Substituted tetrahydrocyclopentyl[c]pyrrole derivatives, methods of preparation, intermediates and uses thereof

Abstract

The present invention relates to compounds of general formula I or pharmaceutically acceptable salts, stereoisomers, tautomers, compositions containing said compounds, processes for their preparation, intermediates, and uses in the pharmaceutical field. JPEG2026500272000136.jpg31105

Description

[Technical Field]

[0001] This application claims priority to Chinese Application No. 202211599295.X, filed on December 12, 2022, entitled "Substituted Tetrahydrocyclopentyl [c] Pyrrole Methyl Ketone Derivatives, Preparation Methods and Uses Thereof," and to Chinese Application No. 202310334144.X, filed on March 31, 2023, entitled "Substituted Tetrahydrocyclopentyl [c] Pyrrole Derivatives, Preparation Methods, Intermediates and Uses Thereof," and to Chinese Application No. 202311606327.9, filed on November 28, 2023, entitled "Substituted Tetrahydrocyclopentyl [c] Pyrrole Derivatives, Preparation Methods, Intermediates and Uses Thereof," the contents of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to the pharmaceutical field, and more particularly to a substituted tetrahydrocyclopentyl[c]pyrrole derivative or a pharmaceutically acceptable salt thereof, a stereoisomer, a tautomer, a composition containing said compound, a preparation method thereof, an intermediate, and a use in the pharmaceutical field. [Background technology]

[0003] There are two types of orexins (also called hypocretins or orexin peptides): orexin-A (hypocretin-1) and orexin-B (hypocretin-2). Orexin peptide signaling is mediated by two receptors and two peptide agonists. Orexin peptide A and orexin peptide B bind to two high-affinity receptors: orexin receptor type 1 (OX1R or OX1) and orexin receptor type 2 (OX2R or OX2). OX1R preferentially selects orexin peptide A, whereas OX2R binds both orexin peptides with similar affinity.

[0004] Orexin receptors are pathologically important and are associated with a variety of diseases, including, for example, sleep disorders, anxiety disorders, panic disorders, obsessive-compulsive disorders, affective neurological disorders, depressive neurological disorders, anxiety neurological disorders, mood disorders, panic attack disorders, behavioral disorders, mood disorders, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive disorders, Parkinson's disease, movement disorders, eating disorders, headache, migraine, pain, insomnia, depression, Alzheimer's disease, and sleep apnea.

[0005] Several drugs targeting OX1 / 2R, such as Merck's Suvoraxant and Eisai's Lemborexant, are already in clinical trials or on the market. However, existing drugs antagonize both OX1R and OX2R receptors, and when they act on OX1R, they affect rapid eye movement sleep (NEM, brain activity is the same as during wakefulness) and non-rapid eye movement sleep (NEREM, deep sleep), meaning that they increase the risk of sleepiness by extending REM time at the expense of NREM time. Furthermore, they do not have antidepressant effects on OX1R.

[0006] Research indicates that sleep-wake cycle disorders may be targets of OX2R receptor modulator activity. Examples of disorders treated with antagonists or other modulators that downregulate OX2R-mediated processes include insomnia, restless legs syndrome, jet lag, and sleep disorders secondary to neurological disorders such as mania, schizophrenia, and pain syndromes. OX2R is selectively expressed in the tuberomammillary nucleus (TMN), paraventricular nucleus (PVN), and nucleus accumbens (NAc). These brain regions are the primary sites of action of orexin neurons in the lateral hypothalamus (LH), which are associated with feeding, sleep, depression, anxiety, drug addiction, and motivational behaviors, making the therapeutic effect more pronounced in the treatment of sleep disorders (Lu et al., 2020, Neurosci Bull, 4:432-448).

[0007] OX2R antagonists have antidepressant effects, and OX2R single receptor antagonists can also have effective therapeutic effects for insomnia. Therefore, selective OX2R antagonists can avoid various side effects, such as drowsiness, caused by OX1R activity. Currently, the only OX2R antagonist in clinical trials is Seltorexant, developed by Janssen, whose primary indications include major depressive disorder (MDD) and primary and secondary insomnia.

[0008] Selective OX2R antagonists have the potential to treat neurological disorders such as insomnia, depression, and anxiety, and there is a great clinical need for them. Selective OX2R antagonists have good prospects for application as medicines. Summary of the Invention

[0009] Hereinafter, several aspects of the present invention will be briefly described, but the present invention is not limited thereto. If the disclosure content of this specification differs from that of the cited document, the disclosure content of this specification shall prevail.

[0010] The present invention aims to provide a substituted tetrahydrocyclopentyl[c]pyrrole derivative or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, a pharmaceutical composition thereof, a preparation method thereof, and an intermediate thereof, for use in preventing or treating diseases associated with orexin receptors.

[0011] In one aspect, the present invention provides a compound represented by the following general formula I:

[0012] [ka]

[0013] During the ceremony, R1 and R2 are each independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen, wherein the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano; Alternatively, R1 and R2, together with the carbon atom to which they are attached, form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or a C3-C8 cycloalkyl, optionally substituted with one or more substituents, said substituents being independently selected from H, D, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano; L1 is one or more substituents R LA a 6- to 14-membered aryl group optionally substituted with one or more substituents R LA and preferably one or more substituents R LA a 6- to 10-membered aryl group optionally substituted with one or more substituents R LA and more preferably one or more substituents R LA a phenyl group optionally substituted with one or more substituents R LA wherein the one or more substituents R are selected from 5- to 6-membered monocyclic heteroaryl groups optionally substituted with LA are independently H, D, halogen, one or more substituents R LB C1-C8 alkyl optionally substituted with one or more substituents R LB C1-C8 alkoxy, cyano, optionally substituted with one or more substituents R LB C2-C8 alkynyl optionally substituted with one or more substituents R LBC2-C8 alkenyl optionally substituted with hydroxy, nitro, one or more substituents R LB C1-C8 alkylthio optionally substituted with one or more substituents R LB and OR4, wherein the one or more substituents R LB is selected from H, D, halogen and hydroxy; R4 is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; L2 is selected from a 6- to 14-membered aryl substituted with 0-4 Rb groups and a 5- to 14-membered heteroaryl substituted with 0-4 Rb groups, preferably a 6- to 10-membered aryl substituted with 0-3 Rb groups and a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rb groups, more preferably a phenyl substituted with 0-3 Rb groups and a 5- to 6-membered heteroaryl substituted with 0-3 Rb groups; each Rb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, wherein said substituents are independently selected from H, D, halogen, and hydroxyl; X1 is N and CR 10 is selected from R 10 are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C3-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen, and said substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, D, halogen and hydroxy; X2 is N and CR 11 is selected from R11 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- to 8-membered heterocyclyl, halogen, hydroxy, nitro, and cyano, the substituents being independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro, and cyano; and X1 and X2 are not N at the same time, and X2 is CR 11 and when X1 is N, then R2 is not H or D.

[0014] In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by Formula I above or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, and optionally further comprising a pharmaceutically acceptable excipient, carrier, adjuvant, solvent, or combination thereof.

[0015] In another aspect, the present invention provides use of a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for treating an orexin receptor associated disorder, or a method of treating an orexin receptor associated disorder in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, including the compound of formula I or the specified compound above, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, or a pharmaceutical composition thereof.

[0016] In one embodiment, the disease associated with the orexin receptor is a sleep disorder, anxiety disorder, panic disorder, obsessive-compulsive disorder, affective neurological disorder, depressive neurological disorder, anxiety neurological disorder, mood disorder, panic attack disorder, behavioral disorder, mood disorder, post-traumatic stress disorder, psychosis, schizophrenia, bipolar disorder, mental confusion, dementia, drug dependence, addiction, cognitive disorder, Parkinson's disease, movement disorder, eating disorder, headache, migraine, pain, insomnia, depression, Alzheimer's disease, or sleep apnea syndrome, preferably insomnia, depression, or a sleep disorder, more preferably major depressive disorder, primary and secondary insomnia, or depression accompanied by insomnia.

[0017] In one embodiment, the subject is a mammal, hi one embodiment, the subject is a human.

[0018] In another aspect, the present invention provides a method for preparing a compound of formula I, comprising the steps of: reacting compound Id with compound If to obtain the desired compound I;

[0019] [ka]

[0020] wherein R1, R2, X1, X2, L1, and L2 are as defined above, and the compound represented by Id is preferably a compound represented by I-dA or I-dB;

[0021] [ka]

[0022] R 1A , R 2A , R 3A is as defined above, and R 1B , R 2B , R 3B is as defined above.

[0023] In another aspect, the present invention provides an intermediate represented by a compound of formula Id:

[0024] [ka]

[0025] wherein R1, R2, X1, and X2 are as defined above, and the compound represented by Id is preferably a compound represented by I-dA or I-dB;

[0026] [ka]

[0027] R 1A , R 2A , R 3A is as defined above, and R 1B , R 2B , R 3B is as defined above. DETAILED DESCRIPTION OF THE INVENTION

[0028] Unless otherwise specified or clearly contradicted by context, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. In the event of a conflict, the definitions provided herein shall prevail. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. All patents, published patent applications, and publications cited herein are hereby incorporated by reference.

[0029] General Terms and Definitions The term "optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where it does not occur.

[0030] The term "optionally substituted" is used interchangeably with the term "substituted or unsubstituted," i.e., the structure or group is unsubstituted or substituted with one or more substituents according to the present invention, where said substitution occurs in any reasonable position on a given structure or group, where valence is allowed.

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

[0032] In general, the term "substituted" means that one or more hydrogen atoms in a given structure or group are replaced with a specified substituent. Unless otherwise specified, a substituent may be substituted at each reasonable position of the group where it is substitutable. When more than one position in a given structural formula may be optionally substituted with one or more specific substituents, the substituents may be the same or different at each reasonable position in the structural formula.

[0033] It should also be explained that unless otherwise specified, the term "independently" used in the present invention may mean that specific options represented by the same symbol in different groups do not affect each other, or that specific options represented by the same symbol in the same group do not affect each other, and should be understood in a broad sense.

[0034] When the lower and upper limits of a numerical range are disclosed, any numerical value within that range and any encompassed range is specifically disclosed. In particular, each possible value range disclosed herein should be understood to mean each value and range encompassed within the broader range. When any variable (e.g., R) and any signed variable (e.g., R, R, R, R, R, R, R, R, etc.) occurs more than once in a compound composition or structure, its definition at each occurrence is independent at every occurrence. For example, if a group is substituted with 0, 1, 2, or 3 R substituents, the group may optionally be substituted with up to 3 R substituents, and all options for each R substituent at each occurrence are independent of each other.

[0035] In each section of this specification, the substituents of the compounds disclosed in this invention are disclosed according to the type of group or range. In particular, it should be noted that the present invention includes each independent subcombination of each member of these types of groups and ranges. For example, the expression m-n used in this specification refers to the range from m to n, and each point value therein, as well as the subrange and each point value.

[0036] The term "alkyl group" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms connected to the rest of the molecule by a single bond. An "alkyl group" may have 1 to 8 carbon atoms, i.e., a "C1-C8 alkyl group", such as C 1-4 Alkyl group, C 1-3 Alkyl group, C 1-2 Alkyl group, C3 alkyl group, C4 alkyl group, C8 alkyl group, C 1-8 Alkyl group, C 3-8 It is an alkyl group having 1 to 3 carbon atoms, i.e., it may be a "C1 to C3 alkyl group", for example, C 1-3 Alkyl group, C 1-2The term "C1-C5 alkyl group" specifically refers to a methyl group, an ethyl group, a C3 alkyl group, a C4 alkyl group, or a C5 alkyl group, which are individually disclosed. Examples of alkyl groups are a methyl group (Me, -CH3), an ethyl group (Et, -CH2CH3), an n-propyl group (n-Pr, -CH2CH2CH3), an isopropyl group (i-Pr, -CH(CH3)2), an n-butyl group (n-Bu, -CH2CH2CH2CH3), an isobutyl group (i-Bu, -CH2CH(CH3)2), a sec-butyl group (s-Bu, -CH(CH3)CH2CH3), a tert-butyl group (t-Bu, -CH (CH3)3), n-pentyl group (-CH2CH2CH2CH2CH3), 2-pentyl group (-CH(CH3)CH2CH2CH3), 3-pentyl group (-CH(CH2CH3)2), 2-methyl-2-butyl group (-C(CH3)2CH2CH3), 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), 2-methyl-1-butyl group (-CH 2CH(CH3)CH2CH3), n-hexyl group (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl group (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl group (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl group (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl group (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl These include, but are not limited to, groups such as (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl group (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl group (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl group (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl group (-CH(CH3)C(CH3)3), n-heptyl group, n-octyl group, and the like.For example, the expression "C1 to C8" or "C1-8" should be understood to encompass the range of 1 to 8 carbon atoms, and any subranges and point values ​​therein, such as C1 to C5, C3 to C4, C2 to C6, C3 to C6, C4 to C6, C4 to C7, C4 to C8, C2 to C4, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. Also, for example, "C1 to C5" or "C. 1-5 " should be understood to encompass the range of 1 to 5 carbon atoms, and any subranges and points therein, for example, C2 to C5, C3 to C4, C1 to C2, C1 to C3, C1 to C4, C1 to C5, etc., and C1, C2, C3, C4, C5, etc. Also, for example, "C2 to C5" or "C 2-5 " should be understood to encompass the range of 2 to 5 carbon atoms, and any subranges and points therein, such as C2 to C5, C3 to C4, C2 to C3, C2 to C4, C3 to C5, C4 to C5, etc., and C2, C3, C4, C5, etc. Also, for example, "C1 to C8" or "C 1-8 The expression "a" should be understood to include the range of 1 to 8 carbon atoms, and any subranges and point values ​​therein, for example, C2 to C5, C3 to C4, C2 to C6, C3 to C6, C4 to C6, C4 to C7, C4 to C8, C2 to C4, etc., as well as C1, C2, C3, C4, C5, C6, C7, C8, etc. Also, for example, the expression "3-membered to 8-membered" should be understood to include any subranges and point values ​​therein, for example, 3-membered to 5-membered, 3-membered to 6-membered, 3-membered to 7-membered, 3-membered to 8-membered, 4-membered to 5-membered, 4-membered to 6-membered, 4-membered to 7-membered, 4-membered to 8-membered, 5-membered to 7-membered, 5-membered to 8-membered, 6-membered to 7-membered, 6-membered to 8-membered, etc., as well as 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, etc. Other similar expressions herein should be understood in an analogous manner.

[0037] The term "one or more" or similar expressions such as "at least one" may mean, for example, one, two, three, four, five, six, seven, eight, nine, ten or more.

[0038] The term "chosen from" refers to one or more elements listed before it that are independently selectable and may include combinations of two or more elements.

[0039] The term "comprises" is an open-ended term, i.e., includes the subject matter specified in the present invention but does not exclude other aspects.

[0040] When it is stated that each carbon atom in a group may be optionally replaced with a heteroatom, the proviso is that the normal valences of all atoms in the group in their current state are not exceeded and a stable compound is formed.

[0041] The term "heteroatom" refers to one or more oxygen (O), sulfur (S), or nitrogen (N), and includes nitrogen (N), sulfur (S) in any oxidation state, primary, secondary, and tertiary amine and quaternary ammonium salt forms, or hydrogen substitution on a nitrogen atom of a heterocycle, e.g., N, NH, NR.

[0042] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated electron system. The term "aryl" can be used interchangeably with the terms "aromatic ring" or "aromatic ring." Aryl groups include 6- to 14-membered aryl groups and 6- to 10-membered aryl groups, specifically phenyl, naphthyl, and the like. The aryl groups may be substituted with one or more substituents described herein.

[0043] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms, 5 to 14 ring atoms, where the heteroatoms are selected from one or more of oxygen, sulfur, and nitrogen. The term "heteroaryl" can be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound." Examples of heteroaryl groups include 5- to 14-membered heteroaryls, 5- to 10-membered heteroaryls, 5- to 10-membered monocyclic or polycyclic heteroaryls, and 5- to 6-membered monocyclic heteroaryls, specifically pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl, pyridazinyl, triazine, oxadiazolyl, isoxazolyl, pyranyl, 1,3,4-triazolyl, furanopyrimidinyl, thienopyrimidinyl, pyrrolopyridinyl, pyranopyrimidinyl, benzothiazolyl, benzoxazolyl, thienopyrimidinyl, indolyl, etc. The heteroaryl groups are optionally substituted with one or more substituents described herein.

[0044] The terms "heterocycle" and "heterocyclyl" are used interchangeably and refer to a monovalent or polyvalent monocyclic, bicyclic, or tricyclic ring system containing 3 to 14 ring atoms, or 3 to 8 ring atoms, or 5 to 6 ring atoms, in which one or more atoms in the ring are independently replaced by a heteroatom, said heteroatom having the meaning described herein, and the ring may be fully saturated or contain one or more degrees of unsaturation. Unless otherwise specified, -CH2- groups on a heterocyclyl may be optionally replaced with -C(=O)-. Ring sulfur atoms may be optionally oxidized to S-oxides. Ring nitrogen atoms may be optionally oxidized to N-oxides. Examples of the heterocyclic group include a 3- to 14-membered heterocyclyl, a 3- to 8-membered heterocyclyl, a 5- to 10-membered heterocyclyl, and a 5- to 10-membered monocyclic or bicyclic heterocyclic group, and specific examples thereof include an ethylene oxide group, an azetidinyl group, an oxetanyl group, a thietanyl group, a pyrrolidinyl group, a 2-pyrrolinyl group, a 3-pyrrolinyl group, a pyrazolinyl group, a pyrazolidinyl group, an imidazolinyl group, an imidazolidinyl group, a tetrahydrofuranyl group, a dihydrofuranyl group, a tetrahydrothiophenyl group, and a dihydrothiophenyl group. Examples of heterocyclyl groups in which a -CH- group is replaced by -C(=O)- include, but are not limited to, a 2-pyridonyl group, a 2-oxopyrrolidinyl group, an oxo-1,3-thiazolidinyl group, a 2-piperidinonyl group, a 3,5-dioxopiperidinyl group, and a pyrimidindionyl group. Examples of heterocyclyl groups in which the sulfur atom is oxidized include, but are not limited to, sulfolane and 1,1-dioxothiomorpholinyl groups, which may be optionally substituted with one or more substituents as described herein.

[0045] The term "alkenyl" is a general term for hydrocarbons containing a carbon-carbon double bond in the molecule, and is an unsaturated aliphatic hydrocarbon. For example, vinyl (CH2=CH-) can be mentioned. The "alkenyl" may have 2 to 8 carbon atoms, i.e., "C2-C8" alkenyl, for example, 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 It may also have 2 to 5 carbon atoms, i.e., "C2-C5 alkenyl", 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, ethenyl (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.

[0046] The term "alkynyl" is a general term for hydrocarbons containing a carbon-carbon triple bond in the molecule, and is an unsaturated aliphatic hydrocarbon. For example, ethynyl (

[0047] [ka]

[0048] The "alkynyl" may have 2 to 8 carbon atoms, that is, a "C2 to C8" alkynyl group, such as C 2-8 Alkynyl, C 2-4 Alkynyl, C 2-5 Alkynyl, C3 alkynyl, C4 alkynyl, C6 alkynyl, C 2-6 Alkynyl, C 3-8 Alkynyl, C 3-6It may also have 2 to 5 carbon atoms, i.e., "C2-C5 alkynyl", for example, C 2-5 Alkynyl, C 2-3 It may be alkynyl, C3 alkynyl, C5 alkynyl, etc. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, and the like.

[0049] The term "hydrogen (H)" refers to a single hydrogen atom; such an atom can be linked to other groups, such as oxygen atoms, to form hydroxy groups.

[0050] The term "deuterium (D or 2H)" is a stable isotope of hydrogen that exists at a natural abundance of 0.015 mole %. The term "deuteration" refers to the replacement of one or more hydrogen atoms H in a group or compound with D.

[0051] The term "halogen" or "halogenated" should be understood to represent fluorine (F), chlorine (Cl), bromine (Br) or iodine (I), preferably a fluorine, chlorine or bromine atom, more preferably a fluorine atom.

