A disubstituted octahydropyrrolo[3,4-c]pyrrole methyl ketone derivative and its application

Abstract

The present invention belongs to the field of medicine, and specifically relates to a compound represented by the following general formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, and a composition containing the compound, a preparation method thereof, and an application in the field of medicine. #imgabs0#

Description

Technical Field

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

[0002] Orexin (also known as hypocretin, orexigenic peptide) has two types: orexin-A (hypocretin-1) and orexin-B (hypocretin-2). Orexin signaling is mediated by two receptors and two peptide agonists. Orexin A and orexin B bind to two high-affinity receptors, orexin receptor type 1 (OX1R or OX1) and orexin receptor type 2 (OX2R or OX2). OX1R has a preference for orexin A, while OX2R has a similar affinity for binding to both orexins.

[0003] A number of evidences indicate that the orexin-mediated wakefulness effect is 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 shows that orexin signaling is the target of sleep-promoting therapy by observing the reduction of orexin content and the loss of orexin-promoting neurons in human narcolepsy patients (Mignot et al., 2001, The American Journal of Human Genetics, 68: 686-699), or in rare cases, is related to mutations in the OX2R receptor gene (Peyron et al., 2000, Nature med., 6: 991-997).

[0004] Thus, it can be seen that orexin receptors are of important pathological significance and are related to various diseases, such as sleep disorders, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, emotional disorder, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, etc.

[0005] Studies have shown that disorders of the sleep-wake cycle are likely to be targets of orexin receptor modulator activity. Examples of disorders that can be treated by antagonists or other modulators that downregulate orexin-mediated processes include insomnia, restless legs syndrome, jet lag (insomnia), and sleep disorders secondary to neurological disorders such as mania, schizophrenia, pain syndromes, etc. OX2R is selectively expressed in the tuberomammillary nucleus (TMN), paraventricular nucleus of the hypothalamus (PVN), and nucleus accumbens (NAc). These brain regions are the main effector sites of orexin neurons in the LH and are related to eating, sleeping, depression, anxiety, drug addiction, and motivated behavior, and 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 with orexin receptor antagonistic activity. The compounds of the present invention have good selectivity and pharmacodynamic activity, and also have excellent physical and chemical properties and pharmacokinetic properties. Therefore, they have good clinical application prospects.

[0007] Only some aspects of the present invention are briefly described below and are not limited thereto. When there are differences between the disclosure of this specification and the cited literature, 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 pharmaceutically acceptable salt, stereoisomer, tautomer thereof, and a pharmaceutical composition thereof. The compounds and pharmaceutical compositions can be used for preventing or treating diseases related to orexin receptors.

[0009] On the one hand, the present invention provides a compound represented by the following general formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,

[0010]

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

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

[0013] Q, W, Y, U are independently selected from C, N, and Y and Q are not both 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 heterocyclic ring, an optionally substituted C3-C8 cycloalkyl, and the substituents are selected from halogen, C1-C8 straight-chain or branched-chain alkyl, C1-C8 alkoxy, and haloalkyl;

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

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

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

[0021] In formula IV, A, B, and M are selected from CH and N, and A, B, and M are not simultaneously CH.

[0022] It should be understood that when 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 the compound represented by formula I as described above or a pharmaceutically acceptable salt, stereoisomer, tautomer, and optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or a combination thereof.

[0024] On the other hand, the present invention provides the use of the compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof and its pharmaceutical composition in the preparation of a medicament for treating diseases related to orexin receptors.

[0025] In one embodiment, the orexin-related diseases are sleep disorders, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, emotional disorder, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive impairment, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, etc.

[0026] In another embodiment, the orexin-related disease is a sleep disorder. Detailed implementation mode

[0027] Unless otherwise specified 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 this invention pertains. In case of conflict, the definitions provided in this application shall prevail. When trade names appear in this text, they are intended to refer to the corresponding products or their active ingredients. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0028] General terms and definitions

[0029] The term "optionally" or "optionally" means that the subsequent described event or situation may or may not occur, and this description includes the situation where the described event or situation occurs and the situation where it does not occur.

[0030] The term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted", that is, the said structure or group is unsubstituted or substituted by one or more substituents described in this invention, wherein the substitution occurs at any reasonable position allowed by any valence of the given structure or group.

[0031] Unless specified otherwise, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent. When the bond of a substituent is shown as passing through the bond connecting two atoms in a ring, then such a substituent can be bonded to any ring-forming atom in the ring that can be substituted.

[0032] Generally speaking, the term "substituted" means that one or more hydrogen atoms in the given structure or group are replaced by specific substituents. Unless otherwise indicated, a substituent can be substituted at any reasonable position where the group can be substituted. When more than one position in the given structural formula can be substituted by one or more specific substituents selected from, then the substituents can be the same or different and be substituted at each reasonable position in the structural formula.

[0033] In addition, it should be noted that unless otherwise explicitly indicated, the description method "each independently is" adopted in this invention should be understood in a broad sense. It can either mean that among different groups, the specific options expressed between the same symbols do not affect each other, or it can mean that within the same group, the specific options expressed between the same symbols do not affect each other.

[0034] When the lower and upper limits of a numerical range are disclosed, any numerical value and any included range falling within that range are specifically disclosed. In particular, each range of values disclosed herein should be understood to represent every numerical value and range subsumed within the broader range. When any variable (e.g., R), and variables with markings (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appear 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 may optionally be substituted with up to four R substituents, and the options for each R substituent in each case are independent of one another.

[0035] In various parts of this specification, the substituents of the compounds disclosed in the present invention are disclosed according to group types or ranges. It is specifically pointed out that the present invention includes each independent secondary combination of each member of these group types and ranges. For example, the expression m - n used herein refers to the range from m to n, as well as the sub - ranges and individual point values composed of the individual point values therein.

