Disubstituted octahydropyrrolo[3,4-c]pyrrole methyl ketone derivatives and their uses

Abstract

The present invention relates to the pharmaceutical field, and specifically to a compound of the following general formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, a composition containing the compound, a method for producing the same, and use in the pharmaceutical field. JPEG2025507883000103.jpg3547

Description

[Technical Field]

[0001] The present invention relates to the pharmaceutical field, and more particularly to a disubstituted octahydropyrrolo[3,4-c]pyrrole methyl ketone derivative or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, a composition containing the compound, and a use in the pharmaceutical field. [Background technology]

[0002] There are two types of orexins (also called hypocretins or orexin peptides): orexin-A (hypocretin-1) and orexin-B (hypocretin-2). Orexin peptide signaling is mediated by two receptors and two peptide agonists. Orexin peptide A and orexin peptide B bind to two high-affinity receptors: orexin receptor type 1 (OX1R or OX1) and orexin receptor type 2 (OX2R or OX2). OX1R preferentially selects orexin peptide A, whereas OX2R binds both orexin peptides with similar affinity.

[0003] Several lines of evidence suggest that orexin-mediated wakefulness effects are related to the projection of orexin neurons to histamine neurons in the tuberomammillary nucleus (Yamanaka et al., 2002, Biochem. Biophys. Res. Comm., 290:1237-1245). Further clinical confirmation that orexin signaling is a target for sleep-promoting therapy has been provided by the observation of reduced orexin content and loss of orexigenic neurons in human patients with sleeplessness (Mignot et al., 2001, The American Journal of Human Genetics, 68:686-699), or, in a very small number of cases, associated with mutations in the OX2R receptor gene (Peyron et al., 2000, Naturemed., 6:991-997).

[0004] As can be seen from this, orexin receptors have important pathological significance and are associated with various diseases such as sleep disorders, depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, affective neurological disorders, depressive neurological disorders, anxiety neurological disorders, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive disorders, Alzheimer's disease, Parkinson's disease, movement disorders, eating disorders, headache, migraine, and pain.

[0005] Research indicates that sleep-wake cycle disorders may be targets of OX2R receptor modulator activity. Examples of disorders that can be treated with antagonists or other modulators that downregulate OX2R-mediated processes include insomnia, restless legs syndrome, jet lag, and sleep disorders secondary to neurological disorders such as mania, schizophrenia, and pain syndromes. OX2R is selectively expressed in the tuberomammillary nucleus (TMN), hypothalamic paraventricular nucleus (PVN), and nucleus accumbens (NAc). These brain regions are the primary sites of action of orexin neurons in the LH, which are associated with feeding, sleep, depression, anxiety, drug addiction, and motivational behaviors, making the therapeutic effect more pronounced in the treatment of sleep disorders (Lu et al., 2020, Neurosci Bull, 4:432-448). Summary of the Invention

[0006] The present invention provides compounds having orexin receptor antagonist activity. The compounds of the present invention have relatively good selectivity and pharmacological activity, as well as excellent physicochemical and pharmacokinetic properties, and therefore have relatively good prospects for clinical application.

[0007] Hereinafter, several aspects of the present invention will be briefly described, but the present invention is not limited thereto. If the disclosure content of this specification differs from that of the cited document, the disclosure content of this specification shall prevail.

[0008] An object of the present invention is to provide a disubstituted octahydropyrrolo[3,4-c]pyrrole methyl ketone derivative or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutical composition thereof for preventing or treating a disease associated with an orexin receptor.

[0009] According to one aspect, the present invention provides a compound of general formula I:

[0010] [ka]

[0011] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, halogen, a C1-C8 linear or branched alkyl group, and a C1-C8 alkoxy group; Alternatively, R1 and R2 form a C3-C8 cycloalkyl group, an aryl group, a heteroaryl group, or a 3- to 8-membered heterocycle, Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C;

[0012] [ka]

[0013] is a single or double bond, R6 is selected from Formula II, Formula III, and Formula IV;

[0014] [ka]

[0015] R9 is an optionally substituted heteroaryl group, an optionally substituted aromatic ring, an optionally substituted 3-8 membered heterocycle, or an optionally substituted C3-C8 cycloalkyl group, the substituents being selected from halogen, a C1-C8 linear or branched alkyl group, a C1-C8 alkoxy group, and a haloalkyl group; In Formula II, Z is selected from C, N, R7 is selected from H, halogen, and C1-C8 straight or branched chain alkyl groups; R8 is absent or independently selected from H, halogen, and a C1-C8 straight or branched chain alkyl group; In formula IV, A, B, and M are selected from CH and N, and A, B, and M are not simultaneously CH.

[0016] [ka]

[0017] It should be understood that when is a single bond, W may actually be CH.

[0018] According to another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I above or a pharmaceutically acceptable salt, stereoisomer, tautomer, and optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof.

[0019] In another aspect, the present invention provides the use of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, and pharmaceutical composition thereof in the manufacture of a medicament for treating a disease associated with an orexin receptor.

[0020] In one embodiment, the orexin receptor-associated disease is a sleep disorder, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neurological disorder, depressive neurological disorder, anxiety neurological disorder, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, etc.

[0021] In another embodiment, the orexin receptor-associated disease is a sleep disorder. DETAILED DESCRIPTION OF THE INVENTION

[0022] Unless otherwise specified or clearly contradicted by context, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are hereby incorporated by reference.

[0023] General Terms and Definitions The term "optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0024] The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted," i.e., the structure or group is unsubstituted or substituted with one or more substituents according to the present invention, where said substitution occurs in any reasonable position on a given structure or group, where valency is allowed.

[0025] Unless otherwise specified, as used herein, the point of attachment of a substituent may be from any suitable position on the substituent. When a substituent is shown to be attached through a bond connecting two atoms in a ring, then such substituent may be attached to any ring atom in that substitutable ring.

[0026] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a specified substituent. Unless otherwise specified, a substituent may be substituted at each reasonable position of the group where it is substitutable. When more than one position in a given structural formula may be optionally substituted with one or more specific substituents, the substituents may be the same or different at each reasonable position in the structural formula.

[0027] It should also be explained that unless otherwise specified, the term "independently" used in the present invention may mean that specific options represented by the same symbol in different groups do not affect each other, or that specific options represented by the same symbol in the same group do not affect each other, and should be understood in a broad sense.

[0028] When the lower and upper limits of a numerical range are disclosed, any numerical value within that range and any encompassed range is specifically disclosed. In particular, each possible value range disclosed herein should be understood to encompass each value and range within the broader range. When any variable (e.g., R) and labeled variable (e.g., R, R, R, R, R, R, R, etc.) occurs more than once in a compound composition or structure, its definition at each occurrence is independent at every occurrence. For example, if a group is substituted with 0, 1, 2, 3, or 4 R substituents, the group may optionally be substituted with up to 4 R substituents, and the options for each R substituent at each occurrence are all independent of each other.

[0029] In each section of this specification, the substituents of the compounds disclosed in this invention are disclosed according to the type of group or range. In particular, it should be noted that the present invention includes each independent subcombination of each member of these types of groups and ranges. For example, the expression m-n used in this specification refers to a subscope consisting of the range from m to n and each point value therein, and each point value therein.

[0030] In the present invention, "*" denotes a point of attachment. For example,

[0031] [ka]

[0032] indicates that the substituent is connected with "*".

[0033] The term "alkyl group" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms connected to the rest of the molecule by a single bond. An "alkyl group" may have 1 to 8 carbon atoms, i.e., a "C1-C8 alkyl group," or it may have 1 to 6 carbon atoms, i.e., a "C1-C6 alkyl group," such as C 1-4 Alkyl group, C 1-3 Alkyl group, C 1-2 Alkyl group, C3 alkyl group, C4 alkyl group, C 1-6 Alkyl group, C 3-6 It is an alkyl group having 1 to 3 carbon atoms, i.e., it may be a "C1 to C3 alkyl group", for example, C 1-3 Alkyl group, C 1-2The term "C1-C5 alkyl group" specifically refers to a methyl group, an ethyl group, a C3 alkyl group, a C4 alkyl group, or a C5 alkyl group, which are individually disclosed. Examples of alkyl groups are a methyl group (Me, -CH3), an ethyl group (Et, -CH2CH3), an n-propyl group (n-Pr, -CH2CH2CH3), an isopropyl group (i-Pr, -CH(CH3)2), an n-butyl group (n-Bu, -CH2CH2CH2CH3), an isobutyl group (i-Bu, -CH2CH(CH3)2), a sec-butyl group (s-Bu, -CH(CH3)CH2CH3), a tert-butyl group (t-Bu, -CH (CH3)3), n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH 2CH(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl These include, but are not limited to, groups such as (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), n-heptyl group, n-octyl group, and the like.For example, the expression "C2 to C8" or "C2-8" should be understood to encompass the range of 2 to 8 carbon atoms, and any subscopes and point values ​​therein, such as C2 to C5, C3 to C4, C2 to C6, C3 to C6, C4 to C6, C4 to C7, C4 to C8, C2 to C4, etc., and C2, C3, C4, C5, C6, C7, C8, etc. Also, for example, "C1 to C5" or "C. 1-5 " should be understood to encompass the range of 1 to 5 carbon atoms, and any subscopes and point values ​​therein, for example, C2 to C5, C3 to C4, C1 to C2, C1 to C3, C1 to C4, C1 to C5, etc., and C1, C2, C3, C4, C5, etc. Also, for example, "C2 to C5" or "C 2-5 " should be understood to encompass the range of 2 to 5 carbon atoms, and any subscopes and point values ​​therein, for example, C2 to C5, C3 to C4, C2 to C3, C2 to C4, C3 to C5, C4 to C5, etc., and C2, C3, C4, C5, etc. Also, for example, "C1 to C8" or "C 1-8 The expression "includes the range of 1 to 8 carbon atoms, and should be understood to include any subscope and each point value therein, for example, C2 to C5, C3 to C4, C2 to C6, C3 to C6, C4 to C6, C4 to C7, C4 to C8, C2 to C4, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. Also, for example, the expression "3-membered to 8-membered" should be understood to include any subscope and each point value therein, for example, 3-membered to 5-membered, 3-membered to 6-membered, 3-membered to 7-membered, 3-membered to 8-membered, 4-membered to 5-membered, 4-membered to 6-membered, 4-membered to 7-membered, 4-membered to 8-membered, 5-membered to 7-membered, 5-membered to 8-membered, 6-membered to 7-membered, 6-membered to 8-membered, etc., as well as 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, etc. Other similar expressions herein should be understood in an analogous manner.

