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

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 its pharma- ceutically acceptable salt, stereoisomer, tautomer, and composition comprising said compound, as well as its use in the pharmaceutical field. [Background technology]

[0002] Orexins (also called hypocretins or orexin peptides) are of two types: orexin-A (hypocretin-1) and orexin-B (hypocretin-2). Orexin peptide signaling is mediated by two receptors and two peptide agonists, and 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] Some evidence suggests that orexin-mediated arousal 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 obtained by observing a decrease in orexin content and a loss of orexigenic neurons in human patients with sleepiness (Mignot et al., 2001, The American Journal of Human Genetics, 68:686-699) or, in a very small number of cases, related to 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 related to various diseases such as 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, and pain.

[0005] Research indicates that disorders of the sleep-wake cycle may be targets of OX2R receptor modulator activity. Examples of disorders treated by antagonists or other modulators that downregulate OX2R-mediated processes include insomnia, restless legs syndrome, jet lag (insomnia) 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), and these brain regions are the main effect sites of orexin neurons in the LH associated with feeding, sleep, depression, anxiety, drug addiction and motivational behavior, 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 a compound having orexin receptor antagonist activity. The compound of the present invention has relatively good selectivity and pharmacological activity, and at the same time, has excellent physicochemical properties and pharmacokinetic properties, and therefore has 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. When the disclosure of this specification differs from the cited document, the disclosure of this specification shall prevail.

[0008] The present invention aims to provide a disubstituted octahydropyrrolo[3,4-c]pyrrole methyl ketone derivative or a pharma- ceutically acceptable salt, stereoisomer, tautomer, and 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; or 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 bond or a 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, 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 linear or branched 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 pharma- ceutically acceptable salt, stereoisomer, tautomer, and optionally further comprising a pharma- ceutically 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 pharma- ceutically 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-related 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 PREFERRED EMBODIMENTS

[0022] Unless otherwise specified or clearly contradictory in 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 contradiction, the definitions provided herein shall prevail. When a trade name appears in this specification, it is intended to refer to the corresponding product or its active ingredient. All patents, previously published patent applications, and publications cited in this specification 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, where valences on a given structure or group are allowed.

[0025] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position on the substituent. When a bond of a substituent is shown to penetrate a bond connecting two atoms in a ring, 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 specific substituent. Unless otherwise specified, a substituent may be substituted at each reasonable position of the group that is substitutable. When more than one position in a given structural formula is optionally substituted with one or more specific substituents, the substituents may be substituted with the same or different substituents 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, and may mean 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 of values ​​disclosed herein should be understood to mean each value and range encompassing the broader range. When any variable (e.g., R) and labeled variable (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) occurs more than once in a composition or structure of a compound, the definition at each occurrence is independent at every occurrence. For example, when a group is substituted with 0, 1, 2, 3 or 4 R substituents, the group may be optionally substituted with up to 4 R substituents, and the options of each R substituent at each occurrence are all independent of each other.

[0029] In each part of this specification, the substituents of the compounds disclosed in the present 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 of m to n and each point value therein, and each point value.

[0030] In the present invention, "*" means a connection point. For example,

[0031] [ka]

[0032] indicates that the substituent is linked 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 remainder 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 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, each of which is disclosed independently. 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, -CH2CH(CH3)2 ... (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 Examples of such groups include, but are not limited to, the following: (-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-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-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., and C2, C3, C4, C5, C6, C7, C8, etc. Also, for example, "C1-C5" or "C. 1-5 " should be understood to include the range of 1 to 5 carbon atoms, and any subscopes and point values ​​therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., and C1, C2, C3, C4, C5, etc. Also, for example, "C2-C5" or "C 2-5 " should be understood to include the range of 2 to 5 carbon atoms, and any subscopes and point values ​​therein, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., and C2, C3, C4, C5, etc. Also, for example, "C1-C8" or "C 1-8 The phrase "3-membered to 8-membered" should be understood to include the range of 1 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 C1, C2, C3, C4, C5, C6, C7, C8, etc. Also, for example, the phrase "3-membered to 8-membered" should be understood to include any subscopes and point values ​​therein, such as 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., and 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 the alkyl group has the meaning as defined in the present invention, 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 is a haloalkyl group, 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 group, iodine-substituted C 1-4 Specifically, fluorine-substituted C 1-4 Alkyl groups include -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CH2CH2CF3, -CH2CF2CHF2, 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 of the elements listed thereafter, which are independently selectable, and may include combinations of two or more elements.

