 mmol, leq) were dissolved in toluene (60 mL) and trifluoroacetic acid (1.2 mL, 17.79 mmol, 1.2 eq) was added. The resulting solution was refluxed with Dean-Stark trap overnight. The reaction mixture was cooled and poured into an aq. sodium bicarbonate solution (200 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL). Combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to get crude compound (4 g) as brown gum. The residue was purified by silica gel (60-120) column chromatography (EtOAc-hexane 1 : 1) to obtain compound 5-120-26 (3.3 g) as an off-white solid.

[0148] Note: Mixture of isomers observed in 1HNMR.

[0149] Step-d: 9 '-isopropyl-5 'H-spiro[cyclohexane-l, 6 '-imiddzo[l, 5-a]pyrido[3,2- e]pyrazin]-4-ol (5-120-27):

[0150] To a stirred solution of Compound 5-120-26 (3.3 g) in methanol (40 mL) was added 10%Pd / C (50% wet) (330 mg). The reaction mixture was stirred under EE balloon pressure for 16h. After completion of the reaction it was filtered through celite pad and washed withMethanol (50mL). Combined filtrate concentrated under reduced pressure to obtain Comp- 120-27 (2 g) as a colourless gummy material. The compound was used in the next step without further purification.

[0151] Note: Mixture of isomers observed in 1HNMR

[0152] 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):

[0153] To a stirred solution of Comp-120-27 (500 mg, 1.67 mmol, 1 eq) in DCM at 25- 30°C was added Et3N (0.47 mL, 3.35 mmol, 2 eq). The reaction mixture was cooled to 0°C, added Methane sulfonyl chloride (0.15 mL, 2.00 mmol, 1.2 eq). The reaction mixture was stirred at 25-30°C for 4-5h. The progress of the reaction was monitored by TLC. After completion of the reaction, it was diluted with DCM (20 mL) and washed with sat. NaHCCf solution (2x 10 mL). Finally, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to get crude compound- 120-28 (500 mg) as brown gum. The crude compound was used in next step without purification.

[0154] 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):

[0155] To the solution of Compound- 120-28 (1g, 2.65 mmol, 1.0 eq) in acetonitrile (10 mL) at 25-30°C was added CS2CO3 (1.7 g, 5.31 mmol, 2 eq) and 2,4-Difluofo phenol (344 mg, 2.65 mmol, 1 eq) The reaction mixture was heated to 80°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion, it was diluted with DCM (50 mL) and washed with water (2 X 20 mL). Finally, the organic layer was dried over anhydrous Na2SO4 filtered and evaporated under reduced pressure to obtain crude (1.2mg) as Brown gum. The crude product was purified by flash reverse phase column (C18-40g), using 40-50% Acetonitrile in water as eluent. Combined product fractions were extracted with DCM (100 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain Comp-120-11 (110 mg) as white solid.1H NMR indicates isomeric mixture.

[0156] Step-g: Chiral separation of Comp-120-11 to get compound 148 and 149:

[0157] The above obtained Comp-5-120-11 (110 mg) of isomeric mixture was further separated by chiral prep HPLC.

[0158] SFC Preparative Conditions:

[0159] Evaporated the Chiral Prep fractions to obtained individual isomers as white solids which contains traces of DEA(diehtyl amine). These isomers dissolved in EtOAc (10 mL) and washed with water (2 X 10 mL). The organic layer was evaporated and further lyophilized to obtain individual isomers.

[0160] Compound 149 (+) isomer: 13 mg; LC retention time: 2.90 min.

[0161] Compound 148 (-) isomer: 30 mg; LC retention time: 2.82 min.Example 6. Synthesis of compounds 121 and 122

[0162] General Scheme 1. - Conditions: a) m-CPBA (70%, 1.0 eq), Chloroform (6 vol), rt, 16h; b) H2SO4 (2 vol), fuming HNO3 (10 eq), 80°C, 48h; c), 2-isopropyl-lH-imidazole (1.2 eq), CS2CO3 (1.5 eq), DMF (5 vol), rt, 3 days; d) Fe Powder (3.5 eq), AcOH (5 vol), 80°C, 3h; e) TFA (1.5 eq), Mixed xylene (3 vol), 180°C, 16h; f) 2,4-difhrorobenzaldehyde (1.5 eq), Pd / C ,MeOH (10 vol), H2 gas, rt, 16h; g) 47% aq HBr, 120°C, seal tube, 16h.

[0163] Step -a: 5-fluoro-2-methoxypyridine 1-oxide (6-146-20):

[0164] To a stirred solution of 5-fluoro-2-methoxypyridine (6-146-19) (25 g, 0.196 mol, 1.0 eq) in chloroform (150 mL) was added m-CPBA (48 g, 0.196 mol, 1.0 eq) at 0°C under nitrogen atmosphere. Continued the stirring for 16 h at room temperature. After completion of thereaction by TLC, the reaction mass was concentrated under vacuum and the obtained crude was purified by silica-gel column chromatography (60-120) using 10-20% Methanol in DCM as eluent to afford the title compound 6-146-20 (20.0 g) as off white solid.

[0165] Step-b: 5-fluoro-2-methoxy-4-nitropyridine (6-146-21):

[0166] To a stirred solution of 5 -fluoro-2-m ethoxypyridine 1-oxide (146-20) (20 g, 0.130 mol, 1.0 eq) in H2SO4 (150 mL) was added fuming HNO3 (58 mL, 1.30 mol, 10 eq) at 0°C. Then the reaction mixture was stirred for 48 h at 100°C. After completion of the reaction by TLC, the reaction mixture was cooled to rt and poured into ice water, adjusted pH to neutral with solid K2CO3 and extracted with DCM (2 x 600 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the target compound 6-146-21 (8.0 g) as a pale-yellow solid.

[0167] Step-c: 5-(2-isopropyl-lH-inudazol-l-yl)-2-methoxy-4-nitropyridine (6-146-16):

[0168] To a stirred solution of 6-146-21 (8.0 g, 0.046 mol, 1.0 eq) in DMF (40 mL) was added CS2CO3 (18.1 g, 0.055 mol), 2-isopropyl-lH-imidazole (6.1 g, 0.055 mol) at rt. Then the reaction mixture was stirred for 3 days at room temperature. After completion of the reaction by TLC, the reaction mixture was diluted with EtOAc (100 mL) and water. The separated organic layer was 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 6-146-16 (3.2 g) as a brown solid.

[0169] Step-d: 5-(2-isopropyl-lH-inudazol-l-yl)-2-methoxypyridin-4-anune (6-146-17):

[0170] To a stirred solution of 6-146-16 (3.0 g, 0.011 mol) in AcOH (200 mL) was added Fe powder (2.5 g, 0.040 mol) at rt. Then the reaction mixture was stirring for 3 h at 80o C. After completion of the reaction by TLC, the 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.

