Substituted tetrahydrocyclopentyl [c] pyrrole derivative, preparation method, intermediate and application thereof

Abstract

The invention provides a compound shown in a general formula I or pharmaceutically acceptable salt, stereoisomer, tautomer, a composition containing the compound, a preparation method, an intermediate and application in the field of medicine. # imgabs0 #

Description

A substituted tetrahydrocyclopentyl[c]pyrrole derivative, preparation method, intermediate and application thereof

[0001] This application claims priority to Chinese application No. 202211599295.X, filed on December 12, 2022, entitled “A substituted tetrahydrocyclopentyl [c] pyrrolmethyl ketone derivative, preparation method and application thereof”, and priority to Chinese application No. 202310334144.X, filed on March 31, 2023, entitled “A substituted tetrahydrocyclopentyl [c] pyrrole derivative, preparation method, intermediate and application thereof”, and priority to Chinese application No. 202311606327.9, filed on November 28, 2023, entitled “A substituted tetrahydrocyclopentyl [c] pyrrole derivative, preparation method, intermediate and application thereof”, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention belongs to the field of medicine, and specifically relates to a substituted tetrahydrocyclopentyl[c]pyrrole derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer and a composition containing the compound, as well as a preparation method, intermediates and applications thereof in the field of medicine. Background Art

[0003] Orexins (also known as hypocretins or orexins) come in two types: orexin-A (hypocretin-1) and orexin-B (hypocretin-2). Orexin signaling is mediated by two receptors and two peptide agonists. 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 preferentially selects orexin A, while OX2R binds to both orexins with similar affinity.

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

[0005] There are already several drugs targeting OX1 / 2R that are in the clinical stage or on the market, such as Merck's Suvoraxant and Eisai's Lemborexant. However, existing drugs have antagonistic effects on both OX1R and OX2R receptors, and the effects on OX1R will affect rapid eye movement sleep (NEM, brain activity is the same as when awake) and non-rapid eye movement sleep (NEREM, deep sleep), that is, sacrificing NREM time and prolonging REM time, thereby increasing the risk of sleepiness, and OX1R has no antidepressant effect.

[0006] Studies have shown that disorders of the sleep-wake cycle are likely targets for the activity of OX2R receptor modulators. Examples of disorders that can be treated by antagonists or other modulators that downregulate OX2R-mediated processes include insomnia, restless legs syndrome, jet lag (insomnia), and sleep disorders secondary to neurological disorders such as mania, schizophrenia, and pain syndromes. OX2R is selectively expressed in the tuberomammillary nucleus (TMN), paraventricular nucleus (PVN), and nucleus accumbens (NAc). These brain regions are the primary effector sites of orexin neurons in the lateral hypothalamus (LH), which are associated with eating, sleep, depression, anxiety, drug addiction, and motivated behaviors. They are more effective in treating sleep disorders (Lu et al., 2020, Neurosci Bull, 4:432–448).

[0007] OX2R antagonists can have antidepressant effects, and OX2R single receptor antagonists can also have sufficient efficacy for insomnia. Therefore, selective OX2R antagonists can avoid the various side effects such as drowsiness caused by the action of OX1R. Currently, the only OX2R antagonist developed by Janssen is Seltorexant in the clinical stage, with the main indications being major depressive disorder (MDD) and primary and secondary insomnia.

[0008] Selective OX2R antagonists have the potential to treat neurological diseases such as insomnia, depression, and anxiety, and have a huge clinical demand. Selective OX2R antagonists have good application prospects as drugs.

[0009] Summary of the Invention

[0010] The following is a summary of some aspects of the present invention and is not intended to limit the present invention. In the event of a discrepancy between the disclosure of this specification and a reference, the disclosure of this specification shall prevail.

[0011] The present invention aims to provide a substituted tetrahydrocyclopentyl[c]pyrrole derivative or a pharmaceutically acceptable salt, stereoisomer, tautomer and pharmaceutical composition thereof, as well as a preparation method and intermediates thereof. The compound and pharmaceutical composition can be used to prevent or treat diseases related to orexin receptors.

[0012] In one aspect, the present invention provides a compound or a pharmaceutically acceptable salt, stereoisomer, or tautomer represented by the following general formula I:

[0013] in,

[0014] R1 and R2 are each independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano;

[0015] or R1, R2 and the carbon atom to which they are attached together form a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl or a C3-C8 cycloalkyl group optionally substituted by one or more substituents, the substituents being independently selected from H, D, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano;

[0016] L1 is selected from the group consisting of one or more substituents R LA substituted 6-14 membered aryl and optionally substituted by one or more substituents R LA The substituted 5-14 membered heteroaryl group is preferably selected from the group consisting of LA substituted 6-10 membered aryl and optionally substituted by one or more substituents R LA The substituted 5-10 membered heteroaryl group is further preferably selected from the group consisting of LA Substituted phenyl and optionally substituted by one or more substituents R LA substituted 5-6 membered monocyclic heteroaryl; the one or more substituents R LA independently selected from H, D, halogen, optionally substituted by one or more R LB Substituted C1-C8 alkyl, optionally substituted by one or more substituents R LB Substituted C1-C8 alkoxy, cyano, optionally substituted by one or more substituents R LB Substituted C2-C8 alkynyl, optionally substituted by one or more substituents R LB Substituted C2-C8 alkenyl, hydroxyl, nitro, optionally substituted by one or more substituents R LB Substituted C1-C8 alkylthio, optionally substituted by one or more substituents R LB substituted C3-C8 cycloalkyl and OR4, the one or more substituents R LBis selected from H, D, halogen and hydroxyl;

[0017] R4 is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0018] L2 is selected from 6-14 membered aryl substituted by 0-4 Rb groups and 5-14 membered heteroaryl substituted by 0-4 Rb groups, preferably selected from 6-10 membered aryl substituted by 0-3 Rb groups and 5-10 membered monocyclic or bicyclic heteroaryl substituted by 0-3 Rb groups, further preferably selected from phenyl substituted by 0-3 Rb groups and 5-6 membered heteroaryl substituted by 0-3 Rb groups;

[0019] Each Rb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; the substituents are independently selected from H, D, halogen and hydroxyl;

[0020] X1 is selected from N and CR 10 ;

[0021] R 10 is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, D, halogen and hydroxy;

[0022] X2 is selected from N and CR 11 ;

[0023] R 11 is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano; said substituents being independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano;

[0024] and X1 and X2 are not N at the same time; and

[0025] When X2 is CR 11 , and when X1 is N, R2 is not H or D.

[0026] 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.

[0027] In another aspect, the present invention provides a use of a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof in the preparation of a medicament for treating a disease associated with orexin receptors, or a method for treating a disease associated with orexin receptors in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, including the compound of Formula I or a specific compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0028] In one embodiment, the orexin-related disease is a sleep disorder, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neurosis, depressive neurosis, anxiety neurosis, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, insomnia, depression, Alzheimer's disease, sleep apnea; preferably insomnia, depression, sleep disorder; further preferably major depressive disorder, primary and secondary insomnia or depression associated with insomnia.

[0029] In one embodiment, the subject is a mammal. In one embodiment, the subject is a human.

[0030] In another aspect, the present invention provides a method for preparing a compound of formula I, comprising the following steps: reacting compound Id with compound If to obtain target compound I:

[0031] Wherein, R1, R2, X1, X2, L1, L2 are as defined above, and preferably the compound represented by Id is a compound represented by I-dA or I-dB. R 1A 、R 2A 、R 3A As defined above; R 1B 、R 2B 、R 3B As defined above.

[0032] In another aspect, the present invention provides an intermediate as shown in the compound of formula Id,

[0033] Wherein, R1, R2, X1, and X2 are as defined above, and preferably, the compound represented by Id is a compound represented by I-dA or I-dB. R 1A 、R 2A 、R 3A As defined above; R 1B 、R 2B 、R 3B As defined above. DETAILED DESCRIPTION

[0034] Unless otherwise indicated or there is an obvious conflict in the context, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears in this article, it is intended to refer to the corresponding commercial product or its active ingredient. All patents, published patent applications and publications cited herein are incorporated herein by reference.

[0035] General Terms and Definitions

[0036] The term "optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.

[0037] The term "optionally substituted" can be used interchangeably with the term "substituted or unsubstituted", i.e., the structure or group is unsubstituted or substituted with one or more substituents described herein, wherein the substitution occurs at any reasonable position on the given structure or group as allowed by valence.

[0038] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent. When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such a substituent may be bonded to any ring atom in the substitutable ring.

[0039] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a specified substituent. Unless otherwise indicated, a substituent may be substituted at every possible position in the group. When more than one position in a given structure can be substituted with one or more of the specified substituents, the substituents may be the same or different at every possible position in the structure.

[0040] In addition, it should be noted that, unless otherwise expressly stated, the description method used in the present invention of "respectively and independently" should be understood in a broad sense, which can mean that in different groups, the specific options expressed by the same symbols do not affect each other, or that in the same group, the specific options expressed by the same symbols do not affect each other.

[0041] When the lower limit and upper limit of a numerical range are disclosed, any numerical value and any included range falling within the scope are specifically disclosed. In particular, each range of values ​​disclosed herein is understood to represent each numerical value and range encompassed within a wider range. When any variable (such as R), and a variable (such as R1, R2, R3, R4, R5, R6, R7, etc.) with a mark occurs more than once in the composition or structure of a compound, its definition in each case is independent at each occurrence. For example, if a group is substituted with 0, 1, 2 or 3 R substituents, the group can optionally be substituted with three R substituents at most, and the options for each R substituent in each case are independent of each other.

[0042] Throughout this specification, substituents of the compounds disclosed herein are disclosed in terms of group classes or ranges. It is specifically noted that the present invention includes each independent subcombination of the individual members of these group classes and ranges. For example, the expression mn as used herein refers to the range from m to n, as well as the subranges consisting of the individual values ​​therein, and the individual values.

[0043] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. "Alkyl" can have 1 to 8 carbon atoms, i.e., "C1-C8 alkyl", for example, C 1-4 Alkyl, C 1-3 Alkyl, C 1-2 Alkyl, C3 alkyl, C4 alkyl, C8 alkyl, C 1-8 Alkyl, C 3-8 Alkyl groups may also have 1-3 carbon atoms, i.e., "C1-C3 alkyl groups," such as C 1-3 Alkyl, C 1-2Alkyl, C3 alkyl. The term "C1-C5 alkyl" specifically refers to methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl as disclosed independently. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), n-propyl (n-Pr, -CH2CH2CH3), isopropyl (i-Pr, -CH(CH3)2), n-butyl (n-Bu, -CH2CH2CH2CH3), isobutyl (i-Bu, -CH2CH(CH3)2), sec-butyl (s-Bu, -CH(CH3)CH2CH3), tert-butyl (t-Bu, -C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1- Butyl (-CH2CH(CH3)CH2CH3), n-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH 3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), n-heptyl, n-octyl, etc. For example, the expression "C1-C8" or "C1-8" encompasses a range of 1-8 carbon atoms and should be understood to also encompass any subranges and individual point values ​​therein, such as C1-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 "C1-C5" or "C 1-5 " covers the range of 1-5 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., as well as C1, C2, C3, C4, C5, etc. For another example, the expression "C2-C5" or "C 2-5" covers the range of 2-5 carbon atoms and should be understood to also cover any subranges and each point value therein, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., as well as C2, C3, C4, C5, etc. For another example, the expression "C1-C8" or "C 1-8 " covers the range of 1-8 carbon atoms, and should be understood to also cover any subranges therein, as well as each point value, such as C2-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. For another example, the expression "ternary to octal" should be understood to cover any subranges therein and each point value, such as ternary to pentyl, ternary to hexayl, ternary to heptyl, ternary to octal, quaternary to pentyl, quaternary to hexayl, quaternary to heptyl, quaternary to octal, quinary to quinary, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, quinary to octal, etc., as well as 3, 4, 5, 6, 7, 8, etc. Other similar expressions herein should also be understood in a similar manner.

[0044] 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.

[0045] The term "selected from..." means one or more elements from the group listed thereafter, selected independently, and may include combinations of two or more elements.

[0046] The term "comprising" is an open expression, that is, including the contents specified in the present invention, but not excluding other contents.

[0047] When it is stated that each carbon atom in a group may be optionally replaced by a heteroatom, the normal valencies of all atoms in the group in the present circumstances are not exceeded and a stable compound is formed.

[0048] The term "heteroatom" refers to one or more oxygen (O), sulfur (S) or nitrogen (N), including nitrogen (N) and sulfur (S) in any oxidation state; primary, secondary, tertiary amines and quaternary ammonium salts; or a nitrogen atom in a heterocyclic ring in which hydrogen is substituted, for example, N, NH, NR.

[0049] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated electron system. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring." Examples of aryl groups include 6- to 14-membered aryl groups and 6- to 10-membered aryl groups, specifically phenyl and naphthyl. The aryl group is optionally substituted with one or more substituents described herein.

[0050] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from one or more of oxygen, sulfur and nitrogen. The term "heteroaryl" can be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include 5-14 membered heteroaryl, 5-10 membered heteroaryl, 5-10 membered monocyclic or polycyclic heteroaryl, 5-6 membered monocyclic heteroaryl, specifically including pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl, pyridazinyl, triazinyl, oxadiazolyl, isoxazolyl, pyranyl, 1,3,4-triazolyl, furopyrimidinyl, thienopyrimidinyl, pyrrolopyridinyl, pyranopyrimidinyl, benzothiazolyl, benzoxazolyl, thienopyrimidinyl, indolyl, etc. The heteroaryl groups are optionally substituted with one or more substituents described herein.

[0051] The terms "heterocycle" and "heterocyclyl" are used interchangeably to refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 3-14 ring atoms, or 3-8 ring atoms, or 5-6 ring atoms, wherein one or more ring atoms are independently replaced by a heteroatom, wherein the heteroatom has the meaning as described herein, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise specified, the -CH2- group in the heterocyclyl group may be optionally replaced by -C(=O)-. The sulfur atom of the ring may be optionally oxidized to form an S-oxide. The nitrogen atom of the ring may be optionally oxidized to form an N-oxide. Examples of heterocyclic groups include 3-14 membered heterocyclic groups, 3-8 membered heterocyclic groups, 5-10 membered heterocyclic groups, 5-10 membered monocyclic or bicyclic heterocyclic groups, specifically including: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, di ... Examples of heterocyclic groups in which the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-pyridonyl, 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 heterocyclyl group may be optionally substituted with one or more substituents described herein.

[0052] The term "alkenyl" refers to a general term for hydrocarbons containing carbon-carbon double bonds in the molecule, which is an unsaturated aliphatic hydrocarbon. For example: vinyl (CH2=CH-). The "alkene" can have 2-8 carbon atoms, that is, "C2-C8" alkenyl, such as C 2- 8-alkenyl, C 2-4 Alkenyl, C 2-5 Alkenyl, C3 alkenyl, C4 alkenyl, C6 alkenyl, C 2-6 Alkenyl, C 3-8 Alkenyl, C 3-6 Alkenyl, etc. It can also have 2-5 carbon atoms, i.e. "C2-C5 alkenyl", such as C 2-5 Alkenyl, C 2-3 Examples of alkenyl groups include, but are not limited to, vinyl (CH2=CH-), propenyl (-CH=CH-CH3), butenyl (-CH=CH-CH2-CH3, -CH2-CH=CH-CH3), pentenyl (-CH=CH-CH2-CH2-CH3, -CH2-CH2-CH=CH-CH3, -CH(CH3)-CH=CH-CH3), hexenyl, heptenyl, octenyl, and the like.

[0053] The term "alkyne" is a general term for hydrocarbons containing a carbon-carbon triple bond in the molecule, which is an unsaturated aliphatic hydrocarbon. For example: ethynyl (). The "alkyne" can have 2-8 carbon atoms, i.e. "C2-C8" alkynyl, for example C 2-8 Alkynyl, C 2-4 Alkynyl, C 2-5 Alkynyl, C3 alkynyl, C4 alkynyl, C6 alkynyl, C 2-6 Alkynyl, C 3-8 Alkynyl, C 3-6 Alkynyl, etc. It can also have 2-5 carbon atoms, i.e. "C2-C5 alkynyl", such as C 2-5 Alkynyl, C 2-3 Alkynyl, C3 alkynyl, C5 alkynyl, etc. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, etc.

[0054] The term "hydrogen (H)" refers to a single hydrogen atom, which may be linked to other groups, such as oxygen atoms, to form a hydroxyl group.

[0055] The term "deuterium (D or 2H)" is a stable isotope of hydrogen that occurs at a natural abundance of 0.015 mol%. The term "deuterated" refers to a group or compound in which one or more hydrogen atoms H are replaced by D.

[0056] 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.

[0057] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein alkyl has the meaning as described herein. In one embodiment, 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.

[0058] The term "alkylthio" refers to an alkyl group attached to the rest of the molecule through a sulfur atom, wherein the alkyl group is as defined herein. In one embodiment, the alkylthio group contains 1-8 carbon atoms. In one embodiment, the alkylthio group contains 1-5 carbon atoms. In another embodiment, the alkylthio group contains 1-3 carbon atoms. The alkylthio group may optionally be substituted with one or more substituents as described herein. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH3), ethylthio (-SCH2CH3), propylthio (-SCH2CH2CH3, -SCH(CH3)2), butylthio (-SCH2CH2CH2CH3, -SCH2CH(CH3)2, -SCH(CH3)CH2CH3, -SC(CH3)3), and the like.

[0059] The term "cycloalkyl" refers to a cyclic hydrocarbon group or cyclic alkenyl group consisting of carbon atoms and hydrogen atoms, preferably containing 1 or 2 rings. The cycloalkyl group can be a monocyclic, fused polycyclic, bridged ring or spirocyclic structure. The cycloalkyl group can have 3-8 carbon atoms, i.e., "C3-C8 cycloalkyl", or can have 3-6 carbon atoms, i.e., "C3-C6 cycloalkyl", such as C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, C3 cycloalkyl. Examples of cycloalkyl groups include C3-C8 cycloalkyl, C3-C6 cycloalkyl, specifically including: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. The term also encompasses situations where a C atom can be substituted by oxo (=O).

[0060] The terms "hydroxyalkyl" and "hydroxy-substituted alkyl" are used interchangeably and refer to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH, -CHOHCH3), hydroxypropyl (-CH2CH2CH2OH, -CH2CHOHCH3, -CHOHCH2CH3, -COHCH3CH3), and hydroxybutyl (-CH2CH2CH2CH2OH, -CH2CH2CHOHCH3, -CHOHCH2CH2CH3, -COHCH3CH2CH3). The above hydroxy substitutions can be mono- or poly-substituted.

[0061] The terms "hydroxyalkoxy" and "hydroxy-substituted alkoxy" are used interchangeably to refer to an alkoxy group substituted with one or more hydroxy groups.