[0052] The term "alkoxy group" refers to an alkyl group linked to the remainder of the molecule via an oxygen atom, wherein alkyl group has the meaning as defined herein. In one embodiment, the alkoxy group contains 1 to 8 carbon atoms. In one embodiment, the alkoxy group contains 1 to 5 carbon atoms, and in another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH), ethoxy (EtO, -OCHCH), 1-propoxy (n-PrO, -OCHCHCH), 2-propoxy (i-PrO, -OCH(CH)), 1-butoxy (n-BuO, -OCHCHCHCH), 2-l-propoxy (i-BuO, -OCHCH(CH)), 2-butoxy (s-BuO, -OCH(CH)CHCH), 2-methyl-2-propoxy (t-BuO, -OC(CH)), and the like.

[0053] The term "alkylthio" refers to an alkyl group attached to the remainder of the molecule via a sulfur atom, where alkyl has the meaning described herein. In one embodiment, the alkylthio group contains 1 to 8 carbon atoms. In one embodiment, the alkylthio group contains 1 to 5 carbon atoms. In another embodiment, the alkylthio group contains 1 to 3 carbon atoms. The alkylthio group may be optionally substituted with one or more substituents described herein. Examples of alkylthio groups include, but are not limited to, methylthio (-SCH), ethylthio (-SCHCH), propylthio (-SCHCHCH, -SCH(CH)), butylthio (-SCHCHCHCH, -SCHCH(CH), -SCH(CH)CHCH, -SC(CH)), and the like.

[0054] The term "cycloalkyl" refers to a cyclic hydrocarbon or cyclic alkenyl group consisting of carbon and hydrogen atoms, preferably containing one or two rings. The cycloalkyl group may be a monocyclic ring, a fused polycyclic ring, a bridged ring, or a spiro ring structure. The cycloalkyl group may have 3 to 8 carbon atoms, i.e., "C3-C8 cycloalkyl," or 3 to 6 carbon atoms, i.e., "C3-C6 cycloalkyl," such as C6 cycloalkyl, C5 cycloalkyl, C4 cycloalkyl, or C3 cycloalkyl. Examples of cycloalkyl groups include C3-C8 cycloalkyl and C3-C6 cycloalkyl, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl. This term also includes cases where a C atom is substituted with oxo (=0).

[0055] The terms "hydroxyalkyl" and "hydroxy-substituted alkyl" are used interchangeably and refer to an alkyl group substituted with one or more hydroxy groups. Examples include, but are not limited to, hydroxymethyl (-CHOH), hydroxyethyl (-CHCHOH, -CHOHCH), hydroxypropyl (-CHCHCHOH, -CHCHOHCH, -CHOHCHCH, -COHCHCH), and hydroxybutyl (-CHCHCHCHOH, -CHCHCHOHCH, -CHOHCHCHCH, -COHCHCHCH), where the hydroxy substitutions may be mono- or polysubstituted.

[0056] The terms "hydroxyalkoxy" and "hydroxy-substituted alkoxy" are used interchangeably and refer to an alkoxy group substituted with one or more hydroxy groups.

[0057] The terms "haloalkyl" and "halogen-substituted alkyl" are used interchangeably and refer to an alkyl group substituted with one or more halogens. Examples include, but are not limited to, halomethyl, haloethyl, halopropyl, halobutyl, halopentyl, etc. The above halo may be substituted with monohalogen, dihalogen, or trihalogen. In the case of trihalogen-substituted methyl, trifluoromethyl is more preferred.

[0058] The terms "haloalkoxy" and "halogen-substituted alkoxy" are used interchangeably and refer to an alkoxy group substituted with one or more halogens. Examples include, but are not limited to, halogenated methoxy, halogenated ethoxy, halogenated propoxy, halogenated butoxy, and halogenated pentoxy. The halogenated groups may be substituted with monohalogens, dihalogens, or trihalogens.

[0059] The terms "haloalkenyl" and "halogen-substituted alkenyl" are used interchangeably and refer to an alkenyl group substituted with one or more halogens. Examples include, but are not limited to, vinyl halides, propenyl halides, butenyl halides, pentenyl halides, and the like. The above halogens may be substituted with monohalogens, dihalogens, or trihalogens.

[0060] The terms "haloalkynyl" and "halo-substituted alkynyl" are used interchangeably and refer to an alkynyl group substituted with one or more halogens. Examples include, but are not limited to, haloethynyl, halopropynyl, halobutynyl, halopentynyl, and the like. The above halogens may be substituted with monohalogens, dihalogens, or trihalogens.

[0061] The term "hydroxy" refers to the group --OH.

[0062] "R1 and R2 together with the carbon atom to which they are linked form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or a C3-C8 cycloalkyl" or "R1 and R2 together with the carbon atom to which they are linked form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or a C3-C8 cycloalkyl" means that R1, R2 and the carbon atom to which they are linked together form a fused polycyclic group. Examples include:

[0063] [ka]

[0064] These groups may be substituted with one or more substituents.

[0065] The term "stereoisomers" refers to compounds that have identical chemical constitution, but in which the atoms or groups are arranged in space in different ways. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0066] The term "tautomer" refers to structural isomers with different energies that are interconvertible via a low energy barrier. When tautomers are possible (e.g., in solution), a chemical equilibrium of the tautomers can be reached. For example, proton tautomers (also called prototropic tautomers) include intertransformations that occur via proton transfer, such as keto-enol isomerization and imine-enamine isomerization.

[0067] The term "pharmaceutically acceptable salt" refers to an organic or inorganic salt of a compound of the present invention.

[0068] The term "pharmaceutically acceptable carrier" refers to a substance that has no appreciable irritating effect on an organism and that does not impair the biological activity and performance of the active compound. "Pharmaceutically acceptable carrier" includes, but is not limited to, a glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, disintegrant, stabilizer, solvent, or emulsifier.

[0069] The following detailed description of the invention is intended to illustrate non-limiting embodiments, allowing those skilled in the art to better understand the technical solution of the present invention, its principles, and its practical applications, so that those skilled in the art can modify and implement the present invention in many ways so as to best suit the requirements of specific applications.

[0070] Compounds of Formula I The present invention provides a compound represented by formula I, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof:

[0071] [ka]

[0072] During the ceremony, R1 and R2 are each independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen, wherein the substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano; Alternatively, R1 and R2, together with the carbon atom to which they are connected, form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or an optionally substituted C3-C8 cycloalkyl, which may be optionally substituted by one or more substituents, and the substituents are independently selected from H, D, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano; L1 is one or more substituents R LA a 6- to 14-membered aryl group optionally substituted with one or more substituents R LA and preferably one or more substituents R LA a 6- to 10-membered aryl group optionally substituted with one or more substituents R LA and more preferably one or more substituents R LA a phenyl group optionally substituted with one or more substituents R LA wherein the one or more substituents R are selected from 5- to 6-membered monocyclic heteroaryl groups optionally substituted with LA are independently H, D, halogen, one or more substituents R LB C1-C8 alkyl optionally substituted with one or more substituents R LB C1-C8 alkoxy, cyano, optionally substituted with one or more substituents R LB C2-C8 alkynyl optionally substituted with one or more substituents R LB C2-C8 alkenyl optionally substituted with hydroxy, nitro, one or more substituents R LB C1-C8 alkylthio optionally substituted with one or more substituents R LB and OR4, wherein the one or more substituents R LB is selected from H, D, halogen and hydroxy; R4 is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; L2 is selected from a 6- to 14-membered aryl substituted with 0-4 Rb groups and a 5- to 14-membered heteroaryl substituted with 0-4 Rb groups, preferably a 6- to 10-membered aryl substituted with 0-3 Rb groups and a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rb groups, more preferably a phenyl substituted with 0-3 Rb groups and a 5- to 6-membered heteroaryl substituted with 0-3 Rb groups; each Rb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, wherein said substituents are independently selected from H, D, halogen, and hydroxyl; X1 is N and CR 10 is selected from R 10 are selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C3-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, halogen, hydroxy, nitro and cyano, preferably selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen, and said substituents are independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro and cyano, preferably selected from H, D, halogen and hydroxy; X2 is N and CR 11 is selected from R 11 is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, halogen, hydroxy, nitro, and cyano, the substituents being independently selected from H, D, halogen, C1-C8 alkoxy, hydroxy, nitro, and cyano; and X1 and X2 are not N at the same time, and X2 is CR 11 and when X1 is N, then R2 is not H or D.

[0073] In one embodiment, the heteroaryl group is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl, 1,3,4-triazolyl, and pyranyl. In a preferred embodiment, the heteroaryl group is selected from imidazolyl, pyrazolyl, thienyl, furanyl, 1,2,3-triazolyl, pyranyl, and thiazolyl. In a more preferred embodiment, the heteroaryl group is thienyl, 1,2,3-triazolyl, pyranyl, thiazolyl, and furanyl.

[0074] In one embodiment, the heterocyclyl group is preferably selected from oxiranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, dihydrothiopyranyl, tetrahydrothiophenyl, dihydrothiophenyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, and pyrrolidinyl. In a preferred embodiment, the heterocyclyl group is selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and dihydropyranyl. In a particularly preferred embodiment, the heterocyclyl group is selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and dihydropyranyl.

[0075] In one embodiment, the C1-C8 alkyl group is selected from a C1-C5 alkyl group and a C1-C3 alkyl group. In particular embodiments, the C1-C8 alkyl group and the C1-C5 alkyl group are each independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and isopentyl. In more particular embodiments, the C1-C8 alkyl, C1-C5 alkyl, and C1-C3 alkyl are each independently selected from methyl, ethyl, propyl, and isopropyl.

[0076] In one embodiment, the propyl group includes, but is not limited to, an n-propyl group (n-Pr, -CH2CH2CH3) or an isopropyl group (i-Pr, -CH(CH3)2). The butyl group includes, but is not limited to, an n-butyl group (n-Bu, -CH2CH2CH2CH3), an isobutyl group (i-Bu, -CH2CH(CH3)2), a sec-butyl group (s-Bu, -CH(CH3)CH2CH3), or a tert-butyl group (t-Bu, -C(CH3)3). The pentyl group includes, but is not limited to, an n-pentyl group (-CH2CH2CH2CH2CH3), a 2-pentyl group (-CH(CH3)CH2CH2CH3), a 3-pentyl group (-CH(CH2CH3)2), a 2-methyl-2-butyl group (-C(CH3)2CH2CH3), a 3-methyl-2-butyl group (-CH(CH3)CH(CH3)2), a 3-methyl-1-butyl group (-CH2CH2CH(CH3)2), or a 2-methyl-1-butyl group (-CH2CH(CH3)CH2CH3).

[0077] In one embodiment, the C1-C8 alkoxy groups are selected from C1-C5 alkoxy groups and C1-C3 alkoxy groups. In particular embodiments, the C1-C8 alkoxy groups and the C1-C5 alkoxy groups are each independently selected from methoxy, ethoxy, propoxy, butoxy, and pentoxy groups. In more particular embodiments, the C1-C8 alkoxy, C1-C5 alkoxy, and C1-C3 alkoxy are each independently selected from methoxy, ethoxy, and propoxy.

[0078] In one embodiment, the C3-C8 cycloalkyl group is preferably a C3-C6 cycloalkyl group. In a preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. In a more preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl groups are selected from cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. In a particularly preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl groups are selected from cyclopentyl and cyclopentenyl.

[0079] 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.

[0080] In one embodiment, the compound of formula I has formula IA:

[0081] [ka]

[0082] In the formula, R 1A , R 2A , R 3Aare 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 H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen, and said substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, D, halogen and hydroxyl; Alternatively, R 1A , R 2A together with the carbon atoms to which they are attached form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl or a C3-C8 cycloalkyl optionally substituted with one or more substituents, said substituents being independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano; L 1A is selected from a 6- to 14-membered aryl group optionally substituted with one or more substituents, and a 5- to 14-membered heteroaryl group optionally substituted with one or more substituents, preferably a 6- to 10-membered aryl group optionally substituted with one or more substituents, and a 5- to 10-membered heteroaryl group optionally substituted with one or more substituents, more preferably a phenyl group optionally substituted with one or more substituents, and a 5- to 6-membered monocyclic heteroaryl group optionally substituted with one or more substituents, wherein 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, hydroxy, nitro, optionally substituted C1-C8 alkylthio, optionally substituted C3-C8 cycloalkyl, and OR 4Aand preferably, independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, hydroxy, optionally substituted C3-C6 cycloalkyl, and OR 4A and more preferably, independently selected from H, halogen, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C6 cycloalkyl, and OR 4A wherein the substituents are selected from H, D, halogen and hydroxy, and the substituents are preferably selected from D, halogen and hydroxy; R 4A is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; L 2A is selected from a 6- to 14-membered aryl substituted with 0-4 Rbbb groups and a 5- to 14-membered heteroaryl substituted with 0-4 Rbbb groups, preferably selected from a 5- to 10-membered aryl substituted with 0-3 Rbbb groups and a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbbb groups, more preferably selected from a phenyl substituted with 0-3 Rbbb groups and a 5- to 6-membered heteroaryl substituted with 0-3 Rbbb groups; Each Rbbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, wherein the substituents are independently selected from H, D, halogen, and hydroxyl.

[0083] In one embodiment, the compound of formula I has formula IA:

[0084] [ka]

[0085] In the formula, R 1A , R 2A , R 3Aare 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 H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen, and said substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably selected from H, halogen and hydroxyl; Alternatively, R 1A , R 2A together with the carbon atoms to which they are attached form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl or a C3-C8 cycloalkyl optionally substituted with one or more substituents, said substituents being independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano; L 1A is selected from a 6- to 14-membered aryl group optionally substituted with one or more substituents, and a 5- to 14-membered heteroaryl group optionally substituted with one or more substituents, preferably a 6- to 10-membered aryl group optionally substituted with one or more substituents, and a 5- to 10-membered heteroaryl group optionally substituted with one or more substituents, more preferably a phenyl group optionally substituted with one or more substituents, and a 5- to 6-membered monocyclic heteroaryl group optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl, and OR 4Aand preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR 4A and more preferably, independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl, and OR 4A is selected from R 4A is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; L 2A is selected from a 6- to 14-membered aryl substituted with 0-4 Rbbb groups and a 5- to 14-membered heteroaryl substituted with 0-4 Rbbb groups, preferably selected from a 5- to 10-membered aryl substituted with 0-3 Rbbb groups and a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbbb groups, more preferably selected from a phenyl substituted with 0-3 Rbbb groups and a 5- to 6-membered heteroaryl substituted with 0-3 Rbbb groups; Each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, wherein the substituents are independently selected from H, halogen, and hydroxyl.

[0086] In one embodiment, R 1A , R 2A , R 3Aare 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 H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl, and halogen, wherein said substituents are independently selected from H, halogen, C1-C8 alkoxy, hydroxyl, nitro, and cyano, preferably H, halogen, and hydroxyl. In one embodiment, the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, more preferably cyclopropyl.

[0087] In one embodiment, R 1A , R 2Atogether with the carbon atoms to which they are attached form a 3-8-membered heterocyclyl, a 5-8-membered heteroaryl, or a C3-C8 cycloalkyl, 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. In one embodiment, the 3-8-membered heterocyclyl is selected from oxiranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrothiophenyl, dihydrothiophenyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, and pyrrolidinyl. In a preferred embodiment, the 3-8-membered heterocyclyl is selected from tetrahydropyranyl and dihydropyranyl. In one embodiment, the 5-8-membered heteroaryl is selected from furanyl, pyranyl, and thienyl. In one embodiment, the C3-C8 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and cyclohexenyl, and in a preferred embodiment, the C3-C8 cycloalkyl is selected from cyclopentyl and cyclopentenyl.

[0088] In certain embodiments, R 1A , R 2A and together with the carbon atom to which they are attached, the following substituents:

[0089] [ka]

[0090] In a more particular embodiment, R 1A , R 2A and together with the carbon atom to which they are attached, the following substituents:

[0091] [ka]

[0092] In particularly particular embodiments, R 1A , R 2A and together with the carbon atom to which they are attached, the following substituents:

[0093] [ka]

[0094] wherein the group is optionally substituted with one or more substituents, the substituents being independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano, preferably H, halogen, C1-C8 alkyl and C1-C8 alkoxy, and more preferably H and halogen.

[0095] In one embodiment, L 1A is selected from a 6- to 14-membered aryl group optionally substituted with one or more substituents, and a 5- to 14-membered heteroaryl group optionally substituted with one or more substituents, preferably a 6- to 10-membered aryl group optionally substituted with one or more substituents, and a 5- to 10-membered heteroaryl group optionally substituted with one or more substituents, more preferably a phenyl group optionally substituted with one or more substituents, and a 5- to 6-membered monocyclic heteroaryl group optionally substituted with one or more substituents, and the above substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl, and OR 4A and preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR 4Aand more preferably, independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl, and OR 4A Selected from R 4A is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0096] In a preferred embodiment, L 1A is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, thiadiazolyl, thienyl and furanyl. 1A is selected from phenyl, pyridinyl, pyrazolyl, thiazolyl and thienyl. In a particularly preferred embodiment, L 1A are phenyl, pyridinyl, and thiazolyl, which groups are optionally substituted with one or more substituents, and the one or more substituents are independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl, and OR 4A and preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR 4A and more preferably, independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl, and OR 4A is selected from R 4A is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0097] In one embodiment, the compound of formula I has formula IA:

[0098] [ka]

[0099] In the formula, R 1A , R 2A , R 3A 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; L 1A is selected from a 6- to 14-membered aryl group optionally substituted by one or more substituents, and a 5- to 14-membered heteroaryl group optionally substituted by one or more substituents, preferably selected from a 6- to 10-membered aryl group optionally substituted by one or more substituents, and a 5- to 10-membered heteroaryl group optionally substituted by one or more substituents, more preferably selected from a phenyl group optionally substituted by one or more substituents, and a 5- to 6-membered monocyclic heteroaryl group optionally 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, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl; L 2A is selected from a 6- to 14-membered aryl substituted with 0-4 Rbbb groups and a 5- to 14-membered heteroaryl substituted with 0-4 Rbbb groups, preferably selected from a 5- to 10-membered aryl substituted with 0-3 Rbbb groups and a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbbb groups, more preferably selected from a phenyl substituted with 0-3 Rbbb groups and a 5- to 6-membered heteroaryl substituted with 0-3 Rbbb groups; Each Rbbb group is independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy.

[0100] In one embodiment, R 1A , R 2A , R 3A 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.

[0101] In a preferred embodiment, L 2A -L 1A The structure is

[0102] [ka]

[0103] In a more preferred embodiment, L 2A -L 1A The structure is

[0104] [ka]

[0105] In a particularly preferred embodiment, L 2A -L 1A The structure is

[0106] [ka]

[0107] is selected from.

[0108] In one embodiment, the L 2A -L 1A L in the structure 1A The group may be substituted with one or more substituents, the one or more substituents being independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl, and OR. 4A and preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C6 cycloalkyl, and OR 4A and more preferably, independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C6 cycloalkyl, and OR 4A Selected from R 4A is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0109] In one embodiment, the L 2A -L 1A L in the structure 1A The group may be substituted with one or more substituents, wherein the one or more substituents are independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, haloalkyl, deuterated C1-C8 alkyl and deuterated C1-C8 alkoxy, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy and deuterated C1-C8 alkyl.

[0110] In one embodiment, L 2Ais selected from a 6- to 14-membered aryl substituted with 0-4 Rbbb groups and a 5- to 14-membered heteroaryl substituted with 0-4 Rbbb groups, preferably selected from a 5- to 10-membered aryl substituted with 0-3 Rbbb groups and a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbbb groups, and more preferably selected from a phenyl substituted with 0-3 Rbbb groups and a 5- to 6-membered heteroaryl substituted with 0-3 Rbbb groups.

[0111] In one embodiment, L 2A is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thienyl, furanyl, and 1,3,4-triazolyl, preferably selected from phenyl, pyrimidinyl, pyridinyl, pyrazolyl, thienyl, imidazolyl, and 1,2,3-triazolyl, more preferably phenyl, pyridinyl, pyrazolyl, thienyl, and 1,2,3-triazolyl, wherein the above groups are optionally substituted with 0 to 4 Rbbb groups.

[0112] In one embodiment, each Rbbb group is independently selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, wherein said substituents are independently selected from H, halogen, and hydroxyl.

[0113] 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.

[0114] In certain embodiments, the compound of formula IA has formula II-A:

[0115] [ka]

[0116] In the formula, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, wherein said substituents are independently selected from H, halogen and hydroxyl.

