Compound, pharmaceutical composition comprising same, preparation method, and use

Abstract

The present application relates to the field of pharmaceutical chemistry, and specifically relates to a compound, a pharmaceutical composition comprising same, a preparation method, and a use. The compound has a structure as shown in formula (I), and is used for preventing or treating M4-mediated diseases or conditions.

Description

Compound, pharmaceutical composition containing the same, preparation method and use thereof

[0001] This application claims priority to Chinese patent application No. 202410346587.5 filed on March 25, 2024, priority to Chinese patent application No. 202411253559.5 filed on September 6, 2024, and priority to Chinese patent application No. 202510077171.2 filed on January 17, 2025, the entire contents of which are incorporated herein by reference in their entirety. Technical Field

[0002] The present invention relates to a compound, a pharmaceutical composition comprising the same, a preparation method thereof and use thereof for preventing or treating diseases or conditions mediated by muscarinic acetylcholine receptor M4. Background Art

[0003] Muscarinic acetylcholine receptor is a G protein coupled receptor (GPCR), which is divided into five subtypes of M1, M2, M3, M4 and M5. These subtypes are widely distributed throughout the periphery and central nervous system, and M1 and M4 subtypes are mainly expressed in CNS, wherein M4 receptors are mainly expressed in cerebral cortex, striatum, hypothalamus and hippocampus (Neuropharmacology 2018, 136, 362-373). M1, M3 and M5 subtypes are mainly coupled with Gq and activate phospholipase C, while M2 and M4 subtypes are mainly coupled with Gi / o and related effector systems.

[0004] A genome-wide association study for schizophrenia identified a single nucleotide polymorphism significantly associated with the disease at locus rs7951870, which includes the M4 gene (Nature Genetics 2018, 50, 381-389). In schizophrenia, a hyperdopaminergic state in the striatum and nucleus accumbens is associated with psychosis and is the target of current antipsychotic drugs that block dopamine D2 receptors.

[0005] In a recent study, it was demonstrated that M4PAM (M4 positive allosteric modulator) can reduce the release of striatal dopamine after amphetamine treatment in wild-type mice, but does not reduce the release of striatal dopamine after amphetamine treatment in wild-type mice with M4 knockout (Neuropsychopharmacology 2014, 39, 1578). Another study showed that M4PAM induced inhibition of glutamate excitatory synaptic transmission at Schaeffer collateral-CA1 synapses in the hippocampus (Hippocampus 2017, 27, 794-810). This indicates that M4PAM enhances the effects of the endogenous agonist acetylcholine, revealing the role of these receptors in controlling dopamine release in the striatum and its role in key synapses that are important for cognition in the hippocampus. By using specific PAM to activate striatal and hippocampal M4 receptors, the high dopaminergic state of the striatum and overstimulation of the hippocampus can be reduced, providing treatment for the psychosis and cognitive impairment of schizophrenia.

[0006] Eli Lilly has published a patent for thienopyridine compounds, which are positive allosteric modulators (M4PAMs) targeting the muscarinic M4 acetylcholine receptor (WO2006047124A1). Vanderbilt University has published several international patent applications targeting muscarinic M4PAMs.

[0007] Pfizer's CVL-231, developed for M4PAM, has entered Phase II clinical trials and has demonstrated promising therapeutic effects in patients with schizophrenia. However, it still suffers from rapid metabolism, and its pharmacokinetic properties need further improvement.

[0008] Recently, clinical studies on patients with Alzheimer's disease have shown that the M1 / M4 agonist xanomeline activates muscarinic receptors to improve cognitive and psychiatric symptoms, such as hallucinations, delusions, and vocalizations (Arch Neurol 1997, 54, 465-73). Therefore, M4PAM can improve cognitive deficits and alleviate psychiatric symptoms in patients with Alzheimer's disease. The combination therapy of xanomeline and trospium chloride (KarXT) has achieved positive results in the treatment of schizophrenia, further demonstrating the therapeutic effect of M receptor agonism in this field. However, xanomeline itself has poor selectivity for M receptors and clinically exhibits strong gastrointestinal side effects. It must be used in conjunction with peripheral M2 and M3 antagonists, which brings inconvenience to clinical application.

[0009] Modulating M4 receptor activity is a promising therapeutic strategy for treating or preventing M4-mediated diseases or conditions. There is a need for new compounds, formulations, treatments, and therapies for treating or preventing M4-mediated diseases or conditions. Therefore, the development of new compounds that modulate M4 receptor activity is needed to address clinical needs. Summary of the Invention

[0010] The present invention provides a novel polycyclic compound, which can be used as a muscarinic acetylcholine receptor M4 activity modulator, in particular a positive allosteric modulator (M4PAM), which can be used to treat M4 receptor-mediated diseases or disorders. The compound has excellent positive allosteric regulation on M4, and has properties such as reduced toxic side effects and good pharmacokinetic properties.

[0011] One aspect of the present invention provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof:

[0012] in:

[0013] Ring A is selected from 5-14 membered heteroaromatic rings and C 6-14 aromatic rings;

[0014] R 1 、R 3 、R 4 、R 5 is independently selected at each occurrence from hydrogen, deuterium, tritium, OR 7 , oxo, hydroxy, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 7 R 8 、-CONR 7 R 8 、-COC 1-6 Alkyl, -NHCOC 1-6 Alkyl, -C(O)OR 7 、-OC(O)R 7 、-OC(O)NR 7 R 8 、-NR 7 C(O)NR 7 R 8 、C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl groups is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 Replace; or

[0015] Two R's attached to the same carbon atom 4 Or two R5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group, which is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace;

[0016] And, R 1 It can also be missing;

[0017] R 7 、R 8 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 Replace; or

[0018] R 7 、R 8 Together with the N atom, it forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 replace;

[0019] R 9 is independently selected at each occurrence from H, deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 、-COCH3、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkylthio, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) independently selected from halogen, -OH, -CN, -NR 7 R 8 、-COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups;

[0020] Ring B is selected from a 4-8 membered carbocyclic ring, a 4-8 membered heterocyclic ring, a 4-8 membered aromatic ring and a 4-8 membered heteroaromatic ring;

[0021] Ring C is selected from a 5-8 membered carbocyclic ring, a 5-8 membered heterocyclic ring or a 5-8 membered heteroaromatic ring;

[0022] L is selected from C, CR a and N;

[0023] R a Selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups;

[0024] R 2 For-PR 6 ;

[0025] P is a single bond, a double bond, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 -, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace;

[0026] R 6 Selected from deletion, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, 5-14 membered heteroaryl and C 6-14 Aryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (eg, 1, 2, 3, 4, 5, 6) R 9replace;

[0027] m, n, and o are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0028] Another aspect of the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers.

[0029] Another aspect of the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, in the preparation of a medicament for preventing or treating a disease or condition mediated by muscarinic acetylcholine receptor M4.

[0030] Another aspect of the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, for use in preventing or treating a disease or condition mediated by muscarinic acetylcholine receptor M4.

[0031] Another aspect of the present invention provides a method for preventing or treating a disease or condition mediated by muscarinic acetylcholine receptor M4, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention.

[0032] Another aspect of the present invention provides a method for preparing a compound of the present invention, comprising the steps of:

[0033] Wherein, X is a hydroxyl group, a halogen (such as iodine, bromine, chlorine, fluorine), or a leaving group (such as methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluene sulfonate), etc.; and the compound IA is connected to R through the L' position. 2 -X reaction, preferably, L' is selected from -NH-.

[0034] Ring A, Ring B, Ring C, L, R 1 、R 2 、R 3 、R 4 、R 5 , m, n, and o are as defined above.

[0035] or,

[0036] wherein X is a hydroxyl group, a halogen (such as iodine, bromine, chlorine, fluorine), or a leaving group (such as methanesulfonate, ethanesulfonate, phenylsulfonate, p-toluenesulfonate), etc.; and

[0037] Ring A, Ring B, Ring C, L, R 1 、R 2 、R 3 、R 4 、R 5 , m, n, o, and P are as defined above.

[0038] definition

[0039] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that would be apparent to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0040] The terms "comprising," "including," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps, even though the additional unrecited elements or method steps are not necessarily present (i.e., these terms also encompass the terms "consisting essentially of" and "consisting of.").

[0041] As used herein, the term "alkyl" is defined as a linear or branched saturated aliphatic hydrocarbon. In some embodiments, the alkyl group has 1 to 12, e.g., 1 to 10, 1 to 9, 1 to 8, 1 to 7, 1 to 6, 1 to 5, 1 to 4, 1 to 3 carbon atoms. For example, as used herein, the term "C 1-10 Alkyl", "C 1-6 Alkyl" and "C 1-4 "Alkyl" refers to a linear or branched group having 1-10 carbon atoms, 1-6 carbon atoms and 1-4 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl), which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents such as halogen (in which case the group is referred to as "haloalkyl") (e.g., CH2F, CHF2, CF3, CCl3, C2F5, C2Cl5, CH2CF3, CH2Cl or -CH2CH2CF3, etc.). The term "C 1-4"Alkyl" refers to a linear or branched aliphatic hydrocarbon chain having from 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl).

[0042] As used herein, the term "heteroalkyl" refers to an alkyl group having one or more backbone atoms independently selected from atoms other than carbon, such as oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, in the backbone carbon atoms of the alkyl group. Numerical ranges (e.g., C 2-6 Assorted alkyl) refers to the number of carbons in the chain, which in this example includes 2-6 carbon atoms. For example, a -CH2OCH2CH3 group is referred to as a C3 assorted alkyl, and a -CH2OCH2CH2NHCH3 group is referred to as a C4 assorted alkyl. Connection to the rest of the molecule can be through heteroatoms or carbon atoms in the assorted alkyl chain.

[0043] As used herein, the term "haloalkyl" refers to an alkyl group substituted by one or more (such as 1 to 3) the same or different halogen atoms. 1-8 Halogenated alkyl, "C 1-6 Haloalkyl" and "C 1-4 The term "haloalkyl" refers to a haloalkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms, and 1-4 carbon atoms, respectively, such as -CF3, -C2F5, -CHF2, -CH2F, -CH2CF3, -CH2Cl, or -CH2CH2CF3.

[0044] As used herein, the term "hydroxyalkyl" refers to a group in which a hydrogen atom in an alkyl group is replaced by one or more hydroxyl groups, for example, C 1-10 Hydroxyalkyl, C 1-6 Hydroxyalkyl or C 1-4 Examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, and the like.

[0045] As used herein, the term "alkoxy" refers to an -O-alkyl group, wherein alkyl is as defined above, for example, C 1-10 Alkoxy, C 1-8 Alkoxy, C 1-6 Alkoxy, C 1-4 Alkoxy or C 1-3 Alkoxy. C 1-6 Representative examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy, and the like, wherein the alkoxy groups are optionally substituted with one or more (such as 1 to 3) identical or different substituents. For example, the term "haloalkoxy" refers to an alkoxy group wherein the hydrogen atoms are substituted with one or more (such as 1 to 3) identical or different halogen atoms.

[0046] As used herein, the term "paracyclic" or "fused ring" refers to a ring system formed by two or more cyclic structures that share two adjacent atoms.

[0047] As used herein, the term "spirocycle" refers to a ring system formed by two or more cyclic structures that share one ring atom with each other.

[0048] As used herein, the term "bridged ring" refers to a ring system formed by two or more cyclic structures sharing two atoms that are not directly connected to each other.

[0049] As used herein, the term "cycloalkyl" refers to a saturated or unsaturated non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring group, including but not limited to monocyclic alkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc.) and bicyclic alkyl, including spirocyclic, annular (condensed) or bridged ring systems (i.e., spirocyclic alkyl, annular (condensed) alkyl and bridged cycloalkyl, such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, etc.). In the present invention, cycloalkyl is optionally substituted with one or more (such as 1 to 3) identical or different substituents. The carbon atoms on the cycloalkyl are optionally substituted with oxo (oxo) groups (i.e., forming C=O). The term "C 3-8 "Cycloalkyl" refers to a cycloalkyl group having 3 to 8 (such as 3, 4, 5, 6, 7, 8) ring carbon atoms, for example, C 3-6 Cycloalkyl, which may be a monocyclic alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, or a bicyclic alkyl, such as C 5-8 Spiroalkyl, C 5-8 Bridged cycloalkyl, C 5-8 Condensed cycloalkyl, C 5-6 Spiroalkyl, C 5-6 Bridged cycloalkyl or C 5-6 Fused cycloalkyl.

[0050] As used herein, the term "cycloalkoxy" refers to -O-cycloalkyl, wherein cycloalkyl is as defined above. Representative examples of cycloalkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.

[0051] As used herein, the term "heterocyclyl" or "heterocycle" refers to an aliphatic monocyclic or polycyclic (e.g., cyclic, spirocyclic or bridged) group having 2 or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14) carbon atoms and one or more (e.g., 1, 2, 3 or 4) heteroatoms, including but not limited to oxygen atoms, nitrogen atoms, sulfur atoms and silicon atoms, wherein the carbon atoms and heteroatoms on the heterocyclyl are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or are optionally substituted with one or more (e.g., 1 to 3) independently selected from halogen and C 1-3 The term "heterocyclic group" or "heterocycle" may have 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms. The term "saturated heterocycle" refers to a fully saturated heterocycle, such as a tetrahydrofuran ring, a piperidine ring, a morpholine ring, a tetrahydropyran ring, a piperazine ring, and the like. The term "partially saturated heterocycle" refers to a heterocycle containing both saturated single bonds and unsaturated double bonds, such as 3,4-dihydro-2H-pyran, 1,2,3,4-tetrahydropyridine, dihydropyrrole, dihydrofuran, 4,5-dihydroisoxazolyl, 4,5-dihydrooxazolyl, 2,5-dihydrooxazolyl, 2,3-dihydrooxazolyl, and the like. As used herein, the term "3-10 membered heterocyclyl" means a heterocyclyl containing 3-10 ring atoms, including but not limited to 4-10 membered heterocyclyl, 4-9 membered heterocyclyl, 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 5-6 membered heterocyclyl, 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 4-7 membered nitrogen-containing heterocyclyl, 4-7 membered oxygen-containing heterocyclyl, 4-7 membered sulfur-containing heterocyclyl, 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered oxygen-containing heterocyclyl, 5-6 membered sulfur-containing heterocyclyl, etc., wherein the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-10 membered heterocyclyls include but are not limited to oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, dihydrofuranyl, dihydropyrrolyl, dihydrothiophenyl, dihydropyranyl. As used herein, the term "3-8 membered heterocyclyl" means a heterocyclyl containing 3-8 ring atoms, including but not limited to 3-8 membered heterocyclyl, 3-7 membered heterocyclyl, 3-6 membered heterocyclyl, 4-8 membered heterocyclyl, 4-7 membered heterocyclyl, 4-6 membered heterocyclyl, 5-6 membered heterocyclyl, 4-7 membered nitrogen-containing heterocyclyl, 4-7 membered oxygen-containing heterocyclyl, 4-7 membered sulfur-containing heterocyclyl, 5-6 membered nitrogen-containing heterocyclyl, 5-6 membered oxygen-containing heterocyclyl, 5-6 membered sulfur-containing heterocyclyl, etc., wherein the "nitrogen-containing heterocyclyl", "oxygen-containing heterocyclyl" and "sulfur-containing heterocyclyl" each optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples of 3-8 membered heterocyclyls include but are not limited to oxiranyl, aziridine, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidonyl (such as ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, dihydrofuranyl, dihydropyrrolyl, dihydrothiophenyl, and dihydropyranyl.

[0052] In the present invention, the heterocyclic group can form a parallel ring structure with a heterocyclic group or a cycloalkyl group, and the connection point of the parallel ring structure with the other groups can be on any heterocyclic group or cycloalkyl group. Therefore, the heterocyclic group of the present invention also includes (but is not limited to) heterocyclic and heterocyclic groups, heterocyclic and cycloalkyl groups, monoheterocyclic and monoheterocyclic groups, and monoheterocyclic and monocycloalkyl groups, such as 3-7 membered (mono) heterocyclic groups and 3-7 membered (mono) heterocyclic groups, 3-7 membered (mono) heterocyclic groups and (mono) cycloalkyl groups, 3-7 membered (mono) heterocyclic groups and C 4-6 (Mono)cycloalkyl, examples of which are not limited to pyrrolidinyl and cyclopropyl, cyclopentyl and aziridine, pyrrolidinyl and cyclobutyl, pyrrolidinyl and pyrrolidinyl, pyrrolidinyl and piperidinyl, pyrrolidinyl and piperazinyl, piperidinyl and morpholinyl,

[0053] In the present invention, the heterocyclic group also includes a bridged heterocyclic group and a spiro heterocyclic group.

[0054] As used herein, the term "bridged heterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, and / or sulfur atoms) formed by two saturated rings sharing two ring atoms that are not directly connected, including but not limited to 7-10 membered bridged heterocycles, 8-10 membered bridged heterocycles, 7-10 membered nitrogen-containing bridged heterocycles, 7-10 membered oxygen-containing bridged heterocycles, 7-10 membered sulfur-containing bridged heterocycles, etc., for example The “nitrogen-containing bridged heterocycle”, “oxygen-containing bridged heterocycle” and “sulfur-containing bridged heterocycle” optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur.

[0055] As used herein, the term "spiroheterocycle" refers to a cyclic structure containing one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen atoms, nitrogen atoms, sulfur atoms) formed by two or more saturated rings sharing a ring atom, including but not limited to 5-10 membered spiroheterocycles, 6-10 membered spiroheterocycles, 6-10 membered nitrogen-containing spiroheterocycles, 6-10 membered oxygen-containing spiroheterocycles, 6-10 membered sulfur-containing spiroheterocycles, etc., for example The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle" and "sulfur-containing spiroheterocycle" optionally further contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl containing a total of 6-10 ring atoms, at least one of which is a nitrogen atom.

[0056] Examples of the group obtained by condensing a heterocyclic group with an aryl group include, but are not limited to:

[0057] As used herein, the term "aryl", "phenyl" or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic aromatic group having a conjugated π electron system. 6-14 Aryl (aromatic ring)", "C 6-10 "Aryl (aromatic ring)" means an aromatic group (aromatic ring) containing 6-14 carbon atoms, 6 to 10 carbon atoms, preferably a phenyl (phenyl ring) or a naphthyl (naphthalene ring). The aryl group is optionally substituted with one or more (such as 1 to 3) identical or different substituents (e.g., halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0058] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more identical or different heteroatoms, including monocyclic heteroaryl groups and bicyclic or polycyclic ring systems containing at least one heteroaromatic ring (an aromatic ring system containing at least one heteroatom), which can have 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, for example 5, 6, 7, 8, 9 or 10 ring atoms, and in each case can be benzo-fused. The heteroatom can be oxygen, nitrogen or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (for example, to form C=O, S(=O) or S(=O)2).

[0059] As used herein, the term "5-14 membered heteroaryl" or "5-14 membered heteroaromatic ring", "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" means a heteroaryl group (heteroaromatic ring) containing 5 to 14 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14), 5 to 10 (e.g., 5 to 6) ring atoms, including 5-14 membered nitrogen-containing heteroaryl, 5-14 membered oxygen-containing heteroaryl, 5-14 membered sulfur-containing heteroaryl, 5-10 membered nitrogen-containing heteroaryl, 5-10 membered oxygen-containing heteroaryl, 5-10 membered sulfur-containing heteroaryl, 5-6 membered nitrogen-containing heteroaryl, 5-6 membered oxygen-containing heteroaryl, 5-6 membered sulfur-containing heteroaryl, etc. The "nitrogen-containing heteroaryl", "oxygen-containing heteroaryl" and "sulfur-containing heteroaryl" each optionally contain one or more other heteroatoms independently selected from oxygen, nitrogen and sulfur. Examples include, but are not limited to, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, etc., or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., as well as 5-14 membered and 5-10 membered cyclic groups containing these groups.

[0060] In the present invention, a heteroaryl group (e.g., a monoheteroaryl group) can share two adjacent atoms with an aryl group (e.g., a monocyclic aryl group, such as a phenyl group), a heterocyclic group (e.g., a monoheterocyclic group), a cycloalkyl group (e.g., a monocycloalkyl group) or another heteroaryl group (e.g., another monoheteroaryl group) to form a parallel ring structure, and the connection point can be on any heteroaryl ring or on other rings, including but not limited to (mono)heteroaryl and (mono)heteroaryl, (mono)heteroaryl and (mono)heterocyclic group and (mono)heteroaryl and (mono)cycloalkyl, such as a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heteroaryl, a 5-6-membered (mono)heteroarylphenyl group, a 5-6-membered (mono)heteroaryl and 5-6-membered (mono)heterocyclic group or a 5-6-membered (mono)heteroaryl and C 4-6 (mono)cycloalkyl (e.g., 5-6 membered heteroarylcyclobutyl, 5-6 membered heteroarylcyclopentyl or 5-6 membered heteroarylcyclohexyl), examples of which are not limited to benzothiazolyl, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, wait.

[0061] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0062] The term "substituted" means that one or more (e.g., one, two, three, four, five, six) hydrogen atoms on the designated atom are replaced with a group selected from the indicated group, provided that the designated atom's normal valence is not exceeded in the current context and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0063] If a substituent is described as being "optionally substituted with one or more...", the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or collectively, with independently selected optional substituents. If a nitrogen of a substituent is described as being optionally substituted with one or more of the listed substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0064] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other. Thus, each substituent may be the same as or different from another (other) substituent.

[0065] As used herein, the term "one or more" means 1 or more than 1, such as 2, 3, 4, 5, 6, 7, 8, 9 or 10, where reasonable.

[0066] Unless otherwise indicated, as used herein, the point of attachment of a substituent may be from any suitable position of the substituent.

[0067] When a bond to a substituent is shown to pass through a bond connecting two atoms in a ring, then such substituent may be bonded to any ring atom in the substitutable ring.

[0068] The present invention also includes all pharmaceutically acceptable isotopically labeled compounds, which are identical to the compounds of the present invention except that one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature. Examples of isotopes suitable for inclusion in the compounds of the present invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2 H), tritium ( 3 H)); carbon isotopes (e.g. 11 C. 13 C and 14 C); isotopes of chlorine (e.g. 36 Cl); isotopes of fluorine (e.g. 18 F); isotopes of iodine (such as 123 I and 125 I); isotopes of nitrogen (e.g.13 N and 15 N); oxygen isotopes (e.g. 15 O. 17 O and 18 O); isotopes of phosphorus (such as 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically labeled compounds of the invention (e.g., those incorporating radioactive isotopes) are useful in drug and / or substrate tissue distribution studies (e.g., assays). 3 H) and carbon-14 (i.e. 14 C) are particularly useful for this purpose because they are easy to incorporate and easy to detect. 11 C. 18 F. 15 O and 13 N) substitution can be used to examine substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of the present invention can be prepared by methods analogous to those described in the accompanying schemes and / or examples and preparations by using appropriate isotopically labeled reagents instead of the non-labeled reagents previously employed. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent is isotopically substituted, for example, D2O, acetone-d6 or DMSO-d6.

[0069] The term "stereoisomer" refers to an isomer formed due to at least one asymmetric center. In a compound with one or more (e.g., one, two, three, or four) asymmetric centers, it can produce a racemic mixture, a single enantiomer, a diastereomeric mixture, and a separate diastereomer. Specific individual molecules can also exist as geometric isomers (cis / trans). Similarly, the compounds of the present invention can exist as mixtures of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers, etc. For example, nitroso-oxime can exist in the following tautomeric form equilibrium in solution:

[0070] It is to be understood that the scope of this application encompasses all such isomers in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) or mixtures thereof.

[0071] In this article, solid lines can be used Solid wedge or virtual wedge The chemical bonds of the compounds of the present invention are depicted. The use of solid lines to depict bonds to asymmetric carbon atoms is intended to indicate that all possible stereoisomers at that carbon atom are included (e.g., specific enantiomers, racemic mixtures, etc.). The use of solid or dashed wedges to depict bonds to asymmetric carbon atoms is intended to indicate that the indicated stereoisomers exist. When present in a racemic mixture, solid and dashed wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise indicated, the compounds of the present invention are intended to exist as stereoisomers, including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, atropisomers, and mixtures thereof. The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0072] The wavy lines used in this article When it represents a bond by itself, it means that the bond configuration is uncertain, such as a wavy line Place on key Indicates that the bond is connected to other atoms, which can be a single bond or a double bond. When located on a ring, it indicates the connection site on the ring.

[0073] The present invention encompasses all possible crystalline forms or polymorphs of the compounds of the present invention, which may be single polymorphs or mixtures of more than one polymorph in any ratio.

[0074] A cocrystal refers to a drug active molecule and other physiologically acceptable acid, base, salt, or non-ionic compound molecules bound in the same crystal lattice by hydrogen bonds, π-π stacking, van der Waals forces, and other non-covalent bonds.

[0075] It should also be understood that certain compounds of the present invention may be used therapeutically in free form or, where appropriate, in the form of pharmaceutically acceptable derivatives thereof. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs that, upon administration to a patient in need thereof, are capable of directly or indirectly providing a compound of the present invention or a metabolite or residue thereof. Therefore, when reference is made herein to a "compound of the present invention," such various derivative forms of the compound are also intended to be encompassed.

[0076] Pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof, such as hexafluorophosphate salts and meglumine salts. For a review of suitable salts, see Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0077] As used herein, the term "ester" refers to esters derived from the compounds of the general formulae herein, including physiologically hydrolyzable esters (which can be hydrolyzed under physiological conditions to release the compounds of the present invention in the form of free acid or alcohol). The compounds of the present invention themselves may also be esters.

[0078] The compounds of the present invention may exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the crystal lattice of the compound, in particular water, methanol or ethanol. The amount of polar solvent, in particular water, may be present in a stoichiometric or non-stoichiometric ratio.

[0079] Those skilled in the art will appreciate that, because nitrogen requires available lone pairs of electrons to be oxidized to oxides, not all nitrogen-containing heterocycles can form N-oxides. Those skilled in the art will recognize nitrogen-containing heterocycles that can form N-oxides. Those skilled in the art will also recognize that tertiary amines can form N-oxides. The synthetic method for preparing the N-oxides of heterocycles and tertiary amines is well known to those skilled in the art, including but not limited to oxidizing heterocycles and tertiary amines with peroxyacids such as Peracetic Acid and Metachloroperbenzoic Acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: TL Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; AR Katritzky and AJ Boulton, Eds., Academic Press; and GWH Cheeseman and ESGWerstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, AR Katritzky and AJ Boulton, Eds., Academic Press.

[0080] Also included within the scope of the present invention are metabolites of the compounds of the invention, i.e., substances formed in vivo upon administration of the compounds of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc. of the administered compound. Thus, the present invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a period of time sufficient to produce a metabolic product thereof.

[0081] The present invention further includes within its scope prodrugs of the compounds of the present invention, which are certain derivatives of the compounds of the present invention that may themselves have little or no pharmacological activity and can be converted into compounds of the present invention having the desired activity by, for example, hydrolytic cleavage when administered to the body or thereon. Typically, such prodrugs will be functional group derivatives of the compounds that are readily converted into the desired therapeutically active compounds in vivo. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985)).

[0082] The present invention also encompasses compounds of the present invention that contain protecting groups. During any process for preparing the compounds of the present invention, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules involved, thereby forming a chemically protected form of the compounds of the present invention. This can be achieved using conventional protecting groups, for example, those described in TW Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference. Protecting groups can be removed at an appropriate subsequent stage using methods known in the art.

[0083] The term "about" means within ±10%, preferably within ±5%, and more preferably within ±2% of the stated numerical value.

[0084] This application is in no way limited to the methods and materials described herein. To the extent that one or more of the incorporated literature, patents, and similar materials differ from or contradict this application (including but not limited to defined terms, term applications, described techniques, etc.), the description herein and the accompanying compound structural formulas shall prevail. In this application, if a chemical name is inconsistent with a chemical structural formula, the chemical structural formula shall prevail.

[0085] Compound

[0086] In some embodiments, the present invention provides a compound of Formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof:

[0087] in:

[0088] Ring A is selected from 5-14 membered heteroaromatic rings and C 6-14 aromatic rings;

[0089] R 1 、R 3 、R 4 、R 5 is independently selected at each occurrence from hydrogen, deuterium, tritium, OR 7 , hydroxyl, oxo, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 7 R 8 、-CONR 7 R 8 、-COC 1-6 Alkyl, -NHCOC 1-6 Alkyl, C(O)OR 7 、-OC(O)R 7 、-OC(O)NR 7 R 8 、-NR 7 C(O)NR 7 R 8 、C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl groups is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 Replace; or

[0090] Two R's attached to the same carbon atom 4 Or two R 5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group, which is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace;

[0091] And, R 1 It can also be missing;

[0092] R 7 、R 8 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 Replace; or

[0093] R 7 、R 8 The N atom to which it is connected together forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 replace;

[0094] R 9 is independently selected at each occurrence from H, deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 、-COCH3、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkylthio, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) independently selected from halogen, -OH, -CN, -NR 7 R 8 、-COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups;

[0095] Ring B is selected from a 4-8 membered carbocyclic ring, a 4-8 membered heterocyclic ring, a 6-10 membered aromatic ring, and a 5-10 membered heteroaromatic ring;

[0096] Ring C is selected from a 5-8 membered carbocyclic ring, a 5-8 membered heterocyclic ring or a 5-10 membered heteroaromatic ring;

[0097] L is selected from C, CR a and N;

[0098] R a Selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups;

[0099] R 2 For-PR 6 ;

[0100] P is a single bond, a double bond, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 -, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace;

[0101] R 6 Selected from deletion, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, 5-14 membered heteroaryl and C 6-14Aryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (eg, 1, 2, 3, 4, 5, 6) R 9 replace;

[0102] m, n, and o are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0103] In certain embodiments, the compounds of formula I provided herein are not Dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyridin[2,3-a]indolizin-7(5H)-one).

[0104] In certain embodiments, the present invention provides compounds of formula I, wherein ring A is selected from a 5-14 membered heteroaromatic ring and a C 6-14 aromatic rings;

[0105] R 1 、R 3 、R 4 、R 5 is independently selected at each occurrence from hydrogen, deuterium, tritium, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 7 R 8 、-CONR 7 R 8 、-COC 1-6 Alkyl, -NHCOC 1-6 Alkyl, C(O)OR 7 、-OC(O)R 7 、-OC(O)NR 7 R 8 、-NR 7 C(O)NR 7 R 8 、C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl groups is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 Replace; or

[0106] Two R's attached to the same carbon atom 4 Or two R5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group, which is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace;

[0107] And, R 1 It can also be missing;

[0108] R 7 、R 8 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 Replace; or

[0109] R 9 is independently selected at each occurrence from deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 、-COCH3、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkylthio, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) independently selected from halogen, -OH, -CN, -NR 7 R 8 、-COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1- 6 alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups;

[0110] Ring B is selected from a partially unsaturated 4-8 membered carbocyclic ring, a partially unsaturated 4-8 membered heterocyclic ring, a 4-8 membered aromatic ring, and a 4-8 membered heteroaromatic ring;

[0111] Ring C is selected from a 5-8 membered carbocyclic ring, a 5-8 membered heterocyclic ring or a 5-8 membered heteroaromatic ring;

[0112] L is selected from C, CR a and N;

[0113] R a Selected from hydrogen, hydroxy, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups;

[0114] R 2 For-PR 6 ;

[0115] P is a single bond, a double bond, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, C 6-10 Aryl and 5-14 membered heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace;

[0116] R 6 Selected from deletion, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, 5-14 membered heteroaryl and C 6-14 Aryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (eg, 1, 2, 3, 4, 5, 6) R 9 replace;

[0117] m, n, and o are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0118] In certain embodiments, in the compound of formula I provided by the present invention, ring A is selected from a benzene ring and a 5-10 membered heteroaromatic ring.

[0119] In certain embodiments, in the compound of formula I provided by the present invention, ring A is selected from a benzene ring, a 5-10 membered oxygen-containing heteroaromatic ring, a 5-10 membered sulfur-containing heteroaromatic ring, and a 5-10 membered nitrogen-containing heteroaromatic ring.

[0120] In certain embodiments, in the compounds of formula I provided herein, ring A is selected from pyridine, pyrrole, furan, thiophene, benzene, quinoline, indole, pyridopyrrole, pyrimidine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, triazolopyridine, pyrazine, and pyridazine rings.

[0121] In certain embodiments, in the compound of formula I provided by the present invention, ring A is selected from a benzene ring and a 5-9 membered heteroaromatic ring.

[0122] In certain embodiments, in the compound of formula I provided by the present invention, ring A is selected from a benzene ring, a 5-9 membered oxygen-containing heteroaromatic ring, a 5-9 membered sulfur-containing heteroaromatic ring, and a 5-9 membered nitrogen-containing heteroaromatic ring.

[0123] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from pyridine, pyrrole, furan, thiophene, benzene, indole, pyridopyrrole, pyrimidine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, triazolopyridine, pyrazine, and pyridazine rings.

[0124] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from pyridine, pyrrole, furan, thiophene, benzene, indole, pyridopyrrole, pyrimidine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, and triazolopyridine rings.

[0125] In certain embodiments, in the compound of formula I provided by the present invention, ring A is selected from a pyridine ring, a furan ring, a pyrrole ring, a thiophene ring, and a pyridazine ring.

[0126] In certain embodiments, the present invention provides compounds of formula I, wherein ring A is selected from a pyridine ring.

[0127] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from

[0128] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from

[0129] In certain embodiments, the present invention provides compounds of formula I wherein ring A is selected from

[0130] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 、R 3 Independently selected from hydrogen, deuterium, tritium, oxo, OR7 , hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -CONR 7 R 8 、-NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl, 3-8 membered heterocyclyl and -NR 7 R 8 The alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl groups are each optionally substituted by one or more R 9 replace.

[0131] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 、R 3 independently selected from hydrogen, deuterium, tritium, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -CONR 7 R 8 、-NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl, 3-8 membered heterocyclic group, -NR 7 R 8 The alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl groups are each optionally substituted by one or more R 9 replace.

[0132] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 、R 3 Independently selected from hydrogen, deuterium, tritium, oxo, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6Alkynyl, -CONR 7 R 8 、-NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl and 5-6 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are each optionally substituted by one or more R 9 replace.

[0133] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 、R 3 are independently selected from hydrogen, hydroxy, halogen, cyano, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, C 2-4 Alkenyl, C 2-4 Alkynyl, -CONR 7 R 8 、-NHCOC 1-4 Alkyl, C 3-5 Cycloalkyl, 5-6 membered heteroaryl, 3-6 membered heterocyclic group, -NHC 1-4 Alkyl, said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are each optionally substituted by one or more R 9 replace;

[0134] R 7 、R 8 Each independently selected from H, C 1-4 alkyl.

[0135] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 、R 3 Independently selected from oxo (=O), CH3, CH2CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, methoxy, -NH-CH3, vinyl, N-heterocyclobutane CH2OH,

[0136] In certain embodiments, the present invention provides compounds of formula I, wherein R 1 、R 3 Independently selected from CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, vinyl, CH2OH, CH2CH3, -OCH3,

[0137] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from 4-8 membered carbocyclic rings, 4-8 membered heterocyclic rings, C 6-10 aromatic rings and 5-10 membered heteroaromatic rings.