[0062] The terms "haloalkyl" and "halogen-substituted alkyl" are used interchangeably and refer to an alkyl group substituted with one or more halogens. Examples include, but are not limited to, halomethyl, haloethyl, halopropyl, halobutyl, and halopentyl. The halo group may be monohalogen-substituted, dihalogen-substituted, or trihalogen-substituted. When the methyl group is trihalogen-substituted, trifluoromethyl may be further preferred.

[0063] The terms "haloalkoxy" and "halogen-substituted alkoxy" are used interchangeably and refer to an alkoxy group substituted with one or more halogens. Examples include, but are not limited to, halomethoxy, haloethoxy, halopropoxy, halobutoxy, and halopentoxy, wherein the halo groups may be monohalogen-substituted, dihalogen-substituted, or trihalogen-substituted.

[0064] The terms "haloalkenyl" and "halogen-substituted alkenyl" are used interchangeably and refer to an alkenyl group substituted with one or more halogens. Examples include, but are not limited to, halovinyl, halopropenyl, halobutenyl, and halopentenyl. The halo groups may be monohalogen-substituted, dihalogen-substituted, or trihalogen-substituted.

[0065] The terms "haloalkynyl" and "halogen-substituted alkynyl" are used interchangeably and refer to an alkynyl group that is substituted with one or more halogens. Examples include, but are not limited to, haloethynyl, halopropynyl, halobutynyl, and halopentynyl. The halo groups may be monohalogen-substituted, dihalogen-substituted, or trihalogen-substituted.

[0066] The term "hydroxy" refers to an -OH group.

[0067] "R1, R2 and the carbon atoms to which they are attached together form a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group, or a C3-C8 cycloalkyl group" or "R1, R2 together form a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group, or a C3-C8 cycloalkyl group" means that R1, R2 and the carbon atoms to which they are attached together form a fused polycyclic group. Examples include, but are not limited to: The groups are optionally substituted with one or more substituents.

[0068] The term "stereoisomers" refers to compounds that have identical chemical constitution but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, and the like.

[0069] The term "tautomer" refers to structural isomers with different energies that can be interconverted through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0070] The term "pharmaceutically acceptable salt" refers to an organic salt or an inorganic salt of a compound of the present invention.

[0071] The term "pharmaceutically acceptable carrier" refers to substances that are non-irritating to organisms and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavorings, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0072] 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.

[0073] Compounds of formula I

[0074] The present invention provides a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

[0075] in,

[0076] R1 and R2 are each independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano;

[0077] or R1, R2 and the carbon atom to which they are attached together form a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl or a C3-C8 cycloalkyl group optionally substituted by one or more substituents, the substituents being independently selected from H, D, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano;

[0078] L1 is selected from the group consisting of one or more substituents R LA substituted 6-14 membered aryl and optionally substituted by one or more substituents R LA The substituted 5-14 membered heteroaryl group is preferably selected from the group consisting of LA substituted 6-10 membered aryl and optionally substituted by one or more substituents R LA The substituted 5-10 membered heteroaryl group is further preferably selected from the group consisting of LA Substituted phenyl and optionally substituted by one or more substituents R LA substituted 5-6 membered monocyclic heteroaryl; the one or more substituents R LA independently selected from H, D, halogen, optionally substituted by one or more R LB Substituted C1-C8 alkyl, optionally substituted by one or more substituents R LB Substituted C1-C8 alkoxy, cyano, optionally substituted by one or more substituents R LBSubstituted C2-C8 alkynyl, optionally substituted by one or more substituents R LB Substituted C2-C8 alkenyl, hydroxyl, nitro, optionally substituted by one or more substituents R LB Substituted C1-C8 alkylthio, optionally substituted by one or more substituents R LB substituted C3-C8 cycloalkyl and OR4, the one or more substituents R LB is selected from H, D, halogen and hydroxyl;

[0079] R4 is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0080] L2 is selected from 6-14 membered aryl substituted by 0-4 Rb groups and 5-14 membered heteroaryl substituted by 0-4 Rb groups, preferably selected from 6-10 membered aryl substituted by 0-3 Rb groups and 5-10 membered monocyclic or bicyclic heteroaryl substituted by 0-3 Rb groups, further preferably selected from phenyl substituted by 0-3 Rb groups and 5-6 membered heteroaryl substituted by 0-3 Rb groups;

[0081] Each Rb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; the substituents are independently selected from H, D, halogen and hydroxyl;

[0082] X1 is selected from N and CR 10 ;

[0083] R 10 is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, D, halogen and hydroxy;

[0084] X2 is selected from N and CR 11 ;

[0085] R 11 is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano; said substituents being independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano;

[0086] and X1 and X2 are not N at the same time; and

[0087] When X2 is CR 11 , and when X1 is N, R2 is not H or D.

[0088] In one embodiment, the heteroaryl is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl, 1,3,4-triazolyl and pyranyl. In a preferred embodiment, the heteroaryl is selected from imidazolyl, pyrazolyl, thienyl, furanyl, 1,2,3-triazolyl, pyranyl and thiazolyl. In a more preferred embodiment, the heteroaryl is thienyl, 1,2,3-triazolyl, pyranyl, thiazolyl and furanyl.

[0089] In one embodiment, the heterocyclic group is preferably selected from the group consisting of oxirane, tetrahydrothiopyranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, dihydrothiopyranyl, tetrahydrothiophenyl, dihydrothiophenyl, azetidinyl, oxetanyl, thietanyl, piperidinyl and pyrrolidinyl. In a preferred embodiment, the heterocyclic group is selected from the group consisting of tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl and dihydropyranyl. In a particularly preferred embodiment, the heterocyclic group is selected from the group consisting of tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl and dihydropyranyl.

[0090] In one embodiment, C1-C8 alkyl is selected from C1-C5 alkyl and C1-C3 alkyl. In a specific embodiment, C1-C8 alkyl and C1-C5 alkyl are independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and isopentyl. In a more specific embodiment, C1-C8 alkyl, C1-C5 alkyl and C1-C3 alkyl are independently selected from methyl, ethyl, propyl and isopropyl.

[0091] 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).

[0092] In one embodiment, C1-C8 alkoxy is selected from C1-C5 alkoxy and C1-C3 alkoxy. In a specific embodiment, C1-C8 alkoxy and C1-C5 alkoxy are independently selected from methoxy, ethoxy, propoxy, butoxy and pentoxy. In a more specific embodiment, C1-C8 alkoxy, C1-C5 alkoxy and C1-C3 alkoxy are independently selected from methoxy, ethoxy and propoxy.

[0093] In one embodiment, the C3-C8 cycloalkyl is preferably a C3-C6 cycloalkyl. In a preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are selected from cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. In a more preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are selected from cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. In a particularly preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl are selected from cyclopentyl and cyclopentenyl.

[0094] In one embodiment, the halogen is selected from fluorine, chlorine, bromine and iodine. In a preferred embodiment, the halogen is selected from fluorine, chlorine and bromine. In a more preferred embodiment, the halogen is selected from fluorine and chlorine. In a particularly preferred embodiment, the halogen is fluorine.

[0095] In one embodiment, the compound of formula I is represented by formula IA,

[0096] Among them, R 1A 、R 2A 、R 3Aindependently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, D, halogen and hydroxy;

[0097] or R 1A 、R 2A Together with the carbon atom to which it is attached, it forms a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl, or a C3-C8 cycloalkyl group optionally substituted by one or more substituents independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano;

[0098] L 1A is selected from 6-14 membered aryl groups optionally substituted by one or more substituents and 5-14 membered heteroaryl groups optionally substituted by one or more substituents, preferably selected from 6-10 membered aryl groups optionally substituted by one or more substituents and 5-10 membered heteroaryl groups optionally substituted by one or more substituents, further preferably selected from phenyl groups optionally substituted by one or more substituents and 5-6 membered monocyclic heteroaryl groups optionally substituted by one or more substituents; the one or more substituents are independently selected from H, D, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, cyano, optionally substituted C2-C8 alkynyl, optionally substituted C2-C8 alkenyl, hydroxyl, nitro, optionally substituted C1-C8 alkylthio, optionally substituted C3-C8 cycloalkyl and OR 4A , preferably independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C3-C6 cycloalkyl and OR 4A , further preferably independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C6 cycloalkyl and OR 4A , the substituent is selected from H, D, halogen and hydroxy, and the substituent is preferably selected from D, halogen and hydroxy;

[0099] R 4A Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0100] L 2Asubstituted by 0-4 Rbbb groups, and 5-14-membered heteroaryl groups substituted by 0-4 Rbbb groups, preferably substituted by 0-3 Rbbb groups, and 5-10-membered monocyclic or bicyclic heteroaryl groups substituted by 0-3 Rbbb groups, and further preferably substituted by 0-3 Rbbb groups, and phenyl groups substituted by 0-3 Rbbb groups, and 5-6-membered heteroaryl groups substituted by 0-3 Rbbb groups;

[0101] Each Rbbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen; and the substituents are independently selected from H, D, halogen, and hydroxy.

[0102] In one embodiment, the compound of formula I is represented by formula IA,

[0103] Among them, R 1A 、R 2A 、R 3A independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, halogen and hydroxy;

[0104] or R 1A 、R 2A Together with the carbon atom to which it is attached, it forms a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl, or a C3-C8 cycloalkyl group optionally substituted by one or more substituents independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano;

[0105] L 1Ais selected from 6-14 membered aryl groups optionally substituted by one or more substituents and 5-14 membered heteroaryl groups optionally substituted by one or more substituents, preferably selected from 6-10 membered aryl groups optionally substituted by one or more substituents and 5-10 membered heteroaryl groups optionally substituted by one or more substituents, further preferably selected from phenyl groups optionally substituted by one or more substituents and 5-6 membered monocyclic heteroaryl groups optionally substituted by one or more substituents; the one or more substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxyl, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A , preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl and OR 4A , further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl and OR 4A ;

[0106] R 4A Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0107] L 2A substituted by 0-4 Rbbb groups, and 5-14-membered heteroaryl groups substituted by 0-4 Rbbb groups, preferably substituted by 0-3 Rbbb groups, and 5-10-membered monocyclic or bicyclic heteroaryl groups substituted by 0-3 Rbbb groups, and further preferably substituted by 0-3 Rbbb groups, and phenyl groups substituted by 0-3 Rbbb groups, and 5-6-membered heteroaryl groups substituted by 0-3 Rbbb groups;

[0108] Each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen; and the substituents are independently selected from H, halogen, and hydroxy.

[0109] In one embodiment, R 1A 、R 2A 、R 3Aindependently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, halogen and hydroxy. In one embodiment, the C3-C8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, more preferably cyclopropyl;

[0110] In one embodiment, R 1A 、R 2A Together with the carbon atom to which it is attached, it forms a 3-8 membered heterocyclic radical, a 5-8 membered heteroaryl or a C3-C8 cycloalkyl radical optionally substituted with one or more substituents, the substituents being independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano. In one embodiment, the 3-8 membered heterocyclic radical is selected from oxirane, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrothiophenyl, dihydrothiophenyl, azetidinyl, oxetanyl, thietanyl, piperidinyl and pyrrolidinyl. In a preferred embodiment, the 3-8 membered heterocyclic radical is selected from tetrahydropyranyl and dihydropyranyl. In one embodiment, the 5-8 membered heteroaryl is selected from furyl, pyranyl and thienyl. In one embodiment, the C3-C8 cycloalkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and cyclohexenyl. In a preferred embodiment, the C3-C8 cycloalkyl group is selected from cyclopentyl and cyclopentenyl.

[0111] In a specific embodiment, R 1A 、R 2A Together with the carbon atom to which it is attached, it forms the following substituent: In a more specific embodiment, R 1A 、R 2A Together with the carbon atom to which it is attached, it forms the following substituent: In a particularly specific embodiment, R 1A 、R 2A Together with the carbon atom to which it is attached, it forms the following substituent: Wherein, the above groups are optionally substituted by one or more substituents, and the substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, halogen, C1-C8 alkyl and C1-C8 alkoxy, and further preferably selected from H and halogen.

[0112] In one embodiment, L 1A is selected from 6-14 membered aryl groups optionally substituted by one or more substituents and 5-14 membered heteroaryl groups optionally substituted by one or more substituents, preferably selected from 6-10 membered aryl groups optionally substituted by one or more substituents and 5-10 membered heteroaryl groups optionally substituted by one or more substituents, further preferably selected from phenyl groups optionally substituted by one or more substituents and 5-6 membered monocyclic heteroaryl groups optionally substituted by one or more substituents; the substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxyl, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A , preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl and OR 4A , further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl and OR 4A ; R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0113] In a preferred embodiment, L 1A is selected from the group consisting of phenyl, pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, thiadiazolyl, thienyl and furyl. In a more preferred embodiment, L 1A is selected from phenyl, pyridyl, pyrazolyl, thiazolyl and thienyl. In a particularly preferred embodiment, L 1A The above groups are optionally substituted by one or more substituents independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxyl, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A, preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl and OR 4A , further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl and OR 4A ;

[0114] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0115] In one embodiment, the compound of formula I is represented by formula IA,

[0116] Among them, R 1A 、R 2A 、R 3A Independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl;

[0117] L 1A 6-14 membered aryl groups optionally substituted by one or more substituents and 5-14 membered heteroaryl groups optionally substituted by one or more substituents, preferably 6-10 membered aryl groups optionally substituted by one or more substituents and 5-10 membered heteroaryl groups optionally substituted by one or more substituents, further preferably phenyl groups optionally substituted by one or more substituents and 5-6 membered monocyclic heteroaryl groups optionally substituted by one or more substituents; the one or more substituents are independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl;

[0118] L 2A substituted by 0-4 Rbbb groups, and 5-14-membered heteroaryl groups substituted by 0-4 Rbbb groups, preferably substituted by 0-3 Rbbb groups, and 5-10-membered monocyclic or bicyclic heteroaryl groups substituted by 0-3 Rbbb groups, and further preferably substituted by 0-3 Rbbb groups, and phenyl groups substituted by 0-3 Rbbb groups, and 5-6-membered heteroaryl groups substituted by 0-3 Rbbb groups;

[0119] Each Rbbb group is independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy; preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy.

[0120] In one embodiment, R 1A 、R 2A 、R 3A Independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl.

[0121] In a preferred embodiment, L 2A -L 1A The structure is selected from In a more preferred embodiment, L 2A -L 1A The structure is selected from In a particularly preferred embodiment, L 2A -L 1A The structure is selected from

[0122] In one embodiment, the above L 2A -L 1A L in the structure 1A The group is optionally substituted with one or more substituents independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A ; preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl and OR 4A ; Further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl and OR 4A ; R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0123] In one embodiment, the above L2A -L 1A L in the structure 1A The group is optionally substituted by one or more substituents independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl.

[0124] In one embodiment, L 2A The group is selected from a 6-14 membered aryl group substituted by 0-4 Rbbb groups and a 5-14 membered heteroaryl group substituted by 0-4 Rbbb groups, preferably selected from a 5-10 membered aryl group substituted by 0-3 Rbbb groups and a 5-10 membered monocyclic or bicyclic heteroaryl group substituted by 0-3 Rbbb groups, further preferably selected from a phenyl group substituted by 0-3 Rbbb groups and a 5-6 membered heteroaryl group substituted by 0-3 Rbbb groups.

[0125] In one embodiment, L 2A is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thienyl, furanyl and 1,3,4-triazolyl, preferably selected from phenyl, pyrimidinyl, pyridinyl, pyrazolyl, thienyl, imidazolyl and 1,2,3-triazolyl, further preferably phenyl, pyridinyl, pyrazolyl, thienyl and 1,2,3-triazolyl; wherein the above groups are optionally substituted by 0-4 Rbbb groups.

[0126] In one embodiment, each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen; and the substituents are independently selected from H, halogen, and hydroxy.

[0127] In one embodiment, each Rbbb group is independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy; preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy.

[0128] In a specific embodiment, the compound of formula IA is represented by formula II-A:

[0129] Among them, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; said substituents are independently selected from H, halogen and hydroxy.

[0130] In a specific embodiment, the compound of formula IA is represented by formula III-A:

[0131] Among them, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; said substituents are independently selected from H, halogen and hydroxy;

[0132] n1A is an integer selected from 0-4, preferably 1;

[0133] R 6A independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A ; preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl and OR 4A ; Further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl and OR 4A ;

[0134] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0135] In some embodiments, n1A is 1, and R 6A is located at the 2-position of the phenyl group, or at the 3-position of the phenyl group, or at the 4-position of the phenyl group, or at the 5-position of the phenyl group, or at the 6-position of the phenyl group. In some embodiments, n1A is 1, and R 6A Located at the 4-position of the phenyl group. In some embodiments, n1A is 1, and R 6A Located at the 6-position of the phenyl group.

[0136] In a more preferred embodiment, R 6A In some embodiments, R 6A is C1-C4 alkoxy, preferably methoxy. 6A is halogen, preferably F.

[0137] In a specific embodiment, the compound of formula IA is represented by formula IV-A:

[0138] Among them, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; said substituents are independently selected from H, halogen and hydroxy;

[0139] n2A is an integer selected from 0-3, preferably 1;

[0140] R 7A independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A ; preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl and OR 4A ; Further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl and OR 4A ;

[0141] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0142] In some embodiments, n2A is 1, and R 7A is located at the 2-position of the pyridyl group, or at the 5-position of the pyridyl group, or at the 6-position of the pyridyl group. In some embodiments, n2A is 1, and R 7A In some embodiments, n2A is 1, and R 7A Located at the 6-position of pyridine.

[0143] In a more preferred embodiment, R 7A In some embodiments, R 7A is C1-C4 alkoxy, preferably methoxy. 7A is halogen, preferably F.

[0144] In a specific embodiment, the compound of formula IA is represented by formula VA:

[0145] Among them, R 5Ais selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; said substituents are independently selected from H, halogen and hydroxy;

[0146] n3A is an integer selected from 0-3, preferably 1;

[0147] R 8A independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A ; preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl and OR 4A ; Further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl and OR 4A ;

[0148] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0149] In some embodiments, n3A is 1, and R 8A is located at the 2-position of the pyridyl group, or at the 5-position of the pyridyl group, or at the 6-position of the pyridyl group. In some embodiments, n3A is 1, and R 7A In some embodiments, n3A is 1, and R 8A Located at the 6-position of pyridine.

[0150] In a more preferred embodiment, R 8A In some embodiments, R 8A is C1-C4 alkoxy, preferably methoxy. 8A is halogen, preferably F.

[0151] In one embodiment, the compound of formula I is represented by formula IB,

[0152] Among them, R 1B 、R 3Bindependently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from halogen, D, C1-C8 alkoxy, hydroxy, nitro and cyano;

[0153] R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F;

[0154] or R 1B 、R 2B Together they form a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl, or a C3-C8 cycloalkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, nitro, and cyano;

[0155] L 1B is selected from optionally substituted phenyl and optionally substituted pyridyl, the substituents being independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio;

[0156] R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0157] L 2Bis a 5-14-membered heteroaryl group substituted by 0-4 Rbb groups, preferably a 5-10-membered monocyclic or bicyclic heteroaryl group substituted by 0-3 Rbb groups, and further preferably a 5-6-membered heteroaryl group substituted by 0-3 Rbb groups;

[0158] Each Rbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, preferably selected from H and C1-C8 alkyl; the substituents are independently selected from D and halogen.