[0036] The present invention uses the expression “*” to denote a connection point. For example It indicates that the substituent is connected at “*”.

[0037] The term “alkyl” refers to a straight - chain or branched - chain saturated aliphatic hydrocarbon group composed of carbon and hydrogen atoms, which is connected to the rest of the molecule by a single bond. “Alkyl” may 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. It may also have 1 - 3 carbon atoms, i.e., “C1 - C3 alkyl”. For example, C 1-3 alkyl, C 1-2Alkyl, C3 alkyl. The term "C1-C5 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl independently disclosed. 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)CH2CH3), 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 sub-range and each point value 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. Again, for 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 sub-range and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., and C1, C2, C3, C4, C5, etc. Again, for example, the expression "C2-C5" or "C 2-5”covers the range of 2 to 5 carbon atoms and should be understood to also cover any sub-range and each point value therein, such as C2-C s , C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., and C2, C3, C4, C5, etc. For another example, the expression "C1-C8" or "C 1-8 ”covers the range of 1 to 8 carbon atoms and should be understood to also cover any sub-range therein, and each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., and C1, C2, C3, C4, C5, C6, C7, C8, etc. For another example, the expression "ternary to octavalent" should be understood to cover any sub-range and each point value therein, such as ternary to pentavalent, ternary to hexavalent, ternary to heptavalent, ternary to octavalent, quaternary to pentavalent, quaternary to hexavalent, quaternary to heptavalent, quaternary to octavalent, pentavalent to heptavalent, pentavalent to octavalent, hexavalent to heptavalent, hexavalent to octavalent, etc., and ternary, quaternary, pentavalent, hexavalent, heptavalent, octavalent, etc. Other similar expressions in this article should also be understood in a similar manner.

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

[0039] The term "haloalkyl" means that the alkyl group is substituted by one or more halogen atoms, where the alkyl group has the meaning as described in the present invention. Such examples include, but are not limited to, -CF3, -CH2F, -CHF2, -CF2CF3, -CH2CF3, -CH2CH2F, CH2CF2CHF2, etc. "Haloalkyl" can have 1 to 8 carbon atoms, that is, C 1-8 haloalkyl. In one embodiment, "haloalkyl" is a lower C 1-4 haloalkyl, where the "C 1-4 haloalkyl" includes fluorine-substituted C 1-4 alkyl, chlorine-substituted C 1-4 alkyl, bromine-substituted C 1-4 alkyl, iodine-substituted C 1-4 alkyl, and so on. Specifically, fluorine-substituted C 1-4The alkyl group includes -CH2F, -CHF2, -CF3, -CH2Cl, -CHCl2, -CCl3, -CH2Br, -CHBr2, -CBr3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH2F, -CF2CHF2, -CF2CF3, -CHFCF3, -CHFCHF2, -CHFCH2F, -CH2CH2CF3, -CH2CF2CHF2, and so on. The haloalkyl group is optionally substituted by one or more substituents described in the present invention.

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

[0041] The terms "comprising" and "including" are open-ended expressions, that is, they include the content specified in the present invention, but do not exclude other aspects.

[0042] When it is described that each carbon atom in a group can optionally be replaced by a heteroatom, provided that the normal valence of all atoms in the group is not exceeded in the current case and a stable compound is formed.

[0043] The term "heteroatom" means one or more oxygen (O), sulfur (S), or nitrogen (N), including any oxidation state forms of nitrogen (N) and sulfur (S); primary, secondary, tertiary amines, and quaternary ammonium salts; or the form in which the hydrogen on the nitrogen atom in a heterocycle is substituted, for example: N, NH, NR.

[0044] The term "aryl" means a monovalent or polyvalent monocyclic, bicyclic, or tricyclic carbocyclic system containing 6 - 14 ring atoms, or 6 - 10 ring atoms, or 6 ring atoms, in which 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 terms "aromatic ring" or "aromatic cycle". Examples of aryl groups can include phenyl, naphthyl, anthracene, and so on. The aryl group is optionally substituted by one or more substituents described in the present invention.

[0045] The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic system that is monovalent or polyvalent and contains 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. The heteroaryl group is usually, but not necessarily, connected to the parent molecule through 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 heteroaryl groups containing 1 - 5 heteroatoms independently selected from nitrogen, oxygen or sulfur, including but not limited to: pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, triazolyl. The heteroaryl group is optionally substituted with one or more substituents described in the present invention.

[0046] The terms "heterocyclic" and "heterocyclic group" are used interchangeably and refer to a monocyclic, bicyclic or tricyclic system that is monovalent or polyvalent and contains 3 - 12 ring atoms, or 3 - 8 ring atoms, wherein one or more atoms in the ring are independently replaced by heteroatoms having the meaning as described in the present invention, and the ring can be fully saturated or contain one or more unsaturations. Unless otherwise specified, the heterocyclic group can be carbon - based or nitrogen - based, and the - CH2 - group can optionally be replaced by - C(=O)-. The sulfur atom in the ring can optionally be oxidized to an S - oxide. The nitrogen atom in the ring can optionally be oxidized to an N - oxide. Examples of heterocyclic 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, tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, 1,3 - dioxolanyl, dithiolanyl, tetrahydropyranyl, dihydropyranyl, 2H - pyranyl, 4H - pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, etc. Examples of the - CH2 - group in the heterocyclic group being replaced by - C(=O)- include, but are not limited to, 2 - oxopyrrolidinyl, oxo - 1,3 - thiazolanyl, 2 - piperidinone, 3,5 - dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolanyl, 1,1 - dioxothiomorpholinyl. The heterocyclic group is optionally substituted with one or more substituents described in the present invention.

[0047] The term "hydrogen (H)" represents a single hydrogen atom, and such an atomic group can be connected to other groups, for example, connected to an oxygen atom to form a hydroxyl group.

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

[0049] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, where the alkyl group has the meaning as described in the present invention. Unless otherwise specified in detail, 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 optionally be substituted by one or more substituents described in the present invention. 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), etc.