[0117] In certain embodiments, the compound of formula IA has formula III-A:

[0118] [ka]

[0119] In the formula, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, said substituents being independently selected from H, halogen, and hydroxyl; n1A is an integer selected from 0 to 4, preferably 1; R 6A are independently H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl, and OR 4A and preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, and OR 4A and more preferably, independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, and OR 4A is selected from R 4Ais selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0120] In some embodiments, n1A is 1 and R 6A is located at the 2-position of the phenyl group, or the 3-position of the phenyl group, or the 4-position of the phenyl group, or the 5-position of the phenyl group, or the 6-position of the phenyl group. In some embodiments, n1A is 1 and R 6A is at the 4-position of the phenyl group. In some embodiments, n1A is 1 and R 6A is at the 6-position of the phenyl group.

[0121] In a more preferred embodiment, R 6A is independently selected from H, D, halogen, and C1-C8 alkoxy. 6A is C1-C4 alkoxy, preferably methoxy. In some embodiments, R 6A is a halogen, preferably F.

[0122] In certain embodiments, the compound of formula IA is represented by formula IV-A:

[0123] [ka]

[0124] In the formula, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, said substituents being independently selected from H, halogen, and hydroxyl; n2A is an integer selected from 0 to 3, preferably 1; R 7Aare independently H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl, and OR 4A and preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, and OR 4A and more preferably, independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, and OR 4A is selected from R 4A is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0125] In some embodiments, n2A is 1 and R 7A is located at the 2-position of the pyridyl group, or the 5-position of the pyridyl group, or the 6-position of the pyridyl group. In some embodiments, n2A is 1 and R 7A is at the 5-position of the pyridyl group. In some embodiments, n2A is 1 and R 7A is at the 6-position of the pyridyl group.

[0126] In a more preferred embodiment, R 7A is independently selected from H, D, halogen, and C1-C8 alkoxy. 7A is C1-C4 alkoxy, preferably methoxy. In some embodiments, R 7A is a halogen, preferably F.

[0127] In certain embodiments, the compound of formula IA has the formula VA:

[0128] [ka]

[0129] In the formula, R 5A is selected from H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, said substituents being independently selected from H, halogen, and hydroxyl; n3A is an integer selected from 0 to 3, preferably 1; R 8A are independently H, halogen, C1-C8 alkyl, C1-C8 alkoxy, cyano, C2-C8 alkynyl, C2-C8 alkenyl, hydroxy, nitro, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C1-C8 alkylthio, C3-C8 cycloalkyl, and OR 4A and preferably independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, hydroxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, C3-C8 cycloalkyl, and OR 4A and more preferably, independently selected from H, halogen, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl, C3-C8 cycloalkyl, and OR 4A is selected from R 4A is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0130] In some embodiments, n3A is 1 and R 8A is located at the 2-position of the pyridyl group, or the 5-position of the pyridyl group, or the 6-position of the pyridyl group. In some embodiments, n3A is 1 and R 7A is at the 5-position of the pyridyl group. In some embodiments, n3A is 1 and R 8A is at the 6-position of the pyridyl group.

[0131] In a more preferred embodiment, R 8A is independently selected from H, D, halogen, and C1-C8 alkoxy. 8A is C1-C4 alkoxy, preferably methoxy. In some embodiments, R 8A is a halogen, preferably F.

[0132] In one embodiment, the compound of formula IB has formula IB:

[0133] [ka]

[0134] In the formula, R 1B , R 3B are independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cycloalkyl and halogen, wherein said substituents are independently selected from halogen, D, C1-C8 alkoxy, hydroxyl, nitro and cyano; R 2Bis selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F; Alternatively, R 1B and R 2B together form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl or a C3-C8 cycloalkyl optionally substituted by one or more substituents, said substituents being independently selected from halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano; L 1B is selected from optionally substituted phenyl and optionally substituted pyridyl, and the 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, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; L 2Bis a 5- to 14-membered heteroaryl substituted with 0-4 Rbb groups, preferably a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbb groups, and more preferably a 5- to 6-membered heteroaryl substituted with 0-3 Rbb groups; Each Rbb group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy and halogen, preferably selected from H and C1-C8 alkyl, wherein said substituents are independently selected from H and halogen.

[0135] In one embodiment, R 1B , R 3B are independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3-8 membered heterocyclyl, halogen, hydroxyl, nitro and cyano, and are preferably H, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C8 cyclo alkyl and halogen, wherein the substituents are independently selected from halogen, D, C1-C8 alkoxy, hydroxyl, nitro, and cyano; the 3-8 membered heterocyclyl is preferably selected from oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, and pyrrolidinyl; the C3-C8 cycloalkyl group is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, preferably cyclopropyl; R 2Bis selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0136] In one embodiment, R 1B and R 2B are taken together to form a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or a C3-C8 cycloalkyl optionally substituted by one or more substituents, wherein the 3- to 8-membered heterocyclyl is preferably selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, and pyrrolidinyl, more preferably tetrahydrofuranyl, tetrahydropyranyl, and dihydropyranyl, the 5- to 8-membered heteroaryl is preferably selected from furanyl, pyranyl, and thienyl, the C3-C8 cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl, more preferably cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl, and the substituents are independently selected from halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro, and cyano.

[0137] In certain embodiments, R 1B , R 2B together with the pyrimidinyl group to which they are attached, can be substituted with the following substituents:

[0138] [ka]

[0139] In a more particular embodiment, R 1B , R 2B together with the pyrimidinyl group to which they are attached, can be substituted with the following substituents:

[0140] [ka]

[0141] wherein the group is optionally substituted with one or more substituents, said substituents being independently selected from halogen, D, C1-C8 alkyl, C1-C8 alkoxy, hydroxyl, nitro and cyano.

[0142] In a preferred embodiment, R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, 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.

[0143] In one embodiment, L 1B is selected from optionally substituted phenyl and optionally substituted pyridyl, and the 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, hydroxy, nitro, cyano, -OR 4Band C1-C8 alkylthio, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio, R 4B is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0144] In a preferred embodiment, L 1B teeth,

[0145] [ka]

[0146] is selected from, preferably

[0147] [ka]

[0148] and more preferably selected from

[0149] [ka]

[0150] wherein the above groups are optionally substituted with one or more substituents, and the one or more substituents are independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4Band C1-C8 alkylthio, preferably independently selected from H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio, R 4B is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl.

[0151] In one embodiment, L 2B is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl, and 1,3,4-triazolyl, preferably selected from pyrazolyl, imidazolyl, and 1,2,3-triazolyl, more preferably 1,2,3-triazolyl, wherein the above groups are optionally substituted with 0 to 4 Rbb groups.

[0152] In one embodiment, each R group is independently selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, preferably selected from H and C1-C8 alkyl, wherein said substituents are independently selected from D and halogen.

[0153] In one embodiment, the heteroaryl group is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl, 1,3,4-triazolyl, and pyranyl. In a preferred embodiment, the heteroaryl group is selected from imidazolyl, pyrazolyl, thienyl, furanyl, 1,2,3-triazolyl, and pyranyl. In a further preferred embodiment, the heteroaryl group is selected from thienyl, furanyl, 1,2,3-triazolyl, and pyranyl.

[0154] In one embodiment, the heterocyclyl group is preferably selected from oxiranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, and pyrrolidinyl. In a preferred embodiment, the heterocyclyl group is selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and dihydropyranyl. In a particularly preferred embodiment, the heterocyclyl group is selected from tetrahydrofuranyl, dihydrofuranyl, and tetrahydropyranyl.

[0155] In one embodiment, the C3-C8 cycloalkyl group is preferably a C3-C6 cycloalkyl group. In a preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl groups are selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. In a more preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl groups are selected from cyclopropyl, cyclopentyl, cyclohexyl, cyclopentenyl, and cyclohexenyl. In a particularly preferred embodiment, the C3-C8 cycloalkyl and C3-C6 cycloalkyl groups are cyclopentyl and cyclopentenyl.

[0156] In certain embodiments, the compound of formula IB is represented by formula II-B:

[0157] [ka]

[0158] In the formula, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, said substituents being independently selected from D and halogen; R 2Bis selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0159] In certain embodiments, the compound of formula IB is represented by formula III-B:

[0160] [ka]

[0161] In the formula, n1B is an integer selected from 0 to 3, R 6B are independently H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; R 2Bis selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0162] In some embodiments, n1B is 1 and R 6B is located at the 2-position of the pyridyl group, or the 5-position of the pyridyl group, or the 6-position of the pyridyl group. In some embodiments, n1B is 1 and R 6B is at the 5-position of the pyridyl group. In some embodiments, n1B is 1 and R 6B is at the 6-position of the pyridyl group.

[0163] In a more preferred embodiment, R 6B is independently selected from H, D, halogen, and C1-C8 alkoxy. 6B is C1-C4 alkoxy, preferably methoxy. In some embodiments, R 6B is a halogen, preferably F.

[0164] In certain embodiments, the compound of formula IB is represented by formula IV-B:

[0165] [ka]

[0166] In the formula, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, said substituents being independently selected from D and halogen; n2B is an integer selected from 0 to 4, preferably 1; R 7B are independently H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio; R 4B is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; R 2B is selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy, nitro and cyano, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0167] In some embodiments, n2B is 1 and R 7B is located at the 2-position of the phenyl group, or the 3-position of the phenyl group, or the 4-position of the phenyl group, or the 5-position of the phenyl group, or the 6-position of the phenyl group. In some embodiments, n2B is 1 and R 7B is at the 4-position of the phenyl group. In some embodiments, n2B is 1 and R 7B is at the 6-position of the phenyl group.

[0168] In a more preferred embodiment, R 7B is independently selected from H, D, halogen, and C1-C8 alkoxy. 7B is C1-C4 alkoxy, preferably methoxy. In some embodiments, R 7B is a halogen, preferably F.

[0169] In certain embodiments, the compound of formula IB has formula VB:

[0170] [ka]

[0171] In the formula, R 5B is selected from H, D, optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, and halogen, said substituents being independently selected from D and halogen; n3B is an integer selected from 0 to 3, preferably 1; R 8B are independently H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C1-C8 haloalkyl, C1-C8 haloalkoxy, hydroxy, nitro, cyano, -OR 4B and C1-C8 alkylthio, preferably H, D, C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 haloalkyl, -OR 4B and C1-C8 alkylthio, R 4B is selected from C3-C8 cycloalkyl and 3-8 membered heterocyclyl, preferably C3-C6 cycloalkyl; R 2Bis selected from C1-C8 alkyl, C1-C8 alkoxy, halogen, C1-C8 deuterated alkyl, C1-C8 deuterated alkoxy, C1-C8 hydroxyalkyl, C1-C8 hydroxyalkoxy, C2-C8 alkenyl, C2-C8 alkynyl, C1-C8 haloalkyl, C1-C8 haloalkoxy, C2-C8 haloalkenyl, C2-C8 haloalkynyl, hydroxy and nitro, preferably selected from C1-C8 alkyl, C1-C8 alkoxy, C1-C8 haloalkyl and halogen, more preferably selected from C1-C8 alkyl, C1-C8 haloalkyl and halogen, and even more preferably F.

[0172] In some embodiments, n3B is 1 and R 8B is located at the 2-position of the pyridyl group, or the 5-position of the pyridyl group, or the 6-position of the pyridyl group. In some embodiments, n3B is 1 and R 8B is at the 5-position of the pyridyl group. In some embodiments, n3B is 1 and R 8B is at the 6-position of the pyridyl group.

[0173] In a more preferred embodiment, R 8B is independently selected from H, D, halogen, and C1-C8 alkoxy. 8B is C1-C4 alkoxy, preferably methoxy. In some embodiments, R 8B is a halogen, preferably F.

[0174] In certain embodiments, the compound of formula I is any of the following compounds:

[0175] [ka]

[0176] [ka]

[0177] [ka]

[0178] [ka]

[0179] [ka]

[0180] [ka]

[0181] is selected from.

[0182] Beneficial technical effects of the present invention Compared with the prior art, the technical solution of the present invention has the following advantages: The present invention relates to a novel structural compound, which is a selective OX2R antagonist and can be used for the prevention, treatment, and / or alleviation of orexin receptor-related diseases, preferably for the treatment of insomnia, depression, Alzheimer's disease, and sleep apnea. As an OX2 receptor antagonist, this compound exhibits excellent selectivity and pharmacodynamic activity, as well as excellent pharmacokinetic properties, improves oral bioavailability in subjects, and significantly reduces autonomic activity in subjects, and has good prospects for clinical application. [Brief explanation of the drawings]

[0183] [Figure 1] 1 is a graph showing the wakefulness time of rats in each time period 12 hours after administration of 30 mg / kg of seltorexant. [Figure 2] 1 is a graph showing the wakefulness time of rats at each time point 12 hours after administration of 30 mg / kg of Compound 1. [Figure 3] 1 is a graph showing the wakefulness time of rats at each time point 12 hours after administration of 30 mg / kg of Compound 5. [Figure 4] 1 is a graph showing the wakefulness time of rats at each time point 12 hours after administration of 30 mg / kg of Compound 22. [Figure 5] 1 is a graph showing the wakefulness time of rats at each time point 12 hours after administration of 30 mg / kg of Compound 41. [Example]

[0184] Examples of the present invention will be described in detail below. The examples described below are illustrative and are used only to explain the present invention, and should not be understood as limiting the present invention. Unless otherwise specified, all ratios, percentages, etc. referred to in this specification are by weight.

[0185] The following examples were prepared using starting materials that are cis-configuration, i.e., tert-butyl cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate as the starting material, resulting in all cis-isomers of the example compounds. Synthesis Examples

[0186] [ka]

[0187] tert-Butyl cis-5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate and N-phenylbistrifluoromethylsulfonimide are subjected to a trifluoromethanesulfonylation reaction to obtain intermediate Ia, which is then subjected to a boric acid esterification reaction with pinacol diboric acid ester to obtain intermediate Ib, which is then reacted with Ib.

[0188] [ka]

[0189] was subjected to a coupling reaction to give intermediate Ic, which was then deprotected from Boc to give intermediate Id.

[0190] [ka]

[0191] and

[0192] [ka]

[0193] was subjected to a coupling reaction to give intermediate Ie, which was then subjected to an ester hydrolysis reaction to give intermediate If, ​​and finally Id and If were subjected to a condensation reaction to give the compound of formula I.

[0194] Example 1: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (1)

[0195] [ka]

[0196] dioxane: dioxane rt: room temperature crude: crude product

[0197] 1.1 A solution of tert-butyl cis-5-oxo-hexahydrocyclopenta[c]pyrrole-2-carboxylate (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 the 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 the addition of water / ice (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 5-[[(trifluoromethyl)sulfonyl]oxy]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 1a) (4.8 g).

[0198] 1.2 A solution of 1a (4.5 g, 12.59 mmol), pinacoldiboron (4.8 g, 18.90 mmol), KOAc (3.5 g, 25.36 mmol), and Pd(dppf)Cl (0.9 g, 1.24 mmol) in dioxane (20 mL) was heated to 80 °C and stirred overnight under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 3.6 g of crude tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 1b), which was used directly in the next step without further purification.

[0199] 1.3 2,4,6-Trichloro-5-fluoropyrimidine (5 g, 24.87 mmol) and iron(III) triacetylacetonate (0.9 g, 2.55 mmol) were dissolved in 20 mL of THF solution and cooled to -78 °C. Under nitrogen protection, MeMgCl (19 mL of a 3.0 M solution in THF) was added dropwise. After the addition was complete, the mixture was reacted at -78 °C for 1 h. The reaction mixture was then left at room temperature for 3 h. Upon completion of the reaction, the mixture was quenched by pouring it into 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).

[0200] 1.4 1b (3.5 g, 10.44 mmol), 1c (1.8 g, 11.48 mmol), K2CO3 (2.9 g, 21.01 mmol), and Pd(dppf)Cl2 (0.76 g, 1.05 mmol) were dissolved in a mixture of dioxane (20 mL) and HO (5 mL) and heated to 100 °C under nitrogen protection. After completion of the reaction, the mixture was cooled to room temperature, diluted with 30 mL of water, and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with saturated brine (2 × 20 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography (PE / EA = 1:1) to give tert-butyl 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 1d) (2.8 g).

[0201] 1.5 Compound 1d (2.8 g, 8.40 mmol) and trifluoroacetic acid (10.00 mL) were added to dichloromethane (30.00 mL) and stirred at room temperature under nitrogen protection for 2 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (Compound 1e). The crude product was used directly in the next step without further purification.

[0202] 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 completion of the reaction, the reaction mixture 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 30 minutes and then separated. The organic phase was discarded, and the pH of the aqueous phase was adjusted to acidic with 2 N hydrochloric acid and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and then 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).

[0203] 1.7 1e (100 mg, 0.43 mmol) and 1f (101 mg, 0.49 mmol) were added to DMF (5 mL), and HATU (262 mg, 0.69 mmol) was added at room temperature under nitrogen protection. DIPEA (119 mg, 0.92 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was completed, the mixture was extracted with ethyl acetate (3 × 15 mL). The organic phase was washed with water (3 × 10 mL), dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure, and separated by column chromatography (petroleum ether / ethyl acetate = 1:2) to obtain 68 mg of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (Compound 1). 1H NMR (400 MHz, Methanol-d4) δ 7.99 - 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), LCMS (ES, m / z): 423 [M+H] + .

[0204] Example 2: Preparation of (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (2)

[0205] [ka]

[0206] 2.1 4-Fluoro-6-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 2a) was prepared according to the method of Example 1-1.6, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced (changed) with 4-fluoro-6-iodobenzoic acid.

[0207] 2.2 (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 2) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 2a. 1H NMR (400 MHz, DMSO-d6) δ 8.13 - 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 = 80.4 Hz, 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] + .

[0208] Example 3: Preparation of (3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (3)

[0209] [ka]

[0210] 3.1 3-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 3a) was prepared according to the method of Example 1-1.6, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced with 3-fluoro-2-iodobenzoic acid.

[0211] 3.2 (3-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 3) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 3a. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 22.4 Hz, 2H), 7.70 - 7.56 (m, 2H), 7.34 (t, J = 6.2 Hz, 1H), 6.60 (d, J = 20.0 Hz, 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] + .

[0212] Example 4: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (4)

[0213] [ka]

[0214] 4.1 5-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 4a) was prepared according to the method of Example 1-1.6, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced with 2-iodo-5-methoxybenzoic acid.

[0215] 4.2 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 4) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 4a. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 23.2 Hz, 2H), 7.68 - 7.51 (m, 2H), 7.14 - 7.07 (m, 1H), 6.51 (d, J = 41.7 Hz, 1H), 3.81 (d, J = 5.6 Hz, 3H), 3.69 - 3.44 (m, 3H), 3.29 - 3.17 (m, 2H), 3.02 - 2.68 (m, 3H), 2.40 (d, J = 5.6 Hz, 6H). LCMS (ES, m / z): 435 [M+H] + .

[0216] Example 5: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (5)

[0217] [ka]

[0218] 5.1 4-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 5a) was prepared according to the method of Example 1-1.6, except that the reaction raw material 2-fluoro-6-iodobenzoic acid was replaced with 2-iodo-4-methoxybenzoic acid.

[0219] 5.2 Using the method of Example 1-1.7, but replacing reactant 1f with 5a, (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 5) was prepared. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J = 26.3 Hz, 2H), 7.38 - 7.33 (m, 2H), 7.07 (td, J = 8.7, 2.5 Hz, 1H), 6.57 (d, J = 78.2 Hz, 1H), 3.87 (d, J = 5.6 Hz, 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] + .

[0220] Example 6: Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (6)

[0221] [ka]

[0222] 6.1 5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 6a) was prepared according to the method of Example 1-1.6, replacing the reaction raw material 2-fluoro-6-iodobenzoic acid with 2-iodo-5-methylbenzoic acid.

[0223] 6.2 Using the method of Example 1-1.7, substituting reactant 1f with 6a, (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 6) was prepared. 1H NMR (400 MHz, DMSO-d6) δ 7.90 (d, J = 24.5 Hz, 2H), 7.53 - 7.42 (m, 2H), 7.23 - 7.11 (m, 1H), 6.53 (d, J = 46.1 Hz, 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] + .

[0224] Example 7: Preparation of (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (7)

[0225] [ka]

[0226] 7.1 2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 7a) was prepared according to the method of Example 1-1.6, replacing the reactant 2-fluoro-6-iodobenzoic acid with 2-iodobenzoic acid.

