A substituted tetrahydrocyclopentyl[c]pyrrole derivative, its preparation method, intermediates and applications

Abstract

Provides a compound of general formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, and composition comprising the compound, its preparation method, intermediates, and application in the pharmaceutical field.

Description

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

[0002] This invention pertains to the pharmaceutical field, specifically relating to a substituted tetrahydrocyclopentyl[c]pyrrole derivative or its pharmaceutically acceptable salt, stereoisomer, tautomer, and composition comprising the compound, its preparation method, intermediates, and applications in the pharmaceutical field. Background Technology

[0003] Orexin (also known as hypothalamic secretion or orexin peptide) exists in two forms: 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 for orexin A, while OX2R binds to both orexin peptides with similar affinity.

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

[0005] Several drugs targeting OX1 / 2R are in clinical trials or already on the market, such as Merck's Suvoraxant and Eisai's Lemborexant. However, existing drugs antagonize both OX1R and OX2R receptors. Acting on OX1R affects both REM sleep (NEM, where brain activity is the same as when awake) and non-REM sleep (NEREM, deep sleep), sacrificing NREM time and prolonging REM time, thereby increasing the risk of drowsiness. Furthermore, OX1R has no antidepressant effect.

[0006] Studies have shown that sleep-wake cycle disorders are likely targets of OX2R receptor modulators. Examples of disorders treatable by antagonists or other modulators that downregulate OX2R-mediated processes include insomnia, restless legs syndrome, jet lag (difficulty sleeping), and sleep disorders secondary to neurological disorders such as mania, schizophrenia, and pain syndromes. OX2R is selectively expressed in the tuberous-papillary nucleus (TMN), paraventricular nucleus (PVN) of the hypothalamus, and nucleus accumbens (NAc), which are major effector sites of orexin neurons in the lateral hypothalamus (LH) and are associated with eating, sleep, depression, anxiety, addiction, and motivational behavior, showing particularly significant efficacy in treating sleep disorders (Lu et al., 2020, Neurosci Bull, 4:432–448).

[0007] OX2R antagonists have antidepressant effects, and OX2R monoreceptor antagonists are also sufficiently effective for insomnia. Therefore, selective OX2R antagonists can avoid various side effects such as drowsiness caused by OX1R action. Currently, the only OX2R antagonist in clinical trials is Seltorexant, developed by Janssen Pharmaceuticals, with primary indications for major depressive disorder (MDD), primary and secondary insomnia, etc.

[0008] Selective OX2R antagonists have the potential to treat neurological disorders such as insomnia, depression, and anxiety, and there is a huge clinical demand for them. Selective OX2R antagonists show promising application prospects as drugs. Summary of the Invention

[0009] The following is only a summary of some aspects of the invention and is not intended to limit it. In the event of any discrepancy between the disclosure in this specification and the cited references, the disclosure in this specification shall prevail.

[0010] 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 method for preparation thereof and intermediates thereof, wherein the compound and pharmaceutical composition can be used to prevent or treat diseases related to orexin receptors.

[0011] On the one hand, the present invention provides a compound or pharmaceutically acceptable salt, stereoisomer, or tautomer of the following general formula I.

[0012]

[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 heterocyclic group, halogen, hydroxyl, 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, hydroxyl, nitro and cyano;

[0015] Alternatively, R1, R2, together with the carbon atom to which they are attached, can form a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group, or a C3-C8 cycloalkyl group, optionally substituted with one or more substituents, wherein the substituents are independently selected from H, D, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, hydroxyl groups, nitro groups, and cyano groups.

[0016] L1 is selected from R, which is arbitrarily substituented by one or more substituents. LA Substituted 6-14 aryl groups and optionally substituents R LA The substituted 5-14 heteroaryl group is preferably selected from those optionally substituented by one or more R groups. LA Substituted 6-10 aryl groups and optionally substituents R LA The substituted 5-10 heteroaryl group, more preferably selected from those optionally substituented by one or more R groups. LA Substituted phenyl groups and optionally substituted with one or more substituents R LA Substituted 5-6 membered monocyclic heteroaryl; said one or more substituents R LA Independently selected from H, D, halogens, optionally substituents R. LB Substituted C1-C8 alkyl groups, optionally substituted with one or more substituents R LB Substituted C1-C8 alkoxy, cyano, optionally with one or more substituents R LB Substituted C2-C8 ynyl group, optionally with one or more substituents R LB Substituted C2-C8 alkenyl, hydroxyl, nitro, optionally with one or more substituents R LB Substituted C1-C8 alkylthio groups, optionally with one or more substituents R LBSubstituted C3-C8 cycloalkyl groups and OR4, wherein one or more substituents R LB Selected from H, D, halogens, and hydroxyl groups;

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

[0018] L2 is selected from 6-14 aryl groups substituted with 0-4 Rb groups and 5-14 heteroaryl groups substituted with 0-4 Rb groups, preferably from 6-10 aryl groups substituted with 0-3 Rb groups and 5-10 monocyclic or bicyclic heteroaryl groups substituted with 0-3 Rb groups, and more preferably from phenyl groups substituted with 0-3 Rb groups and 5-6 heteroaryl groups substituted with 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 The substituent 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, hydroxyl, 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 substituent is independently selected from H, D, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, D, halogen and hydroxyl;

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

[0023] R 11 The substituent 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 heterocyclic groups, halogens, hydroxyl groups, nitro groups, and cyano groups; the substituent is independently selected from H, D, halogens, C1-C8 alkoxy, hydroxyl, nitro, and cyano groups;

[0024] And X1 and X2 are not both N; 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 of 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 combination thereof.

[0027] On the other hand, the present invention provides the 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 orexin receptor-related diseases, or a method for treating orexin receptor-related diseases in a subject, the method comprising administering a therapeutically effective amount of the compound of the present invention to a subject in need, including the compound of Formula I or a specific compound or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof.

[0028] In one implementation, the orexin-related diseases include sleep disorders, anxiety disorders, panic disorders, obsessive-compulsive disorder, affective neurosis, depressive neurosis, anxiety neurosis, mood disorders, panic attack disorder, behavioral disorders, emotional disturbances, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive impairment, Parkinson's disease, movement disorders, eating disorders, headaches, migraines, pain, insomnia, depression, Alzheimer's disease, and sleep apnea; preferably insomnia, depression, and sleep disorders; more preferably major depressive disorder, primary and secondary insomnia, or depression accompanied by insomnia.

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

[0030] On the other hand, the present invention provides a method for preparing the compound shown in Formula I, comprising the following steps: reacting compound Id with compound If to obtain the target compound I:

[0031]

[0032] Wherein, R1, R2, X1, X2, L1, and L2 are as defined above, and preferably, the compound represented by Id is the 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.

[0033] On the other hand, the present invention provides an intermediate as shown in the compound of formula Id.

[0034]

[0035] Wherein, R1, R2, X1, and X2 are as defined above, and preferably, the compound represented by Id is the 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 Implementation

[0036] Unless otherwise stated or there is a clear conflict in the context, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of any discrepancy, the definitions provided herein shall prevail. When trade names appear herein, they are intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are incorporated herein by reference.

[0037] General terms and definitions

[0038] The term “optional” or “optionally” means that the event or situation described below may, but not necessarily, occur, and the description includes both the cases in which the event or situation occurs and the cases in which it does not occur.

[0039] The term “optionally substituted” may be used interchangeably with the term “substituted or unsubstituted”, meaning that the structure or group is unsubstituted or substituted by one or more substituents as described in this invention, wherein the substitution occurs at a reasonable position on the given structure or group where any valence allows.

[0040] Unless otherwise specified, as used herein, the connection point of a substituent may be any suitable location of the substituent. When the bond of a substituent is such that it is a bond that passes through the ring and connects two atoms, such a substituent may be bonded to either cyclic atom in the substituted ring.

[0041] Generally, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced by a specific substituent. Unless otherwise indicated, a substituent may be substituted at any of the reasonable substituted positions in the group. When more than one position in a given structural formula can be substituted by one or more specific substituents selected from the group, the substituents may be substituted at the reasonable positions in the structural formula, either in the same or different ways.

[0042] Additionally, it should be noted that, unless otherwise explicitly stated, the description used in this invention as “each independently” should be interpreted broadly. It can mean either that the specific options expressed by the same symbols in different groups do not affect each other, or that the specific options expressed by the same symbols in the same group do not affect each other.

[0043] When the lower and upper limits of a numerical range are disclosed, any value falling within that range and any included range are specifically disclosed. In particular, each range of values ​​disclosed herein should be understood as representing each value and range encompassed within a wider range. When any variable (e.g., R), and labeled variables (e.g., R1, R2, R3, R4, R5, R6, R7, etc.) appears more than once in the composition or structure of a compound, its definition is independent in each instance. For example, if a group is substituted by 0, 1, 2, or 3 R substituents, the group may optionally be substituted by up to three R substituents, and the option of each R substituent in each instance is independent of each other.

[0044] In various parts of this specification, the substituents of the compounds disclosed herein are disclosed according to the type or range of groups. In particular, this invention includes every independent sub-combination of the members of these types and ranges. For example, the expression mn used herein refers to the range from m to n, as well as the subrange consisting of the individual point values ​​therein, and the individual point values ​​themselves.

[0045] The term "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, connected to the rest of the molecule by single bonds. Alkyl groups can have 1-8 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. They can also have 1-3 carbon atoms, i.e., "C1-C3 alkyl groups", for example, C... 1-3 Alkyl, C 1-2Alkyl, C3 alkyl. The term "C1-C5 alkyl" specifically refers to independently disclosed methyl, ethyl, C3 alkyl, C4 alkyl, and C5 alkyl groups. 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, -CH2CH2CH2CH3), and tert-butyl (t-Bu, -CH2CH(CH3)2). -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" covers a range of 1 to 8 carbon atoms, and should be understood to also cover any subrange and each point value within this range, such as C1-C5, C3-C4, C2-C6, C3-C6, C4-C6, C4-C7, C4-C8, C2-C4, etc., and C1, C2, C3, C4, C5, C6, C7, C8, etc. Another example is the expression "C1-C5" or "C..." 1-5 "Covering a range of 1-5 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C1-C2, C1-C3, C1-C4, C1-C5, etc., and C1, C2, C3, C4, C5, etc. For example, expressing 'C2-C5' or 'C'..." 2-5"Covering a range of 2-5 carbon atoms, and should be understood to also include any subranges within this range and each point value, such as C2-C5, C3-C4, C2-C3, C2-C4, C3-C5, C4-C5, etc., and C2, C3, C4, C5, etc. Another example is expressing "C1-C8" or "C..." 1-8 "The term 'covers' the range of 1 to 8 carbon atoms and should be understood to also include any subranges within this range, 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., and C1, C2, C3, C4, C5, C6, C7, C8, etc. Similarly, the expression 'ternary to octary' should be understood to include any subrange within this range and each point value, such as ternary to pentaneous, ternary to hexavalent, ternary to heptaneous, ternary to octaneous, quaternary to pentaneous, quaternary to hexavalent, quaternary to heptaneous, quaternary to octaneous, pentaneous to heptaneous, pentaneous to octaneous, heptaneous to heptaneous, heptaneous to octaneous, etc., as well as trivalent, quadrivalent, quinary, septvalent, septvalent, septvalent, octaneous, etc. Other similar expressions in this text should also be understood in a similar manner."

[0046] The term "one or more species" or similar expression "at least one species" can mean, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more species.

[0047] The term “selected from…” means one or more elements from the groups listed below, selected independently, and may include combinations of two or more elements.

[0048] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0049] When each carbon atom in the descriptive group can be optionally replaced by a heteroatom, the condition is that the valence of all atoms in the group is not exceeded in the present case, and a stable compound is formed.

[0050] The term “heteroatom” refers to one or more oxygen (O), sulfur (S) or nitrogen (N) atoms, including nitrogen (N) and sulfur (S) in any oxidation state; in the form of primary, secondary, tertiary amines and quaternary ammonium salts; or in the form where hydrogen atom on nitrogen atom in heterocycle is substituted, for example: N, NH, NR.

[0051] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated electronic system. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring". Examples of aryl groups include 6-14-membered aryl groups and 6-10-membered aryl groups, specifically including phenyl, naphthyl, etc. The aryl group may optionally be substituted by one or more substituents described in this invention.

[0052] The term "heteroaryl" refers to a heteroaromatic system comprising 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" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Examples of heteroaryl groups include 5-14 membered heteroaryl groups, 5-10 membered heteroaryl groups, 5-10 membered monocyclic or polycyclic heteroaryl groups, and 5-6 membered monocyclic heteroaryl groups, specifically including pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazoleyl, pyrazolyl, pyrroleyl, 1,2,3-triazolyl, thiadiazolyl, thiopheneyl, furanyl, pyridazinyl, triazinyl, oxadiazolyl, isoxazolyl, pyranyl, 1,3,4-triazolyl, furanopyrimidinyl, thiophenopyrimidinyl, pyrrolopyridinyl, pyranopyrimidinyl, benzothiazolyl, benzoxazolyl, thiophenopyrimidinyl, indolyl, etc. The heteroaryl groups may optionally be substituted by one or more substituents described in this invention.

[0053] The terms "heterocycle" and "heterocyclic group" are used interchangeably to refer to monocyclic, bicyclic, or tricyclic systems comprising 3-14 ring atoms, 3-8 ring atoms, or 5-6 ring atoms, of monovalent or polyvalent form, wherein one or more atoms on the ring are independently replaced by heteroatoms, which have the meaning as described in this invention, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise stated, the -CH2- group on the heterocyclic group may optionally be replaced by -C(=O)-. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide. Examples of heterocyclic groups include 3-14 membered heterocyclic groups, 3-8 membered heterocyclic groups, 5-10 membered heterocyclic groups, and 5-10 membered monocyclic or bicyclic heterocyclic groups, specifically including: ethylene oxide, nitrogen-containing heterocyclic butyl, oxo-heterocyclic butyl, thio-heterocyclic butyl, pyrrolyl, 2-pyrrololinyl, 3-pyrrololinyl, pyrazolinyl, pyrazolylyl, imidazolinyl, imidazolinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, and dihydrofuranyl. Examples of heterocyclic groups that include, but are not limited to, 2-pyridinyl, 1,3-dioxocyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiaranyl, dihydrothiaranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazine, cyclopentadiazine, dihydrofuranopyrimidinyl, dihydropyridinyl, 2-pyridinone, 2-oxopyrrolylyl, oxo-1,3-thiazolyl, etc. Examples of heterocyclic groups where the -CH2- group is replaced by -C(=O)- include, but are not limited to, 2-pyridinone, 2-oxopyrrolylyl, oxo-1,3-thiazolyl, 2-piperidinone, 3,5-dioxopyridinyl, and pyrimidinidone. Examples of heterocyclic groups where the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl. The heterocyclic group may optionally be replaced by one or more substituents described in this invention.