[0050] The term "cycloalkyl" refers to a saturated or unsaturated cyclic hydrocarbon group composed of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl may be a monocyclic, fused polycyclic, bridged or spiro ring structure. The cycloalkyl may have 3 - 8 carbon atoms, i.e., "C3 - C8 cycloalkyl", such as C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, C3 cycloalkyl. Non - limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, etc. The term also encompasses the situation where the C atoms may be substituted by oxo (=O).

[0051] The term "stereoisomer" refers to compounds having the same chemical constitution but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, etc.

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

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

[0054] The term "pharmaceutically acceptable carrier" refers to those substances that do not cause significant irritation to an organism 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, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

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

[0056] Compound of formula I

[0057] On the one hand, the present invention provides a compound of formula I as shown, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,

[0058]

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

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

[0061] Q, W, Y, U are independently selected from C, N, and Y and Q are not both C;

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

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

[0064] R9 is an optionally substituted heteroaryl, an optionally substituted aromatic ring, an optionally substituted 3- to 8-membered heterocycle, or an optionally substituted C3-C8 cycloalkyl, and the substituents are selected from halogen, C1-C8 linear or branched alkyl, C1-C8 alkoxy, and haloalkyl; preferably, R9 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6- to 10-membered monocyclic or bicyclic aromatic ring group, an optionally substituted 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl;

[0065] In Formula II, Z is selected from C and N;

[0066] R7 is selected from H, halogen, C1-C8 linear or branched alkyl;

[0067] R8 is absent or independently selected from H, halogen, C1-C8 linear or branched alkyl;

[0068] In Formula IV, A, B, and M are selected from CH and N, and A, B, and M are not simultaneously CH.

[0069] In one embodiment, R1 is absent or selected from H, halogen, C1-C8 linear or branched alkyl, and C1-C8 alkoxy. In a preferred embodiment, R1 is absent. In a preferred embodiment, R1 is C1-C8 linear or branched alkyl or C1-C8 alkoxy. In a more preferred embodiment, R1 is C1-C5 linear 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, and butoxy. In a more specific embodiment, R1 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and 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.

[0070] In one embodiment, R2 is absent or selected from H, halogen, C1-C8 straight-chain 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, iodine. In a more specific embodiment, R2 is selected from H, fluorine, chlorine, 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.

[0071] In one embodiment, R1 and R2 together form a C3-C8 cycloalkyl, aryl, heteroaryl or 3-8 membered heterocycle. In a preferred embodiment, R1 and R2 together form a C3-C6 cycloalkyl. In one embodiment, R1 and R2 together form a C6-C 10 aryl. In another preferred embodiment, R1 and R2 together form a C3-C6 aryl. In one embodiment, R1 and R2 together form a 5-10 membered heteroaryl, preferably a 5-6 membered heteroaryl. In another preferred embodiment, R1 and R2 together form a C3-C6 heteroaryl. In another preferred embodiment, R1 and R2 together form a 3-6 membered heterocycle. In a specific embodiment, R1 and R2 together form cyclopropane, cyclobutane, cyclopentane, cyclopentenyl, cyclohexane. In a specific embodiment, R1 and R2 together form a benzene ring. In another more specific embodiment, R1 and R2 together form cyclopentenyl. In another specific embodiment, R1 and R2 together form pyridine. In another specific embodiment, R1 and R2 together form thiophene. In another specific embodiment, R1 and R2 together form pyrrole. In another specific embodiment, R1 and R2 together form furan.

[0072] In one embodiment, R3 is absent or selected from H, halogen, C1-C8 straight-chain or branched alkyl, C1-C8 alkoxy. In a preferred embodiment, R3 is absent. In a preferred embodiment, R3 is C1-C8 straight-chain or branched alkyl, C1-C8 alkoxy. In a more preferred embodiment, R3 is C1-C5 straight-chain or branched alkyl, C1-C5 alkoxy. In a specific embodiment, R3 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, methoxy, ethoxy, propoxy, butoxy. In a more specific embodiment, R3 is selected from methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, 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.

[0073] In one embodiment, R4 and R5 are absent or independently selected from H, halogen, C1-C8 straight-chain or branched alkyl, and C1-C8 alkoxy.

[0074] In one embodiment, R4 is C1-C8 straight-chain or branched alkyl. 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.

[0075] In one embodiment, R5 is C1-C8 straight-chain or branched 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.

[0076] In one embodiment, R7 is selected from H, halogen, C 一 -C8 straight-chain or branched alkyl. In a preferred embodiment, R7 is C1-C5 straight-chain 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 yet another particularly specific embodiment, R7 is fluorine. In yet another particularly specific embodiment, R7 is chlorine.

[0077] In one embodiment, R8 is absent or selected from H, halogen, and C1-C8 straight-chain or branched alkyl. In a preferred embodiment, R8 is absent. In a preferred embodiment, R8 is C1-C8 straight-chain 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 yet another particularly specific embodiment, R8 is fluorine. In yet another particularly specific embodiment, R8 is absent.

[0078] In one embodiment, R9 is an optionally substituted heteroaryl group, an optionally substituted aromatic ring, an optionally substituted 3-8 membered heterocyclic ring, or an optionally substituted C3-C8 cycloalkyl group, and the substituents are selected from halogen, C1-C8 straight or branched chain alkyl, C1-C8 alkoxy, and haloalkyl.

[0079] 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, furyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, triazolyl. In another preferred embodiment, the aromatic ring is a phenyl group. In yet another preferred embodiment, the 3-8 membered heterocyclic ring is a 3-6 membered heterocyclic ring. In yet 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, furyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl. In a more specific embodiment, the heteroaryl group is pyridyl, pyrimidinyl, thienyl, furyl, oxazolyl, thiazolyl.

[0080] 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.

