Disubstituted octahydropyrrolo [3, 4-c] pyrrole methyl ketone derivative and application thereof

Abstract

The invention discloses a disubstituted octahydropyrrolo [3, 4-c] pyrrole methyl ketone derivative and an application of the disubstituted octahydropyrrolo [3, 4-c] pyrrole methyl ketone derivative. Belongs to the field of medicine, and particularly relates to a compound shown in the following general formula I or pharmaceutically acceptable salt, stereoisomer, tautomer, a composition containing the compound, a preparation method of the compound and application of the compound in the field of medicine.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a disubstituted octahydropyrrolo[3,4-c]pyrrolmethyl ketone derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer and a composition containing the compound, as well as applications in the field of medicine. Background Art

[0002] Orexins (also known as hypocretins or orexins) come in two types: orexin-A (hypocretin-1) and orexin-B (hypocretin-2). Orexin signaling is mediated by two receptors and two peptide agonists, with orexin A and orexin B binding to two high-affinity receptors, orexin receptor type 1 (OX1R or OX1) and orexin receptor type 2 (OX2R or OX2). OX1R preferentially selects orexin A, while OX2R binds to both orexins with similar affinity.

[0003] Several lines of evidence suggest that orexin-mediated wakefulness is associated with the projection of orexin neurons to histamine neurons in the tuberomammillary nucleus (Yamanaka et al., 2002, Biochem. Biophys. Res. Comm., 290:1237-1245). Orexin signaling has been clinically validated as a target for sleep-promoting therapy by the observation of decreased orexin levels and loss of orexin-stimulating neurons in human narcolepsy (Mignot et al., 2001, The American Journal of Human Genetics, 68:686-699), or in rare cases, by mutations in the OX2R receptor gene (Peyron et al., 2000, Nature Med., 6:991-997).

[0004] It can be seen that orexin receptors are of great significance in pathology and are associated with a variety of diseases, such as sleep disorders, depression, anxiety disorders, panic disorders, obsessive-compulsive disorders, affective neurosis, depressive neurosis, anxiety neurosis, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorder, psychosis, schizophrenia, manic depression, mental disorders, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Parkinson's disease, movement disorders, eating disorders, headaches, migraines, pain, etc.

[0005] Studies have shown that disorders of the sleep-wake cycle are likely targets for the activity of OX2R receptor modulators. Examples of disorders that can be 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), paraventricular nucleus (PVN) of the hypothalamus, and nucleus accumbens (NAc). These brain regions are the primary effector sites of orexin neurons in the LH and are associated with eating, sleep, depression, anxiety, drug addiction, and motivated behaviors. They are more effective in treating sleep disorders (Lu et al., 2020, Neurosci Bull, 4:432–448). Summary of the Invention

[0006] The present invention provides a class of compounds having orexin receptor antagonist activity. The compounds of the present invention have good selectivity and pharmacodynamic activity, as well as excellent physicochemical properties and pharmacokinetic properties. Therefore, they have good clinical application prospects.

[0007] The following is a summary of some aspects of the present invention and is not intended to limit the present invention. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0008] The present invention aims to provide a disubstituted octahydropyrrolo[3,4-c]pyrrolmethyl ketone derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer and pharmaceutical composition thereof. The compound and pharmaceutical composition can be used to prevent or treat diseases related to orexin receptors.

[0009] In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, or tautomer represented by the following general formula I:

[0010]

[0011] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, halogen, C1-C8 linear or branched alkyl, and C1-C8 alkoxy;

[0012] or R1 and R2 form a C3-C8 cycloalkyl, aryl, heteroaryl or 3-8 membered heterocyclic ring;

[0013] Q, W, Y, and U are independently selected from C and N, and Y and Q are not C at the same time;

[0014] is a single bond or a double bond;

[0015] R6 is selected from Formula II, Formula III, Formula IV:

[0016]

[0017] R9 is an optionally substituted heteroaryl, an optionally substituted aromatic ring, an optionally substituted 3-8 membered heterocycle, or an optionally substituted C3-C8 cycloalkyl, wherein the substituent is selected from halogen, C1-C8 straight or branched chain alkyl, C1-C8 alkoxy, or haloalkyl;

[0018] In formula II, Z is selected from C, N;

[0019] R7 is selected from H, halogen, C1-C8 straight or branched alkyl;

[0020] R8 is absent or independently selected from H, halogen, C1-C8 linear or branched alkyl;

[0021] In formula IV, A, B, and M are selected from CH and N, and A, B, and M are not CH at the same time.

[0022] It should be understood that when When it is a single bond, W can actually also be CH.

[0023] On the other hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula I as described above or a pharmaceutically acceptable salt, stereoisomer, or tautomer, optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or a combination thereof.

[0024] In another aspect, the present invention provides a use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, and pharmaceutical composition thereof in the preparation of a drug for treating diseases associated with orexin receptors.

[0025] In one embodiment, the orexin-related disease is a sleep disorder, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neurosis, depressive neurosis, anxiety neurosis, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, etc.

[0026] In another embodiment, the orexin-related disorder is a sleep disorder. DETAILED DESCRIPTION

[0027] Unless otherwise indicated or there is an obvious conflict in the context, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0028] General Terms and Definitions

[0029] The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0030] The term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted", i.e., the structure or group is unsubstituted or substituted with one or more substituents described herein, wherein the substitution occurs at any reasonable position on the given structure or group as allowed by valence.

[0031] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent. When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring atom in the substitutable ring.

[0032] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a specified substituent. Unless otherwise indicated, a substituent may be substituted at every possible position in the group. When more than one position in a given structure can be substituted with one or more of the specified substituents, the substituents may be the same or different at every possible position in the structure.

[0033] In addition, it should be noted that, unless otherwise expressly stated, the description method used in the present invention of "respectively and independently" should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0034] When the lower limit and upper limit of a numerical range are disclosed, any numerical value and any included range falling within the scope are specifically disclosed. In particular, each range of values ​​disclosed herein is understood to represent each numerical value and range encompassed within a wider range. When any variable (such as R), and a variable (such as R1, R2, R3, R4, R5, R6, R7, etc.) with a mark occurs more than once in the composition or structure of a compound, its definition in each case is independent at each occurrence. For example, if a group is substituted with 0, 1, 2, 3 or 4 R substituents, the group can optionally be substituted with four R substituents at most, and the options for each R substituent in each case are independent of each other.

[0035] Throughout this specification, substituents of the compounds disclosed herein are disclosed in terms of group classes or ranges. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the expression mn as used herein refers to the range from m to n, as well as the subranges consisting of the individual values ​​therein, and the individual values.

[0036] In the present invention, “*” indicates a connection point. For example Indicates that the substituent is attached at the "*".