[0054] The term "alkenyl" refers to a general term for hydrocarbons containing carbon-carbon double bonds in their molecules; they are unsaturated aliphatic hydrocarbons. For example, vinyl (CH2=CH-). The term "alkene" can have 2-8 carbon atoms, i.e., a "C2-C8" alkenyl group, 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 groups, etc. They can also have 2-5 carbon atoms, i.e., "C2-C5 alkenyl groups", for example, C... 2-5 alkenyl, C 2-3 Alkenyl, C3 alkenyl, C5 alkenyl, etc. 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, etc.

[0055] The term "alkynyl" refers to a general term for hydrocarbons containing a carbon-carbon triple bond in their molecules; they are unsaturated aliphatic hydrocarbons. For example, ethynyl (). The "alkynyl" can have 2-8 carbon atoms, i.e., a "C2-C8" alkynyl group, for example, C... 2-8 alkynyl group, C 2-4 alkynyl group, C 2-5 Alkynyl, C3 alkynyl, C4 alkynyl, C6 alkynyl, C 2-6 alkynyl group, C 3-8 alkynyl group, C 3-6 Alkyne groups, etc. They can also have 2-5 carbon atoms, i.e., "C2-C5 alkynyl groups", for example, C... 2-5 alkynyl group, C 2-3 Alkynyl, C3 alkynyl, C5 alkynyl, etc. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, penynyl, hexynyl, hepynyl, octyynyl, etc.

[0056] The term "hydrogen (H)" refers to a single hydrogen atom. Such a group of atoms can be attached to other groups, such as oxygen atoms, to form a hydroxyl group.

[0057] The term "deuterium (D or 2H)" is a stable isotope of hydrogen, which exists naturally at an abundance of 0.015 mol%. The term "deuteration" refers to the substitution of one or more hydrogen atoms (H) in a group or compound by the replacement of one hydrogen atom (D).

[0058] The term "halogen" or "halogenated" should be understood to mean fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably fluorine, chlorine or bromine atoms, more preferably fluorine atoms.

[0059] The term "alkoxy group" refers to an alkyl group attached to the remainder of a molecule via an oxygen atom, wherein the alkyl group has the meaning as described in this invention. In one embodiment, the alkoxy group contains 1-8 carbon atoms. In another embodiment, the alkoxy group contains 1-5 carbon atoms; in yet another embodiment, the alkoxy group contains 1-3 carbon atoms. The alkoxy group may optionally be substituted by one or more substituents described in this invention. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH3), ethoxy (EtO, -OCH2CH3), 1-propoxy (n-PrO, n-propoxy, -OCH2CH2CH3), 2-propoxy (i-PrO, i-propoxy, -OCH(CH3)2), 1-butoxy (n-BuO, n-butoxy, -OCH2CH2CH2CH3), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH2CH(CH3)2), 2-butoxy (s-BuO, s-butoxy, -OCH(CH3)CH2CH3), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH3)3), etc.

[0060] The term "alkathio" refers to an alkyl group attached to the remainder of a molecule via a sulfur atom, wherein the alkyl group is as defined herein. In one embodiment, the alkathio group contains 1-8 carbon atoms. In another embodiment, the alkathio group contains 1-5 carbon atoms. In yet another embodiment, the alkathio group contains 1-3 carbon atoms. The alkathio group may optionally be substituted by one or more substituents described herein. Examples of alkathio 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), etc.

[0061] The term "cycloalkyl" refers to a cyclic hydrocarbon group or cyclic alkenyl group composed of carbon and hydrogen atoms, preferably containing one or two rings. The cycloalkyl group can be monocyclic, fused polycyclic, bridged, or spirocyclic. Cycloalkyl groups can have 3-8 carbon atoms, i.e., "C3-C8 cycloalkyl," or 3-6 carbon atoms, i.e., "C3-C6 cycloalkyl," such as C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, and C3 cycloalkyl. Examples of cycloalkyl groups include C3-C8 and C3-C6 cycloalkyl groups, specifically including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, etc. The term also covers cases where the carbon atom can be substituted with an oxygen (=O).

[0062] The terms "hydroxyalkyl" and "hydroxy-substituted alkyl" are used interchangeably, referring to an alkyl group in which one or more hydroxyl groups are substituted. Examples include, but are not limited to: hydroxymethyl (-CH2OH), hydroxyethyl (-CH2CH2OH, -CHOHCH3), hydroxypropyl (-CH2CH2CH2OH, -CH2CHOHCH3, -CHOHCH2CH3, -COHCH3CH3), and hydroxybutyl (-CH2CH2CH2CH2OH, -CH2CH2CHOHCH3, -CHOHCH2CH2CH3, -COHCH3CH2CH3), wherein the hydroxyl substitution can be monosubstituted or polysubstituted.

[0063] The terms “hydroxyalkoxy” and “hydroxy-substituted alkoxy” are used interchangeably and refer to an alkoxy group that is substituted by one or more hydroxyl groups.

[0064] The terms "halogenated alkyl" and "halogen-substituted alkyl" are used interchangeably, referring to an alkyl group in which one or more halogens are substituted. Examples include, but are not limited to, halomethyl, haloethyl, halopropyl, halobutyl, and halopentyl, wherein the halogenation can be monohalogen-substituted, dihalogen-substituted, or trihalogen-substituted; when it is a trihalogen-substituted methyl group, trifluoromethyl is further preferred.

[0065] The terms "haloalkoxy" and "halogen-substituted alkoxy" are used interchangeably and refer to an alkoxy group that is substituted with one or more halogens. Examples include, but are not limited to, halomethoxy, haloethoxy, halopropoxy, halobutoxy, and halopentoxy, wherein the halogenation can be monohalogen substitution, dihalogen substitution, or trihalogen substitution.

[0066] The terms "halogenated alkenyl" and "halogen-substituted alkenyl" are used interchangeably and refer to alkenyl groups that are substituted with one or more halogens. Examples include, but are not limited to, halogenated vinyl, halogenated propenyl, halogenated butenyl, and halogenated pentenyl, wherein the halogenation can be monohalogenated, dihalogenated, or trihalogenated.

[0067] The terms "halogenated alkyne" and "halogen-substituted alkyne" are used interchangeably and refer to the alkyne group being substituted by one or more halogens. Examples include, but are not limited to, halogenated ethynyl, halogenated propynyl, halogenated butynyl, and halogenated pentyyn, wherein the halogenation can be monohalogenated, dihalogenated, or trihalogenated.

[0068] The term "hydroxyl group" refers to the -OH group.

[0069] "R1, R2, together with the carbon atoms they are attached to, form 3-8 membered heterocyclic groups, 5-8 membered heteroaryl groups, or C3-C8 cycloalkyl groups" or "R1, R2, together form 3-8 membered heterocyclic groups, 5-8 membered heteroaryl groups, or C3-C8 cycloalkyl groups" refers to R1, R2, together with the carbon atoms they are attached to, forming fused polycyclic groups. Examples include, but are not limited to: The group may optionally be substituted by one or more substituents.

[0070] The term "stereoisomer" refers to compounds that have the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometrical isomers (cis / trans) isomers, and hindered isomers, etc.

[0071] The term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization.

[0072] The term "pharmaceutically acceptable salt" refers to the organic or inorganic salt of the compounds of this invention.

[0073] The term "pharmaceutically acceptable carrier" refers to substances that do not cause significant irritation to the organism and do not impair the biological activity and properties of the active compound. "Pharmaceutically acceptable carriers" include, but are not limited to, glidants, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, disintegrants, stabilizers, solvents, or emulsifiers.

[0074] The following detailed description of the invention is intended to illustrate non-limiting embodiments, enabling other skilled in the art to more fully understand the technical solutions, principles, and practical applications of the invention, so that other skilled in the art can modify and implement the invention in many forms to best suit the requirements of a particular application.

[0075] Formula I compound

[0076] This invention provides compounds of Formula I or pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.

[0077]

[0078] in,

[0079] 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 heterocyclic group, halogen, hydroxyl, 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, hydroxyl, nitro and cyano;

[0080] Alternatively, R1, R2, together with the carbon atom to which they are attached, can form a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group, or a C3-C8 cycloalkyl group, optionally substituted with one or more substituents, wherein the substituents are independently selected from H, D, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, hydroxyl groups, nitro groups, and cyano groups.

[0081] L1 is selected from R, which is arbitrarily substituented by one or more substituents. LA Substituted 6-14 aryl groups and optionally substituents R LA The substituted 5-14 heteroaryl group is preferably selected from those optionally substituented by one or more R groups. LA Substituted 6-10 aryl groups and optionally substituents R LA The substituted 5-10 heteroaryl group, more preferably selected from those optionally substituented by one or more R groups. LA Substituted phenyl groups and optionally substituted with one or more substituents R LA Substituted 5-6 membered monocyclic heteroaryl; said one or more substituents R LA Independently selected from H, D, halogens, optionally substituents R. LB Substituted C1-C8 alkyl groups, optionally substituted with one or more substituents R LB Substituted C1-C8 alkoxy, cyano, optionally with one or more substituents RLB Substituted C2-C8 ynyl group, optionally with one or more substituents R LB Substituted C2-C8 alkenyl, hydroxyl, nitro, optionally with one or more substituents R LB Substituted C1-C8 alkylthio groups, optionally with one or more substituents R LB Substituted C3-C8 cycloalkyl groups and OR4, wherein one or more substituents R LB Selected from H, D, halogens, and hydroxyl groups;

[0082] R4 is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl;

[0083] L2 is selected from 6-14 aryl groups substituted with 0-4 Rb groups and 5-14 heteroaryl groups substituted with 0-4 Rb groups, preferably from 6-10 aryl groups substituted with 0-3 Rb groups and 5-10 monocyclic or bicyclic heteroaryl groups substituted with 0-3 Rb groups, and more preferably from phenyl groups substituted with 0-3 Rb groups and 5-6 heteroaryl groups substituted with 0-3 Rb groups.

[0084] 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.

[0085] X1 is selected from N and CR 10 ;

[0086] R 10 The substituent 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, hydroxyl, 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 substituent is independently selected from H, D, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, D, halogen and hydroxyl;

[0087] X2 is selected from N and CR. 11 ;

[0088] R 11The substituent 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 heterocyclic groups, halogens, hydroxyl groups, nitro groups, and cyano groups; the substituent is independently selected from H, D, halogens, C1-C8 alkoxy, hydroxyl, nitro, and cyano groups;

[0089] And X1 and X2 are not both N; and

[0090] When X2 is CR 11 And when X1 is N, R2 is not H or D.

[0091] In one embodiment, the heteroaryl group is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrroleyl, 1,2,3-triazolyl, thiadiazolyl, thiophenyl, furanyl, 1,3,4-triazolyl, and pyranyl. In a preferred embodiment, the heteroaryl group is selected from imidazolyl, pyrazolyl, thiophenyl, furanyl, 1,2,3-triazolyl, pyranyl, and thiazolyl. In a more preferred embodiment, the heteroaryl group is thiophenyl, 1,2,3-triazolyl, pyranyl, thiazolyl, and furanyl.

[0092] In one embodiment, the heterocyclic group is preferably selected from ethylene oxide, tetrahydrothiaranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, dihydrothiaranyl, tetrahydrothiophenyl, dihydrothiophenyl, azaheterobutyl, oxoheterobutyl, thioheterobutyl, piperidinyl, and pyrrolidinyl. In a preferred embodiment, the heterocyclic group is selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and dihydropyranyl. In a particularly preferred embodiment, the heterocyclic group is selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and dihydropyran.

[0093] In one embodiment, the C1-C8 alkyl group is selected from C1-C5 alkyl and C1-C3 alkyl groups. In a specific embodiment, the C1-C8 alkyl and C1-C5 alkyl groups are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In a more specific embodiment, the C1-C8 alkyl, C1-C5 alkyl, and C1-C3 alkyl groups are each independently selected from methyl, ethyl, propyl, and isopropyl.

[0094] 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).

[0095] In one embodiment, the C1-C8 alkoxy group is selected from C1-C5 alkoxy and C1-C3 alkoxy groups. In a specific embodiment, the C1-C8 alkoxy and C1-C5 alkoxy groups are each independently selected from methoxy, ethoxy, propoxy, butoxy, and pentoxy groups. In a more specific embodiment, the C1-C8 alkoxy, C1-C5 alkoxy, and C1-C3 alkoxy groups are each independently selected from methoxy, ethoxy, and propoxy groups.

[0096] In one embodiment, the C3-C8 cycloalkyl group is preferably 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, cyclobutenyl, 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 selected from cyclopentyl and cyclopentenyl.

[0097] 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.

[0098] In one embodiment, the compound of formula I is as shown in formula IA.

[0099]

[0100] Among them, R 1A R 2AR 3A The substituent is 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, hydroxyl, 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 substituent is independently selected from H, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, D, halogen and hydroxyl;

[0101] 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 may be optionally substituted with one or more substituents, wherein the substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano.

[0102] L 1A The substituents are selected from 6-14-membered aryl groups optionally substituted with one or more substituents and 5-14-membered heteroaryl groups optionally substituted with one or more substituents, preferably from 6-10-membered aryl groups optionally substituted with one or more substituents and 5-10-membered heteroaryl groups optionally substituted with one or more substituents, and more preferably from phenyl groups optionally substituted with one or more substituents and 5-6-membered monocyclic heteroaryl groups optionally substituted with 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, it is independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxyl, optionally substituted C3-C6 cycloalkyl, and OR. 4A Further preferably independently selected from H, halogens, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, optionally substituted C3-C6 cycloalkyl groups, and OR. 4A The substituent is selected from H, D, halogens and hydroxyl groups, and the substituent is preferably selected from D, halogens and hydroxyl groups;

[0103] R 4A Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl;

[0104] L 2AIt is selected from 6-14 aryl groups substituted with 0-4 Rbbb groups and 5-14 heteroaryl groups substituted with 0-4 Rbbb groups, preferably from 5-10 aryl groups substituted with 0-3 Rbbb groups and 5-10 monocyclic or bicyclic heteroaryl groups substituted with 0-3 Rbbb groups, and more preferably from phenyl groups substituted with 0-3 Rbbb groups and 5-6 heteroaryl groups substituted with 0-3 Rbbb groups;

[0105] Each Rbbb 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.

[0106] In one embodiment, the compound of formula I is as shown in formula IA.

[0107]

[0108] Among them, R 1A R 2A R 3A The substituent is 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, hydroxyl, 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 substituent is independently selected from H, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, halogen and hydroxyl;

[0109] 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 may be optionally substituted with one or more substituents, wherein the substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano.