[0081] In one embodiment, Q, W, Y, and U are independently selected from C and N, and Y and Q are not both 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.

[0082] In one embodiment, the C1-C8 straight or branched chain alkyl is selected from C1-C5 straight or branched chain alkyl. In a specific embodiment, the C1-C8 straight or branched chain alkyl and the C1-C5 straight or branched chain alkyl are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In a more specific embodiment, the C1-C8 straight or branched chain alkyl and the C1-C5 straight or branched chain alkyl are independently selected from methyl, ethyl, propyl, and isopropyl.

[0083] 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).

[0084] In one embodiment, the C1-C8 alkoxy group is selected from C1-C5 alkoxy groups. In a specific embodiment, the C1-C8 alkoxy group and the C1-C5 alkoxy group are each independently selected from methoxy, ethoxy, propoxy, butoxy, pentyloxy. In a more specific embodiment, the C1-C8 alkoxy group and the C1-C5 alkoxy group are each independently selected from methoxy, ethoxy, propoxy.

[0085] In one embodiment, the halogen is fluorine, chlorine, bromine, iodine. In a preferred embodiment, the halogen is fluorine, chlorine, bromine. In a more preferred embodiment, the halogen is fluorine, chlorine. In a particularly preferred embodiment, the halogen is fluorine.

[0086] In a specific embodiment, the compound of formula I is the compound shown in formula V:

[0087]

[0088] wherein, R1, R2, R3, R4, R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0089] or R1 and R2 together 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 heterocyclic group containing 1-3 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0090] Q, W, Y, U are independently selected from C, N, and Y and Q are not both C;

[0091] is a single bond or a double bond;

[0092] Z is selected from C and N;

[0093] R7 is selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl;

[0094] R8 is absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl;

[0095] 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 aryl 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, and the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

[0096] In a specific embodiment, the compound of formula I is a compound represented by formula V-1:

[0097]

[0098] wherein, R1, R2, and R3 are independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy;

[0099] 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;

[0100] Z is selected from C and N;

[0101] R7 is selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl;

[0102] R8 is absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl;

[0103] 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 aryl 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 are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

[0104] In a specific embodiment, the compound of formula I is a compound as shown in formula VI:

[0105]

[0106] Wherein, R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy;

[0107] Or 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 heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0108] Q, W, Y, and U are independently selected from C and N, and Y and Q are not both C at the same time;

[0109] Is a single bond or a double bond;

[0110] 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 aryl ring group, an optionally substituted 3-8 membered monocyclic or bicyclic heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl group; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl.

[0111] In a specific embodiment, the compound of formula I is a compound as shown in formula VII:

[0112]

[0113] Wherein: R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, and propoxy;

[0114] Or 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 heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

[0115] Q, W, Y, and U are independently selected from C and N, and Y and Q are not both C at the same time;

[0116] Is a single bond or a double bond;

[0117] A, B, and M are selected from C and N, and A, B, and M are not simultaneously C;

[0118] R9 is an optionally substituted 5- to 10-membered monocyclic or bicyclic heteroaryl containing 1 to 5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 6- to 10-membered monocyclic or bicyclic aryl ring group, an optionally substituted 3- to 8-membered monocyclic or bicyclic heterocycle containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted C3-C8 cycloalkyl; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, difluoromethyl.

[0119] In a specific embodiment, the compound shown in Formula I is selected from any one of the following compounds:

[0120]

[0121]

[0122]

[0123] Advantageous technical effects of the present invention

[0124] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0125] The compounds provided by the present invention have good selectivity for acting on OX1R and OX2R. The compounds provided by the present invention are used for treating sleep disorder-related diseases. The compounds provided by the present invention have good pharmacodynamic activity and also have excellent physicochemical properties and pharmacokinetic properties.

[0126] Examples

[0127] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention and should not be construed as a limitation to the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are by weight.

[0128] Synthesis examples

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

[0130]

[0131] 1.1 Preparation of ethyl 2-phenylindazole-1-carboxylate

[0132] 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) were added to a 50 mL three-necked round-bottom flask. The reaction was carried out at 78 °C overnight under N2 protection. After the reaction was completed as detected by TLC, it was cooled to room temperature, quenched with saturated aqueous Na2S2O3, extracted with 3×30 mL of EA, washed with brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography on silica gel with ethyl acetate / petroleum ether (1 / 3) gave 0.8 g of a yellowish-brown oily liquid. LCMS (ES, m / z): 266 [M+H] + 。

[0133] 1.2 Preparation of 2-phenylindolizine-1-carboxylic acid

[0134] Ethyl 2-phenylindolizine-1-carboxylate (0.74 g, 2.81 mmol), sodium hydroxide (0.56 g, 14.07 mmol), and EtOH / H2O (10 / 2 mL) were added to a 100 mL single-necked round-bottom flask. The reaction was carried out at 65 °C overnight. After the reaction was completed as detected by TLC, it was cooled to room temperature, and ethanol was removed by concentration. Then, water was added to the residue, and the pH was adjusted to 4-5 with 3N HCl. It was extracted with 3×30 mL of EA, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 0.65 g of a pale yellow solid. LCMS (ES, m / z): 238 [M+H] + 。

[0135] 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

[0136] 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 under an ice bath. The reaction was allowed to proceed for 10 min while maintaining the temperature. 2-(4,6-Dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (562 mg, 2.58 mmol) was added, and the reaction was carried out at room temperature for 2 h. After the reaction was completed as detected by TLC, 30 mL of water was added, and it was extracted with 3×30 mL of DCM, washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel with DCM / MeOH (20 / 1) gave 585 mg of the product. 11H 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] + .

[0137] Example 2 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyridin-2-yl)indazol-1-yl)methanone

[0138]

[0139] Replace the reaction raw material acetophenone with 1-(pyridin-2-yl)ethan-1-one, and prepare the target compound according to the method of Example 1. 1 1H NMR (400 MHz, Chlorofomm-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] + .

