Octahydropyrrolo[3,4-c]pyrrolmethyl ketone derivative and its application

Abstract

The present invention belongs to the field of medicine, and specifically relates to a compound represented by the general formula I shown below or a pharmaceutically acceptable salt, stereoisomer, tautomer and a composition comprising the compound, as well as applications in the field of medicine.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to an 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 called hypocretins, 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 prefers 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 confirmed as a target for sleep-promoting therapy by observing reduced orexin levels and loss of orexin-stimulating neurons in human narcolepsy patients (Mignot et al., 2001, The American Journal of Human Genetics, 68: 686-699), or in rare cases associated with 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, panic disorder, obsessive-compulsive disorder, affective neuropathy, depressive neuropathy, anxiety neuropathy, mood disorders, panic attack disorders, behavioral disorders, emotional 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, pain syndrome, etc. OX2R is selectively expressed in the tuberomammillary nucleus (TMN), paraventricular nucleus (PVN) of the hypothalamus, and nucleus accumbens (NAc). These brain regions are the main effect sites of orexin neurons in the lateral hypothalamus (LH), which are related to eating, sleep, depression, anxiety, drug addiction, and motivated behaviors, 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 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, and therefore have good clinical application prospects.

[0007] The following is a summary of some aspects of the present invention, but is not intended to limit the present invention. When there is a discrepancy between the disclosure of this specification and the referenced document, the disclosure of this specification shall prevail.

[0008] The present invention aims to provide an octahydropyrrolo[3,4-c]pyrrolmethyl ketone derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer and a pharmaceutical composition thereof. The compound and the pharmaceutical composition can be used for preventing or treating diseases associated with 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, W and Q are independently selected from O, C, N, and S;

[0012] U and B are independently selected from C and N;

[0013] A and Z are independently selected from C and N, and are not C at the same time;

[0014] is a single bond or a double bond, and at least two is a double bond;

[0015] R1 is selected from halogen, H, optionally substituted C1-C8 straight or branched alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, and the substituent is halogen;

[0016] R2 is selected from H, halogen, optionally substituted C1-C8 straight or branched alkyl, hydroxyl, wherein the substituent is halogen;

[0017] R3 is selected from the following groups:

[0018] A) an aromatic ring optionally substituted by n Ra groups and substituted in the ortho position by a Rb group;

[0019] B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S;

[0020] n is an integer from 0 to 4;

[0021] Ra is independently selected from H, halogen, C1-C8 straight or branched alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl;

[0022] Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted aromatic ring, and the substituent is a C1-C8 straight or branched chain alkyl, a C1-C8 alkoxy group, or a halogen.

[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 thereof, 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 a pharmaceutical composition thereof in the preparation of a drug for treating diseases associated with orexin receptors.

[0025] In one embodiment, the disease associated with orexin 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, 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 those generally understood by those of ordinary skill in the art to which the invention belongs. If there is a conflict, the definitions provided in the application shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commodity 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 may 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 in the present invention, wherein the substitution occurs at any reasonable position allowed by the valence on the given structure or group.

[0031] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any convenient position of the substituent. When a bond to a substituent is shown as passing through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring-forming 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 by a specific substituent. Unless otherwise indicated, a substituent can be substituted at each reasonable position of the group. When more than one position in the given structural formula can be substituted by one or more specific substituents selected, the substituent can be substituted at each reasonable position in the structural formula in the same or different manner.

[0033] In addition, it should be noted that, unless explicitly stated otherwise, the description method of "respectively and independently" used in the present invention 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 the numerical range are disclosed, any numerical value and any included range falling within the range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood to represent each numerical value and range encompassed in a wider range. When any variable (such as R), and variables with markers (such as R1, R2, R3, R4, R5, R6, R7, etc.) appear more than once in the composition or structure of the compound, its definition in each case is independent at each occurrence. For example, if a group is replaced by 0, 1, 2, 3 or 4 R substituents, the group can be optionally replaced by up to four R substituents, and the options of each R substituent in each case are independent of each other.

[0035] In various parts of this specification, the substituents of the disclosed compounds of the present invention are disclosed according to group types or ranges. It is particularly pointed out that the present invention includes each independent subcombination of the individual members of these group types and ranges. For example, the expression mn used herein refers to the range of m to n and the subranges composed of the individual point values ​​therein and the individual point values.

[0036] 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. An "alkyl" can have 1 to 8 carbon atoms, i.e., a "C1-C8 alkyl", such as 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 to 5 carbon atoms, i.e., "C1-C5 alkyl groups", e.g., C 1-3 Alkyl, C 1-2The term "C1-C5 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl. 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 sub-ranges 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 a 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 sub-ranges 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 sub-ranges 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 "three to eight members" should be understood to cover any sub-ranges therein and each point value, such as three to five members, three to six members, three to seven members, three to eight members, four to five members, four to six members, four to seven members, four to eight members, five to seven members, five to eight members, six to seven members, six to eight members, etc., as well as three, four, five, six, seven, eight members, etc. Other similar expressions herein should also be understood in a similar manner.

[0037] 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.

[0038] The term "selected from..." means that one or more elements in the group listed later are independently selected and may include combinations of two or more elements.

[0039] The term "comprising" is an open expression, that is, including the contents specified in the present invention but not excluding other contents.

[0040] When it is stated that each carbon atom in a group may be optionally replaced by a heteroatom, provided that the normal valencies of all atoms in the group in the present instance are not exceeded and that a stable compound is formed.

[0041] The term "heteroatom" refers to one or more oxygen (O), sulfur (S) or nitrogen (N), including nitrogen (N), sulfur (S) in any oxidation state; primary, secondary, tertiary amines and quaternary ammonium salts; or a form in which the hydrogen on the nitrogen atom in a heterocyclic ring is substituted, for example: N, NH, NR.

[0042] 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, and the like. The aryl group is optionally substituted by one or more substituents described in the present invention.

[0043] The term "heteroaryl" refers to a monocyclic, bicyclic or tricyclic ring system containing 5-14 ring atoms, or 5-10 ring atoms, or 5-8 ring atoms (i.e., 5-8 members), monovalent or polyvalent, 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 term "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaromatic rings include, but are not limited to: pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, triazolyl. The heteroaryl group is optionally substituted with one or more substituents described herein.

[0044] The terms "heterocycle" and "heterocyclyl" are used interchangeably and refer to a monocyclic, bicyclic or tricyclic ring system containing 3-12 ring atoms or 3-8 ring atoms, wherein one or more atoms in the ring are independently replaced by heteroatoms, and the heteroatoms have the meanings as described herein, and the ring can be fully saturated or contain one or more unsaturations. Unless otherwise specified, the heterocyclyl group can be a carbon group or a nitrogen group, and the -CH2- group can be optionally replaced by -C(=O)-. The sulfur atom of the ring can be optionally oxidized to S-oxide. The nitrogen atom of the ring can be optionally oxidized to N-oxide. Examples of heterocyclic groups include, but are 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 a -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 group may be optionally substituted with one or more substituents described herein.

[0045] The term "hydrogen (H)" refers to a single hydrogen atom, which may be attached to other groups, such as an oxygen atom, to form a hydroxyl group.

[0046] 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.

[0047] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule via 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.