[0037] The terms "comprises" and "including" 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 circumstances 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), including any oxidation state of nitrogen (N), sulfur (S), primary, secondary, tertiary amines and quaternary ammonium salts, or hydrogen substitutions on nitrogen atoms of heterocycles, 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 an aromatic ring of the aryl group. The term "aryl group" is used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups may include phenyl, naphthyl, anthracene, and the like. The aryl group is optionally substituted with one or more substituents as described herein.

[0041] The term "heteroaryl group" refers to a mono- 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., 5-6 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 5-10 membered monocyclic or bicyclic heteroaryl groups containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, including, but not limited to, pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazole, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, triazazolyl, and triazazolyl. The heteroaryl groups are optionally substituted with one or more substituents as described herein.

[0042] The term "heterocycle" is used interchangeably with "heterocyclyl group" and refers to a mono- or polyvalent monocyclic, bicyclic or tricyclic 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 in the present invention, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise stated, a heterocyclyl group may be a carbon or nitrogen group, and -CH2- groups may be optionally replaced by -C(=O)-. Sulfur atoms in the ring may be optionally oxidized to S-oxides. Nitrogen atoms in the ring may be optionally oxidized to N-oxides. Examples of heterocyclyl groups include 3-8 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, piperazinyl, and the like. Examples of heterocyclyl groups in which the -CH2- group is replaced by -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 as described herein.

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

[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 in the present invention. Unless otherwise specified, said alkoxy group contains 1 to 8 carbon atoms. In one embodiment, said alkoxy group contains 1 to 5 carbon atoms, and in another embodiment, said alkoxy group contains 1 to 3 carbon atoms. Said alkoxy group may be optionally substituted with one or more substituents as defined in the present invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, -OCH2CH2CH3), 2-propoxy (i-PrO, -OCH(CH3)2), 1-butoxy (n-BuO, -OCH2CH2CH2CH3), 2-l-propoxy (i-BuO, -OCH2CH(CH3)2), 2-butoxy (s-BuO, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, -OC(CH3)3), 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 be a monocyclic, condensed polycyclic, bridged or spiro ring structure. The cycloalkyl group may have 3 to 8 carbon atoms, i.e., a "C3 to C8 cycloalkyl group", such as a C6 cycloalkyl group, a C5 cycloalkyl group, a C4 cycloalkyl group, 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, a cyclohexyl group, and the like. The term also includes cases where a C atom therein may be substituted with an oxo (=O).

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

[0048] The term "tautomers" refers to structural isomers with different energies that are interconvertible by a low energy barrier. When tautomers are possible (e.g., in solution), chemical equilibrium of tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include intertransformations that are carried out by 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 significant irritating effect on an organism and does not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, a glidant, a sweetener, a diluent, a preservative, a dye / colorant, a flavoring agent, a surfactant, a wetting agent, a dispersant, a disintegrant, a stabilizer, a solvent, or an emulsifier.

[0051] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling 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 as may 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 pharma- ceutically 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 3-8 membered heterocycle, preferably R1 and R2 form a C3-C8 cycloalkyl group, a 6-10 membered monocyclic or bicyclic aryl group, a 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 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 bond or a 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 3-8 membered heterocycle, 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, preferably R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6-10 membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 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 linear or branched 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 a particularly preferred embodiment, R2 is halogen. In a specific embodiment, R2 is selected from H, fluorine, chlorine, bromine, and iodine. In a more specific embodiment, R2 is selected from H, fluorine, chlorine, and bromine. In a particularly specific embodiment, R2 is H. In another particularly specific embodiment, R2 is fluorine. In a further particularly specific embodiment, R2 is chlorine.