[0037] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. "Alkyl" can have 1-8 carbon atoms, i.e., "C1-C8 alkyl", or 1-6 carbon atoms, i.e., "C1-C6 alkyl", for example, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C 1-6 Alkyl, C 3-6 Alkyl groups may also have 1-3 carbon atoms, i.e., "C1-C3 alkyl groups," such as C 1-3 Alkyl, C 1-2Alkyl, C3 alkyl. The term "C1-C5 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl as disclosed independently. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-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), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH 3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. For example, the expression "C2-C8" or "C 2-8 " covers the range of 2-8 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., as well as C2, C3, C4, C5, C6, C7, C8, etc. For another example, the expression "C1-C5" or "C 1-5 " covers the range of 1-5 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., as well as C1, C2, C3, C4, C5, etc. For another example, the expression "C2-C5" or "C 2-5" covers the range of 2-5 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., as well as C2, C3, C4, C5, etc. For another example, the expression "C1-C8" or "C 1-8 " covers the range of 1-8 carbon atoms, and should be understood to also cover any subranges therein, as well as each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. For another example, the expression "ternary to octal" should be understood to cover any subranges therein and each point value, such as ternary to pentyl, ternary to hexayl, ternary to heptyl, ternary to octal, quaternary to pentyl, quaternary to hexayl, quaternary to heptyl, quaternary to octal, quinary to quinary, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, etc., as well as 3, 4, 5, 6, 7, 8, etc. Other similar expressions herein should also be understood in a similar manner.

[0038] The term "one or more" or the similar expression "at least one" may mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more.

[0039] The term "haloalkyl" refers to an alkyl group substituted by one or more halogen atoms, wherein the alkyl group has the meaning as described herein, such examples include, but are not limited to -CF3, -CH2F, -CHF2, -CF2CF3, -CH2CF3, -CH2CH2F, CH2CF2CHF2, etc. "Haloalkyl" can have 1-8 carbon atoms, i.e., C 1-8 In one embodiment, "haloalkyl" is a lower C 1-4 Haloalkyl, wherein the "C 1-4 "Haloalkyl" contains fluorine-substituted C 1-4 Alkyl, chlorine-substituted C 1-4 Alkyl, bromine-substituted C 1-4 Alkyl, iodine-substituted C 1-4 Alkyl, etc. Specifically, fluorine-substituted C 1-4Alkyl includes -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CH2CH2CF3, -CH2CF2CHF2, etc. The haloalkyl group is optionally substituted with one or more substituents described herein.

[0040] The term "selected from..." means one or more elements from the group listed thereafter, selected independently, and may include combinations of two or more elements.

[0041] The terms “comprise” and “include” are open expressions, that is, they include the contents specified in the present invention but do not exclude other contents.

[0042] When it is stated that each carbon atom in a group may be optionally replaced by a heteroatom, the normal valencies of all atoms in the group in the present circumstances are not exceeded and a stable compound is formed.

[0043] The term "heteroatom" refers to one or more oxygen (O), sulfur (S) or nitrogen (N), including nitrogen (N) and sulfur (S) in any oxidation state; primary, secondary, tertiary amines and quaternary ammonium salts; or a nitrogen atom in a heterocyclic ring in which hydrogen is substituted, for example, N, NH, NR.

[0044] The term "aryl" refers to a monovalent or polyvalent monocyclic, bicyclic or tricyclic carbocyclic ring system containing 6-14 ring atoms, or 6-10 ring atoms, or 6 ring atoms, wherein at least one ring is aromatic. The aryl group is usually, but not necessarily, connected to the parent molecule through the aromatic ring of the aryl group. The term "aryl" can be used interchangeably with the term "aromatic ring" or "aromatic ring". Examples of aryl groups can include phenyl, naphthyl, anthracene, etc. The aryl group is optionally substituted with one or more substituents described herein.

[0045] The term "heteroaryl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 5-14 ring atoms, or 5-10 ring atoms, or 5-6 ring atoms (i.e., 5-6 membered), wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms. A heteroaryl group is typically, but not necessarily, attached to the parent molecule via the aromatic ring of the heteroaryl group. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." Examples of heteroaromatic rings include 5-10 membered monocyclic or bicyclic heteroaryls containing 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, including, but not limited to, pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, and triazolyl. The heteroaryl group is optionally substituted with one or more substituents described herein.

[0046] The terms "heterocycle" and "heterocyclyl" are used interchangeably to refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 3-12 ring atoms, or 3-8 ring atoms, wherein one or more ring atoms are independently replaced by a heteroatom, wherein the heteroatom has the meaning as described herein, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise specified, a heterocyclyl group may be a carbon group or a nitrogen group, and a -CH2- group may optionally be replaced by a -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclyl groups include 3-8 membered monocyclic or bicyclic heterocycles containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, including but not limited to oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, 1,3-dioxolane, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, and the like. Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-oxopyrrolidinyl, oxo-1,3-thiazolidinyl, 2-piperidonyl, 3,5-dioxopiperidinyl, and pyrimidinedione. Examples of heterocyclic groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic groups may be optionally substituted with one or more substituents described herein.

[0047] The term "hydrogen (H)" refers to a single hydrogen atom, which may be linked to other groups, such as oxygen atoms, to form a hydroxyl group.

[0048] The term "halogen" or "halo" is understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably a fluorine, chlorine or bromine atom, more preferably a fluorine atom.

[0049] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1-8 carbon atoms. In one embodiment, the alkoxy group contains 1-5 carbon atoms; in another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as described herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), and the like.

[0050] The term "cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably comprising 1 or 2 rings. The cycloalkyl group can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. The cycloalkyl group can have 3-8 carbon atoms, i.e., a "C3-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, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, etc. The term also encompasses situations where a C atom can be substituted with an oxo (=O).

[0051] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0052] The term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0053] The term "pharmaceutically acceptable salt" refers to an organic salt or an inorganic salt of a compound of the present invention.

[0054] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0055] The following detailed description of the invention is intended to illustrate non-limiting embodiments so that other technical personnel in the art can more fully understand the technical solutions, principles and practical applications of the present invention, so that other technical personnel in the art can modify and implement the present invention in many forms to best adapt it to the requirements of specific uses.

[0056] Compounds of formula I

[0057] In one aspect, the present invention provides a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,

[0058]

[0059] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, halogen, C1-C8 linear or branched alkyl, and C1-C8 alkoxy;

[0060] or R1 and R2 form a C3-C8 cycloalkyl, aryl, heteroaryl or 3-8 membered heterocyclic ring; preferably R1 and R2 form a C3-C8 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3-8 membered monocyclic or bicyclic heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0061] Q, W, Y, and U are independently selected from C and N, and Y and Q are not C at the same time;

[0062] is a single bond or a double bond;

[0063] R6 is selected from Formula II, Formula III, Formula IV

[0064]

[0065] R9 is an optionally substituted heteroaryl, an optionally substituted aromatic ring, an optionally substituted 3-8 membered heterocycle, an optionally substituted C3-C8 cycloalkyl, wherein the substituent is selected from halogen, C1-C8 straight or branched alkyl, C1-C8 alkoxy, or haloalkyl; preferably, R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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;

[0066] In formula II, Z is selected from C, N;

[0067] R7 is selected from H, halogen, C1-C8 straight or branched alkyl;

[0068] R8 is absent or independently selected from H, halogen, C1-C8 linear or branched alkyl;

[0069] In formula IV, A, B, and M are selected from CH and N, and A, B, and M are not CH at the same time.