[0110] L 1AThe substituents are selected from 6-14-membered aryl groups optionally substituted with one or more substituents and 5-14-membered heteroaryl groups optionally substituted with one or more substituents, preferably from 6-10-membered aryl groups optionally substituted with one or more substituents and 5-10-membered heteroaryl groups optionally substituted with one or more substituents, and more preferably from phenyl groups optionally substituted with one or more substituents and 5-6-membered monocyclic heteroaryl groups optionally substituted with 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, it is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR. 4A Further preferably, the components are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C3-C6 cycloalkyl groups, and OR. 4A ;

[0111] R 4A Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl;

[0112] L 2A It is selected from 6-14 aryl groups substituted with 0-4 Rbbb groups and 5-14 heteroaryl groups substituted with 0-4 Rbbb groups, preferably from 5-10 aryl groups substituted with 0-3 Rbbb groups and 5-10 monocyclic or bicyclic heteroaryl groups substituted with 0-3 Rbbb groups, and more preferably from phenyl groups substituted with 0-3 Rbbb groups and 5-6 heteroaryl groups substituted with 0-3 Rbbb groups;

[0113] Each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen; the substituents are independently selected from H, halogen, and hydroxyl.

[0114] In one implementation, R 1A R 2A R 3AThe substituent is 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, hydroxyl, 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 substituent is independently selected from H, halogen, C1-C8 alkoxy, hydroxyl, nitro, and cyano, preferably selected from H, halogen, and hydroxyl. In one embodiment, the C3-C8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, more preferably cyclopropyl;

[0115] In one implementation, 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, optionally substituted with one or more substituents, wherein the substituents are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, hydroxyl groups, nitro groups, and cyano groups. In one embodiment, the 3-8 membered heterocyclic group is selected from ethylene oxide, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiaranyl, dihydrothiaranyl, tetrahydrothiophenyl, dihydrothiophenyl, azahexacyclobutyl, oxacyclobutyl, thiohexacyclobutyl, piperidinyl, and pyrrolidinyl. In a preferred embodiment, the 3-8 membered heterocyclic group is selected from tetrahydropyranyl and dihydropyranyl. In one embodiment, the 5-8 membered heteroaryl group is selected from furanyl, pyranyl, and thiophenyl. 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.

[0116] In one specific implementation plan, R 1A R 2A Together with the carbon atom it is attached to, they form the following substituents: In a more specific implementation scheme, R 1A R 2A Together with the carbon atom it is attached to, they form the following substituents: In a particularly specific implementation scheme, R 1A R 2A Together with the carbon atom it is attached to, they form the following substituents: Wherein, the above groups may optionally be substituted by one or more substituents, wherein the substituents are independently selected from H, halogens, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, halogens, C1-C8 alkyl and C1-C8 alkoxy, and more preferably selected from H and halogens.

[0117] In one implementation, L 1A The substituents are selected from 6-14-membered aryl groups optionally substituted with one or more substituents and 5-14-membered heteroaryl groups optionally substituted with one or more substituents, preferably from 6-10-membered aryl groups optionally substituted with one or more substituents and 5-10-membered heteroaryl groups optionally substituted with one or more substituents, and more preferably from phenyl groups optionally substituted with one or more substituents and 5-6-membered monocyclic heteroaryl groups optionally substituted with 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, it is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR. 4A Further preferably, the components are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C3-C6 cycloalkyl groups, and OR. 4A ;R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0118] In a preferred embodiment, L 1A The group is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazole, pyrazolyl, pyrroleyl, triazolyl, thiadiazolyl, thiophenyl, and furanyl. In a more preferred embodiment, L 1A Selected from phenyl, pyridyl, pyrazolyl, thiazolyl, and thiophenyl. In a particularly preferred embodiment, L 1A Selected from phenyl, pyridyl, and thiazolyl. The above groups may optionally be substituted with one or more substituents, said 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. 4APreferably, it is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR. 4A Further preferably, the components are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C3-C6 cycloalkyl groups, and OR. 4A ;

[0119] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0120] In one embodiment, the compound of formula I is as shown in formula IA.

[0121]

[0122] 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;

[0123] L 1A The aryl group is selected from 6-14-membered aryl groups optionally substituted with one or more substituents and 5-14-membered heteroaryl groups optionally substituted with one or more substituents, preferably from 6-10-membered aryl groups optionally substituted with one or more substituents and 5-10-membered heteroaryl groups optionally substituted with one or more substituents, and more preferably from phenyl groups optionally substituted with one or more substituents and 5-6-membered monocyclic heteroaryl groups optionally substituted with 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, and preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl;

[0124] L 2A It is selected from 6-14 aryl groups substituted with 0-4 Rbbb groups and 5-14 heteroaryl groups substituted with 0-4 Rbbb groups, preferably from 5-10 aryl groups substituted with 0-3 Rbbb groups and 5-10 monocyclic or bicyclic heteroaryl groups substituted with 0-3 Rbbb groups, and more preferably from phenyl groups substituted with 0-3 Rbbb groups and 5-6 heteroaryl groups substituted with 0-3 Rbbb groups;

[0125] 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.

[0126] In one implementation, R 1A R 2A R 3A The components are 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.

[0127] In a preferred embodiment, L 2A -L 1A Structure selected from In a more preferred embodiment, L 2A -L 1A Structure selected from In a particularly preferred embodiment, L 2A -L 1A Structure selected from

[0128] In one implementation, the above L 2A -L 1A L in the structure 1A The group is optionally substituted by one or more substituents, said 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, it is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR. 4A Further preferably, the components are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C3-C6 cycloalkyl groups, and OR. 4A ;R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0129] In one implementation, the above L2A -L 1A L in the structure 1A The group is optionally substituted by one or more substituents, which 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.

[0130] In one implementation, L 2A The aryl group is selected from 6-14 aryl groups substituted with 0-4 Rbbb groups and 5-14 heteroaryl groups substituted with 0-4 Rbbb groups, preferably from 5-10 aryl groups substituted with 0-3 Rbbb groups and 5-10 monocyclic or bicyclic heteroaryl groups substituted with 0-3 Rbbb groups, and more preferably from phenyl groups substituted with 0-3 Rbbb groups and 5-6 heteroaryl groups substituted with 0-3 Rbbb groups.

[0131] In one implementation, L 2A The group is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, oxazolyl, imidazolyl, pyrazolyl, pyrroleyl, 1,2,3-triazolyl, thiophenyl, furanyl, and 1,3,4-triazolyl, preferably selected from phenyl, pyrimidinyl, pyridinyl, pyrazolyl, thiophenyl, imidazolyl, and 1,2,3-triazolyl, and more preferably phenyl, pyridinyl, pyrazolyl, thiophenyl, and 1,2,3-triazolyl; wherein the above groups are optionally substituted by 0-4 Rbbb groups.

[0132] In one embodiment, each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen; the substituents are independently selected from H, halogen, and hydroxyl.

[0133] 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.

[0134] In one specific implementation, the compound of formula IA is shown as that of formula II-A:

[0135]

[0136] Among them, R 5A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, and halogens; the substituents are independently selected from H, halogens, and hydroxyl groups.

[0137] In one specific implementation, the compound of formula IA is as shown in formula III-A:

[0138]

[0139] Among them, R 5A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, and halogens; the substituents are independently selected from H, halogens, and hydroxyl groups.

[0140] n1A is selected from integers between 0 and 4, preferably 1;

[0141] R 6A 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, it is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, and OR. 4A Further preferably, the components are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C3-C8 cycloalkyl groups, and OR. 4A ;

[0142] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0143] In some implementations, n1A is 1, and R 6A It is located at the 2-position, or the 3-position, or the 4-position, or the 5-position, or 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 It is located at the 6 position of the phenyl group.

[0144] In a more preferred embodiment, R 6A Independently selected from H, D, halogens, and C1-C8 alkoxy groups. In some embodiments, R... 6A It is a C1-C4 alkoxy group, preferably a methoxy group. In some embodiments, R 6A It is a halogen, preferably F.

[0145] In one specific implementation, the compound of formula IA is shown as that of formula IV-A:

[0146]

[0147] Among them, R 5A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, and halogens; the substituents are independently selected from H, halogens, and hydroxyl groups.

[0148] n2A is selected from integers between 0 and 3, preferably 1;

[0149] R 7A 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, it is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, and OR. 4A Further preferably, the components are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C3-C8 cycloalkyl groups, and OR. 4A ;

[0150] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0151] In some implementations, n2A is 1, and R 7A It is located at the 2-position, the 5-position, or the 6-position of the pyridinyl group. In some embodiments, n2A is 1, and R 7A Located at the 5-position of the pyridinyl group. In some embodiments, n2A is 1, and R... 7A It is located at position 6 of pyridine.

[0152] In a more preferred embodiment, R 7A Independently selected from H, D, halogens, and C1-C8 alkoxy groups. In some embodiments, R... 7A It is a C1-C4 alkoxy group, preferably a methoxy group. In some embodiments, R 7A It is a halogen, preferably F.

[0153] In one specific implementation, the compound of formula IA is shown as that of formula VA:

[0154]

[0155] Among them, R 5A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, and halogens; the substituents are independently selected from H, halogens, and hydroxyl groups.

[0156] n3A is selected from integers between 0 and 3, preferably 1;

[0157] R 8A 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, it is independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, and OR. 4A Further preferably, the components are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C3-C8 cycloalkyl groups, and OR. 4A ;

[0158] R 4A It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0159] In some implementations, n3A is 1, and R 8A It is located at the 2 position of the pyridinyl group, or at the 5 position of the pyridinyl group, or at the 6 position of the pyridinyl group. In some embodiments, n3A is 1, and R 7A Located at the 5-position of the pyridinyl group. In some embodiments, n3A is 1, and R 8A It is located at position 6 of pyridine.

[0160] In a more preferred embodiment, R 8A Independently selected from H, D, halogens, and C1-C8 alkoxy groups. In some embodiments, R... 8A It is a C1-C4 alkoxy group, preferably a methoxy group. In some embodiments, R 8A It is a halogen, preferably F.

[0161] In one embodiment, the compound of formula I is as shown in formula IB.

[0162]

[0163] Among them, R 1B R3B The substituent is 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 heterocyclic groups, halogens, hydroxyl groups, nitro groups, and cyano groups, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, and halogens; the substituent is independently selected from halogens, D, C1-C8 alkoxy, hydroxyl, nitro, and cyano groups;

[0164] R 2B The compound 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, hydroxyl, 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;

[0165] or R 1B R 2B Together they form a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group, or a C3-C8 cycloalkyl group, optionally substituted with one or more substituents, wherein the substituents are independently selected from halogens, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano.

[0166] L 1B The substituent is selected from optionally substituted phenyl groups and optionally substituted pyridyl groups, wherein the substituent is 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 groups, 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 groups;

[0167] R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl;

[0168] L 2BIt is a 5-14 membered heteroaryl group substituted with 0-4 Rbb groups, preferably a 5-10 membered monocyclic or bicyclic heteroaryl group substituted with 0-3 Rbb groups, and more preferably a 5-6 membered heteroaryl group substituted with 0-3 Rbb groups.

[0169] Each Rbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, preferably from H and C1-C8 alkyl; the substituents are independently selected from D and halogen.

[0170] In one implementation, R 1B R 3B The substituent is 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 heterocyclic group, halogen, hydroxyl, 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 substituent is independently selected from halogen, D, C1-C8 alkoxy, hydroxyl, nitro and cyano; the 3-8 membered heterocyclic group is preferably selected from ethylene oxide, aziridine, oxetidine, thiohexacyclobutyl, tetrahydrofuranyl, tetrahydrothiaranyl, piperidinyl and pyrrolidinyl; the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, more preferably cyclopropyl;

[0171] R 2B The compound 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 alkyne, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkyne, hydroxyl, 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.

[0172] In one implementation, R 1B R 2BTogether they form a 3-8 membered heterocyclic group, a 5-8 membered heteroaryl group, or a C3-C8 cycloalkyl group optionally substituted with one or more substituents; the 3-8 membered heterocyclic group is preferably selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, azirrobutyl, oxocyclobutyl, thiocyclobutyl, piperidinyl, and pyrrolidinyl, and more preferably selected from tetrahydrofuranyl, tetrahydropyranyl, and dihydropyranyl; the 5-8 membered heteroaryl group is preferably selected from furanyl, pyranyl, and thiophenyl; the C3-C8 cycloalkyl group is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl, and 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.

[0173] In one specific implementation plan, R 1B R 2B Together with the pyrimidine group attached thereto, they form the following substituents: In a more specific implementation scheme, R 1B R 2B Together with the pyrimidine group attached thereto, they form the following substituents: The aforementioned groups may optionally be substituted by one or more substituents, wherein the substituents are independently selected from halogens, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano.

[0174] In a preferred embodiment, R 2B The group is 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, hydroxyl and nitro, 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.

[0175] In one implementation, L 1B The substituent is selected from optionally substituted phenyl groups and optionally substituted pyridyl groups, wherein the substituent is 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 4BAnd C1-C8 alkylthio groups, 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 groups; R 4B It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0176] In a preferred embodiment, L 1B Selected from Preferred selection Further preferred are those selected from Optionally, the aforementioned groups are substituted by one or more substituents, wherein 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 groups, 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 groups; R 4B It is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl.

[0177] In one implementation, L 2B The group is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrroleyl, 1,2,3-triazolyl, thiadiazolyl, thiophenyl, furanyl, and 1,3,4-triazolyl, preferably selected from pyrazolyl, imidazolyl, and 1,2,3-triazolyl, and more preferably selected from 1,2,3-triazolyl; wherein the above groups are optionally substituted by 0-4 Rbb groups.

[0178] 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 from H and C1-C8 alkyl; the substituents are independently selected from D and halogen.

[0179] In one embodiment, the heteroaryl group is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrroleyl, 1,2,3-triazolyl, thiadiazolyl, thiophenyl, furanyl, 1,3,4-triazolyl, and pyranyl. In a preferred embodiment, the heteroaryl group is selected from imidazolyl, pyrazolyl, thiophenyl, furanyl, 1,2,3-triazolyl, and pyranyl. In a more preferred embodiment, the heteroaryl group is thiophenyl, furanyl, 1,2,3-triazolyl, and pyranyl.

[0180] In one embodiment, the heterocyclic group is preferably selected from ethylene oxide, tetrahydrothiaranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, azahexacyclic butyl, oxohexacyclic butyl, thiohexacyclic butyl, piperidinyl, and pyrrolidinyl. In a preferred embodiment, the heterocyclic group is selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and dihydropyranyl. In a particularly preferred embodiment, the heterocyclic group is selected from tetrahydrofuranyl, dihydrofuranyl, and tetrahydropyranyl.

[0181] 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.

[0182] In one specific implementation, the compound of formula IB is shown as that of formula II-B:

[0183]

[0184] Among them, R 5B The substituents are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogens, wherein the substituents are independently selected from D and halogens;

[0185] R 2BThe compound 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 alkyne, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkyne, hydroxyl, 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.

[0186] In one specific implementation, the compound of formula IB is shown as that of formula III-B:

[0187]

[0188] Where n1B is selected from integers between 0 and 3;

[0189] 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, hydroxyl, nitro, cyano, -OR 4B And C1-C8 alkylthio groups, 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 groups;

[0190] R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl;

[0191] R 2B The group 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, hydroxyl, 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.