[0171] 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):

[0172] To a stirred solution of (6-146-17) (2*800 mg, 0.0068 mol) in mixed xylene (10 mL) was added TFA (0.79 mL, 0.0103 mol) at rt in seal tube. Then reaction was stirring for 16 h atI6O0C. After completion of the reaction by TLC reaction mass was concentrated under vacuum and the obtained crude was purified by silica-gel column chromatography (60-120) using 5% Methanol in DCM as eluent to afford the title compound 6-146-18 (0.980 g) as pale-yellow semi solid.

[0173] 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):

[0174] To a stirred solution of 6-146-18 (950 mg, 0.0021 mol) in MeOH (15 mL) was added 2,4-difluorobenzaldehyde (0.452 g, 0.0031 mol), Pd / C (0.5 g) at room temperature under N2 atm. Then reaction mass was stirred under H2 atm for 16 h. After completion of the reaction by TLC, the reaction mixture was filtered through celite pad, filtrate was concentrated. The crude residue was further purified by Prep to give compound 121 (70 mg) as Pale-yellow solid.

[0175] Prep HPLC Conditions:

[0176] 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).

[0177] To a stirred solution of compound 121 (50 mg, 0. mmol) in EtOH (50 mL) was added 47% aq HBr (1 mL) slowly and stirred for 16h at 130° C. After completion of the reaction by TLC, cooled to rt, the mixture was concentrated, the crude residue was further purified by Prep to give compound 122 (20 mg) as Pale-yellow solid.

[0178] Prep HPLC Conditions:Example 7. Synthesis of compound 139Scheme 1. - Conditions: a) 2-isopropyl - I / / -imidazole, DMF, 110°C, 16h; b) Fe powder, NH4C1, EtOH, reflux; c) TFA, Toluene, reflux; d) 10%Pd / C, MeOH; e) STAB, DCE, rt.

[0179] Step -a: 3-(2-isopropyl-lH-imidazol-l-yl)-2-nitropyridine 1-2):

[0180] Compound-7-1 (24.93 g, 157.24 mmol, 1 eq) and 2-isopropyl-l T-imidazole (34.64 g, 314.49 mmol, 2 eq) were mixed in DMF (32 mL) and the resulting mixture was heated at 110 °C overnight. The reaction mixture was cooled and poured into water (150 mL). The resulting mixture was extracted with EtOAc (2 x 200 mL) and combined organic layers were washed with water (3 x 150 mL), brine (150 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by chromatography (EtOAc-hexane, 2: 1) to obtain compound 7-2 (24.82 g)

[0181] Step-b: 3-(2-isopropyl-lH-imidazol-l-yl)pyridin-2-amine (1-3):

[0182] Compound-7-2 (24.82 g, 106.89 mmol, 1 eq) was dissolved in a mixture of EtOH (500 mL) and water (250 mL) and iron powder (59.69 g, 1069 mmol, 10 eq) was added followed by the addition of ammonium chloride (97.2 g, 1817 mmol, 17 eq). The resulting mixture was refluxed for 3 h. The reaction mixture was cooled to 25-30°C, and added EtOAc (750 mL). The resulting mixture was filtered through celite bed, filtrate was transferred to a separation funnel. The organic layer was separated, aqueous layer was extracted with EtOAc (2 x 500 mL). Combined organic layers were dried over Na2SO4, filtered and concentrated invacuo. The residue was purified by silica gel column (60-120) and 30-50%EtOAc in Hexane as eluent. Concentrated the product fractions to afford compound 7-3 (15 g) as yellow solid.

[0183] Step-c: benzyl l-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[2,3-e]pyrazine-4,4'- piperidinej-l '-carboxylate 1-4):

[0184] Compound-7-3 (6.9 g, 34.11 mmol, 1 eq) and benzyl 4-oxopiperi dine- 1 -carboxylate (7.96 g, 34.11 mmol, 1 eq) were dissolved in toluene (150 mL) and trifluoroacetic acid (3.13 mL, 40.94 mmol, 1.2 eq) was added. The resulting solution was refluxed with Dean-Stark trap overnight. The reaction mixture was cooled and poured into an aq. sodium bicarbonate solution (400 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (100 mL X 2). Combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography using EtOAc- hexane (1 : 1) to obtain compound-7-4 (10.9 g) as off white solid.

[0185] Step-d: l-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[2,3-e]pyrazine-4,4'- piperidine] (1-5):

[0186] To a stirred solution of Compound 7-4 (4 g) in methanol (40 mL) was added 10%Pd / C (50% wet) (400 mg). The reaction mixture was stirred under H2 balloon pressure for 16h. After completion of the reaction it was filtered through celite pad and washed with Methanol (50mL). Combined filtrates concentrated under reduced pressure to obtain Comp-7- 5 (2.5 g) as an off white solid.

[0187] Step-e: 1 '-(2,4-difluorobenzyl)-l-isopropyl-5H-spiro[imidazo[l,5-a]pyrido[2,3- e]pyrazine-4,4'-piperidine] (compound 139):

[0188] To a stirred solution of Comp-5 (100 mg, 0.35 mmol, 1 eq) in DCE (5 mL) added 2,4-difluoro benzaldehyde (100 mg, 0.70 mmol, 2 eq) followed by STAB (445 mg, 2.1 mmol, 3 eq) at 25-30°C. The reaction mixture was stirred at 25-30°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction it was diluted with DCM (20 mL) and washed with sat. NaHCCL solution (2x 10 mL). Finally, the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to get crude compound (200 mg) as brown gum. The crude compound was further purified by prep HPLC and isolated compound 139 (20 mg) as off white semi solid.

[0189] Preparative HPLC Conditions:Example 8. Synthesis of compounds 133, 129 and 186

[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,

[0192] Scheme 8-4. - Conditions: a) 2-isopropyl-l / Z-imidazole, DMF, 110°C, 16h; b) Fe powder, NH4C1, EtOH, Reflux; c) TFA, Toluene, reflux; d) 10%Pd / C, MeOH; e) STAB, DCE, rt.

[0193] Compounds 133, 129 and 186 are synthesized according to schemes 8-2, 8-3 and 9-4, and the procedures of example 7.Example 9. Synthesis of compounds 294 and 295

[0194] 1C General conditions: a) KHCO3, DMF, rt, 16h, b) H2O2, AcOH, 100°C c) Aq. HC1, Acetone, d) TFA, DCM,0°C-100°C,32h. e). Prep HPLC.