[0159] In one embodiment, R 1B 、R 3B independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from halogen, D, C1-C8 alkoxy, hydroxy, nitro and cyano; the 3-8 membered heterocyclyl is preferably selected from oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl and pyrrolidinyl; the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, further preferably cyclopropyl;

[0160] R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0161] In one embodiment, R 1B 、R 2BTogether they form a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl or a C3-C8 cycloalkyl group which is optionally substituted by one or more substituents; the 3-8 membered heterocyclyl is preferably selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, azetidinyl, oxetanyl, thietanyl, piperidinyl and pyrrolidinyl, and is further preferably selected from tetrahydrofuranyl, tetrahydropyranyl and dihydropyranyl; the 5-8 membered heteroaryl is preferably selected from furanyl, pyranyl and thienyl; the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, and is further preferably selected from cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl; the substituents are independently selected from halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano.

[0162] In a specific embodiment, R 1B 、R 2B The pyrimidine group connected to it together forms the following substituents: In a more specific embodiment, R 1B 、R 2B The pyrimidine group connected to it together forms the following substituents: Wherein, the above groups are optionally substituted by one or more substituents, and the substituents are independently selected from halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano.

[0163] In a preferred embodiment, R 2B Selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy and nitro, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, further preferably F.

[0164] In one embodiment, L 1B is selected from optionally substituted phenyl and optionally substituted pyridyl, the substituents being independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4Band C1-C8 alkylthio, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0165] In a preferred embodiment, L 1B Selected from Preferably selected from More preferably, it is selected from Wherein, the above groups are optionally substituted by one or more substituents, and the one or more substituents are independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxyl, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

[0166] In one embodiment, L 2B is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl and 1,3,4-triazolyl, preferably selected from pyrazolyl, imidazolyl and 1,2,3-triazolyl, further preferably selected from 1,2,3-triazolyl; wherein the above groups are optionally substituted by 0-4 Rbb groups.

[0167] In one embodiment, each Rbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, preferably selected from H and C1-C8 alkyl; and the substituents are independently selected from D and halogen.

[0168] In one embodiment, the heteroaryl group is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl, 1,3,4-triazolyl and pyranyl. In a preferred embodiment, the heteroaryl group is selected from imidazolyl, pyrazolyl, thienyl, furanyl, 1,2,3-triazolyl and pyranyl. In a more preferred embodiment, the heteroaryl group is thienyl, furanyl, 1,2,3-triazolyl and pyranyl.

[0169] In one embodiment, the heterocyclic group is preferably selected from the group consisting of oxirane, tetrahydrothiopyranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, azetidinyl, oxetanyl, thietanyl, piperidinyl and pyrrolidinyl. In a preferred embodiment, the heterocyclic group is selected from the group consisting of tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl and dihydropyranyl. In a particularly preferred embodiment, the heterocyclic group is selected from the group consisting of tetrahydrofuranyl, dihydrofuranyl and tetrahydropyranyl.

[0170] 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 selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. In a more preferred embodiment, the C3-C8 cycloalkyl group and the C3-C6 cycloalkyl group are selected from cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. In a particularly preferred embodiment, the C3-C8 cycloalkyl group and the C3-C6 cycloalkyl group are cyclopentyl or cyclopentenyl.

[0171] In a specific embodiment, the compound of formula IB is represented by formula II-B:

[0172] Among them, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, said substituents being independently selected from D and halogen;

[0173] R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0174] In a specific embodiment, the compound of formula IB is represented by formula III-B:

[0175] Wherein, n1B is selected from an integer of 0-3;

[0176] R 6B independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio;

[0177] R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0178] R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0179] In some embodiments, n1B is 1, and R 6B is located at the 2-position, or at the 5-position, or at the 6-position of the pyridyl group. In some embodiments, n1B is 1, and R 6B In some embodiments, n1B is 1, and R 6B Located at the 6-position of pyridine.

[0180] In a more preferred embodiment, R 6B In some embodiments, R 6B is C1-C4 alkoxy, preferably methoxy. 6B is halogen, preferably F.

[0181] In a specific embodiment, the compound of formula IB is represented by formula IV-B:

[0182] Among them, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, said substituents being independently selected from D and halogen;

[0183] n2B is an integer selected from 0-4, preferably 1;

[0184] R 7B independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio;

[0185] R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0186] R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, halogen, more preferably C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0187] In some embodiments, n2B is 1, and R 7B is located at the 2-position of the phenyl group, or at the 3-position of the phenyl group, or at the 4-position of the phenyl group, or at the 5-position of the phenyl group, or at the 6-position of the phenyl group. In some embodiments, n2B is 1, and R 7B Located at the 4-position of the phenyl group. In some embodiments, n2B is 1, and R 7B Located at the 6-position of the phenyl group.

[0188] In a more preferred embodiment, R 7BIn some embodiments, R 7B is C1-C4 alkoxy, preferably methoxy. 7B is halogen, preferably F.

[0189] In a specific embodiment, the compound of formula IB is represented by formula VB:

[0190] Among them, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, said substituents being independently selected from D and halogen;

[0191] n3B is an integer selected from 0-3, preferably 1,

[0192] R 8B independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR B and C1-C8 alkylthio; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl;

[0193] R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy and nitro, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0194] In some embodiments, n3B is 1, and R 8B is located at the 2-position, or at the 5-position, or at the 6-position of the pyridyl group. In some embodiments, n3B is 1, and R 8B In some embodiments, n3B is 1, and R 8BLocated at the 6-position of pyridine.

[0195] In a more preferred embodiment, R 8B In some embodiments, R 8B is C1-C4 alkoxy, preferably methoxy. 8B is halogen, preferably F.

[0196] In a specific embodiment, the compound of formula I is selected from any one of the following compounds:

[0197] Beneficial technical effects of the present invention

[0198] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0199] The present invention relates to a class of novel structural compounds, which are selective OX2R antagonists and can be used to prevent, treat and / or alleviate diseases related to orexin receptors, and are preferably used to treat insomnia, depression, Alzheimer's disease and sleep apnea. These compounds exhibit good selectivity and pharmacodynamic activity as OX2 receptor antagonists, as well as good pharmacokinetic properties, increased oral bioavailability in subjects, and significantly reduced autonomous activity in subjects, thus having good prospects for clinical application.

[0200] Figures in the specification

[0201] Figure 1 shows the awake time of rats in each time period for 12 hours after administration of 30 mg / kg of Seltorexant;

[0202] Figure 2 shows the awake time of rats in each time period for 12 hours after administration of 30 mg / kg of compound 1;

[0203] Figure 3 is a graph showing the awake time of rats in each time period for 12 hours after administration of 30 mg / kg of compound 5;

[0204] Figure 4 shows the awake time of rats in each time period for 12 hours after administration of 30 mg / kg of compound 22;

[0205] Figure 5 shows the awake time of rats in each time period for 12 hours after administration of 30 mg / kg of compound 41.

[0206] Example

[0207] The following embodiments of the present invention are described in detail. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, the ratios, percentages, etc. referred to herein are all by weight.

[0208] The following examples are prepared using a cis-structured starting material as an example, i.e., cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester as the starting material to obtain example compounds that are all cis-isomers.

[0209] Synthesis Example

[0210] Cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester reacts with N-phenylbis(trifluoromethylsulfonyl)imide to obtain intermediate Ia, which is then borated with diboronic acid pinacol ester to obtain intermediate Ib. A coupling reaction is performed to obtain intermediate Ic, and Ic is deprotected from Boc to obtain intermediate Id; A coupling reaction with L2-Z is performed to obtain an intermediate Ie, and an ester hydrolysis reaction of Ie is performed to obtain an intermediate If. Finally, Id and If are subjected to a condensation reaction to obtain a compound shown in formula I.

[0211] Example 1: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (1)

[0212] 1.1 A solution of cis-5-oxo-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (5 g, 22.19 mmol) in THF (20 mL) was treated with LiHMDS (5.2 g, 110.95 mmol) at -78 ° C for 2 hours, followed by the addition of N-phenylbis(trifluoromethanesulfonyl)imide (9.51 g, 26.63 mmol) at -78 ° C. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The reaction was quenched by adding water / ice (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 5-[[(trifluoromethyl)sulfonyl]oxy]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 1a) (4.8 g).

[0213] 1.2 A solution of 1a (4.5 g, 12.59 mmol), pinacol diboronate (4.8 g, 18.90 mmol), KOAc (3.5 g, 25.36 mmol), and Pd(dppf)Cl2 (0.9 g, 1.24 mmol) was added to dioxane (20 mL), heated to 80°C, and stirred overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.6 g of crude tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 1b). The crude product was used directly in the next step without further purification.

[0214] 1.3 Dissolve 2,4,6-trichloro-5-fluoropyrimidine (5 g, 24.87 mmol) and iron triacetylacetonate (0.9 g, 2.55 mmol) in 20 mL of THF. Cool to -78°C under nitrogen. Add MeMgCl (3.0 M solution in THF, 19 mL) dropwise. Incubate at -78°C for 1 hour. Then, allow the reaction to proceed at room temperature for 3 hours. Once the reaction is complete, quench the reaction mixture with NH4Cl and extract with EtOAc (3 x 50 mL). The combined organic layers are washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure and eluted with PE / EA (20:1) to yield 3.4 g of 2-chloro-5-fluoro-4,6-dimethylpyrimidine (1c).

[0215] 1.4 Dissolve 1b (3.5 g, 10.44 mmol), 1c (1.8 g, 11.48 mmol), K2CO3 (2.9 g, 21.01 mmol), and Pd(dppf)Cl2 (0.76 g, 1.05 mmol) in a dioxane (20 mL) / H2O (5 mL) mixture under nitrogen protection and heat to 100°C for reaction. After the reaction was completed, the temperature was lowered to room temperature, 30 mL of water was added to dilute, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with saturated brine (2 x 20 mL), dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 1:1) to obtain 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 1d) (2.8 g).

[0216] 1.5 Compound 1d (2.8 g, 8.40 mmol) and trifluoroacetic acid (10.00 mL) were added to dichloromethane (30.00 mL) under nitrogen protection and stirred at room temperature for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain crude 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 1e). The crude product was used directly in the next step without further purification.

[0217] 1.6 Place 2-fluoro-6-iodobenzoic acid (10.0 g, 37.59 mmol), 1,2,3-triazole (5.2 g, 75.29 mmol), cuprous iodide (0.35 g, 1.2 mmol), cesium carbonate (24.5 g, 75.15 mmol), (1R,2R)-N,N-dimethyl-1,2-diaminocyclohexane (1.1 g, 7.73 mmol) and dioxane (100 mL) in a 250 mL round-bottom flask and stir at 85 °C overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, 50 mL of tert-butyl methyl ether and 50 mL of water were added, and stirring was continued for half an hour before separation. The organic phase was discarded and the pH of the aqueous phase was adjusted to acidic with 2N hydrochloric acid. Then, the mixture was extracted with ethyl acetate (50 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 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 1f) (4.6 g).

[0218] 1.7 1e (100 mg, 0.43 mmol) and 1f (101 mg, 0.49 mmol) were added to DMF (5 mL) under nitrogen protection. HATU (262 mg, 0.69 mmol) and DIPEA (119 mg, 0.92 mmol) were added dropwise at room temperature. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was extracted with ethyl acetate (3 x 15 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 give 68 mg of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 1). 1H NMR(400MHz, Methanol-d4)δ7.99–7.78(m,2H),7.75–7.55(m,2H),7.35–7.18(m,1H),6.77–6.45(m,1H),3.99–3.74(m,2H),3.64(d dd,J=24.2,18.9,10.8Hz,2H),3.51–3.35(m,1H),3.26–3.00(m,2H),3.00–2.82(m,1H),2.71–2.39(m,6H).LCMS(ES,m / z):423[M+H] + .

[0219] Example 2: Preparation of (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (2)

[0220] 2.1 The reaction raw material 2-fluoro-6-iodobenzoic acid was replaced with 4-fluoro-6-iodobenzoic acid, and 4-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 2a) was prepared according to the method of Example 1-1.6.

[0221] 2.2 The reaction raw material 1f was replaced with 2a, and (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 2) was prepared according to the method of Example 1-1.7. 1 H NMR (400MHz, DMSO-d6) δ8.13–7.91(m,2H),7.77–7.72(m,1H),7.53–7.48(m,1H),7.43–7.35(m,1H),6.58(d,J =80.4Hz,1H),3.80–3.45(m,3H),3.26–2.90(m,3H),2.84–2.59(m,2H),2.44(s,6H).LCMS(ES,m / z):423[M+H] + .

[0222] Example 3: Preparation of (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (3)

[0223] 3.1 The reaction raw material 2-fluoro-6-iodobenzoic acid was replaced with 3-fluoro-2-iodobenzoic acid, and 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 3a) was prepared according to the method of Example 1-1.6.

[0224] 3.2 The reaction raw material 1f was replaced with 3a, and (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 3) was prepared according to the method of Example 1-1.7. 1 H NMR (400MHz, DMSO-d6) δ7.95(d,J=22.4Hz,2H),7.70–7.56(m,2H),7.34(t,J=6.2Hz,1H),6.60(d,J=20. 0Hz,1H),3.65–3.36(m,3H),3.10–2.81(m,3H),2.67–2.53(m,2H),2.43(s,6H).LCMS(ES,m / z):423[M+H] + .

[0225] Example 4: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl) (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (4)

[0226] 4.1 The reaction raw material 2-fluoro-6-iodobenzoic acid was replaced with 2-iodo-5-methoxybenzoic acid, and 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 4a) was prepared according to the method of Example 1-1.6.

[0227] 4.2 Replace the reaction raw material 1f with 4a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 4) according to the method of Example 1-1.7. 1H NMR (400MHz, DMSO-d6) δ7.91(d,J=23.2Hz,2H),7.68–7.51(m,2H),7.14–7.07(m,1H),6.51(d,J=41.7Hz,1H),3.81(d, J=5.6Hz,3H),3.69–3.44(m,3H),3.29–3.17(m,2H),3.02–2.68(m,3H),2.40(d,J=5.6Hz,6H).LCMS(ES,m / z):435[M+H] + .

[0228] Example 5: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (5)

[0229] 5.1 Replace the starting material 2-fluoro-6-iodobenzoic acid with 2-iodo-4-methoxybenzoic acid and prepare 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 5a) according to the method of Example 1-1.6.

[0230] 5.2 Replace the reaction raw material 1f with 5a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 5) according to the method of Example 1-1.7. 1 H NMR(400MHz,DMSO-d6)δ7.95(d,J=26.3Hz,2H),7.38–7.33(m,2H),7.07(td,J=8.7,2.5Hz,1H),6.57(d,J=78.2Hz,1H) ,3.87(d,J=5.6Hz,3H),3.76–3.41(m,3H),3.30–3.09(m,2H),3.01–2.59(m,3H),2.43(s,6H).LCMS(ES,m / z):435[M+H] + .

[0231] Example 6: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (6)

[0232] 6.1 The reaction raw material 2-fluoro-6-iodobenzoic acid was replaced with 2-iodo-5-methylbenzoic acid, and 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 6a) was prepared according to the method of Example 1-1.6.

[0233] 6.2 Replace the reaction raw material 1f with 6a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 6) according to the method of Example 1-1.7. 1 H NMR(400MHz, DMSO-d6)δ7.90(d,J=24.5Hz,2H),7.53–7.42(m,2H),7.23–7.11(m,1H),6.53(d ,J=46.1Hz,1H),3.63–3.41(m,3H),3.34–3.22(m,2H),3.13–2.64(m,3H),2.56(s,3H),2.38(s 6H).LCMS(ES,m / z):419[M+H] + .

[0234] Example 7: Preparation of (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (7)

[0235] 7.1 2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 7a) was prepared according to the method of Example 1-1.6, except that the starting material 2-fluoro-6-iodobenzoic acid was replaced with 2-iodobenzoic acid.

[0236] 7.2 Replace the reaction raw material 1f with 7a and prepare (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 7) according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ8.04–8.01(m,1H),7.83–7.75(m,2H),7.59–7.53(m,1H),7.50–7.45(m,2H),6.67(d ,J=114.0Hz,1H),4.06–3.69(m,3H),3.56–3.25(m,2H),3.17–2.86(m,3H),2.53(s,6H).LCMS(ES,m / z):405[M+H] + .

[0237] Example 8: Preparation of (5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (8)

[0238] 8.1 2,4-Dichloro-5-fluoro-6-methylpyrimidine (3 g, 16.58 mmol) and sodium methoxide (1.0 g, 18.51 mmol) were added to 10 mL of methanol and reacted at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography using PE / EA (1:1) as the eluent to obtain 2.1 g of 2-chloro-5-fluoro-4-methoxy-6-methylpyrimidine (Compound 8a).

[0239] 8.2 Reaction material 1c was replaced with 8a, and tert-butyl 5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 8b) was prepared according to the method of Example 1-1.4.

[0240] 8.3 Replacing the starting material 1d with 8b, prepare 5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 8c) according to the method of Example 1-1.5.

[0241] 8.4 Reaction material 1e was replaced with 8c, and (5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 8) was prepared according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ8.03–7.78(m,2H),7.68–7.49(m,2H),7.31–7.14(m,1H),6.71–6.62(m,1H),4.04(s,3H),3.98–3. 85(m,1H),3.73–3.32(m,3H),3.19–2.83(m,3H),2.58(d,J=16.7Hz,1H),2.43(dd,J=11.0,3.0Hz,3H).LCMS(ES,m / z):439[M+H] + .

[0242] Example 9: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (9)

[0243] 9.1 2-Chloro-4,5,6-trimethylpyrimidine (Compound 9a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4,6-trichloro-5-methylpyrimidine.

[0244] 9.2 Reaction material 1c was replaced with 9a, and tert-butyl 5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 9b) was prepared according to the method of Example 1-1.4.

[0245] 9.3 Replacing the starting material 1d with 9b, prepare 5-(4,5,6-trimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 9c) according to the method of Example 1-1.5.

[0246] 9.4 Reaction material 1e was replaced with 9c, and (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 9) was prepared according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ7.87–7.76(m,2H),7.64(d,J=26.4Hz,1H),7.48–7.42(m,1H),7.23–6.94(m,1H),6.88 –6.43(m,1H),3.77-3.30(m,3H),3.23–2.92(m,2H),2.81–2.58(m,3H),2.57–2.31(m,9H).LCMS(ES,m / z):419[M+H] + .

[0247] Example 10: Preparation of (5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (10)

[0248] 10.1 Replacing the starting material 1c with 2,5-dichloro-4,6-dimethylpyrimidine, prepare tert-butyl 5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 10a) according to the method of Example 1-1.4.

[0249] 10.2 Replacing the starting material 1d with 10a, prepare 5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 10b) according to the method of Example 1-1.5.