[0140] Example 3 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(3-fluoropyridin-2-yl)indazol-1-yl)methanone

[0141]

[0142] Replace the reaction raw material acetophenone with 1-(3-fluoropyridin-2-yl)ethan-1-one, and prepare the target compound according to the method of Example 1. 11H 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]+.

[0143] 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

[0144]

[0145] Replace the reaction raw material acetophenone with 1-(5-methylthiophen-2-yl)ethan-1-one, and prepare the target compound according to the method of Example 1. 1 1H 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 = 7.6 Hz, 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] + .

[0146] 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

[0147]

[0148] 5.1 Preparation of Ethyl 3-(thiophen-2-yl)propiolate

[0149] 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). N2 was introduced, and the reaction was stirred at 65 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel column chromatography (EA:PE = 0-10%) to obtain 1.5 g of a pale yellow oil.

[0150] 5.2 Preparation of Ethyl 2-(Thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylate

[0151] 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). N2 was introduced, and the reaction was carried out overnight at room temperature. The reaction mixture was concentrated, 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 obtain 500 mg of a pale yellow solid.

[0152] 5.3 Preparation of 2-(Thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic Acid

[0153] 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. The reaction was stirred at 60 °C for 1 h. The reaction mixture was concentrated and adjusted to pH 5-6 with 1 M HCl, extracted with EA (3 x 30 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 400 mg of a white solid.

[0154] 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

[0155] 2-(Thiophen-2-yl)pyrazolo[1,5-a]pyridine-3-carboxylic acid (100 mg, 0.41 mmol) was added to a single-necked flask containing 5 mL of DCM. HATU (171 mg, 0.45 mmol) and DIEA (159 mg, 1.23 mmol) were added. After stirring for 10 min, (3aR,6aS)-2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (98 mg, 0.45 mmol) was added. The reaction was carried out overnight at room temperature. The reaction solution was concentrated and purified by silica gel column chromatography (EA:PE = 0 - 100%), and 80 mg of the product was obtained. 1 1H 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] + .

[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 reaction raw material 2-iodothiophene was replaced with 2-iodopyridine, and the target compound was prepared according to the method of Example 1.

[0159] 1 1H 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]+ .

[0160] Example 7 (2-(3-Fluoropyridin-2-yl)indazol-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), iron(III) acetylacetonate (0.22 g, 0.9 mmol), and tetrahydrofuran (30 mL) were placed in a 100 mL round-bottom flask. Methylmagnesium chloride (3 N, 10.5 mL, 31.6 mmol) was added dropwise thereto at -78 °C. After the addition was complete, the mixture was stirred at this temperature for 1 hour and then transferred to room temperature for stirring. After monitoring the reaction by TLC and confirming its completion, the reaction was quenched by adding 20 mL of water. The mixture was extracted three times with ethyl acetate (30 mL × 3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by suction. Column chromatography separation (petroleum ether / ethyl acetate = 3:1) gave 2.2 g of a white solid product.

[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 at 170 °C for 1.5 hours. After cooling to room temperature, 10 mL of water and 10 mL of ethyl acetate were added for dilution, and then the mixture was filtered through diatomaceous earth. The filtrate was extracted three times with ethyl acetate (20 mL × 3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by suction. Column chromatography separation (petroleum ether / ethyl acetate = 1:3) gave a pale yellow oil, which was dissolved in dichloromethane. Trifluoroacetic acid was added, and the reaction was carried out for 4 hours. The organic phase was washed with saturated sodium carbonate solution, dried, and the solvent was evaporated to give 0.11 g of a yellow oil product.

[0166] 7.3 Preparation of (2-(3-Fluoropyridin-2-yl)indazol-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)indazole-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. After stirring 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 added portionwise, and the mixture was stirred at room temperature overnight. After monitoring the reaction by TLC and confirming its completion, the reaction solution was directly concentrated and then subjected to column chromatography separation (methanol / dichloromethane = 1:30) to obtain 0.45 g of the product. 1 1H NMR (400 MHz, Chloroform-d) δ 8.51 (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] + .

[0168] Example 8 (2-(3-Fluoropyridin-2-yl)indazol-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] Replace the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine with 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine, and prepare the target compound according to the method of Example 7. 11H NMR (400 MHz, Chloroform) 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] + 。

[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] Replace the reaction raw material acetophenone with 2 - acetylthiazole, and prepare the target compound according to the method of Example 1. 1 1H 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] + .

[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] Replace the reaction raw material 2,4 - dichlorofuro[3,2 - d]pyrimidine with 2 - chloroquinoxaline, and prepare the target compound according to the method of Example 7. 11H 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

[0177] 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] + .

[0178] Example 11 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(3-(trifluoromethyl)pyridin-2-yl)indazol-1-yl)methanone

[0179]

[0180] Replace the reaction raw material acetophenone with 2-acetyl-3-trifluoromethylpyridine, and prepare the target compound according to the method of Example 1. 1 1H 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] + .

[0181] 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

[0182]

[0183] Replace the reaction raw material 2-iodothiophene with iodobenzene and 1-aminopyridinium iodide with 1-aminopyrimidinium iodide, and prepare the target compound according to the method of Example 5. 11H 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] + .

[0184] 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

[0185]

[0186] Replace the reaction raw material 2-iodothiophene with iodobenzene and 1-aminopyridinium iodide with 1-aminopyrazinium iodide, and prepare the target compound according to the method of Example 5. 1 1H 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, lH), 630 (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, lH), 3.47 (dd, J = 11.6, 5.1 Hz, 1H), 3.30 - 3.09 (m, 2H), 2.97 (dd, J = 11.0, 4.3 Hz, 1H), 2.89 - 2.65 (m, 2H), 2.29 (s, 6H). LCMS (ES, m / z): 440 [M+H] + .