[0062] In one embodiment, R1 and R2 form a C3-C8 cycloalkyl group, an aryl group, a heteroaryl group, or a 3-8 membered heterocycle. In a preferred embodiment, R1 and R2 form a C3-C6 cycloalkyl group. In one embodiment, R1 and R2 form a C6-C 10In another preferred embodiment, R1 and R2 form a C3-C6 aryl group. In one embodiment, R1 and R2 form a 5-10 membered heteroaryl group, preferably a 5-6 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 3-6 membered heterocycle. In a specific embodiment, R1 and R2 form a cyclopropane, cyclobutane, cyclopentane, cyclopentenyl, cyclohexane. In a specific embodiment, R1 and R2 form a phenyl ring. In a further more specific embodiment, R1 and R2 form a cyclopentenyl group. In another specific embodiment, R1 and R2 form a pyridine. In another specific embodiment, R1 and R2 form a thiophene. In another specific embodiment, R1 and R2 form a pyrrole. In another specific embodiment, R1 and R2 form a 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, R5 are absent or independently selected from H, halogen, a C1-C8 straight or branched chain alkyl group, and a C1-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 linear or branched alkyl group. In a preferred embodiment, R7 is a C1-C5 linear 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, or an isopropyl group. In a 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, C1-C8 linear or branched alkyl group. In a preferred embodiment, R8 is absent. In a preferred embodiment, R8 is a C1-C8 linear or branched 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 a 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, the substituents being 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 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and includes a pyridyl group, a pyridazinyl group, a triazinyl group, a pyrimidinyl group, a thienyl group, a furanyl group, an oxazolyl group, a thiazolyl group, a thiadiazole group, an oxadiazolyl group, an isoxazolyl group, a pyrazolyl group, an imidazolyl group, a pyrrolyl group, a pyranyl group, a pyridazinyl group, a pyrazinyl group, and a triazazolyl group. In another preferred embodiment, the aromatic ring is a phenyl group. In a further preferred embodiment, the 3-8 membered heterocycle is a 3-6 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, a pyranyl group, or a more specific embodiment, the heteroaryl group is a pyridinyl group, a pyrimidinyl group, a thienyl group, a furanyl group, an oxazolyl group, a thiazolyl group.

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

[0072] In one embodiment, Q, W, Y, U are independently selected from C, 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 linear or branched alkyl group is selected from a C1-C5 linear or branched alkyl group. In a specific embodiment, the C1-C8 linear or branched alkyl group and the C1-C5 linear or branched 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 linear or branched alkyl group and the C1-C5 linear or branched 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), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2) or 2-methyl-1-butyl (-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 according to 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 6-10 membered monocyclic or bicyclic aryl group, a 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 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 bond or a 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 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6-10 membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group, the substituents being selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl.

[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 6-10 membered monocyclic or bicyclic aryl group, a 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 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 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6-10 membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group, the substituents being selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl.

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

[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 6-10 membered monocyclic or bicyclic aryl group, a 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 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 bond or a 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 5-10 membered monocyclic or bicyclic heteroaryl group containing 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6-10 membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3-8 membered monocyclic or bicyclic heterocycle containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group, the substituents being selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl.

[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 compound provided by the present invention acts on OX1R and OX2R and has good selectivity. The compound provided by the present invention is used to treat diseases related to sleep disorders. The compound provided by the present invention has good pharmacological activity and also has excellent physicochemical properties and pharmacokinetic properties. EXAMPLES

[0114] The following is a detailed description of the examples of the present invention. The examples described below are illustrative and are used only to interpret 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 In a 50 mL three-neck round bottom flask, 2-pyridineethyl acetate (1.0 g, 6.06 mmol), acetophenone (1.45 g, 12.11 mmol), CuBr2 (0.14 g, 0.61 mmol), I2 (0.31 g, 1.21 mmol), and DTBP (0.89 g, 6.06 mmol) were added, and the mixture was reacted overnight at 78 °C under N2 protection. After the reaction was completed by TLC, the mixture was cooled to room temperature, quenched with saturated aqueous Na2S2O3 solution, extracted with 3 × 30 mL EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product, which was purified by silica gel column chromatography with ethyl acetate / petroleum ether (1 / 3) to give 0.8 g of a brownish-yellow oily liquid. LCMS (ES, m / z): 266 [M+H] + .