[0227] 7.2 (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 7) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 7a. 1H NMR (400 MHz, Chloroform-d) δ 8.04 - 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 = 114.0 Hz, 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] + .

[0228] Example 8: Preparation of (5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (8)

[0229] [ka]

[0230] 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, separated and purified by column chromatography, and eluted with PE / EA (1:1) to obtain 2.1 g of 2-chloro-5-fluoro-4-methoxy-6-methylpyrimidine (compound 8a).

[0231] 8.2 tert-Butyl 5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 8b) was prepared according to the method of Example 1-1.4, replacing reactant 1c with 8a.

[0232] 8.3 5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 8c) was prepared according to the method of Example 1-1.5, substituting reactant 1d with 8b.

[0233] 8.4 (5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 8) was prepared according to the method of Example 1-1.7, replacing reactant 1e with 8c. 1 H NMR (400 MHz, Chloroform-d) δ 8.03 - 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 = 16.7 Hz, 1H), 2.43 (dd, J = 11.0, 3.0 Hz, 3H). LCMS (ES, m / z): 439 [M+H] + .

[0234] Example 9: Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (9)

[0235] [ka]

[0236] 9.1 2-Chloro-4,5,6-trimethylpyrimidine (compound 9a) was prepared according to the method of Example 1-1.3, replacing the reactant 2,4,6-trichloro-5-fluoropyrimidine with 2,4,6-trichloro-5-methylpyrimidine.

[0237] 9.2 tert-Butyl 5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 9b) was prepared according to the method of Example 1-1.4, substituting 9a for reactant 1c.

[0238] 9.3 5-(4,5,6-trimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 9c) was prepared according to the method of Example 1-1.5, substituting 9b for reactant 1d.

[0239] 9.4 (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4,5,6-trimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 9) was prepared according to the method of Example 1-1.7, replacing reactant 1e with 9c. 1 H NMR (400 MHz, Chloroform-d) δ 7.87 - 7.76 (m, 2H), 7.64 (d, J = 26.4 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.23 - 6.94 (m, 1H), 6.88 - 6.43(m, LCMS (ES, m / z): 419 [M+H] + .

[0240] Example 10 Preparation of (5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (10)

[0241] [ka]

[0242] 10.1 tert-Butyl 5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 10a) was prepared according to the method of Example 1-1.4, substituting 2,5-dichloro-4,6-dimethylpyrimidine for reactant 1c.

[0243] 10.2 5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 10b) was prepared according to the method of Example 1-1.5, substituting 10a for reactant 1d.

[0244] 10.3 (5-(5-chloro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 10) was prepared according to the method of Example 1-1.7, substituting reactant 1e with 9c. 1H NMR (400 MHz, Chloroform-d) δ 7.94 - 7.72 (m, 2H), 7.61 (d, J = 25.4 Hz, 1H), 7.46 (h, J = 6.0, 5.4 Hz, 1H), 7.12 (dt, J = 16.2, 8.5 Hz, 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] + .

[0245] Example 11: Preparation of (5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (11)

[0246] [ka]

[0247] 11.1 Ethyl 2-ethyl-3-oxobutanoate (5.0 g, 31.61 mmol) and urea (1.9 g, 31.67 mmol) were added to 60 mL of ethanol. Under nitrogen protection, EtONa (4.3 g, 63.24 mmol) was added, and the temperature was raised to 70 °C for 7 h. After completion of the reaction, the temperature was lowered to room temperature, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with water (2 × 20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The filtrate was purified by column chromatography eluting with PE / EA (10:1) to give 2.1 g of 5-ethyl-6-methylpyrimidine-2,4(3H,5H)-dione (Compound 11a).

[0248] 11.2 11a (1.8 g, 11.68 mmol) and diethylaniline (2 mL) were added to phosphorus oxychloride (20 mL) and reacted at 110 °C for 3 h under nitrogen protection. After completion of the reaction, the temperature was lowered to room temperature, the pH was adjusted to 7 with saturated Na2CO3 solution, extracted with EtOAc (3 × 10 mL), the organic phases were combined, washed with water (2 × 5 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography eluting with PE / EA (3:1) to give 1.2 g of 2,4-dichloro-5-ethyl-6-methylpyrimidine (compound 11b).

[0249] 11.3 2-Chloro-5-ethyl-4,6-dimethylpyrimidine (compound 11c) was prepared according to the method of Example 1-1.3, replacing the reactant 2,4,6-trichloro-5-fluoropyrimidine with 11b.

[0250] 11.4 Prepare tert-butyl 5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 11d) according to the method of Example 1-1.4, substituting 11c for reactant 1c.

[0251] 11.5 5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 11e) was prepared according to the method of Example 1-1.5, substituting 11d for reactant 1d.

[0252] 11.6 (5-(5-ethyl-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 11) was prepared according to the method of Example 1-1.7, substituting 11e for reactant 1e. 1H NMR (400 MHz, Chloroform-d) δ 7.92 - 7.74 (m, 2H), 7.61 (d, J = 31.4 Hz, 1H), 7.46 (ttd, J = 8.4, 6.0, 3.1 Hz, 1H), 7.21 - 6.97 (m, 1H), 6.90 - 6.46 (m, 1H), 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] + .

[0253] Example 12: Preparation of (4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (12)

[0254] [ka]

[0255] 12.1 4-Ethoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 12a) was prepared according to the method of Example 1-1.6, replacing the reactant 2-fluoro-6-iodobenzoic acid with 2-bromo-4-ethoxybenzoic acid.

[0256] 12.2 (4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 12) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 12a. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 24.8 Hz, 2H), 7.33 - 7.28 (m, 2H), 7.09 - 7.05 (m, 1H), 6.52 (d, J = 76.4 Hz, 1H), 3.87 - 3.78 (m, LCMS (ES, m / z): 449 [M+H] + .

[0257] Example 13 Preparation of (4-cyclopropyloxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (13)

[0258] [ka]

[0259] 13.1 2-Bromo-4-hydroxybenzoic acid (5.0 g, 23.04 mmol), cyclopropane bromide (8.4 g, 69.43 mmol), and cesium carbonate (15.0 g, 46.01 mmol) were added to 30 mL of DMF, and the tube was sealed and heated to 100 °C for 10 h. After the reaction was completed, the mixture was cooled to room temperature, 150 mL of water was added, and the mixture was extracted with EtOAc (3 × 50 mL). The combined organic phases were washed with water (2 × 30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting mixture was purified by column chromatography eluting with PE / EA (1:1) to give 1.1 g of 2-bromo-4-cyclopropyloxybenzoic acid (Compound 13a).

[0260] 13.2 4-Cyclopropyloxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 13b) was prepared according to the method of Example 1-1.6, substituting 13a for the reactant 2-fluoro-6-iodobenzoic acid.

[0261] 13.3 (4-Cyclopropyloxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 13) was prepared according to the method of Example 1-1.7, substituting reactant 1f with 13b. 1 H NMR (400 MHz, DMSO-d6) δ 7.99 - 7.93 (m, 2H), 7.40 - 7.31 (m, 2H), 7.14 - 7.07 (m, 1H), 6.46 (d, J= 76.4 Hz, 1H), 4.13 - 4.06 (m, LCMS (ES, m / z): 449 [M+H] + .

[0262] Example 14: (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (14)

[0263] [ka]

[0264] 14.1 2-Chloro-4-methyl-5,6,7,8-tetrahydroquinazoline (compound 14a) was prepared according to the method of Example 1-1.3, replacing the reactant 2,4,6-trichloro-5-fluoropyrimidine with 2,4-dichloro-5,6,7,8-tetrahydroquinazoline.

[0265] 14.2 tert-Butyl 5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 14b) was prepared according to the method of Example 1-1.4, substituting 14a for reactant 1c.

[0266] 14.3 5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 14c) was prepared according to the method of Example 1-1.5, substituting 14b for reactant 1d.

[0267] 14.4 (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-5,6,7,8-tetrahydroquinazolin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 14) was prepared according to the method of Example 1-1.7, substituting 14c for reactant 1e. 1 H NMR (400 MHz, Methanol-d4) δ 7.92 (d, J = 2.0 Hz, 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] + .

[0268] Example 15 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (15)

[0269] [ka]

[0270] 15.1 2-Chloro-4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine (compound 15a) was prepared according to the method of Example 1-1.3, replacing the reactant 2,4,6-trichloro-5-fluoropyrimidine with 2,4-dichloro-7,8-dihydro-6H-pyrano[3,2-d]pyrimidine.

[0271] 15.2 tert-Butyl 5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 15b) was prepared according to the method of Example 1-1.4, substituting 15a for reactant 1c.

[0272] 15.3 5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 15c) was prepared according to the method of Example 1-1.5, substituting 15b for reactant 1d.

[0273] 15.4 (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-6H-pyrano[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 15) was prepared according to the method of Example 1-1.7, substituting 15c for reactant 1e.1 H NMR (400 MHz, Chloroform-d) δ 7.91 - 7.78 (m, 2H), 7.54 (d, J = 25.6 Hz, 1H), 7.49 - 7.42 (m, 1H), 7.15 - 7.13 (m, 1H), 6.89 - 6.42 (m, LCMS (ES, m / z): 447 [M+H] + .

[0274] Example 16 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (16)

[0275] [ka]

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

[0277] 16.2 tert-Butyl 5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 16b) was prepared according to the method of Example 1-1.4, substituting 16a for reactant 1c.

[0278] 16.3 5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 16c) was prepared according to the method of Example 1-1.5, substituting 16b for reactant 1d.

[0279] 16.4 Using the method of Example 1-1.7, substituting 16c for reactant 1e, (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 16) was prepared. 1 H NMR (400 MHz, Chloroform-d) δ 7.96 - 7.69 (m, 2H), 7.61 (dd, J = 23.9, 1.8 Hz, 1H), 7.56 - 7.38 (m, 1H), 7.12 (dt, J = 16.1, 8.5 Hz, 1H), 6.93 - 6.42 (m, 1H), 4.73 (d, J= 8.7 Hz, 2H), 4.29 - 3.77 (m, 4H), 3.78 - 3.33 (m, 3H), 3.27 - 2.79 (m, 5H), 2.51 - 2.22 (m, 3H). LCMS (ES, m / z): 447 [M+H] + .

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

[0281] [ka]

[0282] 17.1 2-Chloro-4-methyl-6,7-dihydro-5H-cyclopentane[d]pyrimidine (compound 17a) was prepared according to the method of Example 1-1.3, replacing the reactant 2,4,6-trichloro-5-fluoropyrimidine with 2,4-dichloro-6,7-dihydro-5H-cyclopentane[d]pyrimidine.

[0283] 17.2 tert-Butyl 5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 17b) was prepared according to the method of Example 1-1.4, substituting 17a for reactant 1c.

[0284] 17.3 5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 17c) was prepared according to the method of Example 1-1.5, substituting 17b for reactant 1d.

[0285] 17.4 (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 17) was prepared according to the method of Example 1-1.7, substituting 17c for reactant 1e. 1H NMR (400 MHz, Methanol-d4) δ 7.96 (d, J = 1.4 Hz, 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, 3H), 3.44 (tdd, J= 12.1, 8.4, 3.7 Hz, 2H), 3.24 - 3.03 (m, 2H), 3.02 - 2.84 (m, 5H), 2.46 - 2.39 (m, 3H), 2.14 (h, J = 7.3 Hz, 2H). LCMS (ES, m / z): 431 [M+H] + .

[0286] 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-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (18)

[0287] [ka]

[0288] 18.1 2-Chloro-4-methylfuro[3,2-d]pyrimidine (compound 18a) was prepared according to the method of Example 1-1.3, substituting 2,4-dichlorofuro[3,2-d]pyrimidine for the reactant 2,4,6-trichloro-5-fluoropyrimidine.

[0289] 18.2 tert-Butyl 5-(4-methylfuro[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 18b) was prepared according to the method of Example 1-1.4, substituting 18a for reactant 1c.

[0290] 18.3 5-(4-methylfuro[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 18c) was prepared according to the method of Example 1-1.5, substituting 18b for reactant 1d.

[0291] 18.4 (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylfuran[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 18) was prepared according to the method of Example 1-1.7, substituting 18c for reactant 1e. 1 H NMR (400 MHz, Methanol-d4) δ 7.91 - 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] + .

[0292] 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-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (19)

[0293] [ka]

[0294] 19.1 18a (2 g, 11.86 mmol), Pd / C (20%, 400 mg), and 10 mL of MeOH were added to a pressure reactor, and the reaction mixture was hydrogenated at 50 °C under 5 psi hydrogen pressure for 6 hours. After completion of the reaction, the mixture was filtered through Celite and concentrated under reduced pressure. The product was purified by column chromatography and eluted with PE / EA (10:1) to give 430 mg of 2-chloro-4-methyl-6,7-dihydrofurano[3,2-d]pyrimidine (compound 19a).

[0295] 19.2 tert-Butyl 5-(4-methyl-6,7-dihydrofuran[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 19b) was prepared according to the method of Example 1-1.4, substituting 19a for reactant 1c.

[0296] 19.3 5-(4-methyl-6,7-dihydrofuran[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 19c) was prepared according to the method of Example 1-1.5, substituting 19b for reactant 1d.

[0297] 19.4 (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-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 19) was prepared according to the method of Example 1-1.7, substituting 19c for reactant 1e. 1H NMR (400 MHz, Chloroform-d) δ 8.12 - 7.78 (m, 2H), 7.73 (s, 1H), 7.47 (tdd, J = 8.3, 5.9, 2.1 Hz, 1H), 7.14 (tdd, J = 8.4, 5.4, 1.0 Hz, 1H), 6.77 - 6.45 (m, 1H), 4.53 (t, J = 8.8 Hz, 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] + .

[0298] 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-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (20)

[0299] [ka]

[0300] 20.1 2-Chloro-4-methyl-5,7-dihydrofurano[3,4-d]pyrimidine (compound 20a) was prepared according to the method of Example 1-1.3, substituting 2,4-dichloro-5,7-dihydrofurano[3,4-d]pyrimidine for the reactant 2,4,6-trichloro-5-fluoropyrimidine.

[0301] 20.2 tert-Butyl 5-(4-methyl-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 20b) was prepared according to the method of Example 1-1.4, substituting 20a for reactant 1c.

[0302] 20.3 5-(4-methyl-5,7-dihydrofuran[3,4-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 20c) was prepared according to the method of Example 1-1.5, substituting 20b for reactant 1d.

[0303] 20.4 (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-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 20) was prepared according to the method of Example 1-1.7, substituting 20c for reactant 1e. 1 H NMR (400 MHz, Methanol-d4) δ 7.96 (s, 1H), 7.87 (td, J = 16.3, 15.7, 7.4 Hz, 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, 2.9 Hz, 2H), 3.99 - 3.77 (m, 2H), 3.62 (tdd, J = 11.5, 8.4, 5.2 Hz, 1H), 3.51 - 3.39 (m, 1H), 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] + .

[0304] Example 21 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (21)

[0305] [ka]

[0306] 21.1 2-Chloro-4-methylthieno[3,2-d]pyrimidine (compound 21a) was prepared according to the method of Example 1-1.3, substituting 2,4-dichlorothieno[3,2-d]pyrimidine for the reactant 2,4,6-trichloro-5-fluoropyrimidine.

[0307] 21.2 tert-Butyl 5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 21b) was prepared according to the method of Example 1-1.4, substituting 21a for reactant 1c.

[0308] 21.3 5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 21c) was prepared according to the method of Example 1-1.5, substituting 21b for reactant 1d.

[0309] 21.4 (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(4-methylthieno[3,2-d]pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 21) was prepared according to the method of Example 1-1.7, substituting 21c for reactant 1e. 1 H NMR (400 MHz, Methanol-d4) δ 7.96 - 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] + .

[0310] Example 22: 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (22)

[0311] [ka]

[0312] 22.1 5-Bromo-4-chloro-2-methoxypyridine (500 mg, 2.247 mmol), TEA (682.3 mg, 6.741 mmol), and Pd(dppf)Cl were added to methanol (5 mL). The reaction mixture was added to a pressure reactor, CO was introduced to 10 atm, and the temperature was raised to 50 °C and reacted overnight. After completion of the reaction, the temperature was lowered to room temperature and extracted with EtOAc (3 × 20 mL). The organic phases were combined, washed with saturated brine (2 × 10 mL), dried over anhydrous NaSO, filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography eluting with PE / EA (5:1) to give 183 mg of 4-chloro-6-methoxypyridine-3-carboxylic acid methyl ester (Compound 22a).

[0313] 22.2 6-Methoxy-4-(2H-1,2,3-triazol-2-yl)nicotinic acid (compound 22b) was prepared according to the method of Example 1-1.6, substituting 22a for the reactant 2-fluoro-6-iodobenzoic acid.

[0314] 22.3 5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (compound 22) was prepared according to the method of Example 1-1.7, substituting 22b for reactant 1f. 1H NMR (400 MHz, Methanol-d4) δ 8.20 (d, J = 7.4 Hz, 1H), 7.89 (s, 2H), 7.39 (d, J = 11.5 Hz, 1H), 6.89 - 6.40 (m, 1H), 4.01 (d, J = 6.8 Hz, 3H), 3.96 - 3.79 (m, 2H), 3.69 - 3.45 (m, 3H), 3.18 - 2.87 (m, 3H), 2.46 (d, J = 6.6 Hz, 6H). LCMS (ES, m / z): 436 [M+H] + .

[0315] Example 23 Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (23)

[0316] [ka]

[0317] 23.1 2-Methoxy-5-(2H-1,2,3-triazol-2-yl)isonicotinic acid (compound 23a) was prepared according to the method of Example 1-1.6, substituting 5-bromo-2-methoxyisonicotinic acid for the reactant 2-fluoro-6-iodobenzoic acid.

[0318] 23.2 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (compound 23) was prepared according to the method of Example 1-1.7, substituting 23a for reactant 1f. 1H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J = 5.0 Hz, 1H), 7.70 (d, J = 13.0 Hz, 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, 2.7 Hz, 6H). LCMS (ES, m / z): 436 [M+H] + .

[0319] Example 24 Preparation of (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (24)

[0320] [ka]

[0321] 24.1 3-(2H-1,2,3-triazol-2-yl)picolinic acid (compound 24a) was prepared according to the method of Example 1-1.6, substituting 3-bromopicolinic acid for 2-fluoro-6-iodobenzoic acid in the reaction mixture.

[0322] 24.2 (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 24) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 24a and 1e with 8c. 1H NMR (400 MHz, Chloroform-d) δ 8.76 - 8.54 (m, 1H), 8.33 - 8.24 (m, 1H), 7.86 (dd, J = 8.5, 3.2 Hz, 1H), 7.53 - 7.29 (m, 2H), 6.62 (d, J = 91.9 Hz, 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 = 16.7 Hz, 1H), 2.43 (dd, J = 11.0, 3.0 Hz, 3H). LCMS (ES, m / z): 422 [M+H] + .

[0323] Example 25 Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (25)

[0324] [ka]

[0325] 25.1 6-Methoxy-3-(2H-1,2,3-triazol-2-yl)picolinic acid (compound 25a) was prepared according to the method of Example 1-1.6, substituting 3-bromo-6-methoxypicolinic acid for the reactant 2-fluoro-6-iodobenzoic acid.

[0326] 25.2 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)methanone (compound 25) was prepared according to the method of Example 1-1.7, substituting 25a for reactant 1f. 1H NMR (400 MHz, Chloroform-d) δ 8.09 (dd, J = 8.7, 4.2 Hz, 1H), 7.79 (t, J = 3.5 Hz, 1H), 7.31 (dd, J = 10.7, 3.2 Hz, 1H), 7.18 - 7.11 (m, 1H), 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= 8.4 Hz, 6H). LCMS (ES, m / z): 436 [M+H] + .

[0327] Example 26: (5-fluoro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (26)

[0328] [ka]

[0329] 26.1 5-Fluoro-3-(2H-1,2,3-triazol-2-yl)picolinic acid (compound 26a) was prepared according to the method of Example 1-1.6, substituting 3-bromo-5-fluoropicolinic acid for the reactant 2-fluoro-6-iodobenzoic acid.

[0330] 26.2 (5-fluoro-3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 26) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 26a and 1e with 8c. 1H NMR (400 MHz, Methanol-d4) δ 8.17 (dd, J = 8.6, 2.7 Hz, 1H), 7.96 - 7.92 (m, 1H), 7.81 (dd, J= 10.2, 3.2 Hz, 1H), 7.61 (dd, J = 3.2, 1.3 Hz, 1H), 6.84 - 6.37 (m, 1H), 4.04 (d, J = 3.8 Hz, 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, 3.0 Hz, 3H). LCMS (ES, m / z): 440 [M+H] + .