[0048] The term "cycloalkyl" refers to a saturated cyclic hydrocarbon group consisting of carbon atoms and hydrogen atoms, preferably comprising 1 or 2 rings. The cycloalkyl can be a monocyclic, fused polycyclic, bridged or spirocyclic structure. The cycloalkyl can 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, cyclohexyl, etc. The term also encompasses situations in which the C atom can be substituted by oxo (=O).

[0049] The terms "para", "meta" and "ortho" are as understood in the art. Thus, for example, a fully substituted phenyl group has substituents at two "ortho" (o) positions adjacent to the point of attachment to the phenyl ring, two "meta" (m) positions and one "para" (p) position opposite the point of attachment, as shown below:

[0050]

[0051] The term "aromatic or heteroaromatic ring substituted by n Ra groups and substituted by Rb groups at the ortho position" means that the aromatic or heteroaromatic ring is substituted by n Ra groups and substituted by Rb groups at the ortho position of its attachment site, which can be represented by: (for example) (“*” indicates a connection site.) This is merely an example and should not be considered as a limitation of the present invention.

[0052] The term "stereoisomers" refers to compounds that have the same chemical constitution, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0053] 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 tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0054] The term "pharmaceutically acceptable salt" refers to an organic salt or an inorganic salt of a compound of the present invention.

[0055] The term "pharmaceutically acceptable carrier" refers to those substances that have no significant irritation to organisms and do not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents or emulsifiers.

[0056] 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.

[0057] Compounds of formula I

[0058] The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0059]

[0060] Wherein, W and Q are independently selected from O, C, N, and S;

[0061] U and B are independently selected from C and N;

[0062] A and Z are independently selected from C and N, and are not C at the same time;

[0063] is a single bond or a double bond, and at least two is a double bond;

[0064] R1 is selected from halogen, H, optionally substituted C1-C8 straight or branched alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, and the substituent is halogen;

[0065] R2 is selected from H, halogen, optionally substituted C1-C8 straight or branched alkyl, hydroxyl, wherein the substituent is halogen;

[0066] R3 is selected from the following groups:

[0067] A) an aromatic ring optionally substituted by n Ra groups and substituted in the ortho position by a Rb group;

[0068] B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S;

[0069] n is an integer from 0 to 4;

[0070] Ra is independently selected from H, halogen, C1-C8 straight or branched alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl;

[0071] Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted aromatic ring, and the substituent is a C1-C8 straight or branched chain alkyl, a C1-C8 alkoxy group, or a halogen.

[0072] In one embodiment, W, Q, U, and B are not C at the same time.

[0073] In one embodiment, A and Z are both N.

[0074] In one embodiment, R1 is selected from halogen, H, optionally substituted C1-C8 straight or branched alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, and the substituent is halogen. In a preferred embodiment, R1 is halogen, H, optionally substituted C1-C5 straight or branched alkyl, optionally substituted C1-C5 alkoxy, optionally substituted C3-C6 cycloalkyl, and the substituent is halogen. In a more preferred embodiment, R1 is halogen, H, optionally substituted C1-C3 straight or branched alkyl, optionally substituted C1-C3 alkoxy, optionally substituted C3-C6 cycloalkyl, and the substituent is fluorine. In a specific embodiment, R1 is fluorine, chlorine, bromine, iodine, H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, methoxy, ethoxy, propoxy, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In a more specific embodiment, R1 is fluorine, chlorine, H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluoromethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl. In another more specific embodiment, R1 is fluorine, H, methyl, fluoromethyl, cyclopropyl. In a particularly specific embodiment, R1 is cyclopropyl. In another particularly specific embodiment, R1 is fluoromethyl. In another particularly specific embodiment, R1 is methyl.

[0075] In one embodiment, R2 is selected from halogen, H, optionally substituted C1-C8 straight or branched alkyl, hydroxyl, and the substituent is halogen. In a preferred embodiment, R2 is halogen, H, optionally substituted C1-C5 straight or branched alkyl, hydroxyl, and the substituent is fluorine. In a more preferred embodiment, R2 is halogen, H, C1-C3 straight or branched alkyl, hydroxyl. In a specific embodiment, R2 is fluorine, chlorine, bromine, iodine, H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, hydroxyl. In a more specific embodiment, R2 is fluorine, chlorine, H, methyl, ethyl, propyl, isopropyl, hydroxyl. In another more specific embodiment, R2 is fluorine, methyl, hydroxyl. In a particularly specific embodiment, R2 is fluorine. In another particularly specific embodiment, R2 is methyl. In another particularly specific embodiment, R2 is hydroxyl.

[0076] In one embodiment, R3 is selected from an aromatic ring optionally substituted by n Ra groups and substituted by Rb groups in the ortho position, wherein n is an integer from 0 to 4. In another embodiment, R3 is selected from a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted by Rb groups in the ortho position, wherein n is an integer from 0 to 4.

[0077] In one embodiment, Ra is selected from H, halogen, C1-C8 straight or branched alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl. In a preferred embodiment, Ra is selected from H, halogen, C1-C5 straight or branched alkyl, C1-C5 alkoxy, C3-C6 cycloalkyl. In a more preferred embodiment, Ra is selected from H, halogen, C1-C3 straight or branched alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl. In a specific embodiment, Ra is selected from H, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, methoxy, ethoxy, propoxy, butoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. In a more specific embodiment, Ra is selected from H, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, cyclopropyl. In a particularly specific embodiment, Ra is selected from fluorine. In another particularly specific embodiment, Ra is selected from methyl. In another particularly specific embodiment, Ra is selected from cyclopropyl.

[0078] In one embodiment, Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, an optionally substituted aromatic ring, and the substituent is a C1-C8 straight or branched alkyl, a C1-C8 alkoxyl group, or a halogen. In a preferred embodiment, Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, an optionally substituted aromatic ring, and the substituent is a C1-C5 straight or branched alkyl, a C1-C5 alkoxyl group, or a halogen. In a more preferred embodiment, Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, an optionally substituted aromatic ring, and the substituent is a C1-C3 straight or branched alkyl, a C1-C3 alkoxyl group, or a halogen. In a particularly preferred embodiment, Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, an optionally substituted aromatic ring, and the substituent is a methyl, ethyl, propyl, isopropyl, fluorine, chlorine, methoxy, or ethoxyl group.

[0079] In a specific embodiment, the aromatic ring is phenyl.

[0080] In one embodiment, the heteroaromatic ring is pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, triazolyl. In a specific embodiment, the heteroaromatic ring is pyridyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, triazolyl. In a more specific embodiment, the heteroaromatic ring is pyridyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, triazolyl.

[0081] In one embodiment, C1-C8 straight or branched alkyl is selected from C1-C5 straight or branched alkyl and C1-C3 straight or branched alkyl. In a specific embodiment, C1-C8 straight or branched alkyl, C1-C5 straight or branched alkyl and C1-C3 straight or branched alkyl are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl. In a more specific embodiment, C1-C8 straight or branched alkyl, C1-C5 straight or branched alkyl and C1-C3 straight or branched alkyl are independently selected from methyl, ethyl, propyl, isopropyl.

[0082] 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).

[0083] In one embodiment, C1-C8 alkoxy is selected from C1-C5 alkoxy and C1-C3 alkoxy. In a specific embodiment, C1-C8 alkoxy, C1-C5 alkoxy and C1-C3 alkoxy are independently selected from methoxy, ethoxy, propoxy, butoxy, pentoxy. In a more specific embodiment, C1-C8 alkoxy, C1-C5 alkoxy and C1-C3 alkoxy are independently selected from methoxy, ethoxy, propoxy.