[0187] 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

[0188]

[0189] Replace the reaction raw material 2-iodothiophene with iodobenzene and 1-aminopyridinium iodide with 1-aminopyridazinium iodide, and prepare the target compound according to the method of Example 5. 1 H NMR(400MHz, DMSO-d6) δ8.55(d, J = 4.0Hz, 1H), 8.20(d, J = 8.0Hz, 1H), 7.74(d, J = 8.0Hz, 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] + .

[0190] 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

[0191]

[0192] Replace the reaction raw material acetophenone with 2-fluoroacetophenone, and prepare the target compound according to the method of Example 1. 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] + .

[0193] 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

[0194]

[0195] Replace the reaction raw material acetophenone with 2-methylacetophenone, and prepare the target compound according to the method of Example 1. 1 HNMR(400MHz, CDCl3)δ7.86(d, J = 6.9Hz, 1H), 7.63(d, J = 9.1Hz, 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] + .

[0196] 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

[0197]

[0198] Replace the reaction raw material acetophenone with 3-acetylthiophene, and prepare the target compound according to the method of Example 1. 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] + .

[0199] 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

[0200]

[0201] Replace the reaction raw material acetophenone with 2-acetyl-3-fluoropyridine, and replace ethyl 2-pyridineacetate with ethyl 2-(5-fluoropyridin-2-yl)acetate, and prepare the target compound according to the method of Example 1. 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] + .

[0202] Example 19 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(6-fluoro-2-(pyridin-2-yl)indazol-1-yl)methanone

[0203]

[0204] Replace the reaction raw material acetophenone with 2-acetylpyridine, and replace ethyl 2-pyridineacetate with ethyl 2-(5-fluoropyridin-2-yl)acetate, and prepare the target compound according to the method of Example 1. 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] + .

[0205] Example 20 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(IH)-yl)(2-(oxazol-2-yl)indazol-1-yl)methanone

[0206]

[0207] Replace the reaction raw material acetophenone with oxazole-2-ethanone, and prepare the target compound according to the method of Example 1. 1HNMR (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 (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] + .

[0208] Example 21 ((3aR, 6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(pyrimidin-2-yl)indazol-1-yl)methanone

[0209]

[0210] Replace the reaction raw material acetophenone with 2-acetylpyrimidine, and prepare the target compound according to the method of Example 1. 1 HNMR (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 (m, 1H), 6.56 (t, J = 6.7 Hz, 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] + .

[0211] Example 22 ((3aR, 6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-(5-methylthiazol-2-yl)indazol-1-yl)methanone

[0212]

[0213] Replace the reaction raw material acetophenone with 2-acetyl-5-methylthiazole, and prepare the target compound according to the method of Example 1. 11H 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] + .

[0214] 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

[0215]

[0216] Replace the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine with 2,4,6-trichloro-5-fluoropyrimidine, and prepare the target compound according to the method of Example 7. 1 1H 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] + .

[0217] 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

[0218]

[0219] Replace the reaction raw material 2-(3-fluoropyridin-2-yl)indolizine-1-carboxylic acid with 2-(pyridin-2-yl)indolizine-1-carboxylic acid, and 2,4-dichlorofuro[3,2-d]pyrimidine with 2,4,6-trichloro-5-fluoropyrimidine, and prepare the target compound according to the method of Example 7. 11H 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] + .

[0220] Example 25 (2-(3-Fluoropyridin-2-yl)indazol-1-yl)((3aR,6aS)-5-(4-methylthieno[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0221]

[0222] Replace the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine with 2,4-dichlorothieno[3,2-d]pyrimidine, and prepare the target compound according to the method of Example 7. 1 1H 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] + .

[0223] Example 26 (2-(3-Fluoropyridin-2-yl)indazol-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

[0224]

[0225] Replace the reaction raw material 2,4-dichlorofuro[3,2-d]pyrimidine with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine, and prepare the target compound according to the method of Example 7. 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), 3.47 - 3.22(m, 4H), 3.09 - 2.68(m, 7H), 2.26(s, 3H). LCMS(ES, m / z): 483[M + H] + .

[0226] 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

[0227]

[0228] Replace the reaction raw material 2-chloro-4-methylfuro[3,2-d]pyrimidine with 3-chloro-2,5-dimethylpyrazine, and prepare the target compound according to the method of Example 7. 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] + .

[0229] 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

[0230]

[0231] Replace the reaction raw material acetophenone with 2-acetylthiophene, and prepare the target compound according to the method of Example 1. 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), 3.783.43(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] + .

[0232] 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

[0233]

[0234] Replace the reaction raw material 2-iodothiophene with 2-iodopyrimidine, and prepare the target compound according to the method of Example 5. 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] + .

[0235] 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

[0236]

[0237] Replace the reaction raw material 1-aminopyridine iodide with 1-amino-3-fluoropyridine iodide, and prepare the target compound according to the method of Example 5.1 1H 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] + .

[0238] 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

[0239]

[0240] Replace the reaction raw material 1-aminopyridinium iodide with 1-amino-3-methylpyridinium iodide, and prepare the target compound according to the method of Example 5. 1 1H 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] + .

[0241] 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

[0242]

[0243] Replace the reaction raw material 2-chloro-4-methylfuro[3,2-d]pyrimidine with 2-chloro-4,6-dimethoxypyrimidine, and prepare the target compound according to the method of Example 7. 11H 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] + .

[0244] 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

[0245]

[0246] 33.1 Preparation of ethyl 2-phenylimidazo[1,2-b]pyridazine-3-carboxylate

[0247] 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. The temperature was raised to 150 °C by microwave reaction and reacted for 6 hours. After the reaction was completed, the temperature was lowered to room temperature, the solvent was removed under reduced pressure, and the product was purified by column chromatography (PE:EA = 10:1) to obtain 0.6 g of the product.