[0070] In one embodiment, R1 is absent or selected from H, halogen, C1-C8 straight or branched alkyl, or C1-C8 alkoxy. In a preferred embodiment, R1 is absent. In a preferred embodiment, R1 is C1-C8 straight or branched alkyl, or C1-C8 alkoxy. In a more preferred embodiment, R1 is C1-C5 straight or branched alkyl, or C1-C5 alkoxy. In a specific embodiment, R1 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, methoxy, ethoxy, propoxy, or butoxy. In a more specific embodiment, R1 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or propoxy. In a particularly specific embodiment, R1 is methyl. In another particularly specific embodiment, R1 is ethyl. In yet another particularly specific embodiment, R1 is methoxy. In yet another particularly specific embodiment, R1 is ethoxy.

[0071] In one embodiment, R2 is absent or selected from H, halogen, C1-C8 straight or branched alkyl, C1-C8 alkoxy. 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 yet another particularly specific embodiment, R2 is chlorine.

[0072] In one embodiment, R1 and R2 form a C3-C8 cycloalkyl, aryl, heteroaryl or 3-8 membered heterocycle. In a preferred embodiment, R1 and R2 form a C3-C6 cycloalkyl. In one embodiment, R1 and R2 form a C6-C8 cycloalkyl. 10 Aryl. In another preferred embodiment, R1 and R2 form a C3-C6 aryl. In one embodiment, R1 and R2 form a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl. In another preferred embodiment, R1 and R2 form a C3-C6 heteroaryl. In another preferred embodiment, R1 and R2 form a 3-6 membered heterocyclic ring. In a specific embodiment, R1 and R2 form cyclopropane, cyclobutane, cyclopentane, cyclopentenyl, or cyclohexane. In a specific embodiment, R1 and R2 form a benzene ring. In another more specific embodiment, R1 and R2 form a cyclopentenyl. In another specific embodiment, R1 and R2 form pyridine. In another specific embodiment, R1 and R2 form thiophene. In another specific embodiment, R1 and R2 form pyrrole. In another specific embodiment, R1 and R2 form furan.

[0073] In one embodiment, R3 is absent or selected from H, halogen, C1-C8 straight or branched alkyl, or C1-C8 alkoxy. In a preferred embodiment, R3 is absent. In a preferred embodiment, R3 is C1-C8 straight or branched alkyl, or C1-C8 alkoxy. In a more preferred embodiment, R3 is C1-C5 straight or branched alkyl, or C1-C5 alkoxy. In a specific embodiment, R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, methoxy, ethoxy, propoxy, or butoxy. In a more specific embodiment, R3 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or propoxy. In a particularly specific embodiment, R3 is methyl. In another particularly specific embodiment, R3 is ethyl. In yet another particularly specific embodiment, R3 is methoxy. In yet another particularly specific embodiment, R3 is ethoxy.

[0074] In one embodiment, R4 and R5 are absent or independently selected from H, halogen, C1-C8 linear or branched alkyl, and C1-C8 alkoxy.

[0075] 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 methyl, ethyl, or propyl. In a particularly specific embodiment, R4 is methyl.

[0076] In one embodiment, R5 is a C1-C8 straight or branched chain alkyl. In a preferred embodiment, R5 is H. In a more preferred embodiment, R5 is absent. In a more specific embodiment, R5 is methyl, ethyl, or propyl. In a particularly specific embodiment, R5 is methyl.

[0077] In one embodiment, R7 is selected from H, halogen, C1-C8 straight or branched alkyl. In a preferred embodiment, R7 is C1-C5 straight or branched alkyl, 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 methyl, ethyl, propyl, and isopropyl. 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 methyl. In another particularly specific embodiment, R7 is fluorine. In another particularly specific embodiment, R7 is chlorine.

[0078] In one embodiment, R8 is absent or selected from H, halogen, C1-C8 straight or branched alkyl. In a preferred embodiment, R8 is absent. In a preferred embodiment, R8 is C1-C8 straight or branched alkyl. 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 methyl, ethyl, and propyl. 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 methyl. In another particularly specific embodiment, R8 is fluorine. In another particularly specific embodiment, R8 is absent.

[0079] In one embodiment, R9 is optionally substituted heteroaryl, optionally substituted aromatic ring, optionally substituted 3-8 membered heterocycle, optionally substituted C3-C8 cycloalkyl, and the substituents are selected from halogen, C1-C8 straight or branched chain alkyl, C1-C8 alkoxy, and haloalkyl.

[0080] 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, including pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, and triazolyl. In another preferred embodiment, the aromatic ring is phenyl. In another preferred embodiment, the 3-8 membered heterocycle is a 3-6 membered heterocycle. In another preferred embodiment, the C3-C8 cycloalkyl group is a C3-C6 cycloalkyl group. In a specific embodiment, the heteroaryl group is pyridyl, pyridazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, and pyranyl. In a more specific embodiment, the heteroaryl group is pyridinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl.

[0081] 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 cyclopropyl, cyclobutyl, cyclopentenyl, cyclopentyl and cyclohexyl. In a more preferred embodiment, the C3-C8 cycloalkyl group and the C3-C6 cycloalkyl group are cyclopropyl, cyclopentenyl, cyclopentyl and cyclohexyl. In a particularly preferred embodiment, the C3-C8 cycloalkyl group and the C3-C6 cycloalkyl group are cyclopentenyl.

[0082] In one embodiment, Q, W, Y, and U are independently selected from C and N, and Y and Q are not C at the same time. 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.

[0083] In one embodiment, the C1-C8 straight or branched alkyl group is selected from a C1-C5 straight or branched alkyl group. In a specific embodiment, the C1-C8 straight or branched alkyl group and the C1-C5 straight or branched alkyl group are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In a more specific embodiment, the C1-C8 straight or branched alkyl group and the C1-C5 straight or branched alkyl group are independently selected from methyl, ethyl, propyl, and isopropyl.

[0084] In one embodiment, the propyl group includes but is not limited to n-propyl (n-Pr, -CH2CH2CH3) or isopropyl (i-Pr, -CH(CH3)2). The butyl group includes but is not limited to n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3) or tert-butyl (t-Bu, -C(CH3)3). The pentyl group includes, but is not limited to, n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-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).

[0085] 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 independently selected from methoxy, ethoxy, propoxy, butoxy, and pentoxy. In a more specific embodiment, the C1-C8 alkoxy group and the C1-C5 alkoxy group are independently selected from methoxy, ethoxy, and propoxy.

[0086] 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.

[0087] In a specific embodiment, the compound of formula I is a compound represented by formula V:

[0088]

[0089] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy;

[0090] or R1 and R2 form a C3-C6 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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;

[0091] Q, W, Y, and U are independently selected from C and N, and Y and Q are not C at the same time;

[0092] is a single bond or a double bond;

[0093] Z is selected from C and N;

[0094] R7 is selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl;

[0095] R8 is absent or independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl;

[0096] R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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, the substituents being selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

[0097] In a specific embodiment, the compound of formula I is a compound represented by formula V-1:

[0098]

[0099] wherein R1, R2, and R3 are independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy;

[0100] or R1 and R2 form a C3-C6 cycloalkyl 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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;

[0101] Z is selected from C and N;

[0102] R7 is selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl;

[0103] R8 is absent or independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl;

[0104] R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

[0105] In a specific embodiment, the compound of formula I is a compound represented by formula VI:

[0106]

[0107] wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy;

[0108] or R1 and R2 form a C3-C6 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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;

[0109] Q, W, Y, and U are independently selected from C and N, and Y and Q are not C at the same time;

[0110] is a single bond or a double bond;

[0111] R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

[0112] In a specific embodiment, the compound of formula I is a compound represented by formula VII:

[0113]

[0114] Wherein: R1, R2, R3, R4, R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0115] or R1 and R2 form a C3-C6 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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;

[0116] Q, W, Y, and U are independently selected from C and N, and Y and Q are not C at the same time;

[0117] is a single bond or a double bond;

[0118] A, B, and M are selected from CH and N, and A, B, and M are not CH at the same time;

[0119] R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

[0120] In a specific embodiment, the compound represented by formula I is selected from any one of the following compounds:

[0121]

[0122]

[0123]

[0124] Beneficial technical effects of the present invention

[0125] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0126] The compounds provided by the present invention have good selectivity for OX1R and OX2R. The compounds provided by the present invention are used to treat diseases related to sleep disorders. The compounds provided by the present invention have good pharmacodynamic activity and also have excellent physicochemical properties and pharmacokinetic properties.