[0138] In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a 4-8 membered carbocyclic ring, a 4-8 membered heterocyclic ring, a 6-8 membered aromatic ring, and a 5-10 membered heteroaromatic ring.

[0139] In the case where the B ring of the present invention is selected from a partially unsaturated 4-8 membered carbocyclic ring or a partially unsaturated 4-8 membered heterocyclic ring, since the A ring is aromatic, the bond formed between the two atoms shared with the A ring in the B ring must be an unsaturated bond. Therefore, the B ring is limited to a partially unsaturated 4-8 membered carbocyclic ring or a partially unsaturated 4-8 membered heterocyclic ring. Except for the unsaturated bond formed by the two atoms shared with the A ring in the B ring, the bonds in other parts may be saturated or unsaturated.

[0140] In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a 5-7 membered partially unsaturated heterocyclic ring, a 5-7 membered partially unsaturated carbocyclic ring, a 5-6 membered heteroaromatic ring, and a benzene ring.

[0141] In certain embodiments, in the compound of formula I provided by the present invention, ring B is selected from a 5-6 membered partially unsaturated heterocyclic ring, a 5-6 membered heteroaromatic ring, and a benzene ring.

[0142] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from benzene, dihydropyrrole, tetrahydropyrrole, pyrrole, thiophene, pyrazole, imidazole, Pyridine, cyclohexene, cyclopentene, dihydrofuran ring and tetrahydropyridine.

[0143] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from benzene, dihydropyrrole, pyrrole, thiophene, pyrazole, imidazole, Pyridine, cyclohexene, cyclopentene and dihydrofuran rings.

[0144] In certain embodiments, the present invention provides compounds of formula I, wherein ring B is selected from benzene, dihydropyrrole, pyrrole, thiophene, pyrazole, imidazole, Pyridine, cyclohexene, cyclopentene and dihydrofuran rings.

[0145] In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from

[0146] In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from

[0147] In certain embodiments, the present invention provides compounds of formula I wherein ring B is selected from

[0148] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 independently selected from hydrogen, deuterium, tritium, oxo, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are each optionally substituted by one or more R 9 Replace; or

[0149] Two R's attached to the same carbon atom 5 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

[0150] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are each optionally substituted by one or more R 9 Replace; or

[0151] Two R's attached to the same carbon atom 5 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

[0152] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 independently selected from hydrogen, deuterium, tritium, oxo, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 1-4 Hydroxyalkoxy, the alkyl, alkoxy optionally with one or more R 9 Replace; or

[0153] Two R's attached to the same carbon atom 5 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

[0154] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy and C 1-4 Hydroxyalkoxy, the alkyl, alkoxy optionally with one or more R 9 Replace; or

[0155] Two R's attached to the same carbon atom 5 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

[0156] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 are independently selected from H, CH3, oxo (=O), F, Cl, Br, CHF2 and CF3; or, two R 5 Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0157] In certain embodiments, the present invention provides compounds of formula I, wherein R 5 are independently selected from H, CH3, F, Cl, Br, CHF2, CF3; or, two R 5 Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0158] In certain embodiments, in the compound of formula I provided by the present invention, ring C is selected from a 5-7 membered carbocyclic ring, a 5-8 membered heterocyclic ring (eg, a nitrogen-containing heterocyclic ring or a Si-containing heterocyclic ring), or a 5-8 membered heteroaromatic ring (eg, a nitrogen-containing heteroaromatic ring).

[0159] In certain embodiments, the present invention provides compounds of formula I wherein ring C is selected from

[0160] In certain embodiments, the present invention provides compounds of formula I wherein ring C is selected from

[0161] In certain embodiments, the present invention provides compounds of formula I wherein ring C is selected from

[0162] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are each optionally substituted by one or more R 9 Replace; or

[0163] Two R's attached to the same carbon atom 4 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

[0164] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 1-4 Hydroxyalkoxy, the alkyl, alkoxy optionally with one or more R 9 Replace; or

[0165] Two R's attached to the same carbon atom 4 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

[0166] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 are independently selected from one or more substituents selected from H, deuterium D, CH3, F, Cl, Br, CHF2 and CF3; or, two R 4 Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0167] In certain embodiments, the present invention provides compounds of formula I, wherein R 4 are independently selected from H, CH3, F, Cl, Br, CHF2, CF3; or, two R 4 Together with the carbon atom to which it is attached, it forms a cyclopropyl group.

[0168] In certain embodiments, the compound of formula I provided herein is a compound of formula II:

[0169] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 4 , L, m, n are as defined above for the compound of formula I;

[0170] Indicates Z in ring B 1 、X 1 、X 2 , Z 2 、X 3 、X 4 Any two adjacent symbols in can be a single bond or a double bond, provided that the two adjacent bonds are not double bonds at the same time;

[0171] X 1 、X 2 are each independently selected from C, N;

[0172] X 3 、X 4 Each independently selected from C, N and CR 5a ;

[0173] Z 1 、Z 2 Each independently selected from a single bond, -(CR 5a R 5b ) q -、CR 5a ,-C(=O)-,-O-,-S-,N,NR 5a 、-CR 5a R 5b -Z 3 --Z 3 -CR 5a R 5b -、=CR 5a -Z 3 -、-Z 3 -CR 5a =、N=CR 5a and-SiR 5a R 5b -;

[0174] R 5a and R 5b As described above for R 5 defined;

[0175] Z3 Selected from -O-, -S- and -NR 5a ;

[0176] q is selected from 1 or 2.

[0177] In certain embodiments, the compound of formula II provided herein is a compound of formula III:

[0178] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、X 3 、X 4 、Z 1 , L, m and n are as defined above for the compound of formula II.

[0179] In certain embodiments, the present invention provides compounds of formula III,

[0180] Z 1 Selected from CR 5a R 5b and CR 5a ;

[0181] X 1 and X 2 Selected from C;

[0182] X 3 Selected from CR 5a or C;

[0183] X 4 Selected from N.

[0184] In certain embodiments, the present invention provides compounds of formula III,

[0185] Z 1 Selected from-CR 5a R 5b -;

[0186] X 1 、X 2 Selected from C;

[0187] X 3 、X 4 Selected from CR 5a R 5b .

[0188] In certain embodiments, the present invention provides compounds of formula III,

[0189] Z 1 Selected from O;

[0190] X 1 、X 2 Selected from C;

[0191] X 3 、X 4 Selected from-CR 5a R 5b -.

[0192] In certain embodiments, the present invention provides compounds of formula III,

[0193] Z 1 Selected from NR 5a ;

[0194] X 1 、X 2 Selected from C;

[0195] X 3 、X 4 Selected from CR 5a .

[0196] In certain embodiments, the present invention provides compounds of formula III,

[0197] Z 1 Selected from S;

[0198] X 1 、X 2 Selected from C;

[0199] X 3 、X 4 Selected from CR 5a .

[0200] In certain embodiments, the present invention provides compounds of formula III,

[0201] Z 1 Selected from NR 5a and S;

[0202] X 1 、X 2 、X 3 、X 4 Selected from C.

[0203] In certain embodiments, the present invention provides compounds of formula III,

[0204] Z 1 Selected from SiR 5a R 5b ;

[0205] X 1 、X 2 Selected from C;

[0206] X 3 、X 4 Selected from CR 5a .

[0207] In certain embodiments, the present invention provides compounds of formula III,

[0208] Z 1 Selected from CR 5a and N;

[0209] X 1 、X 2 、X 3 Selected from C;

[0210] X 4 Selected from N.

[0211] In certain embodiments, the present invention provides compounds of formula III,

[0212] Z 1 Selected from CR 5a ;

[0213] X 1 、X 2 、X 4 Selected from C;

[0214] X 3 Selected from N.

[0215] In certain embodiments, the present invention provides compounds of formula III,

[0216] Z 1 Selected from CR 5a ;

[0217] X 1 Selected from N;

[0218] X 2 、X 3 、X 4 Selected from C.

[0219] In certain embodiments, the present invention provides compounds of formula III,

[0220] Z 1 Selected from N;

[0221] X 1 、X 4 Selected from C;

[0222] X 2 、X 3 Selected from C and N.

[0223] In certain embodiments, the compound of formula II provided herein is a compound of formula IV:

[0224] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 4 、X 1 、X 2 、X 3 、X 4 , Z 1 , L, m and n are as defined above for the compound of formula II.

[0225] In certain embodiments, the present invention provides compounds of formula IV wherein Z 1 Selected from CR 5a ;X 1 、X 2 、X 4 Selected from C;X 3 Selected from N.

[0226] In certain embodiments, the present invention provides compounds of formula II, wherein Z 1 Does not exist; Z 2 Selected from CR 5a ;X 1 、X 2 、X 3 Selected from C;X 4 Selected from N.

[0227] In certain embodiments, the present invention provides compounds of formula II, wherein Z 1 , Z 2 Selected from-CR 5a R 5b -、-C(=O)-、CR 5a 、-O-、-S-、N、-NR 7 -;X 1 、X 2 Selected from C and N; X 3 、X 4 Selected from C, CR 5a and N.

[0228] In certain embodiments, the compound of formula II provided herein is a compound of formula V:

[0229] Among them, ring A, ring C, R 1 、R 2 、R 3 、R 4 , L, m and n are as defined above for the compound of formula II;

[0230] Z 1 , Z 2 Selected from CR 5a R 5b , CR 5a NR 5a , N, O and S;

[0231] X 1 、X 2 Selected from C;

[0232] X 3 、X 4 Selected from C, CR 5a or N.

[0233] In certain embodiments, the compound of formula I provided herein is a compound of formula VI:

[0234] Among them, ring A, ring C, R 1 、R 2 、R 3 , L, m are as defined above for the compound of formula I;

[0235] Indicates Z in ring B 1 、X 1 、X 2 , Z 2 、X 3 、X 4 Any two adjacent symbols in can be a single bond or a double bond, provided that the two adjacent bonds are not double bonds at the same time;

[0236] X 1 、X 2 are each independently selected from C, N;

[0237] X 3 、X 4 Each independently selected from C, N and CR 5a ;

[0238] Z 1 , Z 2 Each independently selected from a single bond, -(CR 5a R 5b ) q -、CR 5a ,-C(=O)-,-O-,-S-,N,NR 5a 、-CR 5a R 5b -Z 3 -、-Z 3 -CR 5a R 5b -、=CR 5a-Z 3 -、-Z 3 -CR 5a =、N=CR 5a and-SiR 5a R 5b -;

[0239] R 5a and R 5b As described above for R 5 defined;

[0240] Z 3 Selected from -O-, -S- and -NR 7 ;

[0241] Y is selected from a single bond, -(CR 4a R 4b ) p -(CR 4a R 4b )-、CR 4a ,-C(=O)-,C,-O-,-S-,N,NR 4a 、-CR 4a =CR 4b -、-CR 4a =N-, -SiR 4a R 4b -、-CR 4a R 4b -Z 3 - and -Z 3 -CR 4a R 4b -;

[0242] R 4a and R 4b As described above for R 4 defined;

[0243] p is selected from 0, 1 or 2;

[0244] q is selected from 1 or 2.

[0245] In certain embodiments, the present invention provides compounds of formula VI wherein Y is selected from -(CR 4a R 4b ) p -(CR 4a R 4b )-、-C(=O)-、-CR 4a =CR 4b -、-CR 4a R 4b =N- and -SiR 4a R 4b -, p is 1, 2, and R4a and R 4b are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, or R 4a and R 4b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group.

[0246] In certain embodiments, the present invention provides compounds of formula VI, wherein Y is selected from -CH2CH2-, -CH(CH3)CH2-, -C(CH3)2CH2-, -CH(CF3)CH2-, CH2, -C(=O)-, (CH2)3, CH(CHF2), -CH(CF3)-, CH=CH, -CH=N-, -C(CH3)=N- and -Si(CH3)2-.

[0247] In certain embodiments, the present invention provides compounds of formula II and formula VI,

[0248] Z 1 Selected from single bond, -CR 5a R 5b -、CR 5a 、-O-、-S-、N、-NR 5a -、-SiR 5a R 5b -;

[0249] Z 2 Selected from single bond, -CR 5a R 5b -、CR 5a ,N,-NR 7 -、-SiR 5a R 5b -.

[0250] In certain embodiments, the present invention provides compounds of formula II and formula VI,

[0251] Z 1 Selected from-CR 5a R 5b -、CR 5a 、-O-、-S-、N、-NR 5a -、-SiR 5a R 5b -;

[0252] Z 2 is selected from single bonds;

[0253] X 1 、X 2 selected from C and N;

[0254] X 3 and X 4 Each independently selected from C, N and CR 5a .

[0255] In certain embodiments, the present invention provides compounds of formula I, Selected from the group represented by Formula 1, Formula 2 or Formula 3:

[0256] Among them, in the group shown in Formula 1,

[0257] R 1 、R 3 、R 5 , L, m, o are as defined above for the compound of formula I or the compound of formula VI;

[0258] Z 1 、X 1 、X 2 , Z 2 、X 3 、X 4 As defined above for compounds of formula II and formula VI;

[0259] Y is as defined above for the compound of formula VI;

[0260] Y 1 Selected from deletion, C, N and CR 3 ;

[0261] Y 2 、Y 3 、Y 4 Each independently selected from C, N, CR 3 NR 3 , O and S;

[0262] Among them, in the group shown in formula 2,

[0263] R 1 、R 3 、R 5 , L, m, o are as defined above for the compound of formula I or the compound of formula VI;

[0264] Z 1 、X 3 、X 4 As defined above for compounds of formula II or formula VI;

[0265] Y is as defined above for the compound of formula VI;

[0266] X 1 、X 2 、Y 2 、Y 3are each independently selected from C and N;

[0267] Y 4 、Y 6 、Y 7 、Y 8 Each independently selected from C, N, CR 3 NR 3 , O and S;

[0268] Y 5 Selected from deletion, C, N, CR 3 NR 3 , O and S;

[0269] Among them, in the group shown in formula 3,

[0270] R 1 、R 3 、R 5 , L, m, o are as defined above for the compound of formula I or the compound of formula VI;

[0271] Z 1 、X 3 、X 4 As defined above for compounds of formula II or formula VI;

[0272] Y is as defined above for the compound of formula VI;

[0273] X 1 、X 2 、Y 1 、Y 2 are each independently selected from C and N;

[0274] Y 3 、Y 4 Each independently selected from CR 3 and N;

[0275] Y 5 、Y 6 、Y 7 Each independently selected from C, N, CR 3 NR 3 , O and S.

[0276] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0277] Among them, R 1 、R 3 、R 5 、Z 1 、X 1 、X 2 、X 3、X 4 、Y 1 、Y 2 、Y 3 、Y 4 , Y, L, m, and o are as defined above for the group of formula 1.

[0278] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0279] Among them, R 1 、R 3 、R 5 、Z 1 、X 1 、X 2 、Z 2 、X 3 、X 4 、Y 1 、Y 2 、Y 3 、Y 4 , Y, L, m, and o are as defined above for the group of formula 1.

[0280] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0281] Among them, R 1 、R 3 、R 5 、Z 1 、X 1 、X 2 、Z 2 、X 3 、X 4 、Y 1 、Y 2 、Y 3 、Y 4 , Y, L, m, o are as defined above for the group of formula 1, and Y 1 Not missing.

[0282] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0283] Among them, R 1 、R 3 、R 5 , L, n, o are as defined above for the compound of formula I and the group of formula 1; R 4 , n is as defined above for the compound of formula I; p is 0, 1 or 2.

[0284] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0285] Among them, R 1 、R 3 、R 5 , L, n, o are as defined above for the compound of formula I and the group of formula 1; R 4 , n is as defined above for the compound of formula I; p is 0, 1 or 2.

[0286] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0287] Among them, R 1 、R 3 、R 4 、R 5 , n, o are as defined above for the compound of formula I or the group of formula 1;

[0288] Z 1 As defined above for compounds of formula VI or groups of formula 1; preferably, Z 1 Selected from-CR 5a R 5b -、CR 5a 、-O-、-S-、N、NR 7 and SiR 5a R 5b .

[0289] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0290] Among them, R 1 、R 3 、R 4 、R 5 , n, o are as defined above for the compound of formula I or the group of formula 1; Z 1 As defined above for compounds of formula VI or groups of formula 1; preferably, Z 1 Selected from-CR 5a R 5b -、CR 5a 、-O-、-S-、N、NR 7 and SiR 5a R 5b .

[0291] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0292] in,

[0293] R 1 、R 3 、R 5 , o is as defined above for the group of formula 1;

[0294] R 4 , n is as defined above for the compound of formula I;

[0295] Or, R 4 As above, R in Formula VI 4a 、R 4b As defined, R 5 As above, R in Formula VI 5a 、R 5b defined;

[0296] Y 1 selected from CH and N;

[0297] Z 1 Selected from CR 5a 、N、NR 5a , O and S;

[0298] X 1 、X 2 、X 3 、X 4 Selected from C and N;

[0299] And, Z 1 、X 1 、X 2 、X 3 、X 4 Not at the same time C.

[0300] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0301] in,

[0302] R 1 、R 3 、R 5 , n, o are as defined above for the group of formula 1;

[0303] R 4 , n is as defined above for the compound of formula I;

[0304] Or, R 4 As above, R in Formula VI 4a 、R 4b As defined, R 5 As above, R in Formula VI 5a 、R 5b defined;

[0305] Y 2 、Y 4 Selected from CR 3 , -O-, -S-, N and NR 3 , and Y 2 、Y 4 Not CR at the same time 3 .

[0306] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 1 is selected from:

[0307] in,

[0308] R 1 、R 5 , o is as defined above for the group of formula 1;

[0309] p is 0, 1, or 2;

[0310] R 4 , n is as defined above for the compound of formula I;

[0311] Or, R 4 As above, R in Formula VI 4a 、R 4b As defined, R 5 As above, R in Formula VI 5a 、R 5b defined;

[0312] Y 2 Selected from -O-, -S-, N and NR 3 ;

[0313] Z 1 、Z 2 Selected from C, CR 5a and N.

[0314] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 2 is selected from formula 2-1:

[0315] Among them, R 1 、R 3 、R 5 、Z 1 、X 1 、X 2 、X 3 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 、Y 8, Y, m, and o are as defined above for the group of formula 2.

[0316] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 2 is selected from:

[0317] Among them, R 1 、R 5 , o is as defined above for the group of formula 2;

[0318] R 4 , n is as defined above for the compound of formula I;

[0319] Or, R 4 As above, R in Formula VI 4a 、R 4b As defined, R 5 As above, R in Formula VI 5a 、R 5b defined;

[0320] Y 5 、Y 6 、Y 7 、Y 8 Selected from CR 3 and N.

[0321] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 3 is selected from the group represented by formula 3-1:

[0322] in,

[0323] R 1 、R 3 、R 5 、X 1 、X 2 、X 3 , Z 1 、Y 1 、Y 2 、Y 3 、Y 4 、Y 5 、Y 6 、Y 7 , Y, m, and o are as defined above for the group of formula 3.

[0324] In certain embodiments, in the compound of formula I provided by the present invention, the group represented by formula 3 is selected from:

[0325] in,

[0326] R 1 、R 5 , o is as defined above for the group of formula 3;

[0327] p is 0, 1, or 2;

[0328] R 4 , n is as defined above for the compound of formula I;

[0329] Or, R 4 As above, R in Formula VI 4a 、R 4b As defined, R 5 As above, R in Formula VI 5a 、R 5b defined;

[0330] Y 5 、Y 6 、Y 7 Each independently selected from CR 3 and N.

[0331] In certain embodiments, the present invention provides compounds of formula I, Selected from:

[0332] In certain embodiments, the present invention provides compounds of formula I, Selected from:

[0333] In certain embodiments, the present invention provides compounds of formula I, Selected from:

[0334] In certain embodiments, the present invention provides compounds of formula I, Selected from:

[0335] In certain embodiments, the present invention provides compounds of formula I, Selected from:

[0336] In certain embodiments, the present invention provides compounds of formula I wherein L is selected from CR 4a and N.

[0337] In certain embodiments, the present invention provides compounds of formula I wherein L is selected from CH and N.

[0338] In certain embodiments, the present invention provides compounds of formula I, wherein P is a single bond, a double bond, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 -, the C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl are each optionally substituted with one or more (eg 1, 2, 3, 4, 5, 6) R 9 replace.

[0339] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from a single bond, a double bond, -C 1-6 Alkyl-(C=O)-NR 7 -、-NR 7 -(C=O)-C 1-6 Alkyl-, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group and C 3-6 Cycloalkyl and C6 aryl and C 3-6 Cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl being each optionally substituted by one or more R 9 replace.

[0340] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from a single bond, a double bond, C3-8 Cycloalkyl and 3-8 membered heterocyclyl, said cycloalkyl or heterocyclyl being each optionally substituted by one or more R 9 replace.

[0341] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from -C 1-4 Alkyl-(C=O)-NR 7 -、-NR 7 -(C=O)-C 1-4 Alkyl-, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and C 3-6 Cycloalkyl and C6 aryl and C 3-6 Cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl being each optionally substituted by one or more R 9 replace.

[0342] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from -C 1-4 Alkyl-(C=O)-NH-, C 1-4 Alkyl, C 1-4 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group and C 3-6 Cycloalkyl and C6 aryl and C 3-6 Cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl being each optionally substituted by one or more R 9 replace.

[0343] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from C 3-6 Cycloalkyl and 3-6 membered heterocyclyl, said cycloalkyl or heterocyclyl being each optionally substituted by one or more R 9 replace.

[0344] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from -C 1-3 Alkyl-(C=O)-NH-, C 1-3 Alkyl, C 1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, wherein the alkyl, cycloalkyl or heterocyclic group is optionally substituted by one or more R 9 replace.

[0345] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from a single bond, a double bond, -C 1-3 Alkyl-(C=O)-NH-, methylene, ethylene, propylene, C 1-3haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and benzocyclopentyl, wherein each of the alkyl, cycloalkyl, benzocyclopentyl or heterocyclic groups is optionally substituted by one or more R 9 replace.

[0346] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from a single bond, a double bond, -C 1-3 Alkyl-(C=O)-NH-, methylene, C 1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and benzocyclopentyl, wherein each of the alkyl, cycloalkyl, benzocyclopentyl or heterocyclic groups is optionally substituted by one or more R 9 Substituted; preferably, P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and the cycloalkyl or heterocyclic group is optionally substituted by one or more R 9 replace.

[0347] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from a single bond, a double bond, a methylene, Cyclobutyl,

[0348] Alternatively, P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CF3,

[0349] In certain embodiments, the present invention provides compounds of formula I, wherein P is selected from Cyclobutyl,

[0350] In certain embodiments, the present invention provides compounds of formula I wherein P is a single bond.

[0351] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from deletion, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, 5-14 membered heteroaryl and C 6-14 Aryl, the C 1-10 Alkyl, C 3-10Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, 5-14 membered heteroaryl and C 6-14 Each aryl group is optionally substituted with one or more (eg, 1, 2, 3, 4, 5, 6) R 9 replace.

[0352] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 is missing, P is C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group or C 6- Aryl C 3-6 Cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl being each optionally substituted by one or more R 9 replace.

[0353] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 is missing, P is C 1-4 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, The alkyl, cycloalkyl or heterocyclic groups are each optionally substituted by one or more R 9 replace.

[0354] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Is missing, P is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CF3,

[0355] In certain embodiments, the compound of formula I provided herein is a compound of formula VII,

[0356] Among them, E 1 、E 2 independently selected from C, CH2, CH, N, NH, O and S;

[0357] m1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0358] m2 is selected from 0, 1, 2 or 3;

[0359] m3 is selected from 1, 2 or 3;

[0360] Ring A, Ring B, Ring C, R 1 、R 3 、R 4 、R 6 、R 9 , L, m, n, and o are as defined above for the compounds of Formula I, Formula II, and Formula VI.

[0361] In certain embodiments, in the compound of formula VII, ring A, ring B, ring C, R 1 、R 3 、R 4 、R 6 、R 9 , L, m and n are as defined above for the compounds of Formula I, Formula II and Formula VI.

[0362] In certain embodiments, E of the compound of Formula VII 1 、E 2 are independently selected from C, CH, N, O and S.

[0363] In certain embodiments, the compound of formula I provided by the present invention is a compound of formula VII-1,

[0364] wherein m2 is selected from 0, 1, 2 or 3;

[0365] m3 is selected from 1, 2 or 3;

[0366] Ring A, Ring B, Ring C, R 1 、R 3 、R 4 、R 6 、R 9 , L, m, n, and o are as defined above for the compounds of Formula I, Formula II, and Formula VI, and m1 is as defined for Formula VII.

[0367] In certain embodiments, in the compound of formula VII-1, ring A, ring B, ring C, R 1 、R 3 、R 4 、R 6 、R 9 , L, m and n are as defined above for the compounds of Formula I, Formula II and Formula VI.

[0368] In certain embodiments, in the compound of formula VII-1, m1 is selected from 0 and 1, and m2 and m3 are both 1.

[0369] In certain embodiments, the compound of formula I provided by the present invention is a compound of formula VII-2,

[0370] wherein m2 is selected from 0, 1, 2 or 3;

[0371] m3 is selected from 1, 2 or 3;

[0372] Ring A, Ring B, Ring C, R 1 、R 3 、R 4 、R 6 、R 9 , L, m, n, and o are as defined above for the compounds of Formula I, Formula II, and Formula VI, and m1 is as defined for Formula VII.

[0373] In certain embodiments, in the compound of formula VII-2, ring A, ring B, ring C, R 1 、R 3 、R 4 、R 6 、R 9 , L, m and n are as defined above for the compounds of Formula I, Formula II and Formula VI.

[0374] In certain embodiments, the compound of formula I provided herein is a compound of formula VIII,

[0375] Among them, E 1 、E 2 Independently selected from C, CH2, CH, N, NH, O, S;

[0376] m1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0377] m2 is selected from 0, 1, 2 or 3;

[0378] m3 is selected from 1, 2 or 3;

[0379] Ring A, Ring B, Ring C, R 1 、R 3 、R 4 、R 9 , L, m, n, and o are as defined above for the compounds of Formula I, Formula II, and Formula VI.

[0380] In certain embodiments, in the compound of formula VIII, ring A, ring B, ring C, R 1 、R 3 、R 4 、R 9 , L, m and n are as defined above for the compounds of Formula I, Formula II and Formula VI.

[0381] In certain embodiments, E of the compound of Formula VIII 1 、E 2 are independently selected from C, CH, N, O and S.

[0382] In certain embodiments, the compound of formula I provided by the present invention is a compound of formula VIII-1,

[0383] in,

[0384] m1 is selected from 0, 1, 2, 3, 4, 5 or 6;

[0385] m2 is selected from 0, 1, 2 or 3;

[0386] m3 is selected from 1, 2 or 3;

[0387] Ring A, Ring B, Ring C, R 1 、R 3 、R 4 、R 9 , L, m, n, and o are as defined above for the compounds of Formula I, Formula II, and Formula VI.

[0388] In certain embodiments, in the compound of formula VIII-1, ring A, ring B, ring C, R 1 、R 3 、R 4 、R 9 , L, m and n are as defined above for the compounds of Formula I, Formula II and Formula VI.

[0389] In certain embodiments, the compound of formula I provided by the present invention is a compound of formula VIII-2,

[0390] wherein m1 is selected from 0, 1, 2, 3, 4, 5 or 6; m2 is selected from 0, 1, 2 or 3; m3 is selected from 1, 2 or 3;

[0391] Ring A, Ring B, Ring C, R 1 、R 3 、R 4 、R 9 , L, m, n, and o are as defined above for the compounds of Formula I, Formula II, and Formula VI.

[0392] In certain embodiments, in the compound of formula VIII-2, ring A, ring B, ring C, R 1 、R 3 、R 4 、R 9 , L, m and n are as defined above for the compounds of Formula I, Formula II and Formula VI.

[0393] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 is absent or selected from 3-10 membered heterocyclyl, 5-14 membered heteroaryl and C 6-14 Aryl, said aryl or heteroaryl each optionally substituted by one or more R 9replace.

[0394] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from Among them, G 1 , G 2 , G 3 , G 4 , G 5 are each independently selected from CH and N, Indicates a single bond or a double bond.

[0395] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from missing, 3-8 membered heterocyclic, 5-14 membered heteroaryl, C 6-14 Aryl, C 1-6 Alkyl, C 1-6 haloalkyl, wherein the alkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more R 9 replace.

[0396] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from 5-10 membered heteroaryl and C 6-10 Aryl, said aryl or heteroaryl each optionally substituted by one or more R 9 replace.

[0397] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from 5-6 membered nitrogen-containing heteroaryl and phenyl, each of the aryl or heteroaryl groups is optionally substituted by one or more R 9 replace.

[0398] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl, thienyl, and benzimidazolyl, the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl, thienyl, and benzimidazolyl are each optionally substituted by one or more R 9 replace.

[0399] In certain embodiments, the present invention provides compounds of formula I, wherein R 6is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl and benzimidazolyl, wherein each of the phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl and benzimidazolyl groups is optionally substituted by one or more R 9 replace.

[0400] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl and benzimidazolyl, each of the aryl or heteroaryl groups being optionally substituted by one or more R 9 replace.

[0401] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from Among them, G 1 , G 2 , G 3 , G 4 , G 5 are each independently selected from CH and N.

[0402] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from

[0403] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from

[0404] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 are each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, -CN, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkoxy, -NH2, -NH(CH2CH3), -N(CH3)2, C 1-4 Halogenated alkylthio, C 3-6 Cycloalkyl and 5-6 membered heteroaryl, said 5-6 membered heteroaryl is optionally substituted by C 1-4 Alkyl, C 1-4 Substituted with a haloalkyl group.

[0405] In certain embodiments, the present invention provides compounds of formula I, wherein R 9Each is independently selected from hydrogen, deuterium, F, Cl, Br, CH3, -CN, -CHF2, -CF3, -CHF2, -OCH3, -OCHF2, trifluoromethoxy, -OCH2CF3, -OCH(CH3)CF3, -NH2, -NH(CH2CH3), -N(CH3)2, -SCF3, cyclopropyl,

[0406] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Select from missing, -CH3, -CH2CF3 and -CH2CH3.

[0407] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from

[0408] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Select from missing, -CH3, -CH2CF3 and -CH2CH3.

[0409] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from

[0410] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from

[0411] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from CH3, CH2CF3 and CH2CH3.

[0412] In certain embodiments, the present invention provides compounds of formula I, wherein R 6 Selected from

[0413] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 are each independently selected from hydrogen, deuterium, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -NR 7 R 8 、CN、C 3-8 Cycloalkyl, C 1-6 Halogenated alkylthio, C 1-6 haloalkyloxy and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more selected from C 1-6 Alkyl substituted.

[0414] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 Each independently selected from H, deuterium, F, Cl, Br, cyclopropyl, -CH2CH3, -CHF2, -CF3, -CH3, -OCH3, -OCH(CH3)CF3, -CH2CF3, -OCHF2, -OCH2CF3, -SCF3, -CN, -NH(CH2CH3), -N(CH3)2, -NH2,

[0415] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 Selected from hydrogen, halogen, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -NR 7 R 8 、CN、C 3-6 Cycloalkyl, C 1-6 Haloalkylthio and C 1-6 Haloalkyloxy.

[0416] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 Selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Halogenated alkyl, C 1-6 Halogenated alkylthio, C 1-6 Alkoxy and -NR 7 R 8 .

[0417] In certain embodiments, the present invention provides compounds of formula I, wherein R 9Selected from H, F, Cl, cyclopropyl, -CH2CH3, -CHF2, -CF3, -CH3, -OCH3, -OCH(CH3)CF3, -CH2CF3, -OCHF2, -OCH2CF3, -SCF3, -CN, -NH(CH2CH3), -N(CH3)2 and -NH2.

[0418] In certain embodiments, the present invention provides compounds of formula I, wherein R 9 Selected from H, F, CHF2, CF3, CH3, -OCH3 and NH2.

[0419] The compounds of the present invention have positive allosteric regulatory activity on muscarinic receptor M4 EC 50 The concentration is 1 to 10000 nM, preferably ≤1000 nM, more preferably ≤200 nM, and even more preferably ≤100 nM.

[0420] In some embodiments, compounds of the present invention include, but are not limited to:

[0421] In the above-mentioned compounds of formula I of the present invention, the groups of all embodiments can be appropriately selected and combined in any combination to obtain different general formula ranges or specific embodiments. These ranges and embodiments are all part of the present invention. The present invention covers compounds obtained by any combination of the various embodiments.

[0422] Preparation method

[0423] The compounds of the present invention can be prepared by any method known in the art. Reagents and starting materials are readily available to those of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers can be separated or split at any convenient point in the synthesis by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Elel and SH. Wilen).

[0424] In certain embodiments, the present invention provides a first method for preparing a compound of formula I, comprising the following steps:

[0425] Compound IA and compound R 2 -X reaction to obtain a compound of formula I;

[0426] Wherein, X is a hydroxyl group, a halogen (such as iodine, bromine, chlorine, fluorine), or a leaving group (such as methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluene sulfonate), etc.; and the compound IA is connected to R through the L' position. 2 -X reaction, preferably, L' is selected from -NH-;

[0427] Ring A, Ring B, Ring C, L, R 1 、R 2 、R 3 、R 4 、R 5 , m, n, and o are as defined above.

[0428] In some embodiments of the present invention, the preparation method of the compound of formula I of the present invention, wherein L is C, or CR a , the compound of formula IA and compound R 2 -X preferably forms a chemical bond through an addition reaction or a metal coupling reaction.

[0429] The addition reaction is carried out in the presence of a suitable base. The base can be selected from NaH, NaOH, LDA, LiHDMS, n-BuLi, K2CO3, Cs2CO3, C S F, DIPEA, TEA, etc. The addition reaction is preferably carried out in a suitable solvent. The solvent can be selected from THF, 1,4-dioxane, DMF, DMSO, NMP, acetonitrile, etc. The reaction is carried out at a suitable temperature, for example, at -78°C to 150°C.

[0430] The metal coupling reaction is preferably a metal-catalyzed C—H activation coupling. The metal coupling reaction is preferably carried out in the presence of a catalyst. The catalyst can be a palladium catalyst (e.g., palladium acetate, palladium chloride, etc.), a metal rhodium catalyst, a metal ruthenium catalyst, a nickel catalyst, etc. The metal coupling reaction can be carried out under conditions described in the literature or similar conditions.

[0431] In some embodiments of the present invention, the preparation method of the compound of formula I of the present invention, wherein L is N, the compound of formula IA and the compound R 2 -X preferably forms a chemical bond through an addition reaction or a metal coupling reaction.

[0432] The addition reaction is carried out in the presence of a suitable base. The base can be selected from NaH, NaOH, LDA, LiHDMS, n-BuLi, K2CO3, Cs2CO3, C S F, DIPEA, TEA, etc. The addition reaction is preferably carried out in a suitable solvent. The solvent can be selected from THF, 1,4-dioxane, DMF, DMSO, NMP, acetonitrile, etc. The reaction is carried out at a suitable temperature, for example, at -78°C to 150°C.