[0034] The term "one or more" or similar expressions such as "at least one" may mean, for example, one, two, three, four, five, six, seven, eight, nine, ten or more.

[0035] The term "haloalkyl group" refers to an alkyl group substituted with one or more halogen atoms, wherein alkyl group has the meaning as defined herein, examples of which include, but are not limited to, -CF3, -CH2F, -CHF2, -CF2CF3, -CH2CF3, -CH2CH2F, CH2CF2CHF2, etc. A "haloalkyl group" has 1 to 8 carbon atoms, i.e., C 1-8 In one embodiment, the "haloalkyl group" is a relatively lower C 1-4 haloalkyl group, wherein the above "C 1-4 "Haloalkyl group" refers to a fluorine-substituted C 1-4 Alkyl group, chlorine-substituted C 1-4 Alkyl, bromine-substituted C 1-4 Alkyl, iodine-substituted C 1-4 Specifically, fluorine-substituted C 1-4 Alkyl groups include -CHF, -CHF, -CF, -CHCl, -CHCl, -CCl, -CHBr, -CHBr, -CBr, -CHCHF, -CHCHF, -CHCF, -CFCHF, -CFCHF, -CFCF, -CHFCF, -CHFCHF, -CHFCHF, -CHCHCF, -CHCFCHF, etc. The haloalkyl groups are optionally substituted with one or more substituents as described herein.

[0036] The term "chosen from" refers to one or more elements in the list thereafter that are independently selectable, and may include combinations of two or more elements.

[0037] The terms "comprises" and "includes" are open-ended terms, i.e., including the subject matter specified in the present invention, but not excluding other aspects.

[0038] When it is stated that each carbon atom in a group may be optionally replaced with a heteroatom, the proviso is that the normal valences of all atoms in the group in their current state are not exceeded and a stable compound is formed.

[0039] The term "heteroatom" refers to one or more oxygen (O), sulfur (S), or nitrogen (N), and includes nitrogen (N), sulfur (S) in any oxidation state, primary, secondary, and tertiary amine and quaternary ammonium salt forms, or hydrogen substitution on a nitrogen atom of a heterocycle, e.g., N, NH, NR.

[0040] The term "aryl group" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 10 ring atoms, or 6 ring atoms, in which at least one ring is aromatic. An aryl group is usually, but not necessarily, linked to the parent molecule through the aromatic ring of the aryl group. The term "aryl group" is used interchangeably with the terms "aromatic ring" or "aromatic ring." Examples of aryl groups may include phenyl, naphthyl, anthracene, etc. The aryl group is optionally substituted with one or more substituents described herein.

[0041] The term "heteroaryl group" refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 5 to 14 ring atoms, or 5 to 10 ring atoms, or 5 to 6 ring atoms (i.e., 5 to 6 members), in which at least one ring is aromatic and at least one ring contains one or more heteroatoms. Heteroaryl groups are usually, but not necessarily, linked to the parent molecule through an aromatic ring of the heteroaryl group. The term "heteroaryl group" is used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." Examples of heteroaromatic rings include 5- to 10-membered monocyclic or bicyclic heteroaryl groups containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, including, but not limited to, pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazole, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, and triazazolyl groups, wherein the heteroaryl groups are optionally substituted with one or more substituents described herein.

[0042] The term "heterocycle" is used interchangeably with "heterocyclyl group" and refers to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, or 3 to 8 ring atoms, in which one or more atoms in the ring are independently replaced by a heteroatom, said heteroatom having the meaning described herein, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise specified, a heterocyclyl group may be a carbon or nitrogen group, and -CH- groups may optionally be replaced by -C(=O)-. Sulfur atoms in the ring may optionally be oxidized to S-oxides. Nitrogen atoms in the ring may optionally be oxidized to N-oxides. Examples of heterocyclyl groups include 3- to 8-membered monocyclic or bicyclic heterocycles containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and include, but are not limited to, ethylene oxide, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl groups. Examples of heterocyclyl groups in which the -CH2- group is replaced with -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidinonyl, 3,5-dioxopiperidinyl, and pyrimidindionyl groups. Examples of heterocyclyl groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl groups. The heterocyclyl groups may be optionally substituted with one or more substituents described herein.

[0043] The term "hydrogen (H)" refers to a single hydrogen atom; such an atom can be linked to other groups, such as oxygen atoms, to form hydroxy groups.

[0044] The term "halogen" or "halogenated" should be understood to represent fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably a fluorine, chlorine or bromine atom, more preferably a fluorine atom.

[0045] The term "alkoxy group" refers to an alkyl group linked to the remainder of the molecule by an oxygen atom, wherein alkyl group has the meaning as defined herein. Unless otherwise specified, such alkoxy groups contain 1 to 8 carbon atoms. In one embodiment, an alkoxy group contains 1 to 5 carbon atoms, and in another embodiment, an alkoxy group contains 1 to 3 carbon atoms. Such alkoxy groups may be optionally substituted with one or more substituents as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH), ethoxy (EtO, -OCHCH), 1-propoxy (n-PrO, -OCHCHCH), 2-propoxy (i-PrO, -OCH(CH)), 1-butoxy (n-BuO, -OCHCHCHCH), 2-l-propoxy (i-BuO, -OCHCH(CH)), 2-butoxy (s-BuO, -OCH(CH)CHCH), 2-methyl-2-propoxy (t-BuO, -OC(CH)), and the like.

[0046] The term "cycloalkyl group" refers to a saturated or unsaturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, preferably containing one or two rings. The cycloalkyl group may have a monocyclic, fused polycyclic, bridged, or spirocyclic structure. The cycloalkyl group may have 3 to 8 carbon atoms, i.e., a "C3-C8 cycloalkyl group," such as a C6 cycloalkyl group, a C5 cycloalkyl group, a C4 cycloalkyl group, or a C3 cycloalkyl group. Non-limiting examples of cycloalkyl groups include, but are not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclopentenyl group, and a cyclohexyl group. The term also encompasses cases where a C atom therein may be substituted with oxo (=O).

[0047] The term "stereoisomers" refers to compounds that have identical chemical constitution, but in which the atoms or groups are arranged in space in different ways. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0048] The term "tautomer" refers to structural isomers with different energies that are interconvertible via a low energy barrier. When tautomers are possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include intertransformations that occur via proton transfer, such as keto-enol isomerization and imine-enamine isomerization.

[0049] The term "pharmaceutically acceptable salt" refers to an organic or inorganic salt of a compound of the present invention.

[0050] The term "pharmaceutically acceptable carrier" refers to a substance that has no appreciable irritating effect on an organism and that does not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, a glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, disintegrant, stabilizer, solvent, or emulsifier.

[0051] The following detailed description of the invention is intended to illustrate non-limiting embodiments, allowing those skilled in the art to better understand the technical solution of the present invention, its principles, and its practical applications, so that those skilled in the art can modify and implement the present invention in many ways so as to best suit the requirements of specific applications.

[0052] Compounds of Formula I According to one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof:

[0053] [ka]

[0054] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, halogen, a C1-C8 linear or branched alkyl group, and a C1-C8 alkoxy group; Alternatively, R1 and R2 form a C3-C8 cycloalkyl group, an aryl group, a heteroaryl group or a 3- to 8-membered heterocycle, preferably R1 and R2 form a C3-C8 cycloalkyl group, a 6- to 10-membered monocyclic or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C;

[0055] [ka]

[0056] is a single or double bond, R6 is selected from Formula II, Formula III, and Formula IV;

[0057] [ka]

[0058] R9 is an optionally substituted heteroaryl group, an optionally substituted aromatic ring, an optionally substituted 3- to 8-membered heterocycle, or an optionally substituted C3-C8 cycloalkyl group, wherein the substituents are selected from halogen, a C1-C8 straight-chain or branched-chain alkyl group, a C1-C8 alkoxy group, and a haloalkyl group; preferably, R9 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6- to 10-membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group;

[0059] In Formula II, Z is selected from C, N, R7 is selected from H, halogen, and C1-C8 straight or branched chain alkyl groups; R8 is absent or independently selected from H, halogen, and a C1-C8 straight or branched chain alkyl group; In formula IV, A, B, and M are selected from CH and N, and A, B, and M are not simultaneously CH.

[0060] In one embodiment, R1 is absent or selected from H, halogen, a C1-C8 linear or branched alkyl group, and a C1-C8 alkoxy group. In a preferred embodiment, R1 is absent. In a preferred embodiment, R1 is a C1-C8 linear or branched alkyl group or a C1-C8 alkoxy group. In a more preferred embodiment, R1 is a C1-C5 linear or branched alkyl group or a C1-C5 alkoxy group. In a specific embodiment, R1 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. In a more specific embodiment, R1 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, and a propoxy group. In a particularly specific embodiment, R1 is a methyl group. In another particularly specific embodiment, R1 is an ethyl group. In a further particularly specific embodiment, R1 is a methoxy group. In a further particularly specific embodiment, R1 is an ethoxy group.

[0061] In one embodiment, R2 is absent or selected from H, halogen, a C1-C8 straight or branched alkyl group, and a C1-C8 alkoxy group. In a preferred embodiment, R2 is H and halogen. In a more preferred embodiment, R2 is H. In an especially preferred embodiment, R2 is halogen. In a specific embodiment, R2 is selected from H, fluorine, chlorine, bromine, and iodine. In an even more specific embodiment, R2 is selected from H, fluorine, chlorine, and bromine. In an especially specific embodiment, R2 is H. In another especially specific embodiment, R2 is fluorine. In a further especially specific embodiment, R2 is chlorine.