[0192] In some implementations, n1B is 1, and R 6BIt is located at the 2 position of the pyridinyl group, or at the 5 position of the pyridinyl group, or at the 6 position of the pyridinyl group. In some embodiments, n1B is 1, and R 6B Located at the 5-position of the pyridinyl group. In some embodiments, n1B is 1, and R 6B It is located at position 6 of pyridine.

[0193] In a more preferred embodiment, R 6B Independently selected from H, D, halogens, and C1-C8 alkoxy groups. In some embodiments, R... 6B It is a C1-C4 alkoxy group, preferably a methoxy group. In some embodiments, R 6B It is a halogen, preferably F.

[0194] In one specific implementation, the compound of formula IB is shown as that of formula IV-B:

[0195]

[0196] Among them, R 5B The substituents are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogens, wherein the substituents are independently selected from D and halogens;

[0197] n2B is selected from integers from 0 to 4, preferably 1;

[0198] 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, hydroxyl, nitro, cyano, -OR 4B And C1-C8 alkylthio groups, 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 groups;

[0199] R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl;

[0200] R 2BThe compound 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 alkyne, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkyne, hydroxyl, 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.

[0201] In some implementations, n2B is 1, and R 7B It is located at the 2-position, or the 3-position, or the 4-position, or the 5-position, or the 6-position of the phenyl group. In some embodiments, n2B is 1, and R 7B It is located at the 4-position of the phenyl group. In some embodiments, n2B is 1, and R... 7B It is located at the 6 position of the phenyl group.

[0202] In a more preferred embodiment, R 7B Independently selected from H, D, halogens, and C1-C8 alkoxy groups. In some embodiments, R... 7B It is a C1-C4 alkoxy group, preferably a methoxy group. In some embodiments, R 7B It is a halogen, preferably F.

[0203] In one specific implementation, the compound of formula IB is shown as that of formula VB:

[0204]

[0205] Among them, R 5B The substituents are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogens, wherein the substituents are independently selected from D and halogens;

[0206] n3B is selected from integers between 0 and 3, preferably 1.

[0207] 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, hydroxyl, nitro, cyano, -OR 4B And C1-C8 alkylthio groups, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR Band C1-C8 alkylthio groups; R 4B Selected from C3-C8 cycloalkyl and 3-8 membered heterocyclic groups, preferably C3-C6 cycloalkyl;

[0208] R 2B The group 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 alkyne, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkyne, hydroxyl and nitro, 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.

[0209] In some implementations, n3B is 1, and R 8B It is located at the 2-position, the 5-position, or the 6-position of the pyridinyl group. In some embodiments, n3B is 1, and R 8B Located at the 5-position of the pyridinyl group. In some embodiments, n3B is 1, and R 8B It is located at position 6 of pyridine.

[0210] In a more preferred embodiment, R 8B Independently selected from H, D, halogens, and C1-C8 alkoxy groups. In some embodiments, R... 8B It is a C1-C4 alkoxy group, preferably a methoxy group. In some embodiments, R 8B It is a halogen, preferably F.

[0211] In one specific implementation, the compound of formula I is selected from any one of the following compounds:

[0212]

[0213]

[0214]

[0215]

[0216] Beneficial technical effects of the present invention

[0217] Compared with the prior art, the technical solution of the present invention has the following advantages:

[0218] This invention relates to a novel class of structural compounds, which are selective OX2R antagonists that can be used to prevent, treat, and / or alleviate orexin receptor-related diseases, preferably for the treatment of insomnia, depression, Alzheimer's disease, and sleep apnea. These compounds exhibit good selectivity and pharmacodynamic activity as OX2 receptor antagonists, while also exhibiting favorable pharmacokinetic properties, improving oral bioavailability in subjects, and significantly reducing spontaneous activity in subjects, thus showing promising clinical application prospects.

[0219] Instruction manual illustrations

[0220] Figure 1 Arousal time in rats at each time point 12 h after administration of 30 mg / kg of Seltorexant;

[0221] Figure 2 Arousal time in rats at each time interval 12 h after administration of compound 1 at 30 mg / kg;

[0222] Figure 3 Arousal time in rats at each time point 12 h after administration of compound 5 at 30 mg / kg;

[0223] Figure 4 Arousal time in rats at each time point 12 h after administration of compound 22 at 30 mg / kg;

[0224] Figure 5 A graph showing the awake time of rats at each time point 12 hours after administration of compound 41 at a dose of 30 mg / kg.

[0225] Example

[0226] The embodiments of the present invention are described in detail below. The embodiments described below are exemplary and are only used to explain the present invention, and should not be construed as limiting the present invention. Unless otherwise specified, all proportions, percentages, etc., referred to herein are by weight.

[0227] The following examples are prepared using cis-structured starting materials, specifically cis-5-oxohexahydrocyclopentadiene[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester, to obtain the example compounds, all of which are cis isomers.

[0228] Synthesis Examples

[0229]

[0230] The cis-5-oxohexahydrocyclopentadienyl[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester undergoes a trifluoromethanesulfonation reaction with N-phenylbis(trifluoromethanesulfonyl)imide to obtain intermediate Ia. Ia then undergoes a borate esterification reaction with pinacol diboronate to obtain intermediate Ib. Ib then reacts with... A coupling reaction is performed to obtain intermediate Ic, and Ic is deprotected from Boc to obtain intermediate Id; The intermediate Ie is obtained by coupling with L2-Z, and Ie undergoes ester hydrolysis to obtain intermediate If. Finally, Id and If undergo a condensation reaction to obtain the compound shown in Formula I.

[0231] Example 1: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) ketone (1)

[0232]

[0233] 1.1 A solution of cis-5-oxo-hexahydrocyclopentane[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 h, followed by dropwise addition of N-phenylbis(trifluoromethanesulfonyl)imide (9.51 g, 26.63 mmol) at -78 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. 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 layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 5-[[(trifluoromethyl)sulfonyl]oxy]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 1a) (4.8 g).

[0234] 1.2 Ia (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) were added to a solution of dioxane (20 mL), and the mixture was heated to 80 °C and stirred overnight under a nitrogen atmosphere. The mixture was then cooled 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 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 1b). The crude product was used directly in the next step without further purification.

[0235] 1.3 2,4,6-Trichloro-5-fluoropyrimidine (5 g, 24.87 mmol) and iron triacetylacetone (0.9 g, 2.55 mmol) were dissolved in 20 mL of THF solution. The solution was cooled to -78 °C under nitrogen protection, and MeMgCl (3.0 M solution in THF, 19 mL) was added dropwise. After the addition was complete, the reaction was carried out at -78 °C for 1 hour, and then at room temperature for 3 hours until the reaction was complete. The reaction solution was quenched in NH4Cl solution and 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 and eluted with PE / EA (20:1) to give 3.4 g of 2-chloro-5-fluoro-4,6-dimethylpyrimidine (1c).

[0236] 1.4 Dissolve 1b (3.5g, 10.44mmol), 1c (1.8g, 11.48mmol), K2CO3 (2.9g, 21.01mmol), and Pd(dppf)Cl2 (0.76g, 1.05mmol) in a mixed solution of dioxane (20mL) and H2O (5mL), and react under nitrogen protection at 100℃. After the reaction was complete, the mixture was cooled to room temperature, diluted with 30 mL of water, extracted with ethyl acetate (3 x 50 mL), washed with saturated brine (2 x 20 mL), dried with anhydrous Na2SO4, filtered, concentrated the filtrate under reduced pressure, and purified by column chromatography (PE / EA = 1:1) to give 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 1d) (2.8 g).

[0237] 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-hexahydrocyclopentane[c]pyrrole (compound 1e). The crude product was used directly in the next step without further purification.

[0238] 1.6 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) were placed in a 250 mL round-bottom flask and stirred overnight at 85 °C under nitrogen protection. After the reaction was complete, the reaction solution was cooled to room temperature, and 50 mL of tert-butyl methyl ether and 50 mL of water were added. The mixture was stirred for another half hour, and then separated. The organic phase was discarded, and the pH of the aqueous phase was adjusted to acidic with 2N hydrochloric acid. The aqueous phase was then 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 give 2-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 1f) (4.6 g).

[0239] 1.7 Add 1e (100 mg, 0.43 mmol) and 1f (101 mg, 0.49 mmol) to DMF (5 mL), under nitrogen protection, add HATU (262 mg, 0.69 mmol) and DIPEA (119 mg, 0.92 mmol) dropwise at room temperature, stir at room temperature for 1 hour. After the reaction is complete, extract with ethyl acetate (3 x 15 mL), wash the organic phase with water (3 x 10 mL), dry with anhydrous Na2SO4, filter, concentrate under reduced pressure, and separate 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) ketone (compound 1). 1 H 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] + .

[0240] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (2)

[0241]

[0242] 2.1 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 4-fluoro-6-iodobenzoic acid, and prepare 4-fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 2a) according to the methods of Examples 1-1.6.

[0243] 2.2 Replace reaction material 1f with 2a and prepare (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 2) according to the methods of Examples 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] + .

[0244] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (3)

[0245]

[0246] 3.1 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 3-fluoro-2-iodobenzoic acid, and prepare 3-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 3a) according to the methods of Examples 1-1.6.

[0247] 3.2 Replace reaction material 1f with 3a and prepare (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 3) according to the methods of Examples 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] + .

[0248] Example 4: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone (4)

[0249]

[0250] 4.1 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 2-iodo-5-methoxybenzoic acid, and prepare 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 4a) according to the methods of Examples 1-1.6.

[0251] 4.2 Replace reaction material 1f with 4a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 4) according to the methods of Examples 1-1.7. 1 H 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] + .

[0252] Example 5: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone (5)

[0253]

[0254] 5.1 Replace the reaction raw 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 methods of Examples 1-1.6.

[0255] 5.2 Replace reaction material 1f with 5a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 5) according to the methods of Examples 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] + .

[0256] Example 6: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone (6)

[0257]

[0258] 6.1 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 2-iodo-5-methylbenzoic acid, and prepare 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 6a) according to the methods of Examples 1-1.6.

[0259] 6.2 Replace reaction material 1f with 6a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 6) according to the methods of Examples 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] + .

[0260] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (7)

[0261]

[0262] 7.1 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 2-iodobenzoic acid, and prepare 2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 7a) according to the methods of Examples 1-1.6.

[0263] 7.2 Replace reaction 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 7) according to the methods of Examples 1-1.7. 1 H 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] + .

[0264] Example 8: Preparation of (5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) ketone (8)

[0265]

[0266] 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 the reaction was completed, the mixture was concentrated under reduced pressure, purified by column chromatography, and eluted with PE / EA (1:1) to give 2.1 g of 2-chloro-5-fluoro-4-methoxy-6-methylpyrimidine (compound 8a).

[0267] 8.2 Replace reactant 1c with 8a and prepare 5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 8b) according to the methods of Examples 1-1.4.

[0268] 8.3 Replace reaction material 1d with 8b and prepare 5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 8c) according to the methods of Examples 1-1.5.

[0269] 8.4 Replace reactant 1e with 8c and prepare (5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 8) according to the methods of Examples 1-1.7. 1 H 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] + .

[0270] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (9)

[0271]

[0272] 9.1 2-Chloro-4,5,6-trimethylpyrimidine (compound 9a) was prepared by replacing the reactant 2,4,6-trichloro-5-fluoropyrimidine with 2,4,6-trichloro-5-methylpyrimidine, following the methods described in Examples 1-1.3.

[0273] 9.2 Replace reactant 1c with 9a and prepare 5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 9b) according to the methods of Examples 1-1.4.

[0274] 9.3 Replace reaction material 1d with 9b, and prepare 5-(4,5,6-trimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 9c) according to the methods of Examples 1-1.5.

[0275] 9.4 Replace reactant 1e with 9c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 9) according to the methods of Examples 1-1.7. 1 H 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] + .

[0276] Example 10: Preparation of (5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) ketone (10)

[0277]

[0278] 10.1 Replace reaction material 1c with 2,5-dichloro-4,6-dimethylpyrimidine and prepare 5-(5-chloro-4,6-dimethylpyrimidine-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 10a) according to the methods of Examples 1-1.4.

[0279] 10.2 Replace reaction material 1d with 10a and prepare 5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 10b) according to the methods of Examples 1-1.5.

[0280] 10.3 Replace reactant 1e with 9c and prepare (5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 10) according to the methods of Examples 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] + .

[0281] Example 11: Preparation of (5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) ketone (11)

[0282]

[0283] 11.1 Ethyl 2-ethyl-3-oxobutyrate (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 mixture was heated to 70 °C and reacted for 7 hours. After the reaction was completed, the mixture was cooled to room temperature and extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with water (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography. The elution was performed with PE / EA (10:1) to give 2.1 g of 5-ethyl-6-methylpyrimidine-2,4(3H,5H)-dione (compound 11a).

[0284] 11.2 11a (1.8 g, 11.68 mmol) and diethylaniline (2 mL) were added to phosphorus oxychloride (20 mL), and the reaction was carried out at 110 °C for 3 hours under nitrogen protection. After the reaction was completed, the mixture was cooled to room temperature, the pH was adjusted to 7 with saturated Na2CO3 solution, and 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, concentrated, and purified by column chromatography. The elution was performed with PE / EA (3:1) to give 1.2 g of 2,4-dichloro-5-ethyl-6-methylpyrimidine (compound 11b).

[0285] 11.3 Replace the reactant 2,4,6-trichloro-5-fluoropyrimidine with 11b and prepare 2-chloro-5-ethyl-4,6-dimethylpyrimidine (compound 11c) according to the methods of Examples 1-1.3.

[0286] 11.4 Replace reactant 1c with 11c and prepare 5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 11d) according to the methods of Examples 1-1.4.

[0287] 11.5 Replace reaction material 1d with 11d and prepare 5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 11e) according to the method of Examples 1-1.5.

[0288] 11.6 Replace reactant 1e with 11e and prepare (5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 11) according to the methods of Examples 1-1.7. 1H 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] + .

[0289] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (12)

[0290]

[0291] 12.1 Replace the reaction raw 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 methods of Examples 1-1.6.

[0292] 12.2 Replace reaction 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 12) according to the methods of Examples 1-1.7. 1 H 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] + .

[0293] Example 13: Preparation of (4-cyclopropoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (13)

[0294]

[0295] 13.1 2-Bromo-4-hydroxybenzoic acid (5.0 g, 23.04 mmol), bromocyclopropane (8.4 g, 69.43 mmol), and cesium carbonate (15.0 g, 46.01 mmol) were added to 30 mL of DMF. The tube was sealed, and the reaction was carried out at 100 °C for 10 hours. After the reaction was completed, the temperature was lowered to room temperature, 150 mL of water was added, and the mixture was extracted with EtOAc (3 × 50 mL). The organic phases were combined, washed with water (2 × 30 mL), dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography. The elution was performed with PE / EA (1:1) to give 1.1 g of 2-bromo-4-cyclopropoxybenzoic acid (compound 13a).