[0084] In one embodiment, the C3-C8 cycloalkyl is a C3-C6 cycloalkyl. In a preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In a more preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are cyclopropyl, cyclopentyl and cyclohexyl. In a particularly preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are cyclopropyl.

[0085] 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.

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

[0087]

[0088] Wherein, Q is selected from O and S;

[0089] A and Z are independently selected from C and N, and are not C at the same time. Preferably, A and Z are N at the same time.

[0090] R1 is selected from fluorine, chlorine, H, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0091] R2 is selected from H, halogen, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxyl;

[0092] R3 is selected from the following groups:

[0093] A) an aromatic ring optionally substituted by n Ra groups and substituted in the ortho position by a Rb group;

[0094] B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S;

[0095] n is an integer from 0 to 4;

[0096] Ra is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0097] Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted aromatic ring, and the substituent is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluorine, or chlorine.

[0098] In a specific embodiment, the compound of formula I is represented by formula III:

[0099]

[0100] Wherein, W, Q, and U are independently selected from N and C, and preferably W, Q, and U are not C at the same time;

[0101] A and Z are independently selected from C and N, and are not C at the same time. Preferably, A and Z are N at the same time.

[0102] R1 is selected from fluorine, chlorine, H, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0103] R2 is selected from H, halogen, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxyl;

[0104] R3 is selected from the following groups:

[0105] A) an aromatic ring optionally substituted by n Ra groups and substituted in the ortho position by a Rb group;

[0106] B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S;

[0107] n is an integer from 0 to 4;

[0108] Ra is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0109] Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted aromatic ring, and the substituent is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluorine, or chlorine.

[0110] In a specific embodiment, the compound of formula I is represented by formula IV:

[0111]

[0112] Wherein, W, Q, and B are independently selected from N and C, and preferably W, Q, and B are not C at the same time;

[0113] A and Z are independently selected from C and N, and are not C at the same time. Preferably, A and Z are N at the same time.

[0114] R1 is selected from fluorine, chlorine, H, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0115] R2 is selected from H, halogen, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxyl;

[0116] R3 is selected from the following groups:

[0117] A) an aromatic ring optionally substituted by n Ra groups and substituted in the ortho position by a Rb group;

[0118] B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S;

[0119] n is an integer from 0 to 4;

[0120] Ra is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0121] Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted aromatic ring, and the substituent is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluorine, or chlorine.

[0122] In a specific embodiment, the compound of formula I is represented by formula V:

[0123]

[0124] Wherein, W is selected from O and S;

[0125] A and Z are independently selected from C and N, and are not C at the same time. Preferably, A and Z are N at the same time.

[0126] R1 is selected from fluorine, chlorine, H, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0127] R2 is selected from H, halogen, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxyl;

[0128] R3 is selected from the following groups:

[0129] A) an aromatic ring optionally substituted by n Ra groups and substituted in the ortho position by a Rb group;

[0130] B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S;

[0131] n is an integer from 0 to 4;

[0132] Ra is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl;

[0133] Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted aromatic ring, and the substituent is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluorine, or chlorine.

[0134] In a specific embodiment, the compound of formula I is selected from any one of the following compounds:

[0135]

[0136]

[0137]

[0138]

[0139] Beneficial technical effects of the present invention

[0140] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0141] The compound provided by the present invention has good selectivity for acting on OX1R and OX2R. The compound provided by the present invention is used to treat diseases related to sleep disorders. The compound provided by the present invention has good pharmacodynamic activity, and also has excellent physicochemical properties and pharmacokinetic properties.

[0142] Example

[0143] 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 cannot be understood as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are all by weight.

[0144] Synthesis Example

[0145] Example 1: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0146]

[0147] 1.1 Preparation of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid:

[0148] 2-Fluoro-6-iodobenzoic acid (6.4 g, 24 mmol), 1,2,3-triazole (3.3 g, 48 mmol), cuprous iodide (0.23 g, 1.2 mmol), cesium carbonate (15.8 g, 48 mmol), (1R,2R)-N,N-dimethyl-1,2-diaminocyclohexane (0.7 g, 4.8 mmol), and dioxane (80 mL) were placed in a 250 mL round-bottom flask and stirred overnight at 95 °C under nitrogen protection. After the reaction solution returned to room temperature, 50 mL of tert-butyl methyl ether and 50 mL of water were added and continued to stir for half an hour, and then the liquid was separated. After the organic phase was discarded, the pH of the aqueous phase was adjusted to acidic with 2N hydrochloric acid, and then extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (petroleum ether / ethyl acetate=1:1) to obtain 4.0 g of a yellow solid product.

[0149] 1. Preparation of tert-butyl 2(3aR, 6aS)-5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:

[0150] 2-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (1.2 g, 5.7 mmol), HATU (2.2 g, 5.7 mmol), DIEA (1.2 g, 9.6 mmol), and dichloromethane (20 mL) were placed in a 100 mL round-bottom flask, stirred at room temperature for 20 minutes, and then cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (1.0 g, 4.8 mmol) was added portionwise, and stirred at room temperature overnight. After TLC monitoring, the reaction solution was directly concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 1.9 g of a white solid product.

[0151] 1.3 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone:

[0152] Place (3aR, 6aS)-5-(2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (1.9 g, 4.7 mmol) and dichloromethane (10 mL) in a 100 mL round-bottom flask, add trifluoroacetic acid (10 mL), and stir at room temperature. After the reaction is complete as monitored by TLC, the reaction solution is directly concentrated and separated by column chromatography (dichloromethane / methanol = 10:1) to obtain 1.4 g of a white solid product.

[0153] 1.4 Preparation of 2-chloro-4-methylfurano[3,2-d]pyrimidine:

[0154] 2,4-Dichlorofurano[3,2-d]pyrimidine (3.0 g, 15.8 mmol), ferric acetylacetonate (0.22 g, 0.9 mmol), and tetrahydrofuran (30 mL) were placed in a 100 mL round-bottom flask, and methylmagnesium chloride (3N, 10.5 mL, 31.6 mmol) was added dropwise at -78°C. After the addition was completed, the mixture was stirred at this temperature for one hour and then moved to room temperature for stirring. After TLC monitoring, 20 mL of water was added to quench the reaction, and the mixture was extracted with ethyl acetate three times (30 mL × 3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated by suction, and separated by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 2.2 g of a white solid product.

[0155] 1.5 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone:

[0156] (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (0.9 g, 3.0 mmol), 2-chloro-4-methylfuran[3,2-d]pyrimidine (0.25 g, 1.5 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 to dilute the mixture, and the mixture was filtered through celite. The filtrate was extracted with ethyl acetate three times (20 mL×3), and the organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated by suction, and separated by column chromatography (petroleum ether / ethyl acetate = 1:3) to obtain 0.45 g of the product. 1 H NMR(400MHz,Chloroform-d)δ7.83(q,J=8.0Hz,2H),7.71(d,J=6.7Hz,2H),7.5 9–7.38(m,1H),7.13(q,J=8.2Hz,1H),6.70(s,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):434[M+H] +Example 2: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylpyrazolo[1,5-a][1,3,5]triazine-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0157]

[0158] 2.1 Preparation of 4-methyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine:

[0159] 4-Chloro-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (0.75 g, 3.75 mmol), trimethylboroxane (3.5 N, 2.2 mL, 7.5 mmol), bis(triphenylphosphine)palladium dichloride (0.26 g, 0.38 mmol), potassium carbonate (1.1 g, 7.5 mmol), and dioxane (30 mL) were placed in a 50 mL round-bottom flask and stirred overnight at 80 ° C under nitrogen protection. After the reaction was complete as monitored by TLC, the reaction solution was directly concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 10:1) to obtain 0.45 g of a yellow solid product.