[0250] 10.3 Replace the reaction raw material 1e with 9c and prepare (5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 10) according to the method of Example 1-1.7. 1 H NMR(400MHz,Chloroform-d)δ7.94–7.72(m,2H),7.61(d,J=25.4Hz,1H),7.46(h,J=6.0,5.4Hz,1H),7.12(dt,J=16.2,8.5Hz,1H),6.92 –6.43(m,1H),4.18–3.78(m,2H),3.75–3.50(m,2H),3.50–3.32(m,1H),3.23–2.83(m,3H),2.74–2.41(m,6H).LCMS(ES,m / z):439[M+H] + .

[0251] Example 11: Preparation of (5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (11)

[0252] 11.1 Ethyl 2-ethyl-3-oxobutanoate (5.0 g, 31.61 mmol) and urea (1.9 g, 31.67 mmol) were added to 60 mL of ethanol under nitrogen protection. EtONa (4.3 g, 63.24 mmol) was added and the temperature was raised to 70°C for 7 hours. After the reaction was complete, the temperature was lowered to room temperature and the mixture was extracted with EtOAc (3 × 50 mL). The organic phases were combined and washed with water (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated and purified by column chromatography using PE / EA (10:1) as the eluent to obtain 2.1 g of 5-ethyl-6-methylpyrimidine-2,4(3H,5H)-dione (Compound 11a).

[0253] 11.2 11a (1.8 g, 11.68 mmol) and diethylaniline (2 mL) were added to phosphorus oxychloride (20 mL) under nitrogen atmosphere and reacted at 110°C for 3 hours. After completion of the reaction, the temperature was cooled to room temperature and the pH was adjusted to 7 with saturated Na2CO3 solution. The mixture was extracted with EtOAc (3 × 10 mL). The organic phases were combined, washed with water (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography using PE / EA (3:1) as the eluent to obtain 1.2 g of 2,4-dichloro-5-ethyl-6-methylpyrimidine (compound 11b).

[0254] 11.3 Replace the starting material 2,4,6-trichloro-5-fluoropyrimidine with 11b and prepare 2-chloro-5-ethyl-4,6-dimethylpyrimidine (Compound 11c) according to the method of Example 1-1.3.

[0255] 11.4 Replacing the starting material 1c with 11c, prepare tert-butyl 5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 11d) according to the method of Example 1-1.4.

[0256] 11.5 Replacing the starting material 1d with 11d, prepare 5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 11e) according to the method of Example 1-1.5.

[0257] 11.6 Replace the reaction raw material 1e with 11e and prepare (5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 11) according to the method of Example 1-1.7. 1 H NMR(400MHz,Chloroform-d)δ7.92–7.74(m,2H),7.61(d,J=31.4Hz,1H),7.46(ttd,J=8.4,6.0,3.1Hz,1H),7.21–6.97(m,1H),6.90–6.46(m,1 H),4.20–3.77(m,1H),3.75–3.30(m,3H),3.27–2.83(m,3H),2.81–2.58 (m,3H),2.57–2.42(m,6H),1.23–1.06(m,3H).LCMS(ES,m / z):433[M+H] + .

[0258] Example 12: Preparation of (4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (12)

[0259] 12.1 Replace the starting material 2-fluoro-6-iodobenzoic acid with 2-bromo-4-ethoxybenzoic acid and prepare 4-ethoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 12a) according to the method of Example 1-1.6.

[0260] 12.2 Replace the reaction raw material 1f with 12a and prepare (4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 12) according to the method of Example 1-1.7. 1H NMR(400MHz, DMSO-d6)δ7.91(d,J=24.8Hz,2H),7.33–7.28(m,2H),7.09–7.05(m,1H),6.52(d,J=76.4Hz,1H),3.87–3.78( m,2H),3.73–3.39(m,3H),3.31–3.07(m,2H),3.01–2.59(m,3H),2.38(s,6H),1.19–1.04(m,3H).LCMS(ES,m / z):449[M+H] + .

[0261] Example 13: Preparation of (4-cyclopropyloxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (13)

[0262] 13.1 2-Bromo-4-hydroxybenzoic acid (5.0 g, 23.04 mmol), cyclopropane bromide (8.4 g, 69.43 mmol) and cesium carbonate (15.0 g, 46.01 mmol) were added to 30 mL of DMF and the reaction was carried out under sealed conditions. The temperature was raised to 100°C for 10 hours. After the reaction was completed, the temperature was lowered to room temperature and 150 mL of water was added. The mixture was extracted with EtOAc (3 × 50 mL). The organic phases were combined and washed with water (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The mixture was separated and purified by column chromatography using PE / EA (1:1) as the eluent to obtain 1.1 g of 2-bromo-4-cyclopropyloxybenzoic acid (Compound 13a).

[0263] 13.2 Replace the starting material 2-fluoro-6-iodobenzoic acid with 13a and prepare 4-cyclopropyloxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 13b) according to the method of Example 1-1.6.

[0264] 13.3 Replacing the starting material 1f with 13b, prepare (4-cyclopropyloxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 13) according to the method of Example 1-1.7. 1H NMR (400MHz, DMSO-d6) δ7.99–7.93(m,2H),7.40–7.31(m,2H),7.14–7.07(m,1H),6.46(d,J=76.4Hz,1H),4.13–4.06(m, 1H),3.68–3.35(m,3H),3.21–3.04(m,2H),2.99–2.56(m,3H),2.34(s,6H),1.18–1.04(m,4H).LCMS(ES,m / z):449[M+H] + .

[0265] Example 14: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (14)

[0266] 14.1 2-Chloro-4-methyl-5,6,7,8-tetrahydroquinazoline (Compound 14a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5,6,7,8-tetrahydroquinazoline.

[0267] 14.2 Reaction material 1c was replaced with 14a, and tert-butyl 5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 14b) was prepared according to the method of Example 1-1.4.

[0268] 14.3 Replacing the starting material 1d with 14b, prepare 5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 14c) according to the method of Example 1-1.5.

[0269] 14.4 Replace the reaction raw material 1e with 14c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 14) according to the method of Example 1-1.7. 1H NMR (400MHz, Methanol-d4) δ7.92 (d, J = 2.0Hz, 1H), 7.88–7.74 (m, 1H), 7.71–7.56 (m, 2H), 7.32–7.23 (m, 1H), 6.77–6.48 (m, 1H), 4. 00–3.53(m,3H),3.46–3.42(m,2H),3.22–2.96(m,2H),3.02–2.84(m,5H),2.41–2.33(m,3H),2.03(m,4H).LCMS(ES,m / z):445[M+H] + .

[0270] Example 15: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (15)

[0271] 15.1 2-Chloro-4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine (Compound 15a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine.

[0272] 15.2 Reaction material 1c was replaced with 15a, and 5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 15b) was prepared according to the method of Example 1-1.4.

[0273] 15.3 Replace the starting material 1d with 15b and prepare 5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 15c) according to the method of Example 1-1.5.

[0274] 15.4 Replace the reaction raw material 1e with 15c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 15) according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ7.91–7.78(m,2H),7.54(d,J=25.6Hz,1H),7.49–7.42(m,1H),7.15–7.13(m,1H),6.89–6.42(m,1H),4 .53–4.48(m,2H),3.89–3.58(m,3H),3.50–3.37(m,3H),3.26–2.91(m,4H),2.26(s,3H),1.21–1.18(m,2H).LCMS(ES,m / z):447[M+H] + .

[0275] Example 16: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (16)

[0276] 16.1 2-Chloro-4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (Compound 16a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine.

[0277] 16.2 Reaction material 1c was replaced with 16a, and 5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 16b) was prepared according to the method of Example 1-1.4.

[0278] 16.3 Replace the starting material 1d with 16b and prepare 5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 16c) according to the method of Example 1-1.5.

[0279] 16.4 Replace the reaction raw material 1e with 16c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 16) according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ7.96–7.69(m,2H),7.61(dd,J=23.9,1.8Hz,1H),7.56–7.38(m,1H),7.12(dt,J=16.1,8.5Hz,1H),6.93–6 .42(m,1H),4.73(d,J=8.7Hz,2H),4.29–3.77(m,4H),3.78–3.33(m,3H),3.27–2.79(m,5H),2.51–2.22(m,3H).LCMS(ES,m / z):447[M+H] + .

[0280] Example 17: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (17)

[0281] 17.1 2-Chloro-4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Compound 17a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine.

[0282] 17.2 Reaction material 1c was replaced with 17a, and 5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 17b) was prepared according to the method of Example 1-1.4.

[0283] 17.3 Replacing the starting material 1d with 17b, prepare 5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 17c) according to the method of Example 1-1.5.

[0284] 17.4 Replace the reaction raw material 1e with 17c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 17) according to the method of Example 1-1.7. 1H NMR(400MHz, Methanol-d4)δ7.96(d,J=1.4Hz,1H),7.92–7.79(m,1H),7.73–7.56(m,2H),7.33–7.21(m,1H),6.81–6.51(m,1H),4.00–3.53(m,3 H),3.44(tdd,J=12.1,8.4,3.7Hz,2H),3.24–3.03(m,2H),3.02–2.84(m,5H),2.46–2.39(m,3H),2.14(h,J=7.3Hz,2H).LCMS(ES,m / z):431[M+H] + .

[0285] Example 18: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylfuro[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (18)

[0286] 18.1 2-Chloro-4-methylfuro[3,2-d]pyrimidine (Compound 18a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichlorofuro[3,2-d]pyrimidine.

[0287] 18.2 Reaction material 1c was replaced with 18a, and tert-butyl 5-(4-methylfuro[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 18b) was prepared according to the method of Example 1-1.4.

[0288] 18.3 Replacing the starting material 1d with 18b, prepare 5-(4-methylfuro[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 18c) according to the method of Example 1-1.5.

[0289] 18.4 Replace the reaction raw material 1e with 18c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylfuro[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 18) according to the method of Example 1-1.7. 1H NMR(400MHz, Methanol-d4)δ7.91–7.82(m,2H),7.76–7.52(m,3H),7.33–7.11(m,2H),6.77–6.45(m, 1H),3.99–3.74(m,2H),3.68-3.31(m,3H),3.26–2.96(m,3H),2.38(s,3H).LCMS(ES,m / z):431[M+H] + .

[0290] Example 19: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (19)

[0291] 19.1 A pressure reactor was charged with 18a (2 g, 11.86 mmol), Pd / C (20%, 400 mg), and 10 mL of MeOH. The reaction mixture was hydrogenated at 50°C under 5 psi of hydrogen pressure for 6 hours. After completion, the reaction was filtered through celite and concentrated under reduced pressure. The product was purified by column chromatography using PE / EA (10:1) to afford 430 mg of 2-chloro-4-methyl-6,7-dihydrofuro[3,2-d]pyrimidine (Compound 19a).

[0292] 19.2 Reaction material 1c was replaced with 19a, and tert-butyl 5-(4-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 19b) was prepared according to the method of Example 1-1.4.

[0293] 19.3 Replacing the starting material 1d with 19b, prepare 5-(4-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 19c) according to the method of Example 1-1.5.

[0294] 19.4 Replace the reaction raw material 1e with 19c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydrofuro[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 19) according to the method of Example 1-1.7. 1H NMR (400MHz, Chloroform-d) δ8.12–7.78(m,2H),7.73(s,1H),7.47(tdd,J=8.3,5.9,2.1Hz,1H),7.14(tdd,J=8.4,5.4,1.0Hz,1H),6. 77–6.45(m,1H),4.53(t,J=8.8Hz,2H),4.12–3.76(m,2H),3.73–3.41(m,5H),3.32–3.13(m,3H),2.21(s,3H).LCMS(ES,m / z):433[M+H] + .

[0295] Example 20: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (20)

[0296] 20.1 2-Chloro-4-methyl-5,7-dihydrofuro[3,4-d]pyrimidine (Compound 20a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5,7-dihydrofuro[3,4-d]pyrimidine.

[0297] 20.2 Reaction material 1c was replaced with 20a, and tert-butyl 5-(4-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 20b) was prepared according to the method of Example 1-1.4.

[0298] 20.3 Replacing the starting material 1d with 20b, prepare 5-(4-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 20c) according to the method of Example 1-1.5.

[0299] 20.4 Reaction raw material 1e was replaced with 20c, and (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,7-dihydrofuro[3,4-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 20) was prepared according to the method of Example 1-1.7. 1H NMR (400MHz, Methanol-d4) δ7.96 (s, 1H), 7.87 (td, J = 16.3, 15.7, 7.4Hz, 1H), 7.74–7 .57(m,2H),7.35–7.22(m,1H),6.90–6.59(m,1H),5.19–5.13(m,2H),4.98(dt,J=10. 2,2.9Hz,2H),3.99–3.77(m,2H),3.62(tdd,J=11.5,8.4,5.2Hz,1H),3.51–3.39(m,1 H),3.24–2.87(m,3H),2.74–2.57(m,1H),2.48–2.42(m,3H).LCMS(ES,m / z):433[M+H] + .

[0300] Example 21: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (21)

[0301] 21.1 2-Chloro-4-methylthieno[3,2-d]pyrimidine (Compound 21a) was prepared according to the method of Example 1-1.3, except that the starting material 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichlorothieno[3,2-d]pyrimidine.

[0302] 21.2 Reaction material 1c was replaced with 21a, and tert-butyl 5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 21b) was prepared according to the method of Example 1-1.4.

[0303] 21.3 Replacing the starting material 1d with 21b, prepare 5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 21c) according to the method of Example 1-1.5.

[0304] 21.4 Replace the reaction raw material 1e with 21c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 21) according to the method of Example 1-1.7. 1H NMR(400MHz, Methanol-d4)δ7.96–7.86(m,2H),7.83–7.61(m,3H),7.32–7.14(m,2H),6.71–6.48(m, 1H),3.91–3.76(m,2H),3.63-3.28(m,3H),3.23–2.92(m,3H),2.33(s,3H).LCMS(ES,m / z):431[M+H] + .

[0305] Example 22: 5-(5-Fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (22)

[0306] 22.1 5-Bromo-4-chloro-2-methoxypyridine (500 mg, 2.247 mmol), TEA (682.3 mg, 6.741 mmol) and Pd(dppf)Cl2 were added to methanol (5 mL). The reaction solution was added to a pressure reactor, and CO was introduced to a pressure of 10 atm. The temperature was raised to 50°C and the reaction was allowed to react overnight. After the reaction was completed, the temperature was lowered to room temperature and extracted with EtOAc (3 x 20 mL). The organic phases were combined, washed with saturated brine (2 x 10 mL), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography eluted with PE / EA (5:1) gave 183 mg of methyl 4-chloro-6-methoxypyridine-3-carboxylate (Compound 22a).

[0307] 22.2 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 22a and prepare 6-methoxy-4-(2H-1,2,3-triazol-2-yl)nicotinic acid (compound 22b) according to the method of Example 1-1.6.

[0308] 22.3 Replace the reaction raw material 1f with 22b and prepare 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (Compound 22) according to the method of Example 1-1.7. 1H NMR (400MHz, Methanol-d4) δ8.20(d,J=7.4Hz,1H),7.89(s,2H),7.39(d,J=11.5Hz,1H),6.89–6.40(m,1H),4.01(d,J =6.8Hz,3H),3.96–3.79(m,2H),3.69–3.45(m,3H),3.18–2.87(m,3H),2.46(d,J=6.6Hz,6H).LCMS(ES,m / z):436[M+H] + .

[0309] Example 23: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (23)

[0310] 23.1 2-Methoxy-5-(2H-1,2,3-triazol-2-yl)isonicotinic acid (Compound 23a) was prepared according to the method of Example 1-1.6, except that the starting material 2-fluoro-6-iodobenzoic acid was replaced with 5-bromo-2-methoxyisonicotinic acid.

[0311] 23.2 Replace the reaction raw material 1f with 23a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (Compound 23) according to the method of Example 1-1.7. 1 H NMR(400MHz,Chloroform-d)δ8.75(d,J=5.0Hz,1H),7.70(d,J=13.0Hz,2H),6.76–6.48(m,2H),4.01–3.91(m,4H ),3.83–3.78(m,1H),3.66–3.27(m,3H),3.10–2.57(m,4H),2.48(dd,J=5.5,2.7Hz,6H).LCMS(ES,m / z):436[M+H] + .

[0312] Example 24: Preparation of (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (24)

[0313] 24.1 Replace the starting material 2-fluoro-6-iodobenzoic acid with 3-bromopicolinic acid and prepare 3-(2H-1,2,3-triazol-2-yl)picolinic acid (Compound 24a) according to the method of Example 1-1.6.

[0314] 24.2 Replace the reaction raw material 1f with 24a and 1e with 8c, and prepare (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 24) according to the method of Example 1-1.7. 1 H NMR(400MHz,Chloroform-d)δ8.76–8.54(m,1H),8.33–8.24(m,1H),7.86(dd,J=8.5,3.2Hz,1H),7.53–7.29(m,2H),6.62(d,J=91.9Hz,1H),4.04 (s,3H),3.98–3.85(m,1H),3.73–3.32(m,3H),3.19–2.83(m,3H),2.58(d,J=16.7Hz,1H),2.43(dd,J=11.0,3.0Hz,3H).LCMS(ES,m / z):422[M+H] + .

[0315] Example 25: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl) (6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (25)

[0316] 25.1 Replace the starting material 2-fluoro-6-iodobenzoic acid with 3-bromo-6-methoxypicolinic acid and prepare 6-methoxy-3-(2H-1,2,3-triazol-2-yl)picolinic acid (Compound 25a) according to the method of Example 1-1.6.

[0317] 25.2 Replace the reaction raw material 1f with 25a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (Compound 25) according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ8.09(dd,J=8.7,4.2Hz,1H),7.79(t,J=3.5Hz,1H),7.31(dd,J=10.7,3.2Hz,1H),7.18–7.11(m,1 H),6.89–6.84(m,1H),4.16-3.94(m,4H),3.89-3.40(m,4H),3.23–2.88(m,3H),2.61(d,J=8.4Hz,6H).LCMS(ES,m / z):436[M+H] + .

[0318] Example 26: (5-Fluoro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (26)

[0319] 26.1 Replace the starting material 2-fluoro-6-iodobenzoic acid with 3-bromo-5-fluoropicolinic acid and prepare 5-fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid (Compound 26a) according to the method of Example 1-1.6.

[0320] 26.2 Replace the reaction raw material 1f with 26a and 1e with 8c, and prepare (5-fluoro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 26) according to the method of Example 1-1.7. 1 H NMR (400MHz, Methanol-d4) δ8.17(dd,J=8.6,2.7Hz,1H),7.96–7.92(m,1H),7.81(dd,J=10.2,3.2Hz,1H),7.61(dd,J=3.2,1.3Hz,1H),6.84–6.3 7(m,1H),4.04(d,J=3.8Hz,3H),3.98–3.64(m,1H),3.62–3.33(m,3H),3.28–2.70(m,2H),2.41(dd,J=10.0,3.0Hz,3H).LCMS(ES,m / z):440[M+H] + .