[0118] 1.2 Preparation of 2-phenylindolizine-1-carboxylic acid In a 100 mL single-necked round-bottom flask, ethyl 2-phenylindolizine-1-carboxylate (0.74 g, 2.81 mmol), sodium hydroxide (0.56 g, 14.07 mmol), EtOH / H2O (10 / 2 mL) were added, and the mixture was reacted at 65°C overnight. After completion of the reaction was detected by TLC, the mixture was cooled to room temperature and concentrated to remove ethanol. Then, the residue was added with water and adjusted to pH 4-5 with 3 N HCl, extracted with 3 x 30 mL of EA, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered by suction and concentrated to obtain 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), Et3N (652 mg, 6.44 mmol), and acetonitrile (10 mL) were added to a 50 mL single-necked round-bottom flask in an ice bath, and the mixture was allowed to react for 10 min while keeping the temperature high. 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (562 mg, 2.58 mmol) was added and the mixture was allowed to react at room temperature for 2 h. After completion of the reaction was detected by TLC, 30 mL of water was added, and the mixture was extracted with 3×30 mL of DCM, washed with 30 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography with DCM / MeOH (20 / 1) to obtain 585 mg of the 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 reacted for 12 h at 65 °C while stirring under N2. The reaction solution was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (EA:PE = 0-10%) to obtain 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 at room temperature overnight under N2. The reaction solution was concentrated and extracted with EA (3 x 30 mL). The organic phase was washed with saturated saline, dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (EA:PE = 0-20%) to obtain 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 at 60°C for 1 h with stirring. The reaction solution was concentrated, then the pH was adjusted to 5-6 with 1 M HCl, extracted with EA (3 x 30 mL), washed with saturated saline, 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, and the mixture was stirred for 10 min. Then, (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 solution was concentrated, and 80 mg of the product was obtained by silica gel column chromatography (EA:PE=0~100%). 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), ferric acetylacetonate (0.22 g, 0.9 mmol), and tetrahydrofuran (30 mL) were placed in a 100 mL round-bottom flask, and methylmagnesium chloride (3 N, 10.5 mL, 31.6 mmol) was added dropwise at -78 °C. After the addition was completed, the mixture was stirred at this temperature for 1 h, and then transferred to room temperature and stirred. After the reaction was completed by TLC, 20 mL of water was added to quench the reaction, and the mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phase was washed with 20 mL of saturated saline, dried over anhydrous sodium sulfate, suction filtered, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 2.2 g of 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 for 1.5 hours. After cooling to room temperature, add 10 mL of water and 10 mL of ethyl acetate to dilute, then filter through diatomaceous earth, extract the filtrate with ethyl acetate three times (20 mL x 3), wash the organic phase with 20 mL of saturated saline, dry with anhydrous sodium sulfate, suction filter and concentrate, separate by column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain a pale yellow oily product, dissolve dichloromethane, add trifluoroacetic acid, react for 4 hours, wash the organic phase with saturated sodium carbonate solution, dry, evaporate the solvent until dry, 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), dichloromethane (20 mL) were placed in a 100 mL round-bottom flask and stirred at room temperature for 20 minutes, after which 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 continued to stir at room temperature overnight. After the reaction was monitored for completion by TLC, the reaction solution was directly concentrated and then separated by column chromatography (methanol / dichloromethane=1:30) to obtain 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 by replacing the reactant 2,4-dichlorofurano[3,2-d]pyrimidine with 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine. 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 the reactant 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 oxazol-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-dichlorofurano[3,2-d]pyrimidine for the reactant. 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 reaction raw material 2-(3-fluoropyridin-2-yl)indolizine-1-carboxylic acid was replaced with 2-(pyridin-2-yl)indolizine-1-carboxylic acid, and 2,4-dichlorofurano[3,2-d]pyrimidine was replaced with 2,4,6-trichloro-5-fluoropyrimidine to prepare the target compound according to the method of Example 7. 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-dichlorofurano[3,2-d]pyrimidine for the reactant 2,4-dichlorothieno[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. 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 2-Bromo-3-oxo-3-phenylpropionic acid ethyl ester (2 g, 7.38 mmol) and pyridazin-3-amine (0.74 g, 7.75 mmol) were dissolved in 10 mL of ethanol, reacted in a microwave, heated to 150° C. and reacted for 6 hours. When the reaction was completed, the temperature was lowered to room temperature, the solvent was removed under reduced pressure, and the product was separated and 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. When the reaction was completed, the mixture was cooled to room temperature, and 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. The product 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 In a 50 mL single-neck round-bottom flask, 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid (0.4 g, 1.67 mmol), HATU (1.27 g, 3.34 mmol), Et3N (0.3 g, 2.97 mmol), and acetonitrile (10 mL) were added in an ice bath, and the mixture was allowed to react for 10 min. Then, 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (0.4 g, 1.84 mmol) was added and the mixture was allowed to react at room temperature for 2 h. After completion of the reaction was detected 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 saline, dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography with DCM / MeOH (20 / 1) to obtain 0.3 g of the 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: 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) Preparation of compounds: Compounds were diluted to 5 mM stock solution with DMSO, then diluted 3.16-fold to a 10 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, and the cells were 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 1×Stimulation buffer and counted using a Countstar cell counter to determine the cell density as 1.71×10 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., about 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 & detection buffer in the Cisbio IP-one detection reagent kit, and the diluted IP1-d2 and Anti-IP1 cryptate were added to the experimental plate at 3 μL / well. After shaking, the experimental plate was left to stand at room temperature for 60 minutes.