[0062] In one embodiment, R1 and R2 form a C3 to C8 cycloalkyl group, an aryl group, a heteroaryl group, or a 3 to 8 membered heterocycle. In a preferred embodiment, R1 and R2 form a C3 to C6 cycloalkyl group. In one embodiment, R1 and R2 form a C6 to C 10In another preferred embodiment, R1 and R2 form a C3-C6 aryl group. In one embodiment, R1 and R2 form a 5- to 10-membered heteroaryl group, preferably a 5- to 6-membered heteroaryl group. In another preferred embodiment, R1 and R2 form a C3-C6 heteroaryl group. In another preferred embodiment, R1 and R2 form a 3- to 6-membered heterocycle. In a specific embodiment, R1 and R2 form cyclopropane, cyclobutane, cyclopentane, cyclopentenyl, or cyclohexane. In a specific embodiment, R1 and R2 form a phenyl ring. In an even more specific embodiment, R1 and R2 form a cyclopentenyl group. In another specific embodiment, R1 and R2 form pyridine. In another specific embodiment, R1 and R2 form thiophene. In another specific embodiment, R1 and R2 form pyrrole. In another specific embodiment, R1 and R2 form furan.

[0063] In one embodiment, R3 is absent or selected from H, halogen, a C1-C8 linear or branched alkyl group, and a C1-C8 alkoxy group. In a preferred embodiment, R3 is absent. In a preferred embodiment, R3 is a C1-C8 linear or branched alkyl group or a C1-C8 alkoxy group. In a more preferred embodiment, R3 is a C1-C5 linear or branched alkyl group or a C1-C5 alkoxy group. In a specific embodiment, R3 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. In a more specific embodiment, R3 is selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, and a propoxy group. In a particularly specific embodiment, R3 is a methyl group. In another particularly specific embodiment, R3 is an ethyl group. In a further particularly specific embodiment, R3 is a methoxy group. In a further particularly specific embodiment, R3 is an ethoxy group.

[0064] In one embodiment, R4 and R5 are absent or independently selected from H, halogen, a C1 to C8 straight or branched chain alkyl group, and a C1 to C8 alkoxy group.

[0065] In one embodiment, R4 is a C1-C8 straight or branched alkyl group. In a preferred embodiment, R4 is H. In a more preferred embodiment, R4 is absent. In a more specific embodiment, R4 is a methyl group, an ethyl group, or a propyl group. In a particularly specific embodiment, R4 is a methyl group.

[0066] In one embodiment, R5 is a C1-C8 straight or branched alkyl group. In a preferred embodiment, R5 is H. In a more preferred embodiment, R5 is absent. In a more specific embodiment, R5 is a methyl group, an ethyl group, or a propyl group. In a particularly specific embodiment, R5 is a methyl group.

[0067] In one embodiment, R7 is selected from H, halogen, and a C1-C8 straight or branched alkyl group. In a preferred embodiment, R7 is a C1-C5 straight or branched alkyl group, H, or halogen. In a more preferred embodiment, R7 is H. In a particularly preferred embodiment, R7 is halogen. In a specific embodiment, R7 is selected from a methyl group, an ethyl group, a propyl group, and an isopropyl group. In an even more specific embodiment, R7 is selected from H. In a particularly specific embodiment, R7 is fluorine, chlorine, bromine, or iodine. In another particularly specific embodiment, R7 is a methyl group. In a further particularly specific embodiment, R7 is fluorine. In a further particularly specific embodiment, R7 is chlorine.

[0068] In one embodiment, R8 is absent or selected from H, halogen, and a C1-C8 straight or branched chain alkyl group. In a preferred embodiment, R8 is absent. In a preferred embodiment, R8 is a C1-C8 straight or branched chain alkyl group. In a more preferred embodiment, R8 is halogen. In a particularly preferred embodiment, R8 is H. In another particularly preferred embodiment, R8 is absent. In a specific embodiment, R8 is selected from a methyl group, an ethyl group, and a propyl group. In an even more specific embodiment, R8 is selected from H. In a particularly specific embodiment, R8 is fluorine, chlorine, bromine, or iodine. In another particularly specific embodiment, R8 is a methyl group. In a further particularly specific embodiment, R8 is fluorine. In a further particularly specific embodiment, R8 is absent.

[0069] In one embodiment, R9 is an optionally substituted heteroaryl group, an optionally substituted aromatic ring, an optionally substituted 3-8 membered heterocycle, or an optionally substituted C3-C8 cycloalkyl group, wherein the substituents are selected from halogen, a C1-C8 straight or branched chain alkyl group, a C1-C8 alkoxy group, and a haloalkyl group.

[0070] In a preferred embodiment, the heteroaryl group is a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and includes a pyridyl group, pyridazinyl group, triazinyl group, pyrimidinyl group, thienyl group, furanyl group, oxazolyl group, thiazolyl group, thiadiazole group, oxadiazolyl group, isoxazolyl group, pyrazolyl group, imidazolyl group, pyrrolyl group, pyranyl group, pyridazinyl group, pyrazinyl group, and triazazolyl group. In another preferred embodiment, the aromatic ring is a phenyl group. In a further preferred embodiment, the 3- to 8-membered heterocycle is a 3- to 6-membered heterocycle. In a further preferred embodiment, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group. In a specific embodiment, the heteroaryl group is a pyridinyl group, a pyridazinyl group, a pyrimidinyl group, a thienyl group, a furanyl group, an oxazolyl group, a thiazolyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, or a pyranyl group. In a more specific embodiment, the heteroaryl group is a pyridinyl group, a pyrimidinyl group, a thienyl group, a furanyl group, an oxazolyl group, or a thiazolyl group.

[0071] In one embodiment, the C3 to C8 cycloalkyl group is a C3 to C6 cycloalkyl group. In a preferred embodiment, the C3 to C8 cycloalkyl group and the C3 to C6 cycloalkyl group are a cyclopropyl group, a cyclobutyl group, a cyclopentenyl group, a cyclopentyl group, and a cyclohexyl group. In a more preferred embodiment, the C3 to C8 cycloalkyl group and the C3 to C6 cycloalkyl group are a cyclopropyl group, a cyclopentenyl group, a cyclopentyl group, and a cyclohexyl group. In a particularly preferred embodiment, the C3 to C8 cycloalkyl group and the C3 to C6 cycloalkyl group are a cyclopentenyl group.

[0072] In one embodiment, Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C. In a preferred embodiment, Y is N and Q is C. In a preferred embodiment, Y is C and Q is N. In another preferred embodiment, Y is N and Q is N.

[0073] In one embodiment, the C1-C8 straight-chain or branched-chain alkyl group is selected from a C1-C5 straight-chain or branched-chain alkyl group. In a specific embodiment, the C1-C8 straight-chain or branched-chain alkyl group and the C1-C5 straight-chain or branched-chain alkyl group are each independently selected from a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, and an isopentyl group. In a more specific embodiment, the C1-C8 straight-chain or branched-chain alkyl group and the C1-C5 straight-chain or branched-chain alkyl group are each independently selected from a methyl group, an ethyl group, a propyl group, and an isopropyl group.

[0074] In one embodiment, the propyl group includes, but is not limited to, an n-propyl group (n-Pr, -CH2CH2CH3) or an isopropyl group (i-Pr, -CH(CH3)2). The butyl group includes, but is not limited to, an n-butyl group (n-Bu, -CH2CH2CH2CH3), an isobutyl group (i-Bu, -CH2CH(CH3)2), a sec-butyl group (s-Bu, -CH(CH3)CH2CH3), or a tert-butyl group (t-Bu, -C(CH3)3). The pentyl group includes, but is not limited to, an n-pentyl group (-CH2CH2CH2CH2CH3), a 2-pentyl group (-CH(CH3)CH2CH2CH3), a 3-pentyl group (-CH(CH2CH3)2), a 2-methyl-2-butyl group (-C(CH3)2CH2CH3), a 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), a 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), or a 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3).

[0075] In one embodiment, the C1-C8 alkoxy group is selected from a C1-C5 alkoxy group. In a specific embodiment, the C1-C8 alkoxy group and the C1-C5 alkoxy group are each independently selected from a methoxy group, an ethoxy group, a propoxy group, a butoxy group, and a pentoxy group. In a more specific embodiment, the C1-C8 alkoxy group and the C1-C5 alkoxy group are each independently selected from a methoxy group, an ethoxy group, and a propoxy group.

[0076] In one embodiment, the halogen is fluorine, chlorine, bromine, or iodine. In a preferred embodiment, the halogen is fluorine, chlorine, or bromine. In a more preferred embodiment, the halogen is fluorine or chlorine. In a particularly preferred embodiment, the halogen is fluorine.

[0077] In one specific embodiment, the compound of formula I is a compound shown in formula V:

[0078] [ka]

[0079] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Alternatively, R1 and R2 form a C3-C6 cycloalkyl group, a 6- to 10-membered monocyclic or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C;

[0080] [ka]

[0081] is a single or double bond, Z is selected from C and N; R7 is selected from H, fluorine, chlorine, a methyl group, an ethyl group, a propyl group, and an isopropyl group; R8 is absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, and isopropyl; R9 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6- to 10-membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group, in which the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl groups.

[0082] In one specific embodiment, the compound of formula I is a compound of formula V-1:

[0083] [ka]

[0084] wherein R1, R2, and R3 are independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Alternatively, R1 and R2 form a C3-C6 cycloalkyl group, a 6- to 10-membered monocyclic or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Z is selected from C and N; R7 is selected from H, fluorine, chlorine, a methyl group, an ethyl group, a propyl group, and an isopropyl group; R8 is absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, and isopropyl; R9 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6- to 10-membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group, in which the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl groups.

[0085] In one specific embodiment, the compound of formula I is a compound shown in formula VI:

[0086] [ka]

[0087] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Alternatively, R1 and R2 form a C3-C6 cycloalkyl group, a 6- to 10-membered monocyclic or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C;

[0088] [ka]

[0089] is a single or double bond, R9 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6- to 10-membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group, in which the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl groups.

[0090] In one specific embodiment, the compound of formula I is a compound shown in formula VII:

[0091] [ka]

[0092] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Alternatively, R1 and R2 form a C3-C6 cycloalkyl group, a 6- to 10-membered monocyclic or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C;

[0093] [ka]

[0094] is a single or double bond, A, B, and M are selected from CH and N, and A, B, and M are not CH at the same time; R9 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6- to 10-membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group, in which the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl groups.