[0433] The metal coupling reaction is preferably an Ullmann coupling reaction, a Buchwald-Hartwig coupling reaction and a Chan-Lam coupling reaction.

[0434] The Ullmann coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a copper catalyst. The Ullmann coupling reaction is preferably carried out in the presence of a ligand. The ligand is preferably a nitrogen-containing ligand. The Ullmann coupling reaction is carried out in the presence of a suitable base. The Ullmann coupling reaction is carried out in a suitable solvent. The Ullmann coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0435] The Buchwald-Hartwig coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a palladium catalyst. The Buchwald-Hartwig coupling reaction is preferably carried out in the presence of a ligand. The Buchwald-Hartwig coupling reaction is carried out in the presence of a suitable base. The Buchwald-Hartwig coupling reaction is carried out in a suitable solvent. The Buchwald-Hartwig coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0436] The Chan-Lam coupling reaction, compound R 2 -X wherein X is boronic acid or boronic ester. The Chan-Lam coupling reaction is carried out in the presence of oxygen or air. The Chan-Lam coupling reaction is carried out in the presence of alkaline conditions. The Chan-Lam coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a copper catalyst.

[0437] In certain embodiments, the present invention provides a second method for preparing a compound of formula I, comprising the steps of:

[0438] Compound IB and compound R 2 -X reaction to obtain a compound of formula I;

[0439] wherein X is a hydroxyl group, a halogen (e.g., iodine, bromine, chlorine, fluorine), or a leaving group (e.g., methanesulfonate, ethanesulfonate, phenylsulfonate, p-toluenesulfonate), etc.;

[0440] Ring A, Ring B, Ring C, L, R 1 、R 2 、R 3 、R 4 、R 5 , P, m, n, o are as defined above.

[0441] In some embodiments of the present invention, the preparation method of the compound of formula I of the present invention is to react the compound of formula IB with the compound R 6 -X preferably forms a chemical bond through an addition reaction or a metal coupling reaction.

[0442] The addition reaction is carried out in the presence of a suitable base. The base can be selected from NaH, NaOH, LDA, LiHDMS, n-BuLi, K2CO3, Cs2CO3, CSF, DIPEA, TEA, etc. The addition reaction is preferably carried out in a suitable solvent. The solvent can be selected from THF, 1,4-dioxane, DMF, DMSO, NMP, acetonitrile, etc. The reaction is carried out at a suitable temperature, for example, at -78°C to 150°C.

[0443] The metal coupling reaction is preferably an Ullmann coupling reaction, a Buchwald-Hartwig coupling reaction and a Chan-Lam coupling reaction.

[0444] The Ullmann coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a copper catalyst. The Ullmann coupling reaction is preferably carried out in the presence of a ligand. The ligand is preferably a nitrogen-containing ligand. The Ullmann coupling reaction is carried out in the presence of a suitable base. The Ullmann coupling reaction is carried out in a suitable solvent. The Ullmann coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0445] The Buchwald-Hartwig coupling reaction is preferably carried out in the presence of a catalyst. The catalyst is preferably a palladium catalyst. The Buchwald-Hartwig coupling reaction is preferably carried out in the presence of a ligand. The Buchwald-Hartwig coupling reaction is carried out in the presence of a suitable base. The Buchwald-Hartwig coupling reaction is carried out in a suitable solvent. The Buchwald-Hartwig coupling reaction is carried out at a suitable temperature, for example, under heating conditions.

[0446] The Chan-Lam coupling reaction, compound R 2 In -X, X is preferably boric acid or boric acid ester. The Chan-Lam coupling reaction is preferably carried out in the presence of oxygen or air. The Chan-Lam coupling reaction is preferably carried out in the presence of a catalyst, preferably a copper catalyst.

[0447] Those skilled in the art will appreciate that, depending on the desired product structure, one or more steps in the above-described preparation method may be omitted, and the order of the reaction steps may be appropriately adjusted, and protection / deprotection reaction steps may be added or omitted as needed.

[0448] Pharmaceutical compositions, preparations and methods of treatment

[0449] In some embodiments, the present invention provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof and one or more pharmaceutically acceptable carriers.

[0450] In some embodiments, the present invention provides a pharmaceutical preparation comprising a preventive or therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer or isotope-labeled compound thereof and one or more pharmaceutically acceptable carriers. The pharmaceutical preparation is preferably a solid preparation, a semisolid preparation, a liquid preparation or a gaseous preparation.

[0451] In some embodiments, the pharmaceutical composition or pharmaceutical formulation may further comprise one or more additional therapeutic agents.

[0452] In some embodiments, the pharmaceutical composition or pharmaceutical formulation is preferably administered orally, intravenously, intraarterially, subcutaneously, intraperitoneally, intramuscularly, or transdermally.

[0453] In some embodiments, the present invention provides use of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention in the preparation of a medicament for preventing or treating an M4-mediated disease or condition.

[0454] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention for the preparation of a medicament for modulating (preferably positive allosteric modulation) M4 activity.

[0455] In some embodiments, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention, for use in preventing or treating an M4-mediated disease or condition.

[0456] In some embodiments, the present invention provides a method for preventing or treating an M4-mediated disease or condition, comprising administering to a subject in need thereof an effective amount of a compound of the present invention or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition of the present invention, or a pharmaceutical formulation of the present invention.

[0457] In some embodiments, the M4-mediated diseases or conditions include Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, Huntington's disease, sleep disorders, cognitive disorders (e.g., mild cognitive impairment, age-related mild cognitive impairment, and amnestic mild cognitive impairment), movement disorders, dry mouth, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis Dutch type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidoses, diabetes, autism, and atherosclerosis.

[0458] In some embodiments, the M4-mediated disease or condition is preferably Alzheimer's disease, schizophrenia, psychosis, Parkinson's disease, pain, addiction, and Huntington's disease.

[0459] The compounds of the present invention have positive allosteric regulatory activity on muscarinic acetylcholine receptor M4 EC 50 The concentration is 1 to 10000 nM, preferably ≤1000 nM, more preferably ≤200 nM, and even more preferably ≤100 nM.

[0460] In the present invention, "pharmaceutically acceptable carrier" refers to a diluent, adjuvant, excipient or vehicle that is administered together with the therapeutic agent and is suitable for contact with the tissues of humans and / or other animals without excessive toxicity, irritation, allergic response or other problems or complications corresponding to a reasonable benefit / risk ratio within the scope of reasonable medical judgment.

[0461] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0462] The pharmaceutical compositions of the present invention can act systemically and / or locally. For this purpose, they can be administered by any suitable route.

[0463] For these administration routes, the pharmaceutical composition of the present invention can be administered in suitable dosage forms.

[0464] As used herein, the term "effective amount" refers to that amount of a compound which, when administered, will relieve to some extent one or more of the symptoms of the condition being treated.

[0465] The dosage regimen can be adjusted to provide the optimal desired response. For example, a single bolus can be administered, several divided doses can be administered over time, or the dose can be proportionally reduced or increased as indicated by the urgency of the therapeutic situation. It is to be noted that dosage values ​​can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the specific dosage regimen should be adjusted over time according to the individual's needs and the professional judgment of the person administering or supervising the administration of the composition.

[0466] The amount of the compound of the present invention administered will depend on the severity of the individual, disease or the patient's condition, the speed of administration, the disposal of the compound and the judgment of the prescribing physician for treatment. Generally speaking, effective dose is about 0.0001 to about 50 mg per kg body weight per day. In some cases, the dosage level not higher than the lower limit of the aforementioned range can be enough, and in other cases, still can adopt larger doses when not causing any harmful side effects, condition is first divided into several smaller doses to be administered throughout the day.

[0467] The compound of the present invention may be contained in a pharmaceutical composition or formulation in an amount ranging from about 0.01 mg to about 1000 mg.

[0468] As used herein, unless otherwise indicated, the term "treating" means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition.

[0469] As used herein, "subject" includes humans and non-human animals. Exemplary human subjects include human subjects suffering from diseases (e.g., the diseases described herein) (referred to as patients) or normal individuals. "Non-human animals" herein include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and / or domesticated animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0470] In some embodiments, the pharmaceutical compositions or pharmaceutical formulations of the present invention may further comprise one or more additional therapeutic or prophylactic agents (e.g., other drugs for treating M4-mediated diseases or conditions). In some embodiments, the therapeutic methods of the present invention may further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other drugs for treating M4-mediated diseases or conditions). DETAILED DESCRIPTION

[0471] Example

[0472] The present invention is further described below with reference to examples, but these examples are not intended to limit the scope of the present invention.

[0473] The abbreviations used in this document have the following meanings:

[0474] The compounds of the present invention are separated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography (Flash column chromatography). 1 The reaction was confirmed by H NMR and / or MS. Reaction monitoring was performed by TLC or LC-MS.

[0475] 1 H NMR spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (model AVACE III HD 400 MHz).

[0476] LC / MS uses Aglient 1260Infinity / Aglient 6120Quadrupole.

[0477] TLC used silica gel GF 254 as the stationary phase.

[0478] Column chromatography generally uses 200-300 mesh silica gel (Qingdao Ocean) as the stationary phase.

[0479] Flash column chromatography was performed using a Biotage flash column chromatograph.

[0480] Prep-HPLC used Agilent 1260 and Waters 2489.

[0481] Microwave reactions were performed using a BiotageInitiator microwave reactor.

[0482] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0483] The reagents used in this application were purchased from Acros Organics, Aldrich Chemical Company, or Teber Chemical Company.

[0484] Synthesis Example:

[0485] Intermediate 1: Synthesis of 2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Int-1)

[0486] Step 1: Synthesis of ethyl 4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound Int-1-2)

[0487] Ethyl 5-amino-1H-pyrrole-2-carboxylate (Compound Int-1-1) (2.0 g, 12.97 mmol) was dissolved in 20 mL of anhydrous ethanol, and pentane-2,4-dione (1.30 g, 12.97 mmol) and concentrated hydrochloric acid (0.2 mL) were added. The mixed solution was heated to 80°C and refluxed for 8 hours, cooled to room temperature, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain Compound Int-1-2 (1.75 g, 8.02 mmol). MS [ESI]: m / z = 219.1, [M+H] + .

[0488] Step 2: Synthesis of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound Int-1-3)

[0489] Compound Int-1-2 (1.75 g, 8.02 mmol) was dissolved in 20 mL of DMF, and N-Boc-bromoethylamine (1.80 g, 8.02 mmol), cesium carbonate (7.84 g, 24.05 mmol), and potassium iodide (1.33 g, 8.02 mmol) were added sequentially. The mixed solution was heated to 80°C and stirred overnight, then cooled to room temperature. Water and ethyl acetate were added to the solution for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound Int-1-3 (1.26 g, 3.49 mmol). MS [ESI]: m / z = 362.2, [M+H] + .

[0490] Step 3: Synthesis of 2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound Int-1)

[0491] First, compound Int-1-3 (1.26 g, 3.49 mmol) was dissolved in 20 mL of DCM and 4 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 0.5 hours. LCMS showed that the reaction was complete and the mixture was concentrated under reduced pressure. The resulting compound was dissolved in 20 mL of anhydrous methanol and anhydrous potassium carbonate (2.41 g, 17.43 mmol) was added. The mixture was stirred at room temperature for 8 hours, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound Int-1 (500 mg, 2.32 mmol). MS [ESI]: m / z = 216.1 [M+H] + , 1H NMR (400MHz, CDCl3) δ7.39 (s, 1H), 6.87 (s, 1H), 6.50 (s, 1H), 4.61-4.53 (m, 2H), 3.84 (t, J = 7.0Hz, 2H), 2.68 (s, 3H), 2.61 (s, 3H).

[0492] Intermediate 2: Synthesis of 2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one

[0493] Step 1: Synthesis of (E)-ethyl 3-(3-cyano-4,6-dimethylpyridin-2-yl)acrylate (Compound Int-2-2)

[0494] To a round-bottom flask, add 2-chloro-4,6-dimethylnicotinonitrile (10 g, 60.02 mmol), 1,4-dioxane (100 mL), and water (10 mL). Then, add ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (20.35 g, 90.03 mmol), potassium carbonate (16.59 g, 120.04 mmol), and Pd(dppf)2Cl2 (4.39 g, 6.00 mmol). After nitrogen replacement, heat to 110°C and stir for 12 hours. The reaction was complete after LCMS detection, and the temperature was restored to room temperature. The mixture was concentrated under reduced pressure to remove 1,4-dioxane, and water was added. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography to obtain compound (E)-ethyl 3-(3-cyano-4,6-dimethylpyridin-2-yl)acrylate (6.2 g, 26.93 mmol). MS [ESI]: m / z = 231.1, [M+H] + .

[0495] Step 2: Synthesis of (2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Compound Int-2-3)

[0496] Compound (E)-ethyl 3-(3-cyano-4,6-dimethylpyridin-2-yl)acrylate (6.2 g, 26.93 mmol) and 60 mL of 5% aqueous sodium hydroxide solution were added to a round-bottom flask. The mixture was reacted at 60°C for 4 hours, then the temperature was raised to 100°C and the reaction continued for 4 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature. Acid was added to adjust the pH to 6-7 under an ice bath, and the mixture was purified by C18 reverse-phase flash column chromatography to yield (2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (3.8 g, 17.25 mmol). MS [ESI]: m / z = 221.1, [M+H] + .

[0497] Step 3: Synthesis of 2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetamide (Compound Int-2-4)

[0498] To a round-bottom flask were added the compound (2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (3.0 g, 13.62 mmol), DMF (10 mL), HATU (7.77 g, 20.43 mmol), and DIPEA (5.28 g, 40.87 mmol) in sequence. After reacting at room temperature for 10 min, a 6 M ammonia methanol solution (1.16 g, 68.11 mmol) was added and the reaction was continued for 2 h. LCMS detected that the reaction was complete, and the solid was filtered. The solid was slurried in 5 mL of methanol and filtered again to give 2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetamide (1.8 g, 8.21 mmol). MS [ESI]: m / z = 220.1, [M+H] + .

[0499] Step 4: Synthesis of 2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethan-1-amine (Compound Int-2-5) Compound (2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetamide (1.8 g, 8.21 mmol) and anhydrous tetrahydrofuran (30 mL) were added to a round-bottom flask. After nitrogen replacement three times, borane tetrahydrofuran complex (82.10 mmol, 10 eq) was slowly added under ice bath. After the addition was completed, the temperature was raised to 70 ° C and the reaction was continued for 2 The reaction was complete after LCMS detection, and the mixture was returned to room temperature. Methanol (100 mL) was added under ice bath to quench the reaction. After no more gas was released, 4 M hydrochloric acid (50 mL) was added, the temperature was raised to 60°C and stirred overnight, and the mixture was cooled to room temperature. Under ice bath, aqueous NaOH solution was added to adjust the pH to 7-8, and the mixture was concentrated under reduced pressure. The mixture was purified by C18 reverse-phase flash column chromatography to obtain 2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethan-1-amine (0.8 g, 4.18 mmol). MS [ESI]: m / z = 192.1, [M+H] + .

[0500] Step 5: Synthesis of 2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound Int-2)

[0501] To a round-bottom flask, add compound 2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethan-1-amine (0.8 g, 4.18 mmol), anhydrous tetrahydrofuran (10 mL), triethylamine (634.84 mg, 6.27 mmol), N,N'-carbonyldiimidazole (813.82 mg, 5.02 mmol), react at room temperature for 2 hours, and then heat to The reaction was continued at 70° C. for 48 hours. LCMS detection showed that the reaction was complete. The mixture was returned to room temperature, concentrated under reduced pressure, and purified by C18 reverse-phase flash column chromatography to give 2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (560 mg, 2.58 mmol, MS[ESI]: m / z=218.1, [M+H]+).

[0502] Intermediate 3: Synthesis of 2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c']dipyridin-6(7H)-one

[0503] Step 1: Synthesis of methyl 4-((4-oxopentan-2-ylidene)amino)thiophene-2-carboxylate (Compound Int-3-2)

[0504] To a round-bottom flask, compound Int-3-1 (5.0 g, 31.8 mmol), anhydrous ethanol (100 mL), pentane-2,4-dione (3.5 g, 35.1 mmol), and zinc chloride (1.3 g, 9.5 mmol) were added. The temperature was raised to 80°C and stirring was continued for 16 h. The reaction solution was cooled to room temperature and quenched with saturated brine. The solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to afford compound Int-3-2 (6.2 g, 25.8 mmol). MS (ESI): m / z = 240.1, [M+H] + .

[0505] Step 2: Synthesis of methyl 5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-3)

[0506] Compound Int-3-2 (6.2 g, 25.8 mmol) and polyphosphoric acid (50 mL) were added to a round-bottom flask. The temperature was raised to 130°C and stirring was continued for 5 h. LCMS indicated that the reaction was complete. While still hot, the reaction solution was added dropwise to water (500 mL) to dilute the mixture and adjust the pH to neutral. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography to afford compound Int-3-3 (3.5 g, 16.1 mmol). MS (ESI): m / z = 222.1, [M+H] + .

[0507] Step 3: Synthesis of methyl 3-bromo-5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-4)

[0508] Compound Int-3-3 (3.5 g, 16.1 mmol) and trifluoroacetic acid / concentrated sulfuric acid (20 mL, 4:1) were added to a round-bottom flask. NBS (5.7 mg, 32.2 mmol) was slowly added with vigorous stirring and the reaction was continued at room temperature for 24 h. LCMS indicated the reaction was complete. The reaction solution was slowly diluted with ice water and the pH was adjusted to neutral. The solution was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by column chromatography to afford compound Int-3-4 (1.5 g, 5.1 mmol). MS (ESI): m / z = 300.1, [M+H] + .

[0509] Step 4: Synthesis of methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-5)

[0510] To a round-bottom flask, compound Int-3-4 (1.5 g, 5.1 mmol), toluene (90 mL), and water (30 mL) were added, followed by potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (2.5 g, 10.2 mmol), cesium carbonate (4.9 g, 15.3 mmol), Ruphos (700 mg, 1.5 mmol), and Pd(OAc)2 (115 mg, 0.51 mmol). The atmosphere was replaced with nitrogen three times, then the temperature was raised to 80°C and stirred for 16 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature and concentrated under reduced pressure to remove toluene. Water was added, and the mixture was extracted three times with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography to afford compound Int-3-5 (501 mg, 1.3 mmol). MS (ESI): m / z = 365.1, [M+H] + .

[0511] Step 5: Synthesis of trifluoroacetic acid salt of methyl 3-(2-aminoethyl)-5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-6)

[0512] Compound Int-3-5 (501 mg, 1.3 mmol) and dichloromethane / trifluoroacetic acid (10 mL, 4:1) were added to a round-bottom flask. The reaction was stirred at room temperature for 2 h. LCMS confirmed the reaction was complete, and the reaction solution was concentrated under reduced pressure to give compound Int-3-6 (337 mg, 1.28 mmol). MS (ESI): m / z = 265.1, [M+H] + .

[0513] Step 6: Synthesis of 2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound Int-3)

[0514] Compound Int-3-6 (337 mg, 1.28 mmol), anhydrous methanol (10 mL), and potassium carbonate (345 mg, 2.5 mmol) were added to a round-bottom flask. The mixture was stirred at room temperature for 2 h. LCMS confirmed the reaction was complete and quenched with saturated aqueous ammonium chloride. The methanol was removed by concentration under reduced pressure, and the residue was added with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by column chromatography to afford compound Int-3 (255 mg, 1.1 mmol). MS (ESI): m / z = 233.1, [M+H] + .

[0515] Intermediate 4: Synthesis of 7-(azetidin-3-yl)-2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c']dipyridin-6(7H)-one

[0516] Step 1: Synthesis of methyl 3-(2-((1-(tert-butoxycarbonyl)azetidin-3-yl)amino)ethyl)-5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-4-1)

[0517] Compound Int-3-6 (4.0 g, 15.13 mmol), tert-butyl 3-oxoazetidine-1-carboxylate (3.89 g, 22.70 mmol), sodium triacetoxyborohydride (10.07 g, 45.39 mmol), and dichloromethane (50 mL) were added to a round-bottom flask. Stir at room temperature for 2 hours. LCMS detected that the reaction was complete, and saturated aqueous ammonium chloride was added to quench the reaction. The mixture was extracted with dichloromethane three times, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound Int-4-1 (2.0 g, 4.77 mmol) was purified by silica gel column chromatography. MS (ESI): m / z=420.3, [M+H] + .

[0518] Step 2: Synthesis of tert-butyl 3-(2,4-dimethyl-6-oxo-8,9-dihydrothiophene[3,2-b:5,4-']dipyridin-7(6H)-yl)azetidine-1-carboxylate (Compound Int-4-2)

[0519] Compound Int-4-1 (2.0 g, 4.77 mmol), potassium carbonate (1.97 g, 14.31 mmol), and methanol (30 ml) were added to a round-bottom flask. Stir at room temperature for 2 hours. LCMS confirmed the reaction was complete, and the mixture was filtered. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded compound Int-4-2 (1.6 g, 4.13 mmol). MS (ESI): m / z = 389.2, [M+H] + .

[0520] Step 3: Synthesis of 7-(azetidin-3-yl)-2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound Int-4)

[0521] Compound Int-4-2 (1.6 g, 4.13 mmol), dichloromethane (20 mL), and trifluoroacetic acid (5 mL) were added to a round-bottom flask and stirred at room temperature for 4 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated under reduced pressure and purified by alkaline prep-HPLC to yield the title compound Int-4 (500 mg, 1.74 mmol). MS (ESI): m / z = 288.5, [M+H] + .

[0522] Intermediate 5: Synthesis of 8-(azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one

[0523] Step 1: Synthesis of 3-(2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetamido)azetidine-1-carboxylate (Compound Int-5-01)

[0524] To a round-bottom flask were added compound (2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (5 g, 22.7 mmol), DMF (50 mL), TCFH (12.7 g, 45.4 mmol), and N-methylimidazole (7.46 g, 90.8 mmol) in sequence. After reacting at room temperature for 10 minutes, 3-aminoazetidine-1-carboxylic acid benzyl ester (7.02 g, 34.1 mmol) was added and the reaction was continued for 12 hours. LCMS detection showed that the reaction was complete. The compound Int-5-01 (6.5 g, 15.9 mmol) was purified by C18 reverse flash column chromatography. MS (ESI): m / z = 409.1, [M+H] + .

[0525] Step 2: Synthesis of 3-((2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)amino)azetidine-1-carboxylate (Compound Int-5-02)

[0526] Compound Int-5-01 (6.5 g, 15.9 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a round-bottom flask. After nitrogen replacement, borane tetrahydrofuran complex (159.1 mmol) was slowly added under ice bath. After the addition was completed, the temperature was raised to 70°C and the reaction was continued for 10 hours. LCMS detection showed that the reaction was complete and the mixture was returned to room temperature. Methanol (200 mL) was added to quench the reaction under ice bath. After no more gas was released, the mixture was dried and dissolved in 50 mL of methanol. 4 M hydrochloric acid (100 mL) was added and the mixture was heated to 60°C and stirred overnight. The mixture was cooled to room temperature and adjusted to pH 7-8 under ice bath. The mixture was extracted with dichloromethane three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The mixture was purified by C18 reverse phase flash column chromatography to give compound Int-5-02 (5 g, 13.14 mmol). MS (ESI): m / z = 381.1, [M+H] + .

[0527] Step 3: Synthesis of 3-(2,4-dimethyl-7-oxo-5,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-8(7H)-yl)azetidine-1-carboxylate (Compound Int-5-03)

[0528] Compound Int-5-02 (5 g, 13.14 mmol), anhydrous tetrahydrofuran (50 mL), triethylamine (1.6 g, 15.7 mmol), and N,N'-carbonyldiimidazole (2.13 g, 13.14 mmol) were added to a round-bottom flask and reacted at room temperature for 2 hours. The temperature was then raised to 70 ° C and the reaction was continued for 48 hours. LCMS detection showed that the reaction was complete. The temperature was returned to room temperature and concentrated under reduced pressure. The compound Int-5-03 (3 g, 7.38 mmol) was prepared and purified by silica gel column chromatography. MS (ESI): m / z = 407.1, [M+H] + .

[0529] Step 4: Synthesis of 8-(azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound Int-5)

[0530] Compound Int-5-03 (3 g, 7.38 mmol), methanol (30 mL), and palladium hydroxide on carbon (5.18 g, 36.9 mmol) were added to a round-bottom flask and reacted at room temperature for 4 hours. The reaction was complete when detected by LCMS. The reaction solution was filtered through celite, washed with methanol, and the filtrate was concentrated under reduced pressure. The product was purified by silica gel column chromatography to give Int-5 (1.9 g, 6.98 mmol). MS (ESI): m / z = 273.1, [M+H] + .

[0531] Intermediate 6: Synthesis of 2-(6-(tert-butoxycarbonyl)-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Int-6)

[0532] Step 1: Synthesis of (2-chloro-4,6-dimethylpyridin-3-yl)methylamine (Compound Int-6-2)

[0533] Compound Int-6-1 (5 g, 30.01 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a round-bottom flask. After nitrogen replacement three times, borane tetrahydrofuran complex (61.1 mmol) was slowly added under ice bath. After the addition was completed, the temperature was raised to 70°C and the reaction was continued for 6 hours. LCMS detection showed that the reaction was complete, and the mixture was returned to room temperature. Methanol (50 mL) was added under ice bath to quench the reaction. After no more gas was released, 4 M hydrochloric acid (30 mL) was added, the temperature was raised to 60°C and the reaction was continued for 6 hours. The mixture was cooled to room temperature and under ice bath, and NaOH aqueous solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product Int-6-2 (4.2 g, 24.61 mmol). MS (ESI): m / z=171.1, [M+H] + .

[0534] Step 2: Synthesis of tert-butyl ((2-chloro-4,6-dimethylpyridin-3-yl)methyl)carbamate (Compound Int-6-3)

[0535] Compound Int-6-2 (4.2 g, 24.61 mmol), dichloromethane (50 mL), and triethylamine (3.74 g, 36.92 mmol) were added to a round-bottom flask and reacted at room temperature for half an hour. Di-tert-butyl dicarbonate (6.45 g, 29.54 mmol) was then added and the reaction continued for 2 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound Int-6-3 (5.6 g, 20.68 mmol). MS (ESI): m / z = 271.1, [M+H] + .

[0536] Step 3: Synthesis of tert-butyl 7-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Int-6-4)

[0537] To a round-bottom flask, compound Int-6-3 (5.6 g, 20.68 mmol), DMF (60 mL), and water (6 mL) were added, followed by (E)-2-(ethoxycarbonyl)vinylboronopinacol ester (7.01 g, 31.02 mmol), cesium carbonate (13.48 g, 41.37 mmol), and cataCXium APd G3 (1.51 g, 2.07 mmol). After nitrogen replacement, the temperature was raised to 110°C and stirred for 36 hours. LCMS analysis confirmed the reaction was complete, and the mixture was returned to room temperature. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to give the title compound Int-6-4 (3.8 g, 11.36 mmol). MS (ESI): m / z = 335.1, [M+H] + .

[0538] Step 4: Synthesis of 2-(6-(tert-butoxycarbonyl)-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Compound Int-6)

[0539] Compound Int-6-4 (3.8 g, 11.36 mmol), methanol (20 mL), water (5 mL), and NaOH (681 mg, 17.04 mmol) were added to a round-bottom flask and reacted at 60°C for 4 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature. Acid was added to adjust the pH to 6-7 under an ice bath, and the mixture was purified by C18 reverse phase preparative purification to afford compound Int-6 (2.8 g, 9.14 mmol). MS (ESI): m / z = 307.1, [M+H] + .

[0540] Intermediate 7: Synthesis of tert-butyl 3-chloro-7-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Int 7)

[0541] Step 1: Synthesis of (2,5-dichloro-4,6-dimethylpyridin-3-yl)methanamine (Compound Int 7-2)

[0542] Compound Int 7-1 (300 g, 1.49 mol) and tetrahydrofuran (500 mL) were added to a four-necked flask. The temperature was then maintained at 0°C, and borane tetrahydrofuran complex (1 M, 3.51 mol, 3.51 L) was slowly added dropwise. After the addition was complete, the temperature was raised to 60°C and stirred for 14 hours. TLC (PE:EA = 2:1) confirmed the reaction was complete. The temperature was then lowered to 0°C, and 300 mL of methanol was slowly added dropwise to the reaction mixture while stirring. After the addition was complete, the mixture was stirred for one hour and concentrated under reduced pressure to obtain compound Int 7-2 (300 g, crude product).

[0543] Step 2: Synthesis of tert-butyl ((2,5-dichloro-4,6-dimethylpyridin-3-yl)methyl)carbamate (Compound Int 7-3)

[0544] Compound Int 7-2 (300 g, crude), triethylamine (320 g, 3.16 mol), and dichloromethane (800 mL) were added to a three-necked flask. The temperature was then maintained at 0°C, and di-tert-butyl dicarbonate (405 g, 1.86 mol) was slowly added dropwise. After the addition was complete, the temperature was raised to 25°C and stirred for 2 hours. TLC (n-heptane:ethyl acetate = 2:1) confirmed the reaction was complete. The mixture was concentrated under reduced pressure to obtain the crude product, which was slurried with n-heptane:ethyl acetate = 10:1 and filtered to obtain compound Int 7-3 (390 g, 1.28 mol).

[0545] Step 3: Synthesis of tert-butyl 3-chloro-7-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound Int 7)

[0546] To a three-necked flask, compound Int 7-3 (65 g, 212.98 mmol), dimethylbutyl 2-(ethoxycarbonyl)vinyl acetate (96.30 g, 425.95 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (12.47 g, 17.04 mmol), cesium carbonate (208.17 g, 638.93 mmol), N,N-dimethylformamide (600 mL), and water (100 mL) were added. After nitrogen replacement three times, the temperature was raised to 110°C and stirred for 15 hours. TLC (n-heptane:ethyl acetate = 3:1) confirmed the reaction was complete. The reaction was quenched by adding 500 mL of saturated sodium chloride solution and extracted with 1500 mL of ethyl acetate. The organic phase was washed with two 300 mL portions of sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to yield the title compound Int 7 (53 g, 143.69 mmol).

[0547] MS (ESI): m / z = 369.1 [M+H] +

[0548] 1 H NMR (400MHz, DMSO-d6) δ5.04 (s, 1H), 4.62 (d, J = 8.0Hz, 1H), 4.49-4.39 (m, 1H), 3 .99-3.91(m,2H),2.99-2.84(m,2H),2.52(s,3H),2.27(s,3H),1.46(s,9H),1.08 -1.03(m,3H).

[0549] Intermediate 8: Synthesis of tert-butyl 7-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Int 8)

[0550] Step 1: Synthesis of (2-chloro-4,6-dimethylpyridin-3-yl)methanamine (Compound Int 8-2)

[0551] Compound Int 8-1 (300 g, 1.80 mol) and tetrahydrofuran (500 mL) were added to a four-necked flask. The temperature was then maintained at 0°C, and borane tetrahydrofuran complex (1 M, 4.5 mol, 4.5 L) was slowly added dropwise. After the addition was complete, the temperature was raised to 60°C and stirred for 14 hours. TLC (PE:EA = 2:1) confirmed the reaction was complete. The temperature was then lowered to 0°C, and 300 mL of methanol was slowly added dropwise to the reaction mixture while stirring. After the addition was complete, the mixture was stirred for one hour and concentrated under reduced pressure to afford compound Int 8-2 (300 g, crude product).

[0552] Step 2: Synthesis of tert-butyl (2-chloro-4,6-dimethylpyridin-3-yl)methyl)carbamate (Compound Int 8-3)

[0553] Compound Int 8-2 (300 g, crude), triethylamine (266.9 g, 2.64 mol), and dichloromethane (1000 mL) were added to a three-necked flask. BOC anhydride (460.5 g, 2.11 mol) was then slowly added dropwise, controlled to 0°C. After the addition was complete, the temperature was raised to 25°C and stirred for 2 hours. TLC (n-heptane:ethyl acetate = 2:1) confirmed the reaction was complete. The mixture was concentrated under reduced pressure to obtain the crude product, which was slurried with n-heptane:ethyl acetate = 10:1 and filtered to obtain compound Int 8-3 (425 g, 1.28 mol).

[0554] Step 3: Synthesis of tert-butyl 7-(2-ethoxy-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound Int 8)

[0555] To a three-necked flask, compound Int 8-3 (60 g, 221.60 mmol), dimethylbutyl 2-(ethoxycarbonyl)vinyl acetate (75.15 g, 332.40 mmol), [n-butyldi(1-adamantyl)phosphine](2-amino-1,1'-biphenyl-2-yl)palladium(II) methanesulfonate (16.1 g, 22.2 mmol), cesium carbonate (144.40 g, 443.20 mmol), N,N-dimethylformamide (600 mL), and water (100 mL) were added. After nitrogen replacement, the temperature was raised to 110°C and stirred for 18 hours. TLC (n-heptane:ethyl acetate = 3:1) confirmed the reaction was complete. The reaction was quenched with saturated sodium chloride solution and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to yield the title compound Int 8 (15 g, 44.85 mmol). MS (ESI): m / z = 335.2 [M+H] + .

[0556] Intermediate 9: Synthesis of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetic acid (Int 9)

[0557] Step 1: Synthesis of methyl 2-(azetidin-3-yl)acetate (Compound Int 9-2)

[0558] Compound Int 9-1 (5 g, 21.81 mmol) and dichloromethane (10 mL) were added to a single-necked flask, followed by trifluoroacetic acid (5 mL). The mixture was stirred at room temperature for 3 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated under reduced pressure to yield compound Int 9-2 (5.0 g, crude, trifluoroacetate salt). MS (ESI): m / z = 130.2 [M+H] +

[0559] Step 2: Synthesis of methyl 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetate (Compound Int 9-3)

[0560] To a single-necked flask were added compound Int 9-2 (5 g, crude), N,N-diisopropylethylamine (2.67 g, 20.6 mmol), N-methylpyrrolidone (30 mL), cesium fluoride (9.41 g, 61.94 mmol), and 4-chloro-2-(trifluoromethyl)pyridine (4.12 g, 22.71 mmol). The mixture was then heated to 80°C and stirred for 15 hours. LCMS confirmed the reaction was complete, and the mixture was quenched with saturated sodium chloride solution. The mixture was extracted with ethyl acetate, and the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The title compound Int 9-3 (5 g, 18.23 mmol) was purified by silica gel column chromatography. MS (ESI): m / z = 275.1 [M+H] +

[0561] Step 3: Synthesis of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetic acid (Compound Int 9)

[0562] To a single-necked flask, compound Int 9-3 (5.0 g, 18.23 mmol), lithium hydroxide monohydrate (2.3 g, 54.81 mmol), methanol (20 mL), and water (5 mL) were added and stirred at 25°C for 2 hours. TLC (n-heptane:ethyl acetate = 2:1) confirmed the reaction was complete. The methanol was concentrated under reduced pressure, the pH was adjusted to 6 with 1 M hydrochloric acid, and the title compound Int 9 (3.75 g, 14.41 mmol) was obtained by filtration.