[0245] (10) Experimental reading: The plate was read on Envision to detect the readings of the 665 nm and 615 nm channels, 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 antagonistic curves of the compound samples against the orexin receptor were fitted using GraphPad Prism software to obtain 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 superior to that against OX1 receptor, with good selectivity.

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

[0250] LC-MS / MS method was used to 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 by the noncompartmental 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 stands for oral, iv stands for 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 divided into groups of 8 or 9 mice according to the principle of weight balance, and blank vehicle and test compounds were administered at 10, 30, and 100 mg / kg, respectively. The animals were immediately placed in the test box after administration, and the activity distance of the animals within 60 minutes was recorded and analyzed using Top Scan Version 3.0. The total activity distance of the animals in each test product administration group and the blank vehicle group was compared to determine whether the test product significantly affected the spontaneous activity of the animals. The experimental data were expressed as mean ± standard error (Mean ± SD), and one-way analysis of variance was performed using SPSS 21.0 statistical software. Pair-by-pair comparisons were performed using Dunnett's test, and were represented as * when p<0.05 was reached.

[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 divided into groups of 8 mice each according to the principle of weight balance, and blank vehicle and 3, 10 and 30 mg / kg of test compound were administered, respectively, and 5 minutes later, 45 mg / kg of pentobarbital sodium was intraperitoneally injected. The time when the righting reflex disappeared and the time when the righting reflex recovered were recorded. Sleep latency period = time when righting reflex disappeared - time when pentobarbital sodium was administered, sleep duration period = time when righting reflex recovered - time when righting reflex disappeared. The sleep latency period and sleep maintenance period of each test product administration group were compared with that of the blank vehicle group to determine whether the test product had a significant effect on the sleep latency period and sleep duration of the animals. The experimental data were expressed as mean ± standard error (Mean ± SD), and one-way analysis of variance was performed using SPSS 21.0 statistical software, and pairwise comparisons were performed using Dunnett's test, and were represented as * when p<0.05 was reached.