[0331] Example 27: (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (27)

[0332] [ka]

[0333] 27.1 (2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4-methoxy-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 27) was prepared according to the method of Example 1-1.7, replacing reactants 1f with 7a and 1e with 8c. 1H NMR (400 MHz, Chloroform-d) δ 7.93 - 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, 1H), 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 = 3.0 Hz, 3H). LCMS (ES, m / z): 421 [M+H] + .

[0334] Example 28 Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone (28)

[0335] [ka]

[0336] 28.1 2-Fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)benzoic acid (compound 28a) was prepared according to the method of Example 1-1.6, replacing the reactant 1,2,3-triazole with 4-methyl-1H-1,2,3-triazole.

[0337] 28.2 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 28) was prepared according to the method of Example 1-1.7, substituting 28a for reactant 1f. 1H NMR (400 MHz, Chloroform-d) δ 7.81 - 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 - 3.79 (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). m / z): 437 [M+H] + .

[0338] Example 29 Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(1H-pyrazol-3-yl)phenyl)methanone (29)

[0339] [ka]

[0340] 29.1 At room temperature, tert-butyl 2-fluoro-6-iodobenzoate (950 mg, 2.949 mmol) and 2H-pyrazol-3-ylboronic acid (396.0 mg, 3.539 mmol) were added to a mixture of 1,4-dioxane (6 mL) and water (1 mL), and K2CO3 (815.2 mg, 5.898 mmol) and Pd(dppf)Cl2 (215.8 mg, 0.295 mmol) were added in batches. Under nitrogen protection, the temperature was raised to 50 °C and the reaction was continued for 4 hours. The residue was concentrated under reduced pressure and purified by column chromatography, eluting with PE / EA (10:1) to give 210 mg of tert-butyl 2-fluoro-6-(2H-pyrazol-3-yl)benzoate (Compound 29a).

[0341] 29.2 29a (87 mg, 0.332 mmol) was added to a solution of HCl in 1,4-dioxane (5 mL), reacted at room temperature for 4 hours, concentrated under reduced pressure, and purified by column chromatography eluting with PE / EA (3:1) to obtain 62 mg of 2-fluoro-6-(1H-pyrazol-3-yl)benzoic acid (compound 29b).

[0342] 29.3 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(1H-pyrazol-3-yl)phenyl)methanone (compound 29) was prepared according to the method of Example 1-1.7, substituting 29b for reactant 1f. 1 H NMR (400 MHz, Chloroform-d) δ 7.61 (d, J = 2.2 Hz, 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] + .

[0343] Example 30: (4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (30)

[0344] [ka]

[0345] 30.1 2-Chloro-5-fluoro-4,6-bis(methyl-d3)pyrimidine (compound 30a) was prepared according to the method of Example 1-1.3, replacing the reaction raw material methylmagnesium chloride with methyl-d3-magnesium iodide.

[0346] 30.2 tert-Butyl 5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylate (compound 30b) was prepared according to the method of Example 1-1.4, substituting 30a for reactant 1c.

[0347] 30.3 5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 30c) was prepared according to the method of Example 1-1.5, substituting 30b for reactant 1d.

[0348] 30.4 (4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 30) was prepared according to the method of Example 1-1.7, substituting reactant 1e with 30c and 1f with 2a. 1 H NMR (400 MHz, DMSO-d6) δ 8.15 - 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 = 80.4 Hz, 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] + .

[0349] Example 31 Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-(methoxy-d3)-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (31)

[0350] [ka]

[0351] 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. After this, ethyl 3-bromo-6-chloropicolinate (1.5 g, 5.67 mmol) was added, and the temperature was raised to 60 °C for 6 hours. After completion of the reaction, the mixture was concentrated under pressure, 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 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 0.8 g of 3-bromo-6-(methoxy-d3)picolinic acid (compound 31a).

[0352] 31.2 6-(methoxy-d3)-3-(2H-1,2,3-triazol-2-yl)picolinic acid (compound 31b) was prepared according to the method of Example 1-1.6, substituting 31a for the reactant 2-fluoro-6-iodobenzoic acid.

[0353] 31.3 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-(methoxy-d3)-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (compound 31) was prepared according to the method of Example 1-1.7, substituting reactant 1f with 31b. 1H NMR (400 MHz, Chloroform-d) δ 8.74 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 13.0 Hz, 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, 2.7 Hz, 6H). LCMS (ES, m / z): 439 [M+H] + .

[0354] Example 32 Preparation of (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (32)

[0355] [ka]

[0356] 32.1 (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)methanone (compound 31) was prepared according to the method of Example 1-1.7, replacing reactant 1f with 23a and 1e with 30c. 1 H NMR (400 MHz, Chloroform-d) δ 8.78 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 13.0 Hz, 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] + .

[0357] Example 33: (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (33)

[0358] [ka]

[0359] 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 added, and the mixture was heated to 60 °C and reacted for 8 hours. After completion of the reaction, the mixture was concentrated under pressure, 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 × 20 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 0.76 g of 2-chloro-5-fluoro-4-(methoxy-d3)-6-methylpyrimidine (compound 33a).

[0360] 33.2 tert-Butyl 5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)carboxylate (compound 33b) was prepared according to the method of Example 1-1.4, substituting 33a for reactant 1c.

[0361] 33.3 5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 33c) was prepared according to the method of Example 1-1.5, substituting reactant 1d with 33b.

[0362] 33.4 (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(5-(5-fluoro-4-(methoxy-d3)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 33) was prepared according to the method of Example 1-1.7, substituting reactant 1e with 33c and 1f with 24a. 1 H NMR (400 MHz, Chloroform-d) δ 8.74 - 8.51 (m, 1H), 8.35 - 8.23 ​​(m, 1H), 7.90 (dd, J = 8.5, 3.2 Hz, 1H), 7.54 - 7.28 (m, 2H), 6.62 (d, J = LCMS (ES, m / z): 425 [M+H] + .

[0363] Example 34 Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (34)

[0364] [ka]

[0365] 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. The temperature was raised to 60 °C under nitrogen protection and the reaction was allowed to proceed overnight. After completion of the reaction, the mixture was concentrated under pressure, water was added, and the mixture was extracted with EtOAc (3 x 30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography eluting with PE:EA = 20:1 to give 0.6 g of 4-chloro-2-(methoxy-d3)pyridine (compound 34a).

[0366] 34.2 34a (0.6 g, 4.08 mmol) and NBS (0.75 g, 4.21 mmol) were added to DMF (10 mL), and the temperature was raised to 90 °C for 8 h. After completion of the reaction, the mixture was diluted with water and extracted with EtOAc (3 × 20 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.3 g of 5-bromo-4-chloro-2-(methoxy-d3)pyridine (compound 34b).

[0367] 34.3 Methyl 4-chloro-6-(methoxy-d3)nicotinate (compound 34c) was prepared according to the method of Example 22-22.1, substituting 34b for the reactant 5-bromo-4-chloro-2-methoxypyridine.

[0368] 34.4 6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)nicotinic acid (compound 34d) was prepared according to the method of Example 1-1.6, substituting 34c for the reactant 2-fluoro-6-iodobenzoic acid.

[0369] 34.5 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-(methoxy-d3)-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (compound 34) was prepared according to the method of Example 1-1.7, substituting reactant 1f with 34d. 1 H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J = 7.4 Hz, 1H), 7.86 (s, 2H), 7.36 (d, J = 11.5 Hz, 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 = 6.6 Hz, 6H). LCMS (ES, m / z): 439 [M+H] + .

[0370] Example 35 Preparation of (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (35)

[0371] [ka]

[0372] 35.1 Following the procedure of Example 1-1.7, substituting reactant 1f with 22b and 1e with 30c, (5-(5-fluoro-4,6-bis(methyl-d3)pyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(6-methoxy-4-(2H-1,2,3-triazol-2-yl)pyridin-3-yl)methanone (compound 35) was prepared. 1H NMR (400 MHz, Methanol-d4) δ 8.21 (d, J = 7.4 Hz, 1H), 7.83 (s, 2H), 7.37 (d, J = 11.5 Hz, 1H), 6.90 - 6.39 (m, 1H), 4.05 (d, J = 6.8 Hz, 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] + .

[0373] Example 36 Preparation of (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (36)

[0374] [ka]

[0375] 36.1 2-Bromo-4-(methoxy-d3)benzoic acid (compound 36a) was prepared according to the method of Example 13-13.1, substituting deuterated iodomethane for the reactant bromocyclopropane.

[0376] 36.2 4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 36b) was prepared according to the method of Example 1-1.6, substituting 36a for the reactant 2-fluoro-6-iodobenzoic acid.

[0377] 26.2 (5-(5-fluoro-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 36) was prepared according to the method of Example 1-1.7, substituting reactant 1f with 36b. 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, J = 26.3 Hz, 2H), 7.41 - 7.34 (m, 2H), 7.09 - 7.02 (m, 1H), 6.55 (d, J = 78.0 Hz, 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] + .

[0378] Example 37 Preparation of (5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (37)

[0379] [ka]

[0380] 37.1 Under nitrogen protection, 2,4-dichloro-5-fluoro-6-methylpyrimidine (6.5 g, 35.9 mmol) was added to a solution of anhydrous DMF (15 mL), followed by the addition of tributyl-(1-ethoxyvinyl)stannane (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 hours, then cooled to room temperature. A saturated solution of potassium fluoride was added, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was filtered through Celite and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography (PE:EA=10:1) to obtain 2-chloro-4-(1-ethoxyvinyl)-5-fluoro-6-methylpyrimidine (6.8 g) (compound 37a).

[0381] 37.2 37a (6.0 g, 27.8 mmol) was dissolved in THF (10 mL), 3N HCl solution (15 mL) was added, and the mixture was allowed to react at room temperature for 1 h. After the reaction was complete, the pH was adjusted to 7-8 with saturated NaHCO3 and extracted with ethyl acetate (3 × 50 mL). The organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give 1-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)ethan-1-one (5.1 g) (compound 37b). The crude product was used directly in the next step without further purification.

[0382] 37.3 2-(2-chloro-5-fluoro-6-methylpyrimidin-4-yl)propan-2-ol (compound 37c) was prepared according to the method of Examples 30-30.1, substituting 37b for the starting 2-chloro-6-methylpyrimidine-4-carboxylic acid methyl ester.

[0383] 37.4 tert-Butyl 5-[5-fluoro-4-(2-hydroxypropyl)-6-methylpyrimidin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 37d) was prepared according to the method of Example 1-1.4, substituting 37c for reactant 1c.

[0384] 37.5 5-[5-fluoro-4-(2-hydroxypropyl)-6-methylpyrimidin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 37e) was prepared according to the method of Example 1-1.5, substituting 37d for reactant 1d.

[0385] 37.6 Following the procedure of Example 1-1.7, substituting 37e for reactant 1e, (5-(5-fluoro-4-(2-hydroxypropan-2-yl)-6-methylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone (compound 37) was prepared. 1H NMR (400 MHz, Chloroform-d) δ 7.89 - 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, 2H), 3.66 - 3.61 (m, 2H), 3.49 - 3.02 (m, 3H), 3.00 - 2.82 (m, 1H), 2.38 (d, J = 2.9 Hz, 3H), 1.53 (s, 6H). LCMS (ES, m / z): 467 [M+H] + .

[0386] Example 38 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (38)

[0387] [ka]

[0388] 38.1 tert-Butyl 5-(5-(ethoxycarbonyl)-4,6-dimethylpyrimidine-5-carboxylic acid ethyl ester) was prepared according to the method of Example 1-1.4, substituting 2-chloro-4,6-dimethylpyrimidine-5-carboxylic acid ethyl ester for reactant 1c.

[0389] 38.2 38a (0.5 g, 1.29 mmol) was added to a 5 mL methanol solution, and LiBH4 (0.56 g, 2.57 mmol) was added. The mixture was allowed to react at room temperature for 6 hours. After completion of the reaction, the mixture was quenched by adding water, extracted with ethyl acetate (3 × 50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was purified and separated by column chromatography (PE:EA = 5:1) to obtain 0.21 g of tert-butyl 5-(5-(hydroxymethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)carboxylate (compound 38b).

[0390] 38.3 38b (0.21 g, 0.61 mmol) was added to dichloromethane (5 mL), and DAST (0.2 g, 1.24 mmol) was added at room temperature. The reaction was allowed to proceed for 3 hours. The reaction was quenched by the addition of water and extracted with dichloromethane (3 x 50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under pressure. The filtrate was purified and separated by column chromatography (PE:EA = 10:1) to give 0.12 g of tert-butyl 5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopentane[c]pyrrole-2(1H)carboxylate (compound 38c).

[0391] 38.4 By replacing reactant 1d with 38c, 5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 38d) was obtained according to the method of Example 1-1.5.

[0392] 38.5 (2-Fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(5-(fluoromethyl)-4,6-dimethylpyrimidin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 38) was prepared according to the method of Example 1-1.7, substituting 38d for reactant 1e. 1H NMR (400 MHz, Methanol-d4) δ 7.96 - 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] + .

[0393] Example 39 Preparation of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (39)

[0394] [ka]

[0395] 39.1 A solution of cis-5-oxo-hexahydrocyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester (5 g, 22.19 mmol) in THF (20 mL) was treated with LiHMDS (5.2 g, 110.95 mmol) at −78 °C for 2 h, followed by the 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 mixture was quenched by the addition of water / ice (10 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (3 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with PE / EA (1:1) to give tert-butyl 5-[[(trifluoromethyl)sulfonyl]oxy]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 39a) (4.8 g).

[0396] 39.2 A solution of 39a (4.5 g, 12.59 mmol), pinacoldiboron (4.8 g, 18.90 mmol), KOAc (3.5 g, 25.36 mmol), and Pd(dppf)Cl (0.9 g, 1.24 mmol) in dioxane (20 mL) was heated to 80 °C and stirred overnight under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with brine (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give 3.6 g of crude tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H,3H,3aH,6H,6aH-cyclopenta[c]pyrrole-2-carboxylate (compound 39b), which was used directly in the next step without further purification.

[0397] 39.3 A solution of 3,5-dibromopyrazin-2-amine (4 g, 15.82 mmol), isoamyl nitrite (5.56 g, 47.45 mmol), and HCl (1.16 mL, 31.79 mmol) in MeOH (80 mL) was stirred at 60 °C under nitrogen protection for 4 h. After cooling to room temperature, the resulting mixture was concentrated under reduced pressure. Extraction with EtOAc (3 × 50 mL) was performed. The combined organic layer was washed with saturated brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. Separation and purification by column chromatography (PE / EA = 7:1) afforded 3.1 g of 3,5-dibromo-2-methoxypyrazine (compound 39c).

[0398] 39.4 A solution of 39c (2 g, 7.47 mmol), 39b (2.7 g, 8.21 mmol), KCO (5.58 g, 39.72 mmol, 3 equiv.), and Pd(dppf)Cl (546.2 mg, 0.75 mmol) in 1,4-dioxane (40 mL) and HO (6 mL) was stirred at 95 °C for 4 h under a nitrogen atmosphere. The mixture was cooled to room temperature. The resulting mixture was extracted with EtOAc (3 × 30 mL). The combined organic layers were washed with brine (2 × 15 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (3:1) to obtain 1.8 g of tert-butyl 5-(6-bromo-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 39d).

[0399] 39.5 39d (1.8 g, 4.54 mmol), trimethylboroxane (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 HO (6 mL). The mixture was heated to 90 °C under nitrogen protection for 1 h. After the reaction was completed, the mixture was cooled to room temperature and extracted with EtOAc (3 × 30 mL). The combined organic layer was washed with saturated brine (3 × 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography, eluting with PE / EA (6:1) to give 720 mg of tert-butyl 5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 39e).

[0400] 39.6 39e (720 mg, 2.17 mmol) was added to a solution of DCM (4 mL) and TFA (16 mL) and stirred at room temperature under nitrogen protection for 3 h. After completion of the reaction, the mixture was concentrated under pressure. The resulting mixture was extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with saturated brine (2 × 9 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The product was purified by column chromatography eluting with PE / EA (1:2) to give 460 mg of 5-(3-methoxy-6-methylpyrazin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 39f).

[0401] 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 completion of the reaction, 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 30 minutes and then separated. The organic phase was discarded, and the pH of the aqueous phase was adjusted to acidic with 2 N hydrochloric acid and extracted with ethyl acetate (50 mL x 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).

[0402] 39.8 39g (100 mg, 0.48 mmol) and 39f (126.1 mg, 0.545 mmol) were added to DMF (2 mL), and triethylamine (137.9 mg, 1.36 mmol) and HATU (259.0 mg, 0.68 mmol) were added in batches with stirring at room temperature. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the product was concentrated under reduced pressure and purified by column chromatography (petroleum ether / ethyl acetate = 3:1). 28.1 mg of (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 39) was obtained. 1 H NMR (400 MHz, Chloroform-d) δ 7.88 - 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] + .

[0403] Example 40 Preparation of (5-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (40)

[0404] [ka]

[0405] 40.1 5-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 40a) was prepared according to the methods of Examples 39-39.7, substituting 2-iodo-5-methoxybenzoic acid for the reactant 4-fluoro-6-iodobenzoic acid.

[0406] 40.2 (5-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 40) was prepared according to the method of Examples 39-39.8, substituting 40a for reactant 39g. 1 H NMR (400 MHz, Chloroform-d) δ 7.95 - 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 - 3.75 (m, 5H), 3.69 - 3.52 (m, 1H), 3.52 - 3.38 (m, 1H), 3.37 - 3.14 (m, 1H), 3.13 - 2.80 (m, 2H), 2.70 (t, J = 18.5 Hz, 1H), 2.53 - 2.36 (m, 3H). LCMS (ES, m / z): 433 [M+H] + .

[0407] Example 41: Preparation of (4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (41)

[0408] [ka]

[0409] 41.1 4-Methoxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 41a) was prepared according to the methods of Examples 39-39.7, substituting 2-iodo-4-methoxybenzoic acid for the reactant 4-fluoro-6-iodobenzoic acid.

[0410] 41.2 (4-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 41) was prepared according to the method of Examples 39-39.8, substituting 41a for reactant 39g. 1 H NMR (400 MHz, DMSO-d6) δ 7.94 - 7.89 (m, 3H), 7.39 - 7.33(m, 2H), 7.07 (t, J = 10.7 Hz, 1H), 6.66 (d, J = 84.6 Hz, 1H), 3.97 (d, J = LCMS (ES, m / z): 433 [M+H] + .

[0411] Example 42: Preparation of (2-methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (42)

[0412] [ka]

[0413] 42.1 2-Methoxy-5-(2H-1,2,3-triazol-2-yl)isonicotinic acid (compound 42a) was prepared according to the methods of Examples 39-39.7, substituting 5-bromo-2-methoxyisonicotinic acid for the reactant 4-fluoro-6-iodobenzoic acid.

[0414] 42.2 (2-Methoxy-5-(2H-1,2,3-triazol-2-yl)pyridin-4-yl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 42) was prepared according to the method of Examples 39-39.8, substituting 42a for reactant 39g. 1 H NMR (400 MHz, Chloroform-d) δ 8.75 (d, J = 11.5 Hz, 1H), 7.79 (d, J = 5.0 Hz, 1H), 7.66 (d, J= 17.0 Hz, 2H), 6.77 - 6.47 (m, 2H), 4.06 - 3.97 LCMS (ES, m / z): 434 [M+H] + .

[0415] Example 43 Preparation of (2-fluoro-6-(pyrimidin-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (43)

[0416] [ka]

[0417] 43.1 tert-Butyl 2-fluoro-6-iodobenzoate (200 mg, 0.62 mmol), cuprous iodide (11.82 mg, 0.06 mmol), and cesium fluoride (18.86 mg, 0.12 mmol) were added to tetrahydrofuran and stirred at room temperature for several minutes under nitrogen protection. Pd(PPh3)4 (43.05 mg, 0.04 mmol) was added at room temperature, followed by 2-(tributyltin)pyrimidine (278.78 mg, 0.75 mmol). The temperature was raised to 100 °C, and the reaction was allowed to proceed overnight. Completion of the reaction was confirmed by LCMS, and the product was purified by column chromatography (PE / EA = 2:1) to yield 160 mg of tert-butyl 2-fluoro-6-(pyrimidin-2-yl)benzoate (Compound 43a).