[0160] 2.2 Preparation of 4-methyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine:

[0161] 4-Methyl-2-(methylthio)pyrazolo[1,5-a][1,3,5]triazine (0.2 g, 1.1 mmol) and dichloromethane (10 mL) were placed in a 50 mL round-bottom flask, and mCPBA (0.4 g, 1.1 mmol) was added at 0 °C under nitrogen protection.

[0162] After stirring for 10 minutes, the mixture was moved to room temperature and stirred overnight. After the reaction was complete, the reaction solution was concentrated and separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 0.18 g of the product.

[0163] 2.3 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylpyrazolo[1,5-a][1,3,5]triazine-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone:

[0164] According to the method of Example 1, (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone was prepared, and 4-methyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine (0.18 g, 0.85 mmol) and (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone were added. 3-Triazol-2-yl)phenyl)((3aR,6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone (0.26 g, 0.86 mmol), DIEA (0.43 g, 3.40 mmol), cesium fluoride (0.26 g, 1.70 mmol), and DMSO (10 mL) were placed in a 50 mL round-bottom flask and stirred overnight at 90 ° C under nitrogen protection. After the reaction solution returned to room temperature, 30 mL of water was added to dilute it, and then ethyl acetate was extracted three times (20 mL×3). The organic phase was washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and separated by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 0.21 g of the product. 1 HNMR(400MHz,Chloroform-d)δ7.90(s,1H),7.89–7.78(m,2H),7.73(s,1H),7.60–7.38(m,1H),7.14(q,J=8.0Hz,1H),6.03(s,1H),4.19–3.82(m,3H) ,3.84–3.62(m,3H),3.59(dd,J=10.7,7.6Hz,1H),3.26(dd,J=10.8,5.3Hz ,1H),3.19–2.96(m,2H),2.80(d,J=4.1Hz,3H); LCMS(ES,m / z):434[M+H]+.

[0165] Example 3: (2-methyl-5-phenylthiazol-4-yl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0166]

[0167] 3.1 Preparation of methyl 2-methyl-5-phenylthiazole-4-carboxylate:

[0168] Add methyl 5-bromo-2-methylthiazole-4-carboxylate (2.0 g, 8.47 mmol), phenylboronic acid (1.55 g, 12.71 mmol), Cs2CO3 (5.52 g, 16.94 mmol), Pd(PPh3)4 (98 mg, 0.08 mmol) and DMF (40 mL) into a 250 mL single-necked bottle, introduce N2, and stir the reaction at 85 °C for 16 h. After the reaction is completed, filter the mixture, extract the filtrate with EA (3 x 50 mL), wash the organic phase with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate by suction, and chromatograph on a silica gel column with ethyl acetate / petroleum ether (0-30%) to obtain 1 g of a yellow solid.

[0169] 3.2 Preparation of 2-methyl-5-phenylthiazole-4-carboxylic acid:

[0170] Methyl 2-methyl-5-phenylthiazole-4-carboxylate (1 g, 4.29 mmol), LiOH (205 mg, 8.55 mmol), and MeOH / H2O (14 / 7 mL) were added to a 100 mL single-necked bottle and reacted at room temperature for 2 h. After the reaction solution was concentrated, the pH was adjusted to 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 0.7 g of a white solid.

[0171] 3.3 Preparation of tert-butyl 5-(2-methyl-5-phenylthiazole-4-carbonyl)pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate:

[0172] 2-Methyl-5-phenylthiazole-4-carboxylic acid (700 mg, 3.19 mmol) was added to a single-necked bottle containing 15 mL of DCM, and HATU (1.34 g, 3.51 mmol) and DIEA (1.24 g, 9.58 mmol) were added. After stirring for 10 min, hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (746 mg, 3.51 mmol) was added. The reaction was allowed to react at room temperature overnight. The reaction solution was concentrated and subjected to silica gel column chromatography (EA:PE=0-50%) to obtain 700 mg of a light yellow solid.

[0173] 3.4 Preparation of [hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](2-methyl-5-phenylthiazol-4-yl)methanone:

[0174] 5-(2-methyl-5-phenylthiazole-4-carbonyl)pyrrolidine[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (700 mg, 1.69 mmol) was added to a 50 mL single-necked bottle containing 10 mL of DCM, and TFA (386 mg, 3.39 mmol) was added. The mixture was reacted at room temperature for 1 h, concentrated, and subjected to silica gel column chromatography (MeOH / DCM: 0-10%) to obtain 500 mg of a light yellow solid.

[0175] 3.5 Preparation of (2-methyl-5-phenylthiazol-4-yl) [(3aR, 6aS) -5- (4-methylfuran [3, 2-d] pyrimidin-2-yl) hexahydropyrrolo [3, 4-c] pyrrol-2 (1H) -yl] ketone:

[0176] 2-Chloro-4-methylfurano[3,2-d]pyrimidine was prepared according to the method of Example 1. 2-Chloro-4-methylfurano[3,2-d]pyrimidine (50 mg, 0.27 mmol), [hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](2-methyl-5-phenylthiazol-4-yl)methanone (93 mg, 0.30 mmol), CsF (82 mg, 0.54 mmol) and DIEA (105 mg, 0.81 mmol) were added to DMSO (2 mL), and N2 was introduced. The reaction was stirred at 80° C. for 12 h. The reaction solution was extracted with EA (3× 30 mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated by suction, and chromatographed on a silica gel column (EA / PE=0-100%) to obtain 40 mg of the product. 1 H NMR(400MHz,Chloroform-d)δ7.94–7.65(m,1H),7.54–7.37(m,2H),7.27(d,J=15.1Hz,1H),4.40–4.09(m,1H),3.79–3. 59(m,1H),3.57–3.31(m,1H),3.16–2.85(m,1H),2.74(s,1H),2.59(s,1H),2.20–1.86(m,1H).LCMS(ES,m / z):446[M+H] + .

[0177] Example 4: (2-Fluoro-6-(1H-pyrazol-1-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0178]

[0179] The target compound was prepared according to the method of Example 1, except that the reaction raw material 1,2,3-triazole was replaced by pyrazole.1 HNMR(400MHz,Chloroform-d)δ7.96(dd,J=14.9,2.9Hz,1H),7.90–7.81(m,2H),7.71–7.54(m,1H),7.47(dd,J=14.9,2.9Hz,1H),7. 43–7.26(m,2H),4.16–3.92(m,2H),3.83–3.51(m,2H),3.43–3.06(m,4H),2.79–2.61(m,2H),2.58(s,3H).LCMS(ES,m / z):433[M+H] + .