[0257] [Table 4]

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

Claims

1. A compound of formula I or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof, 【Chemistry 1】 Here, R 1 , R 2 , R 3 , R 4 , R 5 is absent or independently H, halogen, C 1 ~C 8 Linear or branched alkyl group, C 1 ~C 8 selected from alkoxy groups, Or, R 1 and R 2 is C 3 ~C 8 A cycloalkyl group, an aryl group, a heteroaryl group, or a 3- to 8-membered heterocycle is formed, preferably R 1 and R 2 is C 3 ~C 8 forming a cycloalkyl group, a 6- to 10-membered monocyclic or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing from 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; 【Chemistry 2】 is a single bond or a double bond, R 6 is selected from formula II, formula III, and formula IV; 【Chemistry 3】 R 9 is an optionally substituted heteroaryl group, an optionally substituted aromatic ring, an optionally substituted 3- to 8-membered heterocycle, an optionally substituted C 3 ~C 8 Cycloalkyl groups, the substituents being halogen, C 1 ~C 8 Linear or branched alkyl group, C 1 ~C 8 is selected from an alkoxy group, a haloalkyl group, and preferably R 9 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 C 3 ~C 8 is a cycloalkyl group, 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 pharma- ceutically acceptable salt, stereoisomer, or tautomer thereof.

2. Said C 1 ~C 8 The straight or branched chain alkyl group is 1 ~C 5 and / or selected from linear or branched alkyl groups Said C 1 ~C 8 The alkoxy group is C 1 ~C 5 alkoxy groups, and / or Said C 3 ~C 8 Cycloalkyl groups are C 3 ~C 6 cycloalkyl groups, and / or The 3- to 8-membered heterocycle contains 1 to 3 heteroatoms selected from O, N, and S.

2. A compound of formula I according to claim 1, or a pharma- ceutically 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 the group consisting of 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 pharma- ceutically acceptable salt, stereoisomer or tautomer thereof.

4. The compound of formula I is as shown in formula V: 【Chemistry 4】 Here, 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 or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing from 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; 【Chemistry 5】 is a single bond or a 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 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 C 3 ~C 8 a cycloalkyl group, the substituent being selected from fluorine, chlorine, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, a trifluoromethyl group, a fluoromethyl group, and a difluoromethyl group; A compound of formula I according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof.

5. The compound of formula V is as shown in formula V-1: 【Chemistry 6】 Here, 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 or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing from 1 to 3 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 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 C 3 ~C 8 a cycloalkyl group, the substituent being selected from fluorine, chlorine, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, a trifluoromethyl group, a fluoromethyl group, and a difluoromethyl group; 5. A compound of formula I according to claim 4, or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof.

6. The compound of formula I is as shown in formula VI: 【Chemistry 7】 Here, 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 or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing from 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; 【Chemistry 8】 is a single bond or a double bond, R 9 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 C 3 ~C 8 a cycloalkyl group, the substituent being selected from fluorine, chlorine, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, a trifluoromethyl group, a fluoromethyl group, and a difluoromethyl group; A compound of formula I according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof.

7. The compound of formula I is as shown in formula VII: 【Chemistry 9】 Here, 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 or bicyclic aryl group, a 5- to 10-membered monocyclic or bicyclic heteroaryl group containing from 1 to 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3- to 8-membered monocyclic or bicyclic heterocycle containing from 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; 【Chemistry 10】 is a single bond or a 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 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 C 3 ~C 8 a cycloalkyl group, the substituent being selected from fluorine, chlorine, a methyl group, an ethyl group, a propyl group, an isopropyl group, a methoxy group, an ethoxy group, a propoxy group, a trifluoromethyl group, a fluoromethyl group, and a difluoromethyl group; A compound of formula I according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof.

8. The compound of formula I is selected from any one of the compounds shown below: A compound of formula I according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, stereoisomer or tautomer thereof. 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemical 27】

9. 1. A pharmaceutical composition comprising: A compound of formula I according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt, stereoisomer, tautomer thereof, optionally further comprising a pharma- ceutically acceptable carrier or a combination thereof. A pharmaceutical composition comprising:

10. Use of a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt, stereoisomer, tautomer thereof, or a pharmaceutical composition according to claim 9 in the manufacture of a medicament, comprising The drug is used to treat diseases associated with orexin receptors. use.

11. 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, and pain.

11. The use according to claim 10.

12. The orexin receptor-associated disease is a sleep disorder.

11. The use according to claim 10.

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