[0195] Step-a: 8-((2,4-difluorophenyl) thio)-l,4-dioxaspiro [4.5] decane (Comp-174-4-2)

[0196] To a stirred solution of Comp-174-4-1 (1g, 6.84 mmol,l eq) in DMF (20 mL) was added KHCO3(753mg, 7.53 mmol, 1.1 eq) at 0°C and stirred for 5 min, then added 174-3- 1A (1.5 g, 6.84 mmol, 1 eq). The reaction mixture was stirred for 16h at room temperature. The progress of the reaction was monitored by TLC. After completion, the reaction mass was dissolved in EtOAC and washed with ice-cold water. The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to obtain crude 174-4-2 as colourless crude. The crude product was purified by silica-gel (60-120 mesh) to afford 174-4-2 (800 mg) as a colourless liquid.

[0197] Step-b: 8-((2,4-difluorophenyl) sulfonyl)-!, 4-dioxaspiro [4.5] decane (Comp-174-4- 3)

[0198] To the stirred solution of Compound- 174-4-2 (800 mg, 2.79 mmol, 1 eq) in DCM (20 mL) was added m-CPBA (2.3 g, 13.9 mmol 5 eq) at 0 °C. The reaction mixture was stirred for 4h at 25-30°C and the progress of the reaction was monitored by TLC. After completion, the reaction mass was dissolved in DCM (20 mL) and washed with NaHCCL solution (2x 20 mL). The organic layer was dried over anhydrous Na2SC>4, filtered and evaporated to obtain crude as a white solid. The crude was purified by reverse phase flash chromatography using Cl 8-40 g column and 30-40% Acetonitrile in water as eluent. Evaporated the product fractions to afford the Compound- 174-4-3 (450 mg) as yellow solid.

[0199] Step-c: 4-((2,4-difluorophenyl) sulfonyl) cyclohexan-l-one (Comp-174-4-4)

[0200] To the stirred solution of Compound- 174-4-3 (450 mg, 1.41 mmol, 1 eq) in Acetone (5 mL) was added 6N HC1 (5 mL) at 0°C. The reaction mixture was stirred at rt for 4h and the progress of the reaction was monitored by TLC. After completion, the reaction mass was dissolved in DCM (10 mL) and washed with NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to obtain crude 174-4-4 (250 mg) as a white solid. It is used in the next step with any purification

[0201] 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)

[0202] To the stirred solution of Compound- 174-4-4 (250 mg, 0.91 mmol,l eq) and Compound- 120-24 (183 mg, 0.91 mmol,l eq) in Toluene (5 mL) was added TFA (0.5 eq). The reaction mass temperature was raised to 100-110°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction it was cooled to 0°C, dilutedwith water (15 mL) and basified with sat. NaHCCh solution to adjust the pH 9-10. The reaction mass was extracted with EtOAc (20 mL X 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get crude as a brown gum (300 mg). The crude compound was purified by PREP-HPLC.

[0203] Prep-HPLC Conditions:

[0204] Evaporated the Prep fractions and further lyophilized to afford two isomers.

[0205] _Peak-l : compound 294: 78mg.

[0206] Peak-2: compound 295: 63 mgExample 10. Synthesis of compounds 106 and 108

[0207] Conditions: a) TBAB, K2CO3, Toluene, 100°C, 16h, b) toluene, TFA, 90°C, 16h, c).Chiral separation.

[0208] Step-a: 5-fluoro-l-((4-oxocyclohexyl) methyl) pyridin-2(lH)-one (Comp-174-5-3)

[0209] To a stirred suspension of 5-fluoropyridin-2(lH)-one (174-5-1) (500 mg, 1.0 e q) in Toluene was added 4-(bromomethyl) cyclohexan-l-one (174-5-2) (1.0 eq), TBAB (0.1) and K2CO3(2.0eq) at room temperature. The reaction mixture was heated to 100°C and stirred for 16h. The progress of the reaction was monitored by TLC&LCMS. After completion of the reaction, diluted with water extracted by ethyl acetate (100X2). The combined organic layers were washed with brain solution, dried with anhydrous Na2SO4 and concentrated to get crude. The obtained regio isomers were isolated by 18C column 24g column using 40 to 50%Acetonitrile / water as eluent to afford Comp-174-5-3A (Peak-1): lOOmg and Comp-174- 5-3 (Peak-2): 1 lOmg as colourless gummy liquids.

[0210] 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)

[0211] To a stirred suspension of Comp-174-5-3 (110 mg, 4.95 mmol, 1.0 eq) in toluene was added Comp-120-4 (210 mg, 5.44 mmol, 1.1 e q) and TFA (9.90 mmol, 2.0 e q). The reaction mixture was heated to 90°C stirred for 16h. The progress of the reaction was monitored by TLC&LCMS. After completion of the reaction, diluted with water extracted by ethyl acetate (100X2). The combined organic layers were washed brain solution, dried with Na2SO4, filtered and concentrated to get crude (150 mg). It was purified by reverse phase column chromatography to afford Comp- 174-5 (80 mg) as off white solid. Chiral HPLC showed 1 : 1 isomeric mixture.

[0212] Step-c: Chiral separation:

[0213] The isomeric mixture of Comp-174-5 (80 mg) was further separated by chiral Prep HPLC to isolated individual isomers.

[0214] Chiral Preparative condition:

[0215] Evaporated the product fractions and again dissolved in EtOAc (10 mL) and washed with water (2 X 5 mL) to remove DEA. Concentrated the product fractions to afford individual isomers as off-white solids.

[0216] Compound 106 20 mg. Rt @ Chiral HPLC: 8.12 min

[0217] Compound 108 (Peak-2): 18 9 mg Rt @ Chiral HPLC: 6.90 minExample 11. Synthesis of compounds 109 and 110

[0218] Conditions: 1). TBAB (0.1), K2CO3, Toluene, 100°C, 16h, 2) Toluene, TFA, 90°C, 16h; c). Chiral separation

[0219] Step -a: 4-(((4-fluoropyridin-2-yl) oxy) methyl) cyclohexan-l-one (Comp-174-6- 2A):

[0220] To a stirred suspension of Comp- 174-6-1 (500 mg, 4.42 mmol, 1.0 eq) in toluene was added 4-(bromomethyl) cyclohexan-l-one (174-5-2) (845 mg, 4.42 mmol, 1.0 eq), TBAB (142, mg, 0.44 mmol, 0.1 eq) and K2CO3(1.2 g, 8.84 mmol, 2.0eq) at room temperature. The reaction mixture was heated to 100°C and stirred for 16h. The progress of the reaction was monitored by TLC&LCMS. After completion of the reaction, diluted with water extracted by ethyl acetate (100 mL X2). The combined organic layers were washed with brain solution, dried with anhydrous Na2SO4 and concentrated to get crude. The obtained regio isomers were isolated by 18C column 60g column using 40 to 50%Acetonitrile / water as eluent to afford Comp-174-6-2 (Peak-1): 90 mg and Comp-174-6-2A (Peak-2): 130 mg as colourless gummy liquids.