[0180] Example 5: (2-Fluoro-6-(1H-pyrazol-1-yl)phenyl)((3aR,6aS)-5-(4-methylpyrazolo[1,5-a][1,3,5]triazine-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0181]

[0182] The target compound was prepared according to the method of Example 2, except that the reaction raw material 1,2,3-triazole was replaced by pyrazole. 1 HNMR(400MHz, CDCl3) δ7.88(d,J=10.3Hz,1H),7.75(d,J=14.8Hz,1H),7.56(s,1H),7.49–7. 40(m,1H),7.33(dd,J=28.2,8.0Hz,1H),7.12(dd,J=10.0,6.2Hz,1H),6.40(d,J=34.9Hz,1H ),6.02(s,1H),3.97–3.77(m,2H),3.70(s,1H),3.67–3.50(m,3H),3.46(dd,J=10.6,7.6Hz, 1H),3.15(dd,J=10.7,5.0Hz,1H),3.09–2.96(m,2H),2.79(s,3H).LCMS(ES,m / z):433[M+H] + .

[0183] Example 6: (2-Fluoro-6-(thiazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylpyrazolo[1,5-a][1,3,5]triazine-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0184]

[0185] The target compound was prepared according to the method of Example 2, except that the reaction raw material 1,2,3-triazole was replaced by 2-(tributylstannyl)thiazole. 1 H NMR(400MHz,Chloroform-d)δ7.86(d,J=10.3Hz,1H),7.64(d,J=14.8Hz,1H),7.49–7. 40(m,1H),7.35-7.33(m,1H),7.28(d,J=14.8Hz,1H),6.40(d,J=34.9Hz,1H),6.02(s, 1H),3.97–3.77(m,2H),3.70(s,1H),3.67–3.50(m,3H),3.46(dd,J=10.6,7.6Hz,1H), 3.15(dd,J=10.7,5.0Hz,1H),3.04–2.92(m,2H),2.77(s,3H).LCMS(ES,m / z):450[M+H] +

[0186] Example 7: (2-Fluoro-6-(thiazol-4-yl)phenyl)((3aR,6aS)-5-(4-methylpyrazolo[1,5-a][1,3,5]triazine-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0187]

[0188] The target compound was prepared according to the method of Example 2, except that the reaction raw material 1,2,3-triazole was replaced by 4-(tributylstannyl)thiazole. 1 H NMR(400MHz, DMSO-d6)δ9.10(d,J=76.0Hz,1H),7.96(d,J=16.0Hz,2H),7.80–7.64(m,1H),7.60–7.48(m,1H),7.38–7.26(m,1H),6.03(d, J=20Hz,1H),3.96–3.59(m,3H),3.58–3.40(m,3H),3.27–3.25(m,1H),3.10–2.85(m,3H),2.74(d,J=20.0Hz,3H).LCMS(ES,m / z):450[M+H] + .

[0189] Example 8: (2-Fluoro-6-(thiazol-4-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0190]

[0191] The target compound was prepared according to the method of Example 1, except that the reaction raw material 1,2,3-triazole was replaced by 4-(tributylstannyl)thiazole. 1 H NMR(400MHz, DMSO-d6)δ9.10(d,J=76.0Hz,1H),7.96(d,J=16.0Hz,2H),7.72–7.61(m,1H),7.54–7.43(m,1H),7.24(d,J=16.0Hz,1H),6 .03(d,J=20Hz,1H),3.96–3.59(m,3H),3.58–3.40(m,3H),3.27–3.25(m,1H),3.10–2.85(m,3H),2.78(s,3H).LCMS(ES,m / z):450[M+H] + .

[0192] Example 9: (2-Fluoro-6-(oxazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0193]

[0194] The target compound was prepared according to the method of Example 1, except that the reaction raw material 1,2,3-triazole was replaced by 2-(tri-n-butyltin)oxazole. 1 H NMR (400MHz, DMSO-d6) δ7.82–7.66(m,1H),7.60(d,J=15.1Hz,1H),7.53–7.37(m,1H),7.31(d,J=14.6Hz,1H),7.15(d,J=14.5Hz,1H).6 .03(d,J=20Hz,1H),3.96–3.59(m,3H),3.58–3.40(m,3H),3.27–3.25(m,1H),3.10–2.85(m,3H),2.78(s,3H).LCMS(ES,m / z):434[M+H] + .

[0195] Example 10: (2-Fluoro-6-(oxazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylpyrazolo[1,5-a][1,3,5]triazin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0196]

[0197] The target compound was prepared according to the method of Example 2, except that the reaction raw material 1,2,3-triazole was replaced by 2-(tri-n-butyltin)oxazole. 1 H NMR(400MHz,DMSO-d6)δ7.79–7.63(m,1H),7.54(d,J=15.1Hz,1H),7.48–7.31 (m,1H),7.26(d,J=14.6Hz,1H),7.10(d,J=14.5Hz,1H).6.03(s,1H),4.19–3. 82(m,3H),3.84–3.62(m,3H),3.59(dd,J=10.7,7.6Hz,1H),3.26(dd,J=10.8, 5.3Hz,1H),3.19–2.96(m,2H),2.80(d,J=4.1Hz,3H); LCMS(ES,m / z):434[M+H] + .

[0198] Example 11: (2-methyl-5-phenylthiazol-4-yl)((3aR,6aS)-5-(4-methylpyrazolo[1,5-a][1,3,5]triazine-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0199]

[0200] The target compound was prepared according to the method of Example 3, except that the reaction raw material 2-chloro-4-methylfurano[3,2-d]pyrimidine was replaced with 4-methyl-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazine. 1 H NMR(400MHz, DMSO-d6)δ7.98(s,1H),7.41(d,J=8.0Hz,2H),7.35(t,J=6.0H z,2H),7.22(d,J=28.0Hz,1H),6.01(d,J=16Hz,1H),3.90–3.77(m,1H),3.75 –3.63(m,2H),3.60–3.52(m,1H),3.47–3.42(m,2H),3.27–3.15(m,1H),3.02 –2.89(m,3H),2.73(d,J=12.0Hz,3H),2.67(s,3H).LCMS(ES,m / z):446[M+H] + .

[0201] Example 12: (5-(4-fluorophenyl)-2-methylthiazol-4-yl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0202]

[0203] The target compound was prepared according to the method of Example 3, except that the reaction raw material phenylboronic acid was replaced by 4-fluorophenylboronic acid. 1 HNMR(400MHz,DMSO-d6)δ8.22(d,J=2.0Hz,1H),7.54(d,J=4.0Hz,2H),7.26 (d,J=4.0Hz,2H),6.85(d,J=4.0Hz,1H),3.77–3.67(m,2H),3.60–3.53(m,1H ),3.49–3.46(m,2H),3.35–3.30(m,1H),3.23–3.17(m,1H),3.04–2.96(m,2 H),2.94–2.86(m,1H),2.67(s,3H),2.51(s,3H).LCMS(ES,m / z):464[M+H]+.

[0204] Example 13: (3-Fluoro-[1,1'-biphenyl]-2-yl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0205]

[0206] The target compound was prepared according to the method of Example 1, except that the reaction raw material 1,2,3-triazole was replaced by phenylboronic acid. 1 HNMR(400MHz, DMSO-d6)δ8.21(dd,J=7.5,1.4Hz,1H),7.79(m,1H),7.58–7.35(m,7H),7.25(d,J=7.5Hz,1H),3. 96–3.59(m,3H),3.58–3.40(m,3H),3.27–3.25(m,1H),3.10–2.85(m,3H),2.78(s,3H).LCMS(ES,m / z):464[M+H] + .