[0563] Intermediate 10: Synthesis of benzyl 3-(2-(tert-butoxy)-2-oxoethyl)azetidine-1-carboxylate (Int 10)

[0564] Step 1: Synthesis of benzyl 3-(2-(tert-butoxy)-2-oxoethylidene)azetidine-1-carboxylate (Compound Int 10-3)

[0565] To a three-necked flask, compound Int 10-2 (17.21 g, 68.22 mmol, 16.02 mL) and 200 mL of tetrahydrofuran were added. The mixture was cooled to -10°C under nitrogen, and sodium hydride (3.12 g, 77.97 mmol) was added portionwise. The mixture was stirred at 0°C for 1 hour, followed by compound Int 10-1 (10 g, 48.73 mmol). The reaction mixture was stirred at 25°C under nitrogen for 3 hours. TLC (n-heptane:ethyl acetate = 3:1) confirmed the reaction was complete. The reaction was quenched by adding 300 mL of saturated ammonium chloride solution, extracted with 300 mL of ethyl acetate, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography to afford the title compound Int 10-3 (11 g, 36.26 mmol).

[0566] MS (ESI): m / z = 629.3, [2M + Na] + .

[0567] 1 H NMR (400MHz, DMSO-d6) δ7.38-7.32(m,5H),5.76 -5.73(m,1H),5.07(s,2H),4.78(s,2H),4.64(s,2H),1.42(s,9H).

[0568] Step 2: Synthesis of benzyl 3-(2-(tert-butoxy)-2-oxoethyl)azetidine-1-carboxylate (Compound Int 10)

[0569] To a single-necked flask, compound Int 10-3 (11 g, 36.26 mmol), 4-methylbenzenesulfonylhydrazide (47.27 g, 253.83 mmol, 33.77 mL), sodium acetate (44.62 g, 543.92 mmol, 29.20 mL), 1,4-dioxane (400 mL), and water (100 mL) were added. The atmosphere was replaced with nitrogen three times, then the temperature was raised to 90°C and stirred for 14 hours. TLC (n-heptane:ethyl acetate = 3:1) confirmed the reaction was complete. The reaction was quenched by adding 200 mL of aqueous solution, extracted with 300 mL of ethyl acetate, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography to afford the title compound Int 10 (5.3 g, 17.36 mmol).

[0570] MS (ESI): m / z = 250.2, [M-56] + . 1 H NMR (400MHz, DMSO-d6) δ7.37-7.31(m,5H),5.02(s,2H),4.00(s,2H),3.61(s,2H),2.83-2.79(m,1H),2.55(d,J=8.0Hz,2H),1.38(s,9H).

[0571] Example 1: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 1)

[0572] Step 1: Synthesis of 2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetamide (Compound 1-2)

[0573] Compound Int-2-3 (3.8 g, 17.25 mmol), DMF (10 mL), TCFH (9.68 g, 34.51 mmol), and N-methylimidazole (5.67 g, 69.02 mmol) were added to a round-bottom flask in sequence. After reacting at room temperature for 10 minutes, 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (4.50 g, 20.71 mmol) was added and the reaction was continued for 6 hours. LCMS detection showed that the reaction was complete. The product was purified by C18 reverse flash column chromatography to obtain compound 1-2 (4.8 g, 11.44 mmol), MS [ESI]: m / z = 420.1, [M+H] + .

[0574] Step 2: Synthesis of N-(2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (Compound 1-3)

[0575] Compound 1-2 (4.8 g, 11.44 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a round-bottom flask. After nitrogen substitution three times, borane tetrahydrofuran complex (114.45 mmol) was slowly added under ice bath. After the addition was complete, the temperature was raised to 70°C and the reaction was continued for 24 hours. LCMS detection showed that the reaction was complete, and the mixture was returned to room temperature. Methanol was added under ice bath to quench the reaction. After no more gas was released, 4M hydrochloric acid (50 mL) was added, the temperature was raised to 60°C and stirred overnight, and the mixture was cooled to room temperature. Under ice bath, NaOH aqueous solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane three times. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 1-3 (2.2 g, 5.26 mmol) was purified by C18 reverse phase flash column chromatography. MS [ESI]: m / z = 392.1, [M+H] + .

[0576] Step 3: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 1)

[0577] Compound 1-3 (2.2 g, 5.26 mmol), anhydrous tetrahydrofuran (10 mL), triethylamine (853.09 mg, 8.43 mmol), and N,N'-carbonyldiimidazole (1.09 g, 6.74 mmol) were added to a round-bottom flask. After reacting at room temperature for 2 hours, the temperature was raised to 70 ° C and the reaction was continued for 48 hours. LCMS detection showed that the reaction was complete. The mixture was returned to room temperature and concentrated under reduced pressure. Prep-HPLC was used to prepare and purify the product to give compound 1 (1.4 g, 3.35 mmol, retention time: 5.402 min). MS [ESI]: m / z = 418.1, [M + H] + , 1 H-NMR (400MHz, CDCl3) δ8.24 (d, J = 5.6Hz, 1H), 6.87 (s, 1H), 6.56 (s, 1H), 6.31 (d, J=4.0Hz,1H),5.44-5.29(m,1H),4.88(d,J=15.2Hz,1H),4.73(d,J=11.6Hz,1H),4 .46(d,J=15.2Hz,1H),4.18(dt,J=14.4,8.4Hz,3H),3.97(dd,J=8.4,5.6Hz,1H),3 .63-3.44(m,2H),2.71-2.60(s,1H),2.48(s,3H),2.21(s,3H),1.73-1.62(m,1H).

[0578] Step 4: Split

[0579] Compound 1 (40 mg, 239.56 μmol) was separated by chiral chromatography to obtain compound 1a (17 mg) and compound 1b (19 mg). The separation conditions were as follows: the chromatographic column model was Unichiral CNZ-5H, the mobile phase was n-hexane-anhydrous ethanol (60:40), the retention time of compound 1a was 18.6 minutes, and the retention time of compound 1b was 23.5 minutes.

[0580] Example 2: Synthesis of 2,4-dimethyl-8-(pyridin-2-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 19)

[0581] To a Schlenk flask, add 2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (20 mg, 82.85 μmol) and 1,4-dioxane (1 mL), followed by 2-bromopyridine (19.63 mg, 124.27 μmol), cuprous iodide (3.16 mg, 16.57 μmol), dimethylethylenediamine (3.65 mg, 41.12 μmol), and potassium carbonate (22.90 mg, 165.69 μmol). After nitrogen replacement, heat to 110°C and stir for 12 hours. The reaction was complete after LCMS detection, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. The mixture was purified by reverse phase Prep-HPLC to give compound 19 (4.0 mg, 13.59 μmol). MS [ESI]: m / z = 295.1, [M+H] + . 1 H-NMR (400MHz, CDCl3) δ8.29(d,J=4.0Hz,1H),7.98(d,J=8.4Hz,1H),7.71-7.43(m,1H),7.03-6.90(m,1H),6.87(s,1H),4.97(d,J=15.2H z,1H),4.82(d,J=10.8Hz,1H),4.56-4.48(m,2H),3.74(td,J=12.8,4.0Hz,1H),2.76(s,1H),2.49(s,3H),2.23(s,3H),1.86-1.75(m,1H).

[0582] Example 3: Synthesis of 2,4-dimethyl-8-(pyridin-3-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 20)

[0583] Compound Int-2 (30 mg, 138.08 μmol) and 1,4-dioxane (1 mL) were added to a Schlenk flask, followed by 3-bromopyridine (32.72 mg, 207.12 μmol), cuprous iodide (2.63 mg, 13.81 μmol), dimethylethylenediamine (2.43 mg, 27.62 μmol), and potassium carbonate (38.17 mg, 165.69 μmol). After nitrogen replacement, the temperature was raised to 110°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 20 (3.4 mg, 11.55 μmol) was obtained by reverse phase Prep-HPLC purification. MS [ESI]: m / z = 295.1, [M+H] + . 1 H-NMR (400MHz, CDCl3) δ8.68(s,1H),8.42(d,J=3.6Hz,1H),8.02-7.65(m,1H),7.31(dd,J=8.0,4.8Hz,1H),6.93(s,1H),5.01(d,J =15.2Hz,1H),4.93(d,J=11.6Hz,1H),4.57(d,J=15.2Hz,1H),4.02-3.73(m,2H),2.83-2.77(m,1H),2.54(s,3H),2.28(s,3H),1.96 -1.94(m,1H).

[0584] Example 4: Synthesis of 2,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 32)

[0585] To a Schlenk flask, compound Int-2 (30 mg, 138.08 μmol) and 1,4-dioxane (1 mL) were added, followed by 4-iodo-1-methyl-1H-pyrazole (43.08 mg, 207.12 μmol), cuprous iodide (2.63 mg, 13.81 μmol), dimethylethylenediamine (2.43 mg, 27.62 μmol), and potassium carbonate (38.17 mg, 165.69 μmol). The atmosphere was purged with nitrogen three times, then the temperature was raised to 110°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Reverse-phase Prep-HPLC was used to prepare and purify the mixture to afford compound 32 (6.4 mg, 21.52 μmol, retention time: 4.110 min). MS [ESI]: m / z = 298.1, [M+H] +. NMR: 1 H-NMR (400MHz, CDCl3) δ7.78(s,1H),7.41(s,1H),6.86(s,1H),4.91(d,J=15.2Hz,1H),4.78(d,J=11.6Hz,1H),4.52(d ,J=14.8Hz,1H),3.81(s,3H),3.76-3.60(m,2H),2.67(d,J=15.2Hz,1H),2.47(s,3H),2.21(s,3H),1.88-1.77(m,1H).

[0586] Example 5: Synthesis of 2,4-dimethyl-8-(pyridin-4-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 21)

[0587] Compound Int-2 (30 mg, 138.08 μmol) and 1,4-dioxane (1 mL) were added to a Schlenk flask, followed by 4-iodopyridine (42.46 mg, 207.12 μmol), cuprous iodide (2.63 mg, 13.81 μmol), dimethylethylenediamine (2.43 mg 27.62 μmol), and potassium carbonate (38.17 mg, 165.69 μmol). After nitrogen substitution, the temperature was raised to 110°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 21 (6.6 mg, 22.42 μmol) was obtained by reverse phase Prep-HPLC purification. MS [ESI]: m / z = 295.1, [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.44(d,J=5.2Hz,2H),7.42(d,J=5.2Hz,2H),6.87(s,1H),4.95(d,J=15.2Hz,1H),4.79(d,J=11.2 Hz,1H),4.53(d,J=15.2Hz,1H),4.04-3.65(m,2H),2.77(d,J=13.2Hz,1H),2.47(s,3H),2.22(s,3H),2.12-1.74(m,1H).

[0588] Example 6: Synthesis of 2,4-dimethyl-7-(pyridin-2-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 109)

[0589] Compound (Int-1) (40 mg, 185.83 μmol) was dissolved in 1 ml of dry 1,4-dioxane, and 2-bromopyridine (29.36 mg, 185.83 μmol), anhydrous potassium carbonate (51.37 mg, 371.66 μmol), cuprous iodide (35.4 mg, 185.8 μmol), and DMEDA (32.8 mg, 371.7 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. The reaction was complete by LCMS, and the product was filtered through celite and purified by column chromatography to give compound 109 (5.4 mg, 18.47 μmol). MS [ESI]: m / z = 293.3, [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.38(dd,J=4.8,1.0Hz,1H),8.02(d,J=8.4Hz,1H),7.76-7.58(m,1H),7 .29(s,1H),7.05(dd,J=7.0,5.2Hz,1H),6.79(s,1H),4.50(s,4H),2.57(s,3H),2.49(s,3H).

[0590] Example 7: Synthesis of 2,4-dimethyl-7-(pyridin-3-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 110)

[0591] Compound (Int-1) (40 mg, 185.83 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 3-bromopyridine (29.36 mg, 185.83 μmol), anhydrous potassium carbonate (51.37 mg, 371.66 μmol), cuprous iodide (35.4 mg, 185.8 μmol), and DMEDA (32.8 mg, 371.7 μmol) were added sequentially. The atmosphere was purged with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. The reaction was complete by LCMS, and the mixture was filtered through celite and purified by column chromatography to give compound 110 (6.5 mg, 22.23 μmol). MS [ESI]: m / z = 293.3, [M+H] +1 H NMR (400MHz, CDCl3) δ8.81-8.46 (m, 2H), 7.84 (d, J = 8.2Hz, 1H), 7.44 (s, 1H), 7.3 6(s,1H),6.90(s,1H),4.70(s,2H),4.31-4.19(m,2H),2.68(s,3H),2.58(s,3H).

[0592] Example 8: Synthesis of 2,4-dimethyl-7-(thiazol-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 116)

[0593] Compound (Int-1) (40 mg, 185.83 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 4-bromothiazole (30.48 mg, 185.83 μmol), anhydrous potassium carbonate (51.37 mg, 371.66 μmol), cuprous iodide (35.4 mg, 185.8 μmol), and DMEDA (32.8 mg, 371.7 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. The reaction was complete by LCMS, and the mixture was filtered through celite and purified by column chromatography to give compound 116 (17.2 mg, 57.65 μmol). MS [ESI]: m / z = 299.1, [M+H] + , 1 H NMR (400MHz, CDCl3) δ8.67(d,J=2.4Hz,1H),8.07(d,J=2.4Hz,1H),7.34(s,1H),6.85(s, 1H), 4.73 (dd, J=6.8, 4.6Hz, 2H), 4.58 (dd, J=6.8, 4.6Hz, 2H), 2.63 (s, 3H), 2.56 (s, 3H).

[0594] Example 9: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 111)

[0595] Compound (Int-1) (160 mg, 743.32 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 4-iodopyridine (152.38 mg, 743.32 μmol), anhydrous potassium carbonate (205.46 mg, 1.49 mmol), cuprous iodide (141.6 mg, 743.3 μmol), and DMEDA (131.0 mg, 1.48 mmol) were added sequentially. After nitrogen substitution, the temperature was raised to 110°C and stirred for 8 hours. The reaction was complete by LCMS, and the mixture was filtered through celite and purified by column chromatography to give compound 111 (120 mg, 410.49 μmol). MS [ESI]: m / z = 293.3, [M+H] + , 1H NMR (400MHz, CDCl3) δ8.66(s,2H),7.50(d,J=4.6Hz,2H),7.38(s,1H),6.88(s,1H),4.66-4.56(m,2H),4.34-4.22(m,2H),2.64(s,3H),2.56(s,3H).

[0596] Example 10: Synthesis of azetidin-3-yl)-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 118) and 2,4-dimethyl-7-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 107)

[0597] Step 1: Synthesis of tert-butyl 3-(2,4-dimethyl-6-oxo-8,9-dihydropyridinium[3',2':4,5]pyrrolo[1,2-a]pyrazine-7(6H)-yl)azetidine-1-carboxylate (Compound 10-1)

[0598] Compound Int-1 (100 mg, 464.57 μmol) was dissolved in 2 mL of DMF, and NaH (111.48 mg, 4.65 mmol) was added at 0°C. After stirring at room temperature for 1 hour, tert-butyl 3-iodoazetidine-1-carboxylate (1.32 g, 4.65 mmol) was added. The solution was heated to 80°C and stirred overnight. LCMS detected that the reaction was complete, and the mixture was cooled to room temperature, quenched with water, and purified by column chromatography to obtain compound 10-1 (120 mg, 337.43 μmol). HPLC-MS: m / z = 371.4, [M+H] + .

[0599] Step 2: Synthesis of 7-(azetidin-3-yl)-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 118)

[0600] Compound 10-1 (120 mg, 337.43 μmol) was dissolved in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour, and concentrated under reduced pressure to obtain compound 118 (50 mg, 184.96 μmol). MS [ESI]: m / z = 271.4, M+H + , 1H NMR (400MHz, CDCl3) δ7.19(s,1H),6.83(s,1H),5.54-5.44(m,1H),4.56-4.39(m,2H),4.14-3.95(m,4H),3.83(s,2H),2.61(s,3H),2.52(s,3H).

[0601] Step 3: Synthesis of 2,4-dimethyl-7-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 107)

[0602] Compound 118 (50 mg, 184.96 μmol) was dissolved in 1 mL of N-methylpyrrolidone, and 4-bromo-2-(trifluoromethyl)pyridine (41.80 mg, 184.96 μmol) and cesium fluoride (56.19 mg, 369.92 μmol) were added. The mixture was heated to 80°C and stirred overnight. LCMS confirmed the reaction was complete, and the mixture was cooled to room temperature and purified by column chromatography to yield compound 107 (7.1 mg, 17.09 μmol). MS [ESI]: m / z = 416.4, [M+H] + , 1 H NMR (400MHz, CDCl3) δ8.36(d,J=5.6Hz,1H),7.26(s,1H),6.87(s,1H),6.68(d,J=2.0Hz,1H),6.43(dd,J=5.6,2.0Hz,1H),5.7 5-5.66(m,1H),4.57(s,2H),4.39(t,J=8.4Hz,2H),4.16(dd,J=8.4,5.2Hz,2H),4.00-3.88(m,2H),2.65(s,3H),2.56(s,3H).

[0603] Example 11: Synthesis of 2,4-dimethyl-7-(1-methyl-1H-pyrazol-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 119)

[0604] Compound (Int-1) (40 mg, 185.83 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 4-iodopyridine (38.09 mg, 185.83 μmol), anhydrous potassium carbonate (51.37 mg, 371.66 μmol), cuprous iodide (35.4 mg, 185.8 μmol), and DMEDA (32.8 mg, 371.7 μmol) were added sequentially. The atmosphere was purged with nitrogen, and the mixture was heated to 110°C and stirred for 8 hours. LCMS confirmed the reaction was complete, and the mixture was filtered through celite and purified by column chromatography to yield compound 119 (12.4 mg, 41.99 μmol). MS [ESI]: m / z = 296.3, [M+H] + , 1 H NMR(400MHz,CD3OD)δ8.08(s,1H),7.79(s,1H),7.26(s,1H),6.95(s,1H),4.56(dd,J =6.6,5.0Hz,2H),4.26(dd,J=6.6,5.1Hz,2H),3.93(s,3H),2.61(s,3H),2.57(s,3H).

[0605] Example 12: Synthesis of 2,4-dimethyl-7-(1-(pyridin-3-yl)azetidin-3-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 108)

[0606] Compound 118 (30 mg, 110.98 μmol) was dissolved in 1 mL of 1,4-dioxane, and 3-bromopyridine (17.53 mg, 110.98 μmol), palladium acetate (2.49 mg, 11.10 μmol), cesium carbonate (72.32 mg, 221.95 μmol), and Xantphos (12.84 mg, 22.20 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 100°C and stirred overnight. LCMS analysis confirmed the reaction was complete, and the mixture was cooled to room temperature, filtered through celite, and purified by column chromatography to afford compound 108 (2.5 mg, 7.20 μmol). MS [ESI]: m / z = 348.4, [M+H] + , 1H NMR (400MHz, CD3OD) δ7.91(d,J=4.4Hz,1H),7.83(s,1H),7.25(dd,J=8.4,4.8Hz,1H),7.19(s,1H),6.99(dd,J=8.4,1.6Hz,1H), 6.92(s,1H),5.58-5.45(m,1H),4.48(dd,J=6.6,4.9Hz,2H),4.30(t,J=8.2Hz,2H),4.14-4.07(m,4H),2.57(s,3H),2.54(s,3H).

[0607] Example 13: Synthesis of 2,4,5-trimethyl-7-(pyridin-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 120)

[0608] Step 1: Synthesis of 5-bromo-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 13-1)

[0609] Compound Int-1 (40 mg, 185.83 μmol) was dissolved in 2 mL of DCM, and NBS (33.07 mg, 185.83 μmol) was added and stirred at room temperature for 6 hours. Column chromatography purification gave compound 13-1 (27 mg, 91.79 μmol). MS [ESI]: m / z = 295.1, [M+H] + .

[0610] Step 2: Synthesis of 2,4,5-trimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 13-2)

[0611] Compound 13-1 (27 mg, 91.79 μmol) was dissolved in 5 mL of 1,4-dioxane / water (10 / 1), and trimethylcyclotriboroxane (115.23 mg, 917.91 μmol), cesium carbonate (59.81 mg, 183.58 μmol), and PdCl2(dppf) (33.58 mg, 45.90 μmol) were added in sequence. The atmosphere was replaced with nitrogen, and the temperature was raised to 100°C and stirred for 17 hours. Compound 13-2 (20 mg, 87.23 μmol) was obtained by column chromatography. MS [ESI]: m / z = 230.2, [M+H] + .

[0612] Step 3: Synthesis of 2,4,5-trimethyl-7-(pyridin-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 120)

[0613] Compound (13-2) (20 mg, 87.23 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 4-iodopyridine (17.88 mg, 87.23 μmol), anhydrous potassium carbonate (24.11 mg, 174.46 μmol), cuprous iodide (16.6 mg, 87.2 μmol), and DMEDA (15.4 mg, 174.5 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. The reaction was complete by LCMS, and the mixture was filtered through celite and purified by column chromatography to give compound 120 (2.6 mg, 8.49 μmol). MS [ESI]: m / z = 307.3, [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.58(d,J=4.8Hz,2H),7.51(d,J=6.2Hz,2H),6.83(s,1H),4. 54-4.35(m,2H),4.22(dd,J=6.4,4.6Hz,2H),2.79(s,3H),2.65(s,3H),2.51(s,3H).

[0614] Example 14: Synthesis of 7-cyclobutyl-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 117)

[0615] Compound Int-1 (20 mg, 92.91 μmol) was dissolved in 1 mL of DMF, and NaH (22.30 mg, 929.15 μmol) was added at 0°C. After stirring at room temperature for 1 hour, cyclobutyl bromide (125.44 mg, 929.15 μmol) was added. The solution was heated to 80°C and stirred overnight. LCMS confirmed the reaction was complete, and the mixture was cooled to room temperature, quenched with water, and purified by column chromatography to afford compound 117 (2.5 mg, 9.28 μmol). MS [ESI]: m / z = 270.3, [M+H] + , 1H NMR (400MHz, CDCl3) δ7.18(s,1H),6.82(s,1H),5.33-5.10(m,1H),4.52-4.33(m,2H),3.7 8(dd,J=6.6,5.0Hz,2H),2.61(s,3H),2.52(s,3H),2.31-2.14(m,4H),1.84-1.68(m,2H).

[0616] Example 15: Synthesis of 2,4,9-trimethyl-7-(pyridin-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(7H)-one (Compound 141)

[0617] Step 1: Synthesis of 4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carbohydrazide (Compound 15-1)

[0618] Compound Int-1-2 (500 mg, 2.29 mmol) was dissolved in 5 mL of methanol, and hydrazine hydrate (802.80 mg, 16.04 mmol) was added. The solution was heated to 80°C and stirred overnight. LCMS confirmed the reaction was complete, and the mixture was cooled to room temperature and filtered to obtain compound 15-1 (372 mg, 467.87 μmol). MS [ESI]: m / z = 205.2, [M+H] + .

[0619] Step 2: Synthesis of 2,4,9-trimethylpyridone [3', 2': 4,5] pyrrolo [1,2-d] [1,2,4] triazine-6 ​​(7H) -one (Compound 15-2)

[0620] Compound 15-1 (115 mg, 563.10 μmol) was dissolved in 3 mL of DMF, and triethyl orthoformate (83.4 mg, 563.10 μmol) was added. The solution was heated to 150°C and stirred for 3 hours. LCMS confirmed the reaction was complete, and the mixture was cooled to room temperature and purified by column chromatography to give compound 15-2 (60 mg, 280.08 μmol). MS [ESI]: m / z = 229.2, [M+H] + .

[0621] Step 3: Synthesis of 2,4,9-trimethyl-7-(pyridin-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(7H)-one (Compound 141)

[0622] Compound 15-2 (20 mg, 87.62 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 2-bromopyridine (13.84 mg, 87.62 μmol), anhydrous potassium carbonate (24.22 mg, 175.25 μmol), cuprous iodide (16.7 mg, 87.62 μmol), and DMEDA (15.4 mg, 175.2 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. LCMS detected the reaction to be complete, and the product was filtered through celite and purified by column chromatography to give compound 141 (4.3 mg, 14.08 μmol). MS [ESI]: m / z = 306.3, [M+H] + , 1 H NMR (400MHz, CDCl3) δ8.79(s,1H),7.88-7.85(m,2H),7.53(s,1H),7.35(s,1H),7.07(s,1H),3.19(s,3H),2.66(s,3H),2.62(s,3H).

[0623] Example 16: Synthesis of 2,4-dimethyl-7-(pyridin-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(7H)-one (Compound 136)

[0624] Step 1: Synthesis of 2,4-dimethylpyrido[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(7H)-one (Compound 16-1)

[0625] Compound 15-1 (200 mg, 979.3 μmol) was dissolved in 3 mL of DMF, and trimethyl orthoformate (103.92 mg, 979.3 μmol) was added. The solution was heated to 150°C and stirred for 3 hours. LCMS confirmed the reaction was complete, and the mixture was cooled to room temperature and purified by column chromatography to obtain compound 16-1 (120 mg, 560.16 μmol). MS (ESI): m / z = 215.2, [M+H] + .

[0626] Step 2: Synthesis of 2,4-dimethyl-7-(pyridin-2-yl)pyrido[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(7H)-one (Compound 136)

[0627] Compound 16-1 (60 mg, 280.08 μmol) was dissolved in 2 mL of dry 1,4-dioxane, and 2-bromopyridine (44.25 mg, 280.08 μmol), anhydrous potassium carbonate (77.42 mg, 560.16 μmol), cuprous iodide (53.3 mg, 280.1 μmol), and DMEDA (49.4 mg, 560.2 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. LCMS analysis showed that the reaction was complete, and the product was filtered through celite and purified by column chromatography to give compound 136 (6.0 mg, 20.06 μmol). MS (ESI): m / z = 292.3, [M+H] + , 1 H NMR (400MHz, CDCl3) δ8.99 (ds, 1H), 8.61 (s, 1H), 7.88 (t, J = 7.4Hz, 2H), 7.51 (s, 1H), 7.35 (s, 1H), 7.11 (s, 1H), 2.70 (s, 3H), 2.64 (s, 3H).

[0628] Example 17: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)pyrido[3',2':4,5]pyrrolo[1,2-d][1,2,4]triazine-6(7H)-one (Compound 138)

[0629] Compound 16-1 (20 mg, 93.36 mol) was dissolved in 1 mL of dry 1,4-dioxane, and 4-iodopyridine (19.14 mg, 93.36 μmol), anhydrous potassium carbonate (25.81 mg, 186.72 μmol), cuprous iodide (17.8 mg, 93.36 μmol), and DMEDA (16.5 mg, 186.72 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. The reaction was complete by LCMS, and the product was filtered through celite and purified by column chromatography to give compound 138 (4.3 mg, 14.76 μmol). MS [ESI]: m / z = 292.3, [M+H] + , 1 H NMR (400MHz, CD3OD) δ8.99(s,1H),8.62(d,J=6.2Hz,2H),8.06(dd,J=4.8,1.6Hz,2H),7.61(s,1H),7.25(s,1H),2.69(s,3H),2.67(s,3H).

[0630] Example 18: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-5,7,8,9-tetrahydro-6H-pyrrolo[3,2-b:5,4-c′]dipyridin-6-one (Compound 147)

[0631] Step 1: Synthesis of 2-oxopiperidine-3-carboxylic acid (Compound 18-2)

[0632] Compound 18-1 (6.84 g, 43.52 mmol) was added to a round-bottom flask, and KOH (10.26 g, 182.79 mmol) was dissolved in 5.02 mL of water and added to the round-bottom flask. The mixture was stirred under nitrogen for 30 minutes at room temperature, and then concentrated HCl was added dropwise to quench the mixture. NaCl was added to the solution, and the mixture was extracted with 85 / 15 = CHCl3 / i-PrOH solution. The combined organics were dried over Na2SO4, concentrated in vacuo, and purified by C18 column chromatography to give compound 18-2 (5.47 g, 38.21 mmol). MS [ESI]: m / z = 143.0, [M+H] + .

[0633] Step 2: Synthesis of (Z)-3-(2-(4,6-dimethylpyridin-3-yl)hydrazine)piperidin-2-one (Compound 18-4)

[0634] 4,6-Dimethylpyridin-3-amine (4.27 g, 34.93 mmol) was added to a round-bottom flask and dissolved in water. The mixture was cooled to -10°C and concentrated HCl (1.27 g, 34.93 mmol) was slowly added dropwise. A solution of 4,6-dimethylpyridin-3-amine diazonium (2.41 g, 34.93 mmol) dissolved in water (5 mL) was added to a round-bottom flask to form the diazonium salt 4,6-dimethylpyridin-3-amine diazonium (4.27 g, 34.93 mmol). Compound 18-2 (5.0 g, 34.93 mmol) was dissolved in water and cooled in an ice bath. The cooled solution was then added directly to the prepared diazonium salt mixture. The reaction mixture was stirred overnight. The reaction was neutralized with 2N NaOH aqueous solution, concentrated, and the crude product was purified by silica gel column chromatography to give compound 18-4 (1 g, 8.18 mmol). MS [ESI]: m / z = 232.1, [M + H] + .

[0635] Step 3: Synthesis of 2,4-dimethyl-5,7,8,9-tetrahydro-6H-pyrrolo[3,2-b:5,4-c']dipyridin-6-one (Compound 18-5)

[0636] Compound 18-4 (580 mg, 2.50 mmol) and polyphosphoric acid (4.79 g, 19.98 mmol) were placed in a dry, pressurized tubular reactor and heated at 145°C for 8 hours. The reaction mixture was then concentrated and neutralized with a 2N aqueous solution of NaOH. The crude product was purified by silica gel column chromatography to yield compound 18-5 (268 mg, 1.15 mmol). MS [ESI]: m / z = 215.1, [M+H] + .

[0637] Step 4: Synthesis of 2,4-dimethyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5,7,8,9-tetrahydro-6H-pyrrolo[3,2-b:5,4-c']dipyridin-6-one (Compound 18-6)

[0638] Compound 18-5 (250 mg, 1.16 mmol) was added to a round-bottom flask and dissolved in THF. NaH (27.87 mg, 1.16 mmol) was added and stirred at 0°C for half an hour. 2-(Chloromethoxy)ethyltrimethylsilane (290.45 mg, 1.74 mmol, 308.34 μL) was then added and stirred at 25°C for one hour. The mixture was quenched with ammonium chloride and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 18-6 (180 mg, 0.835 mmol). MS [ESI]: m / z = 345.1, [M+H] + .

[0639] Step 5: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5,7,8,9-tetrahydro-6H-pyrrolo[3,2-b:5,4-c']dipyridin-6-one (Compound 18-7)

[0640] Compound 18-6 (60 mg, 173.66 μmol) was added to a round-bottom flask, and solvent 1,4-dioxane, 4-iodopyridine (106.80 mg, 520.97 μmol), cuprous iodide (16.54 mg, 86.83 μmol), N, N'-dimethylethane-1,2-diamine (7.65 mg, 86.83 μmol, 9.35 μL), potassium carbonate (48.00 mg, 347.31 μmol, 20.96 μL) were added. The mixture was stirred at 110 ° C for 4 hours, and then celite was filtered. The mixture was purified by column chromatography and concentrated to give the title compound 18-7 (50 mg, 144.71 μmol). MS [ESI]: m / z = 422.2, [M + H] + .

[0641] Step 6: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-5,7,8,9-tetrahydro-6H-pyrrolo[3,2-b:5,4-c']dipyridin-6-one (Compound 147)

[0642] Compound 18-7 (50 mg, 118.32 μmol) was added to a round-bottom flask, followed by DCM:TFA (1:1, 213 μL). The reaction was stirred at room temperature for 7 hours and then concentrated in vacuo. The concentrated product was stirred in NH3 / MeOH in DCM (500 μL) at room temperature for 1 hour and then concentrated in vacuo. Prep-HPLC purification afforded the title compound 147 (25 mg, 59.16 μmol). MS [ESI]: m / z = 293.2, [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.57 (dd, J=4.8, 1.6Hz, 2H), 7.63 (dd, J=4.8, 1.6Hz, 2H ),7.11(s,1H),4.31(t,J=6.6Hz,2H),3.36(s,2H),2.64(s,3H),2.60(s,3H).

[0643] Example 19: Synthesis of 2,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 324)

[0644] Compound Int-2 (30 mg, 138.08 μmol) and 1,4-dioxane (1 mL) were added to the reaction, followed by 4-iodo-1-methyl-1H-pyrazole (43 mg, 207.12 μmol), cuprous iodide (2.6 mg, 13.81 μmol), dimethylethylenediamine (2.4 mg, 27.62 μmol), and potassium carbonate (38.2 mg, 165.69 μmol). After nitrogen substitution, the temperature was raised to 110°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. The title compound 324 (6.4 mg, 21.52 μmol) was obtained by Prep-HPLC purification. MS (ESI): m / z = 298.1, [M+H] + . 1H-NMR (400MHz, CDCl3) δ7.78(s,1H),7.41(s,1H),6.86(s,1H),4.91(d,J=15.2Hz,1H),4.78(d,J=11.6Hz,1H),4.52(d ,J=14.8Hz,1H),3.81(s,3H),3.76-3.60(m,2H),2.67(d,J=15.2Hz,1H),2.47(s,3H),2.21(s,3H),1.88-1.77(m,1H).

[0645] Example 20: Synthesis of 2,4-dimethyl-8-(pyridin-4-yl)-8,9,10,10-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 21)

[0646] Step 1: Synthesis of 2,4-dimethyl-8-(pyridin-4-yl)-8,9,10,10-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 21)

[0647] To a reaction flask, compound Int-2 (200 mg, 920.51 μmol) and 1,4-dioxane (5 mL) were added, followed by 4-iodopyridine (283.0 mg, 1.38 mmol), cuprous iodide (35.1 mg, 184.1 μmol), dimethylethylenediamine (36.5 mg, 411.2 μmol), and potassium carbonate (254.4 mg, 1.84 mmol). After nitrogen substitution, the temperature was raised to 110°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through Celite, washed with dichloromethane, and concentrated under reduced pressure. The title compound 21 (113 mg, 383.9 μmol) was obtained by preparative HPLC purification.

[0648] MS (ESI): m / z=295.1, [M+H]+. 1 H NMR (400MHz, CDCl3) δ8.44(d,J=5.2Hz,2H),7.42(d,J=5.2Hz,2H),6.87(s,1H),4.95(d,J=15.2Hz,1H),4.79(d,J=11.2 Hz,1H),4.53(d,J=15.2Hz,1H),4.04-3.65(m,2H),2.77(d,J=13.2Hz,1H),2.47(s,3H),2.22(s,3H),2.12-1.74(m,1H).

[0649] Step 2: Chiral isomer separation

[0650] Compound 21 (85 mg, 288.76 μmol) was separated using a ChiralGel DH 7 μm column and a mobile phase of n-hexane-anhydrous ethanol-triethylamine (85:15:1) to obtain compound 21a (30 mg) and compound 21b (25 mg). The retention time of compound 21a was 28.239 minutes, and the retention time of compound 21b was 43.468 minutes.