[0296] 13.2 Replace the reactant 2-fluoro-6-iodobenzoic acid with 13a and prepare 4-cyclopropoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 13b) according to the methods of Examples 1-1.6.

[0297] 13.3 Replace reactant 1f with 13b and prepare (4-cyclopropoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 13) according to the methods of Examples 1-1.7. 1 H 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] + .

[0298] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (14)

[0299]

[0300] 14.1 The reactant 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5,6,7,8-tetrahydroquinazoline, and 2-chloro-4-methyl-5,6,7,8-tetrahydroquinazoline (compound 14a) was prepared according to the methods of Examples 1-1.3.

[0301] 14.2 Replace reactant 1c with 14a and prepare 5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 14b) according to the method of Examples 1-1.4.

[0302] 14.3 Replace reaction material 1d with 14b and prepare 5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 14c) according to the methods of Examples 1-1.5.

[0303] 14.4 Replace reactant 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 14) according to the methods of Examples 1-1.7. 1 H 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] + .

[0304] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (15)

[0305]

[0306] 15.1 The reactant 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine, and 2-chloro-4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine (compound 15a) was prepared according to the methods of Examples 1-1.3.

[0307] 15.2 Replace reactant 1c with 15a and prepare 5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 15b) according to the method of Examples 1-1.4.

[0308] 15.3 Replace reactant 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-hexahydrocyclopentane[c]pyrrole (compound 15c) according to the methods of Examples 1-1.5.

[0309] 15.4 Replace reactant 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 15) according to the methods of Examples 1-1.7. 1 H 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] + .

[0310] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (16)

[0311]

[0312] 16.1 The reactant 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine, and 2-chloro-4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (compound 16a) was prepared according to the methods of Examples 1-1.3.

[0313] 16.2 Replace reactant 1c with 16a and prepare 5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 16b) according to the method of Examples 1-1.4.

[0314] 16.3 Replace reactant 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-hexahydrocyclopentane[c]pyrrole (compound 16c) according to the method of Examples 1-1.5.

[0315] 16.4 Replace reactant 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 16) according to the methods of Examples 1-1.7. 1 H 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] + .

[0316] Example 17: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydro-5H-cyclopentan[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl) methyl ketone (17)

[0317]

[0318] 17.1 The reactant 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-6,7-dihydro-5H-cyclopentane[d]pyrimidine to prepare 2-chloro-4-methyl-6,7-dihydro-5H-cyclopentane[d]pyrimidine (compound 17a) according to the methods of Examples 1-1.3.

[0319] 17.2 Replace reactant 1c with 17a and prepare 5-(4-methyl-6,7-dihydro-5H-cyclopentane[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 17b) according to the method of Examples 1-1.4.

[0320] 17.3 Replace reaction material 1d with 17b and prepare 5-(4-methyl-6,7-dihydro-5H-cyclopentane[d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 17c) according to the methods of Examples 1-1.5.

[0321] 17.4 Replace reactant 1e with 17c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydro-5H-cyclopentan[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl) methyl ketone (compound 17) according to the methods of Examples 1-1.7. 1 H 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] + .

[0322] Example 18: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylfuran[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (18)

[0323]

[0324] 18.1 The reactant 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichlorofurano[3,2-d]pyrimidine, and 2-chloro-4-methylfurano[3,2-d]pyrimidine (compound 18a) was prepared according to the methods of Examples 1-1.3.

[0325] 18.2 Replace reactant 1c with 18a and prepare 5-(4-methylfurano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 18b) according to the methods of Examples 1-1.4.

[0326] 18.3 Replace reaction material 1d with 18b and prepare 5-(4-methylfurano[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 18c) according to the methods of Examples 1-1.5.

[0327] 18.4 Replace reactant 1e with 18c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylfuran[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 18) according to the methods of Examples 1-1.7. 1 H 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] + .

[0328] Example 19: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydrofuran[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (19)

[0329]

[0330] 19.1 18a (2 g, 11.86 mmol), Pd / c (20%, 400 mg), and 10 mL MeOH were added to a pressure-resistant reactor. The reaction solution was hydrogenated at 50 °C and 5 psi hydrogen pressure for 6 hours. After the reaction was complete, the solution was filtered through diatomaceous earth and concentrated under reduced pressure. The solution was purified by column chromatography, eluted with PE / EA (10:1), to give 430 mg of 2-chloro-4-methyl-6,7-dihydrofuran[3,2-d]pyrimidine (compound 19a).

[0331] 19.2 Replace reactant 1c with 19a and prepare 5-(4-methyl-6,7-dihydrofuran[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 19b) according to the method of Examples 1-1.4.

[0332] 19.3 Replace reactant 1d with 19b and prepare 5-(4-methyl-6,7-dihydrofuran[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 19c) according to the methods of Examples 1-1.5.

[0333] 19.4 Replace reactant 1e with 19c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydrofuran[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 19) according to the methods of Examples 1-1.7. 1 H 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] + .

[0334] Example 20: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (20)

[0335]

[0336] 20.1 The reactant 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichloro-5,7-dihydrofuran[3,4-d]pyrimidine, and 2-chloro-4-methyl-5,7-dihydrofuran[3,4-d]pyrimidine (compound 20a) was prepared according to the methods of Examples 1-1.3.

[0337] 20.2 Replace reactant 1c with 20a and prepare 5-(4-methyl-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 20b) according to the method of Examples 1-1.4.

[0338] 20.3 Replace reaction material 1d with 20b and prepare 5-(4-methyl-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 20c) according to the method of Examples 1-1.5.

[0339] 20.4 Replace reactant 1e with 20c and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 20) according to the methods of Examples 1-1.7. 1 H 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] + .

[0340] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (21)

[0341]

[0342] 21.1 The reactant 2,4,6-trichloro-5-fluoropyrimidine was replaced with 2,4-dichlorothieno[3,2-d]pyrimidine, and 2-chloro-4-methylthieno[3,2-d]pyrimidine (compound 21a) was prepared according to the methods of Examples 1-1.3.

[0343] 21.2 Replace reactant 1c with 21a and prepare 5-(4-methylthiopheno[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 21b) according to the method of Examples 1-1.4.

[0344] 21.3 Replace reaction material 1d with 21b and prepare 5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 21c) according to the methods of Examples 1-1.5.

[0345] 21.4 Replace reactant 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 21) according to the methods of Examples 1-1.7. 1 H 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] + .

[0346] Example 22: 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methyl ketone (22)

[0347]

[0348] 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-resistant reactor, CO was introduced to a pressure of 10 atm, and the temperature was raised to 50 °C and reacted overnight. After the reaction was completed, the temperature was lowered to room temperature, and the mixture was extracted with EtOAc (3 x 20 mL). The organic phases were combined, washed with saturated brine (2 x 10 mL), dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography and eluted with PE / EA (5:1) to give 183 mg of methyl 4-chloro-6-methoxypyridine-3-carboxylic acid (compound 22a).

[0349] 22.2 Replace the reactant 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 Examples 1-1.6.

[0350] 22.3 Replace reactant 1f with 22b and prepare 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) methyl ketone (compound 22) according to the method of Examples 1-1.7. 1 H 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] + .

[0351] Example 23: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl) methyl ketone (23)

[0352]

[0353] 23.1 Replace the reactant 2-fluoro-6-iodobenzoic acid with 5-bromo-2-methoxyisonicotinic acid and prepare 2-methoxy-5-(2H-1,2,3-triazol-2-yl)isonicotinic acid (compound 23a) according to the methods of Examples 1-1.6.

[0354] 23.2 Replace reaction material 1f with 23a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl) methyl ketone (compound 23) according to the method of Examples 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] + .

[0355] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (24)

[0356]

[0357] 24.1 Replace the reactant 2-fluoro-6-iodobenzoic acid with 3-bromopyridinecarboxylic acid and prepare 3-(2H-1,2,3-triazol-2-yl)pyridinecarboxylic acid (compound 24a) according to the methods of Examples 1-1.6.

[0358] 24.2 Replace reaction 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 24) according to the method of Examples 1-1.7. 1H 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] + .

[0359] Example 25: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methyl ketone (25)

[0360]

[0361] 25.1 Replace the reactant 2-fluoro-6-iodobenzoic acid with 3-bromo-6-methoxypyridinecarboxylic acid, and prepare 6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridinecarboxylic acid (compound 25a) according to the methods of Examples 1-1.6.

[0362] 25.2 Replace reaction material 1f with 25a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl) methyl ketone (compound 25) according to the method of Examples 1-1.7. 1 H 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] + .

[0363] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (26)

[0364]

[0365] 26.1 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 3-bromo-5-fluoropyridinecarboxylic acid, and prepare 5-fluoro-3-(2H-1,2,3-triazol-2-yl)pyridinecarboxylic acid (compound 26a) according to the methods of Examples 1-1.6.

[0366] 26.2 Replace reactant 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 26) according to the method of Examples 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] + .

[0367] Example 27: (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)methyl ketone (27)

[0368]

[0369] 27.1 Replace reactant 1f with 7a and 1e with 8c, and prepare (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 27) according to the methods of Examples 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] + .

[0370] Example 28: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl) ketone (28)

[0371]

[0372] 28.1 Replace the reactant 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 methods of Examples 1-1.6.

[0373] 28.2 Replace reaction material 1f with 28a and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 28) according to the method of Examples 1-1.7. 1 H 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] + .

[0374] Example 29: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(1H-pyrazol-3-yl)phenyl) ketone (29)

[0375]

[0376] 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 mixed solution 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 in portions. The reaction was carried out under nitrogen protection at 50 °C for 4 hours. The mixture was concentrated under reduced pressure, purified by column chromatography, and eluted with PE / EA (10:1) to give 210 mg of tert-butyl 2-fluoro-6-(2H-pyrazol-3-yl)benzoate (compound 29a).

[0377] 29.2 29a (87 mg, 0.332 mmol) was added to 5 mL of HCl in 1,4-dioxane solution and reacted at room temperature for 4 hours. The mixture was concentrated under reduced pressure, purified by column chromatography, and eluted with PE / EA (3:1) to give 62 mg of 2-fluoro-6-(1H-pyrazol-3-yl)benzoic acid (compound 29b).

[0378] 29.3 Replace reaction material 1f with 29b and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(1H-pyrazol-3-yl)phenyl) methyl ketone (compound 29) according to the method of Examples 1-1.7. 1 H 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] + .

[0379] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (30)

[0380]

[0381] 30.1 Replace the reaction raw material methyl magnesium 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 Examples 1-1.3.

[0382] 30.2 Replace reactant 1c with 30a and prepare 5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)carboxylic acid tert-butyl ester (compound 30b) according to the method of Examples 1-1.4.

[0383] 30.3 Replace reaction material 1d with 30b and prepare 5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 30c) according to the method of Examples 1-1.5.

[0384] 30.4 Replace reaction 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 30) according to the methods of Examples 1-1.7. 1 H 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] + .

[0385] Example 31: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-(methoxy-d3)-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl) methyl ketone (31)

[0386]

[0387] 31.1 Sodium (1.3 g, 56.52 mmol) was added to deuterated methanol-d4 (30 mL) and stirred at room temperature for 10 minutes. Ethyl 3-bromo-6-chloropyridinecarboxylate (1.5 g, 5.67 mmol) was added, and the mixture was heated to 60 °C and reacted 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, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.8 g of 3-bromo-6-(methoxy-d3)pyridinecarboxylic acid (compound 31a).

[0388] 31.2 Replace the reactant 2-fluoro-6-iodobenzoic acid with 31a and prepare 6-(methoxy-d3)-3-(2H-1,2,3-triazol-2-yl)pyridinecarboxylic acid (compound 31b) according to the methods of Examples 1-1.6.

[0389] 31.3 Replace reaction material 1f with 31b and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-(methoxy-d3)-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl) methyl ketone (compound 31) according to the method of Examples 1-1.7. 1 H 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] + .

[0390] Example 32: Preparation of (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl) methyl ketone (32)

[0391]

[0392] 32.1 Replace reactant 1f with 23a and 1e with 30c, and prepare (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl) methyl ketone (compound 31) according to the method of Examples 1-1.7. 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] + .

[0393] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (33)

[0394]

[0395] 33.1 Sodium (1.5 g, 65.21 mmol) was added to deuterated methanol-d4 (50 mL) and stirred at room temperature for 10 minutes. 2,4-Dichloro-5-fluoro-6-methylpyrimidine (1 g, 5.56 mmol) was then added, and the mixture was heated to 60 °C and reacted for 8 hours. After the reaction was complete, 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, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.76 g of 2-chloro-5-fluoro-4-(methoxy-d3)-6-methylpyrimidine (compound 33a).

[0396] 33.2 Replace reactant 1c with 33a and prepare 5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)carboxylic acid tert-butyl ester (compound 33b) according to the method of Examples 1-1.4.

[0397] 33.3 Replace reaction material 1d with 33b, and prepare 5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 33c) according to the method of Examples 1-1.5.

[0398] 33.4 Replace reaction 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 33) according to the method of Examples 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] + .

[0399] Example 34: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methyl ketone (34)

[0400]

[0401] 34.1 Sodium (1.5 g, 65.21 mmol) was added to deuterated methanol-d4 (50 mL) and 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. Under nitrogen protection, the mixture was heated to 60 °C and reacted overnight. After the reaction was complete, 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 purified by column chromatography, eluted with PE:EA = 20:1, to give 0.6 g of 4-chloro-2-(methoxy-d3)pyridine (compound 34a).

[0402] 34.2 Add 34a (0.6 g, 4.08 mmol) and NBS (0.75 g, 4.21 mmol) to DMF (10 mL), heat to 90 °C and react for 8 hours. After the reaction is complete, dilute with water, extract with EtOAc (3 x 20 mL), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate under reduced pressure to give 0.3 g of 5-bromo-4-chloro-2-(methoxy-d3)pyridine (compound 34b).

[0403] 34.3 Replace the reactant 5-bromo-4-chloro-2-methoxypyridine with 34b, and prepare methyl 4-chloro-6-(methoxy-d3)nicotinic acid (compound 34c) according to the method of Examples 22-22.1.

[0404] 34.4 Replace the reactant 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 methods of Examples 1-1.6.

[0405] 34.5 Replace reaction material 1f with 34d and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) methyl ketone (compound 34) according to the method of Examples 1-1.7. 1 H 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] + .

[0406] Example 35: Preparation of (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) methyl ketone (35)

[0407]

[0408] 35.1 Replace reactant 1f with 22b and 1e with 30c to prepare (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl) methyl ketone (compound 35) according to the method of Examples 1-1.7. 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] + .

[0409] Example 36: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl) ketone (36)

[0410]

[0411] 36.1 Replace the reactant bromocyclopropane with deuterated iodomethane to prepare 2-bromo-4-(methoxy-d3)benzoic acid (compound 36a) according to the methods of Examples 13-13.1.

[0412] 36.2 Replace the reactant 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 methods of Examples 1-1.6.

[0413] 26.2 Replace reactant 1f with 36b and prepare (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 36) according to the method of Examples 1-1.7. 1H 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] + .