[0127] Example

[0128] The following embodiments of the present invention are described in detail. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are all by weight.

[0129] Synthesis Example

[0130] Example 1 ((3aR, 6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylindolizin-1-yl)methanone

[0131]

[0132] 1.1 Preparation of ethyl 2-phenylindoleazine-1-carboxylate

[0133] To a 50 mL three-necked round-bottom flask were added ethyl 2-pyridineacetate (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). The mixture was reacted at 78°C overnight under N2 protection. After completion of the reaction, the mixture was cooled to room temperature and quenched with saturated Na2S2O3 aqueous solution. The mixture was extracted with 3 × 30 mL of EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Silica gel column chromatography with ethyl acetate / petroleum ether (1 / 3) gave 0.8 g of a yellow-brown oily liquid. LCMS (ES, m / z): 266 [M+H] + .

[0134] 1.2 Preparation of 2-phenylindoleazine-1-carboxylic acid

[0135] To a 100 mL single-necked round-bottom flask was added ethyl 2-phenylindole-1-carboxylate (0.74 g, 2.81 mmol), sodium hydroxide (0.56 g, 14.07 mmol), and EtOH / H2O (10 / 2 mL). The reaction was allowed to proceed at 65°C overnight. After completion of the reaction, the mixture was cooled to room temperature and concentrated to remove ethanol. The residue was then added with water and the pH was adjusted to 4-5 with 3N HCl. The mixture was extracted with 3×30 mL of EA and washed with 30 mL of saturated brine. The mixture was dried over anhydrous sodium sulfate and concentrated by suction to give 0.65 g of a light yellow solid. LCMS (ES, m / z): 238 [M+H] + .

[0136] 1. Preparation of 3-((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylindolizine-1-yl)methanone

[0137] To a 50 mL single-necked round-bottom flask under ice bath was added 2-phenylindole-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). The mixture was kept warm for 10 min, and 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (562 mg, 2.58 mmol) was added. The mixture was reacted at room temperature for 2 h. After TLC detection, 30 mL of water was added, and the mixture was extracted with 3×30 mL of DCM, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column chromatography with DCM / MeOH (20 / 1) to give 585 mg of the product. 1H NMR(400MHz,Chloroform-d)δ8.51(dd,J=7.5,1.4Hz,1H),7.67(td,J=7.5,1.4Hz,1H),7.54–7.49(m,3H),7.49–7.34(m,4H),6.74(s,1H),6. 68(td,J=7.5,1.5Hz,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] + .

[0138] 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

[0139]

[0140] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 1-(pyridin-2-yl)ethan-1-one. 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=4.4Hz,1H),7.97(d,J=6.8Hz,1H),7.80(s,1H),7.70–7.59(m,2H),7.55(d,J=9.1Hz,1H),7.07(s ,1H),6.91–6.78(m,1H),6.63(t,J=6.8Hz,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] + .

[0141] 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

[0142]

[0143] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 1-(3-fluoropyridin-2-yl)ethan-1-one. 1H NMR (400MHz, CDCl3) δ8.41(d,J=4.6Hz,1H),7.91(d,J=6.9Hz,1H),7.79(d,J=2.4Hz,1H),7.44(d,J=9.1Hz,1H),7.37(m,1H),7.05(m,1H),6. 77(dd,J=9.1,6.5Hz,1H),6.56(t,J=6.7Hz,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]+.

[0144] 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

[0145]

[0146] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced with 1-(5-methylthiophen-2-yl)ethan-1-one. 1 H NMR(400MHz,Chloroform-d)δ8.51(dd,J=7.5,1.4Hz,1H),7.83(s,1H),7.69–7.65(m,1H),7.44(dd,J=7.5,1.3Hz,1H),7.28(d,J=7 .6Hz,1H),6.74(s,1H),6.70–6.66(m,2H),4.16–3.27(m,8H),2.79–2.57(m,2H),2.44(s,3H),2.25(s,6H).LCMS(ES,m / z):458[M+H] + .

[0147] 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

[0148]

[0149] 5.1 Preparation of ethyl 3-(thiophen-2-yl)propiolate

[0150] 2-Iodothiophene (2.0 g, 9.52 mmol), ethyl propiolate (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-necked flask containing THF (40 mL), and N2 was introduced. The reaction was stirred at 65 ° C for 12 h. The reaction solution was filtered, and the filtrate was concentrated and subjected to silica gel column chromatography (EA: PE = 0-10%) to obtain 1.5 g of a light yellow oil.

[0151] 5.2 Preparation of ethyl 2-(thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0152] Ethyl 3-(thiophen-2-yl)propiolate (500 mg, 2.77 mmol), 1-aminopyridinium iodide (616 mg, 2.77 mmol) and DBU (845 mg, 5.55 mmol) were added to a 100 mL single-necked flask containing MeCN (20 mL), and N2 was introduced. The reaction was allowed to react at room temperature overnight. The reaction solution was concentrated and extracted with EA (3 x 30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (EA:PE = 0-20%) to give 500 mg of a light yellow solid.

[0153] 5.3 Preparation of 2-(thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid

[0154] 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 / H2O (6 / 3 mL) were added to a 50 mL single-necked flask and stirred at 60°C for 1 h. The reaction solution was concentrated and the pH was adjusted to 5-6 with 1M HCl. The solution was extracted with EA (3 x 30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to yield 400 mg of a white solid. 5. Preparation of 4-((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

[0155] 2-(Thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.41 mmol) was added to a single-necked bottle containing 5 mL of DCM, and HATU (171 mg, 0.45 mmol) and DIEA (159 mg, 1.23 mmol) were added. After stirring for 10 min, (3aR, 6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (98 mg, 0.45 mmol) was added. The reaction was allowed to react at room temperature overnight. The reaction solution was concentrated and purified by silica gel column chromatography (EA:PE = 0-100%) to give 80 mg of the product. 1 H NMR(400MHz, Methanol-d4)δ8.46–8.39(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=2.8Hz,6H),.LCMS(ES,m / z):445[M+H] + .

[0156] 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

[0157]

[0158] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2-iodothiophene was replaced by 2-iodopyridine.

[0159] 1 H NMR(400MHz,Chloroform-d)δ8.76–8.52(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=2.8Hz,6H),.LCMS(ES,m / z):440[M+H]+ .