[0418] 43.2 43a (160 mg, 0.573 mmol) was added to 2 mL of dichloromethane. Trifluoroacetic acid (2 mL, 26.926 mmol) was added at room temperature under nitrogen protection, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, the solvent was evaporated under reduced pressure to give 110 mg of 2-fluoro-6-(pyrimidin-2-yl)benzoic acid (compound 43b).

[0419] 43.3 (2-Fluoro-6-(pyrimidin-2-yl)phenyl)(5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl)methanone (compound 43) was prepared according to the method of Examples 39-39.8, substituting 43b for reactant 39g. 1 H NMR (400 MHz, Chloroform-d) δ 8.77 - 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] +.

[0420] Example 44: Preparation of [4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (44)

[0421] [ka]

[0422] 44.1 4-Fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 44a) was prepared according to the methods of Examples 39-39.7, substituting 4-fluoro-2-iodobenzoic acid for the reactant 4-fluoro-6-iodobenzoic acid.

[0423] 44.2 [4-Fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (compound 44) ​​was prepared according to the method of Examples 39-39.8, substituting 44a for reactant 39g. 1 H NMR (400 MHz, DMSO-d6) δ 8.35 - 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] + .

[0424] Example 45: Preparation of [4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (45)

[0425] [ka]

[0426] 45.1 Compound 41a (300 mg, 1.37 mmol) was dissolved in 30 mL of dichloromethane and cooled in an ice-water bath. Under nitrogen protection, a solution of boron tribromide in dichloromethane (1.0 M, 3 mL) was added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to react at room temperature for 3 hours, cooled in an ice-water bath, and quenched by the addition of water. 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 give 230 mg of 4-hydroxy-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 45a). The crude product was used directly in the next step without further purification.

[0427] 45.2 Compound 45a (230 mg, 1.12 mmol), iodoethane (262 mg, 1.68 mmol), and potassium carbonate (464 mg, 3.36 mmol) were added to 30 mL of acetonitrile, and the temperature was raised to 60 °C for 4 hours. After completion of the reaction, the temperature was lowered to room temperature, and the pH was adjusted to 4-5 with 1 M hydrochloric acid solution. The solvent was evaporated under pressure, 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 directly used in the next step without further purification.

[0428] 45.3 [4-ethoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (compound 45) was prepared according to the method of Examples 39-39.8, substituting 45b for reactant 39g. 1 H NMR (400 MHz, DMSO-d6) δ 8.07 - 7.80 (m, 3H), 7.39 - 7.29 (m, 2H), 7.05 (br t, J = 9.9 Hz, 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 = 5.6 Hz, 1H), 3.29 - 3.04 (m, 2H), 2.95 - 2.80 (m, 2H), 2.67 (br s, 1H), 2.39 (br d, J = 18.1 Hz, 3H), 1.40 - 1.34 (m, 3H). LCMS (ES, m / z): 447 [M+H] + .

[0429] Example 46: Preparation of [5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (46)

[0430] [ka]

[0431] 46.1 3,5-Dibromo-2-ethoxypyrazine (compound 46a) was prepared according to the methods of Examples 39-39.3, substituting ethanol for methanol in the reaction feed.

[0432] 46.2 tert-Butyl 5-(6-bromo-3-ethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 46b) was prepared according to the method of Examples 39-39.4, substituting 46a for reactant 39c.

[0433] 46.3 Following the procedures of Examples 39-39.5, substituting 46b for reactant 39d, tert-butyl 5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 46c) was prepared.

[0434] 46.4 5-(3-ethoxy-6-methylpyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 46d) was prepared according to the methods of Examples 39-39.6, substituting 46c for reactant 39e.

[0435] 46.5 By replacing reactant 39f with 46d and 39g with 41a, [5-(3-ethoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 46) was prepared according to the method of Examples 39-39.8. 1 H NMR (400 MHz, DMSO-d6) δ 8.08 - 7.79 (m, 3H), 7.48 - 7.22 (m, 2H), 7.07 (td, J = 8.3, 4.1 Hz, 1H), 6.69 (d, J = 76.7 Hz, 1H), 4.48 - 4.34 (m, 2H), 3.86 (d, J = 6.5, 3H), 3.79 - 3.43 (m, 3H), 3.29 - 2.56 (m, 5H), 2.38 (d, J = 18.0 Hz, 3H), 1.48 - 1.29 (m, 3H). LCMS (ES, m / z): 447 [M+H] + .

[0436] Example 47: Preparation of [5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (47)

[0437] [ka]

[0438] 47.1 tert-Butyl 5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 47a) was prepared according to the method of Examples 39-39.5, substituting ethylboronic acid for the reactant trimethylcyclotriboroxane.

[0439] 47.2 5-(6-ethyl-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 47b) was prepared according to the methods of Examples 39-39.6, substituting 47a for reactant 39e.

[0440] 47.3 By replacing reactant 39f with 47b and 1g with 3a, [5-(6-ethyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 47) was prepared according to the method of Examples 39-39.8. 1H NMR (400 MHz, DMSO) δ 7.91 (d, J= 30.0 Hz, 3H), 7.37 (d, J = 15.1 Hz, 2H), 7.18 - 6.95 (m, 1H), 6.66 (d, J = 83.7 Hz, 1H), 3.97 (d, J = 22.9 Hz, 3H), 3.86 (d, J = 8.1 Hz, 3H), 3.79 - 3.67 (m, 1H), 3.62 (s, 1H), 3.47 (s, 1H), 3.31 - 3.14 (m, 1H), 3.10 (d, J = 9.9 Hz, 1H), 2.99 (dd, J = 16.6, 6.9 Hz, 1H), 2.88 (dd, J = 23.9, 11.7 Hz, 2H), 2.73 (d, J = 7.4 Hz, 1H), 2.62 (dd, J = 22.3, 11.3 Hz, 1H), 1.21 (dt, J = 19.6, 7.4 Hz, 3H). LCMS (ES, m / z): 447 [M+H] + .

[0441] Example 48 Preparation of [4-methoxy-2-(pyrimidin-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (48)

[0442] [ka]

[0443] 48.1 tert-Butyl 4-methoxy-2-(pyrimidin-2-yl)benzoate (compound 48a) was prepared according to the method of Examples 43-43.1, substituting tert-butyl 2-iodo-4-methoxybenzoate for the reactant tert-butyl 2-fluoro-6-iodobenzoate.

[0444] 48.2 4-Methoxy-2-(pyrimidin-2-yl)benzoic acid (compound 48b) was prepared according to the method of Examples 43-43.2, substituting 48a for reactant 43a.

[0445] 48.3 [4-Methoxy-2-(pyrimidin-2-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (compound 48) was prepared according to the method of Examples 39-39.8, substituting 48b for reactant 39g. 1 H NMR (400 MHz, DMSO) δ 8.81 - 8.60 (m, 2H), 7.94 (d, J = 9.9 Hz, 1H), 7.65 (d, J = 14.7 Hz, 1H), 7.27 (dd, J = 19.5, 12.2 Hz, 2H), 7.10 (t, J = 9.4 Hz, 1H), 6.68 (d, J = 97.0 Hz, 1H), 3.97 (d, J = 36.2 Hz, 3H), 3.85 (d, J= 7.9 Hz, 3H), 3.75 (dd, J = 23.7, 13.0 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.48 (s, 1H), 3.21 (d, J = 10.6 Hz, 1H), 3.08 - 2.92 (m, 1H), 2.90 - 2.70 (m, 2H), 2.63 (dd, J = 46.2, 11.3 Hz, 1H), 2.39 (d, J = 27.3 Hz, 3H). LCMS (ES, m / z): 444 [M+H] + .

[0446] Example 49: Preparation of [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (49)

[0447] [ka]

[0448] 49.1 5-Methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 49a) was prepared according to the method of Examples 43-43.1, substituting 2-iodo-5-methylbenzoic acid for the reactant 2-fluoro-6-iodobenzoic acid.

[0449] 49.2 [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 49) was prepared according to the method of Examples 39-39.8, substituting 49a for reactant 39g. 1 H NMR (400 MHz, DMSO-d6) δ 7.93 (br d, J = 4.6 Hz, 3H), 7.74 (br dd, J = 8.3, 14.7 Hz, 1H), 7.40 (br t, J = 8.4 Hz, 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 = 15.7 Hz, 1H), 2.41 - 2.33 (m, 6H). LCMS (ES, m / z): 417 [M+H] + .

[0450] Example 50 Preparation of [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (50)

[0451] [ka]

[0452] 50.1 Compound 39d (300 mg, 0.76 mmol) and sodium methoxide (123 mg, 2.28 mmol) were added to 30 mL of methanol solution, and the temperature was raised to 60 °C for 6 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to obtain 136 mg of tert-butyl 5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 50a).

[0453] 50.2 5-(3,6-dimethoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 50b) was prepared according to the methods of Examples 39-39.6, substituting 50a for reactant 39e.

[0454] 50.3 [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 50) was prepared according to the method of Examples 39-39.8, substituting reactant 39f with 50b and 39g with 44a. 1 H NMR (400 MHz, DMSO) δ 8.29 - 7.82 (m, 3H), 7.76 (d, J = 4.8 Hz, 1H), 7.48 (dd, J = 17.4, 8.7 Hz, 1H), 7.39 (d, J = 8.1 Hz, 1H), 6.69 (d, J = 71.9 Hz, 1H), 3.96 (d, J = 21.2 Hz, 3H), 3.85 (d, J = 26.1 Hz, 3H), 3.79 - 3.60 (m, 2H), 3.52 (s, 1H), 3.21 (dd, J = 11.8, 5.9 Hz, 1H), 3.10 - 2.82 (m, 3H), 2.67 (t, J = 17.2 Hz, 1H). LCMS (ES, m / z): 437 [M+H] + .

[0455] Example 51: Preparation of [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]methanone (51)

[0456] [ka]

[0457] 51.1 tert-Butyl 5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 51a) was prepared according to the method of Examples 39-39.4, substituting 3-bromo-2,5-dimethylpyrazine for reactant 39c.

[0458] 51.2 5-(3,6-dimethylpyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 51b) was prepared according to the methods of Examples 39-39.6, substituting 51a for reactant 39e.

[0459] 51.3 [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 51) was prepared according to the method of Examples 39-39.8, substituting 51b for reactant 39f. 1H NMR (400 MHz, DMSO-d6) δ 8.32 - 8.22 (m, 1H), 8.15 (s, 1H), 7.89 (d, J = 6.1 Hz, 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] + .

[0460] Example 52: Preparation of [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (52)

[0461] [ka]

[0462] 52.1 [5-(3,6-dimethylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 52) was prepared according to the method of Examples 39-39.8, replacing reactant 39f with 51b and 39g with 41a. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J= 5.0 Hz, 1H), 7.98 (d, J = 7.7 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.09 (t, J = 7.8 Hz, 1H), 6.12 (d, J = 76.3 Hz, 1H), 3.87 (d, J = 4.6 Hz, 3H), 3.81 - 3.58 (m, 2H), 3.49 (s, 1H), 3.28 (dd, J= 11.8, 5.9 Hz, 1H), 3.17 - 3.01 (m, 1H), 2.92 (ddd, J = 32.2, 15.1, 7.3 Hz, 2H), 2.80 - 2.65 (m, 1H), 2.56 (d, J = 18.5 Hz, 3H), 2.43 (d, J= 15.4 Hz, 3H). LCMS (ES, m / z): 417 [M+H] + .

[0463] Example 53 Preparation of [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (53)

[0464] [ka]

[0465] 53.1 [5-(3,6-dimethoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 53) was prepared according to the method of Examples 39-39.8, replacing reactant 39f with 50b and 39g with 41a. 1H NMR (400 MHz, DMSO-d6) δ 8.18 - 7.82 (m, 2H), 7.75 (br d, J = 3.9 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.07 (br t, J = 9.5 Hz, 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 = 15.7 Hz, 2H), 2.59 (br d, J = 14.7 Hz, 1H). LCMS (ES, m / z): 449 [M+H] + .

[0466] Example 54 Preparation of [5-(6-chloro-3-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (54)

[0467] [ka]

[0468] 54.1 2-Amino-3-bromo-5-chloropyrazine (3 g, 14.4 mmol) was dissolved in 30 mL of methanol, and tert-butyl nitrite (5.1 g, 43.2 mmol) was added, followed by a methanol solution of HCl. The temperature was raised to 60 °C and the reaction was carried out for 6 hours. After completion of the reaction, the reaction was quenched by adding water, extracted with ethyl acetate, and the layers were 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).

[0469] 54.2 tert-Butyl 5-(6-chloro-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 54b) was prepared according to the method of Examples 39-39.4, substituting 54a for reactant 39c.

[0470] 54.2 5-(6-chloro-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 54c) was prepared according to the methods of Examples 39-39.6, substituting 54b for reactant 39e.

[0471] 54.3 By replacing reactant 39f with 54c and 39g with 41a, [5-(6-chloro-3-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 54) was prepared according to the method of Examples 39-39.8. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J = 2.0 Hz, 1H), 8.09 - 7.76 (m, 2H), 7.40 - 7.29 (m, 2H), 7.06 (t, J = 9.4 Hz, 1H), 6.90 - 6.61 (m, 1H), 4.10 - 3.94 (m, 3H), 3.86 (d, J = 7.1 Hz, 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] + .

[0472] Example 55: Preparation of [5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (55)

[0473] [ka]

[0474] 55.1 tert-Butyl 5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 55a) was prepared according to the method of Examples 39-39.5, substituting cyclopropylboronic acid for the reactant trimethylcyclotriboroxane.

[0475] 55.2 5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 55b) was prepared according to the methods of Examples 39-39.7, substituting 55a for reactant 39e.

[0476] 55.3 [5-(6-cyclopropyl-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 55) was prepared according to the method of Examples 39-39.8, substituting reactant 39f with 55b and 39g with 44a. 1H NMR (400 MHz, DMSO) δ 8.00 (d, J= 6.2 Hz, 3H), 7.74 (dd, J = 12.8, 11.1 Hz, 1H), 7.50 (t, J = 6.6 Hz, 1H), 7.38 (dd, J = 20.5, 9.0 Hz, 1H), 6.65 (d, J = 84.9 Hz, 1H), 3.96 (d, J = 24.1 Hz, 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 = LCMS (ES, m / z): 447 [M+H] + .

[0477] Example 56: Preparation of [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-methoxy-6-(methyl-d3)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (56)

[0478] [ka]

[0479] 56.1 Compound 39d (300 mg, 0.755 mmol) and iron(III) triacetylacetonate (50 mg, 0.14 mmol) were dissolved in 20 mL of tetrahydrofuran solution and cooled in an ice bath. A 1 M solution of methyl-D3-magnesium iodide in tetrahydrofuran (2 mL) was added dropwise. After the addition was complete, the mixture was warmed to room temperature and reacted for 6 hours. After the reaction was complete, water was added to quench the reaction, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (PE:EA = 5:1) to obtain 120 mg of tert-butyl 5-(3-methoxy-6-(methyl-d3)pyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (Compound 56a).

[0480] 56.2 5-(3-methoxy-6-(methyl-d3)pyrazin-2-yl)-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 56b) was prepared according to the method of Examples 39-39.6, substituting 56a for reactant 39e.

[0481] 56.3 [4-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-methoxy-6-(methyl-d3)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (compound 56) was prepared according to the method of Examples 39-39.8, substituting reactant 39f with 56b and 39g with 41a. 1H NMR (400 MHz, DMSO-d6) δ 8.27 - 7.65 (m, 3H), 7.42 - 7.26 (m, 2H), 7.06 (br t, J = 9.9 Hz, 1H), 6.79 - 6.50 (m, 1H), 4.01 - 3.90 (m, 3H), 3.86 (br d, J = 7.1 Hz, 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] + .

[0482] Example 57 Preparation of [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (57)

[0483] [ka]

[0484] 57.1 4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)benzoic acid (compound 57a) was prepared according to the method of Examples 45-45.2, substituting deuterated iodomethane for iodoethane as the reactant.

[0485] 57.2 Using the method of Examples 39-39.8, substituting 57a for reactant 39g, [5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl][4-(methoxy-d3)-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 57) was prepared. 1H NMR (400 MHz, DMSO) δ 8.04 - 7.77 (m, 3H), 7.36 (d, J = 14.3 Hz, 2H), 7.06 (t, J = 9.8 Hz, 1H), 6.65 (d, J = 84.1 Hz, 1H), 3.96 (d, J = 23.1 Hz, 3H), 3.77 - 3.54 (m, 2H), 3.52 - 3.41 (m, 1H), 3.30 - 3.15 (m, 1H), 3.09 (d, J = 9.9 Hz, 1H), 2.92 (ddd, J = 39.8, 24.4, 11.2 Hz, 2H), 2.70 - 2.54 (m, 1H), 2.38 (d, J = 18.4 Hz, 3H). LCMS (ES, m / z): 436 [M+H] + .

[0486] Example 58 Preparation of [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (58)

[0487] [ka]

[0488] 58.1 3,5-Dibromo-2-(methoxy-d3)pyrazine (compound 58a) was prepared according to the methods of Examples 39-39.3, substituting deuterated methanol for the starting methanol.

[0489] 58.2 tert-Butyl 5-[6-bromo-3-(methoxy-d3)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 58b) was prepared according to the method of Examples 39-39.4, substituting 58a for reactant 39c.

[0490] 58.3 tert-Butyl 5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 58c) was prepared according to the method of Examples 39-39.5, substituting 58b for reactant 39d.

[0491] 58.4 5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 58d) was prepared according to the method of Examples 39-39.6, substituting 58c for reactant 39e.

[0492] 58.5 By substituting 41a for reactant 39g and 58d for reactant 39f, [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-[3-(methoxy-d3)-6-methylpyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (compound 58) was prepared according to the method of Examples 39-39.8. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 - 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 = 15.2 Hz, 2H), 2.67 - 2.53 (m, 1H), 2.38 (d, J= 18.3 Hz, 3H). LCMS (ES, m / z): 436 [M+H] + .

[0493] Example 59 Preparation of [5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (59)

[0494] [ka]

[0495] 59.1 Methyl 6-bromo-5-methoxypicolinate (1.0 g, 4.06 mmol) was dissolved in 50 mL of tetrahydrofuran and sodium borohydride (0.9 g, 23.79 mmol) was added. After the addition was complete, the temperature was raised to reflux, 8 mL of methanol was added, and the reaction was continued for 2 hours. After the reaction was complete, 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 in the next step without further purification.

[0496] 59.2 Compound 59a (800 mg, 3.67 mmol) was dissolved in 10 mL of dichloromethane and cooled in an ice bath. Under nitrogen protection, diethylaminosulfur trifluoride (0.78 g, 7.34 mmol) dissolved in 5 mL of dichloromethane was slowly added dropwise. After the addition was complete, the reaction was continued in the ice bath for 30 minutes. After completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The product was purified by column chromatography (PE:EA = 10:1) to give 330 mg of 3-bromo-5-(fluoromethyl)-2-methoxypyrazine (compound 59b).

[0497] 59.3 Following the procedures of Examples 39-39.4, substituting 59b for reactant 39c, tert-butyl 5-(6-(fluoromethyl)-3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 59c) was prepared.

[0498] 59.4 Following the procedures of Examples 39-39.6, substituting 59c for reactant 39e, 5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 59d) was prepared.

[0499] 59.5 Prepare [5-[6-(fluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 59) according to the method of Examples 39-39.8, substituting 41a for reactant 39g and 59d for reactant 39f. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 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= 8.1 Hz, 3H), 3.75 - 3.61 (m, 2H), 3.49 (br d, J = 1.0 Hz, 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] + .

[0500] Example 60 Preparation of [5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (60)

[0501] [ka]

[0502] 60.1 Compound 59a (0.6 g, 2.73 mmol) was dissolved in 20 mL of dichloromethane and Dess-Martin periodinane (1.74 g, 4.11 mmol) was added. After the addition was complete, the mixture was allowed to react 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, and 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 yield 285 mg of 6-bromo-5-methoxypyrazine-2-carbaldehyde (compound 60a).