[0414] Example 37: Preparation of (5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) ketone (37)

[0415]

[0416] 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), followed by tributyl-(1-ethoxy-vinyl)-stanane (14.2 g, 39.3 mmol) and dichlorobis(triphenylphosphine)palladium(II) (500 mg, 0.71 mmol). The mixture was reacted at 100 °C for 10 h, cooled to room temperature, and a saturated solution of potassium fluoride was added. The mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was filtered through diatomaceous earth, extracted with ethyl acetate (3 x 50 mL), washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Column chromatography (PE:EA = 10:1) was used to obtain 2-chloro-4-(1-ethoxyvinyl)-5-fluoro-6-methylpyrimidine (6.8 g) (compound 37a).

[0417] 37.2 Dissolve 37a (6.0 g, 27.8 mmol) in THF (10 mL), then add 3N HCl solution (15 mL), and react at room temperature for 1 hour until the reaction is complete. Adjust the pH to 7-8 with saturated NaHCO3, extract with ethyl acetate (3 x 50 mL), wash the organic phase with water, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate to give 1-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)ethyl-1-one (5.1 g) (compound 37b). The crude product was not purified and directly carried out the next step of the reaction.

[0418] 37.3 Replace the reaction raw material methyl 2-chloro-6-methylpyrimidin-4-carboxylic acid with 37b, and prepare 2-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)prop-2-ol (compound 37c) according to the methods of Examples 30-30.1.

[0419] 37.4 Replace reactant 1c with 37c to prepare 5-[5-fluoro-4-(2-hydroxypropyl)-6-methylpyrimidin-2-yl]-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 37d) according to the method of Examples 1-1.4.

[0420] 37.5 Replace the reaction raw material 1d with 37d to prepare 5-[5-fluoro-4-(2-hydroxypropyl)-6-methylpyrimidin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 37e) according to the method of Examples 1-1.5.

[0421] 37.6 Replace reactant 1e with 37e and prepare (5-(5-fluoro-4-(2-hydroxypropane-2-yl)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl) methyl ketone (compound 37) according to the methods of Examples 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] + .

[0422] Example 38: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (38)

[0423]

[0424] 38.1 Replace reactant 1c with ethyl 2-chloro-4,6-dimethylpyrimidin-5-carboxylate to prepare tert-butyl 5-(5-(ethoxycarbonyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)carboxylate (compound 38a) according to the method of Examples 1-1.4.

[0425] 38.2 Add 38a (0.5 g, 1.29 mmol) to 5 mL of methanol solution, add LiBH4 (0.56 g, 2.57 mmol), react at room temperature for 6 hours. After the reaction is complete, add water to quench the reaction, extract with ethyl acetate (3 x 50 mL), dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify by column chromatography (PE:EA = 5:1) to obtain 0.21 g of 5-(5-(hydroxymethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)carboxylic acid tert-butyl ester (compound 38b).

[0426] 38.3 Add 38b (0.21 g, 0.61 mmol) to dichloromethane (5 mL), add DAST (0.2 g, 1.24 mmol) at room temperature, react at room temperature for 3 hours, quench the reaction with water, extract with dichloromethane (3 x 50 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under pressure, and purify by column chromatography (PE:EA = 10:1) to obtain 0.12 g of 5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)carboxylic acid tert-butyl ester (compound 38c).

[0427] 38.4 Replace reaction material 1d with 38c and prepare 5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 38d) according to the methods of Examples 1-1.5.

[0428] 38.5 Replace reactant 1e with 38d and prepare (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 38) according to the methods of Examples 1-1.7. 1H 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] + .

[0429] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (39)

[0430]

[0431] 39.1 A solution of tert-butyl cis-5-oxo-hexahydrocyclopentane[c]pyrrole-2-carboxylic acid (5 g, 22.19 mmol) in THF (20 mL) was treated with LiHMDS (5.2 g, 110.95 mmol) at -78 °C for 2 h, followed by dropwise 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 layers were washed with brine (3 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give 5-[[(trifluoromethyl)sulfonyl]oxy]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 39a) (4.8 g).

[0432] 39.2 Add 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) to a solution of dioxane (20 mL), heat to 80 °C, and stir overnight under a nitrogen atmosphere. Allow the mixture to cool to room temperature. Dilute the resulting mixture with water (20 mL). Extract the resulting mixture with EtOAc (3 x 50 mL). Wash the combined organic layers with brine (2 x 20 mL) and dry with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 3.6 g of crude 5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H,3H,3aH,6H,6aHcyclopentane[c]pyrrole-2-carboxylic acid tert-butyl ester (compound 39b). The crude product was used directly in the next step without further purification.

[0433] 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 for 4 hours under nitrogen protection. 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) yielded 3.1 g of 3,5-dibromo-2-methoxypyrazine (compound 39c).

[0434] 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 and eluted with PE / EA (3:1) to give 1.8 g of 5-(6-bromo-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 39d).

[0435] 39.5 39d (1.8 g, 4.54 mmol), trimethylcyclotriboroxane (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 nitrogen protection, the mixture was heated to 90 °C and reacted for 1 hour. After the reaction was complete, 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 purified by column chromatography and eluted with PE / EA (6:1) to give 720 mg of 5-(3-methoxy-6-methylpyrazine-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 39e).

[0436] 39.6 39e (720 mg, 2.17 mmol) was added to a solution of DCM (4 mL) and TFA (16 mL), and stirred for 3 hours at room temperature under nitrogen protection. After the reaction was complete, 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. The mixture was purified by column chromatography, eluting with PE / EA (1:2), to give 460 mg of 5-(3-methoxy-6-methylpyrazine-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 39f).

[0437] 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 overnight at 85 °C under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, and 50 mL of tert-butyl methyl ether and 50 mL of water were added. The mixture was stirred for another half hour and then separated. The organic phase was discarded, and the pH of the aqueous phase was adjusted to acidic with 2N hydrochloric acid. The aqueous phase was then 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 39 g).

[0438] 39.8 39 g (100 mg, 0.48 mmol) and 39 f (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 in portions with stirring at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was complete, 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (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] + .

[0439] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) ketone (40)

[0440]

[0441] 40.1 Replace the reactant 4-fluoro-6-iodobenzoic acid with 2-iodo-5-methoxybenzoic acid, and prepare 5-methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 40a) according to the methods of Examples 39-39.7.

[0442] 40.2 Replace 39g of the reaction raw material 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 40) according to the methods of Examples 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] + .

[0443] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (41)

[0444]

[0445] 41.1 Replace the reactant 4-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 41a) according to the methods of Examples 39-39.7.

[0446] 41.2 Replace 39g of the reaction raw material with 41a, and prepare (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 41) according to the methods of Examples 39-39.8. 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] + .

[0447] 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (42)

[0448]

[0449] 42.1 Replace the reactant 4-fluoro-6-iodobenzoic acid with 5-bromo-2-methoxyisonicotinic acid, and prepare 2-methoxy-5-(2H-1,2,3-triazol-2-yl)isonicotinic acid (compound 42a) according to the methods of Examples 39-39.7.

[0450] 42.2 Replace 39g of the reaction raw material 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-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 42) according to the methods of Examples 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] + .

[0451] Example 43: Preparation of (2-fluoro-6-(pyrimidin-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (43)

[0452]

[0453] 43.1 2-Fluoro-6-iodobenzoate tert-butyl ester (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 protection and stirred at room temperature for minutes. 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 mixture was heated to 100 °C and reacted overnight. The reaction was confirmed to be complete by LCMS, and purified by column chromatography (PE / EA = 2:1) to obtain 160 mg of 2-fluoro-6-(pyrimidin-2-yl)benzoate tert-butyl ester (compound 43a).

[0454] 43.2 Add 43a (160 mg, 0.573 mmol) to 2 mL of dichloromethane under nitrogen protection, add trifluoroacetic acid (2 mL, 26.926 mmol) at room temperature, stir for 0.5 hours at room temperature until the reaction is complete, remove the solvent under reduced pressure to obtain 110 mg of 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (compound 43b).

[0455] 43.3 Replace 39g of the reaction raw material with 43b, and prepare (2-fluoro-6-(pyrimidin-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-yl) methyl ketone (compound 43) according to the methods of Examples 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] + .

[0456] 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-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl] ketone (44)

[0457]

[0458] 44.1 Replace the reactant 4-fluoro-6-iodobenzoic acid with 4-fluoro-2-iodobenzoic acid, and prepare 4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 44a) according to the methods of Examples 39-39.7.

[0459] 44.2 Replace 39g of the reaction raw material 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-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl] ketone (compound 44) ​​according to the methods of Examples 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] + .

[0460] 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-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl] ketone (45)

[0461]

[0462] 45.1 Compound 41a (300 mg, 1.37 mmol) was dissolved in 30 mL of dichloromethane solution, cooled in an ice-water bath under nitrogen protection, and boron tribromide dichloromethane solution (1.0 M, 3 mL) was added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 3 hours, cooled in an ice-water bath, and the reaction was quenched with water. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 230 mg of 4-hydroxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 45a). The crude product was used directly for the next reaction without purification.

[0463] 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. The mixture was heated to 60 °C and reacted for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, and 1 M hydrochloric acid solution was added to adjust the pH to 4-5. The solvent was removed by pressure evaporation, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4-ethoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 45b). The crude product was not purified and was directly used in the next reaction.

[0464] 45.3 Replace 39g of the reaction raw material with 45b, and prepare [4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl] ketone (compound 45) according to the methods of Examples 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] + .

[0465] Example 46: Preparation of [5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (46)

[0466]

[0467] 46.1 Replace methanol with ethanol as the reactant and prepare 3,5-dibromo-2-ethoxypyrazine (compound 46a) according to the methods of Examples 39-39.3.

[0468] 46.2 Replace reactant 39c with 46a and prepare 5-(6-bromo-3-ethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 46b) according to the methods of Examples 39-39.4.

[0469] 46.3 Replace reactant 39d with 46b and prepare 5-(3-ethoxy-6-methylpyrazine-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 46c) according to the methods of Examples 39-39.5.

[0470] 46.4 Replace reactant 39e with 46c and prepare 5-(3-ethoxy-6-methylpyrazine-2-yl)-1,2,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 46d) according to the methods of Examples 39-39.6.

[0471] 46.5 Replace reactant 39f with 46d and 39g with 41a, and prepare [5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 46) according to the methods of Examples 39-39.8. 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] + .

[0472] Example 47: Preparation of [5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (47)

[0473]

[0474] 47.1 Replace the reaction raw material trimethylcyclotriboroxane with ethylboronic acid, and prepare 5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 47a) according to the methods of Examples 39-39.5.

[0475] 47.2 Replace reactant 39e with 47a and prepare 5-(6-ethyl-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 47b) according to the methods of Examples 39-39.6.

[0476] 47.3 Replace reactant 39f with 47b and 1g with 3a, and prepare [5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 47) according to the methods of Examples 39-39.8. 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] + .

[0477] Example 48: Preparation of [4-methoxy-2-(pyrimidin-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentadien[c]pyrrole-2(1H)-yl] ketone (48)

[0478]

[0479] 48.1 Replace the reactant tert-butyl 2-fluoro-6-iodobenzoate with tert-butyl 2-iodo-4-methoxybenzoate, and prepare tert-butyl 4-methoxy-2-(pyrimidin-2-yl)benzoate (compound 48a) according to the method of Examples 43-43.1.

[0480] 48.2 Replace reactant 43a with 48a and prepare 4-methoxy-2-(pyrimidin-2-yl)benzoic acid (compound 48b) according to the methods of Examples 43-43.2.

[0481] 48.3 Replace reaction material 39g with 48b, and prepare [4-methoxy-2-(pyrimidin-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentadien[c]pyrrole-2(1H)-yl] ketone (compound 48) according to the methods of Examples 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] + .

[0482] Example 49: Preparation of [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (49)

[0483]

[0484] 49.1 Replace the reaction raw material 2-fluoro-6-iodobenzoic acid with 2-iodo-5-methylbenzoic acid, and prepare 5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 49a) according to the method of Examples 43-43.1.

[0485] 49.2 Replace reaction material 39g with 49a and prepare [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 49) according to the methods of Examples 39-39.8. 1 H NMR (400MHz, DMSO-d6) δ7.93 (br d, J=4.6Hz, 3H), 7.74 (brdd, 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] + .

[0486] Example 50: Preparation of [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (50)

[0487]

[0488] 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, heated to 60 °C and reacted for 6 hours. After the reaction was completed, the solvent was removed by vacuum distillation, and the product was purified by column chromatography (PE:EA = 5:1) to give 136 mg of 5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 50a).

[0489] 50.2 Replace reactant 39e with 50a and prepare 5-(3,6-dimethoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 50b) according to the methods of Examples 39-39.6.

[0490] 50.3 Replace reactant 39f with 50b and 39g with 44a, and prepare [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] methyl ketone (compound 50) according to the methods of Examples 39-39.8. 1 H 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] + .

[0491] Example 51: Preparation of [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl] ketone (51)

[0492]

[0493] 51.1 Replace reactant 39c with 3-bromo-2,5-dimethylpyrazine and prepare 5-(3,6-dimethylpyrazine-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 51a) according to the methods of Examples 39-39.4.

[0494] 51.2 Replace reactant 39e with 51a and prepare 5-(3,6-dimethylpyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 51b) according to the methods of Examples 39-39.6.

[0495] 51.3 Replace reactant 39f with 51b and prepare [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 51) according to the methods of Examples 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] + .

[0496] Example 52: Preparation of [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (52)

[0497]

[0498] 52.1 Replace reactant 39f with 51b and 39g with 41a, and prepare [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 52) according to the methods of Examples 39-39.8. 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),7.0 9(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] + .

[0499] Example 53: Preparation of [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (53)

[0500]

[0501] 53.1 Replace reactant 39f with 50b and 39g with 41a, and prepare [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 53) according to the methods of Examples 39-39.8. 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] + .

[0502] Example 54: Preparation of [5-(6-chloro-3-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (54)

[0503]

[0504] 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, followed by HCl methanol solution. The mixture was heated to 60 °C and reacted for 6 hours. After the reaction was completed, water was added to quench the reaction. The mixture was extracted with ethyl acetate and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and 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).

[0505] 54.2 Replace reactant 39c with 54a and prepare 5-(6-chloro-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 54b) according to the methods of Examples 39-39.4.

[0506] 54.2 Replace reactant 39e with 54b and prepare 5-(6-chloro-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 54c) according to the methods of Examples 39-39.6.

[0507] 54.3 Replace reactant 39f with 54c and 39g with 41a, and prepare [5-(6-chloro-3-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 54) according to the methods of Examples 39-39.8. 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] + .

[0508] Example 55: Preparation of [5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (55)

[0509]

[0510] 55.1 Replace the reaction raw material trimethylcyclotriboroxane with cyclopropylboronic acid, and prepare 5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 55a) according to the methods of Examples 39-39.5.