[0160] Example 7 (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methylfuro[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0161]

[0162] 7.1 Preparation of 2-chloro-4-methylfuro[3,2-d]pyrimidine

[0163] 2,4-Dichlorofuro[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. Methylmagnesium chloride (3N, 10.5 mL, 31.6 mmol) was added dropwise at -78°C. After stirring at this temperature for one hour, the mixture was moved to room temperature and stirred. After TLC monitoring, the reaction was quenched with 20 mL of water and extracted three times with ethyl acetate (30 mL x 3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Separation by column chromatography (petroleum ether / ethyl acetate = 3:1) afforded 2.2 g of the product as a white solid.

[0164] 7.2 Preparation of 2-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-methylfuro[3,2-d]pyrimidine

[0165] 2-Chloro-4-methylfuro[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-necked flask and reacted in a microwave oven at 170°C for 1.5 hours. After cooling to room temperature, the mixture was diluted with 10 mL of water and 10 mL of ethyl acetate, filtered through celite, and the filtrate was extracted three times with ethyl acetate (20 mL x 3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (petroleum ether / ethyl acetate = 1:3) afforded a light yellow oil, which was dissolved in dichloromethane. Trifluoroacetic acid was added and the reaction was continued for 4 hours. The organic phase was washed with saturated sodium carbonate solution, dried, and the solvent evaporated to afford 0.11 g of the product as a yellow oil.

[0166] 7. Preparation of 3-(2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methylfuro[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0167] 2-(3-Fluoropyridin-2-yl)indolizine-1-carboxylic acid (0.38 g, 1.5 mmol) (Example 3), HATU (0.76 g, 2.0 mmol), DIEA (0.39 g, 3.0 mmol), and dichloromethane (20 mL) were placed in a 100 mL round-bottom flask and stirred at room temperature for 20 minutes. 2-(Hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-methylfuro[3,2-d]pyrimidine (0.29 g, 1.2 mmol) was then added portionwise and stirred at room temperature overnight. After completion of the reaction as monitored by TLC, the reaction solution was concentrated and separated by column chromatography (methanol / dichloromethane = 1:30) to obtain 0.45 g of the product. 1 H NMR(400MHz,Chloroform-d)δ8.51(dd,J=14.9,3.1Hz,1H),8.36(dd,J=14.9,3.1Hz,1H) ,7.77–7.54(m,2H),7.52–7.34(m,4H),7.24(d,J=14.9Hz,1H),6.72-6.38(m,1H),4.12(q ,J=7.1Hz,1H),4.04–3.88(m,2H),3.76(ddd,J=24.6,13.2,5.3Hz,2H),3.70–3.55(m,2H) ,3.27(td,J=10.6,5.2Hz,1H),3.20–2.96(m,2H),2.58(s,3H);.LCMS(ES,m / z):483[M+H] + .

[0168] 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

[0169]

[0170] The target compound was prepared according to the method of Example 7, except that the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine was replaced with 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine. 1H NMR(400MHz,Chloroform)δ8.44(dd,J=14.9,3.1Hz,1H),8.31(dd,J=14.9,3.1Hz,1H),7.74–7.55(m,2H),7.51–7.31(m,4H),6.72-6.64(m,1H),6.5 7(t,J=7.5Hz,1H),6.36(dd,J=7.5,1.5Hz,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] + .

[0171] 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

[0172]

[0173] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-acetylthiazole. 1 HNMR(400MHz, CDCl3)δ7.90(d,J=7.0Hz,1H),7.82–7.72(m,2H),7.43(d,J=9.1Hz,1H),7.22(d,J=3.2Hz,1H),6.81(m,1H),6.60(t,J=6.7Hz,1H),6 .29(s,1H),3.96(d,J=57.8Hz,2H),3.69(d,J=58.0Hz,3H),3.44(s,2H),3 .07(d,J=35.3Hz,2H),2.88(s,1H),2.31(s,6H).LCMS(ES,m / z):445[M+H] + .

[0174] 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

[0175]

[0176] The target compound was prepared according to the method of Example 7, except that the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine was replaced with 2-chloroquinoxaline. 1H NMR (400MHz, CDCl3) δ8.35(d,J=4.6Hz,1H),8.31(s,1H),7.91(t,J=6.8Hz,2H),7.78(d,J=2.5Hz,1H),7.60(t,J=7.5Hz,1H),7.49–7.36 (m,2H),7.33(t,J=9.5Hz,1H),6.94(s,1H),6.78(m,1H),6.57(t,J=6.7Hz,1H),4.06–3.40(m,8H),3.14(s,2H).LCMS(ES,m / z):479[M+H] + .

[0177] 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

[0178]

[0179] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-acetyl-3-trifluoromethylpyridine. 1 H NMR (400MHz, CDCl3): δ8.83(d,J=4.8Hz,1H),7.98(t,J=6.4Hz,2H),7.55(d,J=8.7Hz,2H),7.23(dd,J=8.0,4.8Hz,1H),6.92–6.84(m, 1H),6.65(t,J=6.7Hz,1H),6.36(s,1H),3.77(s,4H),3.49(dd,J=11.6,3.8Hz,4H),2.95(s,2H),2.37(s,6H).LCMS(ES,m / z):507[M+H] + .

[0180] 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

[0181]

[0182] The target compound was prepared according to the method of Example 5, except that the reaction raw material 2-iodothiophene was replaced by iodobenzene, and 1-aminopyridine iodide was replaced by 1-aminopyrimidine iodide. 1H NMR (400MHz, CDCl3) δ8.74 (d, J=7.0, 1.7Hz, 1H), 8.63–8.56 (m, 1H), 7.92 (d, J=7. 6Hz,2H),7.46(t,J=7.5Hz,2H),7.38(t,J=7.3Hz,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] + .

[0183] 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

[0184]

[0185] The target compound was prepared according to the method of Example 5, except that the reaction raw material 2-iodothiophene was replaced by iodobenzene, and 1-aminopyridine iodide was replaced by 1-aminopyrazine iodide. 1 H NMR (400MHz, CDCl3) δ9.18(s,1H),8.39(d,J=4.7Hz,1H),7.98(d,J=4.7Hz,1H),7.76(d,J=7.9Hz ,2H),7.40(t,J=7.6Hz,2H),7.31–7.18(m,1H),6.30(s,1H),3.96(dd,J=12.7,7.6Hz,1H),3.78(d dd,J=17.1,12.2,6.1Hz,2H),3.56(dd,J=11.5,7.2Hz,1H),3.47(dd,J=11.6,5.1Hz,1H),3.30–3. 09(m,2H),2.97(dd,J=11.0,4.3Hz,1H),2.89–2.65(m,2H),2.29(s,6H).LCMS(ES,m / z):440[M+H] + .

[0186] 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

[0187]

[0188] The target compound was prepared according to the method of Example 5, except that the reaction raw material 2-iodothiophene was replaced by iodobenzene, and 1-aminopyridine iodide was replaced by 1-aminopyridazine iodide. 1 H NMR (400MHz, DMSO-d6) δ8.55(d,J=4.0Hz,1H),8.20(d,J=8.0Hz,1H),7.74(d,J=8.0 Hz,2H),7.40(t,J=8.0Hz,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] + .