[0095] In one specific embodiment, the compound of formula I is selected from any one of the compounds shown below:

[0096] [ka]

[0097] [ka]

[0098] [ka]

[0099] [ka]

[0100] [ka]

[0101] [ka]

[0102]

change

[0103]

change

[0104]

change

[0105]

change

[0106]

change

[0107]

change

[0108]

change

[0109]

change

[0110]

change

[0111]

change

[0112] [ka]

[0113] Beneficial technical effects of the present invention Compared with the prior art, the technical solution of the present invention has the following advantages: The compounds provided by the present invention have good selectivity by acting on OX1R and OX2R. The compounds provided by the present invention are used to treat diseases associated with sleep disorders. The compounds provided by the present invention have good pharmacological activity and also have excellent physicochemical and pharmacokinetic properties. [Example]

[0114] Examples of the present invention will be described in detail below. The examples described below are illustrative and are used only to explain the present invention, and should not be understood as limiting the present invention. Unless otherwise specified, all ratios, percentages, etc. referred to in this specification are by weight.

[0115] Synthesis Examples Example 1 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylindolizin-1-yl)methanone

[0116] [ka]

[0117] 1.1 Preparation of ethyl 2-phenylindolizine-1-carboxylate A 50 mL three-necked round-bottom flask was charged with ethyl 2-pyridine (1.0 g, 6.06 mmol), acetophenone (1.45 g, 12.11 mmol), CuBr (0.14 g, 0.61 mmol), I (0.31 g, 1.21 mmol), and DTBP (0.89 g, 6.06 mmol). The reaction was heated overnight at 78 °C under N protection. After completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature, quenched with saturated aqueous NaSO, extracted with 3 × 30 mL of EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. 0.8 g of a brownish-yellow liquid was obtained by silica gel column chromatography using ethyl acetate / petroleum ether (1 / 3). LCMS (ES, m / z): 266 [M+H]. + .

[0118] 1.2 Preparation of 2-phenylindolizine-1-carboxylic acid Ethyl 2-phenylindolizine-1-carboxylate (0.74 g, 2.81 mmol), sodium hydroxide (0.56 g, 14.07 mmol), and EtOH / HO (10 / 2 mL) were added to a 100 mL single-necked round-bottom flask and reacted at 65 °C overnight. After completion of the reaction was confirmed by TLC, the mixture was cooled to room temperature and concentrated to remove ethanol. The residue was then added with water and the pH was adjusted to 4-5 with 3 N HCl. The mixture was extracted with 3 × 30 mL of EA, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, and concentrated to give 0.65 g of a pale yellow solid. LCMS (ES, m / z): 238 [M+H] + .

[0119] 1.3 Preparation of ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylindolizin-1-yl)methanone 2-Phenylindolizine-1-carboxylic acid (510 mg, 2.15 mmol), HATU (1.63 g, 4.29 mmol), EtN (652 mg, 6.44 mmol), and acetonitrile (10 mL) were added to a 50 mL single-neck round-bottom flask in an ice bath and allowed to react for 10 min. 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (562 mg, 2.58 mmol) was added and the reaction was allowed to proceed at room temperature for 2 h. After completion of the reaction was confirmed by TLC, 30 mL of water was added, and the mixture was extracted with 30 mL of DCM (3 × 30 mL), washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography with DCM / MeOH (20 / 1) to give 585 mg of product. 1 H NMR (400 MHz, Chloroform-d ) δ 8.51 (dd, J = 7.5, 1.4 Hz, 1H), 7.67 (td, J = 7.5, 1.4 Hz, 1H), 7.54 - 7.49 (m, 3H), 7.49 - 7.34 (m, 4H), 6.74 (s, 1H), 6.68 (td, J = 7.5, 1.5 Hz, 1H), 4.04-3.99 (m, 2H), 3.79 - 3.58 (m, 4H), 3.38-3.33 (m, 2H), 2.80 - 2.62 (m, 2H), 2.25 (s, 6H); LCMS (ES, m / z): 438 [M+H] + .

[0120] Example 2 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyridin-2-yl)indolizin-1-yl)methanone

[0121] [ka]

[0122] The target compound was prepared according to the method of Example 1, substituting 1-(pyridin-2-yl)ethan-1-one for the reactant acetophenone. 1 H NMR (400 MHz, Chloroform-d) δ 8.62 (d, J = 4.4 Hz, 1H), 7.97 (d, J = 6.8 Hz, 1H), 7.80 (s, 1H), 7.70 - 7.59 (m, 2H), 7.55 (d, J= 9.1 Hz, 1H), 7.07 (s, 1H), 6.91 - 6.78 (m, 1H), 6.63 (t, J = 6.8 Hz, 1H), 6.34 (s, 1H), 4.23 - 3.19 (m, 8H), 3.02-2.84 (m, 2H), 2.35 (s, 6H). LCMS (ES, m / z): 439 [M+H] + .

[0123] Example 3 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(3-fluoropyridin-2-yl)indolizin-1-yl)methanone

[0124] [ka]

[0125] The target compound was prepared according to the method of Example 1, substituting 1-(3-fluoropyridin-2-yl)ethan-1-one for the reactant acetophenone. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 4.6 Hz, 1H), 7.91 (d, J= 6.9 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.37 (m, 1H), 7.05 (m, 1H), 6.77 (dd, J = 9.1, 6.5 Hz, 1H), 6.56 (t, J = 6.7 Hz, 1H), 6.29 (s, 1H), 3.94 - 3.47 (m, 7H), 3.07 - 2.88 (m, 3H), 2.32 (s, 6H). LCMS (ES, m / z): 457 [M+H]+.

[0126] Example 4 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(5-methylthiophen-2-yl)indolizin-1-yl)methanone

[0127] [ka]

[0128] The target compound was prepared according to the method of Example 1, substituting 1-(5-methylthiophen-2-yl)ethan-1-one for the reactant acetophenone. 1 H NMR (400 MHz, Chloroform-d) δ 8.51 (dd, J = 7.5, 1.4 Hz, 1H), 7.83 (s, 1H), 7.69 - 7.65(m, 1H), 7.44 (dd, J = 7.5, 1.3 Hz, 1H), 7.28 (d, J = LCMS (ES, m / z): 458 [M+H] + .

[0129] Example 5 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(thiophen-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanone

[0130] [ka]

[0131] [ka]

[0132] 5.1 Preparation of ethyl 3-(thiophen-2-yl)propionate 2-Iodothiophene (2.0 g, 9.52 mmol), ethyl propionate (3.74 g, 38.09 mmol), (PPh3)2PdCl2 (134 mg, 0.19 mmol), CuI (73 mg, 0.38 mmol), and K2CO3 (2.63 g, 19.04 mmol) were added to a 100 mL single-neck flask containing THF (40 mL), and the mixture was stirred at 65 °C under N2 for 12 h. The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (EA:PE = 0-10%) to give 1.5 g of a pale yellow oil.

[0133] 5.2 Preparation of ethyl 2-(thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate Ethyl 3-(thiophen-2-yl)propionate (500 mg, 2.77 mmol), 1-aminoiodopyridine (616 mg, 2.77 mmol), and DBU (845 mg, 5.55 mmol) were added to a 100 mL single-neck flask containing MeCN (20 mL), and the mixture was reacted overnight at room temperature under N2. The reaction mixture was concentrated and extracted with EA (3 × 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE = 0-20%) to give 500 mg of a pale yellow solid.

[0134] 5.3 Preparation of 2-(thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid Ethyl 2-(thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (500 mg, 1.84 mmol), LiOH (88 mg, 3.67 mmol), and EtOH / HO (6 / 3 mL) were added to a 50 mL single-neck flask and reacted with stirring at 60 °C for 1 h. The reaction solution was concentrated, then the pH was adjusted to 5–6 with 1 M HCl, extracted with EA (3 × 30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give 400 mg of a white solid.

[0135] 5.4 Preparation of ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(thiophen-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanone 2-(Thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.41 mmol) was added to a single-neck flask containing 5 mL of DCM. HATU (171 mg, 0.45 mmol) and DIEA (159 mg, 1.23 mmol) were added. After stirring for 10 min, (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (98 mg, 0.45 mmol) was added and the mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated and purified by silica gel column chromatography (EA:PE = 0-100%) to give 80 mg of the product. 1 H NMR (400 MHz, Methanol-d4) δ 8.46 - 8.39 (m, 2H), 7.35 - 7.19 (m, 1H), 7.18 - 7.05 (m, 2H), 6.98 - 6.87 (m, 1H), 6.85 - 6.61 (m, 1H), 6.42 (s, 1H), 3.52 - 3.47 (m, 1H), 3.39 - 3.33 (m, 1H), 4.01 - 3.81 (m, 2H), 3.75 - 3.66 (m, 1H), 3.63 - 3.56 (m, 1H), 3.53 - 3.47 (m, 1H), 3.45 - 3.39 (m, 1H), 3.26 - 3.19 (m, 1H), 3.16 - 3.11 (m, 1H), 3.07 - 2.91 (m, 2H), 2.29 (d, J = 2.8 Hz, 6H),. LCMS (ES, m / z): 445 [M+H] + .

[0136] Example 6 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyridin-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanone

[0137] [ka]

[0138] The target compound was prepared according to the method of Example 1, substituting 2-iodopyridine for the reactant 2-iodothiophene. 1 H NMR (400 MHz, Chloroform-d) δ 8.76 - 8.52 (m, 1H), 7.73 - 7.53 (m, 1H), 7.46 - 7.23 (m, 2H), 7.18 - 7.12 (m, 1H), 7.08- 6.91 (m, 3H), 6.53 (s, 1H), 3.52-3.11(m, 8H), 3.07 - 2.91 (m, 2H), 2.29 (d, J = 2.8 Hz, 6H),. LCMS (ES, m / z): 440 [M+H] + .

[0139] Example 7 (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methylfurano[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0140] [ka]

[0141] 7.1 Preparation of 2-chloro-4-methylfurano[3,2-d]pyrimidine 2,4-Dichlorofurano[3,2-d]pyrimidine (3.0 g, 15.8 mmol), iron acetylacetonate (0.22 g, 0.9 mmol), and tetrahydrofuran (30 mL) were placed in a 100 mL round-bottom flask. Methylmagnesium chloride (3N, 10.5 mL, 31.6 mmol) was added dropwise at -78 °C. After the addition was complete, the mixture was stirred at this temperature for 1 h and then transferred to room temperature. After completion of the reaction was monitored by TLC, the reaction was quenched by adding 20 mL of water and extracted three times with ethyl acetate (30 mL × 3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 2.2 g of a white solid product.