[0503] 60.2 Compound 60a (285 mg, 1.31 mmol) was dissolved in 10 mL of dichloromethane and cooled in an ice bath. Under nitrogen protection, diethylaminosulfur trifluoride (635 mg, 3.34 mmol) dissolved in 5 mL of dichloromethane was slowly added dropwise. After the addition was complete, the mixture was allowed to react at room temperature for 2 hours, then the temperature was raised to reflux and the mixture was allowed to react overnight. After the reaction was complete, the reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the mixture was purified by column chromatography (PE:EA = 10:1) to give 340 mg of 3-bromo-5-(difluoromethyl)-2-methoxypyrazine (compound 60b).

[0504] 60.3 tert-Butyl 5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 60c) was prepared according to the method of Examples 39-39.4, substituting 60b for reactant 39c.

[0505] 60.4 5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 60d) was prepared according to the methods of Examples 39-39.6, substituting 60c for reactant 39e.

[0506] 60.5 By replacing reactant 39g with 44a and 39f with 60d, [5-[6-(difluoromethyl)-3-methoxypyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 60) was prepared according to the method of Examples 39-39.8. 1 H NMR (400 MHz, DMSO) δ 8.40 (s, 1H), 8.22 - 7.84 (m, 2H), 7.74 (dd, J = 15.1, 9.8 Hz, 1H), 7.51 (dd, J= 12.8, 6.2 Hz, 1H), 7.39 (dd, J = 19.8, 8.8 Hz, 1H), 7.10 (dd, J= 54.5, 21.9 Hz, 1H), 6.95 - 6.58 (m, 1H), 4.07 (d, J = 26.8 Hz, 3H), 3.90 - 3.70 (m, 1H), 3.67 (s, 1H), 3.53 (d, J = 1.5 Hz, 1H), 3.25 (dd, J= 12.2, 5.2 Hz, 1H), 3.15 (t, J = 10.6 Hz, 1H), 3.09 - 2.93 (m, 1H), 2.94 - 2.79 (m, 1H), 2.79 - 2.54 (m, 1H). m / z): 457 [M+H] + .

[0507] Example 61: Preparation of [4-fluoro-2-(1H-pyrazol-1-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (61)

[0508] [ka]

[0509] 61.1 4-Fluoro-2-(1H-pyrazol-1-yl)benzoic acid (compound 61a) was prepared according to the methods of Examples 39-39.7, replacing the reactants 4-fluoro-6-iodobenzoic acid with 4-fluoro-2-iodobenzoic acid and 1,2,3-triazole with 1H-pyrazole.

[0510] 61.2 [4-Fluoro-2-(1H-pyrazol-1-yl)phenyl][5-(3-methoxy-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrol-2(1H)-yl]methanone (compound 61) was prepared according to the method of Examples 39-39.8, substituting 61a for reactant 39g. 1 H NMR (400 MHz, DMSO) δ 7.94 (d, J= 8.2 Hz, 1H), 7.84 (d, J = 4.9 Hz, 1H), 7.53 (t, J = 10.6 Hz, 2H), 7.45 - 7.33 (m, 1H), 7.28 (s, 1H), 6.86 (d, J = 28.0 Hz, 1H), 6.65 (d, J = 55.1 Hz, 1H), 3.96 (d, J = 15.8 Hz, 3H), 3.65 (dd, J= 18.1, 9.2 Hz, 2H), 3.26 - 3.09 (m, 2H), 3.07 - 2.89 (m, 1H), 2.87 - 2.66 (m, 2H), 2.59 (d, J = 16.1 Hz, 1H), 2.39 (d, J = 15.7 Hz, 3H). LCMS (ES, m / z): 420 [M+H] + .

[0511] Example 62: Preparation of 3-[2-[4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-methylpyrazine-2-carbonitrile (62)

[0512] [ka]

[0513] 62.1 tert-Butyl 5-(6-chloro-3-cyanopyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 62a) was prepared according to the method of Examples 39-39.4, substituting 3,5-dichloropyrazine-2-carbonitrile for reactant 39c.

[0514] 62.2 tert-Butyl 5-(3-cyano-6-methylpyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 62b) was prepared according to the method of Examples 39-39.5, substituting 62a for reactant 39d.

[0515] 62.3 3-(1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-5-methylpyrazine-2-carbonitrile (compound 62c) was prepared according to the methods of Examples 39-39.6, substituting 62b for reactant 39d.

[0516] 62.4 3-[2-[4-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrol-5-yl]-5-methylpyrazine-2-carbonitrile (compound 62) was prepared according to the method of Examples 39-39.8, replacing reactant 39g with 44a and 39f with 62c. 1H NMR (400 MHz, DMSO) δ 8.89 (d, J= 23.5 Hz, 1H), 7.98 (s, 2H), 7.73 (t, J = 10.8 Hz, 1H), 7.51 (s, 1H), 7.38 (dd, J = 16.8, 8.3 Hz, 1H), 6.85 (d, J = 91.0 Hz, 1H), 3.76 (t, J = 13.8 Hz, 1H), 3.67 (t, J = 12.2 Hz, 2H), 3.52 (s, 1H), 3.22 - 2.91 (m, 2H), 2.91 - 2.74 (m, 2H), 2.68 (d, J = 10.2 Hz, 3H). LCMS (ES, m / z): 416 [M+H] + .

[0517] Example 63: Preparation of [4-methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (63)

[0518] [ka]

[0519] 63.1 tert-Butyl 5-(3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 63a) was prepared according to the methods of Examples 39-39.4, substituting 2-chloro-3-methoxypyrazine for reactant 39c.

[0520] 63.2 5-(3-methoxypyrazin-2-yl)-1,2,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 63b) was prepared according to the method of Examples 39-39.6, substituting 63a for reactant 39d.

[0521] 63.3 [4-Methoxy-2-(2H-1,2,3-triazol-2-yl)phenyl][5-(3-methoxypyrazin-2-yl)-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl]methanone (compound 63) was prepared according to the method of Examples 39-39.8, substituting 41a for reactant 39g and 63b for reactant 39f. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (d, J= 18.8 Hz, 1H), 8.07 (s, 1H), 8.04 - 7.68 (m, 2H), 7.41 - 7.28 (m, 2H), 7.07 (d, J = 10.8 Hz, 1H), 6.82 - 6.54 (m, 1H), 4.08 - 3.95 (m, 3H), 3.85 (d, J = 8.6 Hz, 3H), 3.76 - 3.59 (m, 2H), 3.47 (s, 1H), 3.31 - 3.04 (m, 2H), 2.84 (d, J = 15.2 Hz, 2H), 2.57 (d, J = 15.2 Hz, 1H). LCMS (ES, m / z): 419 [M+H] + .

[0522] Example 64 Preparation of [5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (64)

[0523] [ka]

[0524] 64.1 1-(3-chloropyrazin-2-yl)ethanone (600 mg, 3.83 mmol) was dissolved in 10 mL of carbon tetrachloride, diethylaminosulfur trifluoride (1.85 g, 11.49 mmol) was added, and the mixture was heated to 90 °C under nitrogen protection and reacted overnight. After completion of the reaction, the temperature was lowered to room temperature, and the reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (PE:EA = 5:1) to give 220 mg of 2-chloro-3-(1,1-difluoroethyl)pyrazine (Compound 64a).

[0525] 64.2 tert-Butyl 5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (compound 64b) was prepared according to the method of Examples 39-39.4, substituting 64a for reactant 39c.

[0526] 64.3 5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-1,2,3,3a,4,6a-hexahydrocyclopenta[c]pyrrole (compound 64c) was prepared according to the method of Examples 39-39.6, substituting 64b for reactant 39d.

[0527] 64.4 [5-[3-(1,1-difluoroethyl)pyrazin-2-yl]-3,3a,4,6a-tetrahydrocyclopentyl[c]pyrrol-2(1H)-yl][4-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (compound 64) was prepared according to the method of Examples 39-39.8, substituting 41a for reactant 39g and 64c for reactant 39f. 1H NMR (400 MHz, DMSO) δ 8.80 (d, J= 11.3 Hz, 1H), 8.64 (d, J = 5.4 Hz, 1H), 8.09 (s, 2H), 7.77 (d, J= 9.7 Hz, 1H), 7.50 (t, J = 6.8 Hz, 1H), 7.42 (t, J = 8.1 Hz, 1H), 6.10 - 5.71 (m, 1H), 3.91 - 3.39 (m, 3H), 3.23 - 2.99 (m, 2H), 2.93 (d, J= 12.3 Hz, 1H), 2.77 - 2.62 (m, 1H), 2.48 - 2.29 (m, 1H), 2.07 (t, J = 19.3 Hz, 3H). LCMS (ES, m / z): 441 [M+H] + .

[0528] Biological test examples Test Example 1 Orexin target function test 1. Purpose of the experiment: Utilizing the Cisbio HTRF IP-one kit, an ELISA instrument was used to detect changes in IP-one concentration in the orexin receptor (OX1 / OX2) signaling pathway and determine the IC of the compound. 50 The values ​​were calculated to evaluate the antagonistic activity of the compounds on OX1 and OX2 receptors.

[0529] 2. Experimental materials: Cell lines: CHO-K1-OX1 and CHO-K1-OX2 stable cell lines (Nanjing Genscript Biotechnology Co., Ltd.) Cell culture conditions: F12+10%FBS+400μg / ml G418 Reagents and consumables: F12 (Gibco, C11765500BT) FBS (Gibco, 10099-141C) Geneticin (G418) (Gibco, 11811031) PBS (Meilunbio, MA0015) Trypsin (Gibco, 25200-072) Orexin A (MCE, HY-106224) Orexin 2 receptor agonist (MCE, HY19320) 96-cell plate (cisbio, 66PL96025) IP-One-Gq Kit (cisbio, 62IPAPEC) CO2 incubator (Thermo, 311) Centrifuge (Shanghai Anting, TGL-16C) Cell counter (Countstar, IC1000) Microplate reader (PerkinElmer, EnVision)

[0530] 3. Experimental Method: (1) Preparation of reaction buffer (1x Stimulation buffer) required for the experiment: The 5x Stimulation buffer in the Cisbio IP-one kit was diluted with ddH2O at a ratio of 1:4 and prepared for use. (2) Compound preparation: Compounds were diluted to 5 mM stock solution with DMSO, then diluted 3.16 times to a 10 gradient, and then diluted to the corresponding concentration (4x) with stimulation buffer for use. (3) Cell preparation: CHO-K1-OX1 and CHO-K1-OX2 cells in a petri dish were digested with trypsin, eluted with culture medium, and collected in a 5 mL centrifuge tube. The mixture was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. 3 mL of PBS was added and mixed evenly by gently pipetting with a pipette. The mixture was centrifuged at 1000 rpm for 5 minutes, and the supernatant was discarded. The cells were resuspended in 1x stimulation buffer and counted using a Countstar cell counter to determine a cell density of 1.71 x 10 6 The concentration was adjusted to 1 / mL and prepared for use. (4) Addition of cells: The cell suspension was added to the experimental plate at 7 μL / well (i.e., approximately 12,000 cells / well). (5) Addition of compounds: Compounds diluted with stimulation buffer were added to the above experimental plate at 3.5 μL / well. (6) Reaction incubation: After gentle shaking, the experimental plate was incubated at 37°C for 30 minutes. (7)EC 80 Addition of agonist:EC 80 4× Orexin A (OX1 receptor) and 4× Orexin 2 receptor agonist (OX2 receptor) solutions were added at 3.5 μL / well. (8) Reaction incubation: After gentle shaking, the experimental plate was incubated at 37°C for 45 minutes. (9) Addition of detection reagent: IP1-d2 and Anti-IP1 cryptate were diluted 1:20 using the lysis and detection buffer provided in the Cisbio IP-one detection reagent kit, and 3 μL of each diluted IP1-d2 and Anti-IP1 cryptate were added to the experimental plate. After shaking, the experimental plate was left at room temperature for 60 minutes. (10) Reading of experimental values: The plate was read on Envision, the readings of the 665 nm and 615 nm channels were detected, and the ratio of the 665 nm / 615 nm readings was calculated.

[0531] 4. Data Analysis: Based on the antagonistic effect values ​​for different concentration test points of the compound samples, the antagonism curves of the compound samples on the orexin receptor were fitted using GraphPad Prism software, and the IC 50 was calculated.

[0532] [Table 1-1]

[0533] [Table 1-2]

[0534] The compounds of the present invention have good inhibitory activity against OX2 receptors, and the inhibitory effect of the compounds against OX2 receptors is significantly superior to that against OX1 receptors, showing good selectivity.

[0535] Test Example 2 Measurement of pharmacokinetic parameters of test substance in rat plasma Healthy male SD rats aged 6-9 weeks were selected and randomly divided into two groups of three. One group received 1 mg / kg of the test compound via intravenous injection, while the other group received 30 mg / kg of the test compound via oral gavage. Whole blood samples were collected from both the intravenous and oral gavage groups before and after administration at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, 10.0, and 24.0 hours, and plasma samples were obtained by centrifugation.

[0536] Quantitative analysis was performed on all biological samples using LC-MS / MS with WinNonlin™ Version 7.0 (Pharsight, Mountain View, CA) pharmacokinetic software, and relevant drug kinetic parameters were calculated using the non-compartmental linear-logarithmic trapezoidal method. AUC 0-last represents the area under the plasma concentration-time curve from time zero to the last detectable concentration time point, PO represents oral, iv represents intravenous, and C max represents the peak concentration, and F% represents the oral bioavailability.

[0537] [Table 2]

[0538] In a pharmacokinetic evaluation experiment in rats, the example compounds of the present invention showed good bioavailability after oral administration.

[0539] Test Example 3 Spontaneous activity in rats Male SD rats aged 6 to 9 weeks were randomly assigned to groups of eight rats each according to the weight balance principle and administered either a blank vehicle or 10, 30, or 50 mg / kg of test compound. The animals were immediately placed in the test box after administration, and the animal's activity distance within 60 minutes was recorded and analyzed using TopScan Version 3.0. The total activity distance of animals in each test compound treatment group was compared with that of the blank vehicle group to determine whether the test compound significantly affected the animals' spontaneous activity. Experimental data are presented as mean ± standard error (Mean ± SD). One-way analysis of variance was performed using SPSS 21.0 statistical software. Pairwise comparisons were performed using Dunnett's test. * indicates a difference when p<0.05.

[0540] [Table 3]

[0541] In a spontaneous activity experiment using rats, the compounds of the examples of the present invention were able to significantly reduce the spontaneous activity distance of rats, and the minimum effective dose was equal to or greater than that of Seltorexant.

[0542] Test Example 3 Measurement of blood-brain barrier permeability of test substances in rats Twelve male SD rats were randomly divided into four groups, with three rats in each group. The animals were fasted for 8 hours before the experiment and had free access to water. A 30 mg / kg dose of the test substance was administered orally by gavage. 0.3 mL of blood was collected from the jugular plexus of the rats before and 0.25 hours after administration. The rats were then anesthetized, their chests were opened, the right atrial appendage was cut, and rapid perfusion was performed from the back of the left ventricle. Perfusion was stopped when the outflowing fluid was clear and blood-free. Brain tissue was then removed, wiped dry with filter paper, weighed, and homogenized in an appropriate amount of saline (1:4, v / v) to prepare brain tissue homogenates. The whole blood samples were centrifuged at 4000 rpm for 10 minutes to obtain plasma.

[0543] An established LC-MS / MS method was used to detect the concentrations of test substances in plasma and brain tissue homogenates. The blood-brain ratio (Kb / p) of the test substance was obtained by dividing the drug concentration in brain tissue by the drug concentration in plasma. A larger Kb / p indicates a higher blood-brain barrier permeability of the test substance.

[0544] [Table 4]

[0545] Conclusion: The compounds of the examples of the present invention can penetrate the blood-brain barrier well after oral administration to rats, and have a higher blood-brain ratio.

[0546] Test Example 4: Effects of test substances on sleep in SD rats Experimental process: 1. Surgical implantation of electrodes: Animals were placed in a 14-hour / 10-hour automatic light / dark cycle and allowed to acclimate for at least four days (lights off at 9:00 PM, lights on at 7:00 AM). On the day of the experiment, animals were anesthetized with sodium pentobarbital (intraperitoneal injection, 60 mg / kg). After anesthesia, the brain was fixed in a stereotaxic apparatus, the skin at the surgical site on the head was prepared, and a hole was drilled in the skull to implant the electrode. 2. Postoperative care: After surgery, rats were carefully placed in a clean recovery cage on their side to prevent airway obstruction. The light and darkness cycled automatically (lights off at 9:00 PM, lights on at 7:00 AM), and the temperature and relative humidity were maintained at 20-26°C and 40-70%, respectively. After surgery, the rats were cared for for 3 days, at which point they were given an intramuscular injection of 80,000 units of penicillin sodium per rat. Experiments were performed after at least 7 days of recovery. 3. Dosing schedule and monitoring parameters: After at least 7 days of postoperative recovery, baseline electroencephalography (EEG) and electromyography (EMG) recordings were performed. Medication was initiated after baseline EEG and EMG recordings were completed. Prior to administration, animals were allowed to acclimate in the test cage for at least 24 hours, and one dose was administered 1 hour after lights were turned off. EEG and EMG were recorded 12 hours after administration. 4. Test endpoint: rats' hourly wakefulness time 12 hours after drug administration. Data were analyzed using t-test, and P<0.05 indicated significant difference. The experimental results are shown in the attached figures.

[0547] The results show that in the sleep effect test of rats, the example compounds of the present invention can significantly shorten the total waking time and increase the total sleep time at a lower dose, which indicates that the example compounds of the present invention have a good promoting effect on rat sleep.