[0189] 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

[0190]

[0191] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-fluoroacetophenone. 1 HNMR(400MHz, CDCl3)δ7.94(d,J=6.9Hz,1H),7.60(d,J=9.1Hz,1H),7.49–7.47(m,1H),7.35(s,1H),7.3 1–7.29(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] + .

[0192] 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

[0193]

[0194] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-methylacetophenone. 1 HNMR (400MHz, CDCl3) δ7.86 (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=7.6Hz,2H),7.11(d,J=7.6Hz,1H),6.81(m, 1H),6.57(t,J=6.8Hz,1H),6.28(s,1H),3.84(d,J=51.0Hz,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] + .

[0195] 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

[0196]

[0197] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 3-acetylthiophene. 1 HNMR(400MHz, CDCl3)δ7.80(d,J=6.6Hz,1H),7.64(s,1H),7.53(d,J=9.1Hz,1H),7.30(s,1H),7.18–7.15(m,2H),6.73–6.69(m,1H ),6.53–6.51(m,1H),6.25(s,1H),3.93–3.88(m,2H),3.78–3.43(m,3H),3.26-2.88(m,5H),2.34(s,6H).LCMS(ES,m / z):443[M+H] + .

[0198] 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

[0199]

[0200] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-acetyl-3-fluoropyridine, and ethyl 2-pyridineacetate was replaced by ethyl 2-(5-fluoropyridin-2-yl)acetate. 1 H NMR (400MHz, CDCl3) δ8.40(d,J=4.4Hz,1H),7.85(t,J=3.1Hz,1H),7.78(s,1H),7.48–7.30(m,2H),7.04(d,J=7.5Hz, 1H),6.71(t,J=9.0Hz,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] + .

[0201] 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

[0202]

[0203] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-acetylpyridine, and ethyl 2-pyridineacetate was replaced by ethyl 2-(5-fluoropyridin-2-yl)acetate. 1 H NMR (400MHz, CDCl3) δ8.55 (d, J=4.4Hz, 1H), 7.79 -7.75(m,2H),7.71(s,1H),7.48–7.30(m,2H),7.04(d,J=7.5Hz,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] + .

[0204] 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

[0205]

[0206] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by oxazole-2-ethanone. 1HNMR(400MHz, CDCl3)δ7.94(d,J=6.7Hz,1H),7.86–7.78(m,2H),7.43(s,1H),7.27(d,J=3.2Hz,1H),6.83(m,1H),6.63–6 .61(m,1H),6.29(s,1H),3.99-3.95(m,2H),3.69-3.44(m,3H),3.07-2.88(m,3H),2.33(s,6H).LCMS(ES,m / z):429[M+H] + .

[0207] 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

[0208]

[0209] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-acetylpyrimidine. 1 HNMR(400MHz, CDCl3)δ8.41(d,J=4.3Hz,1H),7.94(d,J=6.6Hz,1H),7.78–7.73(m,2H),7.37(m,1H),7.05(m,1H),6.79 -6.77(m,1H),6.56(t,J=6.7Hz,1H),6.29(s,1H),3.94–3.89(m,2H),3.78-3.47(m,3H),3.07-2.88(m,2H),2.30(s,6H).LCMS(ES,m / z):440[M+H] + .

[0210] 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

[0211]

[0212] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-acetyl-5-methylthiazole. 1H NMR (400MHz, CDCl3) δ7.88(d,J=6.9Hz,1H),7.76–7.72(m,2H),7.43(d,J=9.1Hz,1H),6.81(m,1H),6.60(t,J=6.7Hz,1H),6. 29(s,1H),3.96(d,J=57.8Hz,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] + .

[0213] 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

[0214]

[0215] The target compound was prepared according to the method of Example 7, except that the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine was replaced with 2,4,6-trichloro-5-fluoropyrimidine. 1 H NMR (400MHz, CDCl3) δ8.38(d,J=4.7Hz,1H),7.89(d,J=6.6Hz,1H),7.73(d,J=2.4Hz,1H),7.49(d,J=9.1Hz,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] + .

[0216] 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

[0217]

[0218] The reaction raw material 2-(3-fluoropyridin-2-yl)indolizine-1-carboxylic acid was replaced by 2-(pyridin-2-yl)indolizine-1-carboxylic acid, and 2,4-dichlorofuro[3,2-d]pyrimidine was replaced by 2,4,6-trichloro-5-fluoropyrimidine. The target compound was prepared according to the method of Example 7. 1H NMR (400MHz, CDCl3) δ8.61(d,J=4.8Hz,1H),7.90(d,J=6.8Hz,1H),7.79(s,1H),7.67–7.55(m,2H),7.48(d,J=9.1Hz,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] + .

[0219] Example 25 (2-(3-fluoropyridin-2-yl)indolizin-1-yl)((3aR,6aS)-5-(4-methylthienyl[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0220]

[0221] The target compound was prepared according to the method of Example 7, except that the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine was replaced with 2,4-dichlorothieno[3,2-d]pyrimidine. 1 H NMR (400MHz, CDCl3) δ8.38(d,J=4.6Hz,1H),7.90(d,J=7.0Hz,1H),7.77(d,J =2.4Hz,1H),7.72(m,1H),7.44(d,J=9.1Hz,1H),7.38–7.29(m,1H),7.28–7.1 9(m,1H),6.96(s,1H),6.75(m,1H),6.55(t,J=6.7Hz,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] + .

[0222] 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

[0223]

[0224] The target compound was prepared according to the method of Example 7, except that the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine was replaced with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine. 1 H NMR (400MHz, CDCl3) δ8.52(d,J=4.3Hz,1H),7.97(d,J=6.4Hz,1H),7.80(d,J=2.4Hz,1H),7.53(d,J=8.9Hz,1H),7.38–7.36(m,1H),7.07–7.10( m,1H),6.81–6.78(m,1H),6.56(t,J=6.7Hz,1H),3.92-3.66(m,5H),3.4 7–3.22(m,4H),3.09-2.68(m,7H),2.26(s,3H).LCMS(ES,m / z):483[M+H] + .

[0225] 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

[0226]

[0227] The target compound was prepared according to the method of Example 7, except that the reaction raw material 2-chloro-4-methylfuro[3,2-d]pyrimidine was replaced with 3-chloro-2,5-dimethylpyrazine. 1 H NMR (400MHz, CDCl3) δ8.54(d,J=4.8Hz,1H),7.96(d,J=6.9Hz,1H),7.84(d,J=2.4Hz,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=6.7Hz,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] + .

[0228] 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

[0229]

[0230] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-acetylthiophene. 1 HNMR (400MHz, CDCl3) δ7.87(d,J=6.9Hz,1H),7.50(d,J=9.1Hz,1H),7.39(s,1H),7.14(m,2H),6.95(t,J=4.4Hz,1H),6.79(m,1H),6.56(t,J=6. 7Hz,1H),6.29(s,1H),3.91(d,J=48.6Hz,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] + .

[0231] 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

[0232]

[0233] The target compound was prepared according to the method of Example 5, except that the reaction raw material 2-iodothiophene was replaced by 2-iodopyrimidine. 1 HNMR (400MHz, Chloroform-d): δ8.74(d,J=4.7Hz,1H),8.55(d,J=7.0Hz,2H),8.04(d,J=7.9Hz,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=11.7,6.1Hz,2H),3.52–3.39(m,2H),3.18-2.90(m,3H),2.32(s,6H).LCMS(ES,m / z):441[M+H] + .