[0142] 7.2 Preparation of 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-methylfurano[3,2-d]pyrimidine 2-Chloro-4-methylfurano[3,2-d]pyrimidine (0.25 g, 1.5 mmol), tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.42 g, 2.0 mmol), and N-methylpyrrolidone (2 mL) were placed in a 10 mL three-neck flask and reacted at 170°C in a microwave oven for 1.5 hours. After cooling to room temperature, the mixture was diluted with 10 mL of water and 10 mL of ethyl acetate, then filtered through diatomaceous earth, and the filtrate was extracted three times with ethyl acetate (20 mL x 3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered and concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain a pale yellow oily product. Dichloromethane was dissolved, and trifluoroacetic acid was added and reacted for 4 hours. The organic phase was washed with saturated sodium carbonate solution, dried, and the solvent was evaporated to dryness to obtain 0.11 g of a yellow oily product.

[0143] 7.3 Preparation of (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methylfurano[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone 2-(3-Fluoropyridin-2-yl)indolizine-1-carboxylic acid (0.38 g, 1.5 mmol) (Example 3), HATU (0.76 g, 2.0 mmol), DIEA (0.39 g, 3.0 mmol), and dichloromethane (20 mL) were placed in a 100 mL round-bottom flask and stirred at room temperature for 20 minutes. 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-methylfurano[3,2-d]pyrimidine (0.29 g, 1.2 mmol) was added in portions and the mixture was stirred overnight at room temperature. After completion of the reaction was monitored by TLC, the reaction mixture was directly concentrated and then separated by column chromatography (methanol / dichloromethane = 1:30) to give 0.45 g of product. 1 H NMR (400 MHz, Chloroform-d) δ8.51 (dd, J = 14.9, 3.1 Hz, 1H), 8.36 (dd, J = 14.9, 3.1 Hz, 1H), 7.77 - 7.54 (m, 2H), 7.52 - 7.34 (m, 4H), 7.24 (d, J = 14.9 Hz, 1H), 6.72-6.38 (m, 1H), 4.12 (q, J = 7.1 Hz, 1H), 4.04 - 3.88 (m, 2H), 3.76 (ddd, J = 24.6, 13.2, 5.3 Hz, 2H), 3.70 - 3.55 (m, 2H), 3.27 (td, J = 10.6, 5.2 Hz, 1H), 3.20 - 2.96 (m, 2H), 2.58 (s, 3H);. LCMS (ES, m / z): 483 [M+H] + .

[0144] Example 8 (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methylpyrrolo[2,1-f][1,2,4]triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0145] [ka]

[0146] The target compound was prepared according to the method of Example 7, substituting 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine for the reactant 2,4-dichlorofurano[3,2-d]pyrimidine. 1 H NMR (400 MHz, Chloroform-d) δ 8.44 (dd, J = 14.9, 3.1 Hz, 1H), 8.31 (dd, J = 14.9, 3.1 Hz, 1H), 7.74 - 7.55 (m, 2H), 7.51 - 7.31 (m, 4H), 6.72-6.64 (m, 1H), 6.57 (t, J = 7.5 Hz, 1H), 6.36 (dd, J= 7.5, 1.5 Hz, 1H), 4.29 - 4.03 (m, 2H), 3.93 - 3.61 (m, 4H), 3.57 - 3.23 (m, 2H), 2.89 - 2.57 (m, 5H). LCMS (ES, m / z): 482 [M+H] + .

[0147] Example 9 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(thiazol-2-yl)indolizin-1-yl)methanone

[0148] [ka]

[0149] The target compound was prepared according to the method of Example 1, substituting 2-acetylthiazole for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 7.0 Hz, 1H), 7.82 - 7.72 (m, 2H), 7.43 (d, J = 9.1 Hz, 1H), 7.22 (d, J = 3.2 Hz, 1H), 6.81 (m, 1H), 6.60 (t, J = 6.7 Hz, 1H), 6.29 (s, 1H), 3.96 (d, J= 57.8 Hz, 2H), 3.69 (d, J = 58.0 Hz, 3H), 3.44 (s, 2H), 3.07 (d, J= 35.3 Hz, 2H), 2.88 (s, 1H), 2.31 (s, 6H). LCMS (ES, m / z): 445[M+H] + .

[0150] Example 10 (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(quinoxalin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0151] [ka]

[0152] The target compound was prepared according to the method of Example 7, substituting 2-chloroquinoxaline for the reactant 2,4-dichlorofurano[3,2-d]pyrimidine. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 4.6 Hz, 1H), 8.31 (s, 1H), 7.91 (t, J = 6.8 Hz, 2H), 7.78 (d, J = 2.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.49 - 7.36 (m, 2H), 7.33 (t, J = 9.5 Hz, 1H), 6.94 (s, 1H), 6.78 (m, 1H), 6.57 (t, J = 6.7 Hz, 1H), 4.06 - 3.40 (m, 8H), 3.14 (s, 2H). LCMS (ES, m / z): 479[M+H] + .

[0153] Example 11 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)indolizin-1-yl)methanone

[0154] [ka]

[0155] The target compound was prepared according to the method of Example 1, substituting 2-acetyl-3-trifluoromethylpyridine for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3): δ 8.83 (d, J = 4.8 Hz, 1H), 7.98 (t, J = 6.4 Hz, 2H), 7.55 (d, J= 8.7 Hz, 2H), 7.23 (dd, J = 8.0, 4.8 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.65 (t, J = 6.7 Hz, 1H), 6.36 (s, 1H), 3.77 (s, 4H), 3.49 (dd, J = 11.6, 3.8 Hz, 4H), 2.95 (s, 2H), 2.37 (s, 6H). LCMS (ES, m / z): 507[M+H] + .

[0156] Example 12 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanone

[0157] [ka]

[0158] The target compound was prepared according to the method of Example 5, substituting iodobenzene for the reactant 2-iodothiophene and 1-aminoiodopyridine for 1-aminoiodopyrimidine. 1 H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 7.0, 1.7 Hz, 1H), 8.63 - 8.56 (m, 1H), 7.92 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.5 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 6.95 (m, 1H), 6.34 (s, 1H), 4.12 (m, 1H), 3.90 (m, 1H), 3.79 (m, 1H), 3.71 (m, 1H), 3.60 (m, 2H), 3.37 (m, 1H), 3.18 (m, 1H), 3.13 - 3.02 (m, 1H), 2.92 (m, 1H), 2.34 (s, 6H). LCMS (ES, m / z): 440[M+H] + .

[0159] Example 13 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylpyrazolo[1,5-a]pyrazin-3-yl)methanone

[0160] [ka]

[0161] The target compound was prepared according to the method of Example 5, substituting iodobenzene for the reactant 2-iodothiophene and 1-aminoiodopyrazine for 1-aminoiodopyridine. 1 H NMR (400 MHz, CDCl3) δ 9.18 (s, 1H), 8.39 (d, J= 4.7 Hz, 1H), 7.98 (d, J = 4.7 Hz, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.40 (t, J = 7.6 Hz, 2H), 7.31 - 7.18 (m, 1H), 6.30 (s, 1H), 3.96 (dd, J = 12.7, 7.6 Hz, 1H), 3.78 (ddd, J = 17.1, 12.2, 6.1 Hz, 2H), 3.56 (dd, J = 11.5, 7.2 Hz, 1H), 3.47 (dd, J = 11.6, LCMS (ES, m / z): 440[M+H] + .

[0162] Example 14 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylpyrazolo[1,5-b]pyridazin-3-yl)methanone

[0163] [ka]

[0164] The target compound was prepared according to the method of Example 5, substituting iodobenzene for the reactant 2-iodothiophene and 1-aminoiodopyridine for 1-aminoiodopyridazine. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 8.0 Hz, 2H), 7.40 (t, J = 8.0 Hz, 2H), 7.34 - 7.25 (m, 2H), 6.38 (s, 1H), 3.87 - 3.76 (m, 1H), 3.74 - 3.64 (m, 1H), 3.61 - 3.52 (m, 1H), 3.50 - 3.40 (m, 2H), 3.32 - 3.23(m, 1H), 3.15 - 3.06 (m, 1H), 3.01 - 2.90 (m, 1H), 2.88 - 2.72 (m, 2H), 2.20 (s, 6H). LCMS (ES, m / z): 440[M+H] + .

[0165] Example 15 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(2-fluorophenyl)indolizin-1-yl)methanone

[0166] [ka]

[0167] The target compound was prepared according to the method of Example 1, substituting 2-fluoroacetophenone for the reactant acetophenone. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 6.9 Hz, 1H), 7.60 (d, J = 9.1 Hz, 1H), 7.49 - 7.47 (m, 1H), 7.35 (s, 1H), 7.31 - 7.29 (m, 2H), 7.13 - 7.11 (m, 1H), 6.79 (m, 1H), 6.53 - 6.52 (m, 1H), 6.28 (s, 1H), 3.85 - 3.82 (m, 2H), 3.68 -3.14 (m, 5H), 2.83 -2.65 (m, 1H), 2.29 (s, 6H). LCMS (ES, m / z): 456[M+H] + .

[0168] Example 16 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(o-tolyl)indolizin-1-yl)methanone

[0169] [ka]

[0170] The target compound was prepared according to the method of Example 1, substituting 2-methylacetophenone for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3) δ 7.86 (d, J = 6.9 Hz, 1H), 7.63 (d, J = 9.1 Hz, 1H), 7.44 - 7.42 (m, 2H), 7.30 (s, 1H), 7.30 (t, J= 7.6 Hz, 2H), 7.11 (d, J = 7.6 Hz, 1H), 6.81 (m, 1H), 6.57 (t, J= 6.8 Hz, 1H), 6.28 (s, 1H), 3.84 (d, J = 51.0 Hz, 2H), 3.62 - 3.20 (m, 5H), 2.79 - 2.61 (m, 3H), 2.29 (s, 6H), 2.17 (s, 3H). LCMS (ES, m / z): 452[M+H] + .