[0248] 33.2 Preparation of 2-phenylimidazo[1,2-b]pyridazine-3-carboxylic acid

[0249] 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 then 2 mL of ethanol was added. The temperature was raised to 75 °C and reacted for 1 hour. After the reaction was completed, the temperature was lowered to room temperature, ethanol was removed 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, which was directly used in the next step without further purification.

[0250] 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

[0251] Under an ice bath, 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 to a 50 mL single-necked round-bottom flask. The mixture was kept warm for reaction for 10 min, then 2-(4,6-dimethylpyrimidin-2-yl)octahydropyrrolo[3,4-c]pyrrole (0.4 g, 1.84 mmol) was added. The reaction was carried out at room temperature for 2 h. After the reaction was completed as detected by TLC, 30 mL of water was added, and the mixture was extracted with 3×30 mL of DCM, then washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel with DCM / MeOH (20 / 1) was used to obtain 0.3 g of the product. 1 1H 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, 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] + .

[0252] 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

[0253]

[0254] Replace the reaction raw material 2-iodothiazole with 4-iodopyridine, and prepare the target compound according to the method of Example 5. 1 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] + .

[0255] Example 35 ((3aR,6aS)-5-(4,6-dimethylpyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(3-methyl-2-(pyridin-2-yl)indazol-1-yl)methanone

[0256]

[0257] Replace the reaction raw material acetophenone with 2-propionylpyridine, and prepare the target compound according to the method of Example 1. 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,4H),2.93 - 2.73(m,3H),2.48(s,3H),2.30(s,6H).LCMS(ES,m / z):453[M + H] + .

[0258] 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

[0259]

[0260] Replace the reaction raw material 2-iodothiophene with 3-iodopyridine, and prepare the target compound according to the method of Example 5. 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] + .

[0261] 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

[0262]

[0263] Replace the reaction raw material 1-aminopyridine iodide with 1-amino-3-fluoropyridine iodide, and prepare the target compound according to the method of Example 5. 1 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] + .

[0264] Pharmacological test example:

[0265] Test example 1 In vitro activity test

[0266] (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 at a ratio of 1:4 and set aside.

[0267] (2) Compound preparation: Dilute the compound with DMSO to a stock solution of 5 mM, then dilute it 3.16-fold into 10 gradients, and then dilute the prepared compound with Stimulation buffer to the corresponding concentration (4x) and set aside.

[0268] (3) Cell preparation: Digest the CHO-K1-OX1 and CHO-K1-OX2 cells on the culture dish with trypsin, wash the cells with the medium and collect them into a 5 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes, discard the supernatant. Add 3 mL of PBS, gently pipette and mix well. Centrifuge at 1000 rpm again for 5 minutes, discard the supernatant. Resuspend the cells with 1x Stimulation buffer, count the cells using a Countstar cell counter, and adjust the cell density to 1.71x10 6 cells / mL and set aside.

[0269] (4) Cell addition: Add the cell suspension to the experimental plate, 7 μL per well (i.e., approximately 12,000 cells per well).

[0270] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate, 3.5 μL per well.

[0271] (6) Reaction incubation: After gentle shaking, place the experimental plate in an incubator at 37 °C for 30 minutes.

[0272] (7) EC 80 agonist addition: Add the 4x Orexin A (OX1 receptor), 4x Orexin 2 receptor agonist (OX2 receptor) solution of EC 80 , 3.5 μL per well.

[0273] (8) Reaction incubation: After gentle shaking, place the experimental plate in an incubator at 37 °C for 45 minutes.

[0274] (9) Add detection reagent: Dilute IP1-d2 and Anti-IP1 cryptate in the Lysis & detection buffer of the Cisbio IP-one detection kit at a ratio of 1:20 respectively. Add the diluted IP1-d2 and Anti-IP1 cryptate to the experimental plate, 3 μL per well each. After shaking, let the experimental plate stand at room temperature for 60 minutes.

[0275] (10) Experimental reading: Read the plate on Envision, detect the readings at 665 nm and 615 nm channels, and calculate the ratio of the 665 nm / 615 nm readings.

[0276] According to the antagonistic effect values of different concentration test points of the compound sample, use GraphPad Prism software to fit the antagonistic curve of the compound sample against the orexin receptor and calculate the IC 50 . The results are shown in Table 1:

[0277] Table 1

[0278]

[0279]

[0280] IC 50 value < 100 nM: +++ ; IC 50 value is 100 - 300 nM: ++ ; IC 50 value is 300 - 1000 nM: + ; IC 50 value > 1000 nM: -

[0281] Data shows that the compound of the present invention has good inhibitory activity against the OX2 receptor, and the inhibitory effect of the compound on the OX2 receptor is significantly better than that on the OX1 receptor, showing good selectivity.

[0282] Determination of Pharmacokinetic Parameters of Test Substances in Rat Plasma in Test Example 2

[0283] Six to nine-week-old healthy male SD rats were randomly divided into two groups, with 3 rats in each group. One group was intravenously injected with the test compound at 1 mg / kg, and the other group was orally administered the test compound at 10 mg / kg. Whole blood was collected from the animals in the intravenous group and the oral group before dosing and at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, 10.0, and 24.0 hours after dosing, and plasma samples were obtained by centrifugation.

[0284] All biological samples were quantitatively analyzed by LC-MS / MS method. Using WinNonlinTM Version 7.0 (Pharsight, Mountain View, CA) pharmacokinetic software, relevant pharmacokinetic parameters were calculated by the non-compartmental model linear logarithmic trapezoidal method. AUC 0-last represents the area under the plasma concentration-time curve from the zero time point to the time point of the last detectable concentration; PO represents oral administration; iv represents intravenous injection, and C max represents the peak concentration, and F% represents the oral bioavailability. The results are shown in Table 2:

[0285] Table 2

[0286]

[0287] Data shows that in the rat pharmacokinetic evaluation experiment, the compound of the embodiment of the present invention showed good in vivo exposure and good bioavailability after oral administration.