[0511] 55.2 Replace reactant 39e with 55a and prepare 5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 55b) according to the methods of Examples 39-39.7.

[0512] 55.3 Replace reactant 39f with 55b and 39g with 44a, and prepare [5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 55) according to the methods of Examples 39-39.8. 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] + .

[0513] 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]pyrrole-2(1H)-yl] methyl ketone (56)

[0514]

[0515] 56.1 Compound 39d (300 mg, 0.755 mmol) and iron triacetylacetone (50 mg, 0.14 mmol) were dissolved in 20 mL of tetrahydrofuran solution, cooled in an ice bath, and methyl-D3-magnesium iodide tetrahydrofuran solution (1 M, 2 mL) was added dropwise. After the addition was complete, the mixture was brought to room temperature and reacted for 6 hours. After the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was then purified by column chromatography (PE:EA = 5:1) to give 120 mg of 5-(3-methoxy-6-(methyl-d3)pyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 56a).

[0516] 56.2 Replace reactant 39e with 56a and prepare 5-(3-methoxy-6-(methyl-d3)pyrazin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 56b) according to the methods of Examples 39-39.6.

[0517] 56.3 Replace reactant 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]pyrrole-2(1H)-yl] methyl ketone (compound 56) according to the methods of Examples 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] + .

[0518] Example 57: Preparation of [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl][4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (57)

[0519]

[0520] 57.1 Replace the reactant iodoethane with deuterated iodomethane to prepare 4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 57a) according to the methods of Examples 45-45.2.

[0521] 57.2 Replace 39g of the reaction raw material with 57a, and prepare [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-yl][4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 57) according to the methods of Examples 39-39.8. 1 H 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] + .

[0522] 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]pyrrole-2(1H)-yl] methyl ketone (58)

[0523]

[0524] 58.1 Replace methanol with deuterated methanol and prepare 3,5-dibromo-2-(methoxy-d3)pyrazine (compound 58a) according to the methods of Examples 39-39.3.

[0525] 58.2 Replace reactant 39c with 58a and prepare 5-[6-bromo-3-(methoxy-d3)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 58b) according to the methods of Examples 39-39.4.

[0526] 58.3 Replace reactant 39d with 58b and prepare 5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 58c) according to the methods of Examples 39-39.5.

[0527] 58.4 Replace reactant 39e with 58c and prepare 5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 58d) according to the methods of Examples 39-39.6.

[0528] 58.5 Replace 39g of the reaction raw material 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]pyrrole-2(1H)-yl] methyl ketone (compound 58) according to the methods of Examples 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] + .

[0529] Example 59: Preparation of [5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (59)

[0530]

[0531] 59.1 Methyl 6-bromo-5-methoxypyridinylcarboxylate (1.0 g, 4.06 mmol) was dissolved in 50 mL of tetrahydrofuran, followed by the addition of sodium borohydride (0.9 g, 23.79 mmol). After the addition was complete, the mixture was heated to reflux, and then 8 mL of methanol was added. The reaction was continued for 2 hours. After the reaction was complete, a saturated ammonium chloride solution was added to quench the reaction. The mixture was extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 800 mg of (6-bromo-5-methoxypyrazin-2-yl)methanol (compound 59a). The crude product was used directly for the next reaction without purification.

[0532] 59.2 Compound 59a (800 mg, 3.67 mmol) was dissolved in 10 mL of dichloromethane solution, cooled in an ice bath, and protected with nitrogen. Diethylaminotrifluoride (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. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography (PE:EA = 10:1) to give 330 mg of 3-bromo-5-(fluoromethyl)-2-methoxypyrazine (compound 59b).

[0533] 59.3 Replace reactant 39c with 59b and prepare 5-(6-(fluoromethyl)-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 59c) according to the methods of Examples 39-39.4.

[0534] 59.4 Replace reactant 39e with 59c and prepare 5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 59d) according to the methods of Examples 39-39.6.

[0535] 59.5 Replace 39g of the reaction raw material with 41a and 39f with 59d, and prepare [5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrole-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 59) according to the methods of Examples 39-39.8. 1H 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),6.88-6.61(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(brd,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] + .

[0536] Example 60: Preparation of [5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (60)

[0537]

[0538] 60.1 Compound 59a (0.6 g, 2.73 mmol) was dissolved in 20 mL of dichloromethane, and then Dysmartin oxidant (1.74 g, 4.11 mmol) was added. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours. After the reaction was complete, saturated sodium bicarbonate solution was added to quench the reaction. The mixture was extracted with dichloromethane, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (PE:EA = 30:1) to give 285 mg of 6-bromo-5-methoxypyrazine-2-carboxaldehyde (compound 60a).

[0539] 60.2 Compound 60a (285 mg, 1.31 mmol) was dissolved in 10 mL of dichloromethane solution, cooled in an ice bath under nitrogen protection, and diethylaminotrifluoride (635 mg, 3.34 mmol) dissolved in 5 mL of dichloromethane was slowly added dropwise. After the addition was complete, the reaction was allowed to proceed at room temperature for 2 hours, then heated to reflux and allowed to proceed overnight. After the reaction was complete, the reaction was quenched with saturated sodium bicarbonate solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and purified by column chromatography (PE:EA = 10:1) to give 340 mg of 3-bromo-5-(difluoromethyl)-2-methoxypyrazine (compound 60b).

[0540] 60.3 Replace reactant 39c with 60b and prepare 5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 60c) according to the methods of Examples 39-39.4.

[0541] 60.4 Replace reactant 39e with 60c and prepare 5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 60d) according to the methods of Examples 39-39.6.

[0542] 60.5 Replace 39g of the reaction raw material with 44a and 39f with 60d, and prepare [5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (compound 60) according to the methods of Examples 39-39.8. 1 H 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] + .

[0543] Example 61: Preparation of [4-fluoro-2-(1H-pyrazol-1-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl] ketone (61)

[0544]

[0545] 61.1 Replace the reactant 4-fluoro-6-iodobenzoic acid with 4-fluoro-2-iodobenzoic acid and 1,2,3-triazole with 1H-pyrazole, and prepare 4-fluoro-2-(1H-pyrazole-1-yl)benzoic acid (compound 61a) according to the methods of Examples 39-39.7.

[0546] 61.2 Replace 39g of the reaction raw material with 61a, and prepare [4-fluoro-2-(1H-pyrazol-1-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-yl] ketone (compound 61) according to the methods of Examples 39-39.8. 1 H 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] + .

[0547] Example 62: Preparation of 3-[2-[4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,2,3,3a,4,6a-hexahydrocyclopentan[c]pyrrolo-5-yl]-5-methylpyrazine-2-onitrile (62)

[0548]

[0549] 62.1 Replace reactant 39c with 3,5-dichloropyrazine-2-onitrile and prepare 5-(6-chloro-3-cyanopyrazine-2-yl)-3,3a,4,6a-tetrahydrocyclopentan[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 62a) according to the methods of Examples 39-39.4.

[0550] 62.2 Replace reactant 39d with 62a and 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 methods of Examples 39-39.5.

[0551] 62.3 Replace reactant 39d with 62b and prepare 3-(1,2,3a,4,6a-hexahydrocyclopentan[c]pyrrolo-5-yl)-5-methylpyrazine-2-onitrile (compound 62c) according to the methods of Examples 39-39.6.

[0552] 62.4 Replace 39g of the reaction raw material 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-hexahydrocyclopentan[c]pyrrolo-5-yl]-5-methylpyrazine-2-onitrile (compound 62) according to the methods of Examples 39-39.8. 1 H 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] + .

[0553] 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]pyrrole-2(1H)-yl] methyl ketone (63)

[0554]

[0555] 63.1 Replace reactant 39c with 2-chloro-3-methoxypyrazine and prepare 5-(3-methoxypyrazine-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 63a) according to the methods of Examples 39-39.4.

[0556] 63.2 Replace reactant 39d with 63a and prepare 5-(3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 63b) according to the methods of Examples 39-39.6.

[0557] 63.3 The reaction raw material 39g was replaced with 41a and 39f was replaced with 63b, and the preparation of [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrole-2(1H)-yl] methyl ketone was carried out according to the methods of Examples 39-39.8 (Compound 63). 1 H 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] + .

[0558] Example 64: Preparation of [5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] ketone (64)

[0559]

[0560] 64.1 1-(3-chloropyrazin-2-yl)acetone (600 mg, 3.83 mmol) was dissolved in 10 mL of carbon tetrachloride, and diethylaminosulfur trifluoride (1.85 g, 11.49 mmol) was added. Under nitrogen protection, the mixture was heated to 90 °C and reacted overnight. After the reaction was complete, the mixture was cooled to room temperature, and the reaction was quenched with saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 5:1) to give 220 mg of 2-chloro-3-(1,1-difluoroethyl)pyrazine (compound 64a).

[0561] 64.2 Replace reactant 39c with 64a and prepare 5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (compound 64b) according to the methods of Examples 39-39.4.

[0562] 64.3 Replace reactant 39d with 64b and prepare 5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopentane[c]pyrrole (compound 64c) according to the methods of Examples 39-39.6.

[0563] 64.4 The reaction raw material 39g was replaced with 41a and 39f was replaced with 64c, and the preparation of [5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrole-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl] methyl ketone was carried out according to the methods of Examples 39-39.8 (Compound 64). 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] + .

[0564] Biological test cases

[0565] Test Example 1: Orexin Target Function Test

[0566] 1. Experimental objective:

[0567] Using the Cisbio HTRF IP-one kit, changes in IP-one concentration in the orexin receptor (OX1 / OX2) signaling pathway were detected by microplate reader, and the IC50 of the compounds was calculated. 50 The values ​​are used to evaluate the antagonistic effects of compounds on OX1 and OX2 receptors.

[0568] 2. Experimental materials:

[0569] Cell lines: CHO-K1-OX1 and CHO-K1-OX2 stable transgenic cell lines (Nanjing Genscript Biotech Co., Ltd.)

[0570] Cell culture conditions: F12 + 10% FBS + 400 μg / ml G418

[0571] Reagents and consumables:

[0572] F12 (Gibco, C11765500BT)

[0573] FBS (Gibco, 10099-141C)

[0574] Geneticin(G418)(Gibco, 11811031)

[0575] PBS (meilunbio, MA0015)

[0576] Pancreatic enzyme (Gibco, 25200-072)

[0577] Orexin A (MCE, HY-106224)

[0578] Orexin 2receptor agonist (MCE, HY19320)

[0579] 96-cell plate (Cisbio, 66PL96025)

[0580] IP-One-Gq kit (cisbio, 62IPAPEC)

[0581] CO2 incubator (Thermo, 311)

[0582] Centrifuge (Shanghai Anting, TGL-16C)

[0583] Cell counter (Countstar, IC1000)

[0584] Microplate reader (PerkinElmer, EnVision)

[0585] 3. Experimental methods:

[0586] (1) Prepare the reaction buffer (1x Stimulation buffer) required for the experiment: Dilute the 5x Stimulation buffer in the Cisbio IP-one kit with ddH2O at a ratio of 1:4 and set aside.

[0587] (2) Compound preparation: Dilute the compound to a 5 mM stock solution with DMSO, then dilute it 3.16 times to 10 gradients, and then dilute the prepared compound to the corresponding concentration (4x) with Stimulation buffer for later use.

[0588] (3) Cell preparation: CHO-K1-OX1 and CHO-K1-OX2 cells on the culture dish were digested with trypsin, and the cells were washed with culture medium and collected into 5 mL centrifuge tubes. Centrifuge at 1000 rpm for 5 minutes and discard the supernatant. Add 3 mL of PBS and gently mix with a pipette. Centrifuge again at 1000 rpm for 5 minutes and discard the supernatant. Resuspend the cells in 1x Stimulation buffer, count the cells using a Countstar cell counter, and adjust the cell density to 1.71 x 10⁻⁶ cells / mL. 6 Quantity / mL, for later use.

[0589] (4) Cell addition: Add the cell suspension to the experimental plate at 7 μL / well (i.e., about 12,000 cells / well).

[0590] (5) Compound addition: Add the compound diluted with Stimulation buffer to the above experimental plate at a rate of 3.5 μL / well.

[0591] (6) Reaction incubation: After slow shaking, place the experimental plate at 37°C for 30 minutes.

[0592] (7)EC 80 Addition of agonist: Add EC 80 4x Orexin A (OX1 receptor) and 4x Orexin 2 receptoragonist (OX2 receptor) solutions, 3.5 μL / well.

[0593] (8) Reaction incubation: After slow shaking, place the experimental plate at 37°C for 45 minutes.

[0594] (9) Add detection reagents: Dilute IP1-d2 and Anti-IP1cryptate 1:20 with Lysis & detection buffer from the Cisbio IP-one detection kit, and add 3 μL of each diluted IP1-d2 and Anti-IP1cryptate to the experimental plate. After shaking, let the experimental plate stand at room temperature for 60 minutes.

[0595] (10) Experimental readings: Read the plate on the Envision and detect the readings of the 665nm and 615nm channels. Calculate the ratio of the 665nm / 615nm readings.

[0596] 4. Data Analysis:

[0597] Based on the antagonistic effect values ​​of the compound samples at different concentration test points, the antagonistic effect curves of the compound samples on orexin receptors were fitted using GraphPad Prism software, and the IC50 was calculated. 50 .

[0598] Table 1

[0599]

[0600]

[0601]

[0602] The compounds of this invention exhibit good inhibitory activity against OX2 receptors, and their inhibitory effect on OX2 receptors is significantly better than that on OX1 receptors, demonstrating good selectivity.

[0603] Test Example 2: Determination of pharmacokinetic parameters of the test substance in rat plasma.

[0604] Healthy male SD rats aged 6-9 weeks were randomly divided into two groups of 3 rats each. One group was administered the test compound 1 mg / kg intravenously, while the other group was administered the test compound 30 mg / kg by gavage. Whole blood samples were collected from both the intravenous and gavage groups at 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.

[0605] Quantitative analysis of all biological samples was performed using LC-MS / MS. Relevant pharmacokinetic parameters were calculated using the WinNonlin™ Version 7.0 (Pharsight, Mountain View, CA) pharmacokinetic software with a non-compartmental model linear logarithmic trapezoidal method. AUC 0-last The area under the plasma concentration-time curve represents the plasma concentration from time zero to the last detectable concentration point; PO represents oral administration; iv represents intravenous administration; C max The value represents the peak concentration, and F% represents oral bioavailability.

[0606] Table 2

[0607]

[0608]

[0609] In a pharmacokinetic evaluation experiment in rats, the compounds of the present invention showed good bioavailability after oral administration.

[0610] Test Example 3: Spontaneous Activity of Rats

[0611] Male SD rats aged 6-9 weeks were randomly divided into groups of 8 rats each, based on a balanced body weight principle. Each group was administered a blank solvent and the test compound at doses of 10, 30, and 50 mg / kg, respectively. Immediately after administration, the animals were placed in a testing chamber, and their activity distances over 60 minutes were recorded and analyzed using Top Scan Version 3.0. The total activity distances of the test compound groups were compared with those of the blank solvent group to determine whether the test compound had a significant effect on spontaneous activity. Experimental data are expressed as mean ± standard error (Mean ± SD). One-way ANOVA was performed using SPSS 21.0 statistical software, and Dunnett's test was used for pairwise comparisons. A p-value < 0.05 was considered as *.