[0171] Example 17 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(thiophen-3-yl)indolizin-1-yl)methanone

[0172] [ka]

[0173] The target compound was prepared according to the method of Example 1, substituting 3-acetylthiophene for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 6.6 Hz, 1H), 7.64 (s, 1H), 7.53 (d, J = 9.1 Hz, 1H), 7.30 (s, 1H), 7.18 - 7.15 (m, 2H), 6.73 - 6.69 LCMS (ES, m / z): 443[M+H] + .

[0174] Example 18 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(3-fluoropyridin-2-yl)indolizin-1-yl)methanone

[0175] [ka]

[0176] The target compound was prepared according to the method of Example 1, substituting 2-acetyl-3-fluoropyridine for the reactant acetophenone and ethyl 2-pyridineacetate with ethyl 2-(5-fluoropyridin-2-yl)acetate. 1 H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 4.4 Hz, 1H), 7.85 (t, J = 3.1 Hz, 1H), 7.78 (s, 1H), 7.48 - 7.30 (m, 2H), 7.04 (d, J= 7.5 Hz, 1H), 6.71 (t, J = 9.0 Hz, 1H), 6.28 (s, 1H), 3.97 - 3.62 (m, 5H), 3.42 - 2.86 (m, 5H), 2.29 (s, 6H). LCMS (ES, m / z): 475[M+H] + .

[0177] Example 19 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(pyridin-2-yl)indolizin-1-yl)methanone

[0178] [ka]

[0179] The target compound was prepared according to the method of Example 1, substituting 2-acetylpyridine for the reactant acetophenone and ethyl 2-pyridineacetate with ethyl 2-(5-fluoropyridin-2-yl)acetate. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 4.4 Hz, 1H), 7.79 -7.75 (m, 2H), 7.71 (s, 1H), 7.48 - 7.30 (m, 2H), 7.04 (d, J = 7.5 Hz, 1H), 6.76 - 6.71 (m, 1H), 6.28 (s, 1H), 3.95 - 3.67 (m, 5H), 3.46 - 2.81 (m, 5H), 2.34 (s, 6H). LCMS (ES, m / z): 457[M+H] + .

[0180] Example 20 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(oxazol-2-yl)indolizin-1-yl)methanone

[0181] [ka]

[0182] The target compound was prepared according to the method of Example 1, substituting oxazole-2-ethanone for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 6.7 Hz, 1H), 7.86 - 7.78 (m, 2H), 7.43 (s, 1H), 7.27 (d, J = 3.2 Hz, 1H), 6.83 (m, 1H), 6.63 - 6.61 LCMS (ES, m / z): 429[M+H] + .

[0183] Example 21 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyrimidin-2-yl)indolizin-1-yl)methanone

[0184] [ka]

[0185] The target compound was prepared according to the method of Example 1, substituting 2-acetylpyrimidine for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3) δ 8.41 (d, J = 4.3 Hz, 1H), 7.94 (d, J = 6.6 Hz, 1H), 7.78 - 7.73 (m, 2H), 7.37 (m, 1H), 7.05 (m, 1H), 6.79 -6.77 LCMS (ES, m / z): 440[M+H] + .

[0186] Example 22 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(5-methylthiazol-2-yl)indolizin-1-yl)methanone

[0187] [ka]

[0188] The target compound was prepared according to the method of Example 1, substituting 2-acetyl-5-methylthiazole for the reactant acetophenone. 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J = 6.9 Hz, 1H), 7.76 - 7.72 (m, 2H), 7.43 (d, J = 9.1 Hz, 1H), 6.81 (m, 1H), 6.60 (t, J = 6.7 Hz, 1H), 6.29 (s, 1H), 3.96 (d, J= 57.8 Hz, 2H), 3.63 - 3.48 (m, 4H), 3.11 - 2.93 (m, 4H), 2.46 (s, 3H), 2.34 (s, 6H). LCMS (ES, m / z): 459[M+H] + .

[0189] Example 23 ((3aR,6aS)-5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(3-fluoropyridin-2-yl)indolizin-1-yl)methanone

[0190] [ka]

[0191] The target compound was prepared according to the method of Example 7, substituting 2,4,6-trichloro-5-fluoropyrimidine for the reactant 2,4-dichlorofurano[3,2-d]pyrimidine. 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 4.7 Hz, 1H), 7.89 (d, J = 6.6 Hz, 1H), 7.73 (d, J= 2.4 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.33 (m, 1H), 7.05 (m, 1H), 6.78 - 6.76 (m, 1H), 6.57 - 6.55 (m, 1H), 3.91 - 3.74 (m, 5H), 3.56 - 3.02 (m, 5H), 2.28 (s, 6H). LCMS (ES, m / z): 475[M+H] + .

[0192] Example 24 ((3aR,6aS)-5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyridin-2-yl)indolizin-1-yl)methanone

[0193] [ka]

[0194] The target compound was prepared according to the method of Example 7, substituting 2-(3-fluoropyridin-2-yl)indolizine-1-carboxylic acid for the reactant 2-(pyridin-2-yl)indolizine-1-carboxylic acid and 2,4-dichlorofurano[3,2-d]pyrimidine for 2,4,6-trichloro-5-fluoropyrimidine. 1 H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 4.8 Hz, 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.79 (s, 1H), 7.67 - 7.55 (m, 2H), 7.48 (d, J= 9.1 Hz, 1H), 7.03 (s, 1H), 6.80 - 6.78 (m, 1H), 6.55 - 6.53 (m, 1H), 3.97 - 3.80 (m, 3H), 3.55- 3.31 (m, 4H), 2.97 - 2.79 (m, 3H), 2.31 (s, 6H). LCMS (ES, m / z): 457[M+H] + .

[0195] Example 25 (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methylthieno[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0196] [ka]

[0197] The target compound was prepared according to the method of Example 7, substituting 2,4-dichlorothieno[3,2-d]pyrimidine for the reactant 2,4-dichlorofurano[3,2-d]pyrimidine. 1 H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 4.6 Hz, 1H), 7.90 (d, J = 7.0 Hz, 1H), 7.77 (d, J= 2.4 Hz, 1H), 7.72 (m, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.28 - 7.19 (m, 1H), 6.96 (s, 1H), 6.75 (m, 1H), 6.55 (t, J = 6.7 Hz, 1H), 3.94 - 3.81 (s, 3H), 3.69 - 3.49 (m, 4H), 3.09 - 2.91 (m, 3H), 2.61 (s, 3H). LCMS (ES, m / z): 499[M+H] + .

[0198] Example 26 (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0199] [ka]

[0200] The target compound was prepared according to the method of Example 7, substituting 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine for the reactant 2,4-dichlorofurano[3,2-d]pyrimidine. 1H NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.3 Hz, 1H), 7.97 (d, J = 6.4 Hz, 1H), 7.80 (d, J = 2.4 Hz, 1H), 7.53 (d, J= 8.9 Hz, 1H), 7.38 - 7. 36 (m, 1H), 7.07 - 7.10 (m, 1H), 6.81 - 6.78 (m, 1H), 6.56 (t, J = 6.7 Hz, 1H), 3.92-3.66 (m, 5H), 3.47 - 3.22 (m, 4H), 3.09 - 2.68 (m, 7H), 2.26 (s, 3H).LCMS (ES, m / z): 483[M+H] + .

[0201] Example 27 ((3aR,6aS)-5-(3,6-dimethylpyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(3-fluoropyridin-2-yl)indolizin-1-yl)methanone

[0202] [ka]

[0203] The target compound was prepared according to the method of Example 7, substituting 3-chloro-2,5-dimethylpyrazine for the reactant 2-chloro-4-methylfurano[3,2-d]pyrimidine. 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 4.8 Hz, 1H), 7.96 (d, J = 6.9 Hz, 1H), 7.84 (d, J = 2.4 Hz, 1H), 7.47 - 7.42 (m, 2H), 7.38 - 7.35 (m, 1H), 7.07 - 7.03(m, 1H), 6.79 - 6.67 (m, 1H), 6.52 (t, J = 6.7 Hz, 1H), 3.87 - 3.63 (m, 5H), 3.43 - 2.81 (m, 5H), 2.43 (s, 3H), 2.31 (s, 3H). LCMS (ES, m / z): 457[M+H] + .

[0204] Example 28 (3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(thiophen-2-yl)indolizin-1-yl)methanone

[0205] [ka]

[0206] The target compound was prepared according to the method of Example 1, substituting 2-acetylthiophene for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 6.9 Hz, 1H), 7.50 (d, J = 9.1 Hz, 1H), 7.39 (s, 1H), 7.14 (m, 2H), 6.95 (t, J = 4.4 Hz, 1H), 6.79 (m, 1H), 6.56 (t, J= 6.7 Hz, 1H), 6.29 (s, 1H), 3.91 (d, J = 48.6 Hz, 2H), 3.78 - 3.43 (m, 3H), 3.32 (s, 2H), 2.97 (s, 2H), 2.78 (s, 1H), 2.30 (s, 6H). LCMS (ES, m / z): 444[M+H] + .

[0207] Example 29 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyrimidin-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanone

[0208] [ka]

[0209] The target compound was prepared according to the method of Example 5, substituting 2-iodopyrimidine for the reactant 2-iodothiophene. 1 H NMR (400 MHz, Chloroform-d): δ 8.74 (d, J = 4.7 Hz, 1H), 8.55 (d, J = 7.0 Hz, 2H), 8.04 (d, J = 7.9 Hz, 1H), 7.30 - 7.10 (m, 2H), 6.92 - 6.90 (m, 1H), 6.33 (s, 1H), 4.05 - 3.89 (m, 3H), 3.68 (dd, J = 11.7, 6.1 Hz, 2H), 3.52 - 3.39 (m, 2H), 3.18 - 2.90 (m, 3H), 2.32 (s, 6H). LCMS (ES, m / z): 441[M+H] + .

[0210] Example 30 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(pyridin-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanone

[0211] [ka]

[0212] The target compound was prepared according to the method of Example 5, substituting 1-aminoiodo-3-fluoropyridine for the reactant 1-aminoiodopyridine.1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 4.6 Hz, 1H), 8.37 (d, J = 6.9 Hz, 1H), 8.17 - 7.95 (m, 1H), 7.81 - 7.78 (m, 1H), 7.21 - 7.18 (m, 1H), 7.02 - 6.70 (m, 2H), 6.34 (s, 1H), 3.95 - 3.91 (m, 2H), 3.85 - 3.52 (m, 6H), 3.23 - 3.05 (m, 2H), 2.46 (s, 6H). LCMS (ES, m / z): 458[M+H] + .