[0651] Example 21: Synthesis of 2,4-dimethyl-7-(2-(trifluoromethyl)pyridin-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 112)

[0652] Compound Int-1 (20 mg, 92.91 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 4-bromo-2-(trifluoromethyl)pyridine (21 mg, 92.91 μmol), anhydrous potassium carbonate (25.7 mg, 185.83 μmol), cuprous iodide (17.7 mg, 92.91 μmol), and DMEDA (16.4 mg, 185.83 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. LCMS analysis confirmed the reaction was complete, and the mixture was filtered through celite and concentrated to obtain the crude product, which was then purified by Prep-HPLC to yield the title compound 112 (7.8 mg, 21.65 μmol). MS (ESI): m / z = 361.3, [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.74(d,J=5.6Hz,1H),7.84(d,J=2.0Hz,1H),7.63(dd,J=5.6,2.0Hz,1H ),7.39(s,1H),6.89(s,1H),4.66-4.58(m,2H),4.34-4.25(m,2H),2.64(s,3H),2.57(s,3H).

[0653] Referring to the synthesis method of Example 21, the following compound can be synthesized:

[0654] Example 25: Synthesis of 2,4,10-trimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 326)

[0655] Step 1: Synthesis of (E)-ethyl 3-(3-cyano-4,6-dimethylpyridin-2-yl)acrylate (Compound 25-2)

[0656] To a round-bottom flask, add 2-chloro-4,6-dimethylnicotinonitrile (Int-2-1, 5 g, 30.01 mmol), 1,4-dioxane (50 mL), and water (5 mL). Then, add (Z)-(4-ethoxy-4-oxo-2-buten-2-yl)boronic acid pinacol ester (10.81 g, 45.02 mmol), potassium carbonate (8.3 g, 60.02 mmol), and Pd(dppf)2Cl2 (2.20 g, 3.00 mmol). After nitrogen replacement, heat to 110°C and stir for 12 hours. The reaction was complete after LCMS detection. The temperature was restored to room temperature and the mixture was concentrated under reduced pressure to remove 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound (4.1 g, 16.78 mmol) was purified by column chromatography. MS (ESI): m / z = 245.1, [M+H] + .

[0657] Step 2: Synthesis of 2-(2,4,7-trimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Compound 25-3)

[0658] Compound 25-2 (2 g, 8.19 mmol) and 20 mL of 5% aqueous sodium hydroxide solution were added to a round-bottom flask and reacted at 60°C for 4 hours. The temperature was then raised to 100°C and the reaction continued for another 4 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature. Acid was added to adjust the pH to 6-7 under an ice bath. Purification by C18 preparative purification afforded 25-3 (1.2 g, 5.12 mmol). MS (ESI): m / z = 235.1, [M+H] + .

[0659] Step 3: Synthesis of N-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-2-(2,4,7-trimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetamide (Compound 25-5)

[0660] Compound 25-3 (0.5 g, 2.13 mmol), DMF (5 mL), TCFH (1.2 g, 4.27 mmol), and N-methylimidazole (0.70 g, 8.54 mmol) were added to a round-bottom flask in sequence. After reacting at room temperature for 10 minutes, 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (0.69 g, 3.2 mmol) was added and the reaction was continued for 6 hours. LCMS detection showed that the reaction was complete. The target compound 25-5 (0.68 g, 1.57 mmol) was purified by reverse phase preparative chromatography. MS (ESI): m / z = 434.1, [M+H] + .

[0661] Step 4: Synthesis of 1-(2-(trifluoromethyl)pyridin-4-yl)-N-(2-(2,4,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)azetidine-3-amine (Compound 25-6)

[0662] Compound 25-5 (0.68 g, 1.57 mmol) and anhydrous tetrahydrofuran (5 mL) were added to a round-bottom flask. After nitrogen substitution three times, borane tetrahydrofuran complex (15.7 mmol) was slowly added under ice-cooling. After the addition was complete, the temperature was raised to 70°C and the reaction was continued for 24 hours. LCMS confirmed the reaction was complete and the mixture was returned to room temperature. Methanol (50 mL) was added under ice-cooling to quench the reaction. After gas evolution ceased, 4 M hydrochloric acid (10 mL) was added and the temperature was raised to 60°C with stirring overnight. The mixture was cooled to room temperature and under ice-cooling, and aqueous NaOH solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound 25-6 (0.35 g, 0.86 mmol) was obtained by C18 preparative purification. MS (ESI): m / z = 406.1, [M+H] + .

[0663] Step 5: Synthesis of 2,4,12,4,10-trimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyridino[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 326)

[0664] Compound 25-6 (0.1 g, 0.24 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (37.4 mg, 0.37 mmol), and N,N'-carbonyldiimidazole (47.9 mg, 0.29 mmol) were added to a round-bottom flask. After reacting at room temperature for half an hour, the temperature was raised to 70 ° C and the reaction was continued for 12 hours. LCMS detection showed that the reaction was complete. The temperature was returned to room temperature, concentrated under reduced pressure, and purified by Prep-HPLC to obtain the title compound (60 mg, 0.13 mmol).

[0665] MS (ESI): m / z = 432.1, [M+H] + , 1 H NMR (400MHz, CDCl3) δ8.24(d,J=5.6Hz,1H),6.82(s,1H),6.56(d,J=2.0Hz,1H),6.31(dd,J=5.6,2.0Hz,1H),5.49-5.24(m, 1H),4.84(d,J=15.2Hz,1H),4.42(d,J=15.2Hz,1H),4.28-4.03(m,3H),4.00-3.91(m,1H),3.67-3.60(m,1H),3.49-3.40(m 1H),2.46(s,3H),2.45-2.40(m,1H),2.20(s,3H),1.88-1.67(m,1H),1.40(s,3H).

[0666] Example 26: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-8,9-dihydrothieno[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound 154)

[0667] To a round-bottom flask, compound Int-3 (255 mg, 1.1 mmol) and 1,4-dioxane (20 mL) were added, followed by 4-iodopyridine (450 mg, 2.2 mmol), potassium carbonate (455 mg, 3.3 mmol), DMEDA (193 mg, 2.2 mmol), and cuprous iodide (110 mg, 0.55 mmol). After nitrogen replacement, the temperature was raised to 95°C and stirred for 16 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford the title compound (34 mg, 0.11 mmol).

[0668] MS (ESI): m / z = 310.1, [M+H] + . 1H NMR (400MHz, CDCl3) δ 8.65 (s, 2H), 7.51 (d, J = 5.2Hz, 2H), 7.12 (s, 1H), 4.27 (t, J = 6.8Hz, 2H), 3.45 (t, J = 6.8Hz, 2H), 2.70 (s, 3H), 2.59 (s, 3H).

[0669] Example 27: Synthesis of 2,4,9-trimethyl-7-(pyridin-4-yl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 327)

[0670] Step 1: Synthesis of ethyl 1-(1-((tert-Butoxycarbonyl)amino)propan-2-yl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 27-02)

[0671] Compound Int-1-2 (1.75 g, 8.02 mmol) was dissolved in 20 mL of DMF, and tert-butyl (2-bromopropyl)carbamate (27-01) (1.80 g, 8.02 mmol), cesium carbonate (7.84 g, 24.05 mmol), and potassium iodide (1.33 g, 8.02 mmol) were added sequentially. The mixed solution was heated to 80°C and stirred overnight, then cooled to room temperature. The solution was extracted three times with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 27-02 (1.26 g, 3.49 mmol). MS (ESI): m / z = 376.2, [M+H] + .

[0672] Step 2: Synthesis of 2,4,9-trimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 27-03)

[0673] First, compound 27-02 (1.26 g, 3.49 mmol) was dissolved in 20 mL of DCM and 4 mL of trifluoroacetic acid was added. The mixture was stirred at room temperature for 0.5 hours. LCMS showed that the reaction was complete and the mixture was concentrated under reduced pressure. The crude compound was dissolved in 20 mL of anhydrous methanol and anhydrous potassium carbonate (2.41 g, 17.43 mmol) was added. The mixture was stirred at room temperature for 8 hours, concentrated under reduced pressure, and purified by silica gel column chromatography to obtain compound 27-03 (500 mg, 2.32 mmol). MS (ESI): m / z = 230.1, [M+H] + .

[0674] Step 3: Synthesis of 2,4,9-trimethyl-7-(pyridin-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 327)

[0675] Compound 27-03 (20 mg, 87.23 μmol) was dissolved in 1 mL of dry 1,4-dioxane. 4-Iodopyridine (17.9 mg, 87.23 μmol), anhydrous potassium carbonate (24.1 mg, 174.46 μmol), cuprous iodide (16.6 mg, 87.23 μmol), and DMEDA (15.6 mg, 174.46 μmol) were added sequentially. The atmosphere was replaced with nitrogen and the mixture was heated to 110°C and stirred for 8 hours. The reaction was complete by LCMS, filtered through celite, and the filtrate was concentrated to obtain the crude product. This crude product was then purified by Prep-HPLC to yield the title compound 327 (7.8 mg, 19.17 μmol).

[0676] MS (ESI): m / z = 307.3, [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ8.62(d,J=6.4Hz,2H),7.58(dd,J=4.8,1.6Hz,2H),7.30(s,1H),6.95(s,1H ),4.74-4.62(m,1H),4.51(qd,J=13.2,3.2Hz,2H),2.55(s,3H),2.54(s,3H),1.26(d,J=6.4Hz,3H).

[0677] Example 29: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyridino[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 329)

[0678] Step 1: Synthesis of 5-chloro-2-hydroxy-4,6-dimethylnicotinonitrile (Compound 29-02)

[0679] To a round-bottom flask, 2-hydroxy-4,6-dimethylnicotinonitrile (6 g, 40.50 mmol) and acetonitrile (100 mL) were added, and chlorosulfonyl chloride (8.20 g, 60.74 mmol) was slowly added dropwise at 0°C. LCMS confirmed the reaction was complete, and water was added to quench the reaction. The pH was adjusted to 7-8, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to afford compound 29-02 (7 g, 38.33 mmol). MS (ESI): m / z = 183.1, [M+H]+ .

[0680] Step 2: Synthesis of 2-bromo-5-chloro-4,6-dimethylnicotinonitrile (Compound 29-03)

[0681] Compound 29-02 (7 g, 38.33 mmol) and toluene (100 mL) were added to a round-bottom flask. Phosphorus oxybromide (16.48 g, 57.50 mmol) was slowly added at room temperature, and the temperature was then raised to 110°C for 6 hours. LCMS confirmed the reaction was complete, and water was added to quench the reaction. The pH was adjusted to 7-8, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to afford compound 29-03 (7.5 g, 30.55 mmol). MS (ESI): m / z = 246.1, [M+H] + .

[0682] Step 3: Synthesis of (2-bromo-5-chloro-4,6-dimethylpyridin-3-yl)methylamine (Compound 29-04)

[0683] Compound 29-03 (7.5 g, 30.55 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a round-bottom flask. After nitrogen substitution three times, borane tetrahydrofuran complex (61.1 mmol) was slowly added under ice-bath. After the addition was complete, the temperature was raised to 70°C and the reaction was continued for 6 hours. LCMS confirmed the reaction was complete and the mixture was returned to room temperature. Methanol (50 mL) was added under ice-bath to quench the reaction. After no more gas was released, 4 M hydrochloric acid (30 mL) was added and the temperature was raised to 60°C for 6 hours. The mixture was cooled to room temperature and an aqueous NaOH solution was added under ice-bath to adjust the pH to 7-8. The mixture was extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product 29-04 (5 g, 20.04 mmol). MS (ESI): m / z = 250.1, [M+H] + .

[0684] Step 4: Synthesis of tert-butyl (2-bromo-5-chloro-6-methylpyridin-3-yl)methylcarbamate (Compound 29-05)

[0685] Compound 29-04 (5 g, 20.04 mmol), dichloromethane (50 mL), triethylamine (3.04 g, 30.06 mmol), and DMAP (489.5 mg, 4.01 mmol) were added to a round-bottom flask and reacted at room temperature for half an hour. Then, di-tert-butyl dicarbonate (5.25 g, 24.04 mmol) was added and the reaction continued for 2 hours. LCMS analysis confirmed the reaction was complete, and the mixture was concentrated under reduced pressure. The crude product was purified by column chromatography to give compound 29-05 (5.6 g, 16.69 mmol). MS (ESI): m / z = 350.1, [M+H]+ .

[0686] Step 5: Synthesis of (E)-ethyl 3-(3-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-4,6-dimethylpyridin-2-yl)acrylate (Compound 29-06)

[0687] To a round-bottom flask, compound 29-05 (4 g, 11.92 mmol), 1,4-dioxane (40 mL), and water (4 mL) were added, followed by (E)-2-(ethoxycarbonyl)vinylboronic acid pinacol ester (1.77 g, 17.88 mmol), potassium carbonate (3.29 g, 23.84 mmol), and Pd(dppf)2Cl2 (0.87 g, 1.19 mmol). After nitrogen replacement, the temperature was raised to 110°C and stirred for 12 hours. LCMS confirmed the reaction was complete. The mixture was returned to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography to yield the title compound 29-06 (2.8 g, 11.92 mmol). MS (ESI): m / z = 369.1, [M+H] + .

[0688] Step 6: Synthesis of 2-(6-(tert-butoxycarbonyl)-3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Compound 29-07)

[0689] Compound 29-06 (2.8 g, 11.92 mmol) and 30 mL of 5% aqueous sodium hydroxide solution were added to a round-bottom flask and reacted at 60°C for 4 hours. The temperature was then raised to 100°C and the reaction continued for another 4 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature. Acid was added to adjust the pH to 6-7 under an ice bath. Compound 29-07 (1.8 g, 5.28 mmol) was then purified by C18 reverse phase preparative purification. MS (ESI): m / z = 341.1, [M+H] + .

[0690] Step 7: Synthesis of tert-butyl 3-chloro-2,4-dimethyl-7-(2-oxo-2-((1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)amino)ethyl)-5,7-dihydro-6-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 29-08)

[0691] Compound 29-07 (1 g, 2.93 mmol), DMF (20 mL), TCFH (1.65 g, 5.87 mmol), and N-methylimidazole (0.96 g, 11.74 mmol) were added to a round-bottom flask in sequence. After reacting at room temperature for 10 minutes, 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (0.95 g, 4.40 mmol) was added and the reaction was continued for 6 hours. LCMS detection showed that the reaction was complete. The target compound 29-08 (1.2 g, 2.93 mmol) was obtained by reverse phase preparative purification. MS (ESI): m / z = 541.1, [M+H] + .

[0692] Step 8: Synthesis of 2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetamide (Compound 29-09)

[0693] Compound 29-08 (1.2 g, 2.93 mmol) and DCM (10 mL) were added to a round-bottom flask in sequence. 12 N hydrochloric acid solution was slowly added dropwise at room temperature and allowed to react for 4 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated and dried to give the crude product, compound 29-09 (0.7 g, 1.59 mmol). MS (ESI): m / z = 441.1, [M+H] + .

[0694] Step 9: Synthesis of N-(2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (Compound 29-10)

[0695] Compound 29-09 (0.7 g, 1.59 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a round-bottom flask. After nitrogen replacement, borane tetrahydrofuran complex (3.2 mmol) was slowly added under ice-bath. After the addition was complete, the temperature was raised to 70°C and the reaction was continued for 6 hours. LCMS confirmed the reaction was complete and the mixture was returned to room temperature. Methanol (5 mL) was added under ice-bath to quench the reaction. After no more gas was released, 4 M hydrochloric acid (2 mL) was added and the temperature was raised to 60°C for 2 hours. The mixture was cooled to room temperature and under ice-bath, a NaOH aqueous solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product compound 29-10 (0.42 g, 0.98 mmol). MS (ESI): m / z = 427.1, [M+H] + .

[0696] Step 10: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 329)

[0697] Compound 29-10 (0.1 g, 0.98 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (35.6 mg, 0.35 mmol), and N,N'-carbonyldiimidazole (45.6 mg, 0.28 mmol) were added to a round-bottom flask. After reacting at room temperature for half an hour, the temperature was raised to 70 ° C and the reaction was continued for 12 hours. LCMS detection showed that the reaction was complete. The temperature was returned to room temperature, concentrated under reduced pressure, and purified by Prep-HPLC to obtain the target compound (56 mg, 0.12 mmol).

[0698] MS (ESI): m / z = 452.1, [M+H] + , 1 H-NMR (400MHz, CDCl3) δ8.32(d,J=5.6Hz,1H),6.63(d,J=2.0Hz,1H),6.38(dd,J =5.6,2.0Hz,1H),5.51-5.33(m,1H),4.96(d,J=15.2Hz,1H),4.76(d,J=11.2Hz, 1H),4.55(d,J=15.2Hz,1H),4.30-4.20(m,3H),4.04(dd,J=8.4,5.6Hz,1H),3.6 6-3.51(m,2H),2.90-2.64(m,1H),2.64(s,3H),2.33(s,3H),1.74-1.69(m,1H).

[0699] Step 11: Chiral separation (Compound 329a and Compound 329b)

[0700] Compound 329 (873 mg, 1.93 mmol) synthesized by the above method was chirally resolved using the following method: at room temperature, compound 329 (873 mg, 1.93 mmol) was dissolved in the mobile phase at a sample concentration of 1 mg / ml and filtered through a 0.45 μm organic filter membrane; the chromatographic column model was Unichiral CNZ-5H, size: 20 mm ID × 250 mm L, the mobile phase was n-hexane-anhydrous ethanol (60:40), the column temperature was 30°C, the flow rate was 25 ml / min, and the detection wavelength was 254 nm. Compound 329a (451 mg, yield 52.8%, RT = 25.650 min, >99% ee.) and compound 329b (400 mg, yield 46.9%, RT = 28.303 min, >99% ee.) were obtained by chiral chromatographic column separation. The chiral analysis conditions were as follows: Daicel AD-H, n-hexane-anhydrous ethanol-triethylamine (85:15:1), column temperature 35°C, flow rate 1.0 mL, and detection wavelength 260 nm.

[0701] Compound 329a: MS (ESI): m / z = 452.1, [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.31(d,J=5.6Hz,1H),6.62(d,J=2.2Hz,1H),6.38(dd,J=5 .6,2.0Hz,1H),5.47-5.37(m,1H),4.96(d,J=15.2Hz,1H),4.79-4.73(m,1H),4.5 4(d,J=15.2Hz,1H),4.31-4.19(m,3H),4.06(dd,J=8.4,5.6Hz,1H),3.60(dd,J= 8.8,2.8Hz,2H),2.75-2.66(m,1H),2.64(s,3H),2.33(s,3H),1.78-1.64(m,1H).

[0702] Compound 329b: MS (ESI): m / z = 452.1, [M+H] + . 1H NMR (400MHz, CDCl3) δ8.32 (d, J=5.6Hz, 1H), 6.62 (d, J=2.0Hz, 1H), 6.39 (dd, J= 5.6,2.0Hz,1H),5.46-5.37(m,1H),4.96(d,J=15.2Hz,1H),4.76(d,J=11.2Hz,1 H),4.54(d,J=15.2Hz,1H),4.32-4.20(m,3H),4.06(dd,J=8.4,5.6Hz,1H),3.6 3-3.55(m,2H),2.75-2.67(m,1H),2.64(s,3H),2.33(s,3H),1.78-1.65(m,1H).

[0703] Example 30: Synthesis of 2-methyl-4-(trifluoromethyl)-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 330)

[0704] Step 1: Synthesis of (2-chloro-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methanamine (Compound 30-02)

[0705] Compound 30-01 (2 g, 9.07 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a round-bottom flask. After nitrogen substitution three times, borane tetrahydrofuran complex (19.95 mmol) was slowly added under ice-bath. After the addition was complete, the temperature was raised to 70°C and the reaction was continued for 6 hours. LCMS confirmed the reaction was complete and the mixture was returned to room temperature. Methanol (50 mL) was added under ice-bath to quench the reaction. After no more gas was released, 4 M hydrochloric acid (30 mL) was added and the temperature was raised to 60°C for 6 hours. The mixture was cooled to room temperature and an aqueous NaOH solution was added under ice-bath to adjust the pH to 7-8. The mixture was extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product compound 30-02 (1.4 g, 6.23 mmol). MS (ESI): m / z = 225.1, [M+H] + .

[0706] Step 2: Synthesis of tert-butyl (2-chloro-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methyl)carbamate (Compound 30-03)

[0707] Compound 30-02 (1.4 g, 6.23 mmol), dichloromethane (5 mL), triethylamine (0.94 g, 9.35 mmol), and DMAP (152.3 mg, 1.25 mmol) were added to a round-bottom flask and reacted at room temperature for half an hour. Di-tert-butyl dicarbonate (1.63 g, 7.48 mmol) was then added and the reaction continued for 2 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated under reduced pressure and purified by column chromatography to give compound 30-03 (1.2 g, 3.7 mmol). MS (ESI): m / z = 325.1, [M+H] + .

[0708] Step 3: Synthesis of (E)-ethyl 3-(3-(((tert-butoxycarbonyl)amino)methyl)-6-methyl-4-(trifluoromethyl)pyridin-2-yl)acrylate (Compound 30-04)

[0709] To a round-bottom flask were added compound 30-03 (1.2 g, 3.7 mmol), 1,4-dioxane (10 mL), and water (1 mL), followed by (E)-2-(ethoxycarbonyl)vinylboronic acid pinacol ester (0.54 g, 5.54 mmol), potassium carbonate (1.02 g, 7.39 mmol), and Pd(dppf)2Cl2 (0.27 g, 0.36 mmol). After nitrogen replacement, the temperature was raised to 110°C and stirred for 12 hours. LCMS analysis confirmed the completion of the reaction. The mixture was returned to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded compound 30-04 (0.8 g, 2.06 mmol). MS (ESI): m / z = 389.1, [M+H] + .

[0710] Step 4: Synthesis of 2-(6-(tert-butoxycarbonyl)-2-methyl-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Compound 30-05)

[0711] Compound 30-04 (0.8 g, 2.06 mmol) and 10 mL of 5% aqueous sodium hydroxide solution were added to a round-bottom flask and reacted at 60°C for 4 hours. The temperature was then raised to 100°C and the reaction continued for another 4 hours. LCMS confirmed the reaction was complete. The mixture was returned to room temperature and, under ice, acid was added to adjust the pH to 6-7. Compound 30-05 (0.6 g, 1.67 mmol) was purified by C18 reverse-phase flash chromatography. MS (ESI): m / z = 361.1, [M+H] + .

[0712] Step 5: Synthesis of tert-butyl 3-chloro-2,4-dimethyl-7-(2-oxo-2-((1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)amino)ethyl)-5,7-dihydro-6-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 30-06)

[0713] Compound 30-05 (0.6 g, 1.67 mmol), DMF (5 mL), TCFH (0.934 g, 3.33 mmol), and N-methylimidazole (0.54 g, 6.66 mmol) were added to a round-bottom flask in sequence. After reacting at room temperature for 10 minutes, 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (0.54 g, 2.5 mmol) was added and the reaction was continued for 6 hours. The reaction was complete after LCMS detection. Compound 30-06 (0.7 g, 1.25 mmol) was purified by reverse phase flash chromatography. MS (ESI): m / z = 560.3, [M+H] + .

[0714] Step 6: Synthesis of 2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)-N-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetamide (Compound 30-07)

[0715] Compound 30-06 (0.7 g, 1.25 mmol) and DCM (10 mL) were added to a round-bottom flask in sequence. 12 N hydrochloric acid solution was slowly added dropwise at room temperature and allowed to react for 4 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated and dried to give the crude product 30-07 (0.62 g, 1.35 mmol). MS (ESI): m / z = 460.3, [M+H] + .

[0716] Step 7: Synthesis of N-(2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (Compound 30-08)

[0717] Compound 30-07 (0.62 g, 1.35 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a round-bottom flask. After nitrogen substitution, borane tetrahydrofuran complex (3.2 mmol) was slowly added under ice-bath. After the addition was complete, the temperature was raised to 70°C and the reaction was continued for 6 hours. LCMS confirmed the reaction was complete and the mixture was returned to room temperature. Methanol (5 mL) was added under ice-bath to quench the reaction. After no more gas was released, 4 M hydrochloric acid (2 mL) was added and the temperature was raised to 60°C for 2 hours. The mixture was cooled to room temperature and under ice-bath, a NaOH aqueous solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product compound 30-08 (0.42 g, 0.94 mmol). MS (ESI): m / z = 446.1, [M+H] + .

[0718] Step 8: Synthesis of 2-methyl-4-(trifluoromethyl)-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 330)

[0719] Compound 30-08 (0.10 g, 0.22 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (34.08 mg, 0.33 mmol), and N,N'-carbonyldiimidazole (43.6 mg, 0.27 mmol) were added to a round-bottom flask. After reacting at room temperature for half an hour, the temperature was raised to 70°C and the reaction was continued for 12 hours. LCMS detection showed that the reaction was complete. The temperature was returned to room temperature and concentrated under reduced pressure. The target compound 330 (60 mg, 0.12 mmol) was obtained by prep-HPLC purification.

[0720] MS (ESI): m / z = 472.2, [M+H] + . 1 H-NMR (400MHz, CDCl3) δ8.32(d,J=5.6Hz,1H),7.31(s,1H),6.63(d,J=2.0Hz,1 H),6.40(dd,J=5.6,2.0Hz,1H),5.56-5.36(m,1H),5.19(d,J=16.0Hz,1H),4.81 (d,J=11.2Hz,1H),4.69(d,J=16.0Hz,1H),4.38-4.21(m,3H),4.09(dd,J=8.4,5 .6Hz,1H),3.66-3.62(m,2H),2.87-2.69(m,1H),2.66(s,3H)1.84-1.70(m,1H).

[0721] Example 31: Synthesis of 3-chloro-2,4-dimethyl-8-(2-(trifluoromethyl)pyridin-4-yl)-8,9,10,10-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 331)

[0722] Step 1: Synthesis of tert-butyl 3-chloro-7-(cyanomethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 31-01)

[0723] To a round-bottom flask, add tert-butyl (2-bromo-5-chloro-4,6-dimethylpyridin-3-yl)methylcarbamate (29-05) (1 g, 2.86 mmol) and 1,4-dioxane (10 mL). Then, add acrylonitrile (227.6 mg, 4.29 mmol), potassium acetate (561.4 mg, 5.72 mmol), palladium chloride (50.7 mg, 0.28 mmol), and BINAP (356.2 mg, 0.57 mmol). After nitrogen substitution, heat to 130°C and stir for 12 hours. The reaction was complete after LCMS detection. The temperature was restored to room temperature and the mixture was concentrated under reduced pressure to remove 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The target compound 31-01 (420 mg, 1.31 mmol) was purified by silica gel column chromatography. MS (ESI): m / z = 322.2, [M+H] + .

[0724] Step 2: Synthesis of tert-butyl 7-(2-aminoethyl)-3-chloro-2,4-dimethyl-5,7-dihydro-6-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 31-02)

[0725] Compound 31-01 (420 mg, 1.31 mmol), methanol (5 mL), and Raney nickel (42 mg) were added to a round-bottom flask. After hydrogen substitution, the temperature was raised to 60°C and stirred for 6 hours. LCMS confirmed the reaction was complete. The mixture was returned to room temperature, filtered, washed with methanol, and concentrated to dryness to obtain the crude product 31-02 (310 mg, 0.95 mmol). MS (ESI): m / z = 326.2, [M+H] + .

[0726] Step 3: Synthesis of 2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethan-1-amine (Compound 31-03)

[0727] Compound 31-02 (310 mg, 0.95 mmol) and DCM (5 mL) were added to a round-bottom flask. 12N hydrochloric acid solution (1 mL) was slowly added dropwise at room temperature and allowed to react for 2 hours. LCMS confirmed the reaction was complete. 2N sodium hydroxide solution was added to adjust the pH to 7-8, and the mixture was concentrated. The product was purified by C18 reverse phase preparative purification to afford compound 31-03 (150 mg, 0.66 mmol). MS (ESI): m / z = 226.2, [M+H]+.

[0728] Step 4: Synthesis of 3-chloro-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 31-04)

[0729] Compound 31-03 (150 mg, 0.66 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (100.9 mg, 0.99 mmol), and N,N'-carbonyldiimidazole (107.8 mg, 0.66 mmol) were added to a round-bottom flask. After reacting at room temperature for half an hour, the temperature was raised to 60 ° C and the reaction was continued for 6 hours. LCMS detection showed that the reaction was complete. The temperature was returned to room temperature and concentrated under reduced pressure. The product was purified by C18 reverse phase preparative purification to give compound 31-04 (108 mg, 0.42 mmol), MS (ESI): m / z = 252.2, [M+H] +.

[0730] Step 5: Synthesis of 3-chloro-2,4-dimethyl-8-(pyridin-4-yl)-8,9,10,10-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 331)

[0731] To a Schlenk flask, compound 31-04 (108 mg, 0.39 mmol) and 1,4-dioxane (2 mL) were added, followed by 4-iodopyridine (122.2 mg, 0.59 mmol), cuprous iodide (7.6 mg, 39.7 μmol), dimethylethylenediamine (7 mg, 79.46 μmol), and potassium carbonate (164.7 mg, 1.19 mmol). After nitrogen substitution, the temperature was raised to 110°C and stirred. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. The target compound 331 (40 mg, 0.12 mmol) was obtained by preparative HPLC purification.

[0732] MS (ESI): m / z=329.2, [M+H]+. 1H NMR (400MHz, CDCl3) δ8.53(s,2H),7.54(s,2H),5.05(d,J=15.2Hz,1H),4.87(d,J=11.6Hz,1H),4.63(d,J=15.2 Hz,1H),4.05-3.89(m,1H),3.89-3.76(m,1H),2.96-2.75(m,1H),2.65(s,3H),2.37(s,3H),1.99-1.83(m,1H).

[0733] Example 35: Synthesis of 7,9-dimethyl-2-(pyridin-4-yl)-3,4-dihydroimidazo[1,2-a:4,5-c']dipyridin-1(2H)-one (Compound 194)

[0734] Step 1: Synthesis of ethyl 6,8-dimethylimidazo[1,2-a]pyridine-2-carboxylate (Compound 35-03)

[0735] To a round-bottom flask were added compound 35-01 (5.0 g, 40.9 mmol), 35-02 (8.4 g, 42.2 mmol), 1,4-dioxane (100 mL), and sodium bicarbonate (6.9 g, 81.9 mmol). The temperature was raised to 100°C and stirring was continued for 16 hours. The reaction solution was cooled to room temperature and quenched with dilute hydrochloric acid. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to yield the title compound 35-03 (7.1 g, 32.3 mmol). MS (ESI): m / z = 219.1, [M+H] + .

[0736] Step 2: Synthesis of ethyl 3-bromo-6,8-dimethylimidazo[1,2-a]pyridine-2-carboxylate (Compound 35-04)

[0737] Compound 35-03 (7.1 g, 32.3 mmol) and DCM (100 mL) were added to a round-bottom flask. NBS (5.7 g, 32.2 mmol) was slowly added with stirring, and the reaction was continued at room temperature for 5 hours. LCMS confirmed the completion of the reaction, and water was added to quench the reaction. The organic phase was separated, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The organic phase was purified by column chromatography to obtain the title compound 35-04 (4.1 g, 13.6 mmol). MS (ESI): m / z = 297.1, [M+H] + .

[0738] Step 3: Synthesis of ethyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-6,8-dimethylimidazo[1,2-a]pyridine-2-carboxylate (Compound 35-05)

[0739] To a round-bottom flask were added compound 35-04 (1.5 g, 5.1 mmol), toluene (90 mL), and water (30 mL), followed by potassium (2-((tert-butoxycarbonyl)amino)ethyl)trifluoroborate (2.5 g, 10.2 mmol), cesium carbonate (4.9 g, 15.3 mmol), Ruphos (700 mg, 1.5 mmol), and Pd(OAc)2 (115 mg, 0.51 mmol). After nitrogen replacement, the temperature was raised to 80°C and stirred for 16 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature and concentrated under reduced pressure to remove toluene. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded the title compound 35-05 (202 mg, 0.56 mmol). MS (ESI): m / z = 365.1, [M+H] + .

[0740] Step 4: Synthesis of ethyl 3-(2-aminoethyl)-6,8-dimethylimidazo[1,2-a]pyridine-2-carboxylate (Compound 35-06)

[0741] Compound 35-05 (202 mg, 0.56 mmol) and dichloromethane / trifluoroacetic acid (10 mL, 4:1) were added to a round-bottom flask. The reaction was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and the reaction solution was concentrated under reduced pressure to give the title compound 35-06 (143 mg, 0.55 mmol). MS (ESI): m / z = 262.1, [M+H] + .

[0742] Step 5: Synthesis of 7,9-dimethyl-3,4-dihydroimidazo[1,2-a:4,5-c']dipyridin-1(2H)-one (Compound 35-07)

[0743] Compound 35-06 (143 mg, 0.55 mmol), anhydrous methanol (10 mL), and potassium carbonate (150 mg, 1.1 mmol) were added to a round-bottom flask. Stir at room temperature for 2 h. LCMS confirmed the reaction was complete, and saturated aqueous ammonium chloride was added to quench the reaction. The methanol was removed by concentration under reduced pressure, and the residue was added with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded the title compound 35-07 (105 mg, 0.49 mmol). MS (ESI): m / z = 216.1, [M+H] + .

[0744] Step 6: Synthesis of 7,9-dimethyl-2-(pyridin-4-yl)-3,4-dihydroimidazo[1,2-a:4,5-c']dipyridin-1(2H)-one (Compound 194)

[0745] To a round-bottom flask were added compound 35-07 (105 mg, 0.49 mmol) and 1,4-dioxane (20 mL), followed by 4-iodopyridine (230 mg, 101 mmol), potassium carbonate (230 mg, 1.5 mmol), DMEDA (100 mg, 1.1 mmol), and cuprous iodide (60 mg, 0.3 mmol). After nitrogen replacement, the temperature was raised to 95°C and stirred for 16 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Prep-HPLC afforded the title compound 194 (23 mg, 0.08 mmol). MS (ESI): m / z = 293.1, [M+H] + , 1 H NMR (400MHz, CD3OD) δ8.77(s,2H),8.10(s,1H),7.65(s,2H),7.12(s,1H),4.35(t,J=6.6Hz,2H),3.40(t,J=6.6Hz,2H),2.65(s,3H),2.35(s,3H).

[0746] Example 36: Synthesis of 2,4-dimethyl-8-((S)-tetrahydrofuran-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 335)

[0747] Step 1: Synthesis of 2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)-N-((S)-tetrahydrofuran-3-yl)acetamide (Compound 36-01)

[0748] Compound Int-2-3 (0.5 g, 2.27 mmol), DMF (10 mL), TCFH (1.27 g, 4.54 mmol), and N-methylimidazole (0.74 g, 9.08 mmol) were added to a round-bottom flask in sequence. The mixture was reacted at room temperature for 10 minutes. (S)-tetrahydrofuran-3-amine (0.29 g, 3.41 mmol) was then added to react for 2 hours. The reaction was complete as determined by LCMS. Compound 36-01 (0.48 g, 1.66 mmol) was obtained by reverse phase preparative purification. MS (ESI): m / z = 290.1, [M+H] +.