[0221] 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)

[0222] To a solution Comp-174-6-2A (130mg, 5.82 mmol, 1.0 eq) in toluene at 25-30°C was added was 2-(2-isopropyl-lH-imidazol-l-yl)pyridin-3-amine (129 mg, 6.41 mmol, 1.1 e q) followed by TFA (130 mg, 11.81mmol, 2.0 eq). Reaction mixture was heated to 90°C and stirred for 16h. Progress of the reaction mixture was monitored by TLC&LCMS. After completion of the reaction it was allowed to ambient temperature, diluted with water (20 mL)and extracted Ethyl acetate (10 mLX2). Combined organic layer was washed with brain solution (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated to get crude (200 mg) as brown gum. The crude product was purified by flash reverse phase (30 g) column using 10 % to 50% acetonitrile in water as mobile phase, Concentrated product fractions to afford isomeric mixture of Comp-174-6.

[0223] Step-c: Chiral separation:

[0224] The above isomeric mixture of Comp- 174-6 (70 mg) was further separated by Chiral Prep and isolated both isomers.

[0225] Chiral Prep condition:

[0226] Evaporated the product fractions and again dissolved in EtOAc (10 mL) and washed with water (2 X 5 mL) to remove DEA. Concentrated the product fractions to afford individual isomers as off-white solids.

[0227] Peak-1 (compound 109): 2.2 mg. Rt @ Chiral HPLC: 6.65 min

[0228] Peak-2 (compound 110): 10.4 mg. Rt @ Chiral HPLC: 7.49 minExample 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.

[0230] Step-cr. 4-methoxy-5,6-dihydropyridin-2(lH)-one (174-7-5):

[0231] To a stirred solution of Comp-174-7-2 (2.0g, 17.699 mmol, 1 eq) in dry MeOH (25 mL) at 25-30°C was added PTSA (1.21g, 7.029mmol, 0.4eq) followed by trimethyl orthoformate (4mL, 2.0 vol) The reaction mixture was heated to 70°C for 16h. The progress of the reaction was monitored by TLC as well as LCMS. After completion of the reaction, cooled to room temperature and diluted with ice-cold water (30 mL), compound extracted with ethyl acetate (2x 50 mL). The organic layer washed with sat. NaHCO3 solution (50 mL) followed by brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated under vacuum to get crude compound (3 g) as brown gum. The crude was purified by silica gel column (100-200 mesh) using 60-80% EtOAc in hexane as eluent. The product fractions were concentrated to afford Comp-174-7-5 (1.9 g) as colorless liquid.

[0232] Step-lr. l-(2,5-difluorobenzyl)-4-methoxy-5,6-dihydropyridin-2(lH)-one (174-7- 6):

[0233] To a stirred solution of Comp-174-7-5 (1.9 g, 17.960mmol, 1 eq) in DMF (50 mL) at 0°C was added NaH 60% (0.71 g, 29.92mmol, 2.0 eq). The reaction mixture was stirred for 30min at 0°C, then added Comp-174-7-1 (4.6g, 22.44 mmol, 1.5 eq). The reaction mixture temperature was raised to 25-30°C and stirred for 2-3h. The progress of the reaction was monitored by TLC as well as LCMS. After completion of the reaction. The reaction mixture was quenched with ice cold water (50 mL), extracted with Ethyl acetate (2 x 100 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to get crude (3 g) as white solid. The crude compound was purified by silica gel column (100-200 mesh), using 30- 40%EtOAc in hexane as eluent. The product fractions were concentrated to afford Comp-174- 7-6 (1.4 g) as off white solid.

[0234] Step-c. l-(2,5-difluorobenzyl)piperidine-2, 4-dione (174-7-2):

[0235] To a stirred Solution of Comp-174-7-6 (1.4 g, 5.533 mmol, 1.0 eq) in THF (50 mL) at 0°C was added 6N HC1 (Aq) (4.2ml, 3 vol). The reaction mixture was stirred for 4h at 25-30°C. The progress of the reaction was monitored by TLC. After completion of the reaction, remove the solvent under reduced pressure, residue was dissolved in EtOAc (50 mL) and washed with sat. NaHCOs solution (20 mL). The organic layer was dried over anhydrous Na2SO4, filteredand concentrated to get crude (800 mg) as off white solid. The crude compound was triturated with n-Pentane (10 mL) to afford Comp-174-7-2 (650 mg) as an off-white solid.

[0236] Step-d'. 1 '-(2,5-difluorobenzyl)-9-isopropyl-5H-spiro [imidazo [1,5-a] pyrido [3,2- e]pyrazine-6,4'-piperidin]-2'-one (174-7)

[0237] To the stirred solution of Compound- 174-7-2 (650mg, 2.719mmol,l eq) and Compound- 120-24 (0.5 g, 2.719 mmol,l eq) in Toluene (10 mL) was added TFA (2.5mL). The reaction mass temperature was raised to 100-110°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction it was cooled to 0°C, diluted with water (15 mL) and basified with sat. NaHCCL solution to adjust the pH 9-10. The reaction mass was extracted with Ethyl acetate (50 mL X 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get crude as brown gum (400mg). The crude compound was purified by PREP-HPLC.

[0238] Prep conditions:

[0239] Collect the prep HPLC fractions distilled under reduced pressure to get Comp- 174-7 (50 mg) as an isomeric mixture (1 : 1) as off white solid. The above isomeric mixture was further purified by chiral Prep HPLC:

[0240] Chiral prep conditions:

[0241] Evaporated the product fractions and again dissolved in EtOAc (10 mL) and washed with water (2 X 5 mL) to remove DEA. Concentrated the product fractions to afford individual isomers as off-white solids.

[0242] Peak-1 (compound 104): 3.4 mg. Rt @Chiral HPLC: 5.97 min

[0243] Peak-2 (compound 105): 4.9 mg. Rt @ Chiral HPLC: 8.57 minExample 13. Synthesis of compound 284 and 285

[0244] S Conditions: a). NaH, DMF, rt, b) THF, Aq.HCl, c) TF A, Toluene, Reflux, 16h; d) Chiral separation.