[0321] Example 27: (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (27)

[0322] 27.1 Reaction raw materials 1f were replaced with 7a, 1e was replaced with 8c, and (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 27) was prepared according to the method of Example 1-1.7. 1 H NMR(400MHz,Chloroform-d)δ7.93–7.86(m,1H),7.79–7.69(m,2H),7.53–7.48(m,1H),7.43–7.38(m,2H),6.69–6.61(m,1 H),4.08(s,3H),3.95–3.82(m,1H),3.73–3.32(m,3H),3.21–2.52(m,4H),2.46(d,J=3.0Hz,3H).LCMS(ES,m / z):421[M+H] + .

[0323] Example 28: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone (28)

[0324] 28.1 Replace the reaction raw material 1,2,3-triazole with 4-methyl-1H-1,2,3-triazole and prepare 2-fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid (Compound 28a) according to the method of Example 1-1.6.

[0325] 28.2 Replace the reaction raw material 1f with 28a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 28) according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ7.81–7.71(m,1H),7.46–7.41(m,1H),7.33(s,1H),7.13–7.01(m,1H),6.89–6.82(m,1H),4.19–3.7 9(m,2H),3.75–3.30(m,3H),3.21–2.88(m,3H),2.76–2.58(m,1H),2.47–2.44(m,6H),2.40–2.14(m,2H).LCMS(ES,m / z):437[M+H] + .

[0326] Example 29: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(1H-pyrazol-3-yl)phenyl)methanone (29)

[0327] 29.1 At room temperature, tert-butyl 2-fluoro-6-iodobenzoate (950 mg, 2.949 mmol) and 2H-pyrazol-3-ylboronic acid (396.0 mg, 3.539 mmol) were added to a mixture of 1.4-dioxane (6 mL) and water (1 mL). K2CO3 (815.2 mg, 5.898 mmol) and Pd(dppf)Cl2 (215.8 mg, 0.295 mmol) were added portionwise. Under nitrogen protection, the temperature was raised to 50°C and the reaction was allowed to react for 4 hours. The product was concentrated under reduced pressure and purified by column chromatography using PE / EA (10:1) to give 210 mg of tert-butyl 2-fluoro-6-(2H-pyrazol-3-yl)benzoate (Compound 29a).

[0328] 29.2 29a (87 mg, 0.332 mmol) was added to a solution of HCl in 1,4-dioxane (5 mL), and the mixture was reacted at room temperature for 4 hours. The mixture was concentrated under reduced pressure and purified by column chromatography using PE / EA (3:1) as the eluent to obtain 62 mg of 2-fluoro-6-(1H-pyrazol-3-yl)benzoic acid (compound 29b).

[0329] 29.3 Replacing the reaction raw material 1f with 29b, prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(1H-pyrazol-3-yl)phenyl)methanone (Compound 29) according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ7.61(d,J=2.2Hz,1H),7.54–7.27(m,3H),7.17–6.98(m,1H),6.76–6.38(m, 2H),4.03–3.76(m,1H),3.67–2.96(m,5H),2.95–2.64(m,2H),2.63–2.37(m,6H).LCMS(ES,m / z):422[M+H] + .

[0330] Example 30: (4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (30)

[0331] 30.1 Replace the reaction raw material methylmagnesium chloride with methyl-d3-magnesium iodide and prepare 2-chloro-5-fluoro-4,6-bis(methyl-d3)pyrimidine (Compound 30a) according to the method of Example 1-1.3.

[0332] 30.2 Reaction material 1c was replaced with 30a, and tert-butyl 5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylate (Compound 30b) was prepared according to the method of Example 1-1.4.

[0333] 30.3 Replacing the starting material 1d with 30b, prepare 5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 30c) according to the method of Example 1-1.5.

[0334] 30.4 Replace the reaction raw material 1e with 30c and 1f with 2a, and prepare (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 30) according to the method of Example 1-1.7. 1H NMR (400MHz, DMSO-d6) δ8.15–7.92(m,2H),7.74–7.70(m,1H),7.55–7.44(m,1H),7.43–7.35(m,1H),6. 58(d,J=80.4Hz,1H),3.80–3.45(m,3H),3.26–2.90(m,3H),2.84–2.59(m,2H).LCMS(ES,m / z):429[M+H] + .

[0335] Example 31: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-(methoxy-d3)-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (31)

[0336] 31.1 Sodium (1.3 g, 56.52 mmol) was added to deuterated methanol-d4 (30 mL), stirred at room temperature for 10 minutes, and ethyl 3-bromo-6-chloropicolinate (1.5 g, 5.67 mmol) was added. The temperature was raised to 60°C and the reaction was carried out for 6 hours. After the reaction was completed, the mixture was concentrated under pressure and the pH was adjusted to 5-6 with citric acid solution. 100 mL of water was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 0.8 g of 3-bromo-6-(methoxy-d3)picolinic acid (Compound 31a).

[0337] 31.2 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 31a and prepare 6-(methoxy-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid (compound 31b) according to the method of Example 1-1.6.

[0338] 31.3 Replace the reaction raw material 1f with 31b and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-(methoxy-d3)-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (Compound 31) according to the method of Example 1-1.7. 1H NMR(400MHz,Chloroform-d)δ8.74(d,J=5.0Hz,1H),7.72(d,J=13.0Hz,2H),6.76–6.48(m,2H),3.87–3 .74(m,2H),3.64–3.22(m,3H),3.10–2.57(m,4H),2.46(dd,J=5.5,2.7Hz,6H).LCMS(ES,m / z):439[M+H] + .

[0339] Example 32: Preparation of (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (32)

[0340] 32.1 Reaction raw material 1f was replaced by 23a, 1e was replaced by 30c, and the method of Example 1-1.7 was used to prepare (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (Compound 31). 1 H NMR(400MHz,Chloroform-d)δ8.78(d,J=5.0Hz,1H),7.72(d,J=13.0Hz,2H),6.74–6.42(m,2H),4. 06–3.86(m,4H),3.83–3.78(m,1H),3.66–3.27(m,3H),3.10–2.57(m,4H).LCMS(ES,m / z):442[M+H] + .

[0341] Example 33: (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (33)

[0342] 33.1 Sodium (1.5 g, 65.21 mmol) was added to deuterated methanol-d4 (50 mL), stirred at room temperature for 10 minutes, and 2,4-dichloro-5-fluoro-6-methylpyrimidine (1 g, 5.56 mmol) was added thereto. The temperature was raised to 60°C and the reaction was carried out for 8 hours. After the reaction was completed, the mixture was concentrated under pressure and the pH was adjusted to 5-6 with citric acid solution. 100 mL of water was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 0.76 g of 2-chloro-5-fluoro-4-(methoxy-d3)-6-methylpyrimidine (compound 33a).

[0343] 33.2 Replace the reaction raw material 1c with 33a and prepare tert-butyl 5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylate (compound 33b) according to the method of Example 1-1.4.

[0344] 33.3 Replacing the reaction raw material 1d with 33b, prepare 5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 33c) according to the method of Example 1-1.5.

[0345] 33.4 Replace the reaction raw material 1e with 33c and 1f with 24a, and prepare (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 33) according to the method of Example 1-1.7. 1 H NMR(400MHz,Chloroform-d)δ8.74–8.51(m,1H),8.35–8.23(m,1H),7.90(dd,J=8.5,3.2Hz,1H),7.54–7.28(m,2H),6.62(d,J=9 1.9Hz,1H),3.94–3.41(m,4H),3.19–2.83(m,3H),2.58(d,J=16.7Hz,1H),2.41(dd,J=11.0,3.0Hz,3H).LCMS(ES,m / z):425[M+H] + .

[0346] Example 34: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl) (6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (34)

[0347] 34.1 Sodium (1.5 g, 65.21 mmol) was added to deuterated methanol-d4 (50 mL), and the mixture was stirred at room temperature for 10 minutes. 2,4-Dichloropyridine (1.0 g, 6.76 mmol), CuI (0.2 g, 1.05 mmol), and N,N,N',N'-tetramethylethylenediamine (0.7 g, 6.03 mmol) were added to the solution. The mixture was protected by nitrogen and heated to 60°C for overnight. After completion of the reaction, the mixture was concentrated under pressure, water was added, and the mixture was extracted with EtOAc (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was separated and purified by column chromatography using PE:EA = 20:1 as the eluent to obtain 0.6 g of 4-chloro-2-(methoxy-d3)pyridine (compound 34a).

[0348] 34.2 34a (0.6 g, 4.08 mmol) and NBS (0.75 g, 4.21 mmol) were added to DMF (10 mL), and the temperature was raised to 90°C for 8 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc (3 x 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.3 g of 5-bromo-4-chloro-2-(methoxy-d3)pyridine (compound 34b).

[0349] 34.3 Replacing the starting material 5-bromo-4-chloro-2-methoxypyridine with 34b, 4-chloro-6-(methoxy-d3)nicotinate methyl ester (compound 34c) was prepared according to the method of Example 22-22.1.

[0350] 34.4 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 34c and prepare 6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)nicotinic acid (compound 34d) according to the method of Example 1-1.6.

[0351] 34.5 The reaction raw material 1f was replaced with 34d, and the method of Example 1-1.7 was used to prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (Compound 34). 1H NMR(400MHz, Methanol-d4)δ8.21(d,J=7.4Hz,1H),7.86(s,2H),7.36(d,J=11.5Hz,1H),6.84–6.38(m,1H) ,3.93–3.77(m,2H),3.69–3.45(m,3H),3.20–2.82(m,3H),2.44(d,J=6.6Hz,6H).LCMS(ES,m / z):439[M+H] + .

[0352] Example 35: Preparation of (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (35)

[0353] 35.1 Reaction starting material 1f was replaced with 22b, and 1e was replaced with 30c. The reaction mixture was prepared according to the method of Example 1-1.7: (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (Compound 35). 1 H NMR(400MHz, Methanol-d4)δ8.21(d,J=7.4Hz,1H),7.83(s,2H),7.37(d,J=11.5Hz,1H),6.90–6.39(m,1H) ,4.05(d,J=6.8Hz,3H),3.98–3.76(m,2H),3.63–3.41(m,3H),3.16–2.81(m,3H).LCMS(ES,m / z):442[M+H] + .

[0354] Example 36: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (36)

[0355] 36.1 Replace the starting material of bromocyclopropane with deuterated iodomethane and prepare 2-bromo-4-(methoxy-d3)benzoic acid (Compound 36a) according to the method of Example 13-13.1.

[0356] 36.2 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 36a and prepare 4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 36b) according to the method of Example 1-1.6.

[0357] 26.2 Replace the reaction raw material 1f with 36b and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 36) according to the method of Example 1-1.7. 1 H NMR(400MHz, DMSO-d6)δ7.91(d,J=26.3Hz,2H),7.41–7.34(m,2H),7.09–7.02(m,1H),6.55(d,J=78.0H z,1H),3.72–3.38(m,3H),3.31–3.02(m,2H),2.97–2.52(m,3H),2.43(s,6H).LCMS(ES,m / z):438[M+H] + .

[0358] Example 37: Preparation of (5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (37)

[0359] 37.1 Under nitrogen protection, 2,4-dichloro-5-fluoro-6-methylpyrimidine (6.5 g, 35.9 mmol) was added to anhydrous DMF (15 mL). Tributyl-(1-ethoxyvinyl)-stannane (14.2 g, 39.3 mmol) and dichlorobis(triphenylphosphine)palladium(II) (500 mg, 0.71 mmol) were then added. The mixture was reacted at 100°C for 10 hours, cooled to room temperature, and a saturated solution of potassium fluoride was added. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was filtered through celite and extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE:EA = 10:1) afforded 2-chloro-4-(1-ethoxyvinyl)-5-fluoro-6-methylpyrimidine (6.8 g) (Compound 37a).

[0360] 37.2 37a (6.0 g, 27.8 mmol) was dissolved in THF (10 mL), and 3N HCl solution (15 mL) was added. The reaction was allowed to react at room temperature for 1 hour. The pH was adjusted to 7-8 with saturated NaHCO3, and the mixture was extracted with ethyl acetate (3 x 50 mL). The organic phase was washed with water and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)ethan-1-one (5.1 g) (compound 37b). The crude product was directly used in the next step without purification.

[0361] 37.3: Substitute 37b for the starting material 2-chloro-6-methylpyrimidine-4-carboxylic acid methyl ester and prepare 2-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)propan-2-ol (Compound 37c) according to the method of Example 30-30.1.

[0362] 37.4 Reaction raw material 1c was replaced with 37c, and 5-[5-fluoro-4-(2-hydroxypropyl)-6-methylpyrimidin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 37d) was prepared according to the method of Example 1-1.4.

[0363] 37.5 The reaction raw material 1d was replaced with 37d, and 5-[5-fluoro-4-(2-hydroxypropyl)-6-methylpyrimidin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 37e) was prepared according to the method of Example 1-1.5.

[0364] 37.6 Reaction raw material 1e was replaced with 37e, and (5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 37) was prepared according to the method of Example 1-1.7. 1 H NMR(400MHz,Chloroform-d)δ7.89–7.71(m,2H),7.63–7.48(m,2H),7.35–7.18(m,1H),6.69–6.42(m,1H),3.99–3.74(m,2 H),3.66–3.61(m,2H),3.49–3.02(m,3H),3.00–2.82(m,1H),2.38(d,J=2.9Hz,3H),1.53(s,6H).LCMS(ES,m / z):467[M+H] + .

[0365] Example 38: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (38)

[0366] 38.1 Reaction material 1c was replaced with 2-chloro-4,6-dimethylpyrimidine-5-carboxylic acid ethyl ester, and 5-(5-(ethoxycarbonyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylic acid tert-butyl ester (Compound 38a) was prepared according to the method of Example 1-1.4.

[0367] 38.2 38a (0.5 g, 1.29 mmol) was added to 5 mL of methanol solution, and LiBH4 (0.56 g, 2.57 mmol) was added. The reaction was allowed to react at room temperature for 6 h. After completion of the reaction, water was added to quench the reaction, and the product was extracted with ethyl acetate (3 x 50 mL). The product was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA=5:1) to obtain 0.21 g of tert-butyl 5-(5-(hydroxymethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylate (compound 38b).

[0368] 38.3 38b (0.21 g, 0.61 mmol) was added to dichloromethane (5 mL), and DAST (0.2 g, 1.24 mmol) was added at room temperature. The reaction was allowed to react at room temperature for 3 h. The reaction was quenched by water and extracted with dichloromethane (3 x 50 mL). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under pressure and purified by column chromatography (PE:EA=10:1) to give 0.12 g of tert-butyl 5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylate (compound 38c).

[0369] 38.4 Reaction starting material 1d was replaced with 38c, and 5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 38d) was prepared according to the method of Example 1-1.5.

[0370] 38.5 The reaction raw material 1e was replaced with 38d, and the method of Example 1-1.7 was used to prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 38). 1 H NMR(400MHz, Methanol-d4)δ7.96–7.82(m,2H),7.72–7.56(m,2H),7.33–7.23(m,1H),6.88–6.63(m,1H ),5.65–5.50(m,2H),3.99–3.39(m,5H),3.25–2.88(m,3H),2.73–2.57(m,6H).LCMS(ES,m / z):437[M+H] + .

[0371] Example 39: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (39)

[0372] 39.1 A solution of cis-5-oxo-hexahydrocyclopenta [c] pyrrole-2-carboxylic acid tert-butyl ester (5 g, 22.19 mmol) in THF (20 mL) was treated with LiHMDS (5.2 g, 110.95 mmol) at -78 ° C for 2 hours, followed by the addition of N-phenylbis(trifluoromethanesulfonyl)imide (9.51 g, 26.63 mmol) at -78 ° C. The resulting mixture was stirred overnight under a nitrogen atmosphere at room temperature. The reaction was quenched by adding water / ice (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography using PE / EA (1:1) as eluent to give tert-butyl 5-[[(trifluoromethyl)sulfonyl]oxy]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 39a) (4.8 g).

[0373] 39.2 A solution of 39a (4.5 g, 12.59 mmol), pinacol diboronate (4.8 g, 18.90 mmol), KOAc (3.5 g, 25.36 mmol), and Pd(dppf)Cl2 (0.9 g, 1.24 mmol) was added to dioxane (20 mL), heated to 80°C, and stirred overnight under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford 3.6 g of crude tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H,3H,3aH,6H,6aH-cyclopenta[c]pyrrole-2-carboxylate (Compound 39b). The crude product was used directly in the next step without further purification.

[0374] 39.3 A solution of 3,5-dibromopyrazin-2-amine (4 g, 15.82 mmol), isoamyl nitrite (5.56 g, 47.45 mmol), and HCl (1.16 mL, 31.79 mmol) in MeOH (80 mL) was stirred at 60°C under nitrogen for 4 hours. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Extraction was performed with EtOAc (3 x 50 mL). The combined organic layers were washed with saturated brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Purification by column chromatography (PE / EA = 7:1) afforded 3.1 g of 3,5-dibromo-2-methoxypyrazine (Compound 39c).

[0375] 39.4 A solution of 39c (2 g, 7.47 mmol), 39b (2.7 g, 8.21 mmol), K2CO3 (5.58 g, 39.72 mmol, 3 equivalents) and Pd(dppf)Cl2 (546.2 mg, 0.75 mmol) in 1,4-dioxane (40 mL) and H2O (6 mL) was stirred at 95°C for 4 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 15 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1) to give 1.8 g of tert-butyl 5-(6-bromo-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 39d).

[0376] 39.5 39d (1.8 g, 4.54 mmol), trimethylboroxine (684.2 mg, 5.45 mmol), K2CO3 (1.88 g, 13.63 mmol), and Pd(dppf)Cl2 (332.4 mg, 0.45 mmol) were added to 1,4-dioxane (40 mL) and H2O (6 mL) under a nitrogen atmosphere. The temperature was raised to 90°C for 1 hour. After completion of the reaction, the mixture was cooled to room temperature and extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with saturated brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was separated and purified by column chromatography using PE / EA (6:1) as the eluent to obtain 720 mg of tert-butyl 5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 39e).

[0377] 39.6 39e (720 mg, 2.17 mmol) was added to a solution of DCM (4 mL) and TFA (16 mL) under nitrogen protection and stirred at room temperature for 3 hours. After the reaction was completed, the mixture was concentrated under pressure. The resulting mixture was extracted with EtOAc (3 x 15 mL). The combined organic layers were washed with saturated brine (2 x 9 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Column chromatography was performed and purified using PE / EA (1:2) to obtain 460 mg of 5-(3-methoxy-6-methylpyrazin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 39f).