[0213] Example 31 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-methyl-2-(pyridin-2-yl)pyrazolo[1,5-a]pyridin-3-yl)methanone

[0214] [ka]

[0215] The target compound was prepared according to the method of Example 5, substituting 1-aminoiodo-3-methylpyridine for the reactant 1-aminoiodopyridine. 1 H NMR (400 MHz, CDCl3) δ 8.61 (d, J = 4.9 Hz, 1H), 8.32 (d, J = 6.7 Hz, 1H), 8.11 - 7.89 (m, 1H), 7.68 - 7.63 (m, 1H), 7.16 - 7.14 (m, 1H), 7.06 - 6.78 (m, 2H), 6.31 (s, 1H), 3.91 - 3.88 (m, 2H), 3.81 - 3.41 (m, 6H), 3.21 - 3.01 (m, 2H), 2.41 (s, 6H). LCMS (ES, m / z): 458[M+H] + .

[0216] Example 32 (5-(4,6-Dimethoxypyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(3-fluoropyridin-2-yl)indolizin-1-yl)methanone

[0217] [ka]

[0218] The target compound was prepared according to the method of Example 7, substituting 2-chloro-4-methylfurano[3,2-d]pyrimidine for the reactant 2-chloro-4,6-dimethoxypyrimidine. 1 H NMR (400 MHz, CDCl3) δ 8.48 (d, J = 4.4 Hz, 1H), 7.95 (d, J = 6.7 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.44 (d, J= 9.1 Hz, 1H), 7.40 - 7.78 (m, 1H), 7.11 - 7.08 (m, 1H), 6.77 (dd, J = 9.1, 6.5 Hz, 1H), 6.56 (t, J = 6.7 Hz, 1H), 6.06 (s, 1H), 4.06 - 3.73 (m, 9H), 3.62 - 3.41 (m, 5H), 3.07 - 2.83 (m, 3H). LCMS (ES, m / z): 489[M+H] + .

[0219] Example 33 (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylimidazo[1,2-b]pyridazin-3-yl)methanone

[0220] [ka]

[0221] 33.1 Preparation of ethyl 2-phenylimidazo[1,2-b]pyridazine-3-carboxylate Ethyl 2-bromo-3-oxo-3-phenylpropionate (2 g, 7.38 mmol) and pyridazin-3-amine (0.74 g, 7.75 mmol) were dissolved in 10 mL of ethanol and reacted in a microwave oven. The temperature was raised to 150°C and the reaction was continued for 6 hours. Upon completion of the reaction, the temperature was lowered to room temperature, the solvent was removed under reduced pressure, and the mixture was purified by column chromatography (PE:EA=10:1) to obtain 0.6 g of the product.

[0222] 33.2 Preparation of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid Ethyl 2-phenylimidazo[1,2-b]pyridazine-3-carboxylate (0.6 g, 2.24 mmol) and sodium hydroxide (0.18 g, 4.48 mmol) were added to 5 mL of water, and 2 mL of ethanol was added. The mixture was heated to 75°C and reacted for 1 hour. Upon completion of the reaction, the mixture was cooled to room temperature, the ethanol was removed under reduced pressure, the pH was adjusted to 1 with 1 M HCl solution, the mixture was filtered, and the filter cake was dried to obtain 0.42 g, which was directly used in the next reaction without further purification.

[0223] 33.3 Preparation of (5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylimidazo[1,2-b]pyridazin-3-yl)methanone 2-Phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (0.4 g, 1.67 mmol), HATU (1.27 g, 3.34 mmol), EtN (0.3 g, 2.97 mmol), and acetonitrile (10 mL) were added to a 50 mL single-neck round-bottom flask in an ice bath and allowed to react for 10 min. 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (0.4 g, 1.84 mmol) was added and the reaction mixture was allowed to react at room temperature for 2 h. After completion of the reaction was confirmed by TLC, 30 mL of water was added, and the mixture was extracted with 3 x 30 mL of DCM, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography with DCM / MeOH (20 / 1) to give 0.3 g of product. 1 H NMR (400 MHz, CDCl3) δ 8.63 - 8.61 (m, 1H), 8.07 (dd, J = 9.1, 1.7 Hz, 1H), 7.88 - 7.74 (m, 2H), 7.52 - 7.41 (m, 2H), 7.28 - 7.23 (m, LCMS (ES, m / z): 458[M+H] + .

[0224] Example 34 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyridin-4-yl)pyrazolo[1,5-a]pyridin-3-yl)methanone

[0225] [ka]

[0226] The target compound was prepared according to the method of Example 5, substituting 4-iodopyridine for the reactant 2-iodothiazole. 1H NMR (400 MHz, CDCl3): δ 8.71 (d, J = 4.9 Hz, 1H), 8.23 ​​- 8.14 (m, 2H), 7.74 - 7.61 (m, 2H), 7.32 - 7.11 (m, 2H), 6.90 (td, J= 6.9, 1.3 Hz, 1H), 6.33 (s, 1H), 3.95 - 3.81 (m, 3H), 3.62 - 3.35 (m, 4H), 3.18 - 2.95 (m, 3H), 2.31 (s, 6H). LCMS (ES, m / z): 440[M+H] + .

[0227] Example 35 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-methyl-2-(pyridin-2-yl)indolizin-1-yl)methanone

[0228] [ka]

[0229] The target compound was prepared according to the method of Example 1, substituting 2-propionylpyridine for the reactant acetophenone. 1 H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 4.9 Hz, 1H), 7.92 (d, J = 6.9 Hz, 1H), 7.67 - 7.55 (m, 2H), 7.48 (d, J = 9.1 Hz, 1H), 7.05 - 7.01 (m, 1H), 6.79 - 6.69 (m, 1H), 6.57 (t, J = 6.7 Hz, 1H), 6.29 (s, 1H), 3.95 - 3.76 (m, 3H), 3.53 - 3.28 (m, 4H), 2.93 - 2.73 (m, 3H), 2.48 (s, 3H), 2.30 (s, 6H). LCMS (ES, m / z): 453[M+H] + .

[0230] Example 36 [(3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl][2-(pyridin-3-yl)pyrazolo[1,5-a]pyridin-3-yl]methanone

[0231] [ka]

[0232] The target compound was prepared according to the method of Example 5, substituting 3-iodopyridine for the reactant 2-iodothiophene. 1 H NMR (400 MHz, DMSO-d6) δ 8.94 (s, 1H), 8.83 (d, J = 6.9 Hz, 1H), 8.52 (d, J = 4.7 Hz, 1H), 8.16 - 8.03 (m, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.48 - 7.30 (m, 2H), 7.07 (t, J = 7.0 Hz, 1H), 6.40 (s, 1H), 3.83 - 3.40 (m, 6H), 3.17 - 2.85 (m, 4H), 2.22 (s, 6H). LCMS (ES, m / z): 440[M+H] + .

[0233] Example 37 [(3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl][6-fluoro-2-(thiophen-2-yl)pyrazolo[1,5-a]pyridin-3-yl]methanone

[0234] [ka]

[0235] The target compound was prepared according to the method of Example 5, substituting 1-aminoiodo-3-fluoropyridine for the reactant 1-aminoiodopyridine. 1H NMR (400 MHz, DMSO-d6) δ 8.46 - 8.39 (m, 2H), 7.54 - 7.26 (m, 2H), 7.22 - 7.07 (m, 1H), 6.93 - 6.82 (m, 1H), 6.85 - 6.61 (m, 1H), 6.41 (s, 1H), 4.01 - 3.85 (m, 2H), 3.75 - 3.56 (m, 2H), 3.53 -3.39 (m, 2H), 3.26 - 3.11 (m, 2H), 3.07 - 2.91 (m, 2H), 2.27 (s, 6H). LCMS (ES, m / z): 463[M+H] + .

[0236] Pharmacological test examples: Test Example 1 Inhydro Activity Test (1) Preparation of reaction buffer (1x Stimulation buffer) required for the experiment: The 5x Stimulation buffer in the Cisbio IP-one reagent kit was diluted with ddH2O at a ratio of 1:4 and prepared for use.

[0237] (2) Compound preparation: Compounds were diluted to 5 mM stock solution with DMSO, then diluted 3.16 times to a 10-fold gradient, and then diluted to the corresponding concentration (4x) with stimulation buffer for use.

[0238] (3) Cell preparation: CHO-K1-OX1 and CHO-K1-OX2 cells in culture dishes were digested with pancreatin, eluted with culture medium, and collected in a 5 mL centrifuge tube. The cells were centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 3 mL of PBS was added and mixed evenly by gently blowing with a pipette. The cells were centrifuged again at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1x stimulation buffer and counted using a Countstar cell counter. The cell density was found to be 1.71 x 10 6 The concentration was adjusted to 1 / mL and prepared for use.

[0239] (4) Addition of cells: The cell suspension was added to the experimental plate at 7 μL / well (i.e., approximately 12,000 cells / well).

[0240] (5) Addition of compounds: Compounds diluted with stimulation buffer were added to the above experimental plate at 3.5 μL / well.

[0241] (6) Reaction incubation: After gentle shaking, the experimental plate was incubated at 37°C for 30 minutes.

[0242] (7)EC 80 Addition of agonist:EC 80 4× Orexin A (OX1 receptor) and 4× Orexin 2 receptor agonist (OX2 receptor) solutions were added at 3.5 μL / well.

[0243] (8) Reaction incubation: After gentle shaking, the experimental plate was incubated at 37°C for 45 minutes.

[0244] (9) Addition of detection reagent: IP1-d2 and Anti-IP1 cryptate were diluted 1:20 using the lysis and detection buffer provided in the Cisbio IP-one detection reagent kit, and 3 μL of each diluted IP1-d2 and Anti-IP1 cryptate were added to the experimental plate. After shaking, the experimental plate was left at room temperature for 60 minutes.

[0245] (10) Reading of experimental values: The plate was read on Envision, the readings of the 665 nm and 615 nm channels were detected, and the ratio of the 665 nm / 615 nm readings was calculated.