[0245] Step-cr. l-(2,4-difluorobenzyl)-4-methoxy-5,6-dihydropyridin-2(lH)-one (174-7- 6):

[0246] To a stirred solution of Comp-174-7-5 (1 g, 7.87 mmol, 1 eq) in DMF (20 mL) at 0°C was added NaH 60% (377 mg, 15.74 mmol, 2.0 eq). The reaction mixture was stirred for 30min at 0°C, then added Comp-174-8-1 (2.4 g, 11.80 mmol, 1.5 eq). The reaction mixture temperature was raised to 25-30°C and stirred for 2-3h. Progress of the reaction was monitored by TLC as well as LCMS. After completion of the reaction. The reaction mixture was quenched with ice cold water (50 mL), extracted with Ethyl acetate (100 x 2 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to get crude (1.5 g) as white solid. The crude compound was purified by silica gel column (100-200mesh). using 30-40%EtOAc in hexane as eluent. The product fractions were concentrated to afford Comp-174-7-6 (0.5 g) as off white solid.

[0247] Step-b'. l-(2,4-difluorobenzyl)piperidine-2, 4-dione (174-8-2):

[0248] To a stirred solution of Comp-174-7-6 (0.5 g) in THF (10 mL) at 0°C was added 6N HC1 (Aq) (1.5 mL, 3 Vol). The reaction mixture was stirred for 4h at 25-30°C. The progress of the reaction was monitored by TLC. After completion of the reaction, it was distilled under reduced pressure ad dissolved the residue in EtOAc (50 mL) and washed with sat. HaHCO3solution (20 mL X 1). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to get crude (400 mg) as off white solid. The crude compound was triturated with n-Pentane (10 mL) to afford Comp-174-8-2 (300 mg) as off-white solid.

[0249] 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):

[0250] To the stirred solution of Compound- 174-8-2 (300 mg, 1.25 mmol,l eq) and Compound- 120-24 (253 g, 1.25 mmol,l eq) in Toluene (50 mL) was added TFA (1 mL). The reaction mass temperature was raised to 100-110°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction it was cooled to 0°C, diluted with water (15 mL) and basified with sat. NaHCCL solution to adjust the pH 9-10. The reaction mass was extracted with Ethyl acetate (50 mL X 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get crude as brown gum (400mg). The crude compound was purified by PREP-HPLC.

[0251] Prep conditions:

[0252] Collected the prep HPLC fractions distilled under reduced pressure to get Comp- 174-8 (100 mg) as isomeric mixture (1 : 1) as off white solid.

[0253] The above isomeric mixture was further purified by chiral Prep HPLC:

[0254] Chiral prep conditions:

[0255] Peak-1 (Compound 284): 21.4 mg. Rt @ Chiral HPLC: 5.40 min

[0256] Peak-2 (compound 285): 23.8 mg. Rt @Chiral HPLC: 11.25 minExample 14. Synthesis of compound 118, 117, 101 and 160

[0257] d General Scheme-1- Conditions: a) TFA, Toluene, Reflux, 16h; b). Acetone, Aq. HC1, rt, 4h; c); NaH 15-Crown-5, THF 0°C to RT, 6h; d) Chiral SFC; e) Pd / C, MeOH, H2gas RT 16h, f) Chiral separation; g). Neat Tri ethyl phosphite, 150°C, 16h

[0258] Step-g: diethyl (2,4-difluorobenzyl) phosphonate (139-1-2):

[0259] To the Comp-139-1-1 (5 g, 24.27 mmol, 1 eq) at 25-30°C was added Neat Triethyl phosphite (4.2 mL, 24.27 mmol, 1 eq). The reaction mixture was heated to 150°C for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction, it was cooled to room temperature, directly used for silica gel (100-200) column and eluted in 30-40% EtOAc in hexane. The product fractions were concentrated to afford Comp-139-1-2 (4.5 g) as a colorless liquid.

[0260] 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):

[0261] To the stirred solution of comp-120-24 (8 g, 39 mmol, 1 eq) and Comp-121-21 (9.1 g, 58.5 mmol, 1.5 eq) in Toluene (80 mL) was added TFA (4.5 mL, 58.5 mmol, 1.5 eq). The reaction mass temperature was raised to 100-110°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion of the reaction it was cooled to 0°C, diluted with water (100 mL) and slowly basified with sat. NaHCO3 solution to pH 9-10. The reaction mass was extracted with EtOAc (100 mL X 2). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to get crude (10 g) as brown gum.The crude compound was purified by silica gel column (60-120). Compound was eluted in 30- 40%EtOAc in hexane. The product fractions were concentrated to afford Comp-121-22 (3 g) as off white solid.

[0262] Step-b: 9’-isopropyl-5’H-spiro[cyclohexane-l,6’-imidazo[l,5-a] pyrido[3,2- ejpyr azin] -4-one (121-23):

[0263] To the neat comp-121-22 (3 g) in Acetone (30 mL) at 0°C was added 6N HC1 (9 mL, 3 Vol) at 0°C. The reaction mixture temperature was raised to 25-30°C, stirred for 5-6h until complete consumption of starting material. After completion of the reaction it was cooled to 0°C, diluted with water (50 mL) and slowly basified with sat. NaHCO3 solution to pH 9-10. The reaction mass was extracted with EtOAc (60 mL X 2). Combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford Comp-121-23 (2 g) as off white solid.

[0264] 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):

[0265] To a stirred solution of Comp-139-1-2 (4.5 g, 17.04 mmol, 1 eq) in THF (50 mL) at 0°C was added 15-Crown-5 (0.375 g, 1.170mmol, 0.1 eq). The reaction mixture was stirred for 5min, then added NaH 60% (0.8 g, 34.07 mmol, 2.0 eq) at same temperature and stirred for 30 minutes. After 30 min added Comp-121-23 (5.01g, 17.05 mmol, 1 eq). The reaction mixture temperature was raised to 25-30°C and stirred for 16h. The progress of the reaction was monitored by TLC as well as LCMS. After completion of the reaction. The reaction mixture was quenched with ice cold water (100 mL) at 0°C, extracted with Ethyl acetate (100 x 2 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated to get crude as brown gum. The crude compound was purified by silica gel column (100-200), eluted in 10- 20%EtOAc in hexane. The product fractions were concentrated to afford Comp-139-03 (Isomeric mixture 1 : 1 by chiral HPLC) (3 g) as an off white solid.

[0266] Step-d: Chiral separation of MLT-139-03 to get compound 118 and 117:

[0267] The isomeric mixture of Comp-139-03 (300 mg) was further separated by chiral SFC.

[0268] SFC Preparative Conditions:

[0269] Evaporated the Chiral SFC fractions to obtained individual isomers as white solids which contains traces of DEA. These isomers dissolved in EtOAc (50 mL) and washed with water (2 X 25 mL). The organic layer was evaporated and further lyophilized to obtain individual isomers.