[0378] 39.7 2-Fluoro-6-iodobenzoic acid (10.0 g, 37.59 mmol), 1,2,3-triazole (5.2 g, 75.29 mmol), cuprous iodide (0.35 g, 1.2 mmol), cesium carbonate (24.5 g, 75.15 mmol), (1R,2R)-N,N-dimethyl-1,2-diaminocyclohexane (1.1 g, 7.73 mmol) and 1,4-dioxane (100 mL) were placed in a 250 mL round-bottom flask and stirred at 85 °C overnight under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, 50 mL of tert-butyl methyl ether and 50 mL of water were added, and stirring was continued for half an hour before separation. The organic phase was discarded and the pH of the aqueous phase was adjusted to acidic with 2N hydrochloric acid. Then, the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether / ethyl acetate = 1:1) to obtain 4.6 g of 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 39g).

[0379] 39.8 Compound 39g (100 mg, 0.48 mmol) and compound 39f (126.1 mg, 0.545 mmol) were added to DMF (2 mL). Triethylamine (137.9 mg, 1.36 mmol) and HATU (259.0 mg, 0.68 mmol) were added portionwise with stirring at room temperature. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3:1). 28.1 mg of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 39) was obtained. 1 H NMR(400MHz,Chloroform-d)δ7.88–7.74(m,3H),7.64–7.41(m,2H),7.22–7.03(m,1H),6.89–6.11(m,1H),4.11–3 .93(m,4H),3.92–3.81(m,1H),3.78–3.28(m,3H),3.22–2.65(m,3H),2.51–2.38(m,3H).LCMS(ES,m / z):421[M+H] + .

[0380] Example 40: Preparation of (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (40)

[0381] 40.1 Replacing the starting material 4-fluoro-6-iodobenzoic acid with 2-iodo-5-methoxybenzoic acid, 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 40a) was prepared according to the method of Example 39-39.7.

[0382] 40.2 Replace the reaction raw material 39g with 40a and prepare (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 40) according to the method of Example 39-39.8. 1H NMR(400MHz,Chloroform-d)δ7.95–7.77(m,2H),7.73–7.46(m,2H),7.10–6. 96(m,1H),6.96–6.85(m,1H),6.82–6.10(m,1H),4.07–3.96(m,3H),3.95–3.7 5(m,5H),3.69–3.52(m,1H),3.52–3.38(m,1H),3.37–3.14(m,1H),3.13–2.8 0(m,2H),2.70(t,J=18.5Hz,1H),2.53–2.36(m,3H).LCMS(ES,m / z):433[M+H] + .

[0383] Example 41: Preparation of (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (41)

[0384] 41.1 Replacing the starting material 4-fluoro-6-iodobenzoic acid with 2-iodo-4-methoxybenzoic acid, prepare 4-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 41a) according to the method of Example 39-39.7.

[0385] 41.2 Reaction material 39g was replaced with 41a, and the method of Example 39-39.8 was used to prepare (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 41). 1 H NMR (400MHz, DMSO-d6) δ7.94–7.89(m,3H),7.39–7.33(m,2H),7.07(t,J=10.7Hz,1H),6.66(d,J=84.6Hz,1H),3.97(d,J=23.2Hz,3H ),3.86(d,J=7.6Hz,3H),3.79–3.42(m,3H),3.32–3.02(m,2H),3.01–2.55(m,3H),2.39(d,J=18.5Hz,3H).LCMS(ES,m / z):433[M+H] + .

[0386] Example 42: Preparation of (2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (42)

[0387] 42.1 Replacing the starting material 4-fluoro-6-iodobenzoic acid with 5-bromo-2-methoxyisonicotinic acid, 2-methoxy-5-(2H-1,2,3-triazol-2-yl)isonicotinic acid (Compound 42a) was prepared according to the method of Example 39-39.7.

[0388] 42.2 Replace the reaction raw material 39g with 42a and prepare (2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 42) according to the method of Example 39-39.8. 1 H NMR(400MHz,Chloroform-d)δ8.75(d,J=11.5Hz,1H),7.79(d,J=5.0Hz,1H),7.66(d,J=17.0Hz,2H),6.77–6.47(m,2H),4.06–3.97( m,6H),3.95–3.75(m,2H),3.60(d,J=53.8Hz,1H),3.50–3.24(m,2H),3.14–2.89(m,3H),2.51–2.39(m,3H).LCMS(ES,m / z):434[M+H] + .

[0389] Example 43: Preparation of (2-fluoro-6-(pyrimidin-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (43)

[0390] 43.1 tert-Butyl 2-fluoro-6-iodobenzoate (200 mg, 0.62 mmol), cuprous iodide (11.82 mg, 0.06 mmol), and cesium fluoride (18.86 mg, 0.12 mmol) were added to tetrahydrofuran under nitrogen and stirred at room temperature for 1 minute. Pd(PPh3)4 (43.05 mg, 0.04 mmol) was then added at room temperature, followed by 2-(tributyltin)pyrimidine (278.78 mg, 0.75 mmol). The temperature was raised to 100°C and the reaction was allowed to react overnight. LCMS confirmed the reaction was complete, and the product was purified by column chromatography (PE / EA = 2:1) to obtain 160 mg of tert-butyl 2-fluoro-6-(pyrimidin-2-yl)benzoate (Compound 43a).

[0391] 43.2 43a (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. The mixture was stirred at room temperature for 0.5 h. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain 110 mg of 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (compound 43b).

[0392] 43.3 Reaction material 39g was replaced with 43b, and (2-fluoro-6-(pyrimidin-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (Compound 43) was prepared according to the method of Example 39-39.8. 1 H NMR(400MHz,Chloroform-d)δ8.77–8.54(m,2H),7.83 7.78(m,1H),7.61–7.38(m,2H),7.25–7.06(m,2H),6.72–6.24(m,1H),4.16–3.87(m,4H),3.82– 3.74(m,1H),3.69–3.17(m,3H),3.11–2.61(m,3H),2.48–2.32(m,3H).LCMS(ES,m / z):432[M+H] + .

[0393] Example 44: Preparation of [4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (44)

[0394] 44.1 Replacing the starting material 4-fluoro-6-iodobenzoic acid with 4-fluoro-2-iodobenzoic acid, prepare 4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 44a) according to the method of Example 39-39.7.

[0395] 44.2 Replace the reaction raw material 39g with 44a and prepare [4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (Compound 44) ​​according to the method of Example 39-39.8. 1 H NMR (400MHz, DMSO-d6) δ8.35-7.80(m,3H),7.79-7.67(m,1H),7.49(s,1H),7.42-7.32(m,1H),6.80-6.49(m,1H),4.05-3.88(m,3H),3.64(br s,2H),3.55-3.34(m,1H),3.12(br s,1H),3.06-2.65(m,3H),2.63-2.51(m,1H),2.43-2.32(m,3H).LCMS(ES,m / z):421[M+H] + .

[0396] Example 45: Preparation of [4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (45)

[0397] Compound 41a (300 mg, 1.37 mmol) was dissolved in 30 mL of dichloromethane, cooled in an ice-water bath, and nitrogen was applied. Boron tribromide in dichloromethane (1.0 M, 3 mL) was added dropwise to the reaction mixture. After completion of the addition, the mixture was allowed to react at room temperature for 3 hours. The mixture was then cooled in an ice-water bath and quenched with water. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to yield 230 mg of 4-hydroxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 45a). The crude product was directly carried on to the next step without purification.

[0398] 45.2 Compound 45a (230 mg, 1.12 mmol), iodoethane (262 mg, 1.68 mmol) and potassium carbonate (464 mg, 3.36 mmol) were added to 30 mL of acetonitrile and the temperature was raised to 60°C for 4 hours. After the reaction was completed, the temperature was lowered to room temperature and a 1 M hydrochloric acid solution was added to adjust the pH to 4-5. The solvent was evaporated under pressure and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give compound 4-ethoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 45b). The crude product was directly subjected to the next step without purification.

[0399] 45.3 Replacing the reaction raw material 39g with 45b, and preparing [4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (Compound 45) according to the method of Example 39-39.8. 1 H NMR(400MHz,DMSO-d6)δ8.07-7.80(m,3H),7.39-7.29(m,2H),7.05(br t,J=9.9Hz,1H),6.79-6.53(m,1H),4.13(s,2H),4.01-3.89(m,3H),3.77-3.57(m,2H),3.46(br d,J=5.6Hz,1H),3.29-3.04(m,2H),2.95-2.80(m,2H),2.67(br s,1H),2.39(br d,J=18.1Hz,3H),1.40-1.34(m,3H).LCMS(ES,m / z):447[M+H] + .

[0400] Example 46: Preparation of [5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (46)

[0401] 46.1 Replace the reaction raw material methanol with ethanol and prepare 3,5-dibromo-2-ethoxypyrazine (Compound 46a) according to the method of Example 39-39.3.

[0402] 46.2 Replacing the reaction raw material 39c with 46a, the method of Example 39-39.4 was used to prepare tert-butyl 5-(6-bromo-3-ethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 46b).

[0403] 46.3 Replacing the starting material 39d with 46b, the reaction mixture was prepared according to the method of Example 39-39.5, tert-butyl 5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 46c).

[0404] 46.4 Replacing the starting material 39e with 46c, the method of Example 39-39.6 was followed to prepare 5-(3-ethoxy-6-methylpyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 46d).

[0405] 46.5 Reaction raw material 39f was replaced by 46d, 39g was replaced by 41a, and the method of Example 39-39.8 was used to prepare [5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 46). 1 H NMR (400MHz, DMSO-d6) δ8.08–7.79(m,3H),7.48–7.22(m,2H),7.07(td,J=8.3,4.1Hz,1H),6.69(d,J=76.7Hz,1H),4.48–4.34(m,2 H),3.86(d,J=6.5,3H),3.79–3.43(m,3H),3.29–2.56(m,5H),2.38(d,J=18.0Hz,3H),1.48–1.29(m,3H).LCMS(ES,m / z):447[M+H] + .

[0406] Example 47: Preparation of [5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (47)

[0407] 47.1 Replace the starting material trimethylboroxine with ethylboronic acid and prepare tert-butyl 5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 47a) according to the method of Example 39-39.5.

[0408] 47.2 Replacing the starting material 39e with 47a, the method of Example 39-39.6 was followed to prepare 5-(6-ethyl-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 47b).

[0409] 47.3 Reaction raw material 39f was replaced by 47b, 1g was replaced by 3a, and the method of Example 39-39.8 was used to prepare [5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 47). 1 H NMR (400MHz, DMSO) δ7.91(d,J=30.0Hz,3H),7.37(d,J=15.1Hz,2H),7.18–6.95(m,1H),6.66(d,J=83.7 Hz,1H),3.97(d,J=22.9Hz,3H),3.86(d,J=8.1Hz,3H),3.79–3.67(m,1H),3.62(s,1H),3.47(s,1H),3.3 1–3.14(m,1H),3.10(d,J=9.9Hz,1H),2.99(dd,J=16.6,6.9Hz,1H),2.88(dd,J=23.9,11.7Hz,2H),2.73 (d,J=7.4Hz,1H),2.62(dd,J=22.3,11.3Hz,1H),1.21(dt,J=19.6,7.4Hz,3H).LCMS(ES,m / z):447[M+H] + .

[0410] Example 48: Preparation of [4-methoxy-2-(pyrimidin-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (48)

[0411] 48.1 Replacing the starting material 2-fluoro-6-iodobenzoic acid tert-butyl ester with 2-iodo-4-methoxybenzoic acid tert-butyl ester was followed by the method of Example 43-43.1 to prepare tert-butyl 4-methoxy-2-(pyrimidin-2-yl)benzoate (Compound 48a).

[0412] 48.2 Reaction material 43a was replaced with 48a, and 4-methoxy-2-(pyrimidin-2-yl)benzoic acid (Compound 48b) was prepared according to the method of Example 43-43.2.

[0413] 48.3 Replacing the reaction raw material 39g with 48b, prepare [4-methoxy-2-(pyrimidin-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (Compound 48) according to the method of Example 39-39.8. 1 H NMR (400MHz, DMSO) δ8.81–8.60(m,2H),7.94(d,J=9.9Hz,1H),7.65(d,J=14.7Hz,1H),7.27(dd,J=19.5, 12.2Hz,2H),7.10(t,J=9.4Hz,1H),6.68(d,J=97.0Hz,1H),3.97(d,J=36.2Hz,3H),3.85(d,J=7.9Hz,3H ),3.75(dd,J=23.7,13.0Hz,1H),3.68–3.59(m,1H),3.48(s,1H),3.21(d,J=10.6Hz,1H),3.08–2.92(m, 1H),2.90–2.70(m,2H),2.63(dd,J=46.2,11.3Hz,1H),2.39(d,J=27.3Hz,3H).LCMS(ES,m / z):444[M+H] + .

[0414] Example 49: Preparation of [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (49)

[0415] 49.1 Replacing the starting material 2-fluoro-6-iodobenzoic acid with 2-iodo-5-methylbenzoic acid, 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 49a) was prepared according to the method of Example 43-43.1.

[0416] 49.2 Replacing the reaction raw material 39g with 49a, and preparing [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 49) according to the method of Example 39-39.8. 1H NMR (400MHz, DMSO-d6) δ7.93 (br d, J=4.6Hz, 3H), 7.74 (br dd, J=8.3, 14.7Hz, 1H), 7.40 (br t,J=8.4Hz,1H),7.26-7.17(m,1H),6.87-6.47(m,1H),4.02-3.92(m,3H),3.62(br s,2H),3.56-3.33(m,1H),3.23-3.08(m,1H),3.07-2.70(m,3H),2.59(br d,J=15.7Hz,1H),2.41-2.33(m,6H).LCMS(ES,m / z):417[M+H] + .

[0417] Example 50: Preparation of [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (50)

[0418] 50.1 Compound 39d (300 mg, 0.76 mmol) and sodium methoxide (123 mg, 2.28 mmol) were added to 30 mL of methanol solution, and the temperature was raised to 60°C for 6 hours. After completion of the reaction, the solvent was evaporated under reduced pressure and purified by column chromatography (PE:EA=5:1) to obtain 136 mg of tert-butyl 5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 50a).

[0419] 50.2 Replacing the starting material 39e with 50a, the reaction mixture was prepared according to the method of Example 39-39.6, using 5-(3,6-dimethoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 50b).

[0420] 50.3 Reaction raw material 39f was replaced by 50b, and 39g was replaced by 44a. The method of Example 39-39.8 was used to prepare [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 50). 1H NMR (400MHz, DMSO) δ8.29–7.82(m,3H),7.76(d,J=4.8Hz,1H),7.48(dd,J=17.4,8.7Hz,1H),7.39(d,J=8.1Hz,1H),6.69(d,J=71.9Hz, 1H),3.96(d,J=21.2Hz,3H),3.85(d,J=26.1Hz,3H),3.79–3.60(m,2H),3.52(s,1H),3.21( dd,J=11.8,5.9Hz,1H),3.10–2.82(m,3H),2.67(t,J=17.2Hz,1H).LCMS(ES,m / z):437[M+H] + .

[0421] Example 51: Preparation of [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]methanone (51)

[0422] 51.1 Replacing the starting material 39c with 3-bromo-2,5-dimethylpyrazine, prepare tert-butyl 5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 51a) according to the method of Example 39-39.4.

[0423] 51.2 Replacing the starting material 39e with 51a, prepare 5-(3,6-dimethylpyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 51b) according to the method of Example 39-39.6.

[0424] 51.3 Replacing the reaction raw material 39f with 51b, and preparing [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 51) according to the method of Example 39-39.8. 1H NMR (400MHz, DMSO-d6) δ8.32-8.22(m,1H),8.15(s,1H),7.89(d,J=6.1Hz,1H),7.84-7.75(m,1H),7.72-7.58(m,1H),7.50-7.33(m,1H),6 .30-6.05(m,1H),3.80-3.45(m,3H),3.26-2.96(m,2H),2.92-2.72(m,1H),2.71-2.56(m,5H),2.48-2.37(m,3H).LCMS(ES,m / z):405[M+H] + .

[0425] Example 52: Preparation of [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (52)

[0426] 52.1 Reaction raw material 39f was replaced by 51b, and 39g was replaced by 41a. The method of Example 39-39.8 was used to prepare [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 52). 1 H NMR (400MHz, DMSO) δ8.26(d,J=5.0Hz,1H),7.98(d,J=7.7Hz,2H),7.38(d,J=7.6Hz,2H),7.09(t,J=7.8Hz,1H) ,6.12(d,J=76.3Hz,1H),3.87(d,J=4.6Hz,3H),3.81–3.58(m,2H),3.49(s,1H),3.28(dd,J=11.8,5.9Hz,1H), 3.17–3.01(m,1H),2.92(ddd,J=32.2,15.1,7.3Hz,2H),2.80–2.65(m,1H),2.56(d,J=18.5Hz,3H),2.43(d,J=15.4Hz,3H).LCMS(ES,m / z):417[M+H] + .

[0427] Example 53: Preparation of [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (53)

[0428] 53.1 Reaction raw material 39f was replaced by 50b, and 39g was replaced by 41a. The method of Example 39-39.8 was used to prepare [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 53). 1 H NMR (400MHz, DMSO-d6) δ8.18-7.82(m,2H),7.75(br d,J=3.9Hz,1H),7.41-7.30(m,2H),7.07(br t,J=9.5Hz,1H),6.81-6.50(m,1H),4.04-3.90(m,3H),3.90-3.77(m,6H),3.76-3.57(m,2H),3.47(br s,1H),3.29-3.02(m,2H),2.85(br d,J=15.7Hz,2H),2.59(br d,J=14.7Hz,1H).LCMS(ES,m / z):449[M+H] + .

[0429] Example 54: Preparation of [5-(6-chloro-3-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (54)

[0430] 54.1 2-Amino-3-bromo-5-chloropyrazine (3 g, 14.4 mmol) was dissolved in 30 mL of methanol solution, tert-butyl nitrite (5.1 g, 43.2 mmol) was added, and then HCl methanol solution was added. The temperature was raised to 60°C for 6 hours. After the reaction was completed, water was added to quench the reaction, and the liquid was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA=10:1) to obtain 2 g of 3-bromo-5-chloro-2-methoxypyrazine (compound 54a).

[0431] 54.2 Replacing the reaction raw material 39c with 54a, the method of Example 39-39.4 was used to prepare tert-butyl 5-(6-chloro-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 54b).

[0432] 54.2 Replacing the starting material 39e with 54b, the reaction mixture was prepared according to the method of Example 39-39.6, using 5-(6-chloro-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 54c).

[0433] 54.3 Reaction starting material 39f was replaced by 54c, and 39g was replaced by 41a. The method of Example 39-39.8 was followed to prepare [5-(6-chloro-3-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 54). 1 H NMR (400MHz, DMSO-d6) δ8.19(d,J=2.0Hz,1H),8.09-7.76(m,2H),7.40-7.29(m,2H),7.06(t,J=9.4Hz,1H),6.90-6.61(m,1H),4.10-3.94( m,3H),3.86(d,J=7.1Hz,3H),3.62(s,2H),3.58-3.37(m,1H),3.33-3.03(m,2H),2.93(s,1H),2.86-2.66(m,2H).LCMS(ES,m / z):453[M+H] + .

[0434] Example 55: Preparation of [5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (55)

[0435] 55.1 The reaction starting material trimethylboroxine was replaced with cyclopropylboronic acid, and tert-butyl 5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 55a) was prepared according to the method of Example 39-39.5.