[0288] Test Example 3 Spontaneous Activity of Mice

[0289] Six to nine-week-old male ICR mice were randomly divided into groups according to the principle of body weight balance, with 8 or 9 mice in each group, and were respectively given blank solvent and the test compound at 10, 30, and 100 mg / kg. The animals were immediately placed in the test box after dosing, and the activity distance of the animals within 60 minutes was recorded and analyzed using TopScan Version 3.0. The total activity distance of the animals in each dosing group of the test article was compared with that of the blank solvent group to determine whether the test article had a significant effect on the spontaneous activity of the animals. The experimental data was expressed as mean ± standard error (Mean ± SD), and one-way analysis of variance was performed using SPSS 21.0 statistical software. Dunnett test was used for pairwise comparison, and p < 0.05 was represented as *.

[0290] Table 3

[0291]

[0292] Conclusion: The compound of the present invention can significantly reduce the spontaneous activity distance of mice.

[0293] Test Example 4 Pentobarbital Sodium Synergistic Sleep Test

[0294] Male ICR mice aged 6 - 9 weeks were randomly divided into groups of 8 according to the principle of body weight balance, and were given blank solvent and the test compound at 3, 10, and 30 mg / kg respectively. After 5 minutes, 45 mg / kg of pentobarbital sodium was injected intraperitoneally. The time when the righting reflex disappeared and the time when the righting reflex recovered in the mice were recorded. Sleep latency = the time when the righting reflex disappeared - the time of pentobarbital sodium administration, and sleep duration = the time when the righting reflex recovered - the time when the righting reflex disappeared. The sleep latency and sleep maintenance time of each test article administration group were compared with those of the blank solvent group to determine whether the test article had a significant effect on the sleep latency and sleep duration of the animals. The experimental data were expressed as mean ± standard error (Mean ± SD), one-way analysis of variance was performed using SPSS 21.0 statistical software, and Dunnett's test was used for pairwise comparison. A p < 0.05 was considered *.

[0295] Table 4

[0296]

[0297] Conclusion: The compound of the present invention can shorten the sleep latency of mice and prolong the sleep duration of mice.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof, Among them, wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, halogen, C1-C8 straight-chain or branched alkyl, and C1-C8 alkoxy; Q, W, Y, and U are independently selected from C and N, and Y and Q are not both C at the same time; is a double bond; R6 is selected from Formula II: * represents a connection point; R9 is an optionally substituted 5-10 membered monocyclic heteroaryl containing 1-5 heteroatoms independently selected from nitrogen or sulfur, or an optionally substituted 6-10 membered monocyclic aryl ring group, and the substituents are selected from halogen, C1-C8 straight-chain or branched alkyl, C1-C8 alkoxy, and C1-C8 haloalkyl; In formula II, Z is N; R7 is selected from H, halogen, C1-C8 straight-chain or branched alkyl; R8 is absent.

2. The compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 1, wherein: The C1-C8 straight-chain or branched alkyl is selected from C1-C5 straight-chain or branched alkyl; and / or The C1-C8 alkoxy is selected from C1-C5 alkoxy; and / or 3. The compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 2, wherein: The halogen is fluorine, chlorine, bromine, or iodine; and / or The C1-C5 straight-chain or branched alkyl is selected from methyl, ethyl, propyl, butyl, and pentyl; and / or The C1-C5 alkoxy is selected from methoxy, ethoxy, propoxy, butoxy, and pentyloxy; and / or and / or the heteroaryl is selected from pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, thiazolyl, thiadiazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyrazinyl, and triazolyl; and / or The haloalkyl is selected from fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl.

4. The compound represented by formula I as described in any one of claims 1-3, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that: The compound of formula I is as shown in formula V: wherein R1, R2, R3, R4, and R5 are absent or independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy; Q, W, Y, and U are independently selected from C and N, and Y and Q are not both C at the same time; is a double bond; Z is N; R7 is selected from H, fluorine, chlorine, methyl, ethyl, and propyl; R8 is absent; R9 is an optionally substituted 5-10 membered monocyclic heteroaryl containing 1-5 heteroatoms independently selected from nitrogen or sulfur, or an optionally substituted 6-10 membered monocyclic aryl ring group, and the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl.

5. The compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof according to claim 4, wherein: The compound of formula V is as shown in formula V-1: wherein R1, R2, and R3 are independently selected from H, fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, and propoxy; R7 is selected from H, fluorine, chlorine, methyl, ethyl, and propyl; R8 is absent; R9 is an optionally substituted 5-10 membered monocyclic heteroaryl containing 1-5 heteroatoms independently selected from nitrogen or sulfur, or an optionally substituted 6-10 membered monocyclic aryl ring group; the substituents are selected from fluorine, chlorine, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, trifluoromethyl, fluoromethyl, and difluoromethyl.

6. The compound of formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to claim 1, wherein: The compound of formula I is selected from any one of the following compounds:

7. A pharmaceutical composition, characterized in that Comprising the compound of formula I as claimed in claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, optionally further comprising a pharmaceutically acceptable carrier.

8. Use of the compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 7 in the manufacture of a medicament, wherein, The drug is used for preparing a medicament for treating an orexin receptor-related disease.

9. The use according to claim 8, wherein the orexin receptor-related disease is sleep disorder, depression, anxiety, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorder, panic attack disorder, behavioral disorder, emotional disorder, post-traumatic stress disorder, psychosis, dementia, drug dependence, addiction, cognitive disorder, Alzheimer's disease, Parkinson's disease, movement disorder, eating disorder, pain.

10. The use according to claim 8, wherein the orexin receptor-related disease is sleep disorder, schizophrenia, bipolar disorder, mental confusion, headache.

11. The use according to claim 8, wherein the orexin receptor-related disease is migraine.

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