[0207] Example 14: (2-Fluoro-6-(pyridin-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0208]

[0209] The target compound was prepared according to the method of Example 1, except that the reaction raw material 1,2,3-triazole was replaced by 2-tri-n-butylstannylpyridine. 1 H NMR (400MHz, DMSO-d6) δ8.37(dd,J=15.0,3.0Hz,1H),8.11(dd,J=14.9,3.1Hz,1H),7.78-7.65(m,1H),7.54–7.23(m,4H),7.14(dd,J=14.9,3.1Hz,1 H),6.90(td,J=14.9,3.1Hz,1H).3.96–3.59(m,3H),3.58–3.40(m,3H),3. 27–3.25(m,1H),3.10–2.85(m,3H),2.78(s,3H).LCMS(ES,m / z):444[M+H] + .

[0210] Example 15: (5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0211]

[0212] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced by 2-iodo-5-methylbenzoic acid. 1 H NMR (400MHz, Chloroform-d) δ8.02(s,2H),7.88(d,J=1.2Hz,1H),7.68–7.61(m,1H),7.43–7.38(m,1H),7.26–7.21(m,1H),6.98(d,J=1. 2Hz,1H),4.01–3.81(m,4H),3.75–3.68(m,2H),3.64–3.51(m,2H),3.02–2.98(m,2H),2.72(s,3H),2.33(s,3H).LCMS(ES,m / z):430[M+H] + .

[0213] Example 16: (2-Fluoro-6-(thiazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0214]

[0215] 16.1 Preparation of tert-butyl (3aR, 6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrole-2(1H)-carboxylate

[0216] cis-2-Boc-hexahydropyrrolo[3,4-c]pyrrole (2.5 g, 12.0 mmol), 2-chloro-4-methylfuran[3,2-d]pyrimidine (1.0 g, 6.0 mmol) and N-methylpyrrolidone (8 mL) were placed in a three-necked flask and reacted in a microwave at 170°C for 2.0 hours. After cooling to room temperature, 50 mL of water and 50 mL of ethyl acetate were added for dilution and then filtered through diatomite. The filtrate was extracted with ethyl acetate three times (30 mL×3), and the organic phase was washed with 30 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated by suction, and separated by column chromatography (petroleum ether / ethyl acetate=10:1) to obtain 1.3 g of (3aR, 6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylic acid tert-butyl ester.

[0217] 16.2 Preparation of 2-((3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-methylfurano[3,2-d]pyrimidine

[0218] Tert-butyl (3aR, 6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (1.3 g, 3.8 mmol) was added to 2 ml of dichloromethane under nitrogen protection. Trifluoroacetic acid (3 mL) was added at room temperature and stirred for 0.5 hour at room temperature. The reaction was completed and the solvent was evaporated under reduced pressure to obtain 2-((3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrole-2(1H)-yl)-4-methylfuran[3,2-d]pyrimidine (0.9 g). The crude product was used directly in the next step without further purification.

[0219] 16.3 Preparation of tert-butyl 2-fluoro-6-(1,3-thiazol-2-yl)benzoate

[0220] 2-Fluoro-6-iodobenzoic acid tert-butyl ester (2.0 g, 7.2 mmol), cuprous iodide (0.12, 0.6 mmol), cesium fluoride (0.19 g, 1.3 mmol) were added to tetrahydrofuran, nitrogen was protected, and stirred at room temperature for minutes. Pd(PPh3)4 (0.4 g, 0.34 mmol) was added at room temperature, and then 2-(tributyltinyl)-1,3-thiazole (2.8 g, 7.5 mmol) was added. The temperature was raised to 100°C and the reaction was allowed to proceed overnight. The reaction was complete, and column chromatography was used for separation and purification (PE / EA=2:1) ​​to obtain 2-fluoro-6-(1,3-thiazol-2-yl)benzoic acid tert-butyl ester (1.8 g).

[0221] 16.4 Preparation of 2-fluoro-6-(1,3-thiazol-2-yl)benzoic acid

[0222] Tert-butyl 2-fluoro-6-(1,3-thiazol-2-yl)benzoate (160 mg, 0.573 mmol) was added to 2 ml of dichloromethane under nitrogen protection. Trifluoroacetic acid (2 mL, 26.926 mmol) was added at room temperature and stirred for 0.5 hour at room temperature. The reaction was completed and the solvent was evaporated under reduced pressure to obtain 2-fluoro-6-(1,3-thiazol-2-yl)benzoic acid (118 mg). The crude product was used directly in the next step without further purification.

[0223] 16.5 Preparation of (2-fluoro-6-(thiazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0224] 2-((3aR, 6aS)-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-4-methylfuran[3,2-d]pyrimidine (0.2 g, 0.8 mmol) and 2-fluoro-6-(1,3-thiazol-2-yl)benzoic acid (0.2 g, 0.9 mmol) were added to DMF (5 mL) under nitrogen protection. HATU (0.6 g, 1.6 mmol) and DIPEA (0.2 g, 1.6 mmol) were added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was extracted with ethyl acetate (3 x 10 mL). The organic phase was washed with water (3 x 10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain 0.21 g of (2-fluoro-6-(thiazol-2-yl)phenyl)((3aR, 6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone. 1 H NMR(400MHz,Chloroform-d)δ7.84(d,J=1.6Hz,1H),7.74–7.68(m,2H),7.60–7.54(m,1H),7.39– 7.36(m,1H),7.26–7.23(m,1H),7.09(d,J=1.4Hz,1H),3.86–3.79(m,4H),3.73–3.68(m,2H),3.63 -3.60(m,2H),3.14–3.06(m,2H),2.72(s,3H).LCMS(ES,m / z):450[M+H] + .

[0225] Example 17: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylthieno[3,2-d]pyrimidin-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0226]

[0227] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2,4-dichlorofurano[3,2-d]pyrimidine was replaced by 2,4-dichlorothieno[3,2-d]pyrimidine. 1 H NMR(400MHz,Chloroform-d)δ7.96-7.86(m,2H),7.76–7.74(m,1H),7.58–7.51(m,2H),7.40(d,J=3.6Hz,1H),7.20–7.17( m,1H),3.85–3.81(m,4H),3.71–3.68(m,2H),3.62–3.59(m,2H),3.06–3.01(m,2H),2.74(s,3H).LCMS(ES,m / z):450[M+H] + .

[0228] Example 18: (3-(1H-pyrazol-1-yl)pyridin-2-yl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0229]

[0230] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced by 3-bromo-2-pyridinecarboxylic acid and 1,2,3-triazole was replaced by 1H-pyrazole. 1 H NMR(400MHz,Chloroform-d)δ8.70–8.68(m,1H),8.08–8.06(m,1H),7.86–7.82(m,1H),7.79(d,J=1.6Hz,1H),7.67–7.63(m,1H),7.47–7.44(m, 1H),7.11(d,J=1.4Hz,1H),6.46–6.44(m,1H),3.90–3.78(m,4H),3.71– 3.67(m,4H),3.11–3.05(m,2H),2.70(s,3H),.LCMS(ES,m / z):416[M+H] + .