[0436] 55.2 Replacing the starting material 39e with 55a, the reaction mixture was prepared according to the method of Example 39-39.7, using 5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 55b).

[0437] 55.3 Reaction raw material 39f was replaced by 55b, and 39g was replaced by 44a. The method of Example 39-39.8 was used to prepare [5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 55). 1 H NMR (400MHz, DMSO) δ8.00 (d, J=6.2Hz, 3H), 7.74 (dd, J=12.8, 11.1Hz, 1H), 7.50 (t, J=6.6Hz ,1H),7.38(dd,J=20.5,9.0Hz,1H),6.65(d,J=84.9Hz,1H),3.96(d,J=24.1Hz,3H),3.87–3 .71(m,1H),3.64(s,1H),3.48(s,1H),3.31–3.05(m,2H),3.05–2.89(m,1H),2.80(d,J=13. 9Hz,1H),2.75–2.54(m,1H),2.22–1.97(m,1H),1.07–0.65(m,4H).LCMS(ES,m / z):447[M+H] + .

[0438] Example 56: Preparation of [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-methoxy-6-(methyl-d3)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (56)

[0439] 56.1 Compound 39d (300 mg, 0.755 mmol) and ferric triacetylacetonate (50 mg, 0.14 mmol) were dissolved in 20 mL of tetrahydrofuran solution and cooled in an ice bath. Methyl-d3-magnesium iodide tetrahydrofuran solution (1 M, 2 mL) was added dropwise. After the addition was complete, the temperature was raised to room temperature and the reaction was allowed to proceed for 6 hours. After completion of the reaction, the reaction was quenched by adding water, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the product was separated and purified by column chromatography (PE:EA=5:1) to obtain 120 mg of tert-butyl 5-(3-methoxy-6-(methyl-d3)pyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 56a).

[0440] 56.2 Replace the reaction raw material 39e with 56a and prepare 5-(3-methoxy-6-(methyl-d3)pyrazin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 56b) according to the method of Example 39-39.6.

[0441] 56.3 Replace the reaction raw material 39f with 56b, and 39g with 41a, and prepare [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-methoxy-6-(methyl-d3)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (Compound 56) according to the method of Example 39-39.8. 1 H NMR (400MHz, DMSO-d6) δ8.27-7.65(m,3H),7.42-7.26(m,2H),7.06(br t,J=9.9Hz,1H),6.79-6.50(m,1H),4.01-3.90(m,3H),3.86(br d,J=7.1Hz,3H),3.61(br s,2H),3.52-3.35(m,1H),3.30-3.04(m,2H),2.98-2.81(m,2H),2.65-2.53(m,1H).LCMS(ES,m / z):436[M+H] + .

[0442] Example 57: Preparation of [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (57)

[0443] 57.1 Replace the starting material iodoethane with deuterated iodomethane and prepare 4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)benzoic acid (Compound 57a) according to the method of Example 45-45.2.

[0444] 57.2 Replace the reaction raw material 39g with 57a and prepare [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 57) according to the method of Example 39-39.8. 1H NMR (400MHz, DMSO) δ8.04–7.77(m,3H),7.36(d,J=14.3Hz,2H),7.06(t,J=9.8Hz ,1H),6.65(d,J=84.1Hz,1H),3.96(d,J=23.1Hz,3H),3.77–3.54(m,2H),3.52–3 .41(m,1H),3.30–3.15(m,1H),3.09(d,J=9.9Hz,1H),2.92(ddd,J=39.8,24.4,1 1.2Hz,2H),2.70–2.54(m,1H),2.38(d,J=18.4Hz,3H).LCMS(ES,m / z):436[M+H] + .

[0445] Example 58: Preparation of [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (58)

[0446] 58.1 Replace the reaction raw material methanol with deuterated methanol and prepare 3,5-dibromo-2-(methoxy-d3)pyrazine (Compound 58a) according to the method of Example 39-39.3.

[0447] 58.2 Replace the reaction raw material 39c with 58a and prepare 5-[6-bromo-3-(methoxy-d3)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 58b) according to the method of Example 39-39.4.

[0448] 58.3 Replacing the reaction raw material 39d with 58b, the method of Example 39-39.5 was used to prepare tert-butyl 5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 58c).

[0449] 58.4 Replacing the starting material 39e with 58c, the reaction mixture was prepared according to the method of Example 39-39.6, using 5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 58d).

[0450] 58.5 Replace the reaction raw material 39g with 41a, and 39f with 58d, and prepare [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (Compound 58) according to the method of Example 39-39.8. 1 H NMR(400MHz,DMSO-d6)δ8.12-7.67(m,3H),7.43-7.25(m,2H),7.13-6.99(m,1H),6.80-6.51(m,1H),4.07-3.89(m,3H),3.61(s,2H) ,3.52-3.35(m,1H),3.28-2.98(m,2H),2.83(d,J=15.2Hz,2H),2.67-2.53(m,1H),2.38(d,J=18.3Hz,3H).LCMS(ES,m / z):436[M+H] + .

[0451] Example 59: Preparation of [5-[6-(Fluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (59)

[0452] 59.1 Methyl 6-bromo-5-methoxypicolinate (1.0 g, 4.06 mmol) was dissolved in 50 mL of tetrahydrofuran, and sodium borohydride (0.9 g, 23.79 mmol) was added. After the addition was complete, the temperature was raised to reflux, and 8 mL of methanol was added. The reaction was continued for 2 hours. After completion, saturated ammonium chloride solution was added to quench the reaction. Extraction was performed with ethyl acetate, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 800 mg of (6-bromo-5-methoxypyrazin-2-yl)methanol (Compound 59a). The crude product was directly used in the next step without purification.

[0453] 59.2 Compound 59a (800 mg, 3.67 mmol) was dissolved in 10 mL of dichloromethane solution, cooled in an ice bath, and protected by nitrogen. Diethylaminosulfur trifluoride (0.78 g, 7.34 mmol) dissolved in 5 mL of dichloromethane was slowly added dropwise. After the addition was complete, the reaction was continued in an ice bath for 30 minutes. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was separated and purified by column chromatography (PE:EA=10:1) to obtain 330 mg of 3-bromo-5-(fluoromethyl)-2-methoxypyrazine (compound 59b).

[0454] 59.3 Replacing the starting material 39c with 59b, the reaction mixture was prepared according to the method of Example 39-39.4, tert-butyl 5-(6-(fluoromethyl)-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 59c).

[0455] 59.4 Replacing the starting material 39e with 59c, the reaction mixture was prepared according to the method of Example 39-39.6, using 5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 59d).

[0456] 59.5 Reaction raw material 39g was replaced by 41a, 39f was replaced by 59d, and the method of Example 39-39.8 was used to prepare [5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 59). 1 H NMR(400MHz,DMSO-d6)δ8.26-8.21(m,1H),8.02-7.76(m,2H),7.40-7.31(m,2H),7.11-7.02(m,1H),6.8 8-6.61(m,1H),5.56-5.32(m,2H),4.09-3.99(m,3H),3.86(d,J=8.1Hz,3H),3.75-3.61(m,2H),3.49(br d,J=1.0Hz,1H),3.29-3.17(m,1H),3.13-2.95(m,1H),2.94-2.80(m,2H),2.68-2.53(m,1H).LCMS(ES,m / z):451[M+H] + .

[0457] Example 60: Preparation of [5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (60)

[0458] Compound 59a (0.6 g, 2.73 mmol) was dissolved in 20 mL of dichloromethane, and Dess-Martin periodinane (1.74 g, 4.11 mmol) was added. The mixture was allowed to react at room temperature for 2 hours. Upon completion, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 30:1) to afford 285 mg of 6-bromo-5-methoxypyrazine-2-carbaldehyde (Compound 60a).

[0459] Compound 60a (285 mg, 1.31 mmol) was dissolved in 10 mL of dichloromethane, cooled in an ice bath, and nitrogen was applied. Diethylaminosulfur trifluoride (635 mg, 3.34 mmol) dissolved in 5 mL of dichloromethane was slowly added dropwise. The mixture was allowed to react at room temperature for 2 hours, then the temperature was raised to reflux and allowed to react overnight. After completion, saturated sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The mixture was then purified by column chromatography (PE:EA = 10:1) to afford 340 mg of 3-bromo-5-(difluoromethyl)-2-methoxypyrazine (compound 60b).

[0460] 60.3 Replacing the starting material 39c with 60b, the reaction mixture was prepared according to the method of Example 39-39.4, tert-butyl 5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 60c).

[0461] 60.4 Replacing the starting material 39e with 60c, the reaction mixture was prepared according to the method of Example 39-39.6, using 5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 60d).

[0462] 60.5 Reaction raw material 39g was replaced by 44a, 39f was replaced by 60d, and the method of Example 39-39.8 was used to prepare [5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 60). 1H NMR (400MHz, DMSO) δ8.40(s,1H),8.22–7.84(m,2H),7.74(dd,J=15.1,9.8Hz,1H),7.51(dd,J=12.8,6 .2Hz,1H),7.39(dd,J=19.8,8.8Hz,1H),7.10(dd,J=54.5,21.9Hz,1H),6.95–6.58(m,1H),4.07(d,J= 26.8Hz,3H),3.90–3.70(m,1H),3.67(s,1H),3.53(d,J=1.5Hz,1H),3.25(dd,J=12.2,5.2Hz,1H),3.1 5(t,J=10.6Hz,1H),3.09–2.93(m,1H),2.94–2.79(m,1H),2.79–2.54(m,1H).LCMS(ES,m / z):457[M+H] + .

[0463] Example 61: Preparation of [4-fluoro-2-(1H-pyrazol-1-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (61)

[0464] 61.1 Replacing the starting material 4-fluoro-6-iodobenzoic acid with 4-fluoro-2-iodobenzoic acid and 1,2,3-triazole with 1H-pyrazole, prepare 4-fluoro-2-(1H-pyrazol-1-yl)benzoic acid (Compound 61a) according to the method of Example 39-39.7.

[0465] 61.2 Replace the reaction raw material 39g with 61a and prepare [4-fluoro-2-(1H-pyrazol-1-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (Compound 61) according to the method of Example 39-39.8. 1H NMR (400MHz, DMSO) δ7.94(d,J=8.2Hz,1H),7.84(d,J=4.9Hz,1H),7.53(t,J=10.6Hz,2H) ,7.45–7.33(m,1H),7.28(s,1H),6.86(d,J=28.0Hz,1H),6.65(d,J=55.1Hz,1H),3.96(d ,J=15.8Hz,3H),3.65(dd,J=18.1,9.2Hz,2H),3.26–3.09(m,2H),3.07–2.89(m,1H),2.8 7–2.66(m,2H),2.59(d,J=16.1Hz,1H),2.39(d,J=15.7Hz,3H).LCMS(ES,m / z):420[M+H] + .

[0466] Example 62: Preparation of 3-[2-[4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-methylpyrazine-2-carbonitrile (62)

[0467] 62.1 Reaction material 39c was replaced with 3,5-dichloropyrazine-2-carbonitrile, and 5-(6-chloro-3-cyanopyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 62a) was prepared according to the method of Example 39-39.4.

[0468] 62.2 Replacing the reaction raw material 39d with 62a, prepare 5-(3-cyano-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 62b) according to the method of Example 39-39.5.

[0469] 62.3 Replacing the starting material 39d with 62b, prepare 3-(1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-5-methylpyrazine-2-carbonitrile (Compound 62c) according to the method of Example 39-39.6.

[0470] 62.4 Replace the reaction raw material 39g with 44a and 39f with 62c, and prepare 3-[2-[4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-methylpyrazine-2-carbonitrile (Compound 62) according to the method of Example 39-39.8. 1H NMR (400MHz, DMSO) δ8.89(d,J=23.5Hz,1H),7.98(s,2H),7.73(t,J=10.8Hz,1H),7.51(s,1H),7.38(dd,J=16.8,8.3Hz,1H),6.85(d,J=91.0Hz,1H), 3.76(t,J=13.8Hz,1H),3.67(t,J=12.2Hz,2H),3.52(s,1H),3.22–2.91(m ,2H),2.91–2.74(m,2H),2.68(d,J=10.2Hz,3H).LCMS(ES,m / z):416[M+H] + .

[0471] Example 63: Preparation of [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (63)

[0472] 63.1 Replacing the starting material 39c with 2-chloro-3-methoxypyrazine, prepare tert-butyl 5-(3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 63a) according to the method of Example 39-39.4.

[0473] 63.2 Replacing the starting material 39d with 63a, the reaction mixture was prepared according to the method of Example 39-39.6, using 5-(3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 63b).

[0474] 63.3 Replace the reaction raw material 39g with 41a, and 39f with 63b. Prepare [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (Compound 63) according to the method of Example 39-39.8. 1H NMR(400MHz,DMSO-d6)δ8.19(d,J=18.8Hz,1H),8.07(s,1H),8.04-7.68(m,2 H),7.41-7.28(m,2H),7.07(d,J=10.8Hz,1H),6.82-6.54(m,1H),4.08-3.95( m,3H),3.85(d,J=8.6Hz,3H),3.76-3.59(m,2H),3.47(s,1H),3.31-3.04(m, 2H),2.84(d,J=15.2Hz,2H),2.57(d,J=15.2Hz,1H).LCMS(ES,m / z):419[M+H] + .

[0475] Example 64: Preparation of [5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (64)

[0476] 64.1 1-(3-Chloropyrazin-2-yl)ethanone (600 mg, 3.83 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethylaminosulfur trifluoride (1.85 g, 11.49 mmol) was added. The mixture was heated to 90°C under nitrogen and allowed to react overnight. After completion of the reaction, the temperature was lowered to room temperature and quenched by the addition of saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 5:1) to afford 220 mg of 2-chloro-3-(1,1-difluoroethyl)pyrazine (Compound 64a).

[0477] 64.2 Reaction material 39c was replaced with 64a, and 5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (Compound 64b) was prepared according to the method of Example 39-39.4.

[0478] 64.3 Replacing the starting material 39d with 64b, the reaction mixture was prepared according to the method of Example 39-39.6, using 5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 64c).

[0479] 64.4 Replace the reaction raw material 39g with 41a, and 39f with 64c. Prepare [5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (Compound 64) according to the method of Example 39-39.8. 1 H NMR(400MHz,DMSO)δ8.80(d,J=11.3Hz,1H),8.64(d,J=5.4Hz,1H),8.09(s,2H) ,7.77(d,J=9.7Hz,1H),7.50(t,J=6.8Hz,1H),7.42(t,J=8.1Hz,1H),6.10–5.7 1(m,1H),3.91–3.39(m,3H),3.23–2.99(m,2H),2.93(d,J=12.3Hz,1H),2.77–2 .62(m,1H),2.48–2.29(m,1H),2.07(t,J=19.3Hz,3H).LCMS(ES,m / z):441[M+H] + .

[0480] Biological test cases

[0481] Test Example 1 Orexin target function test

[0482] 1. Experimental purpose:

[0483] The concentration of IP-one in the orexin receptor (OX1 / OX2) signaling pathway was detected by a microplate reader using the Cisbio HTRF IP-one kit, and the IC value of the compound was calculated. 50 The antagonistic effect of the compound on OX1 and OX2 receptors was evaluated by RT-PCR.

[0484] 2. Experimental Materials:

[0485] Cell lines: CHO-K1-OX1, CHO-K1-OX2 stable cell lines (Nanjing GenScript Biotechnology Co., Ltd.)

[0486] Cell culture conditions: F12 + 10% FBS + 400 μg / ml G418

[0487] Reagents and consumables:

[0488] F12 (Gibco, C11765500BT)

[0489] FBS (Gibco, 10099-141C)

[0490] Geneticin(G418)(Gibco, 11811031)

[0491] PBS (meilunbio, MA0015)

[0492] Pancreatin (Gibco, 25200-072)

[0493] Orexin A (MCE, HY-106224)

[0494] Orexin 2receptor agonist (MCE, HY19320)

[0495] 96-cell plate (cisbio, 66PL96025)

[0496] IP-One-Gq kit (cisbio, 62IPAPEC)

[0497] CO2 incubator (Thermo, 311)

[0498] Centrifuge (Shanghai Anting, TGL-16C)

[0499] Cell counter (Countstar, IC1000)

[0500] Microplate reader (PerkinElmer, EnVision)

[0501] 3. Experimental methods:

[0502] (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.

[0503] (2) Compound preparation: Dilute the compound to a 5 mM stock solution with DMSO, then dilute it 3.16-fold to form 10 gradients, and then dilute the prepared compound to the corresponding concentration (4x) with stimulation buffer for later use.

[0504] (3) Cell preparation: Digest the CHO-K1-OX1 and CHO-K1-OX2 cells on the culture dish with trypsin, wash the cells with culture medium and collect them in a 5 mL centrifuge tube. Centrifuge at 1000 rpm for 5 minutes and discard the supernatant. Add 3 mL of PBS and mix thoroughly by gently pipetting. Centrifuge again at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the cells in 1x Stimulation buffer and count them using a Countstar cell counter. Adjust the cell density to 1.71 x 106 / mL, for future use.

[0505] (4) Cell addition: Add the cell suspension to the experimental plate, 7 μL / well (i.e., approximately 12,000 cells / well).

[0506] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate, 3.5 μL / well.

[0507] (6) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 30 minutes.

[0508] (7)EC 80 Agonist added: Add EC 80 4x Orexin A (OX1 receptor) and 4x Orexin 2 receptor agonist (OX2 receptor) solution, 3.5 μL / well.

[0509] (8) Reaction incubation: After slow shaking, incubate the experimental plate at 37°C for 45 minutes.

[0510] (9) Add detection reagents: Dilute IP1-d2 and Anti-IP1cryptate at a 1:20 ratio using the Lysis & Detection Buffer in the Cisbio IP-one Detection Kit. Add 3 μL of each diluted IP1-d2 and Anti-IP1cryptate to the assay plate at each well. After shaking, incubate the plate at room temperature for 60 minutes.

[0511] (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.

[0512] 4. Data Analysis:

[0513] 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 .

[0514] Table 1

[0515] The compound of the present invention has good inhibitory activity on OX2 receptors, and the inhibitory effect of the compound on OX2 receptors is significantly better than that on OX1 receptors, and has good selectivity.

[0516] Test Example 2 Determination of pharmacokinetic parameters of the test substance in rat plasma

[0517] Healthy male Sprague-Dawley rats aged 6-9 weeks were randomly divided into two groups, 3 in each. One group received the test compound at 1 mg / kg via intravenous injection, while the other group received the test compound at 30 mg / kg via oral gavage. Whole blood was collected from both the intravenous and oral gavage groups before and 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, 10.0, and 24.0 hours after administration, and plasma samples were obtained by centrifugation.

[0518] LC-MS / MS was used for quantitative analysis of all biological samples, and WinNonlin™ Version 7.0 (Pharsight, Mountain View, CA) pharmacokinetic software was used to calculate relevant pharmacokinetic parameters using the non-compartmental linear logarithmic trapezoidal method. 0-last represents the area under the plasma concentration-time curve from time zero to the last detectable concentration time point; PO stands for oral administration; iv stands for intravenous administration, C max represents peak concentration, and F% represents oral bioavailability.