[0749] Step 2: Synthesis of (3S)-N-(2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)tetrahydrofuran-3-amine (Compound 36-02)

[0750] Compound 36-01 (0.48 g, 1.66 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a round-bottom flask. After nitrogen substitution, borane tetrahydrofuran complex (16.6 mmol) was slowly added under ice-bath. After addition, the temperature was raised to 70°C and the reaction was continued for 24 hours. LCMS analysis showed that the reaction was complete and the mixture was returned to room temperature. Methanol (20 mL) was added under ice-bath to quench the reaction. After gas evolution ceased, 4 M hydrochloric acid was added and the mixture was heated to 60°C and stirred overnight. The mixture was cooled to room temperature and under ice-bath, and aqueous NaOH solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 36-02 (0.31 g, 1.19 mmol) was obtained by reverse phase preparative purification. MS (ESI): m / z = 262.1, [M+H] + .

[0751] Step 3: Synthesis of 2,4-dimethyl-8-((S)-tetrahydrofuran-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 335)

[0752] Compound 36-02 (0.1 g, 0.38 mmol), anhydrous tetrahydrofuran (2 mL), triethylamine (58.07 mg, 0.57 mmol), and N,N'-carbonyldiimidazole (74 mg, 0.45 mmol) were added to a round-bottom flask. After reacting at room temperature for 2 hours, the temperature was raised to 70 ° C and the reaction was continued for 48 hours. LCMS detection showed that the reaction was complete. The temperature was returned to room temperature, concentrated under reduced pressure, and purified by reverse phase preparative method to obtain compound 335 (58 mg, 0.20 mmol).

[0753] MS (ESI): m / z = 288.2, [M+H] + . 1H-NMR (400MHz, CDCl3), δ6.89 (s, 1H), 5.43-5.15 (m, 1H), 4.95 (d, J = 15.2Hz ,1H),4.81-4.62(m,1H),4.51(d,J=15.2Hz,1H),4.08-4.02(m,1H),3.97-3. 62(m,1H),3.78-3.59(m,2H),3.52-3.36(m,2H),2.72-2.60(m,1H),2.52(s ,3H),2.40-2.28(m,1H),2.25(s,3H),2.25-2.01(m,1H),1.81-1.72(m,1H).

[0754] Referring to the synthesis method of Example 36, the following compound can be synthesized:

[0755] Example 37: Synthesis of 2,4-dimethyl-8-((R)-tetrahydrofuran-3-yl)-8,9,10,10a-tetrahydropyrimidin[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 336)

[0756] Step 1: Synthesis of tert-butyl 2,4-dimethyl-7-(2-oxo-2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 37-03)

[0757] Compound 37-01 (250.0 mg, 0.82 mmol), (3R)-tetrahydrofuran-3-amine (85.3 mg, 0.98 mmol), NMI (268.0 mg, 3.26 mmol), TCFH (457.9 mg, 1.63 mmol), and DMF (5 mL) were added to a round-bottom flask and stirred at room temperature for 2 hours. LCMS analysis indicated that the reaction was complete. Water was added to quench the reaction, followed by extraction with DCM and concentration under reduced pressure. The mixture was purified by silica gel column chromatography to afford compound 37-03 (245.6 mg, 0.65 mmol). MS [ESI]: m / z = 376.2, [M+H] + .

[0758] Step 2: Synthesis of tert-butyl 2,4-dimethyl-7-(2-(R)-tetrahydrofuran-3-yl)amino)ethyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 37-04)

[0759] Compound 37-03 (245.6 mg, 0.65 mmol), borane tetrahydrofuran complex (5 mL), and THF (5 ml) were added to a round-bottom flask and stirred at 60°C for 2 hours. LCMS confirmed the reaction was complete, and the mixture was quenched with water. The mixture was extracted with ethyl acetate and concentrated under reduced pressure. The crude product was used for the next reaction (205.3 mg, 0.57 mmol). MS [ESI]: m / z = 362.2, [M+H] + .

[0760] Step 3: Synthesis of (3R)-N-(2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)tetrahydrofuran-3-amine (Compound 37-05)

[0761] Compound 37-04 (205.3 mg, 0.57 mmol), 12N HCl (2 mL), and THF (5 mL) were added to a round-bottom flask and stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. Aqueous sodium hydroxide solution was added to adjust the pH to 7, and the mixture was extracted with dichloromethane and concentrated under reduced pressure. The crude product was used for the next reaction (142.4 mg, 0.54 mmol). MS [ESI]: m / z = 262.2, [M+H] + .

[0762] Step 4: Synthesis of 2,4-dimethyl-8-((R)-tetrahydrofuran-3-yl)-8,9,10,10a-tetrahydropyrimidin[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 336)

[0763] To a round-bottom flask, compound 37-05 (50.0 mg, 0.19 mmol), CDI (37.2 mg, 0.23 mmol), and TEA (19.4 mg, 0.19 mmol) were added and heated with stirring at 90°C overnight. The reaction was complete by LCMS, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford the title compound 336 (30.4 mg, 0.11 mmol).

[0764] MS (ESI): m / z = 288.2, [M+H] + . 1H NMR (400MHz, CDCl3) δ6.88 (s, 1H), 5.35-5.14 (m, 1H), 4.94 (d, J = 15.0Hz, 1H), 4. 75-4.63(m,1H),4.49(d,J=15.0Hz,1H),4.10-3.98(m,1H),393-3.78(m,1H),3. 76-3.56(m,2H),3.49-3.34(m,2H),2.69-2.55(m,1H),2.51(s,3H),2.41-2.26( m,0.5H),2.25(s,3H)2.21-1.98(m,1H),1.83-1.69(m,0.5H),1.70-1.53(m,1H).

[0765] Example 39: Synthesis of 7-(pyridin-4-yl)-2,4-bis(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 338)

[0766] Step 1: Synthesis of ethyl 4,6-bis(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 39-01)

[0767] To a round-bottom flask, compound Int-1-1 (500 mg, 3.24 mmol), anhydrous ethanol (2 mL), 1,1,1,5,5,5-hexafluoropentane-2,4-dione (1.35 g, 6.49 mmol, 918.08 μL), and 12N HCl (1 mL) were added. The temperature was raised to 80°C and stirring was continued for 16 hours. The reaction mixture was cooled to room temperature and quenched with saturated brine. The mixture was extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound 39-01 (350 mg, 1.07 mmol) was purified by column chromatography. MS (ESI): m / z = 327.0, [M+H]+.

[0768] Step 2: Synthesis of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4,6-bis(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 39-02)

[0769] To a round-bottom flask, compound 39-01 (300 mg, 919.70 μmol) was added, along with DMF, potassium iodide (152.67 mg, 919.70 μmol, 48.93 μL), and cesium carbonate (599.31 mg, 1.84 mmol). The mixture was heated to 80°C and stirred for 3 hours. The reaction mixture was cooled to room temperature and quenched with saturated brine. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded the title compound 39-02 (280 mg, 596.54 μmol). MS (ESI): m / z = 470.1, [M+H]+.

[0770] Step 3: Synthesis of 1-(2-aminoethyl)-4,6-bis(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid ethyl ester (Compound 39-03)

[0771] Compound 39-02 (280 mg, 596.54 μmol) and dichloromethane / trifluoroacetic acid (10 mL, 4:1) were added to a round-bottom flask. The mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and the reaction solution was concentrated under reduced pressure to yield crude compound 39-03 (273 mg, 739.31 μmol). MS (ESI): m / z = 370.0, [M+H]+.

[0772] Step 4: Synthesis of 2,4-bis(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 39-04)

[0773] To a round-bottom flask, crude compound 39-03 (270 mg, 731.19 μmol), anhydrous methanol (10 mL), and potassium carbonate (707.38 mg, 5.12 mmol) were added. Stir at room temperature for 3 hours. LCMS confirmed the reaction was complete. The product was quenched with saturated aqueous ammonium chloride and concentrated under reduced pressure to remove the methanol. The residue was added with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded the title compound 39-04 (200 mg, 618.82 μmol). MS (ESI): m / z = 324.0, [M+H]+.

[0774] Step 5: Synthesis of 7-(pyridin-4-yl)-2,4-bis(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 338)

[0775] To a round-bottom flask, compound 39-04 (20 mg, 61.88 μmol) and 1,4-dioxane (1 mL) were added, followed by 4-iodopyridine (25.4 mg, 123.76 μmol), potassium carbonate (17.1 mg, 123.76 μmol, 7.47 μL), DMEDA (16.4 mg, 185.65 μmol), and cuprous iodide (11.8 mg, 61.88 μmol). After nitrogen purging, the temperature was raised to 95°C and stirred for 16 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water was added, and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Prep-HPLC afforded the title compound 338 (13 mg, 32.48 μmol).

[0776] MS (ESI): m / z = 401.0, [M+H] + . 1 H NMR(400MHz,CD3OD)δ8.60(d,J=5.4Hz,2H),7.88(s,1H),7.65(dd,J=4.8,1.4Hz, 2H),7.49-7.41(m,1H),4.76(dd,J=6.6,4.9Hz,2H),4.46(dd,J=6.6,4.9Hz,2H).

[0777] Example 44: Synthesis of 7-cyclopropyl-2,4-dimethyl-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 342)

[0778] Step 1: Synthesis of ethyl 1-(2-bromoethyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 44-02)

[0779] Compound Int-1-2 (100 mg, 458.19 μmmol) was dissolved in 2 mL of DMF. Sodium hydride (32 mg, 1.37 mmol) was added under ice-cooling. After stirring for 20 minutes, 1,2-dibromoethane (103 mg, 549.83 μmol) was added. The mixture was moved to an 80°C oil bath and heated for 12 hours. LCMS confirmed the reaction was complete, and the mixture was quenched with water. The mixture was purified on a silica gel column to give compound 44-02 (66 mg, 202.95 μmol). MS (ESI): m / z = 325.1, [M+H] + .

[0780] Step 2: Synthesis of 7-cyclopropyl-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 342)

[0781] Compound 44-02 (66 mg, 202.95 μmol) was dissolved in 2 mL of acetonitrile. Anhydrous potassium carbonate (70 mg, 507.38 μmol) and cyclopropylamine (58 mg, 1.01 mmol) were added sequentially. The mixture was heated to 60°C and allowed to react for 18 hours. LCMS confirmed the reaction was complete. The target compound 342 (10.8 mg, 42.30 μmol) was purified by Prep-HLPC.

[0782] MS (ESI): m / z 256.1, [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.20(s,1H),6.81(s,1H),4.37(dd,J=6.6,5.0Hz,2H),3.78(dd,J=6.6,5 .0Hz,2H),2.89-2.81(m,1H),2.60(s,3H),2.52(s,3H),1.00-0.93(m,2H),0.83-0.74(m,2H).

[0783] Example 46: Synthesis of 7-(bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 344)

[0784] Step 1: Synthesis of 4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Compound 46-01)

[0785] Ethyl 4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (120 mg, 549.83 μmol) was added to a 25 mL reaction flask, followed by 3 mL of anhydrous ethanol and stirred at room temperature. Sodium hydroxide (55 mg, 1.38 mmol) was weighed and dissolved in 1 mL of water. The solution was slowly added dropwise to the reaction flask, and the substrate gradually dissolved. Stirring was maintained at room temperature for 3 hours. The reaction was monitored for completion by TLC. The pH was adjusted to approximately 6 with 1N HCl, and the mixture was extracted with ethyl acetate and concentrated to yield 104 mg of the crude product.

[0786] Step 2: Synthesis of N-(bicyclo[1.1.1]pentan-1-yl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (Compound 46-03)

[0787] 4,6-Dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (104 mg, 546.80 μmol) was dissolved in DMF (3 mL), and HATU (208 mg, 546.80 μmol) and DIPEA (66.4 mg, 656.16 μmol) were added. The mixture was stirred at room temperature for 10 minutes, and then bicyclo[1.1.1]pentan-1-amine hydrochloride (78.5 mg, 656.16 μmol) was added. The mixture was stirred at room temperature for 3 hours. LC-MS monitoring confirmed the complete reaction of the starting material. After concentration to remove DMF, the mixture was extracted with ethyl acetate. The organic phase was concentrated and purified by C18 reverse phase column chromatography to give compound 46-03 (29 mg, 113.6 μmol). MS (ESI): m / z = 256.1, [M+H + ].

[0788] Step 3: Synthesis of 7-(bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 344)

[0789] In a 50 mL reaction vial, compound 46-03 (26 mg, 101.84 μmol) was dissolved in DMF (2 mL) and reacted with NaH (4.5 mg, 112.02 μmol) at 0°C for 30 minutes. 1,2-Dibromoethane (21.0 mg, 112.02 μmol) was then added to the reaction vial and allowed to react at room temperature for 2 hours. LC-MS analysis revealed a small amount of product, with significant residual starting material. The reaction was stirred at room temperature overnight, and NaH (4.5 mg, 112.02 μmol) was added. The reaction was continued at 80°C for 16 hours, with an increase in product. Continued heating showed no significant change in the product. The DMF was removed by concentration, and the organic phase was extracted with ethyl acetate. The crude product was concentrated and separated by Prep-HPLC to yield compound 344 (2.2 mg, 7.82 μmol).

[0790] MS (ESI): m / z = 282.1, [M+H + ], 1 H NMR (400MHz, CDCl3) δ7.16(s,1H),6.82(s,1H),4.43-4.38(m,2H),3.76-3.68(m,2H),2.61(s,3H),2.53(s,3H),2.28(s,6H),2.01(d,J=1.2Hz,1H).

[0791] Example 49: Synthesis of 2-(2,4-dimethyl-6-oxo-8,9-dihydropyridin-3',2':4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide (Compound 347)

[0792] Step 1: Synthesis of 2-bromo-N-(1-methyl-1H-pyrazol-4-yl)acetamide (Compound 49-03)

[0793] Compound 49-01 (1 g, 7.49 mmol) was dissolved in 10 mL of DCM, and triethylamine (833.3 mg, 8.23 ​​mmol) and compound 49-02 (1.18 g, 7.49 mmol) were added. The mixture was stirred at room temperature under nitrogen for 2 hours. The reaction was monitored for completion by LC-MS. Compound 49-03 (530 mg, 2.43 mmol) was purified by silica gel column chromatography. MS (ESI): m / z = 218.1, [M+H] + .

[0794] Step 2: Synthesis of 2-(2,4-dimethyl-6-oxo-8,9-dihydropyridin-3', 2': 4,5]pyrrolo[1,2-a]pyrazin-7(6H)-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide (Compound 347)

[0795] Compound Int-1 (20 mg, 92.91 μmol) was dissolved in 1 mL of DMF. NaH (7 mg, 278.74 mmol) was added at 0°C and stirred at room temperature for 0.5 hours. Compound 49-03 (20.3 mg, 92.91 μmol) was then added and stirred at room temperature for 8 hours. The reaction was complete as monitored by LC-MS. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried and concentrated to afford the crude product, which was then purified by Prep-HPLC to afford compound 347 (9.1 mg, 25.82 μmol).

[0796] MS (ESI): m / z = 353.1, [M+H] + . 1 H NMR(400MHz, CDCl3)δ8.60(s,1H),7.85(s,1H),7.42(s,1H),7.23(s,1H),6.83(s,1H), 4.57(s,2H),4.35(s,2H),3.97(t,J=5.6Hz,2H),3.84(s,3H),2.64(s,3H),2.53(s,3H).

[0797] Example 50: Synthesis of 2,4-dimethyl-7-(2,2,2-trifluoroethyl)-8,9-dihydrothieno[3,2-b:5,4-']dipyridin-6(7H)-one (Compound 348)

[0798] To a round-bottom flask, 2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound Int-3) (100 mg, 0.43 mmol), DMF (2 mL), and NaH (20 mg, 0.52 mmol) were added and stirred in an ice bath for 10 minutes. 2,2,2-Trifluoroethyl trifluoromethanesulfonate (100 mg, 0.43 mmol) was then slowly added dropwise, the mixture was allowed to cool to room temperature, and stirring was continued for 2 hours. LCMS indicated the disappearance of the substrate and the reaction was complete. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Prep-HPLC afforded the title compound 348 (27 mg, 0.086 mmol).

[0799] MS (ESI): m / z = 315.2, [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.30 (s, 1H), 4.35 (q, J = 9.2Hz, 2H), 3.98 (t, J = 6.8Hz, 2H), 3.31 (d, J = 6.8Hz, 2H), 2.69 (s, 3H), 2.62 (s, 3H).

[0800] Referring to the synthesis method of Example 50, the following compound can be synthesized:

[0801] Example 53: Synthesis of 2,4-dimethyl-7-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9-dihydrothieno[3,2-b:5,4-c′]bispyridin-6(7H)-one (Compound 156)

[0802] To a round-bottom flask was added intermediate Int-4 (100 mg, 0.35 mmol), 4-bromo-2-(trifluoromethyl)pyridine (78 mg, 0.35 mmol), NMP (2 mL), and cesium fluoride (105 mg, 0.7 mmol). The mixture was heated to 90°C and stirred for 2 hours. LCMS confirmed the reaction was complete, and the mixture was quenched by addition of saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Prep-HPLC afforded the title compound (42 mg, 0.097 mmol).

[0803] MS (ESI): m / z = 432.2, [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.28(d,J=5.8Hz,1H),7.27(s,1H),6.81(d,J=2.2Hz,1H),6.62(dd,J=5.8,2.2Hz,1H),5.55-5.37(m,1 H), 4.34 (t, J = 8.8Hz, 2H), 4.23 (dd, J = 9.4, 5.6Hz, 2H), 3.90 (t, J = 6.8Hz, 2H), 3.19 (t, J = 6.8Hz, 2H), 2.59 (s, 3H), 2.53 (s, 3H).

[0804] Example 54: Synthesis of 7-(1-(1,3,4-thiadiazol-2-yl)azetidin-3-yl)-2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c′]dipyridin-6(7H)-one (Compound 351)

[0805] To a round-bottom flask were added intermediate Int-4 (315 mg, 1.1 mmol) and 1,4-dioxane (20 mL), followed by 2-bromo-1,3,4-thiadiazole (358 mg, 2.2 mmol), potassium carbonate (455 mg, 3.3 mmol), DMEDA (193 mg, 2.2 mmol), and cuprous iodide (110 mg, 0.55 mmol). After nitrogen purging, the temperature was raised to 95°C and stirred for 16 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature and concentrated under reduced pressure to remove the 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to afford the title compound 351 (5.2 mg, 0.014 mmol).

[0806] MS (ESI): m / z = 372.2, [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.62(s,1H),7.16(s,1H),5.45-5.35(m,1H),4.44-4.31(m,4H),3.90(t,J=6.8Hz,2H),3.24(s,2H),2.56(s,3H),2.49(s,3H).

[0807] Example 55: Synthesis of 7-(2,3-dihydro-1H-inden-2-yl)-2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c′]dipyridin-6(7H)-one (Compound 352)

[0808] Step 1: Synthesis of methyl 3-(2-((2,3-dihydro-1H-inden-2-yl)amino)ethyl)-5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound 55-01)

[0809] To a round-bottom flask was added compound Int-3-6 (337 mg, 1.28 mmol), 2-indanone (253 mg, 1.92 mmol), sodium triacetoxyborohydride (852 mg, 3.84 mmol), and dichloromethane (10 mL). The mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and the mixture was quenched with saturated aqueous ammonium chloride. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound 55-01 (145 mg, 0.38 mmol) was purified by silica gel column chromatography. MS (ESI): m / z = 380.2, [M+H] + .

[0810] Step 2: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-8,9-dihydrothieno[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound 352)

[0811] To a round-bottom flask was added compound 55-01 (145 mg, 0.38 mmol), potassium carbonate (212 mg, 1.54 mmol), and methanol (10 ml). The mixture was stirred at room temperature for 2 hours. The reaction was complete by LCMS, filtered, and purified by Prep-HPLC to afford the title compound 352 (17 mg, 0.049 mmol).

[0812] MS (ESI): m / z = 349.3, [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.17-7.13(m,3H),7.09-7.07(m,2H),5.52-5.45(m,1H),3.55( t,J=6.8Hz,2H),3.18(d,J=8.4Hz,2H),3.11-3.01(m,4H),2.54(s,3H),2.48(s,3H).

[0813] Example 56: Synthesis of 2,4-dimethyl-7-(1-(pyrimidin-5-yl)azetidin-3-yl)-8,9-dihydrothieno[3,2-b:5,4-c′]dipyridin-6(7H)-one (Compound 353)

[0814] To a round-bottom flask were added intermediate Int-4 (100 mg, 0.35 mmol) and 1,4-dioxane (10 mL), followed by 5-bromopyrimidine (110 mg, 0.7 mmol), cesium carbonate (341 mg, 1.05 mmol), Ruphos (32 mg, 0.07 mmol), and Ruphos Pd G3 (31 mg, 0.035 mmol). After nitrogen replacement, the temperature was raised to 95°C and stirred for 5 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature and concentrated under reduced pressure to remove the 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by Prep-HPLC afforded the title compound 353 (5.2 mg, 0.014 mmol).

[0815] MS (ESI): m / z = 366.2, [M+H] + . 1 H NMR (400MHz, CD3OD) δ8.54(s,1H),8.11(s,2H),7.24(s,1H),5.50(tt,J=7.8,5.6Hz,1H),4.39(t,J=8.2Hz ,2H),4.24(dd,J=8.4,5.6Hz,2H),4.02(t,J=6.8Hz,2H),3.32(d,J=2.2Hz,2H),2.65(s,3H),2.58(s,3H).

[0816] Referring to the synthesis method of Example 56, the following compound can be synthesized:

[0817] Example 60: Synthesis of 3-chloro-8-(3,3-difluorocyclobutyl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 357)

[0818] Step 1: Synthesis of (2,5-dichloro-4,6-dimethylpyridin-3-yl)methylamine (Compound 60-02)

[0819] Compound 2,5-dichloro-4,6-dimethylnicotinonitrile (7.5 g, 30.55 mmol) and anhydrous tetrahydrofuran (50 mL) were added to a round-bottom flask. After nitrogen replacement three times, borane tetrahydrofuran complex (61.1 mmol) was slowly added under ice bath. After the addition was completed, the temperature was raised to 70°C and the reaction was continued for 6 hours. The reaction was complete after LCMS detection, and the temperature was returned to room temperature. Methanol (50 mL) was added under ice bath to quench the reaction. After no more gas was released, 4 M hydrochloric acid (30 mL) was added, and the temperature was raised to 60° C. for 6 hours. The mixture was cooled to room temperature and adjusted to pH 7-8 under ice bath by adding aqueous NaOH. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product (2,5-dichloro-4,6-dimethylpyridin-3-yl)methanamine 60-02 (5 g, 20.04 mmol). MS (ESI): m / z=205.1, [M+H] + .

[0820] Step 2: Synthesis of tert-butyl (2,5-dichloro-4,6-dimethylpyridin-3-yl)methyl)carbamate (Compound 60-03)

[0821] To a round-bottom flask, add (2,5-dichloro-4,6-dimethylpyridin-3-yl)methanamine (5 g, 20.04 mmol), dichloromethane (50 mL), triethylamine (3.04 g, 30.06 mmol), and DMAP (489.5 mg, 4.01 mmol). After reacting at room temperature for half an hour, add di-tert-butyl dicarbonate (5.25 g, 24.04 mmol) and continue the reaction for 2 hours. LCMS analysis showed that the reaction was complete, and the product was concentrated under reduced pressure and purified by column chromatography to give compound 60-03 (5.6 g, 16.69 mmol). MS (ESI): m / z = 305.1, [M+H] + .

[0822] Step 3: Synthesis of (E)-ethyl 3-(3-(((tert-Butoxycarbonyl)amino)methyl)-5-chloro-4,6-dimethylpyridin-2-yl)acrylate (Compound 60-05)

[0823] To a round-bottom flask, compound 60-03 (4 g, 11.92 mmol), 1,4-dioxane (40 mL), and water (4 mL) were added, followed by (E)-2-(ethoxycarbonyl)vinylboronic acid pinacol ester (1.77 g, 17.88 mmol), potassium carbonate (3.29 g, 23.84 mmol), and Pd(dppf)2Cl2 (0.87 g, 1.19 mmol). After nitrogen replacement, the temperature was raised to 110°C and stirred for 12 hours. LCMS confirmed the reaction was complete. The mixture was returned to room temperature and concentrated under reduced pressure to remove 1,4-dioxane. Water was added and the mixture was extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded compound 60-05 (2.8 g, 11.92 mmol). MS (ESI): m / z = 369.1, [M+H] + .

[0824] Step 4: Synthesis of 2-(6-(tert-butoxycarbonyl)-3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Compound 60-06)

[0825] Compound 60-05 (2.8 g, 11.92 mmol) and 30 mL of 5% aqueous sodium hydroxide solution were added to a round-bottom flask and reacted at 60°C for 4 hours. The temperature was then raised to 100°C and the reaction continued for another 4 hours. LCMS confirmed the reaction was complete. The mixture was returned to room temperature and, under ice, acid was added to adjust the pH to 6-7. Compound 60-06 (1.8 g, 5.28 mmol) was purified by C18 reverse-phase flash chromatography. MS (ESI): m / z = 341.1, [M+H] + .

[0826] Step 5: Synthesis of tert-butyl 3-chloro-7-(2-((3,3-difluorocyclobutyl)amino)-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 60-08)

[0827] Compound 60-06 (1 g, 2.93 mmol), DMF (20 mL), TCFH (1.65 g, 5.87 mmol), and N-methylimidazole (0.96 g, 11.74 mmol) were added to a round-bottom flask in sequence. After reacting at room temperature for 10 minutes, 3,3-difluorocyclobutane-1-amine (0.95 g, 4.40 mmol) was added and the reaction was continued for 6 hours. The reaction was complete after LCMS detection. The product was purified by C18 reverse phase flash chromatography to give 60-08 (1.2 g, 2.93 mmol). MS (ESI): m / z = 430.1, [M+H] + .

[0828] Step 6: Synthesis of tert-butyl 3-chloro-7-(2-((3,3-difluorocyclobutyl)amino)ethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 60-09)

[0829] Compound 60-08 (0.7 g, 1.59 mmol) and anhydrous tetrahydrofuran (10 mL) were added to a round-bottom flask. After nitrogen substitution three times, borane tetrahydrofuran complex (3.2 mmol) was slowly added under ice-cooling. After addition, the temperature was raised to 70°C and the reaction was continued for 6 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature. Methanol (5 mL) was added under ice-cooling to quench the reaction. After gas evolution ceased, Pd / C was added, and the temperature was raised to 60°C with stirring for 2 hours. Filtering and concentration under reduced pressure gave the crude product 60-09 (0.42 g, 0.98 mmol). MS (ESI): m / z = 316.1, [M+H] + .

[0830] Step 7: Synthesis of N-(2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)-3,3-difluorocyclobutane-1-amine (Compound 60-10)

[0831] Compound 60-09 (1.2 g, 2.93 mmol) and DCM (10 mL) were added to a round-bottom flask in sequence. 12 N hydrochloric acid solution was slowly added dropwise at room temperature and allowed to react for 4 hours. LCMS confirmed the reaction was complete. NaOH aqueous solution was added to adjust the pH to 7-8. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate and concentrated to dryness to afford the crude product, compound 60-10 (0.7 g, 1.59 mmol). MS (ESI): m / z = 330.1, [M+H] + .

[0832] Step 8: Synthesis of 3-chloro-8-(3,3-difluorocyclobutyl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 357)

[0833] Compound 60-10 (0.1 g, 0.98 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (35.6 mg, 0.35 mmol), and N,N'-carbonyldiimidazole (45.6 mg, 0.28 mmol) were added to a round-bottom flask. After reacting at room temperature for half an hour, the temperature was raised to 70°C and the reaction was continued for 12 hours. LCMS detection showed that the reaction was complete. The temperature was returned to room temperature, concentrated under reduced pressure, and purified by Prep-HPLC to obtain the target compound 357 (56 mg, 0.12 mmol).

[0834] MS (ESI): m / z = 342.1, [M+H] + . 1 H NMR(400MHz, CDCl3) δ4.93(d,J=15.2Hz,1H),4.81-4.67(m,2H),4.52(d,J=15.2Hz,1H ),3.48-3.34(m,2H),2.93-2.64(m,5H),2.62(s,3H),2.31(s,3H),1.70-1.59(m,1H).

[0835] Referring to the synthesis method of Example 60, the following compound can be synthesized:

[0836] Example 65: Synthesis of 7-((1H-pyrazol-4-yl)methyl)-2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c′]dipyridin-6(7H)-one (Compound 362)

[0837] Step 1: Synthesis of methyl (1H-pyrazol-4-yl) trifluoromethanesulfonate (Compound 65-02)

[0838] Compound 65-01 (1.0 g, 10.2 mmol), dichloromethane (100 mL), and triethylamine (2.1 g, 20.4 mmol) were added to a round-bottom flask and placed in an ice-water bath. Trifluoromethanesulfonic anhydride (2.8 g, 10.2 mmol) was slowly added dropwise with stirring. The mixture was returned to room temperature and stirred for 2 hours. LCMS indicated the reaction was complete. The reaction solution was quenched with saturated brine, the organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography afforded the title compound 65-02 (1.4 g, 6.3 mmol). MS (ESI): m / z = 230.2, [M+H] + .

[0839] Step 2: Synthesis of 7-((1H-pyrazol-4-yl)methyl)-2,4-dimethyl-8,9-dihydrothiophene[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound 362)

[0840] Compound Int-3 (100 mg, 0.43 mmol), DMF (2 mL), and NaH (20 mg, 0.52 mmol) were added to a round-bottom flask and stirred in an ice bath for 10 minutes. Methyl (1H-pyrazol-4-yl)trifluoromethanesulfonate (99 mg, 0.43 mmol) was then slowly added dropwise, the mixture was returned to room temperature, and stirring was continued for 2 hours. LCMS showed that the substrate disappeared and the reaction was complete. The mixture was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound 362 (16 mg, 0.051 mmol) was purified by Prep-HPLC. MS (ESI): m / z = 312.2, [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ12.73(s,1H),7.61(s,2H),7.24(s,1H),4.57(s,2H),3.67(t,J=7.2Hz,2H),3.10(t,J=7.2Hz,2H),2.57(s,3H),2.52(s,3H).

[0841] Example 66: Synthesis of 2,4-dimethyl-7-(2-methylpyridin-4-yl)-5-(trifluoromethyl)-8,9-dihydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 363)

[0842] Step 1: Synthesis of 5-iodo-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 66-01)

[0843] Compound Int-1 (100 mg, 464 μmol) was dissolved in 2 mL of ACN, and NIS (105 mg, 464 μmol) was added. The mixture was stirred at room temperature for 3 hours. LC-MS confirmed the reaction was complete, and silica gel column purification afforded compound 66-01 (140 mg, 41 μmol). MS (ESI): m / z = 342.1, [M+H] + .

[0844] Step 2: Synthesis of 2,4-dimethyl-5-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 66-02)

[0845] Compound 66-01 (140 mg, 410 μmol) was dissolved in 2 mL of DMF, and methyl fluorosulfonyldifluoroacetate (158 mg, 820 μmol) and cuprous iodide (235 mg, 1.23 mmol) were added sequentially. The mixture was heated to 80°C under nitrogen atmosphere for 10 hours. LC-MS analysis confirmed the reaction was complete, and silica gel column purification afforded compound 66-02 (58 mg, 205 μmol). MS (ESI): m / z = 284.1, [M+H] + .

[0846] Step 3: Synthesis of 2,4-dimethyl-7-(2-methylpyridin-4-yl)-5-(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (363)

[0847] Compound 66-02 (58 mg, 205 μmol) was dissolved in 1 mL of dry 1,4-dioxane, and 4-bromo-2-methylpyridine (53 mg, 307 μmol), anhydrous potassium carbonate (57 mg, 409 μmol), cuprous iodide (39 mg, 205 μmol), and DMEDA (36 mg, 409 μmol) were added sequentially. The atmosphere was replaced with nitrogen, and the temperature was raised to 110°C and stirred for 8 hours. LCMS analysis showed that the reaction was complete, and the product was filtered through celite and purified by column chromatography to give compound 363 (13.8 mg, 36.86 μmol). MS (ESI): m / z = 375.3, [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.54(d,J=5.6Hz,1H),7.38(s,1H),7.22(d,J=4.2Hz,1H),6.98(s,1 H),4.69-4.57(m,2H),4.30-4.20(m,2H),2.65(d,J=2.2Hz,3H),2.63(s,3H),2.60(s,3H).

[0848] Example 67: Synthesis of 2,4-dimethyl-8-(1-(2-methylpyridin-4-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 11)

[0849] To a Schlenk flask, compound Int-5 (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL) were added, followed by 4-bromo-2-methylpyridine (37.9 mg, 220.3 μmol), Ruphos Pd G3 (14.78 mg, 18.36 μmol), Ruphos (25.7 mg, 55.08 μmol), and cesium carbonate (179.45 mg, 550.76 μmol). After nitrogen replacement, the temperature was raised to 90°C and stirred for 12 hours. LCMS analysis confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 11 (22.3 mg, 60.53 μmol) was obtained by preparative HPLC purification.

[0850] MS (ESI): m / z = 364.2, [M+H] + . 1 H-NMR (400MHz, CDCl3) δ8.14(d,J=6.4Hz,1H),6.92(s,1H),6.23(dd,J=6.4,2.4Hz,1H ),6.14(d,J=2.4Hz,1H),5.42-5.22(m,1H),4.92(d,J=15.2Hz,1H),4.76(d,J=9.6Hz, 1H),4.52(d,J=15.2Hz,1H),4.41-4.27(m,3H),4.18(dd,J=9.6,5.6Hz,1H),3.76-3.4 7(m,2H),2.79-2.67(m,1H),2.57(s,3H),2.53(s,3H),2.26(s,3H),1.79-1.66(m,1H).

[0851] Referring to the synthesis method of Example 67, the following compound can be synthesized:

[0852] Example 69: Synthesis of 2,4-dimethyl-8-(1-(3-methyl-1,2,4-thiadiazol-5-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 365)

[0853] To a sealed tube, compound Int-5 (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL) were added, followed by 5-chloro-3-methyl-1,2,4-thiadiazole (29.6 mg, 220.3 μmol), cesium fluoride (33.5 mg, 220.3 μmol), and triethylamine (28 mg, 220.3 μmol). The temperature was raised to 90°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 365 (27.2 mg, 72.88 μmol) was obtained by preparative HPLC purification.

[0854] MS (ESI): m / z = 371.2, [M+H] + . 1 H NMR (400MHz, CDCl3) δ6.92(s,1H),5.61-5.43(m,1H),4.93(d,J=15.2Hz,1H),4.78(d,J=11.2Hz,1H),4.52(d,J=15.2Hz,1H),4.43-4.30( m,3H),4.19(dd,J=9.2,5.6Hz,1H),3.70-3.53(m,2H),2.76(d,J=12.0Hz,1H),2.53(s,3H),2.43(s,3H),2.26(s,3H),1.81-1.63(m,1H).