[0270] Peak-1 (compound 118): 29 mg. PEAK-2 (compound 117): 65 mg

[0271] 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 ):

[0272] To a stirred Solution of Comp-139-03 (3 g) in MeOH (50 mL) at 25°C was added 10% Pd / C (50% wet) (250 mg). The reaction mixture was stirred under H2 balloon for 16h at rt. Progress of the reaction was monitored by TLC. After completion of the reaction, it was filtered through celite bed, washed the celite with Methanol (10 mL). Combined filtrates evaporated under reduced pressure to afford MLT-139-01 (isomeric mixture; 77% + 22% by chiral HPLC) (2.7g) as off-white solid.

[0273] The isomeric mixture of Comp-139-03 (300 mg) was further separated by chiral SFC.

[0274] SFC Preparative Conditions:

[0275] Evaporated the Chiral SFC fractions to obtained individual isomers as white solids which contains traces of DEA. These isomers dissolved in EtOAc (50 mL) and washed with water (2 X 25 mL). The organic layer was evaporated and further lyophilized to obtain individual isomers.

[0276] Peak-1 (compound 101) (+) Isomer: 900 mg.

[0277] Peak-2 (compound 160) (-) Isomer: 200 mg.Example 15. Synthesis of compound 125 and 114

[0278] Conditions: a). Neat Triethyl phosphite, 150°C, 16h; b). NaH 15-Crown-5, THF 0°C to RT, 6h; c). Chiral separation.

[0279] Step -a: Diethyl (2,5-difluorobenzyl) phosphonate (166-4):

[0280] To a neat Comp-166-3 (5 g, 24.39 mmol, 1 eq) was added triethylphosphite (4.04 g, 24.39 mmol, 1 eq). The reaction mixture was heated to 150°C for 16h. Progress of the reaction was monitored by TLC. After completion of the reaction it was cooled to room temperature directly loaded on to silica gel (100-200) column and eluted in 30-40% EtOAc in hexane. Product fractions were concentrated under reduced pressure to afford Comp- 166-4 (5 g) as colorless liquid.

[0281] 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):

[0282] To a stirred solution of Comp- 166-4(890 mg, 3.37 mmol, 1 eq) in THF (20 mL) at 0°C was added 15-Crown-5 (74 mg, 0.33 mmol, 0.1 eq). The reaction mixture was stirred for 5min, then added NaH (486 mg, 10.13mmol, 3 eq at same temperature and stirred for 30 minutes. After 30 min added Comp-121-23 (1 g, 3.37 mmol, 1 eq). The reaction mixture temperature was raised to 25-30°C and stirred for 16h. Progress of the reaction was monitored by TLC as well as LCMS. After completion of the reaction. The reaction mixture was quenched with ice cold water (100 mL) at 0°C, extracted with Ethyl acetate (100 x 2 mL). The combined organic layer was dried overNa2SO4, filtered and concentrated to get crude (1.2 g) as brown gum. The crude compound was purified by silica gel column (100-200), eluted in 30-40%EtOAc in hexane. The product fractions were concentrated to afford Comp-166-2 (Isomeric mixture 1 : 1 by chiral HPLC) (800 mg) as off white solid.

[0283] Step-c: Chiral separation of Comp-166-2 to get: compound 125 and 114

[0284] The isomeric mixture of Comp-166-2 (100 mg) was further separated by chiral SFC.

[0285] SFC Preparative Conditions:

[0286] Evaporated the Chiral SFC fractions to obtained individual isomers as white solids which contains traces of DEA. These isomers dissolved in EtOAc (20 mL) and washed with water (2 X 20 mL). The organic layer was evaporated and further lyophilized to obtain individual isomers.

[0287] 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.

[0289] Step -a: 2-(2-bromo-lH-inudazol-l-yl)-3-nitro pyridine) (183-1-5):

[0290] To the stirred suspension of comp-120-21 (10 g, 63.05 mmol, 1 eq) in DMF (100 mL) at RT. added K2CO3(26 mg, 189.27mmol, 3 eq) followed by Comp-183-1-4 (7.4 g, 50.47 mmol, 0.8 eq). The reaction mixture heated to 120°C, stirred for 16h. The progress of the reaction was monitored by TLC. As well as LCMS. After completion of the reaction, it was diluted with DCM (100 mL) and washed with ice cold water (100 mL X 2). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to get crude (15 g) as brown gum. The crude compound was purified by silica gel column (60-120 mesh), eluted with 40-50% EtOAc in Hexane. Concentrated the product fractions to afford comp- 183 -1-5 (7 g) as yellow solid.

[0291] Step-b: 2-(2-(2-methylprop-l-en-l-yl)-lH-inndazol-l-yl)-3-nitropyridine (183-1-9):

[0292] To as stirred solution of compound -183-1-5 (7 g, 26.02 mmol, 1 eq), 4, 4,5,5- tetramethyl-2-(2-methylprop-l-en-l-yl)-l,3,2-dioxaborolane (9.4 g, 52.04 mmol, 2 eq) in 1,4 dioxane / water (4: 1) (70 mL) was added K2CO3 (10.77 g, 78.06 mmol, 3 eq) at 25-30°C. The heterogeneous mixture was degassed with nitrogen for 10-15 min then added Pd(dppfC12). DCM (2.1 g, 2.60 mmol, 0.1 eq) and further degassed for another 10 min. The reaction mixture was heated to 100°C and stirred for 16h. The progress of the reaction was monitored by TLC. After completion, it was cooled to 25-30°C, diluted with EtOAc (100 mL), filtered through celite. The celite was washed with EtOAc (100 mL). Combined filtrates were concentrated under reduced pressure to obtain crude (10 g) as black gum. The crude product was purified by silica gel (60-10) column and 40% EtOAc in Hexane as eluent. Evaporated the product fractions to afford the Compound- 183 -1-9 (4 g) as brown liquid.

[0293] Step-c: 2-(2-(2-methylprop-l-en-l-yl)-lH-inudazol-l-yl) pyridin-3-amine (183-1- 10):

[0294] To the solution of comp-183-1-9 (4g, 16.3 mmol, 1.0 eq) in EtOH / H2O (4: 1) (40 mL) at 0°C was added NH4CI (15.3, 295mmol, 18 eq) stirred for lOmin then added Fe powder (9.1 g, 163 mmol, 10 eq). The reaction mixture was heated to 80°C and stirred for 6h. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was filtered through celite bed, washed the celite bed with excess of EtOH (100 mL). Combinedfiltrates were concentrated under reduced pressure to obtain crude (5.2 g) as black gum. 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.