[0612] Table 3

[0613]

[0614] In rat spontaneous activity experiments, the compounds of the present invention significantly reduced the distance of spontaneous activity in rats, with the lowest effective dose being equivalent to or better than Seltorexant.

[0615] Test Example 3: Determination of blood-brain barrier permeability of the test substance in rats

[0616] Twelve male SD rats were randomly divided into four groups of three. Rats were fasted for 8 hours before the experiment but allowed free access to water. Rats were administered 30 mg / kg of the test drug via gavage. Blood samples of 0.3 mL were collected from the jugular venous plexus before and 0.25 h after administration. The rats were then anesthetized, the thoracic cavity was opened, the right atrial appendage was cut open, and perfusion was rapidly initiated from the left ventricle. Perfusion was stopped when the outflowing fluid was clear and free of blood. Brain tissue was then removed, blotted dry with filter paper, weighed, and homogenized with an appropriate amount of physiological saline (1:4, v / v) to prepare a brain tissue homogenate. Whole blood samples were centrifuged at 4000 rpm for 10 min to separate plasma.

[0617] The concentration of the test substance in plasma and brain tissue homogenate was detected using the established LC-MS / MS method. The brain-blood ratio (Kb / p) of the test substance was 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.

[0618] Table 4

[0619]

[0620] Conclusion: After oral administration to rats, the compounds of the present invention can cross the blood-brain barrier well and have a high brain-blood ratio.

[0621] Test Example 4: Effect of the test substance on sleep in SD rats

[0622] Experimental procedure:

[0623] 1. Surgical electrode implantation: Animals were placed in an automatically alternating light and dark environment for at least 4 days to acclimatize (lights off at 21:00, lights on at 7:00). On the day of the experiment, animals were anesthetized with sodium pentobarbital (ip, 60mg / kg). After anesthesia, the brain stereotaxic instrument was used for fixation, the surgical area of ​​the head was prepared, holes were drilled in the skull, and electrodes were implanted.

[0624] 2. Postoperative care: After surgery, carefully place the rats in a clean recovery cage in a lateral recumbent position to ensure a clear airway. The light and dark environment should be automatically alternated (lights off at 9:00 PM, lights on at 7:00 AM), with a constant temperature of 20-26℃ and relative humidity of 40-70%. Provide the animals with 3 days of postoperative care, and administer an intramuscular injection of 80,000 units of sodium penicillin per animal. Experiments should be conducted at least 7 days after recovery.

[0625] 3. Administration regimen and indicator monitoring: Basic EEG and EMG recordings were performed at least 7 days after surgery. Drug administration was initiated after the basic EEG and EMG recordings were completed. Animals were placed in the experimental cage for at least 24 hours to acclimatize before drug administration. A single dose was administered 1 hour after lights out, and EEG and EMG were recorded 12 hours after drug administration.

[0626] 4. Experimental Indicator: The time of awakening in rats within each hourly time period 12 hours after drug administration. The t-test was used for analysis, with P < 0.05 indicating a significant difference. Experimental results are shown in the attached figures in the instruction manual.

[0627] The results showed that in the rat sleep effect test, the compounds of the present invention, even at low doses, significantly reduced total wakefulness time and increased total sleep time. This suggests that the compounds of the present invention have a good sleep-promoting effect on rats.

[0628] Those skilled in the art will recognize that many modifications and variations can be made to the invention without departing from its spirit and scope. The specific embodiments described herein are provided by way of example only and are not intended to limit the scope in any way. The true scope and spirit of the invention are shown in the appended claims, and the description and embodiments are merely exemplary.

Claims

1. A compound as shown in Formula IA, or a pharmaceutically acceptable salt thereof, in, R 1A The substituents are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, halogens, and hydroxyl groups; the substituents are independently selected from H, D, and halogens. R 2A Selected from H, D and halogens; R 3A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, halogens, hydroxyl groups, and cyano groups; the substituents are independently selected from H, D, halogens, and hydroxyl groups. L 1A Selected from phenyl groups optionally substituted with one or more substituents and pyridyl groups optionally substituted with one or more substituents; the one or more substituents are independently selected from H, D, halogens, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, and optionally substituted C1-C8 alkylthio groups, wherein the substituents are selected from H, D, halogens, and hydroxyl groups; L 2A It is a 1,2,3-triazolyl group substituted with 0-4 Rbbb groups; Each Rbbb group is independently selected from H, D and optionally substituted C1-C8 alkyl groups; the substituents are independently selected from H, D, halogens and hydroxyl groups.

2. The compound of formula IA as claimed in claim 1, characterized in that, R 1A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, optionally substituted C3-C8 cycloalkyl groups, and halogens; the substituents are independently selected from H and halogens. R 2A For H; R 3A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, halogens, and cyano groups; the substituents are independently selected from H, D, halogens, and hydroxyl groups. L 1A Selected from phenyl groups optionally substituted with one or more substituents and pyridyl groups optionally substituted with one or more substituents; the one or more substituents are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C1-C8 haloalkoxy groups, C1-C8 alkylthio groups and C3-C8 cycloalkyl groups; L 2A It is a 1,2,3-triazolyl group substituted with 0-4 Rbbb groups; Each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl groups; the substituents are independently selected from H, halogens and hydroxyl groups.

3. The compound of formula IA as claimed in claim 1, characterized in that, One or more of the following conditions must be met: (1) R 1A Selected from H, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, halogen and deuterated C1-C8 alkyl; R 2A For H; R 3A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, and halogens; the substituents are independently selected from H, D, halogens, and hydroxyl groups; (2) L 1A Selected from phenyl and pyridyl, wherein the phenyl and pyridyl are optionally substituted by one or more substituents, wherein the one or more substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C1-C8 alkylthio and C3-C6 cycloalkyl; (3) L 2A It is 1,2,3-triazolyl; wherein, this group is optionally substituted by 0-4 Rbbb groups.

4. The compound of formula IA as claimed in claim 1, characterized in that, R 1A Selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 cycloalkyl, halogen and deuterated C1-C8 alkyl; R 2A It consists of H and halogens; R 3A Selected from C1-C8 alkyl, C1-C8 alkoxy, cyano, hydroxy, halogenated C1-C8 alkyl, deuterated C1-C8 alkyl, and deuterated C1-C8 alkoxy; L 1A Selected from phenyl groups optionally substituted with one or more substituents and pyridyl groups optionally substituted with one or more substituents; the one or more substituents are independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, halo-C1-C8 alkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy; L 2A It is 1,2,3-triazolyl; wherein, this group is optionally substituted by 0-4 Rbbb groups; Each Rbbb group is independently selected from H and C1-C8 alkyl groups.

5. The compound of formula IA as claimed in claim 1, characterized in that: Compounds of formula IA are shown as those of formula II-A: Among them, R 5A Selected from H and methyl; R 1A The substituents are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, halogens, and hydroxyl groups; the substituents are independently selected from H, D, and halogens. R 2A Selected from H, D and halogens; R 3A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, halogens, hydroxyl groups, and cyano groups; the substituents are independently selected from H, D, halogens, and hydroxyl groups. L 1A The substituents are selected from phenyl groups optionally substituted with one or more substituents and pyridyl groups optionally substituted with one or more substituents; the one or more substituents are independently selected from H, D, halogens, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, and optionally substituted C1-C8 alkylthio groups, wherein the substituents are selected from H, D, halogens, and hydroxyl groups.

6. The compound of formula IA as claimed in claim 2, characterized in that: Compounds of formula IA are shown as those of formula II-A: Among them, R 5A Selected from H and methyl; R 1A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, optionally substituted C3-C8 cycloalkyl groups, and halogens; the substituents are independently selected from H and halogens. R 2A For H; R 3A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, halogens, hydroxyl groups, and cyano groups; the substituents are independently selected from H, D, halogens, and hydroxyl groups. L 1A The substituents are selected from phenyl groups optionally substituted with one or more substituents and pyridyl groups optionally substituted with one or more substituents; the one or more substituents are independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C1-C8 haloalkoxy groups, C1-C8 alkylthio groups and C3-C8 cycloalkyl groups.

7. The compound of formula IA as claimed in claim 1, characterized in that: Compounds of formula IA are shown as those of formula III-A: Among them, R 5A Selected from H and C1-C8 alkyl groups; n1A is 1; R 6A Independently selected from halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C1-C8 haloalkoxy groups, and C1-C8 alkylthio groups; R 1A The substituents are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, halogens, and hydroxyl groups; the substituents are independently selected from H, D, and halogens. R 2A Selected from H, D and halogens; R 3A The substituent is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, halogen, hydroxyl and cyano; the substituent is independently selected from H, D, halogen and hydroxyl.

8. The compound of formula IA as claimed in claim 2, characterized in that: Compounds of formula IA are shown as those of formula III-A: Among them, R 5A Selected from H and C1-C8 alkyl groups; n1A is 1; R 6A Independently selected from halogens, C1-C8 alkyl groups, C1-C8 alkoxy groups, C1-C8 haloalkyl groups, C1-C8 haloalkoxy groups, and C1-C8 alkylthio groups; R 1A The substituents are selected from H, optionally substituted C1-C8 alkyl groups, optionally substituted C1-C8 alkoxy groups, optionally substituted C3-C8 cycloalkyl groups, and halogens; the substituents are independently selected from H and halogens. R 2A For H; R 3A The substituent is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, halogen, and cyano; the substituent is independently selected from H, D, halogen, and hydroxyl.

9. A compound as shown in formula II-B or a pharmaceutically acceptable salt thereof, in, R 2B For F; R 1B R 3B The substituents are independently selected from H, D, optionally substituted C1-C8 alkyl groups and optionally substituted C1-C8 alkoxy groups; the substituents are independently selected from D and hydroxyl groups; L 1B The substituent is selected from optionally substituted phenyl and optionally substituted pyridyl groups, wherein the substituent is independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkoxy and C1-C8 alkylthio. And L 1B With the L to its left 2B And the relative positions of the carbonyl groups on its right are selected from , , and ; L 2B As shown in Equation II-B, the one R 5B 1,2,3-triazolyl group with substituent group; R 5B Selected from H and C1-C8 alkyl groups.

10. The compound of formula II-B as claimed in claim 9, or a pharmaceutically acceptable salt thereof. in, R 1B The substituents are selected from H, optionally substituted C1-C8 alkyl groups, and optionally substituted C1-C8 alkoxy groups; the substituents are independently selected from hydroxyl and D; R 3B The substituents are optionally substituted C1-C8 alkyl groups; the substituents are independently selected from D and hydroxyl groups.

11. The compound of claim 9 or a pharmaceutically acceptable salt thereof, wherein: L 1B For any n1B substituents R 6B Substituted pyridinyl group; And L 1B With the L to its left 2B And the relative positions of the carbonyl groups on its right are as follows: ; Where n1B is selected from integers between 0 and 3; R 6B It is independently selected from H, C1-C8 alkoxy and C1-C8 deuterated alkoxy.

12. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein: L 1B For any n1B substituents R 6B Substituted pyridinyl group; And L 1B With the L to its left 2B And the relative positions of the carbonyl groups on its right are as follows: ; Where n1B is selected from integers between 0 and 3; R 6B It is independently selected from H, C1-C8 alkoxy and C1-C8 deuterated alkoxy.

13. The compound of claim 9 or a pharmaceutically acceptable salt thereof, characterized in that: Compounds of formula II-B are shown in formula VB: Among them, R 5B Selected from H and C1-C8 alkyl groups; n3B is 1; R 8B Independently selected from H, halogens, C1-C8 alkoxy groups and C1-C8 deuterated alkoxy groups; R 2B For F; R 1B R 3B The substituents are independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy; the substituents are independently selected from D and hydroxyl.

14. The compound of claim 10 or a pharmaceutically acceptable salt thereof, characterized in that: Compounds of formula II-B are shown in formula VB: Among them, R 5B Selected from H and C1-C8 alkyl groups; n3B is 1. R 8B Independently selected from H, halogens, C1-C8 alkoxy groups and C1-C8 deuterated alkoxy groups; R 2B For F; R 1B The substituents are selected from H, optionally substituted C1-C8 alkyl groups, and optionally substituted C1-C8 alkoxy groups; the substituents are independently selected from hydroxyl and D; R 3B The substituents are optionally substituted C1-C8 alkyl groups; the substituents are independently selected from D and hydroxyl groups.

15. A compound as shown in formula IV-B, or a pharmaceutically acceptable salt thereof, in, R 5B Selected from H and C1-C8 alkyl groups; n2B is 1; R 7B Independently selected from H, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkoxy and C1-C8 alkylthio; R 2B For F; R 1B R 3B The substituents are independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy; the substituents are independently selected from D and hydroxyl.

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein: R 1B The substituents are selected from H, optionally substituted C1-C8 alkyl groups, and optionally substituted C1-C8 alkoxy groups; the substituents are independently selected from hydroxyl and D; R 3B The substituents are optionally substituted C1-C8 alkyl groups; the substituents are independently selected from D and hydroxyl groups.

17. The compound or a pharmaceutically acceptable salt thereof as described in any one of claims 1, 9 or 15, characterized in that, Selected from the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 。 18. A pharmaceutical composition, characterized in that... It contains a compound as described in any one of claims 1-17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

19. The use of a compound or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-17, or the use of a pharmaceutical composition as claimed in claim 18 in the preparation of a medicament, wherein the medicament is used to prevent, treat and / or alleviate diseases associated with orexin receptors.

20. The use as claimed in claim 19, wherein the orexin receptor-related disease is selected from one or more of the following: sleep disorders, anxiety disorders, panic disorders, obsessive-compulsive disorder, affective neurosis, anxiety neurosis, mood disorders, panic attack disorder, behavioral disorders, emotional disturbances, post-traumatic stress disorder, psychosis, schizophrenia, mental disorder, dementia, drug dependence, addiction, cognitive impairment, Parkinson's disease, movement disorders, eating disorders, headaches, migraines, pain, insomnia, and sleep apnea.

21. A method for preparing the compound according to any one of claims 1-14 and 17, characterized in that: The reaction includes the following steps: Compound I-dA or I-dB reacts with compound If to obtain the target compound: or Among them, group R 1A R 2A R 3A As defined in claims 1-8 or claim 17, group R 1B R 2B R 3B The corresponding groups are defined as in claims 9-14 or claim 17; wherein, for the reaction involving formula I-dA, the groups L2 or L1 in formula If are respectively the corresponding groups L in claims 1-8 or claim 17. 2A or L 1A Definition; for the reaction involving formula I-dB, the group L2 or L1 in formula If corresponds to the group L in claims 9-14 or claim 17, respectively. 2B or L 1B Definition.

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