[0855] Referring to the synthesis method of Example 69, the following compound can be synthesized:

[0856] Example 75: Synthesis of 8-(1-(2-cyclopropyl-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 371)

[0857] Step 1: Synthesis of 8-(1-(2-chloro-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 75-01)

[0858] Compound Int-5 (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL) were added to a sealed tube, followed by 2,4-dichloro-5-fluoropyrimidine (36 mg, 220.3 μmol), cesium fluoride (33.5 mg, 220.3 μmol), and triethylamine (28 mg, 220.3 μmol). The temperature was raised to 90°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Purification was performed on a silica gel column to obtain compound 75-01 (62 mg, 153.90 μmol). MS (ESI): m / z = 403.1, [M+H] + .

[0859] Step 2: Synthesis of 8-(1-(2-cyclopropyl-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 371)

[0860] To a Schlenk flask, compound 75-01 (62 mg, 153.90 μmol), 1,4-dioxane (2 mL), and water (0.2 mL) were added, followed by cyclopropylboronic acid (19.2 mg, 223.4 μmol), Pd(dppf)2Cl2 (12.2 mg, 14.89 μmol), and potassium carbonate (61.8 mg, 446.81 μmol). After nitrogen substitution, the temperature was raised to 90°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through Celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 371 (35.2 mg, 85.68 μmol) was obtained by preparative HPLC.

[0861] MS (ESI): m / z = 409.1, [M+H] + . 1H NMR(400MHz,DMSO-d6)δ8.02(d,J=4.4Hz 1H),7.01(s,1H),5.27-5.16(m,1H),4.85-4.67(m,2H),4.48-4.17(m,5H),3.58(dd,J=8.8,2.8Hz,2H) ,2.53-2.52(m,1H),2.43(s,3H),2.23(s,3H),1.99-1.93(m,1H),1.63-1.48(m,1H),0.93-0.81(m,4H).

[0862] Chiral separation:

[0863] Compound 371 (580 mg) was separated by chiral chromatography to obtain compound 371a (264.9 mg) and compound 371b (262.9 mg). The separation conditions were: the chromatographic column model was UniChiral YMC-CMD-5H, and the mobile phase was n-hexane-anhydrous ethanol (60:40).

[0864] Compound 371a: retention time RT = 14.409 min, LC-MS: m / z = 409.2 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ8.02(d,J=4.4Hz,1H),7.01(s,1H),5.24-5.18(m,1H),4.76(d,J=15.2Hz,1H),4.71(d,J=12.0Hz,1H),4.42-4.30(m,4H),4 .25(d,J=6.0Hz,1H),3.61-3.54(m,2H),2.52(d,J=4.0Hz,1H),2.43(s,3 H),2.23(s,3H),1.98-1.92(m,1H),1.62-1.54(m,1H),0.89-0.84(m,4H).

[0865] Compound 371b: retention time RT = 16.052 min, LC-MS: m / z = 409.2 [M+H] + , 1H NMR (400MHz, DMSO-d6) δ8.02(d,J=4.4Hz,1H),7.01(s,1H),5.24-5.18(m,1H),4.76(d,J=15.2Hz,1H),4.71(d,J=12.0Hz,1H),4.42-4.30(m,4H),4 .25(d,J=6.0Hz,1H),3.61-3.54(m,2H),2.52(d,J=4.0Hz,1H),2.43(s,3 H),2.23(s,3H),1.98-1.92(m,1H),1.62-1.54(m,1H),0.89-0.84(m,4H).

[0866] Example 86: Synthesis of 8-(1-(2-(ethylamino)pyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 380) and 8-(1-(2-dimethylaminopyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2,3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 381)

[0867] Step 1: 8-(1-(2-chloropyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one

[0868] To a sealed tube, add 2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL), followed by 2,4-dichloropyrimidine (32.8 mg, 220.3 μmol), cesium fluoride (33.5 mg, 220.3 μmol), and triethylamine (28 mg, 220.3 μmol). The temperature was raised to 90°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 86-01 (42 mg, 109.13 μmol) was obtained by reverse phase preparative purification. MS (ESI): m / z = 385.1, [M+H] + .

[0869] Step 2: Synthesis of 8-(1-(2-(ethylamino)pyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 380) and 8-(1-(2-dimethylaminopyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 381)

[0870] Compound 86-01 (42 mg, 109.13 μmol) and N,N-dimethylacetamide (2 mL) were added to a microwave tube, followed by ethylamine (5.9 mg, 130.9 μmol), cesium fluoride (19.9 mg, 130.9 μmol), and triethylamine (13.2 mg, 130.9 μmol). Microwave conditions were set at 130°C and 400 W for 3 hours. The reaction was complete by LCMS. The mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give Compound 380 (8.1 mg, 20.33 μmol) and Compound 381 (12.2 mg, 31.0 μmol).

[0871] Compound 380: MS (ESI): m / z = 394.2, [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ7.78(d,J=5.6Hz,1H),7.01(s,1H),6.53(t,J=5.6Hz,1H),5.6 3(d,J=5.6Hz,1H),5.25-5.09(m,1H),4.85-4.66(m,2H),4.39(d,J=14.8Hz,1H),4.15 -4.04(m,3H),3.96(dd,J=9.0,5.6Hz,1H),3.62-3.49(m,2H),3.22(q,J=7.2Hz,2H),2 .54-2.52(m,1H),2.43(s,3H),2.23(s,3H),1.59-1.55(m,1H),1.06(t,J=7.2Hz,3H).

[0872] Compound 381: MS (ESI): m / z = 394.2, [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.85(d,J=5.6Hz,1H),7.01(s,1H),5.65(d,J=5.6Hz,1 H),5.26-5.12(m,1H),4.76(d,J=15.2Hz,1H),4.71(d,J=11.2Hz,1H),4.39(d,J =15.2Hz,1H),4.19-4.07(m,3H),3.98(dd,J=9.2,5.6Hz,1H),3.62-3.46(m,2H ),3.04(s,6H),2.54-2.52(m,1H),2.43(s,3H),2.23(s,3H),1.65-1.50(m,1H).

[0873] Example 87: Synthesis of 8-(1-(2-fluoropyridin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 13)

[0874] Step 1: Synthesis of 8-(1-(2-fluoropyridin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 13)

[0875] To a Schlenk flask, compound Int-5 (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL) were added, followed by 2-fluoro-4-iodopyridine (49.13 mg, 220.3 μmol), Ruphos Pd G3 (14.78 mg, 18.36 μmol), Ruphos (25.7 mg, 55.08 μmol), and cesium carbonate (179.45 mg, 550.76 μmol). After nitrogen substitution, the temperature was raised to 90°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 13 (27.2 mg, 74.03 μmol) was obtained by preparative HPLC purification.

[0876] MS (ESI): m / z = 368.2, [M+H] + . 1H NMR(400MHz,DMSO-d6)δ7.78(d,J=5.6Hz,1H),7.01(s,1H),6.32(dt,J=5.6,2.0 Hz,1H),6.01(d,J=2.0Hz,1H),5.27-5.18(m,1H),4.77(d,J=15.2Hz,1H),4.72(d ,J=11.6Hz,1H),4.40(d,J=15.2Hz,1H),4.19-4.10(m,3H),4.04-3.95(m,1H),3. 59-3.47(m,2H),2.55-2.52(m,1H),2.43(s,3H),2.23(s,3H),1.65-1.49(m,1H).

[0877] Step 2: Chiral separation

[0878] Compound 13 (3.0 g, 8.16 mmol) was separated by chromatography on a CHIRALPAK AS (30*250 mm 5 μm) (Daicel) column with a mobile phase of carbon dioxide:methanol (65:35) to obtain compound 13a (1.1 g) and compound 13b (1.1 g). The retention time of compound 13a was 31.618 minutes, and the retention time of compound 13b was 41.429 minutes.

[0879] Compound 13a: MS [ESI]: m / z = 368.2, [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.78 (d, J=5.6Hz, 1H), 6.88 (s, 1H), 6.10 (dt, J=5.6, 1.6Hz, 1H),5.75(d,J=1.6Hz,1H),5.36(d,J=5.6Hz,1H),4.88(d,J=15.2Hz,1H),4.71(s, 1H),4.46(d,J=15.2Hz,1H),4.21-4.04(m,3H),3.91(dd,J=8.4,5.6Hz,1H),3.59- 3.50(m,2H),2.74(d,J=11.2Hz,1H),2.49(s,3H),2.21(s,3H),1.72-1.57(m,1H).

[0880] Compound 13b: MS [ESI]: m / z = 368.2, [M+H] + . 1H NMR (400MHz, CDCl3) δ7.85 (d, J = 5.8Hz, 1H), 6.95 (s, 1H), 6.21-6.16 (m, 1H), 5.8 2(d,J=2.0Hz,1H),5.46-5.35(m,1H),4.95(d,J=15.2,1H),4.81(d,J=11.2Hz,1H ),4.53(d,J=15.2Hz,1H),4.26-4.13(m,3H),3.99(dd,J=8.4,5.6Hz,1H),3.68-3 .55(m,2H),2.83(d,J=12.0Hz,1H),2.57(s,3H),2.27(s,3H),1.78-1.58(m,1H).

[0881] Example 89: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 383)

[0882] Step 1: Synthesis of tert-butyl 7-(2-((1-((benzyloxy)carbonyl)azetidin-3-yl)amino)-2-oxoethyl)-3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 89-01)

[0883] Compound 29-07 (3.0 g, 8.8 mmol), benzyl 3-aminoheterocyclobutane-1-carboxylate (2.2 g, 10.56 mmol), NMI (2.9 g, 35.29 mmol), TCFH (4.94 g, 17.61 mmol), and DMF (25 mL) were added to a round-bottom flask and stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete, and water was added to quench the reaction. The mixture was extracted with DCM and concentrated under reduced pressure. Purification by column chromatography afforded compound 89-01 (3.6 g, 6.80 mmol). MS [ESI]: m / z = 529.2, [M+H] + .

[0884] Step 2: Synthesis of tert-butyl 7-(2-((1-((benzyloxy)carbonyl)azetidin-3-yl)amino)ethyl)-3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 89-02)

[0885] Compound 89-01 (3.6 g, 6.80 mmol), borane tetrahydrofuran complex (25 mL), and THF (25 ml) were added to a round-bottom flask and stirred at 60°C for 2 hours. LCMS confirmed the reaction was complete, and methanol was added to quench the reaction. The reaction was concentrated under reduced pressure, and the crude product was used for the next reaction (3.3 g, 6.41 mmol). MS [ESI]: m / z = 515.2, [M+H] + .

[0886] Step 3 Synthesis of benzyl ((2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)amino)azetidine-1-carboxylate (Compound 89-03)

[0887] To a round-bottom flask, crude compound 89-02 (3.6 g, 6.80 mmol) and HCl / 1,4-dioxane (10 mL) were added and stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. Aqueous sodium hydroxide solution was added to adjust the pH to 7, and the mixture was extracted with dichloromethane and concentrated under reduced pressure. The crude product was then used for the next reaction (2.74 g, 6.6 mmol). MS [ESI]: m / z = 415.2, [M+H] + .

[0888] Step 4: Synthesis of 3-(3-chloro-2,4-dimethyl-7-oxo-5,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-8(7H)-yl)azetidine-1-carboxylate (Compound 89-04)

[0889] To a round-bottom flask, crude compound 89-03 (2.74 g, 6.6 mmol), TEA (0.79 g, 7.81 mmol), and CDI (0.94 g, 6.51 mmol) were added and heated at 90°C with stirring overnight. LCMS confirmed the reaction was complete, and the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound 89-04 (2.4 g, 5.44 mmol). MS [ESI]: m / z = 441.2, [M+H] + .

[0890] Step 5: Synthesis of 3-(3-chloro-2,4-dimethyl-7-oxo-5,9,10,10a-tetrahydropyridin-2',3':3,4]pyrrolo[1,2-c]pyrimidin-8(7H)-yl)azetidin-1-amine (Compound 89-05)

[0891] Compound 89-04 (2.4 g, 5.44 mmol), MeOH (20 mL), and palladium hydroxide on carbon (480 mg, 20 wt%) were added to a round-bottom flask and stirred overnight at room temperature under a H2 atmosphere. LCMS confirmed the reaction was complete, and the mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to afford compound 89-05 (0.81 g, 2.61 mmol). MS [ESI]: m / z = 307.2, [M+H] + .

[0892] Step 6: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2,2,2-trifluoroethyl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 383)

[0893] Compound 89-05 (25.0 mg, 0.082 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (28.4 mg, 0.12 mmol), and DMF (3 mL) were added to a round-bottom flask and stirred overnight at room temperature. LCMS confirmed the reaction was complete, and the title compound was purified by Prep-HPLC to yield the title compound (15.2 mg, 0.038 mmol). MS [ESI]: m / z = 389.1, [M+H] + . 1 H NMR (400MHz, CDCl3) δ4.94-4.85(m,2H),4.71(dd,J=11.2,2.0Hz,1H),4.50(d,J=15.2Hz,1H),3.84-3.67(m,2H),3.61-3.56(m,1H ),3.54-3.44(m,2H),3.38(t,J=7.2Hz,1H),3.04(q,J=9.2Hz,2H),2.68-2.64(m,1H),2.62(s,3H),2.31(s,3H),1.71-1.61(m,1H).

[0894] Example 90: Synthesis of 3-chloro-2,4-dimethyl-8-(1-methylazetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 384)

[0895] Compound 89-05 (25.0 mg, 0.082 mmol), DCM (3 mL), aqueous formaldehyde (6.8 mg, 0.12 mmol), and sodium borohydride (34.54 mg, 0.016 mmol) were added to a round-bottom flask and stirred overnight at room temperature. LCMS confirmed the reaction was complete, and pre-HPLC purification afforded compound 384 (10.5 mg, 0.038 mmol). MS [ESI]: m / z = 321.1, [M+H] + . 1 H NMR (400MHz, CDCl3) δ4.92(d,J=15.2Hz,1H),4.76-4.60(m,4H),4.53(d,J=15.2Hz,1H),4.29(s,1H),3.57(td,J=12.0, 3.6Hz, 1H), 3.33 (dd, J = 11.2, 4.4Hz, 1H), 3.03 (s, 3H), 2.62 (s, 3H), 2.32 (s, 3H), 2.28-1.96 (m, 2H), 1.76-1.64 (m, 1H).

[0896] Example 91: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)-8,9,10,10a-tetrahydropyridino[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 385)

[0897] Step 1: Synthesis of tert-butyl (1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)carbamate (Compound 91-02)

[0898] To a round-bottom flask were added tert-butylpyrrolidin-3-ylcarbamate (1.0 g, 5.37 mmol), 4-chloro-2-(trifluoromethyl)pyridine (1.17 g, 6.44 mmol), potassium carbonate (1.48 g, 10.74 mmol), Ruphos Pd G3 (449.2 mg, 0.54 mmol), and dioxane (10 ml). The mixture was stirred at 90°C overnight under nitrogen. LCMS confirmed the reaction was complete, and the reaction was quenched with water. The mixture was extracted with DCM and concentrated under reduced pressure. Compound 91-02 (1.52 g, 4.59 mmol) was purified by column chromatography. MS [ESI]: m / z = 332.2, [M+H] + .

[0899] Step 2: Synthesis of 1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-amine (Compound 91-03)

[0900] Compound 91-02 (1.52 g, 4.59 mmol), HCl (2 ml), and DCM / MeOH (10:1, 10 ml) were added to a round-bottom flask and stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. Aqueous sodium hydroxide solution was added to adjust the pH to 7, and the mixture was extracted with dichloromethane and concentrated under reduced pressure. The crude product was used for the next reaction (1.0 g, 4.32 mmol). MS [ESI]: m / z = 232.2, [M+H] + .

[0901] Step 3: Synthesis of tert-butyl 3-chloro-2,4-dimethyl-7-(2-oxo-2-(((1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)amino)ethyl)-5,7-dihydro-6H-pyrrolyl[3,4-b]pyridine-6-carboxylate (Compound 91-04)

[0902] To a round-bottom flask was added crude compound 91-03 (325.6 mg, 1.41 mmol), 2-(6-(tert-butoxycarbonyl)-3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (400.0 mg, 1.17 mmol), NMI (385.5 mg, 4.69 mmol), TCFH (658.6 mg, 2.35 mmol), and DMF (10 ml). The mixture was stirred at room temperature for 2 hours. LCMS analysis indicated that the reaction was complete. Water was added to quench the reaction, followed by extraction with DCM and concentration under reduced pressure. The mixture was purified by column chromatography to afford compound 91-04 (452.4 mg, 0.82 mmol). MS [ESI]: m / z = 553.2, [M+H] + .

[0903] Step 4: Synthesis of tert-butyl 3-chloro-2,4-dimethyl-7-(2-((1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)amino)ethyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 91-05)

[0904] Compound 91-04 (452.4 mg, 0.82 mmol), borane tetrahydrofuran complex (5 ml), and THF (5 ml) were added to a round-bottom flask and stirred at 60°C for 2 hours. LCMS confirmed the reaction was complete, and the mixture was quenched with water. The mixture was extracted with ethyl acetate and concentrated under reduced pressure. The crude product was used for the next reaction (421.5 mg, 0.78 mmol). MS [ESI]: m / z = 540.2, [M+H] + .

[0905] Step 5: Synthesis of N-(2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)-1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-amine (Compound 91-06)

[0906] To a round-bottom flask, crude compound 91-05 (421.5 mg, 0.78 mmol), HCl (2 ml), and THF (5 ml) were added and stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. Aqueous sodium hydroxide solution was added to adjust the pH to 7, and the mixture was extracted with dichloromethane and concentrated under reduced pressure. The crude product was then used for the next reaction (323.2 mg, 0.73 mmol). MS [ESI]: m / z = 240.2, [M+H] + .

[0907] Step 6: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-yl)-8,9,10,10a-tetrahydropyridin[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 385)

[0908] To a round-bottom flask, crude compound 91-06 (50.0 mg, 0.11 mmol), CDI (18.4 mg, 0.11 mmol), and TEA (13.8 mg, 0.14 mmol) were added and heated at 90°C with stirring overnight. LCMS confirmed the reaction was complete, and the mixture was filtered, concentrated under reduced pressure, and purified by Prep-HPLC to afford compound 385 (23.2 mg, 0.049 mmol). MS [ESI]: m / z = 466.2, [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.29 (t, J=5.6Hz, 1H), 6.74 (dd, J=7.2, 2.4Hz, 1H), 6.5 2-6.33(m,1H),5.37-5.14(m,1H),5.04-4.89(m,1H),4.81-4.66(m,1H),4.5 4(d,J=15.2Hz,1H),3.68-3.50(m,2H),3.50-3.15(m,4H),2.66(dd,J=13.6, 3.0Hz,1H),2.62(s,3H),2.32(s,3H),2.31-2.11(m,2H),1.73-1.57(m,1H).

[0909] Example 93: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 63)

[0910] Step 1: Synthesis of tert-butyl 7-(2-hydroxyethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 93-1)

[0911] To a three-necked flask, add Int-8 (4.0 g, 13.1 mmol) and tetrahydrofuran (20 ml). The atmosphere was replaced with nitrogen, and the temperature was lowered to subzero. Lithium aluminum tetrahydride (600 mg, 15.7 mmol) was added, and the reaction mixture was slowly allowed to warm to room temperature and stirred for 1 hour. TLC (n-heptane:ethyl acetate = 3:1) confirmed the reaction was complete. The reaction mixture was temperature-controlled, and water and 15% aqueous sodium hydroxide solution were slowly added dropwise. 10 g of anhydrous sodium sulfate was added, stirred, filtered, and the filtrate was concentrated under reduced pressure to yield the title compound 93-1 (3.8 g, 12.8 mmol). MS [ESI]: m / z = 293.2 [M+H] + .

[0912] Step 2: Synthesis of 2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethanol-1-ol (Compound 93-2)

[0913] Compound 93-1 (3.8 g, 12.8 mmol) and dioxane hydrochloride solution (4.0 M, 15 mL) were added to a 100 mL single-necked bottle and stirred at 25°C. The reaction was complete as determined by LCMS and concentrated under reduced pressure to give the title compound 93-2 (2.4 g, crude product). MS [ESI]: m / z = 193.2 [M+H] + .

[0914] Step 3: Synthesis of 1-(7-(2-hydroxyethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 93-3)

[0915] To a 100 mL single-necked flask was added 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetic acid (3.7 g, 13.7 mmol), (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.7 g, 15.0 mmol), N,N-diisopropylethylamine (4.8 g, 37.8 mmol), and dichloromethane (20 mL). The mixture was stirred at 25°C for 1 hour, and compound 93-2 (2.4 g, 12.7 mmol) was added. The reaction was complete as determined by LCMS, and the reaction was quenched by addition of saturated sodium chloride solution. The mixture was extracted, concentrated under reduced pressure, and purified by normal phase column chromatography to give the title compound 93-3 (2.5 g, 5.8 mmol). MS [ESI]: m / z = 435.2 [M+H] + .

[0916] Step 4: Synthesis of 1-(7-(2-iodoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 93-4)

[0917] Imidazole (0.78 g, 11.5 mmol), triphenylphosphine (3.0 g, 11.5 mmol), iodine (2.19 g, 8.6 mmol), and dichloromethane (20 ml) were added to a single-necked flask and reacted at 25°C for 30 minutes. Compound 93-3 was then added and reacted at 25°C for 15 hours. The mixture was quenched by adding saturated sodium sulfite solution, extracted, concentrated under reduced pressure, and purified by normal phase column chromatography to obtain the title compound 93-4 (1.5 g, 2.8 mmol). MS [ESI]: m / z = 545.2 [M+H] + .

[0918] Step 5: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 63)

[0919] Compound 93-4 (0.15 g, 0.27 mmol) and tetrahydrofuran (10 mL) were added to a three-necked flask and replaced with nitrogen three times. Potassium tert-butoxide tetrahydrofuran solution (1 M, 0.81 mmol, 0.82 mL) was added dropwise under ice bath. The reaction was carried out at 25 °C for 2 hours. LCMS showed that the reaction was complete. The reaction was quenched by adding saturated sodium chloride solution, extracted, concentrated under reduced pressure, and purified by Prep-HPLC to give the title compound 63 (50.2 mg, 0.12 mmol).

[0920] MS [ESI]: m / z = 417.2 [M+H] + . 1H NMR (400MHz, CDCl3) δ8.21(dd,J=5.6,2.8Hz,1H),6.85(d,J=5.2Hz,1H),6.52(dd,J =6.0,2.4Hz,1H),6.39-6.10(m,1H),5.12-4.82(m,1H),4.78-4.58(m,1H),4.48-4.2 8(m,1H),4.27-4.17(m,1H),4.16-3.82(m,2H),3.81-3.68(m,1H),3.20-2.92(m,1H) ,2.72-2.52(m,2H),2.47(s,3H),2.20(s,3H),2.20-2.08(m,1H),1.60-1.39(m,2H).

[0921] Compound 63 was chirally separated using a Unichiral CNZ-5H column with n-hexane-anhydrous ethanol (50:50) as the mobile phase to obtain compound 63a (7.6 mg, RT = 40.76 min), compound 63b (10 mg, RT = 52.71 min), compound 63c (8.5 mg, RT = 29.71 min), and compound 63d (9.4 mg, RT = 33.09 min).

[0922] Compound 63a

[0923] 1 H NMR (400MHz, CD3OD) δ8.05 (d, J=5.6Hz, 1H), 6.98 (s, 1H), 6.67 (s, 1H), 6.46 (d, J= 5.6Hz,1H),4.90(d,J=15.6Hz,1H),4.75-4.70(m,1H),4.33(d,J=15.6Hz,1H),4. 21-4.17(m,1H),4.13-4.10(m,2H),3.93-3.89(m,1H),3.20-3.08(m,1H),2.73-2 .66(m,1H),2.60-2.53(m,1H),2.41(s,3H),2.30-2.15(m,4H),1.67-1.46(m,2H)

[0924] Compound 63b

[0925] 11H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.00 (s, 1H), 6.68 (s, 1H), 6.46 (s, 1H), 4.90 (d, J = 15.6 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.44 (d, J = 15.2 Hz, 1H), 4.26 - 4.14 (m, 2H), 3.92 - 3.84 (m, 2H), 3.05 - 2.95 (m, 1H), 2.82 - 2.79 (m, 1H), 2.48 - 2.42 (m, 4H), 2.30 - 2.08 (m, 4H), 1.59 - 1.35 (m, 2H).

[0926] Compound 63c

[0927] 1 1H NMR (400 MHz, CD3OD) δ 8.05 (d, J = 5.6 Hz, 1H), 6.97 (s, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.43 (d, J = 5.6, 2.0 Hz, 1H), 4.90 (d, J = 15.6 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.33 (d, J = 15.6 Hz, 1H), 4.18 - 4.14 (m, 1H), 4.11 - 4.05 (m, 2H), 3.89 - 3.85 (m, 1H), 3.21 - 3.07 (m, 1H), 2.72 - 2.66 (m, 1H), 2.60 - 2.56 (m, 1H), 2.41 (s, 3H), 2.30 - 2.05 (m, 4H), 1.67 - 1.46 (m, 2H).

[0928] Compound 63d

[0929] 1 1H NMR (400 MHz, CD3OD) δ 8.04 (d, J = 5.6 Hz, 1H), 6.99 (s, 1H), 6.65 (d, J = 2.0 Hz, 1H), 6.44 (d, J = 5.6, 2.0 Hz, 1H), 4.90 (d, J = 15.2 Hz, 1H), 4.75 - 4.70 (m, 1H), 4.44 (d, J = 15.2 Hz, 1H), 4.25 (t, J = 8.4 Hz, 1H), 4.13 (t, J = 8.4 Hz, 1H), 3.92 - 3.88 (m, 1H), 3.84 - 3.80 (m, 1H), 3.05 - 2.95 (m, 1H), 2.84 - 2.77 (m, 1H), 2.52 - 2.47 (m, 1H), 2.42 (s, 3H), 2.23 - 2.15 (m, 4H), 1.56 - 1.41 (m, 2H).

[0930] Example 94: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 84)

[0931] Step 1: Synthesis of tert-butyl 3-chloro-7-(2-hydroxyethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 94-1)

[0932] Compound Int 7 (16 g, 43.38 mmol) and 200 mL of tetrahydrofuran were added to a three-necked flask. After nitrogen replacement, the temperature was cooled to subzero. Lithium aluminum tetrahydride (1.98 g, 52.05 mmol) was added, and the reaction solution was slowly warmed to 0°C and stirred. TLC (n-heptane:ethyl acetate = 3:1) confirmed the reaction was complete. The reaction solution was then cooled to 0°C and slowly added dropwise with aqueous sodium hydroxide and 30 g of anhydrous sodium sulfate. The mixture was stirred, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 94-1 (14 g, 42.84 mmol).

[0933] Step 2: Synthesis of tert-butyl 3-chloro-7-(2-iodoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 94-2)

[0934] To a three-necked flask, add imidazole (4.37 g, 64.26 mmol), triphenylphosphine (16.85 g, 64.26 mmol), and dichloromethane (300 mL). The temperature was maintained at 0°C with stirring. Elemental iodine (16.31 g, 64.26 mmol) was added and stirred. Compound 94-1 (14 g, 42.84 mmol) was then added. The reaction mixture was slowly warmed to 25°C. TLC confirmed the reaction was complete. The reaction was quenched with saturated sodium bisulfite solution, extracted, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography to afford compound 94-2 (12 g, 27.48 mmol).

[0935] Step 3: Synthesis of tert-butyl 7-(3-(1-(benzyloxy)carbonyl)azetidin-3-yl)-4-(tert-butoxy)-4-oxobutyl)-3-chloro-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 94-3)

[0936] Compound 94-2 (3.72 g, 8.51 mmol), Int 10 (2 g, 6.55 mmol), and tetrahydrofuran (30 mL) were added to a three-necked flask. The temperature was lowered to -30°C, and lithium bistrimethylsilylamide (1 M, 10.48 mmol, 10.48 mL) was slowly added dropwise. The reaction solution was slowly warmed to 25°C and stirred under nitrogen. LCMS confirmed the reaction was complete. The reaction was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and concentrated under reduced pressure. Compound 94-3 (1.2 g, 1.95 mmol) was purified by silica gel column chromatography. MS [ESI]: m / z = 614.3, [M+H] + .

[0937] Step 4: Synthesis of 2-(1-(benzyloxy)carbonyl)azetidin-3-yl)-4-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)butanoic acid (Compound 94-4)

[0938] Compound 94-3 (1.2 g, 1.95 mmol) and dichloromethane (6 mL) were added to a single-necked flask, followed by the slow addition of trifluoroacetic acid (3 mL). The reaction mixture was stirred at 25°C. LCMS confirmed the reaction was complete, and the mixture was concentrated under reduced pressure to afford compound 94-4 (850 mg, 1.86 mmol). MS [ESI]: m / z = 458.2, [M+H] + .

[0939] Step 5: Synthesis of 3-(3-chloro-2,4-dimethyl-7-oxo-5,7,8,9,10,10-hexahydropyrido[2,3-a]indolizin-8-yl)azetidine-1-carboxylic acid benzyl ester (Compound 94-5)

[0940] Compound 94-4 (850 mg, 1.86 mmol), N,N-diisopropylethylamine (1.2 g, 9.28 mmol), and N,N-dimethylacetamide (30 mL) were added to a single-necked flask and stirred. (7-Azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.28 g, 3.34 mmol) was added and the reaction mixture was stirred at 25°C. LCMS confirmed the reaction was complete. The mixture was quenched with saturated sodium chloride solution, extracted, concentrated under reduced pressure, and purified by silica gel column chromatography to afford compound 94-5 (500 mg, 1.14 mmol). MS [ESI]: m / z = 440.2, [M+H] + .

[0941] Step 6: Synthesis of 8-(azetidin-3-yl)-3-chloro-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 94-6)

[0942] Compound 94-5 (500 mg, 1.14 mmol), methanol (5 mL), and tetrahydrofuran (5 mL) were added to a 100 mL single-necked flask. The atmosphere was purged with nitrogen three times, and palladium on carbon (240 mg) was added. LCMS confirmed the reaction was complete, and the filtrate was filtered and concentrated under reduced pressure to give the title compound 94-6 (300 mg, 981.03 μmol, crude product). MS [ESI]: m / z = 306.1, [M+H] + .

[0943] Step 7: Synthesis of 3-chloro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 84)

[0944] To a 100 mL single-necked vial was added 94-6 (300 mg, 981.03 μmol, crude), N-methylpyrrolidone (5 mL), 4-chloro-2-(trifluoromethyl)pyridine (214 mg, 1.18 mmol), and cesium fluoride (298.04 mg, 1.96 mmol). The reaction mixture was stirred at 90°C for 12 hours. LCMS confirmed the reaction was complete. The mixture was then added with 10 mL of saturated sodium chloride solution and extracted with 30 mL of ethyl acetate. The mixture was concentrated under reduced pressure and purified by Prep-HPLC to afford compound 84 (51 mg, 113.11 μmol).

[0945] MS [ESI]: m / z = 451.1, [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ8.21(dd,J=5.6,2.8Hz,1H),6.72(t,J=2.8Hz,1H),6.56-6.53(m,1H),4.96-4.77(m,2H),4.50-4.36(m,1 H),4.22-4.03(m,3H),3.88-3.76(m,1H),3.12-2.94(m,1H),2.86-2.63(m,1H),2.55(s,3H),2.44-2.33(m,1H),2.31(s,3H),2.17 -2.10(m,1H),1.63 -1.38(m,2H).

[0946] Chiral separation (compounds 84a, 84b, 84c and 84d)

[0947] Compound 84 was separated using a chiral chromatographic column with Unichiral CNZ-5H and a mobile phase of n-hexane-anhydrous ethanol (50:50) to give compound 84a (5.5 mg, RT = 32.25 minutes), compound 84b (7.2 mg, RT = 39.32 minutes), compound 84c (6.1 mg, RT = 26.80 minutes), and compound 84d (7.5 mg, RT = 54.38 minutes).

[0948] Compound 84a:

[0949] 1 H NMR (400MHz, CD3OD) δ8.15(d,J=5.6Hz,1H),6.72(d,J=2.4Hz,1H),6.52(dd,J=5.6,2 .4Hz,1H),5.03(d,J=15.6Hz,1H),4.84-4.80(m,1H),4.46(d,J=16.0Hz,1H),4.25(t, J=8.4Hz,1H),4.20-4.18(m,2H),3.96(dd,J=8.4,6.4Hz,1H),3.24-3.13(m,1H),2.8 1-2.75(m,1H),2.66-2.61(m,4H),2.38(s,3H),2.34-2.28(m,1H),1.77-1.56(m,2H).

[0950] Compound 84b:

[0951] 1 H NMR (400MHz, CD3OD) δ8.14(d,J=6.0Hz,1H),7.00(d,J=2.0Hz,1H),6.51(dd,J=6.0,2.0 Hz,1H),4.91-4.87(m,2H),4.56(d,J=15.6Hz,1H),4.31(t,J=8.4Hz,1H),4.20(t,J=8. 4Hz,1H),3.96(dd,J=8.4,6.0Hz,1H),3.87(dd,J=8.4,6.0Hz,1H),3.14-3.03(m,1H),2 .92-2.85(m,1H),2.61-2.53(m,4H),2.38(s,3H),2.32-2.22(m,1H),1.74-1.50(m,2H).

[0952] Compound 84c:

[0953] 1H NMR (400MHz, CD3OD) δ8.14(d,J=5.6Hz,1H),6.72(d,J=2.0Hz,1H),6.52(dd,J=5.6,2 .0Hz,1H),5.03(d,J=15.6Hz,1H),4.84-4.80(m,1H),4.46(d,J=15.6Hz,1H),4.25(t, J=8.4Hz,1H),4.20-4.16(m,2H),3.96(dd,J=8.4,6.4Hz,1H),3.24-3.16(m,1H),2.8 1-2.75(m,1H),2.66-2.54(m,4H),2.38(s,3H),2.34-2.27(m,1H),1.77-1.56(m,2H).

[0954] Compound 84d:

[0955] 1 H NMR (400MHz, CD3OD) δ8.14(d,J=6.0Hz,1H),7.00(d,J=2.0Hz,1H),6.51(dd,J=6.0,2.0Hz,1H ),4.90(d,J=5.6Hz,1H),4.87-4.85(m,1H),4.56(d,J=15.6Hz,1H),4.31(t,J=8.4Hz,1H),4. 19(t,J=8.4Hz,1H),3.96(dd,J=8.4,6.0Hz,1H),3.87(dd,J=8.4,6.0Hz,1H),3.13-3.04(m,1 H),2.92-2.85(m,1H),2.61-2.53(m,4H),2.38(s,3H),2.32-2.23(m,1H),1.67-1.50(m,2H).