[0295] 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):

[0296] To the stirred solution of 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). 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). The organic layer was dried Na2SO4, filtered and evaporated to obtain crude (3.2 g) as brown gum. The crude compound was purified by flash reverse phase column (40 g) using 70-80% Acetonitrile in water as eluent. Concentrated the product fractions to afford comp-compound 283 (2g) as yellow solid.

[0297] 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):

[0298] To the stirred solution of t-BuOH / Water (1 : 1) (10 mL) at 0°C was added P-Admix (1.29 g, 0.23 mmol, 7 eq), followed by Methane sulfonamide (22 mg, 0.23 mmol,l eq). The reaction mixture was stirred for 15 min then added slowly Comp-183-1-7 (100 mg, 0.23 mmol, 1 eq, dissolved in 2mL of t-BuOH). The reaction mixture was allowed to 25-30°C, stirred for 48h. Progress of the reaction was monitored by TLC. After completion of the reaction it was quenched with sat. ISfeSCU solution (10 mL) and extracted with EtOAc (20 mL X 2). Combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get crude (60 mg) as brown gum. The crude compound was purified by prep-HPLC. Evaporated the prep HPLC fraction and further lyophilized to afford comp-183-1 (9.9 mg) as off white solid.

[0299] Prep HPLC conditions:

[0300] Step-f: l-(2,5-difluorobenzyl) piperidin-4-one (183-1-3):

[0301] To the stirred suspension of comp-183-1-1 (10 g, 74.07 mmol, 1 eq) in DMF (100 mL) at 25-30°C was added K2CO3 (30.6 mg, 222.22 mmol, 3 eq) followed by Comp-183-1-2 (15.3 g, 77.07 mmol, 1 eq). The reaction mixture stirred for 16h at RT. The progress of the reaction was monitored by TLC. After completion of the reaction, it was diluted with DCM (100 mL) and washed with cool water (100 mL X 2). The organic layer was dried over anhydrous Na2SO4, filtered and evaporated to get crude (18 g) as brown gum. The crude product was purified by silica gel column (60-120) using 30-40% EtOAc in Hexane as eluent. Concentrated the product fractions to afford comp-183-1-3 (10 g) as yellow liquid.INCORPORATION BY REFERENCE

[0302] All references, articles, publications, patents, patent publications, and patent applications cited herein are incorporated by reference in their entireties for all purposes. However, mention of any reference, article, publication, patent, patent publication, and patent application cited herein is not, and should not be taken as, an acknowledgment or any form of suggestion that they constitute valid prior art or form part of the common general knowledge in any country in the world.

Claims

CLAIMSWhat is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X; provided that when L is CH2, then J is not, ,X is C, CRbor N;= represents a single bond or a double bond; each of M1and M2is independently C, CRc, N, or NRd, wherein at least one of M1and M2is N or NRd;Ring Q is 5-6 membered heterocyclylene, or 5-6 membered heteroarylene;Ring Z is 5-6 membered heterocyclylene, or 5-6 membered heteroarylene, wherein Ring Z comprises at least one nitrogen atom; each of R1, R2and R3is independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -0-, -S-, -S(=0)-, or -S(=0)2-; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3 or 4;each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; provided that when m is 1 and R2is OCH3, then J is notwhen n is i and R1is C(=O)NReRf, then J is notwhen X is C(=O), then J is not2. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:whereinJ is aryl substituted with 1-4 Ra, or heteroaryl substituted with 1-4 Ra,L is a bond, C1-6alkylene, C1-6alkenylene, C1-6alkynylene, -N(Rd)-, -O-, -S-, - S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X; provided that when L is CH2, then J is notX is C, CRbor N;= represents a single bond or a double bond; each of M1and M2is independently C, CRc, N, or NRd, wherein at least one of M1and M2is N or NRd;Ring Q is 5-6 membered heterocyclylene or 5-6 membered heteroarylene;Ring Z is 5-6 membered heterocyclylene or 5-6 membered heteroarylene, wherein Ring Z comprises at least one nitrogen atom; each of R1, R2and R3 is each independently selected from halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, -CN, OH, =0, alkylene-NReRf, NReRf, -C(=O)alkyl, - C(=O)Oalkyl, -C(=0)NReRf, cycloalkyl, heterocyclyl, aryl or heteroaryl;E is -C(Rc)2-, -NRd-, -0-, -S-, -S(=0)-, or -S(=0)2-; n is 1, 2, 3, or 4; m is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3 or 4; each of Ra, Rb, and Rcis independently selected from H, alkyl, alkenyl, alkynyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, -CN, or cycloalkyl; each of Rd, Reand Rfis independently selected from H, alkyl, alkenyl, alkynyl, haloalkyl, C(=O)alkyl, -C(=O)Oalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl; provided that the compound of formula (I) is not any one of the following compounds3. The compound of claim 1 or 2, wherein L is selected from a bond, C1-6alkylene, C1-6alkenylene, -N(Rd)-, -O-, -S-, -S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=0)-0-Co-6 alkylene-, -C(=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X.

4. The compound of claim 3, wherein Rbis absent, H, OH, Ci-3alkyl or halogen.

5. The compound of any one of claims 1-4, wherein L is a bond, -CH2-, -C(=O)-, CH, - CH(CH3)-, -CHF-, -CF2-, -CH(OH)-, -C(CH3)(OH)-, -O-, -S(=O)2-, *-CH2O-, *-C(=0)0CH2- or, wherein * represents the point of attachment to X.

6. The compound of any one of claims 1-5, wherein L is -CH2-, -C(=O)- or -S(=O)2-.

7. The compound of any one of claims 1-6, wherein L is -C(=O)-.

8. The compound of any one of claims 1-6, wherein L is -CH2-.

9. The compound of any one of claims 1-6, wherein L is -S(=O)2-.

10. The compound of any one of claims 1-9, wherein = represents a single bond.

11. The compound of any one of claims 1-10, wherein X is N, CH or C.

12. The compound of any one of claims 1-10, wherein X is N or CH, and = represents a single bond.

13. The compound of any one of claims 1-12, wherein X is N, and = represents a single bond.

14. The compound of any one of claims 1-12, wherein X is CH, and = represents a single bond.

15. The compound of any one of claims 1-14, wherein p is 0.

16. The compound of any one of claims 1-14, wherein p is 1 and R3is =0.

17. The compound of claim 1-14 or 16, wherein18. The compound of any one of claims 1-17, wherein J is aryl substituted with 1-4 Ra.