[0234] 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

[0235]

[0236] The target compound was prepared according to the method of Example 5, except that the reaction raw material 1-aminopyridine iodide was replaced with 1-amino-3-fluoropyridine iodide.1 H NMR(400MHz, CDCl3)δ8.69(d,J=4.6Hz,1H),8.37(d,J=6.9Hz,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] + .

[0237] 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

[0238]

[0239] The target compound was prepared according to the method of Example 5, except that the reaction raw material 1-aminopyridine iodide was replaced with 1-amino-3-methylpyridine iodide. 1 H NMR(400MHz, CDCl3)δ8.61(d,J=4.9Hz,1H),8.32(d,J=6.7Hz,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] + .

[0240] 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

[0241]

[0242] The target compound was prepared according to the method of Example 7, except that the reaction raw material 2-chloro-4-methylfuro[3,2-d]pyrimidine was replaced with 2-chloro-4,6-dimethoxypyrimidine. 1H NMR (400MHz, CDCl3) δ8.48(d,J=4.4Hz,1H),7.95(d,J=6.7Hz,1H),7.81(d,J=2.4Hz,1H),7.44(d,J=9.1Hz,1H),7.40–7.78(m,1H),7.11–7.08(m,1H ),6.77(dd,J=9.1,6.5Hz,1H),6.56(t,J=6.7Hz,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] + .

[0243] 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

[0244]

[0245] 33.1 Preparation of Ethyl 2-Phenylimidazolo[1,2-b]pyridazine-3-carboxylate

[0246] Ethyl 2-bromo-3-oxo-3-phenylpropionate (2 g, 7.38 mmol) and pyridazin-3-amine (0.74 g, 7.75 mmol) were dissolved in 10 ml of ethanol and subjected to microwave reaction at 150 ° C for 6 hours. After the reaction was completed, the temperature was lowered to room temperature and the solvent was evaporated under reduced pressure. The product was separated and purified by column chromatography (PE: EA = 10:1) to obtain 0.6 g of the product.

[0247] 33.2 Preparation of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid

[0248] 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (0.6 g, 2.24 mmol) and sodium hydroxide (0.18 g, 4.48 mmol) were added to 5 mL of water, and then 2 mL of ethanol was added. The temperature was raised to 75 ° C. and the reaction was reacted for 1 hour. After the reaction was completed, the temperature was lowered to room temperature, and the ethanol was evaporated under reduced pressure. The pH was adjusted to 1 with 1 M HCl solution, filtered, and the filter cake was dried to obtain 0.42 g. Without further purification, the next step was directly carried out.

[0249] Preparation of 33.3(5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-phenylimidazo[1,2-b]pyridazin-3-yl)methanone

[0250] To a 50 mL single-necked round-bottom flask under ice bath was added 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). The mixture was kept warm for 10 min, and 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (0.4 g, 1.84 mmol) was added. The mixture was reacted at room temperature for 2 h. After TLC detection, 30 mL of water was added, and the mixture was extracted with 3×30 mL of DCM, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The mixture was purified by silica gel column chromatography with DCM / MeOH (20 / 1) to obtain 0.3 g of the product. 1 H NMR(400MHz, CDCl3)δ8.63–8.61(m,1H),8.07(dd,J=9.1,1.7Hz,1H),7.88–7.74(m,2H),7.52–7.41(m,2H),7.28–7.2 3(m,1H),6.44(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] + .

[0251] 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

[0252]

[0253] The target compound was prepared according to the method of Example 5, except that the reaction raw material 2-iodothiazole was replaced by 4-iodopyridine. 1 HNMR (400MHz, CDCl3): δ8.71(d,J=4.9Hz,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, 1.3Hz,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] + .

[0254] 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

[0255]

[0256] The target compound was prepared according to the method of Example 1, except that the reaction raw material acetophenone was replaced by 2-propionylpyridine. 1 HNMR(400MHz, CDCl3)δ8.56(d,J=4.9Hz,1H),7.92(d,J=6.9Hz,1H),7.67–7.55(m,2H),7.48(d,J=9.1Hz,1H),7.05–7.01(m,1H),6.79–6.69(m,1H ),6.57(t,J=6.7Hz,1H),6.29(s,1H),3.95-3.76(m,3H),3.53-3.28(m,4 H),2.93-2.73(m,3H),2.48(s,3H),2.30(s,6H).LCMS(ES,m / z):453[M+H] + .

[0257] 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

[0258]

[0259] The target compound was prepared according to the method of Example 5, except that the reaction raw material 2-iodothiophene was replaced by 3-iodopyridine. 1 HNMR (400MHz, DMSO-d6) δ8.94(s,1H),8.83(d,J=6.9Hz,1H),8.52(d,J=4.7Hz,1H),8.16–8.03(m,1H),7.66(d,J=8.9Hz,1H),7. 48–7.30(m,2H),7.07(t,J=7.0Hz,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] + .

[0260] Example 37 [(3aR, 6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl][6-fluoro-2-(thien-2-yl)pyrazolo[1,5-a]pyridin-3-yl]methanone

[0261]

[0262] The target compound was prepared according to the method of Example 5, except that the reaction raw material 1-aminopyridine iodide was replaced with 1-amino-3-fluoropyridine iodide. 1 H NMR (400MHz, DMSO-d6) δ8.46–8.39(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] + .

[0263] Pharmacological test examples:

[0264] Test Example 1 In vitro activity test

[0265] (1) Prepare the reaction buffer (1x Stimulation buffer) required for the experiment: dilute the 5x Stimulation buffer in the Cisbio IP-one kit with ddH2O in a ratio of 1:4 and set aside.

[0266] (2) Compound preparation: Dilute the compound to a 5 mM stock solution with DMSO, then dilute it 3.16-fold to form 10 gradients, and then dilute the prepared compound to the corresponding concentration (4x) with stimulation buffer for later use.

[0267] (3) Cell preparation: Digest the CHO-K1-OX1 and CHO-K1-OX2 cells on the culture dish with trypsin, wash the cells with culture medium and collect them in a 5 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes and discard the supernatant. Add 3 mL of PBS and mix thoroughly by gently pipetting. Centrifuge again at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the cells in 1xStimulation buffer and count them using a Countstar cell counter. Adjust the cell density to 1.71x10 6 / mL, for future use.

[0268] (4) Cell addition: Add the cell suspension to the experimental plate, 7 μL / well (i.e., approximately 12,000 cells / well).

[0269] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate, 3.5 μL / well.

[0270] (6) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 30 minutes.

[0271] (7)EC 80 Agonist added: Add EC 80 4x Orexin A (OX1 receptor) and 4x Orexin2 receptor agonist (OX2 receptor) solution, 3.5 μL / well.

[0272] (8) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 45 minutes.

[0273] (9) Add detection reagents: Dilute IP1-d2 and Anti-IP1 cryptate at a 1:20 ratio using the Lysis & Detection Buffer in the Cisbio IP-one Detection Kit. Add 3 μL of each diluted IP1-d2 and Anti-IP1 cryptate to the assay plate at each well. After shaking, incubate the plate at room temperature for 60 minutes.