[0956] Example 95: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one-8-deuterium (499)

[0957] Step 1: Synthesis of tert-butyl 3-(2-(7-(2-hydroxyethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-oxoethyl)azetidine-1-carboxylate (Compound 95-1)

[0958] To a single-necked flask, 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (10.35 g, 48.09 mmol), (7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23.90 g, 62.52 mmol), N,N-diisopropylethylamine (31.08 g, 240.47 mmol), and dichloromethane (300 ml) were added. The mixture was stirred at 25°C, and compound 93-2 (11 g, 48.09 mmol, hydrochloride) was added. The mixture was stirred at room temperature for an additional period of time. LCMS confirmed the reaction was complete, and the reaction was quenched by addition of saturated sodium chloride solution. The mixture was extracted with dichloromethane, concentrated under reduced pressure, and purified by normal phase column chromatography to give the title compound 95-1 (23 g, crude product). MS [ESI]: m / z = 390.2 [M+H] + .

[0959] Step 2: Synthesis of tert-butyl 3-(2-(7-(2-bromoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)-2-oxoethyl)azetidine-1-carboxylate (Compound 95-2)

[0960] Compound 95-1 (23 g, crude product), triphenylphosphine (17.78 g, 67.78 mmol), and dichloromethane (300 mL) were added to a single-necked flask. The temperature was maintained at 0°C under nitrogen protection. N-bromosuccinimide (12.06 g, 67.78 mmol) was added and stirred at 0°C for 3 hours. The reaction was complete as determined by TLC. Saturated sodium bisulfite solution was added to quench the reaction, and the mixture was extracted with dichloromethane. The mixture was concentrated under reduced pressure to obtain compound 95-2 (30 g, crude product). MS [ESI]: m / z = 452.1 [M+H] + .

[0961] Step 3: Synthesis of tert-butyl 3-(2,4-dimethyl-7-oxo-5,7,8,9,10,10-hexahydropyrido[2,3-a]indolizin-8-yl)azetidine-1-carboxylate (Compound 95-3)

[0962] Compound 95-2 (30 g, crude product) and tetrahydrofuran (200 ml) were added to a three-necked flask, the atmosphere was replaced with nitrogen, the temperature was lowered to -70°C with stirring, and lithium bistrimethylsilylamide (1 M, 60.79 mmol, 60.79 mL) was slowly added dropwise. The temperature was slowly raised and stirred. The reaction was complete as determined by LCMS. Saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The mixture was concentrated under reduced pressure and purified by normal phase column chromatography to obtain compound 95-3 (6.3 g, 16.96 mmol). MS [ESI]: m / z = 372.2, [M+H] + .

[0963] Step 4: Synthesis of tert-butyl 3-(2,4-dimethyl-7-oxo-5,7,8,9,10,10-hexahydropyrido[2,3-a]indolizin-8-yl-8-deuterio)azetidine-1-carboxylate (Compound 95-4)

[0964] Compound 95-3 (1 g, 2.69 mmol) and tetrahydrofuran (20 ml) were added to a three-necked flask. The atmosphere was replaced with nitrogen and the temperature was lowered to below zero with stirring. Sodium bistrimethylsilylamide (2 M, 4.04 mmol, 2.02 mL) was slowly added dropwise. After stirring, deuterated methanol (485.45 mg, 13.46 mmol) was added. The mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, concentrated under reduced pressure, and purified by normal phase column chromatography to obtain the title compound 95-4 (360 mg, 966.50 μmol). MS [ESI]: m / z = 373.2 [M+H] +

[0965] Step 5: Synthesis of 8-(azetidin-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indolizine-7(5H)-one-8-deuterium (Compound 95-5)

[0966] Compound 95-4 (360 mg, 966.50 μmol) and dichloromethane (10 mL) were added to a single-necked flask. Trifluoroacetic acid (3 mL) was slowly added with stirring, and the reaction mixture was stirred at 25°C for 16 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated under reduced pressure to yield compound 95-5 (350 mg, 908.20 μmol, trifluoroacetate salt). MS [ESI]: m / z = 273.2 [M+H] +

[0967] Step 6: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one-8-deuterium (Compound 499)

[0968] To a single-necked flask, compound 95-5 (100 mg, 367.16 μmol), N-methylpyrrolidone (2 mL), 4-chloro-2-(trifluoromethyl)pyridine (66.65 mg, 367.16 μmol), cesium fluoride (167.32 mg, 1.10 mmol), and triethylamine (185.76 mg, 1.84 mmol) were added. The reaction mixture was heated to 100°C and stirred for 3 hours. LCMS confirmed the reaction was complete. The product was then added with 10 mL of saturated sodium chloride solution and extracted with 30 mL of ethyl acetate. The product was concentrated under reduced pressure and purified by Prep-HPLC to afford the title compound 499 (27 mg, 60.69 μmol).

[0969] MS [ESI]: m / z = 418.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ8.28 (dd, J=6.4, 2.4Hz, 1H), 6.97 (d, J=6.0Hz, 1H), 6.59 (dd, J=6.0, 2.4Hz, 1H), 6.37-6. 33(m,1H),5.08(d,J=16.0Hz,0.5H),4.92(d,J=16.0Hz,0.5H),4.87-4.77(m,1H),4.51(d,J=16.0Hz,0.5H),4. 40(d,J=16.0Hz,0.5H),4.34(t,J=8.4Hz,0.5H),4.28(d,J=8.4Hz,0.5H),4.22-4.14(m,1.5H),3.97(dd,J=8. 4,6.0Hz,0.5H),3.87-3.77(m,1H),3.20-3.10(m,1H),2.82-2.68(m,1H),2.58(s,3H),2.31-2.20(m,4H),1.69 -1.53(m,2H).

[0970] Example 96: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 507A)

[0971] Step 1: Compound 95-3 was separated using a Unichiral CNZ-5H column and n-hexane-anhydrous ethanol (50:50 and 80:20) as the mobile phase to obtain compound 95-3A (520 mg, RT = 9.37 minutes), compound 95-3B (500 mg, RT = 11.91 minutes), compound 95-3C (550 mg, RT = 15.18 minutes), and compound 95-3D (550 mg, RT = 16.26 minutes).

[0972] Step 2: Synthesis of 8-(azetidin-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 507A-1)

[0973] 95-3D (550 mg, 1.48 mmol) and dichloromethane (5 mL) were added to a single-necked flask. Trifluoroacetic acid (2 mL) was slowly added while stirring. The reaction solution was stirred at 25°C for 5 hours. LCMS confirmed the reaction was complete, and the mixture was concentrated under reduced pressure to give compound 507A-1 (720 mg, crude product).

[0974] Step 3: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 507A)

[0975] To a single-necked flask were added 507A-1 (100 mg, 368.52 μmol), dioxane (5 mL), cesium carbonate (360.21 mg, 1.11 mmol), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (35 mg, 73.70 μmol), methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (31 mg, 36.85 μmol), and 2-fluoro-4-iodo-6-methylpyridine (131 mg, 552.78 μmol). The atmosphere was replaced with nitrogen, and the temperature was raised to 90°C and stirred for 12 hours. The reaction was complete after LCMS detection. Saturated sodium chloride solution was added, extracted with ethyl acetate, and concentrated under reduced pressure. The title compound 507A (9.7 mg, 25.50 μmol) was obtained after purification by Prep-HPLC.

[0976] MS [ESI]: m / z = 381.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δ7.08 (s, 1H), 6.13 (s, 1H), 5.74 (d, J = 1.6Hz, 1H), 4.87-4 .83(m,2H),4.53(d,J=15.2Hz,1H),4.24(t,J=8.4Hz,1H),4.12(t,J=8.4Hz,1 H),3.88(dd,J=8.8,6.0Hz,1H),3.80(dd,J=8.0,6.0Hz,1H),3.08-3.01(m,1H ),2.90-2.83(m,1H),2.62-2.55(m,1H),2.51(s,3H),2.32-2.24(m,7H),1.62 -1.50(m,2H).

[0977] Referring to the synthesis method of Example 96, the following compound can be synthesized:

[0978] Example 97: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indolizin-7(5H)-one (Compound 507B)

[0979] Referring to the synthesis method of Example 96, the following compound can be synthesized

[0980] Example 105: Synthesis of 8-(1-(5-fluoropyridin-3-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 442)

[0981] Step 1: Synthesis of 8-(1-(5-fluoropyridin-3-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 442)

[0982] To a Schlenk flask, Int-5 (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL) were added, followed by 3-bromo-5-fluoropyridine (38.7 mg, 270.3 μmol), Ruphos Pd G3 (14.78 mg, 18.36 μmol), Ruphos (25.7 mg, 55.08 μmol), and cesium carbonate (179.45 mg, 550.76 μmol). After nitrogen substitution, the temperature was raised to 90°C and stirred for 12 hours. LCMS confirmed the reaction was complete, and the mixture was returned to room temperature, filtered through Celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 442 (22.2 mg, 60.42 μmol) was obtained by preparative HPLC purification.

[0983] MS [ESI]: m / z = 368.2, [M+H] + . NMR: 1H NMR(400MHz, CDCl3)7.88(d,J=2.0Hz,1H),7.70(s,1H),6.96(s,1H),6.51-6.44(m,1H) ,5.46-5.36(m,1H),4.96(dd,J=15.2,2.0Hz,1H),4.82(d,J=11.2Hz,1H),4.53(d,J=15 .2Hz,1H),4.27-4.18(m,2H),4.13(dd,J=8.0,5.6Hz,1H),3.95(dd,J=8.0,5.6Hz,1H), 3.67-3.56(m,2H),2.84(d,J=11.2Hz,1H),2.58(s,3H),2.29(s,3H),1.80-1.64(m,1H).

[0984] Step 2: Chiral separation

[0985] Compound 442 (300 mg) was separated using a Unichiral YMC-CMD-5H chiral column with anhydrous ethanol (100%) as the mobile phase to obtain compounds 442a (110 mg) and 442b (110 mg). The retention time of compound 442a was 5.727 minutes, and the retention time of compound 442b was 7.142 minutes.

[0986] Compound 442a: MS [ESI]: m / z = 368.2, [M+H] + , 1 H NMR (400MHz, CDCl3) δ7.88 (d, J = 2.0Hz, 1H), 7.70 (s, 1H), 6.96 (s, 1H), 6.51-6.44 (m, 1H ),5.46-5.36(m,1H),4.96(dd,J=15.2,2.0Hz,1H),4.82(d,J=11.2Hz,1H),4.53(d,J=15 .2Hz,1H),4.27-4.18(m,2H),4.13(dd,J=8.0,5.6Hz,1H),3.95(dd,J=8.0,5.6Hz,1H), 3.67-3.56(m,2H),2.84(d,J=11.2Hz,1H),2.58(s,3H),2.29(s,3H),1.80-1.66(m,1H).

[0987] Compound 442b: MS [ESI]: m / z = 368.2, [M+H] + , 1H NMR (400MHz, CDCl3) δ7.88 (d, J = 2.0Hz, 1H), 7.70 (s, 1H), 6.97 (s, 1H), 6.52-6.44 (m, 1H),5.46-5.34(m,1H),5.04-4.90(m,1H),4.83(d,J=11.2Hz,1H),4.54(d,J=15.2Hz ,1H),4.27-4.18(m,2H),4.13(dd,J=8.0,6.0Hz,1H),3.96(dd,J=8.0,5.6Hz,1H),3. 67-3.54(m,2H),2.83(d,J=11.2Hz,1H),2.55(s,3H),2.30(s,3H),1.80-1.64(m,1H).

[0988] Example 111: Synthesis of 8-(1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2′,3′:3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 497)

[0989] Step 1: Synthesis of tert-butyl (1-(2-bromo-5-fluoropyrimidin-4-yl)azetidin-3-yl)carbamate (Compound 111-2)

[0990] Compound 111-1 (5 g, 29.03 mmol) and 1,4-dioxane (50 mL) were added to a Schlenk flask, followed by 2,4-dibromo-5-fluoropyrimidine (8.91 g, 34.87 mmol), Ruphos Pd G3 (2.43 g, 2.9 mmol), Ruphos (1.35 g, 2.9 mmol), and cesium carbonate (18.92 g, 58.06 mmol). After nitrogen substitution, the temperature was raised and stirred for 12 hours. LCMS analysis showed that the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 111-2 (6.2 g, 17.86 mmol) was obtained by column chromatography. MS [ESI]: m / z = 348.2, [M+H] + .

[0991] Step 2: Synthesis of tert-butyl (1-(5-fluoro-2-(methoxy(methyl)carbamoyl)pyrimidin-4-yl)azetidin-3-yl)carbamate (Compound 111-3)

[0992] Compound 111-2 (6.2 g, 17.86 mmol) and DMF (50 mL) were added to a Schlenk flask, followed by Pd(dppf)2Cl2 (1.31 g, 1.79 mmol), N,O-dimethylhydroxylamine hydrochloride (2.09 g, 21.43 mmol), and cesium carbonate (11.64 g, 58.06 mmol). Carbon monoxide was then replaced, and the temperature was raised to 90°C and stirred for 12 hours. LCMS analysis showed that the reaction was complete, and the mixture was returned to room temperature, filtered through celite, washed with dichloromethane, and concentrated under reduced pressure. Compound 111-3 (3.5 g, 9.85 mmol) was obtained by column chromatography. MS [ESI]: m / z = 356.2, [M+H] + .

[0993] Step 3: Synthesis of tert-butyl (1-(5-fluoro-2-formylpyrimidin-4-yl)azetidin-3-yl)carbamate (Compound 111-4)

[0994] Compound 111-3 (3.5 g, 9.85 mmol) and THF (30 mL) were added to a round-bottom flask, the atmosphere was replaced with N2, and the mixture was brought to -20°C. DIBAL-H (2.1 g, 14.77 mmol) was slowly added, and the temperature was slowly raised to room temperature and stirred for 4 hours. LCMS detected that the reaction was complete, and HCl (15 mL, 1 N) was slowly added dropwise at 0°C to quench the reaction. NaOH (15 mL, 1 N) was then added to pH = 7, and the mixture was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. Compound 111-4 (1.2 g, 4.05 mmol) was obtained by column chromatography. MS [ESI]: m / z = 297.2, [M+H] + .

[0995] Step 4: Synthesis of tert-butyl (1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)azetidin-3-yl)carbamate (Compound 111-5)

[0996] Compound 111-4 (1.2 g, 4.05 mmol) and DCM (10 mL) were added to a round-bottom flask, the atmosphere was replaced with N2 three times, and the mixture was moved to an ice bath. DAST (1.96 g, 12.15 mmol) was slowly added, and the mixture was slowly warmed to room temperature and stirred for 12 hours. LCMS detected that the reaction was complete, and saturated NaHCO3 was added to quench the reaction, adjusted to pH = 7, and then extracted with EA. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. Compound 111-5 (800 mg, 2.51 mmol) was obtained by column chromatography. MS [ESI]: m / z = 319.2, [M + H] +.

[0997] Step 5: Synthesis of 1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)azetidin-3-amine (Compound 111-6)

[0998] Compound 111-5 (800 mg, 2.51 mmol) and DCM (10 mL) were added to a round-bottom flask, and a 4N HCl / 1,4-dioxane solution was slowly added dropwise. The mixture was reacted at room temperature for 4 hours. The reaction was complete after LCMS analysis. The reaction solution was concentrated and dried to give compound 111-6 (600 mg). MS [ESI]: m / z = 219.2, [M+H] + .

[0999] Step 6: Synthesis of tert-butyl 7-(2-hydroxyethyl)-2,4-dimethyl-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (Compound 111-7)

[1000] Compound Int-6-4 (5 g, 14.95 mmol) and THF (100 mL) were added to a round-bottom flask. LAH (5 g, 14.95 mmol) was slowly added at -78 ° C. and stirred at -78 ° C for 0.5 h. It was then heated to 25 ° C and stirred for 4 hours. LCMS detected that the reaction was complete. NH4CI (50 mL) was slowly added at 0 ° C to quench the reaction, then diluted with H2O (30 mL) and extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to give compound 111-7 (3.8 g, 13.00 mmol). MS [ESI]: m / z = 293.2, [M + H] + .

[1001] Step 7: Synthesis of tert-butyl 2,4-dimethyl-7-(2-oxoethyl)-5,7-dihydropyrrolo[3,4-b]pyridine-6-carboxylate (Compound 111-8)

[1002] To a three-necked round-bottom flask, oxalyl chloride (3.30 g, 25.99 mmol) and DCM (20 mL) were added, the atmosphere was replaced with nitrogen, and DMSO (4.06 g, 51.99 mmol) was slowly added dropwise at -70°C. After the addition was complete, a solution of compound 111-7 (3.8 g, 13.00 mmol) in DCM (10 mL) was added dropwise. The reaction was continued for 2 hours. LCMS detected that the reaction was complete. TEA (7.89 g, 77.98 mmol) was then added dropwise, and the mixture was slowly heated to 25°C and stirred for 2 hours. H2O was added to the reaction mixture and extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue. Compound 111-8 (2.2 g, 7.58 mmol) was obtained by column chromatography (MS [ESI]: m / z = 291.2, [M+H] + .

[1003] Step 8: Synthesis of tert-butyl 7-(2-((1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)azetidin-3-yl)amino)ethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 111-9)

[1004] Compound 111-8 (300 mg, 1.03 mmol), DCM (5 mL), 111-6 (315.7 mg, 1.24 mmol), and AcOH were added to a round-bottom flask. After 15 minutes of reaction, NaBH(OAc)3 (328 mg, 1.55 mmol) was added. The mixture was stirred at 25°C for 4 hours. LCMS confirmed the reaction was complete, and the mixture was quenched with saturated brine, followed by extraction with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a residue, which was purified by column chromatography to obtain compound 111-9 (400 mg, 812.1 μmol). MS [ESI]: m / z = 493.2, [M+H] + .

[1005] Step 9: Synthesis of 1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)-N-(2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)azetidin-3-amine (Compound 111-10)

[1006] Compound 111-9 (400 mg, 812.1 μmol) and DCM (10 mL) were added to a round-bottom flask, and 5 mL of 4N HCl / 1,4-dioxane solution was slowly added dropwise. The mixture was reacted at room temperature for 4 hours. The reaction was complete when detected by LCMS. The reaction solution was concentrated to dryness and saturated NaHCO3 was added to adjust the pH to 7. The mixture was then extracted with EA, and the combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 111-10 (220 mg, 560.6 μmol). MS [ESI]: m / z = 393.2, [M+H] + .

[1007] Step 10: Synthesis of 8-(1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 497)

[1008] Compound 111-10 (60 mg, 152.89 μmol), 1,4-dioxane (1 mL), CDI (29.75 mg, 183.47 μmol), and TEA (23.21 mg, 229.34 μmol) were added to a sealed tube, followed by heating and stirring. The reaction was detected to be complete by LCMS, and compound 497 (31 mg, 74.1 μmol) was obtained by purification by Prep-HPLC.

[1009] MS [ESI]: m / z = 419.2, [M+H] + , NMR: 1 H NMR (400MHz, CDCl3) δ8.00(d,J=4.0Hz,1H),6.87(s,1H),6.33(t,J=54.8Hz,1H),5.36(t,J=6.4Hz,1H),4.87(d,J=15.2Hz,1H),4.72(d,J=11 .6Hz,1H),4.46(d,J=15.2Hz,4H),4.35-4.22(m,1H),3.55(dd,J=8.8,2.8Hz,2H),2.71(s,1H),2.48(s,3H),2.21(s,3H),1.73-1.63(m,1H).

[1010] Example 112: Synthesis of 8-(1-(5-fluoro-6-deuteropyridin-3-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 498)

[1011] Step 1: Synthesis of 3-bromo-5-fluoro-6-deuteropyridine (Compound 112-2)

[1012] Compound 2,5-dibromo-3-fluoropyridine (1 g, 3.92 mmol) and THF...

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof: in: Ring A is selected from 5-14 membered heteroaromatic rings and C 6-14 aromatic rings; R 1 、R 3 、R 4 、R 5 is independently selected at each occurrence from hydrogen, deuterium, tritium, OR 7 , hydroxyl, oxo, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -NR 7 R 8 、-CONR 7 R 8 、-COC 1-6 Alkyl, -NHCOC 1-6 Alkyl, C(O)OR 7 、-OC(O)R 7 、-OC(O)NR 7 R 8 、-NR 7 C(O)NR 7 R 8 、C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 membered heteroaryl, wherein each of the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl groups is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 Replace; or Two R's attached to the same carbon atom 4 Or two R 5 Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group, which is optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace; And, R 1 It can also be missing; R 7 、R 8 Each independently selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein the alkyl, cycloalkyl and heterocyclic groups are each optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 Replace; or R 7 、R 8 The N atom to which it is connected together forms a 3-8 membered heterocyclic group, wherein the heterocyclic group is optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 replace; R 9 is independently selected at each occurrence from H, deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 、-COCH3、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkylthio, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) independently selected from halogen, -OH, -CN, -NR 7 R 8 、-COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups; Ring B is selected from a 4-8 membered carbocyclic ring, a 4-8 membered heterocyclic ring, a 6-10 membered aromatic ring, and a 5-10 membered heteroaromatic ring; Ring C is selected from a 5-8 membered carbocyclic ring, a 5-8 membered heterocyclic ring or a 5-10 membered heteroaromatic ring; L is selected from C, CR a and N; R a Selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups; R 2 For-PR 6 ; P is a single bond, a double bond, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, C 6-10 Aryl, 5-14 membered heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 -, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 replace; R 6 Selected from deletion, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic group, C 6-10 Aryl C 3-8 Cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclic group, C 6-10 Aryl and 3-8 membered heterocyclic group, 5-14 membered heteroaryl and C 3-8 Cycloalkyl, 5-14 membered heteroaryl and C 6-14 Aryl, the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups are each optionally substituted by one or more (eg, 1, 2, 3, 4, 5, 6) R 9 replace; m, n, and o are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Ring A is selected from C 6-10 aromatic rings and 5-10 membered heteroaromatic rings.

3. The compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Ring A is selected from 4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 1 、R 3 Independently selected from hydrogen, deuterium, tritium, oxo, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, -CONR 7 R 8 、-NHCOC 1-6 Alkyl, C 3-8 Cycloalkyl, 5-6 membered heteroaryl, 3-8 membered heterocyclyl and -NR 7 R 8 The alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl groups are each optionally substituted by one or more R 9 replace.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 1 、R 3 Independently selected from oxo (=O), CH3, CH2CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, methoxy, -NH-CH3, vinyl, N-heterocyclobutane, CH2OH, 6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Ring B is selected from a partially unsaturated 4-8 membered carbocyclic ring, a partially unsaturated 4-8 membered heterocyclic ring, a 6-10 membered aromatic ring and a 5-10 membered heteroaromatic ring.

7. The compound according to claim 6 or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug, wherein: Ring B is selected from benzene ring, dihydropyrrole, tetrahydropyrrole, pyrrole, thiophene, pyrazole, imidazole, Pyridine, cyclohexene, cyclopentene, dihydrofuran ring and tetrahydropyridine.

8. The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Ring B is selected from 9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 5 independently selected from hydrogen, deuterium, tritium, hydroxy, oxo, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy and C 1-6 Hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are each optionally substituted by one or more R 9 Substitution; or, two R attached to the same carbon atom 5 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: R 4 independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl are each optionally substituted by one or more R 9 Substitution; or, two R attached to the same carbon atom 4 Together with the carbon atom to which it is attached, it forms a 3-5 membered cycloalkyl group, which is optionally substituted by one or more R 9 replace.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: The C ring is selected from a 5- to 7-membered carbocyclic ring, a 5- to 8-membered heterocyclic ring (eg, a nitrogen-containing heterocyclic ring or a Si-containing heterocyclic ring), or a 5- to 8-membered heteroaromatic ring (eg, a nitrogen-containing heteroaromatic ring).

12. The compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: The C ring is selected from 13. The compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The compound has the structure shown in Formula II: in, Indicates Z in ring B 1 、X 1 、X 2 , Z 2 、X 3 、X 4 Any two adjacent symbols in can be a single bond or a double bond, provided that the two adjacent bonds are not double bonds at the same time; X 1 、X 2 are each independently selected from C, N; X 3 、X 4 Each independently selected from C, N and CR 5a ; Z 1 , Z 2 Each independently selected from a single bond, -(CR 5a R 5b ) q -、CR 5a , -C(=O)-, -O-, -S-, N, NR 5a 、-CR 5a R 5b -Z 3 --Z 3 -CR 5a R 5b -、=CR 5a -Z 3 -、-Z 3 -CR 5a =、N=CR 5a and-SiR 5a R 5b -; R 5a and R 5b As claimed in claim 1 R 5 defined; Z 3 Selected from -O-, -S- and -NR 5a ; q is selected from 1 or 2; L is selected from C, CR a and N, and the remaining groups are as defined in any one of claims 1 to 12.

14. The compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The compound has a structure shown in Formula III: in, Z 1 Selected from CR 5a R 5b and CR 5a ; X 1 and X 2 Selected from C; X 3 Selected from CR 5a and C; X 4 Selected from N; or, Z 1 Selected from-CR 5a R 5b -;X 1 and X 2 Selected from C;X 3 and X 4 Selected from CR 5a R 5b ; or, Z 1 Select from O; X 1 and X 2 Selected from C;X 3 and X 4 Selected from-CR 5a R 5b -; or, Z 1 Selected from NR 5a ;X 1 and X 2 Selected from C;X 3 and X 4 Selected from CR 5a ; or, Z 1 Selected from S;X 1 and X 2 Selected from C;X 3 and X 4 Selected from CR 5a ; or, Z 1 Selected from NR 5a and S;X 1 、X 2 、X 3 and X 4 Selected from C; or, Z 1 Selected from SiR 5a R 5b ;X 1 and X 2 Selected from C;X 3 and X 4 Selected from CR 5a ; or, Z 1 Selected from CR 5a and N;X 1 、X 2 and X 3 Selected from C;X 4 Selected from N; or, Z 1 Selected from CR 5a ;X 1 、X 2 and X 4 Selected from C;X 3 Selected from N; or, Z 1 Selected from CR 5a ;X 1 Select from N;X 2 、X 3 and X 4 Selected from C; or, Z 1 Select from N;X 1 and X 4 Selected from C;X 2 and X 3 Selected from C and N; R 5a 、R 5b As claimed in claim 1 R 5 As defined, L is selected from C, CR a and N, and the remaining groups are as defined in any one of claims 1 to 13.

15. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The compound has a structure shown in Formula IV: in, Z 1 Selected from CR 5a ; X 1 、X 2 、X 4 Selected from C; X 3 Selected from N; L is selected from C, CR a and N, and the remaining groups are as defined in any one of claims 1 to 14.

16. The compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotope-labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: Z 1 does not exist; Z 2 Selected from CR 5a ; X 1 、X 2 、X 3 Selected from C; X 4 is selected from N; and Ring B is a pyrrole ring.

17. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The compound has a structure shown in Formula V: in, Z 1 and Z 2 Selected from CR 5a R 5b , CR 5a NR 5a , N, O and S; X 1 and X 2 Selected from C; X 3 and X 4 Selected from C, CR 5a or N; L is selected from C, CR a and N, and the remaining groups are as defined in any one of claims 1 to 15.

18. The compound of any one of claims 1 to 17, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The compound has the structure shown in Formula VI, Wherein, Y is selected from a single bond, -(CR 4a R 4b ) p -(CR 4a R 4b )-、CR 4a ,-C(=O)-,C,-O-,-S-,N,NR 4a 、-CR 4a =R 4b -、-CR 4a =N-, -SiR 4a R 4b -、-CR 4a R 4b -Z 3 - and -Z 3 -CR 4a R 4b -; R 4a and R 4b As claimed in claim 1 R 4 defined; p is selected from 0, 1 or 2; L is selected from C, CR a and N, and the remaining groups are as defined in any one of claims 1 to 15.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: Y is selected from -(CR 4a R 4b ) p -(CR 4a R 4b )-、-C(=O)-、-CR 4a =R 4b -、-CR 4a R 4b =N- and -SiR 4a R 4b -, p is 1, 2, and R 4a and R 4b are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl, or R a and R b Together with the carbon atom to which it is attached, it forms a 3-6 membered cycloalkyl group.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: is selected from the group represented by Formula 1, Formula 2 or Formula 3, Wherein, in the group of formula 1, Y 1 Selected from deletion, C, N and CR 3 ; Y 2 、Y 3 、Y 4 Each independently selected from C, N, CR 3 NR 3 , O and S; Wherein, in the group of formula 2, X 1 、X 2 、Y 2 、Y 3 are each independently selected from C and N; Y 4 、Y 6 、Y 7 、Y 8 Each independently selected from C, N, CR 3 NR 3 , O and S; Y 5 Independently selected from deletion, C, N, CR 3 NR 3 , O and S; Wherein, in the group of formula 3, X 1 、X 2 、Y 1 、Y 2 are each independently selected from C and N; Y 3 、Y 4 Each independently selected from CR 3 and N; Y 5 、Y 6 、Y 7 Each independently selected from C, N, CR 3 NR 3 , O and S; L in Formula 1, Formula 2 and Formula 3 are independently selected from C, CR a and N, and the remaining groups are as defined in any one of claims 1 to 19.

21. The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The group represented by formula 1 is selected from: Preferably, the group represented by Formula 1 is selected from: Among them, Y 1 Not missing; More preferably, the group represented by Formula 1 is selected from: wherein p is selected from 0, 1 or 2; Preferably, Z 1 Selected from-CR 5a R 5b -、CR 5a 、-O-、-S-、N、NR 7 and SiR 5a R 5b .

22. The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The group represented by formula 1 is selected from: Among them, Y 1 selected from CH and N; Z 1 Selected from CR 5a 、N、NR 5a , O and S; X 1 、X 2 、X 3 、X 4 Selected from C and N; And, Z 1 、X 1 、X 2 、X 3 、X 4 Not at the same time C; Alternatively, the group represented by Formula 1 is selected from: Among them, Y 2 、Y 4 Selected from CR 3 , -O-, -S-, N and NR 3 , and Y 2 、Y 4 Not CR at the same time 3 ; Alternatively, the group represented by Formula 1 is selected from: Among them, Y 2 Selected from -O-, -S-, N and NR 3 ; Z 1 , Z 2 Selected from C, CR 5a and N.

23. The compound of claim 20 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: The group of formula 2 is selected from formula 2-1: Preferably, the group represented by formula 2 is selected from: Among them, Y 5 、Y 6 、Y 7 、Y 8 Selected from CR 3 and N.

24. The compound of claim 20, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The group represented by formula 3 is selected from formula 3-1: Preferably, the group represented by formula 3 is selected from: Where p is 0, 1, or 2; Preferably, Y 5 、Y 6 、Y 7 Each independently selected from CR 3 and N.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: Selected from:

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: L is selected from CR 9a and N; Preferably, L is selected from CH and N.

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: P is selected from single bond, double bond, -C 1-6 Alkyl-(C=O)-NR 7 -、-NR 7 -(C=O)-C 1-6 Alkyl-, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group and C 3-6 Cycloalkyl and C6 aryl and C 3-6 Cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl being each optionally substituted by one or more R 9 replace.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: P is selected from a bond, a double bond, -C 1-3 Alkyl-(C=O)-NH-, methylene, ethylene, propylene, C 1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and benzocyclopentyl, wherein each of the alkyl, cycloalkyl, benzocyclopentyl or heterocyclic groups is optionally substituted by one or more R 9 replace.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: P is selected from a bond, a double bond, a methylene group, Cyclobutyl, Alternatively, P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, <h2 style=";text-align:left;direction:ltr">-CH2CF3、<h2 style=";text-align:left;direction:ltr"> 30. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: The compound has the structure shown in Formula VII: Among them, E 1 、E 2 Independently selected from C, CH2, CH, N, NH, O, S; m1 is selected from 0, 1, 2, 3, 4, 5 or 6; m2 is selected from 0, 1, 2 or 3; m3 is selected from 1, 2 or 3; Ring A, Ring B, Ring C, R 1 、R 3 、R 4 、R 5 、R 6 、R 9 , n, o as defined in any one of claims 1-27.

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 6 Selected from missing, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 Aryl, C 1-6 Alkyl and C 1-6 haloalkyl, said alkyl, aryl or heteroaryl being each optionally substituted by one or more R 9 replace.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 6 Selected from R 9 is independently selected at each occurrence from H, deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 、-COCH3、C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Alkylthio, C 1-6 Halogenated alkylthio, C 2-6 Heteroalkyl, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl or heteroaryl are each independently optionally substituted by one or more (e.g., 1, 2, 3, 4, 5, 6) selected from halogen, -OH, -CN, -NR 7 R 8 、-COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-6 Cycloalkyl, C 3-8 Substitution of cycloalkoxy and 3-8 membered heterocyclic groups; Preferably, R 9 Selected from hydrogen, deuterium D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -NR 7 R 8 、CN、C 3-8 Cycloalkyl, C 1-6 Halogenated alkylthio, C 1-6 haloalkyloxy and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more selected from C 1-6 More preferably, R 9 is independently selected at each occurrence from H, deuterium D, F, Cl, Br, cyclopropyl, -CH2CH3, -CHF2, -CF3, -CH3, -OCH3, -OCH(CH3)CF3, -CH2CF3, -OCHF2, -OCH2CF3, -SCF3, -CN, -NH(CH2CH3), -N(CH3)2, -NH2, m1 is selected from 0, 1, 2, 3, 4, 5 and 6.

33. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 9 Selected from hydrogen, deuterium D, halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, -NR 7 R 8 、CN、C 3-8 Cycloalkyl, C 3-8 Halogenated cycloalkoxy, C 1-6 Halogenated alkylthio, C 1-6 haloalkyloxy and 5-10 membered heteroaryl, wherein the 5-10 membered heteroaryl is optionally substituted by one or more selected from C 1-6 alkyl; preferably, R 9 are each independently selected from hydrogen, deuterium, halogen, C 1-4 Alkyl, -CN, C 1-4 Halogenated alkyl, C 1-4 Alkoxy, C 1-4 Halogenated alkoxy, C 3-6 Halogenated cycloalkoxy, -NH2, -NH(CH2CH3), -N(CH3)2, C 1-4 Halogenated alkylthio, C 3-6 Cycloalkyl and 5-6 membered heteroaryl, said 5-6 membered heteroaryl is optionally substituted by C 1-4 Alkyl, C 1-4 substituted with a haloalkyl group; Preferably, R 9 Each is independently selected from hydrogen, deuterium, F, Cl, Br, CH3, -CN, -CHF2, -CF3, -CHF2, -OCH3, -OCHF2, trifluoromethoxy, -OCH2CF3, -OCH(CH3)CF3, -NH2, -NH(CH2CH3), -N(CH3)2, -SCF3, cyclopropyl, 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein: R 6 Selected from 35. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, wherein: The compound is selected from:

36. A pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound according to any one of claims 1 to 35 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof and one or more pharmaceutically acceptable carriers.

37. Use of a compound according to any one of claims 1 to 35, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite or prodrug thereof, or a pharmaceutical composition according to claim 36, in the preparation of a medicament for preventing or treating a disease or condition mediated by muscarinic acetylcholine receptor M4.

38. A method for preparing a compound according to any one of claims 1 to 35, comprising the following steps: Route A in X is a hydroxyl group or a halogen group, or a leaving group; and the compound IA is connected to R through the L' position. 2 -X reaction; Route B in X is a hydroxyl group or a halogen, or a leaving group.

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