[0548] It will be apparent to those skilled in the art that many modifications and variations of this invention can be made without departing from the spirit and scope of the invention. The specific embodiments described herein are offered by way of example only and are not intended to be limiting in any way. The true scope and spirit of the invention is indicated by the appended claims, and the specification and examples are intended to be illustrative only.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, 【Chemistry 1】 During the ceremony, R １ , R ２ are each independently H, D, or optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ is selected from cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ８ cycloalkyl and halogen, wherein the substituents are independently H, D, halogen, C １ ~C ８ selected from alkoxy, hydroxyl, nitro and cyano; Or, R １ , R ２ together with the carbon atom to which they are attached, represent a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or an optionally substituted C ３ ~C ８ cycloalkyl, wherein the substituents are independently H, D, halogen, C １ ~C ８ Alkyl, C １ ~C ８ selected from alkoxy, hydroxyl, nitro and cyano; L １ is one or more substituents R ＬＡ a 6- to 14-membered aryl group optionally substituted with one or more substituents R ＬＡ and preferably one or more substituents R ＬＡ a 6- to 10-membered aryl group optionally substituted with one or more substituents R ＬＡ and more preferably one or more substituents R ＬＡ a phenyl group optionally substituted with one or more substituents R ＬＡ wherein the one or more substituents R ＬＡ are independently H, D, halogen, one or more substituents R ＬＢ C optionally substituted with １ ~C ８ alkyl, one or more substituents R ＬＢ C optionally substituted with １ ~C ８ alkoxy, cyano, one or more substituents R ＬＢ C optionally substituted with ２ ~C ８ alkynyl, one or more substituents R ＬＢ C optionally substituted with ２ ~C ８ alkenyl, hydroxy, nitro, one or more substituents R ＬＢ C optionally substituted with １ ~C ８ alkylthio, one or more substituents R ＬＢ C optionally substituted with ３ ~C ８ cycloalkyl, and OR ４ wherein said one or more substituents R ＬＢ is selected from H, D, halogen and hydroxy; R ４ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, L ２ is selected from 6- to 14-membered aryl substituted with 0-4 Rb groups and 5- to 14-membered heteroaryl substituted with 0-4 Rb groups, preferably selected from 6- to 10-membered aryl substituted with 0-3 Rb groups and 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rb groups, more preferably selected from phenyl substituted with 0-3 Rb groups and 5- to 6-membered heteroaryl substituted with 0-3 Rb groups; Each Rb group is independently H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ alkoxy and halogen, said substituents being independently selected from H, D, halogen and hydroxyl; X １ is N and CR １０ is selected from R １０ is H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ３ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ selected from cycloalkyl, halogen, hydroxy, nitro and cyano, preferably H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ８ cycloalkyl and halogen, wherein the substituents are independently selected from H, D, halogen, C １ ~C ８ selected from alkoxy, hydroxy, nitro and cyano, preferably selected from H, D, halogen and hydroxy; X ２ is N and CR １１ is selected from R １１ is H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, halogen, hydroxy, nitro, and cyano, wherein the substituents are independently selected from H, D, halogen, C １ ~C ８ selected from alkoxy, hydroxy, nitro and cyano, and X １ , X ２ is not N at the same time, and X ２ is CR １１ , and X １ If is N, then R ２ is not H or D, A compound of formula I or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

2. The compound of formula I is represented by formula IA: 【Chemistry 2】 In the formula, R １Ａ , R ２Ａ , R ３Ａ are independently H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ selected from cycloalkyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ８ cycloalkyl and halogen, wherein the substituents are independently H, halogen, C １ ~C ８ selected from alkoxy, hydroxyl, nitro, cyano, preferably selected from H, D, halogen and hydroxyl; Or, R １Ａ , R ２Ａ together with the carbon atom to which they are attached, represent a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or C ３ ~C ８ cycloalkyl, wherein the substituents are independently H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ selected from alkoxy, hydroxyl, nitro and cyano; L １Ａ is selected from a 6- to 14-membered aryl group optionally substituted with one or more substituents, and a 5- to 14-membered heteroaryl group optionally substituted with one or more substituents, preferably a 6- to 10-membered aryl group optionally substituted with one or more substituents, and a 5- to 10-membered heteroaryl group optionally substituted with one or more substituents, more preferably a phenyl group optionally substituted with one or more substituents, and a 5- to 6-membered monocyclic heteroaryl group optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from H, D, halogen, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, cyano, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ２ ~C ８ Alkenyl, hydroxy, nitro, optionally substituted C １ ~C ８ alkylthio, optionally substituted C ３ ~C ８ cycloalkyl, and OR ４Ａ and preferably independently selected from H, halogen, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, hydroxy, optionally substituted C ３ ~C ６ cycloalkyl, and OR ４Ａ and more preferably, independently selected from H, halogen, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ６ cycloalkyl, and OR ４Ａ wherein the substituents are selected from H, D, halogen and hydroxy, and the substituents are preferably selected from D, halogen and hydroxy; R ４Ａ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, L ２Ａ is selected from 6- to 14-membered aryl substituted with 0-4 Rbbb groups and 5- to 14-membered heteroaryl substituted with 0-4 Rbbb groups, preferably selected from 5- to 10-membered aryl substituted with 0-3 Rbbb groups and 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbbb groups, more preferably selected from phenyl substituted with 0-3 Rbbb groups and 5- to 6-membered heteroaryl substituted with 0-3 Rbbb groups; Each Rbbb group is independently H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ 2. The compound of formula I according to claim 1, wherein each of the substituents is independently selected from H, D, halogen, and hydroxyl, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

3. R １Ａ , R ２Ａ , R ３Ａ are independently H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ selected from cycloalkyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ８ cycloalkyl and halogen, wherein the substituents are independently H, halogen, C １ ~C ８ selected from alkoxy, hydroxyl, nitro, and cyano, preferably selected from H, halogen, and hydroxyl; Or, R １Ａ , R ２Ａ together with the carbon atom to which they are attached, represent a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or C ３ ~C ８ cycloalkyl, wherein the substituents are independently H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ selected from alkoxy, hydroxyl, nitro and cyano; L １Ａ is selected from a 6- to 14-membered aryl group optionally substituted with one or more substituents, and a 5- to 14-membered heteroaryl group optionally substituted with one or more substituents, preferably a 6- to 10-membered aryl group optionally substituted with one or more substituents, and a 5- to 10-membered heteroaryl group optionally substituted with one or more substituents, more preferably a phenyl group optionally substituted with one or more substituents, and a 5- to 6-membered monocyclic heteroaryl group optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, cyano, C ２ ~C ８ Alkynyl, C ２ ~C ８ Alkenyl, hydroxy, nitro, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C １ ~C ８ Alkylthio, C ３ ~C ８ cycloalkyl, and OR ４Ａ and preferably independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, hydroxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ３ ~C ６ cycloalkyl, and OR ４Ａ and more preferably, independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkyl, C ３ ~C ６ cycloalkyl, and OR ４Ａ is selected from R ４Ａ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, L ２Ａ is selected from 6- to 14-membered aryl substituted with 0-4 Rbbb groups and 5- to 14-membered heteroaryl substituted with 0-4 Rbbb groups, preferably selected from 5- to 10-membered aryl substituted with 0-3 Rbbb groups and 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbbb groups, more preferably selected from phenyl substituted with 0-3 Rbbb groups and 5- to 6-membered heteroaryl substituted with 0-3 Rbbb groups; Each Rbbb group is independently H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ 3. The compound of formula IA, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, according to claim 2, wherein each of the substituents is selected from alkoxy and halogen, and said substituents are independently selected from H, halogen, and hydroxyl.

4. A compound of formula IA or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to claim 2 or 3, characterized in that it satisfies one or more of the following conditions: (1) R １Ａ , R ２Ａ , R ３Ａ are independently H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ selected from cycloalkyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ８ cycloalkyl and halogen, wherein the substituents are independently H, halogen, C １ ~C ８ is selected from alkoxy, hydroxyl, nitro, and cyano, and is preferably selected from H, halogen, and hydroxyl; ３ ~C ８ cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl; Or, R １Ａ , R ２Ａ together with the carbon atom to which they are attached, represent a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or C ３ ~C ８ and forming a cycloalkyl, wherein the 3- to 8-membered heterocyclyl is preferably selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, tetrahydrothiophenyl, dihydrothiophenyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, and pyrrolidinyl, more preferably tetrahydrofuranyl, tetrahydropyranyl, and dihydropyranyl, and the 5- to 8-membered heteroaryl is preferably selected from furanyl, pyranyl, and thienyl, and the C ３ ~C ８ Cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl and cyclohexenyl, more preferably selected from cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, and is preferably selected from or R １Ａ , R ２Ａ and together with the carbon atoms to which they are attached may be substituted with one or more substituents. 【Transformation 3】 and preferably optionally substituted with one or more substituents. 【Chemistry 4】 and is preferably optionally substituted with one or more substituents. 【Transformation 5】 wherein the substituents are independently H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ selected from alkoxy, hydroxyl, nitro and cyano; (2) L １Ａ is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, triazolyl, thiadiazolyl, thienyl and furanyl, preferably selected from phenyl, pyridinyl, pyrazolyl, thiazolyl and thienyl, more preferably phenyl, pyridinyl and thiazolyl, and the above groups are optionally substituted with one or more substituents, the one or more substituents being independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, cyano, C ２ ~C ８ Alkynyl, C ２ ~C ８ Alkenyl, hydroxy, nitro, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C １ ~C ８ Alkylthio, C ３ ~C ８ cycloalkyl, and OR ４Ａ and preferably independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, hydroxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ３ ~C ６ cycloalkyl, and OR ４Ａ and more preferably, independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkyl, C ３ ~C ６ cycloalkyl, and OR ４Ａ is selected from R ４Ａ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, (3) L ２Ａ is selected from phenyl, pyrimidinyl, pyridinyl, pyrazinyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thienyl, furanyl and 1,3,4-triazolyl, preferably selected from phenyl, pyrimidinyl, pyridinyl, pyrazolyl, thienyl, imidazolyl and 1,2,3-triazolyl, more preferably phenyl, pyridinyl, pyrazolyl, thienyl and 1,2,3-triazolyl, wherein said groups are optionally substituted with 0 to 4 Rbbb groups.

5. R １Ａ , R ２Ａ , R ３Ａ are independently H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, haloalkyl, deuterated C １ ~C ８ Alkyl and deuterated C １ ~C ８ Alkoxy, preferably H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy and deuterated C １ ~C ８ alkyl, L １Ａ is selected from a 6- to 14-membered aryl group optionally substituted with one or more substituents, and a 5- to 14-membered heteroaryl group optionally substituted with one or more substituents, preferably a 6- to 10-membered aryl group optionally substituted with one or more substituents, and a 5- to 10-membered heteroaryl group optionally substituted with one or more substituents, more preferably a phenyl group optionally substituted with one or more substituents, and a 5- to 6-membered monocyclic heteroaryl group optionally substituted with one or more substituents, wherein the one or more substituents are independently selected from H, D, C ... １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, haloalkyl, deuterated C １ ~C ８ Alkyl and deuterated C １ ~C ８ alkoxy, preferably independently selected from H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy and deuterated C １ ~C ８ alkyl, L ２Ａ is selected from 6- to 14-membered aryl substituted with 0-4 Rbbb groups and 5- to 14-membered heteroaryl substituted with 0-4 Rbbb groups, preferably selected from 5- to 10-membered aryl substituted with 0-3 Rbbb groups and 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbbb groups, more preferably selected from phenyl substituted with 0-3 Rbbb groups and 5- to 6-membered heteroaryl substituted with 0-3 Rbbb groups; Each Rbbb group is independently H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, haloalkyl, deuterated C １ ~C ８ Alkyl and deuterated C １ ~C ８ Alkoxy, preferably H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, deuterated C １ ~C ８ Alkyl and deuterated C １ ~C ８ selected from alkoxy, 3. The compound of formula IA according to claim 2, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

6. The compound of formula IA is represented by formula II-A: 【Transformation 6】 In the formula, R ５Ａ is H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ alkoxy and halogen, said substituents being independently selected from H, halogen and hydroxyl; 6. A compound of formula IA according to any one of claims 2 to 5, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

7. The compound of formula IA is represented by formula III-A: 【Transformation 7】 In the formula, R ５Ａ is H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ alkoxy and halogen, said substituents being independently selected from H, halogen and hydroxyl; n1A is an integer selected from 0 to 4, preferably 1; R ６Ａ are independently H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, cyano, C ２ ~C ８ Alkynyl, C ２ ~C ８ Alkenyl, hydroxy, nitro, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C １ ~C ８ Alkylthio, C ３ ~C ８ cycloalkyl, and OR ４Ａ and preferably independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, hydroxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ３ ~C ６ cycloalkyl, and OR ４Ａ and more preferably, independently selected from H, halogen, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkyl, C ３ ~C ６ cycloalkyl, and OR ４Ａ is selected from R ４Ａ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, 7. A compound of formula IA according to any one of claims 2 to 6, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

8. The compound of formula I is represented by formula I-B, 【Transformation 8】 In the formula, R １Ｂ , R ３Ｂ are independently H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ is selected from cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, halogen, hydroxyl, nitro and cyano, preferably H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ８ cycloalkyl and halogen, wherein the substituents are independently halogen, D, C １ ~C ８ selected from alkoxy, hydroxyl, nitro, and cyano; R ２Ｂ is C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Haloalkenyl, C ２ ~C ８ haloalkynyl, hydroxy, nitro and cyano, preferably C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ is selected from haloalkyl and halogen, more preferably C １ ~C ８ Alkyl, C １ ~C ８ selected from haloalkyl and halogen, even more preferably F; Or, R １Ｂ and R ２Ｂ are taken together to represent a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or C ３ ~C ８ cycloalkyl, wherein the substituents are independently halogen, D, C １ ~C ８ Alkyl, C １ ~C ８ selected from alkoxy, hydroxyl, nitro and cyano; L １Ｂ is selected from optionally substituted phenyl and optionally substituted pyridyl, and the substituents are independently selected from H, D, C, １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, hydroxy, nitro, cyano, -OR ４Ｂ and C １ ~C ８ alkylthio, preferably H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Haloalkyl, -OR ４Ｂ and C １ ~C ８ alkylthio; R ４Ｂ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, L ２Ｂ is a 5- to 14-membered heteroaryl substituted with 0-4 Rbb groups, preferably a 5- to 10-membered monocyclic or bicyclic heteroaryl substituted with 0-3 Rbb groups, and more preferably a 5- to 6-membered heteroaryl substituted with 0-3 Rbb groups; Each R group is independently H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ selected from alkoxy and halogen, preferably H and C １ ~C ８ alkyl, wherein said substituents are independently selected from H and halogen; 2. A compound of formula I according to claim 1, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

9. 9. The compound of formula I-B or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof according to claim 8, wherein the compound satisfies one or more of the following conditions: (1) R １Ｂ , R ３Ｂ are independently H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ２ ~C ８ Alkenyl, optionally substituted C ２ ~C ８ Alkynyl, optionally substituted C ３ ~C ８ cycloalkyl, optionally substituted 3- to 8-membered heterocyclyl, halogen, hydroxyl, nitro and cyano, and preferably independently H, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ Alkoxy, optionally substituted C ３ ~C ８ cycloalkyl and halogen, wherein the substituents are independently halogen, D, C １ ~C ８ alkoxy, hydroxyl, nitro, and cyano, wherein the 3- to 8-membered heterocyclyl is preferably selected from oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, tetrahydrothiopyranyl, piperidinyl, and pyrrolidinyl, and wherein the C ３ ~C ８ the cycloalkyl group is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, preferably cyclopropyl; R ２Ｂ is C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Haloalkenyl, C ２ ~C ８ haloalkynyl, hydroxy, nitro and cyano, preferably C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ is selected from haloalkyl and halogen, more preferably C １ ~C ８ Alkyl, C １ ~C ８ selected from haloalkyl and halogen, even more preferably F; Or, R １Ｂ and R ２Ｂ are taken together to represent a 3- to 8-membered heterocyclyl, a 5- to 8-membered heteroaryl, or C ３ ~C ８ and forming a cycloalkyl, wherein the 3- to 8-membered heterocyclyl is preferably selected from tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, dihydropyranyl, azetidinyl, oxetanyl, thietanyl, piperidinyl, and pyrrolidinyl, more preferably selected from tetrahydrofuranyl, tetrahydropyranyl, and dihydropyranyl, and the 5- to 8-membered heteroaryl is preferably selected from furanyl, pyranyl, and thienyl, and the C ３ ~C ８ Cycloalkyl is preferably selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, more preferably cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl, wherein the substituents are independently selected from halogen, D, C ... １ ~C ８ Alkyl, C １ ~C ８ selected from alkoxy, hydroxyl, nitro and cyano; (2) L １Ｂ is selected from optionally substituted phenyl and optionally substituted pyridyl, and the substituents are independently selected from H, D, C, １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, hydroxy, nitro, cyano, -OR ４Ｂ and C １ ~C ８ alkylthio, preferably independently selected from H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Haloalkyl, -OR ４Ｂ and C １ ~C ８ alkylthio; R ４Ｂ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, (3) L ２Ｂ is selected from pyrimidinyl, pyridinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl, pyrazolyl, pyrrolyl, 1,2,3-triazolyl, thiadiazolyl, thienyl, furanyl and 1,3,4-triazolyl, preferably selected from pyrazolyl, imidazolyl and 1,2,3-triazolyl, more preferably 1,2,3-triazolyl, wherein said groups are optionally substituted with 0 to 4 Rbb groups.

10. A compound of formula I-B according to any one of claims 8 to 9, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, which satisfies one or more of the following conditions: (1) L １Ｂ teeth, 【Chemistry 9】 is selected from, preferably 【Chemistry 10】 and more preferably selected from 【Chemistry 11】 wherein the groups are optionally substituted with one or more substituents, each of which is independently selected from H, D, C, １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, hydroxy, nitro, cyano, -OR ４Ｂ and C １ ~C ８ alkylthio, preferably independently selected from H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Haloalkyl, -OR ４Ｂ and C １ ~C ８ alkylthio; R ４Ｂ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, (2) R ２Ｂ is C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Haloalkenyl, C ２ ~C ８ haloalkynyl, hydroxy, nitro and cyano, preferably C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ is selected from haloalkyl and halogen, more preferably C １ ~C ８ Alkyl, C １ ~C ８ It is selected from haloalkyl and halogen, and even more preferably is F.

11. The compound of formula I-B is represented by formula II-B: 【Chemistry 12】 In the formula, R ５Ｂ is H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ alkoxy and halogen, said substituents being independently selected from D and halogen; R ２Ｂ is C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Haloalkenyl, C ２ ~C ８ haloalkynyl, hydroxy, nitro and cyano, preferably C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ is selected from haloalkyl and halogen, more preferably C １ ~C ８ Alkyl, C １ ~C ８ selected from haloalkyl and halogen, even more preferably F; The compound of formula IB according to any one of claims 8 to 10, or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.

12. The compound of formula I-B is represented by formula III-B: 【Chemistry 13】 wherein n1B is an integer selected from 0 to 3; R ６Ｂ H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, hydroxy, nitro, cyano, -OR ４Ｂ and C １ ~C ８ alkylthio, preferably H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Haloalkyl, -OR ４Ｂ and C １ ~C ８ alkylthio; R ４Ｂ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, R ２Ｂ is C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Haloalkenyl, C ２ ~C ８ haloalkynyl, hydroxy, nitro and cyano, preferably C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ is selected from haloalkyl and halogen, more preferably C １ ~C ８ Alkyl, C １ ~C ８ selected from haloalkyl and halogen, even more preferably F; 12. The compound according to any one of claims 8 to 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

13. The compound of formula I-B is represented by formula IV-B, 【Chemistry 14】 In the formula, R ５Ｂ is H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ alkoxy and halogen, said substituents being independently selected from D and halogen; n2B is an integer selected from 0 to 4, preferably 1; R ７Ｂ are independently H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, hydroxy, nitro, cyano, -OR ４Ｂ and C １ ~C ８ alkylthio, preferably H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Haloalkyl, -OR ４Ｂ and C １ ~C ８ alkylthio; R ４Ｂ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, R ２Ｂ is C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Haloalkenyl, C ２ ~C ８ haloalkynyl, hydroxy, nitro and cyano, preferably C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ is selected from haloalkyl and halogen, more preferably C １ ~C ８ Alkyl, C １ ~C ８ selected from haloalkyl and halogen, even more preferably F; 12. The compound according to any one of claims 8 to 11, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

14. The compound of formula I-B is represented by formula V-B, 【Chemistry 15】 In the formula, R ５Ｂ is H, D, optionally substituted C １ ~C ８ Alkyl, optionally substituted C １ ~C ８ alkoxy and halogen, said substituents being independently selected from D and halogen; n3B is an integer selected from 0 to 3, preferably 1; R ８Ｂ are independently H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, hydroxy, nitro, cyano, -OR ４Ｂ and C １ ~C ８ alkylthio, preferably H, D, C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Haloalkyl, -OR ４Ｂ and C １ ~C ８ alkylthio; R ４Ｂ is C ３ ~C ８ cycloalkyl and 3- to 8-membered heterocyclyl, preferably C ３ ~C ６ is cycloalkyl, R ２Ｂ is C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, halogen, C １ ~C ８ Deuterated alkyl, C １ ~C ８ Deuterated alkoxy, C １ ~C ８ Hydroxyalkyl, C １ ~C ８ Hydroxyalkoxy, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C １ ~C ８ Haloalkyl, C １ ~C ８ Haloalkoxy, C ２ ~C ８ Haloalkenyl, C ２ ~C ８ haloalkynyl, hydroxy and nitro, preferably C １ ~C ８ Alkyl, C １ ~C ８ Alkoxy, C １ ~C ８ is selected from haloalkyl and halogen, more preferably C １ ~C ８ Alkyl, C １ ~C ８ selected from haloalkyl and halogen, even more preferably F; 13. The compound according to any one of claims 8 to 12, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

15. The following compounds: 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】 【Chemistry 20】 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, selected from the group consisting of:

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

17. Use of a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof, or a pharmaceutical composition according to claim 16, in the preparation of a medicament, wherein the medicament is used for the prevention, treatment and / or alleviation of a disease associated with an orexin receptor.

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

19. A process for the preparation of compounds of formula I according to any one of claims 1 to 15, comprising the following steps: reacting compound I-d with compound If to obtain the desired compound I, 【Chemistry 21】 In the formula, R １ , R ２ , X １ , X ２ , L １ , L ２ are as defined for the corresponding groups in claims 1 to 15, and preferably the compound represented by I-d is a compound represented by I-dA or I-dB, 【Chemistry 22】 R １Ａ , R ２Ａ , R ３Ａ is as defined for the corresponding radicals in claims 1 to 7 or 15, and R １Ｂ , R ２Ｂ , R ３Ｂ is as defined for the corresponding radicals in claims 1 or 8-15.

20. A compound of formula Id, 【Chemistry 23】 In the formula, R １ , R ２ , X １ , X ２ are as defined for the corresponding groups in claims 1 to 15, and preferably the compound represented by I-d is a compound represented by I-dA or I-dB, 【Chemistry 24】 R １Ａ , R ２Ａ , R ３Ａ is as defined for the corresponding radicals in claims 1 to 7 or 15, and R １Ｂ , R ２Ｂ , R ３Ｂ is as defined for the corresponding group in claims 1 or 8-15.

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