[0231] Example 19: (2-Fluoro-6-(pyrimidin-2-yl)phenyl)((3aR,6aS)-5-(4-methylfurano[3,2-d]pyrimidin-2-)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0232]

[0233] The target compound was prepared according to the method of Example 16, except that the reaction raw material 2-(tributyltin)-1,3-thiazole was replaced by 2-(tributyltin)pyrimidine. 1 H NMR(400MHz,Chloroform-d)δ8.72(d,J=4.0Hz,2H),7.93–9.91(m,1H),7.80(d,J=1.6Hz,1H),7.64–7.60(m,1H),7.31–7.27(m,1H), 7.11–7.05(m,2H),3.84–3.80(m,4H),3.71–3.68(m,2H),3.61–3.58(m,2H),2.74(s,3H),2.31–2.20(m,2H).LCMS(ES,m / z):445[M+H] + .

[0234] Example 21: (2-Fluoro-6-(thiazol-4-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[2,3-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0235]

[0236] The target compound was prepared according to the method of Example 16, except that the reaction raw material 2-(tributyltin)-1,3-thiazole was replaced by 4-(tri-n-butyltin)thiazole. 1 H NMR(400MHz,Chloroform-d)δ8.91–8.89(m,1H),7.82(d,J=1.6Hz,1H),7.74(d,J=2.4Hz,1H),7.62–7.58(m,1H),7.46–7.43(m,1H),7.28–7.24( m,1H),7.01(d,J=2.8Hz,1H),3.85–3.80(m,4H),3.73–3.64(m,2H),3.6 6–3.60(m,2H),3.10–3.04(m,2H),2.66(s,3H).LCMS(ES,m / z):450[M+H] + .

[0237] Example 22: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylthieno[2,3-d]pyrimidin-2-yl]hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0238]

[0239] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2,4-dichlorofurano[3,2-d]pyrimidine was replaced by 2,4-dichlorothieno[2,3-d]pyrimidine. 1 H NMR(400MHz,Chloroform-d)δ7.91–7.88(m,2H),7.76–7.74(m,1H),7.58–7.54(m,2H),7.45(d,J=5.6Hz,1H),7.20–7.16( m,1H),3.85–3.81(m,4H),3.73–3.66(m,2H),3.60–3.57(m,2H),3.02–2.97(m,2H),2.80(s,3H),LCMS(ES,m / z):450[M+H] + .

[0240] Example 23: (2-cyclopropyl-5-phenylthiazol-4-yl)(5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0241]

[0242] The target compound was prepared according to the method of Example 3, except that the reaction raw material 5-bromo-2-methylthiazole-4-carboxylic acid methyl ester was replaced by 5-bromo-2-cyclopropylthiazole-4-carboxylic acid methyl ester. 1 H NMR(400MHz,Chloroform-d)δ7.73(d,J=1.2Hz,1H),7.61–7.58(m,2H),7.44–7.39(m,3H),7.09(d,J=1.2Hz,1H),3.87 –3.82(m,4H),3.69–3.63(m,4H),2.79–2.74(m,4H),2.62–2.58(m,2H),1.17(d,J=4.0Hz,4H).LCMS(ES,m / z):472[M+H] + .

[0243] Example 24: (2-methyl-5-(pyridin-2-yl)thiazol-4-yl)(5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0244]

[0245] The target compound was prepared according to the method of Example 3, except that the reaction raw material phenylboronic acid was replaced by dimethyl pyridine-2-borate. 1 H NMR(400MHz,Chloroform-d)δ8.41(m,1H),7.79–7.61(m,3H),7.26–7.23(m,1H),7.09(d,J=1.2Hz,1H),3. 87–3.80(m,4H),3.69–3.61(m,4H),3.01-2.93(m,2H),2.81(s,3H),2.62(s,3H).LCMS(ES,m / z):447[M+H] + .

[0246] Example 25: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[2,3-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0247]

[0248] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2,4-dichlorofurano[3,2-d]pyrimidine was replaced with 2,4-dichlorofurano[2,3-D]pyrimidine. 1 H NMR(400MHz,Chloroform-d)δ7.91–7.88(m,2H),7.75–7.72(m,2H),7.54–7.52(m,1H),7.20–7.17(m,1H),6.90( d,J=1.2Hz,1H),4.02-3.76(m,4H),3.70–3.30(m,4H),3.11–3.02(m,2H),2.61(s,3H); LCMS(ES,m / z):434[M+H] + .

[0249] Example 26: ((3aR, 6aS)-5-(4,7-dimethylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-ylphenyl)methanone

[0250]

[0251] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2,4-dichlorofurano[3,2-d]pyrimidine was replaced with 2,4-dichloro-5-methylfurano[2,3-d]pyrimidine. 1 H NMR(400MHz,Chloroform-d)δ7.96–7.95(m,1H),7.91–7.83(m,2H),7.73–7,71(m,1H),7.58–7.54(m,1H),7.20–7.17(m,1 H),3.86–3.77(m,4H),3.71-3.61(m,4H),3.03–2.96(m,2H),2.71(s,3H),2.33(d,J=0.7Hz,3H).LCMS(ES,m / z):448[M+H] + .

[0252] Example 27: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(7-methylpyrazolo[1,5-a]pyrimidin-5-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0253]

[0254] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2,4-dichlorofurano[3,2-d]pyrimidine was replaced by 5,7-dichloropyrazolo[1,5-a]pyrimidine. 1 H NMR(400MHz,Chloroform-d)δ7.95-7.93(m,1H),7.91–7.88(m,2H),7.75–7.73(m,1H),7.58–7.54(m,1H),7.20–7.18(m,1H),6.83(d,J= 3.2Hz,1H),6.16–6.15(m,1H),3.85–3,74(m,4H),3.63-3.51(m,4H),3.32–3.22(m,2H),2.63(d,J=1.3Hz,3H).LCMS(ES,m / z):433[M+H] + .

[0255] Example 28: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylpyrrolo[2,1-f][1,2,4]triazine-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0256]

[0257] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2,4-dichlorofurano[3,2-d]pyrimidine was replaced by 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine. 1 H NMR(400MHz,Chloroform-d)δ8.15–8.13(m,1H),7.86–7.83(m,2H),7.76–7.74(m,1H),7.58–7.54(m,1H),7.20–7.16(m,1H),6.9 4–6.92(m,1H),6.78–6.74(m,1H),3.87–3.78(m,4H),3.71–3.48(m,4H),3.04–3.00(m,2H),2.72(s,3H).LCMS(ES,m / z):433[M+H] + .

[0258] Example 29: ((3aR, 6aS)-5-(4-cyclopropylpyrrolo[2,1-f][1,2,4]triazine-2-yl)hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0259]

[0260] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2,4-dichlorofurano[3,2-d]pyrimidine was replaced by 2,4-dichloropyrrolo[2,1-f][1,2,4]triazine, and methylmagnesium chloride was replaced by cyclopropylmagnesium bromide. 1 H NMR(400MHz,Chloroform-d)δ8.13–8.11(m,1H),7.93–7.89(m,2H),7.76–7.75(m,1H),7.58–7.53(m,1H),7.20–7.16(m,1H),7.0 9–7.07(m,1H),6.76–6.73(m,1H),3.87–3.78(m,4H),3.69–3.56(m,4H),2.64–2.48(m,2H),2.49–2.29(m,2H),1.12–1.02(m,4H).