[0274] (10) Experimental reading: Read the plate on Envision, detect the readings of the 665nm and 615nm channels, and calculate the ratio of 665nm / 615nm readings.

[0275] According to the antagonistic effect values ​​of the compound samples at different concentrations, the antagonistic effect curves of the compound samples on orexin receptors were fitted using GraphPad Prism software, and the IC 50 The results are shown in Table 1:

[0276] Table 1

[0277]

[0278]

[0279] IC 50 Value <100nM:+++; IC 50 Value is 100~300nM:++;IC 50 The value is 300~1000nM:+;IC 50 Value>1000nM:-

[0280] The data show that the compounds of the present invention have good inhibitory activity on OX2 receptors, and the inhibitory effect of the compounds on OX2 receptors is significantly better than that on OX1 receptors, and have good selectivity.

[0281] Test Example 2 Determination of pharmacokinetic parameters of the test substance in rat plasma

[0282] Healthy male Sprague-Dawley rats aged 6-9 weeks were randomly divided into two groups, 3 in each. One group received the test compound at 1 mg / kg via intravenous injection, while the other group received the test compound at 10 mg / kg via oral gavage. Whole blood was collected from both the intravenous and oral gavage groups before and 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, 10.0, and 24.0 hours after administration, and plasma samples were obtained by centrifugation.

[0283] LC-MS / MS was used for quantitative analysis of all biological samples, and WinNonlin™ Version 7.0 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method. 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 administration; iv stands for intravenous administration, C max represents peak concentration, and F% represents oral bioavailability. The results are shown in Table 2:

[0284] Table 2

[0285]

[0286] The data showed that in the pharmacokinetic evaluation experiment in rats, the example compounds of the present invention showed good in vivo exposure and good bioavailability after administration.

[0287] Test Example 3: Autonomous activity of mice

[0288] Male ICR mice aged 6-9 weeks were randomly divided into groups according to the principle of weight balance, with 8 or 9 mice in each group, and were given blank solvent and 10, 30 and 100 mg / kg of the test compound, respectively. The animals were placed in the test box immediately 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 sample administration group was compared with that in the blank solvent group to determine whether the test sample had a significant effect on the spontaneous activity of the animals. The experimental data were expressed as mean ± standard error (Mean ± SD). SPSS 21.0 statistical software was used for one-way analysis of variance, and Dunnett's test was used for pairwise comparison. P < 0.05 was indicated as *.

[0289] Table 3

[0290]

[0291] Conclusion: The compound of the present invention can significantly reduce the spontaneous activity distance of mice.

[0292] Test Example 4 Pentobarbital sodium synergistic sleep test

[0293] Male ICR mice aged 6-9 weeks were randomly divided into groups based on the principle of weight balance, with 8 mice in each group. They were given blank solvent and 3, 10 and 30 mg / kg of the test compound, respectively. 5 minutes later, 45 mg / kg of sodium pentobarbital was injected intraperitoneally. The time when the righting reflex of the mice disappeared and the time when the righting reflex was restored were recorded. Sleep latency = time when the righting reflex disappeared - time when sodium pentobarbital was administered, sleep duration = time when the righting reflex was restored - time when the righting reflex disappeared. The sleep latency and sleep maintenance time of each test sample group were compared with the blank solvent group to determine whether the test sample had a significant effect on the sleep latency and sleep duration of the animals. Experimental data are represented by mean ± standard error (Mean ± SD). SPSS21.0 statistical software was used for one-way analysis of variance, and Dunnett's test was used for pairwise comparison. P < 0.05 is indicated as *.

[0294] Table 4

[0295]

[0296] Conclusion: The compounds of the present invention can shorten the sleep latency and prolong the sleep duration of mice.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, R1, R2, R3, R4, R5 are absent or independently selected from H, halogen, C1-C8 linear or branched alkyl, C1-C8 alkoxy; or R1 and R2 form a C3-C8 cycloalkyl, aryl, heteroaryl or 3-8 membered heterocyclic ring; preferably R1 and R2 form a C3-C8 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl containing 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur, or a 3-8 membered monocyclic or bicyclic heterocyclic ring 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 C at the same time; is a single bond or a double bond; R6 is selected from Formula II, Formula III, Formula IV: R9 is an optionally substituted heteroaryl, an optionally substituted aromatic ring, an optionally substituted 3-8 membered heterocycle, an optionally substituted C3-C8 cycloalkyl, wherein the substituent is selected from halogen, C1-C8 straight or branched alkyl, C1-C8 alkoxy, or haloalkyl; preferably, R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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; In formula II, Z is selected from C, N; R7 is selected from H, halogen, C1-C8 straight or branched alkyl; R8 is absent or independently selected from H, halogen, C1-C8 linear or branched alkyl; In formula IV, A, B, and M are independently selected from CH and N, and A, B, and M are not CH at the same time.

2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The C1-C8 straight chain or branched chain alkyl group is selected from C1-C5 straight chain or branched chain alkyl group; and / or The C1-C8 alkoxy group is selected from C1-C5 alkoxy groups; and / or The C3-C8 cycloalkyl group is selected from C3-C6 cycloalkyl groups; and / or The 3-8 membered heterocyclic ring contains 1-3 heteroatoms, and the heteroatoms are selected from O, N, and S.

3. The compound of formula I according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The halogen is fluorine, chlorine, bromine, or iodine; and / or The C1-C5 straight or branched alkyl group is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and pentyl; and / or The C1-C5 alkoxy group is selected from methoxy, ethoxy, propoxy, butoxy, pentoxy; and / or The C3-C6 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and cyclohexyl; and / or The heteroaryl group is selected from pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyrazinyl, triazolyl; and / or The haloalkyl group is selected from fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

4. The compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula I is shown in formula V: wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; or R1 and R2 form a C3-C6 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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 C at the same time; is a single bond or a double bond; Z is selected from C and N; R7 is selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl; R8 is absent or independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl; R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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, the substituents being selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

5. The compound of formula I according to claim 4 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula V is shown in formula V-1: wherein R1, R2, and R3 are independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; or R1 and R2 form a C3-C6 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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, methyl, ethyl, propyl, isopropyl; R8 is absent or independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl; R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

6. The compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound represented by formula I is represented by formula VI: wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; or R1 and R2 form a C3-C6 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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 C at the same time; is a single bond or a double bond; R9 is an optionally substituted 5-10 membered monocyclic or bicyclic heteroaryl 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; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

7. The compound of formula I according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound represented by formula I is represented by formula VII: wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy; or R1 and R2 form a C3-C6 cycloalkyl, a 6-10 membered monocyclic or bicyclic aryl, a 5-10 membered monocyclic or bicyclic heteroaryl 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 C at the same time; 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 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; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

8. The compound of formula I according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula I is selected from any one of the following compounds:

9. A pharmaceutical composition, characterized in that Containing the compound of formula I according to any one of claims 1 to 8 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, optionally further comprising a pharmaceutically acceptable carrier or a combination thereof.

10. Use of the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the pharmaceutical composition according to claim 9 in the preparation of a medicament, wherein: The medicine is used for preparing the medicine for treating diseases related to orexin receptors.

11. The method of claim 10, wherein the disease associated with orexin receptors is sleep disorder, depression, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain.

12. The use according to claim 10, wherein the disease associated with orexin receptor is a sleep disorder.

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