19. The compound of any one of claims 1-18, wherein J is phenyl substituted with 1-4 Ra.

20. The compound of any one of claims 18-19, wherein Rais H, halogen, C1-6alkyl, C1-6alkoxy or CN.

21. The compound of any one of claims 1-19, wherein J is, wherein Rais C1-3 alkyl, halogen, C1-3 alkoxy or CN.

22. The compound of any one of claims 1-21, wherein J is23. The compound of any one of claims 1-22, whereinwherein p is 0, 1 or 2, and Rais C1-3 alkyl, halogen, C1-3 alkoxy or CN.

24. The compound of any one of claims 1-17, wherein J is heteroaryl optionally substituted with 1-4 Ra.

25. The compound of any one of claim 24, wherein Rais H, halogen or =0.

26. The compound of any one of claims 1-17 or 24-25, wherein J is27. The compound of any one of claims 1-26, wherein E is NRd.

28. The compound of any one of claims 1-27, wherein E is NH, NCH3 or NC(=0)CH3. ,29. The compound of any one of claims 1-28, wherein E is NH.

30. The compound of any one of claims 1-29, wherein one of M1and M2is N, and the other one of M1and M2is C.

31. The compound of any one of claims 1-30, wherein is M2is N, and M1is C.

32. The compound of any one of claims 1-30, wherein is M1is N, and M2is C.

33. The compound of any one of 1-32, wherein Ring Q is 5-membered heteroarylene.

34. The compound of any one of claims 1-33, wherein Ring35. The compound of any one of claims 1-34, wherein36. The compound of any one of claims 1-35, whereinhas the structure of37. The compound of any one of claims 1-36, wherein n is 1.

38. The compound of any one of claims 1-37, whereinhas the structure of39. The compound of any one of claims 1-38, whereinhas the structure of40. The compound of any one of claims 1-39, wherein R1is C1-6alkyl, haloalkyl or cycloalkyl.

41. The compound of any one of claims 1-40, wherein R1is CH3, CH2CH3, isopropyl, cyclopropyl or CF3.

42. The compound of any one of claims 1-41, wherein R1is isopropyl.

43. The compound of any one of claims 1-37, wherein n is 1 and R1is isopropyl.

44. The compound of any one of claims 1-43, wherein Ring Z is 6-membered heterocyclylene or 6-membered heteroarylene.

45. The compound of any one of claims 1-44, wherein Ring Z is 6-membered heteroarylene.

46. The compound of any one of claims 1-45, wherein Ring Z is pyridylene or pyrazinylene.

47. The compound of any one of claims 1-45, wherein Ring48. The compound of any one of claims 1-44, wherein Ring Z is49. compound of any one of claims 1-44, wherein Ring Z is50. The compound of any one of claims 1-49, wherein m is 0.

51. The compound of any one of claims 1-47, whereinstructure52. The compound of any one of claims 1-47, wherein53. The compound of claim 1, wherein the compound is a compound of formula (la), (lb),Formu a (I ).

54. The compound of claim 53, wherein the compound is the compound is a compound of formula (la)55. The compound of claim 53, wherein the compound is the compound is a compound of formula (lb):

56. The compound of claim 53, wherein the compound is the compound is a compound of formula (Ic):

57. The compound of claim 53, wherein the compound is the compound is a compound of formula58. The compound of any one of claims 53-57, wherein L is selected from a bond, C1-6alkylene, Ci-6alkenylene, -N(Rd)-, -O-, -S-, -S(=O)-, -S(=O)2-, -O-C1-6alkylene-*, *-C(=O)- O-Co-6 alkylene-, -(C=O)-, each of which is substituted with 1-4 Rb, and wherein * represents the point of attachment to X.

59. The compound of claim 58, wherein Rbis absent, H, OH, Ci-3alkyl or halogen.

60. The compound of claim 53-57, wherein L is a bond, -CH2-, -C(=O)-, CH, -CH(CH -,-CHF-, -CF2-, -CH(OH)-, -C(CH3)(OH)-, -O-, -S(=O)2, *-CH2O-, *-C(=O)OCH2- or wherein * represents the point of attachment to X.

61. The compound of claim 53-57, wherein L is -CH2-, -C(=O)- or -S(=O)2-.

62. The compound of any one of claims 53-57, wherein L is -C(=O)-.

63. The compound of any one of claims 53-57, wherein L is -CH2-.

64. The The compound of any one of claims 53-57, wherein L is -S(=O)2-.

65. The compound of any one of claims 53-61, wherein = represents a single bond.

66. The compound of any one of claims 53-65, wherein X is N, CH or C.

67. The compound of any one of claims 53-66, wherein X is N or CH, and = represents a single bond.

68. The compound of any one of claims 53-67, wherein X is N, and = represents a single bond.

69. The compound of any one of claims 53-68, wherein X is CH, and = represents a single bond.

70. The compound of any one of claims 53-69, wherein p is 0.

71. The compound of any one of claims 53-69, wherein p is 1 and R3is =0.

72. The compound of claim 71, wherein73. The compound of any one of claims 53-72, wherein J is aryl substituted with 1-4 Ra.

74. The compound of any one of claims 53-73, wherein J is phenyl substituted with 1-4Ra75. The compound of any one of claims 53-74, wherein Rais H, halogen, C1-6alkyl, C1-6alkoxy or CN.

76. The compound of any one of claims 53-75, wherein J iswherein Rais C1-3 alkyl, halogen, C1-3 alkoxy or CN.

77. The compound of any one of claims 53-76, wherein J is78. The compound of any one of claims 53-77, whereinwherein p is 0, 1 or 2, and Rais C1-3 alkyl, halogen, C1-3 alkoxy or CN.

79. The compound of any one of claims 53-72, wherein J is heteroaryl optionally substituted with 1-4 Ra.

80. The compound of any one of claim 79, wherein Rais H, halogen or =0.

81. The compound of any one of claims 53-72 or 79-80, wherein J is82. The compound of any one of claims 53-81, wherein E is NRd.

83. The compound of any one of claims 53-82, wherein E is NH, NCH3 or NC(=O)CH3.

84. The compound of any one of claims 53-83, wherein E is NH.

85. The compound of any one of claims 53-84, wherein R1is C1-6 alkyl, haloalkyl or cycloalkyl.

86. The compound of any one of claims 53-85, wherein R1is CH3, CH2CH3, isopropyl, cyclopropyl or CF3.

87. The compound of any one of claims 53-86, wherein R1is isopropyl.

88. A compound selected from any one of the compounds in Table 1.

89. A pharmaceutically composition comprising a compound or a pharmaceutical acceptable salt thereof of any one of claims 1-88.

90. A pharmaceutical composition comprising any one of the compounds in Table 1 or a pharmaceutically acceptable salt thereof.

91. A compound selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

92. The compound any one of claims 1-91, wherein the compound contains one or more deuterium atoms.

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