[0246] Based on the antagonistic effect values ​​for different concentration test points of the compound samples, the antagonism curves of the compound samples on the orexin receptor were fitted using GraphPad Prism software, and the IC 50 was calculated, and the results are shown in Table 1:

[0247] [Table 1]

[0248] The data show that the compounds of the present invention have good inhibitory activity against OX2 receptor, and the inhibitory effect of the compounds against OX2 receptor is significantly better than that against OX1 receptor, showing good selectivity.

[0249] Test Example 2 Measurement of pharmacokinetic parameters of test substance in rat plasma Healthy male SD rats aged 6-9 weeks were selected and randomly divided into two groups of three. One group received 1 mg / kg of the test compound via intravenous injection, while the other group received 10 mg / kg of the test compound via oral gavage. Whole blood samples were collected from both the intravenous and oral gavage groups before and at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, 10.0, and 24.0 hours post-dose, and plasma samples were obtained by centrifugation.

[0250] LC-MS / MS method, WinNonlin TM Quantitative analysis was performed on all biological samples using Version 7.0 (Pharsight, Mountain View, CA) pharmacokinetic software, and relevant drug kinetic parameters were calculated using the non-compartmental linear-logarithmic trapezoidal method. AUC 0-last represents the area under the plasma concentration-time curve from time zero to the last detectable concentration time point, PO represents oral, iv represents intravenous, and C max represents the peak concentration and F% represents the oral bioavailability. The results are shown in Table 2:

[0251] [Table 2]

[0252] The data showed that in rat pharmacokinetic evaluation experiments, the compounds of the examples of the present invention exhibited good in vivo exposure and good bioavailability after administration.

[0253] Test Example 3 Spontaneous activity of mice Male ICR mice aged 6 to 9 weeks were randomly assigned to groups of 8 or 9 mice based on weight balance and administered either a blank vehicle or 10, 30, or 100 mg / kg of test compound. The animals were immediately placed in the test box after administration, and the animal's activity distance within 60 minutes was recorded and analyzed using TopScan Version 3.0. The total activity distance of animals in each test compound group was compared with that of the blank vehicle group to determine whether the test compound significantly affected the animals' spontaneous activity. Experimental data are presented as mean ± standard error (mean ± SD). One-way analysis of variance was performed using SPSS 21.0 statistical software. Pairwise comparisons were performed using Dunnett's test. * indicates a difference when p<0.05.

[0254] [Table 3]

[0255] Conclusion: The compounds of the present invention can significantly reduce the spontaneous activity distance of mice.

[0256] Test Example 4 Pentobarbital sodium synergistic sleep test Male ICR mice aged 6 to 9 weeks were randomly assigned to groups of eight mice each according to the weight balance principle. They were administered either a blank vehicle or 3, 10, or 30 mg / kg of test compound. Five minutes later, 45 mg / kg of pentobarbital sodium was intraperitoneally injected. The time points at which the mice lost their righting reflex and regained their righting reflex were recorded. Sleep latency = time point at which the righting reflex was lost minus time point at which pentobarbital sodium was administered, and sleep duration = time point at which the righting reflex was regained minus time point at which the righting reflex was lost. The sleep latency and sleep maintenance times of each test compound group were compared with those of the blank vehicle group to determine whether the test compound significantly affected the animals' sleep latency and sleep duration. Experimental data are presented as mean ± standard error (mean ± SD). One-way analysis of variance was performed using SPSS 21.0 statistical software. Pairwise comparisons were performed using Dunnett's test. Pairwise comparisons were indicated by * when p<0.05.

[0257] [Table 4]

[0258] Conclusion: The compounds of the present invention can shorten the sleep latency period and prolong the sleep duration in mice.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, 【Chemistry 1】 where R 1 , R 2 , R 3 , R 4 , R 5 is absent or independently H, halogen, C 1 ~C 8 Straight or branched chain alkyl group, C 1 ~C 8 selected from alkoxy groups, Alternatively, R and R 2 is C 3 ~C 8 forming a cycloalkyl group, a 6- to 10-membered monocyclic aryl group, or a 5- to 10-membered monocyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C; 【Chemistry 2】 is a single or double bond, R 6 is selected from formula II, formula III and formula IV, 【Transformation 3】 R 9 is an optionally substituted 5- to 10-membered monocyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 6- to 10-membered monocyclic aromatic ring group, the substituents being selected from halogen, C 1 -C 8 straight or branched chain alkyl groups, C 1 -C 8 alkoxy groups, and haloalkyl groups; In Formula II, Z is selected from C, N, R 7 H, halogen, C 1 ~C 8 selected from linear or branched alkyl groups, R 8 is absent or independently H, halogen, C 1 ~C 8 selected from linear or branched alkyl groups, In formula IV, A, B, and M are independently selected from CH and N, and A, B, and M are not simultaneously CH; A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

2. Said C 1 ~C 8 The straight or branched chain alkyl group is C 1 ~C 5 selected from linear or branched alkyl groups, and / or Said C 1 ~C 8 The alkoxy group is C 1 ~C 5 alkoxy groups, and / or Said C 3 ~C 8 The cycloalkyl group is C 3 ~C 6 selected from cycloalkyl groups, 2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

3. the halogen is fluorine, chlorine, bromine, iodine, and / or Said C 1 ~C 5 the linear or branched alkyl group is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and / or Said C 1 ~C 5 the alkoxy groups are selected from methoxy, ethoxy, propoxy, butoxy, pentoxy groups, and / or Said C 3 ~C 6 the cycloalkyl group is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and / or the heteroaryl group is selected from pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazole, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyrazinyl, triazazolyl, and / or The haloalkyl group is selected from a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a fluoroethyl group, a difluoroethyl group, and a trifluoroethyl group.

3. A compound of formula I according to claim 2, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

4. The compound of formula I is as shown in formula V: 【Chemistry 4】 where R 1 , R 2 , R 3 , R 4 , R 5 is absent or is independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Or, R 1 and R 2 is C 3 ~C 6 forming a cycloalkyl group, a 6- to 10-membered monocyclic aryl group, or a 5- to 10-membered monocyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C; 【Transformation 5】 is a single or double bond, Z is selected from C and N; R 7 is selected from H, fluorine, chlorine, a methyl group, an ethyl group, a propyl group, and an isopropyl group; R 8 is absent or is independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, and isopropyl; R 9 is an optionally substituted 5- to 10-membered monocyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 6- to 10-membered monocyclic aromatic ring group, wherein the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl; 2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

5. R 1 , R 2 , R 3 , R 4 , and R 5 are absent or independently selected from H, halogen, C 1 to C 8 straight or branched chain alkyl groups, and C 1 to C 8 alkoxy groups; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C; 【Transformation 6】 is a double bond, R 6 is of formula II, 【Transformation 7】 R 9 is an optionally substituted 5- to 10-membered monocyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen or sulfur, or an optionally substituted 6- to 10-membered monocyclic aromatic ring group, the substituents being selected from halogen, C 1 -C 8 straight or branched chain alkyl groups, C 1 -C 8 alkoxy groups, and C 1 -C 8 haloalkyl groups; In Formula II, Z is N; R 7 is selected from H, halogen, C 1 -C 8 straight or branched chain alkyl groups; R 8 is absent, 2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

6. The compound of formula V is as shown in formula V-1: 【Transformation 8】 where R 1 , R 2 , R 3 are independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Or, R 1 and R 2 is C 3 ~C 6 forming a cycloalkyl group, a 6- to 10-membered monocyclic aryl group, or a 5- to 10-membered monocyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Z is selected from C and N; R 7 is selected from H, fluorine, chlorine, a methyl group, an ethyl group, a propyl group, and an isopropyl group; R 8 is absent or is independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, and isopropyl; R 9 is an optionally substituted 5- to 10-membered monocyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 6- to 10-membered monocyclic aromatic ring group, wherein the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl; 5. A compound of formula I according to claim 4, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

7. The compound of formula I is as shown in formula VI: 【Chemistry 9】 where R 1 , R 2 , R 3 , R 4 , R 5 is absent or is independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Or, R 1 and R 2 is C 3 ~C 6 forming a cycloalkyl group, a 6- to 10-membered monocyclic aryl group, or a 5- to 10-membered monocyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C; 【Chemistry 10】 is a single or double bond, R 9 is an optionally substituted 5- to 10-membered monocyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 6- to 10-membered monocyclic aromatic ring group, wherein the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl; 2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

8. The compound of formula I is as shown in formula VII: 【Chemistry 11】 where R 1 , R 2 , R 3 , R 4 , R 5 is absent or is independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; Or, R 1 and R 2 is C 3 ~C 6 forming a cycloalkyl group, a 6- to 10-membered monocyclic aryl group, or a 5- to 10-membered monocyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Q, W, Y, and U are independently selected from C and N, and Y and Q are not simultaneously C; 【Chemistry 12】 is a single or double bond, A, B, and M are selected from CH and N, and A, B, and M are not CH at the same time; R 9 is an optionally substituted 5- to 10-membered monocyclic heteroaryl group containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 6- to 10-membered monocyclic aromatic ring group, wherein the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl; 2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

9. The compound of formula I is selected from any one of the compounds shown below:

2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof. 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemistry 29】

10. 1. A pharmaceutical composition comprising:

10. A compound of formula I according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, optionally further comprising a pharmaceutically acceptable carrier or a combination thereof. A pharmaceutical composition comprising:

11. 1. A pharmaceutical composition comprising:

11. The pharmaceutical composition according to claim 10, wherein the pharmaceutical composition is used to treat a disease associated with an orexin receptor.

12. 12. The pharmaceutical composition according to claim 11, wherein the orexin receptor-associated disease is a sleep disorder, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neurological disorder, depressive neurological disorder, anxiety neurological disorder, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, headache, migraine, or pain.

13. 12. The pharmaceutical composition according to claim 11, wherein the orexin receptor-associated disease is a sleep disorder.

14. Use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof in the manufacture of a medicament, wherein the medicament is used to treat a disease associated with an orexin receptor. use.

15. The orexin receptor-associated diseases are sleep disorders, depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, affective neurological disorders, depressive neurological disorders, anxiety neurological disorders, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorders, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive disorders, Alzheimer's disease, Parkinson's disease, movement disorders, eating disorders, headache, migraine, and pain.

15. The use according to claim 14.

16. 15. The use according to claim 14, wherein the orexin receptor-related disease is a sleep disorder.

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