[0519] Table 2

[0520] In the pharmacokinetic evaluation experiment in rats, the example compounds of the present invention showed good bioavailability after oral administration.

[0521] Test Example 3: Rat Autonomic Activity

[0522] Male SD rats aged 6-9 weeks were randomly divided into groups according to the principle of weight balance, with 8 rats in each group, and were given blank solvent and 10, 30 and 50 mg / kg of the test compound respectively. The animals were placed in the test box immediately after administration, and the activity distance of the animals within 60 minutes was recorded and analyzed using Top Scan Version 3.0. The total activity distance of the animals in each test sample administration group was compared with that in the blank solvent group to determine whether the test sample had a significant effect on the spontaneous activity of the animals. The experimental data were represented by mean ± standard error (Mean ± SD), and SPSS 21.0 statistical software was used for one-way analysis of variance. The Dunnett test was used for pairwise comparison. The value of p < 0.05 was expressed as *.

[0523] Table 3

[0524] In the rat spontaneous activity experiment, the compounds of the embodiments of the present invention can significantly reduce the spontaneous activity distance of rats, and the lowest effective dose is equivalent to or better than Seltorexant.

[0525] Test Example 3: Blood-brain barrier permeability determination of the test substance in rats

[0526] Twelve male SD rats were randomly divided into four groups, with three rats in each group. They were fasted for 8 hours before the experiment and had free access to water. The rats were gavage-administered 30 mg / kg of the test substance solution. 0.3 mL of blood was collected from the jugular venous plexus of the rats before and 0.25 hours after administration. The rats were then anesthetized, the chest cavity was opened, the right atrial appendage was cut, and rapid perfusion was performed from the back of the left ventricle. When the outflowing liquid was transparent and bloodless, the perfusion was stopped. The brain tissue was then removed, dried with filter paper, weighed, and homogenized with an appropriate amount of saline (1:4, v / v) to prepare a brain tissue homogenate. The whole blood sample was centrifuged at 4000 r / min for 10 minutes to separate the plasma.

[0527] The established LC-MS / MS method is used to detect the concentration of the test substance in plasma and brain tissue homogenate. The brain-to-blood ratio (Kb / p) of the test substance can be obtained by dividing the drug concentration in brain tissue by the drug concentration in plasma. The larger the Kb / p, the better the blood-brain barrier permeability of the test substance.

[0528] Table 4

[0529] Conclusion: After oral administration to rats, the compounds of the present invention can well penetrate the blood-brain barrier and have a high brain-blood ratio.

[0530] Test Example 4: Effect of the Test Substance on Sleep in SD Rats

[0531] Experimental process:

[0532] 1. Surgical Implantation of Electrodes: Animals were acclimated to a 14h / 10h light / dark cycle for at least 4 days (lights off at 21:00, lights on at 7:00). On the day of the experiment, animals were anesthetized with sodium pentobarbital (ip, 60 mg / kg). After anesthesia, the brain was fixed in a stereotaxic apparatus, the surgical area of ​​the head was prepared, and a hole was drilled in the skull for implantation of electrodes.

[0533] 2. Postoperative Care: After surgery, rats were carefully placed in a clean recovery cage in the lateral recumbent position to ensure airway patency. The cage was maintained in an automatic light-dark cycle (lights off at 9:00 PM, lights on at 7:00 AM), with a constant temperature of 20-26°C and a relative humidity of 40-70%. Animals were given 3 days of postoperative care and 80,000 units of penicillin sodium per animal. Experiments were performed after at least 7 days of recovery.

[0534] 3. Dosage regimen and monitoring indicators: Baseline EEG and EMG recordings were performed at least 7 days after postoperative recovery. Dosing began after baseline EEG and EMG recordings were completed. Animals were acclimated to the experimental cage for at least 24 hours before dosing. A single dose was administered 1 hour after lights were turned off, and EEG and EMG were recorded for 12 hours after dosing.

[0535] 4. Test Indicator: Time spent awake in rats per hour for 12 hours after administration. Analyze using a t-test; P < 0.05 indicates a significant difference. See the accompanying figures for experimental results.

[0536] The results show that in the rat sleep effect test, the Example compounds of the present invention can significantly reduce the total awake time and increase the total sleep time at a relatively low dose, indicating that the Example compounds of the present invention have a good promoting effect on rat sleep.

[0537] It will be clear to those skilled in the art that many modifications and variations of the present invention may be made without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not intended to be limiting in any way. The true scope and spirit of the present invention are shown by the appended claims, and the description and examples are merely exemplary.

Claims

1. A compound as shown in formula I or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, in, R1 and R2 are each independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano; or R1, R2 and the carbon atom to which they are attached together form a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl or a C3-C8 cycloalkyl group optionally substituted by one or more substituents, the substituents being independently selected from H, D, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano; L1 is selected from the group consisting of one or more substituents R LA substituted 6-14 membered aryl and optionally substituted by one or more substituents R LA The substituted 5-14 membered heteroaryl group is preferably selected from the group consisting of LA substituted 6-10 membered aryl and optionally substituted by one or more substituents R LA The substituted 5-10 membered heteroaryl group is further preferably selected from the group consisting of LA Substituted phenyl and optionally substituted by one or more substituents R LA substituted 5-6 membered monocyclic heteroaryl; the one or more substituents R LA independently selected from H, D, halogen, optionally substituted by one or more R LB Substituted C1-C8 alkyl, optionally substituted by one or more substituents R LB Substituted C1-C8 alkoxy, cyano, optionally substituted by one or more substituents R LB Substituted C2-C8 alkynyl, optionally substituted by one or more substituents R LB Substituted C2-C8 alkenyl, hydroxyl, nitro, optionally substituted by one or more substituents R LB Substituted C1-C8 alkylthio, optionally substituted by one or more substituents R LB substituted C3-C8 cycloalkyl and OR4, the one or more substituents R LB is selected from H, D, halogen and hydroxyl; R4 is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; L2 is selected from 6-14 membered aryl substituted by 0-4 Rb groups and 5-14 membered heteroaryl substituted by 0-4 Rb groups, preferably selected from 6-10 membered aryl substituted by 0-3 Rb groups and 5-10 membered monocyclic or bicyclic heteroaryl substituted by 0-3 Rb groups, further preferably selected from phenyl substituted by 0-3 Rb groups and 5-6 membered heteroaryl substituted by 0-3 Rb groups; Each Rb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; the substituents are independently selected from H, D, halogen and hydroxyl; X1 is selected from N and CR 10 ; R 10 is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, Nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, D, halogen and hydroxy; X2 is selected from N and CR 11 ; R 11 is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano; said substituents being independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano; and X1 and X2 are not N at the same time; and When X2 is CR 11 , and when X1 is N, R2 is not H or D.

2. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: The compound of formula I is shown in formula IA, Among them, R 1A 、R 2A 、R 3A independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxy, nitro, cyano, preferably selected from H, D, halogen and hydroxy; or R 1A 、R 2A Together with the carbon atom to which it is attached, it forms a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl, and a C3-C8 cycloalkyl group optionally substituted by one or more substituents independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano; L 1A is selected from 6-14 membered aryl groups optionally substituted by one or more substituents and 5-14 membered heteroaryl groups optionally substituted by one or more substituents, preferably selected from 6-10 membered aryl groups optionally substituted by one or more substituents and 5-10 membered heteroaryl groups optionally substituted by one or more substituents, further preferably selected from phenyl groups optionally substituted by one or more substituents and 5-6 membered monocyclic heteroaryl groups optionally substituted by one or more substituents; the one or more substituents are independently selected from H, D, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, cyano, optionally substituted C2-C8 alkynyl, optionally substituted C2-C8 alkenyl, hydroxyl, nitro, optionally substituted C1-C8 alkylthio, optionally substituted C3-C8 cycloalkyl and OR 4A , preferably independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C3-C6 cycloalkyl and OR 4A , further preferably independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C6 cycloalkyl and OR 4A , the substituent is selected from H, D, halogen and hydroxy, and the substituent is preferably selected from D, halogen and hydroxy; R 4A Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; L 2A substituted by 0-4 Rbbb groups, and 5-14-membered heteroaryl groups substituted by 0-4 Rbbb groups, preferably substituted by 0-3 Rbbb groups, and 5-10-membered monocyclic or bicyclic heteroaryl groups substituted by 0-3 Rbbb groups, and further preferably substituted by 0-3 Rbbb groups, and phenyl groups substituted by 0-3 Rbbb groups, and 5-6-membered heteroaryl groups substituted by 0-3 Rbbb groups; Each Rbbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen; and the substituents are independently selected from H, D, halogen, and hydroxy.

3. The compound of formula IA according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R 1A 、R 2A 、R 3A independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, halogen and hydroxy; or R 1A 、R 2A Together with the carbon atom to which it is attached, it forms a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl, or a C3-C8 cycloalkyl group optionally substituted by one or more substituents independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano; L 1A is selected from 6-14 membered aryl groups optionally substituted by one or more substituents and 5-14 membered heteroaryl groups optionally substituted by one or more substituents, preferably selected from 6-10 membered aryl groups optionally substituted by one or more substituents and 5-10 membered heteroaryl groups optionally substituted by one or more substituents, further preferably selected from phenyl groups optionally substituted by one or more substituents and 5-6 membered monocyclic heteroaryl groups optionally substituted by one or more substituents; the one or more substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxyl, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A , preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl and OR 4A , further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl and OR 4A ; R 4A Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; L 2A The 6-14 membered aryl group substituted by 0-4 Rbbb groups and the 5-14 membered heteroaryl group substituted by 0-4 Rbbb groups are preferably selected from the 5-10 membered aryl group substituted by 0-3 Rbbb groups and the 5-10 membered monocyclic or bicyclic heteroaryl group substituted by 0-3 Rbbb groups, and further preferably selected from the phenyl group substituted by 0-3 Rbbb groups and the phenyl group substituted by 0-3 Rbbb groups. substituted 5-6 membered heteroaryl; Each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen; and the substituents are independently selected from H, halogen, and hydroxy.

4. The compound of formula IA or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to claim 2 or 3, wherein: One or more of the following conditions are met: (1)R 1A 、R 2A 、R 3A independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, halogen, hydroxy; the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl; or R 1A 、R 2A Together with the carbon atom to which it is attached, it forms a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group or a C3-C8 cycloalkyl group which is optionally substituted by one or more substituents; the 3-8 membered heterocyclic group is preferably selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrothienyl, dihydrothienyl, azetidinyl, oxetanyl, thietanyl, piperidinyl and pyrrolidinyl, and is further preferably selected from tetrahydrofuranyl, tetrahydropyranyl and dihydropyranyl; the 5-8 membered heteroaryl group is preferably selected from furanyl, pyranyl and thienyl; the C3-C8 cycloalkyl group is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl and cyclohexenyl, and is further preferably selected from cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl; preferably or R 1A 、R 2A Together with the carbon atom to which it is attached, it forms a Preferably, it is optionally substituted with one or more substituents Preferably, it is optionally substituted with one or more substituents The substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, nitro and cyano; (2)L 1A Selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, Pyrrolyl, triazolyl, thiadiazolyl, thienyl and furyl, preferably selected from phenyl, pyridyl, pyrazolyl, thiazolyl and thienyl, more preferably phenyl, pyridyl and thiazolyl, the above groups are optionally substituted by one or more substituents, the one or more substituents being independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxyl, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A , preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl and OR 4A , further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl and OR 4A ; R 4A Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; (3)L 2A is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thienyl, furanyl and 1,3,4-triazolyl, preferably selected from phenyl, pyrimidinyl, pyridinyl, pyrazolyl, thienyl, imidazolyl and 1,2,3-triazolyl, further preferably phenyl, pyridinyl, pyrazolyl, thienyl and 1,2,3-triazolyl; wherein the above groups are optionally substituted by 0-4 Rbbb groups.

5. The compound of formula IA according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R 1A 、R 2A 、R 3A Independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl; L 1A 6-14 membered aryl groups optionally substituted by one or more substituents and 5-14 membered heteroaryl groups optionally substituted by one or more substituents, preferably 6-10 membered aryl groups optionally substituted by one or more substituents and 5-10 membered heteroaryl groups optionally substituted by one or more substituents, further preferably phenyl groups optionally substituted by one or more substituents and 5-6 membered monocyclic heteroaryl groups optionally substituted by one or more substituents; the one or more substituents are independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl; L 2A substituted by 0-4 Rbbb groups, and 5-14-membered heteroaryl groups substituted by 0-4 Rbbb groups, preferably substituted by 0-3 Rbbb groups, and 5-10-membered monocyclic or bicyclic heteroaryl groups substituted by 0-3 Rbbb groups, and further preferably substituted by 0-3 Rbbb groups, and phenyl groups substituted by 0-3 Rbbb groups, and 5-6-membered heteroaryl groups substituted by 0-3 Rbbb groups; Each Rbbb group is independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy; preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy.

6. The compound of formula IA according to any one of claims 2 to 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula IA is shown in formula II-A: Among them, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; said substituents are independently selected from H, halogen and hydroxy.

7. The compound of formula IA according to any one of claims 2 to 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula IA is shown in formula III-A: Among them, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen; said substituents are independently selected from H, halogen and hydroxy; n1A is an integer selected from 0-4, preferably 1; R 6A independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl and OR 4A ; preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl and OR 4A ; Further preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl and OR 4A ; R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, and is preferably C3-C6 cycloalkyl.

8. The compound of formula I according to claim 1 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: The compound of formula I is shown in formula IB, Among them, R 1B 、R 3B independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from halogen, D, C1-C8 alkoxy, hydroxy, nitro and cyano; R 2B is selected from the group consisting of C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from the group consisting of C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, further preferably F; or R 1B 、R 2B Together they form a 3-8 membered heterocyclyl, a 5-8 membered heteroaryl, or a C3-C8 cycloalkyl group optionally substituted with one or more substituents independently selected from the group consisting of halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, nitro, and cyano; L 1B is selected from optionally substituted phenyl and optionally substituted pyridyl, the substituents being independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; L 2B is a 5-14-membered heteroaryl group substituted by 0-4 Rbb groups, preferably a 5-10-membered monocyclic or bicyclic heteroaryl group substituted by 0-3 Rbb groups, and further preferably a 5-6-membered heteroaryl group substituted by 0-3 Rbb groups; Each Rbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, preferably selected from H and C1-C8 alkyl; the substituents are independently selected from D and halogen.

9. The compound of formula IB according to claim 8, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: One or more of the following conditions are met: (1)R 1B 、R 3B independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxy, nitro and cyano, preferably independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy , optionally substituted C3-C8 cycloalkyl and halogen; the substituents are independently selected from halogen, D, C1-C8 alkoxy, hydroxy, nitro and cyano; the 3-8 membered heterocyclic group is preferably selected from oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl and pyrrolidinyl; the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl; R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F; or R 2B 、R 1B Together they form a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group or a C3-C8 cycloalkyl group which is optionally substituted by one or more substituents; the 3-8 membered heterocyclic group is preferably selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydro pyranyl, azetidinyl, oxetanyl, thietanyl, piperidinyl and pyrrolidinyl, more preferably selected from tetrahydrofuranyl, tetrahydropyranyl and dihydropyranyl; the 5-8 membered heteroaryl is preferably selected from furanyl, pyranyl and thienyl; the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, more preferably selected from cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl; the substituents are independently selected from halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano; (2)L 1B is selected from optionally substituted phenyl and optionally substituted pyridyl, the substituents being independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; (3)L 2B is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl and 1,3,4-triazolyl, preferably selected from pyrazolyl, imidazolyl and 1,2,3-triazolyl, further preferably 1,2,3-triazolyl; wherein the above groups are optionally substituted by 0-4 Rbb groups.

10. The compound of formula IB according to any one of claims 8 to 9, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: One or more of the following conditions are met: (1)L 1B Selected from Preferably selected from More preferably, it is selected from Wherein, the above groups are optionally substituted by one or more substituents, and the one or more substituents are independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxyl, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; (2)R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkoxy It is preferably alkyl or halogen, and more preferably F.

11. The compound of formula IB according to any one of claims 8 to 10, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula IB is shown in formula II-B: Among them, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, said substituents being independently selected from D and halogen; R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

12. The compound according to any one of claims 8 to 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula IB is shown in formula III-B: wherein n1B is selected from an integer between 0 and 3; R 6B independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

13. The compound according to any one of claims 8 to 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula IB is shown in formula IV-B: Among them, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, said substituents being independently selected from D and halogen; n2B is an integer selected from 0-4, preferably 1; R 7B independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, halogen, more preferably C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

14. The compound according to any one of claims 8 to 12, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, characterized in that: The compound of formula IB is shown in formula VB: Among them, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, said substituents being independently selected from D and halogen; n3B is an integer selected from 0-3, preferably 1, R 8B independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR B and C1-C8 alkylthio; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic group, preferably C3-C6 cycloalkyl; R 2B Selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 Hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy and nitro, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, further preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, further preferably F.

15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: Selected from the following compounds:

16. A pharmaceutical composition, characterized in that Contains the compound of formula I according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable carrier.

17. Use of the compound according to any one of claims 1 to 15 or its pharmaceutically acceptable salt, stereoisomer, tautomer, or the pharmaceutical composition according to claim 16 in the preparation of a medicament, wherein: The medicament is used for preventing, treating and / or alleviating diseases related to orexin receptors.

18. The use according to claim 17, wherein the disease associated with orexin receptors is sleep disorder, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neurosis, depressive neurosis, anxiety neurosis, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, psychosis, schizophrenia, manic depression, mental disorder, dementia, drug dependence, addiction, cognitive disorder, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, insomnia, depression, Alzheimer's disease, sleep apnea; preferably insomnia, depression, sleep disorder; more preferably major depressive disorder, primary and secondary insomnia, or depression associated with insomnia.

19. A method for preparing a compound of formula I according to any one of claims 1 to 15, characterized in that: The method comprises the following steps: Compound Id reacts with Compound If to obtain target Compound I: Wherein, R1, R2, X1, X2, L1, L2 are as defined in the corresponding groups of claims 1-15, and preferably, the compound represented by Id is a compound represented by I-dA or I-dB. R 1A 、R 2A 、R 3A As defined in claims 1 to 7 or the corresponding groups in claim 15; R 1B 、R 2B 、R 3B As defined in claim 1 or the corresponding groups in claims 8-15.

20. A compound as shown in formula Id, in, R1, R2, X1, X2 are as defined in the corresponding groups of claims 1-15, wherein the compound represented by Id is preferably a compound represented by I-dA or I-dB. R 2A 、R 3A As defined in claims 1 to 7 or the corresponding groups in claim 15; R 1B 、R 2B 、R 3B As defined in claim 1 or the corresponding groups in claims 8-15.

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