[0261] Example 31: (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0262]

[0263] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced by 2-iodo-5-methoxybenzoic acid. 1 H NMR(400MHz,Chloroform-d)δ7.91(s,2H),7.86(d,J=7.6Hz,1H),7.79(d,J=1.3Hz,1H),7.21(d,J=2.3Hz,1H),7 .09–7.04(m,2H),3.86–3.81(m,7H),3.71–3.62(m,4H),3.11–3.06(m,2H),2.64(s,3H).LCMS(ES,m / z):446[M+H] + .

[0264] Example 32: (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuran[3,2-d]pyrimidin-2-yl]pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0265]

[0266] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced by 4-fluoro-2-iodobenzoic acid. 1 H NMR(400MHz,Chloroform-d)δ7.93(s,2H),7.79–7.76(m,2H),7.28–7.19(m,2H),7.09(d,J=1.2Hz, 1H),3.87–3.81(m,4H),3.71–3.61(m,4H),3.12–3.05(m,2H),2.74(s,3H).LCMS(ES,m / z):434[M+H] + .

[0267] Example 33: (3-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)((3aR,6aS)-5-(4-methylfuro[3,2-d]pyrimidin-2-yl)pyrrolo[3,4-c]pyrrol-2(1H)-yl)methanone

[0268]

[0269] The target compound was prepared according to the method of Example 1, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced by 3-fluoro-2-iodobenzoic acid. 1H NMR(400MHz,Chloroform-d)δ7.88(s,2H),7.79(d,J=1.2Hz,1H),7.57–7.51(m,2H),7.32–7.28(m,1H),7.09(d,J=1.2Hz ,1H),3.85–3.81(m,4H),3.71–3.68(m,2H),3.64–3.62(m,2H),3.03–2.99(m,2H),2.68(s,3H).LCMS(ES,m / z):434[M+H] + .

[0270] Pharmacological Examples:

[0271] In vitro activity test

[0272] (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.

[0273] (2) Compound preparation: The compound was diluted with DMSO to a 5 mM stock solution, then diluted 3.16-fold to form 10 gradients, and then diluted with Stimulation buffer to the corresponding concentration (4x) for later use.

[0274] (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 PBS and mix by gently pipetting. Centrifuge again at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the cells in 1x Stimulation buffer and count them using a Countstar cell counter. Adjust the cell density to 1.71x10 6 pcs / mL, for future use.

[0275] (4) Cell addition: Add the cell suspension to the experimental plate, 7 μL / well (i.e., approximately 12,000 cells / well).

[0276] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above test plate, 3.5 μL / well.

[0277] (6) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 30 minutes.

[0278] (7)EC 80 Agonist addition: Add EC80 4x Orexin A (OX1 receptor), 4x Orexin 2 receptoragonist (OX2 receptor) solution, 3.5 μL / well.

[0279] (8) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 45 minutes.

[0280] (9) Add detection reagents: Dilute IP1-d2 and Anti-IP1 cryptate at a ratio of 1:20 using the Lysis & detection buffer in the Cisbio IP-one detection kit, and add the diluted IP1-d2 and Anti-IP1 cryptate to the test plate, 3 μL / well each. After shaking, let the test plate stand at room temperature for 60 minutes.

[0281] (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.

[0282] 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:

[0283] Table 1

[0284]

[0285]

[0286] IC 50 Value <100nM:+++; IC 50 Value is 100~300nM:++;IC 50 The value is 300~1000nM:+;IC 50 Value>1000nM:-

[0287] Experimental conclusion: 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 has good selectivity.

[0288] Healthy male SD rats aged 6-9 weeks were selected and randomly divided into two groups, 3 rats in each group. One group was given 1 mg / kg of the test compound by intravenous injection, and the other group was given 30 mg / kg of the test compound by oral gavage. Whole blood was collected from the animals in the intravenous group and the oral gavage group before administration 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.

[0289] LC-MS / MS was used for quantitative analysis of all biological samples, and WinNonlinTM 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; iv stands for intravenous, C max represents peak concentration, and F% represents oral bioavailability. The results are shown in Table 2:

[0290] Table 2

[0291]

[0292]

[0293] Conclusion: The data show that in the pharmacokinetic evaluation experiment in rats, the compound of the present invention exhibits better in vivo exposure and better bioavailability after administration.

Claims

1. A compound of formula II or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: Wherein, Q is selected from O and S; A and Z are both N; R1 is selected from methyl, ethyl, propyl, isopropyl; R2 is selected from H, halogen, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxyl; R3 is selected from the following groups: A) a 6-10 membered aromatic ring which is optionally substituted by n Ra groups and substituted in the ortho position by Rb groups; B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S; n is an integer from 0 to 4; Ra is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl; Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted 6-10 membered aromatic ring, and the substituent is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluorine, or chlorine.

2. A compound of formula III or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: in, W is CH; U and Q are both N; A and Z are both N; R1 is selected from methyl, ethyl, propyl, isopropyl; R2 is selected from H, halogen, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, hydroxyl; R3 is selected from the following groups: A) a 6-10 membered aromatic ring optionally substituted by n Ra groups and substituted in the ortho position by a Rb group; B) a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted in the ortho position by Rb groups, the heteroatoms being selected from O, N, S; n is an integer from 0 to 4; Ra is independently selected from H, fluoro, chloro, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl; Rb is an optionally substituted 3-8 membered heterocyclic ring, an optionally substituted 5-8 membered heteroaromatic ring, or an optionally substituted 6-10 membered aromatic ring, and the substituent is methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, fluorine, or chlorine.

3. The compound of formula II or III as claimed in claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The 6-10 membered aromatic ring is phenyl; the 5-8 membered heteroaromatic ring is pyridyl, pyridazinyl, triazinyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, thiadiazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, imidazolyl, pyrrolyl, pyranyl, pyridazinyl, pyrazinyl, or triazolyl.

4. The compound of formula II or III as claimed in claim 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: R3 is selected from phenyl optionally substituted by n Ra groups and substituted by Rb groups at the ortho position, wherein n is an integer from 0 to 4, and the Rb group is an optionally substituted 5-8 membered heteroaromatic ring selected from pyridyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, and triazolyl.

5. The compound of formula II or III as claimed in claim 3, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: R3 is selected from a 5-8 membered heteroaromatic ring optionally substituted by n Ra groups and substituted by a Rb group at the ortho position, wherein n is an integer from 0 to 4, the Rb group is an optionally substituted phenyl group, and the 5-8 membered heteroaromatic ring is selected from pyridyl, pyrimidinyl, thienyl, furanyl, oxazolyl, thiazolyl, pyrazolyl, imidazolyl, and triazolyl.

6. The compound of formula II or III as claimed in claim 1 or 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that , the compound of formula II or formula III is selected from any one of the following compounds:

7. A pharmaceutical composition, characterized in that Contains a compound of formula II or formula III according to any one of claims 1 to 6 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, and a pharmaceutically acceptable carrier.

8. Use of the compound according to any one of claims 1 to 6 or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the pharmaceutical composition according to claim 7 in the preparation of a drug, wherein: The medicament is used for preventing, treating and / or alleviating diseases related to orexin receptors.

9. The use according to claim 8, wherein the disease associated with orexin receptors 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, headache, pain.

10. The use according to claim 8, wherein the disease associated with orexin is sleep disorder, schizophrenia, manic depression, psychosis, or migraine.

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