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

Abstract

Provided are a compound, a pharmaceutical composition comprising same, a preparation method therefor, and a use thereof. The compound has a structure represented by formula I, is used for preventing or treating M4-mediated diseases or conditions, relates to the field of pharmaceutical chemistry.

Description

Compounds, pharmaceutical compositions comprising the same, and methods of making and uses thereof

[0001] This application claims priority to Chinese Patent Application No. 202411253559.5, filed September 6, 2024, Chinese Patent Application No. 202510077171.2, filed January 17, 2025, PCT Application No. PCT / CN2025 / 082368, filed March 13, 2025, and Chinese Patent Application No. 202511140976.3, filed August 14, 2025, the entire contents of which are incorporated herein by reference in their entirety. TECHNICAL FIELD

[0002] The present application relates to a compound, a pharmaceutical composition comprising the same, a method of making the same, and uses thereof for preventing or treating a muscarinic acetylcholine receptor M4-mediated disease or condition. BACKGROUND

[0003] Muscarinic acetylcholine receptors (mAChRs) are a class of GPCRs, including M1-M5 five subtypes. Among them, M4 receptor is highly expressed in the striatum, hippocampus and other regions of the central nervous system, and inhibits adenylyl cyclase activity through Gi / o protein coupling. Genome-wide association studies have confirmed that M4 locus rs7951870 is significantly associated with schizophrenia (Neuropharmacology 2018, 136, 362-373). High dopaminergic state in the striatum and nucleus accumbens is associated with psychosis, and is the target of current antipsychotic drugs that block dopamine D2 receptors.

[0004] M4 positive allosteric modulators (PAMs) can regulate dopamine pathways (inhibit striatal dopamine release) and synaptic plasticity (inhibit hippocampal glutamate hyperexcitation) by enhancing endogenous acetylcholine activity (Neuropsychopharmacology, 2014, 39, 1578; Hippocampus, 2017, 27, 794-810). However, current M4 PAMs have problems of inadequate pharmacokinetic performance and poor subtype selectivity.

[0005] Although M4 PAMs show therapeutic value in schizophrenia (improving psychotic symptoms) and Alzheimer's disease (relieving cognitive impairment), it is still an urgent need to develop new compounds that modulate M4 receptor activity to improve drug selectivity, pharmacokinetics, and safety, etc. to meet clinical needs. SUMMARY

[0006] This invention provides a novel polycyclic compound that can act as a modulator of muscarinic acetylcholine receptor M4 activity, especially a positive allosteric modulator (M4 PAM), and can be used to treat M4 receptor-mediated diseases or disorders. The compound has excellent positive allosteric modulation of M4 and has fewer toxic side effects and good pharmacokinetic properties.

[0007] One aspect of the invention provides compounds of Formula I or thereof, or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, polymorphs, solvates, N-oxides, metabolites, or prodrugs thereof:

[0008] in:

[0009] Ring A is selected from 5-14 membered heteroaryl rings and C. 6-14 Aromatic rings;

[0010] R 1 R 3 R 4 R 5 Each time it appears, it is independently selected from hydrogen, deuterium, tritium, OR 7 Oxygen, hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 7 R 8 -CONR 7 R 8 -COC 1-6 Alkyl, -HCOC 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 groups, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or

[0011] Two R atoms bonded to the same carbon atom 4 Or two Rs 5Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group, wherein the cycloalkyl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R... 9 replace;

[0012] Furthermore, R 1 It can also be missing;

[0013] R 7 R 8 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein each of the alkyl, cycloalkyl, and heterocyclic groups is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or

[0014] R 7 R 8 Together with N atoms, they form 3-8 membered heterocyclic groups, wherein the heterocyclic group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R atoms. 9 replace;

[0015] R 9 Each time it appears, it is independently selected from H, deuterium, tritium, halogen, -OH, -CN, oxo, and -NR. 7 R 8 -COCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thio, C 1-6 Haloalkylthio, C 2-6 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10 The aryl group and 5-10 heteroaryl group, wherein the alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclic, aryl, or heteroaryl group is optionally each selected independently by one or more (e.g., 1, 2, 3, 4, 5, 6) of a halogen, -OH, -CN, or -NR. 7 R 8 -COC 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 3-6 cycloalkyl, C 3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0016] B ring is selected from 4-8 membered carbocyclic, 4-8 membered heterocyclic, 4-8 membered aromatic, and 4-8 membered heteroaromatic ring;

[0017] C ring is selected from 5-8 membered carbocyclic, 5-8 membered heterocyclic, or 5-8 membered heteroaromatic ring;

[0018] L is selected from C, CR a , and N;

[0019] R a is selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl;

[0020] R 2 is -P-R 6 ;

[0021] P is a single bond, a double bond, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and C 3-8 cycloalkyl, 5-14 membered heteroaryl, and 3-8 membered heterocyclyl, C 6-10 aryl, and 3-8 membered heterocyclyl, 5-14 membered heteroaryl, and C 3-8 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -R 7 -(C=0)-N(R 8 )-, -N(R 8 )-(C=0)-R 7 -, said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 ;

[0022] R 6 is selected from absent, H, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, and C 3-8 cycloalkyl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl, C 6-10 aryl, and 3-8 membered heterocyclyl, 5-14 membered heteroaryl, and C 3-8 cycloalkyl, 5-14 membered heteroaryl, and C 6-14 aryl, said alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 ;

[0023] each of m, n, o is independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0024] Another aspect of the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application 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.

[0025] Another aspect of the present application provides the use of a compound of the present application 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 application, in the manufacture of a medicament for the prevention or treatment of a muscarinic acetylcholine receptor M4-mediated disease or condition.

[0026] Another aspect of the present application provides a compound of the present application 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 application, for use in the prevention or treatment of a muscarinic acetylcholine receptor M4-mediated disease or condition.

[0027] Another aspect of the present application provides a method of preventing or treating a muscarinic acetylcholine receptor M4-mediated disease or condition, comprising administering to an individual in need thereof an effective amount of a compound of the present application 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 application.

[0028] Another aspect of the present application provides a method of making a compound of the present application, comprising the steps of:

[0029] wherein X is hydroxyl, halogen (e.g., iodine, bromine, chlorine, fluorine), or a leaving group (e.g., methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluenesulfonate), etc.; and, the compound I-A is reacted with R 2 , preferably, L’ is selected from -NH-.

[0030] ring A, ring B, ring C, L, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, o are as defined above.

[0031] or,

[0032] wherein X is a hydroxyl, a halogen (e.g., iodine, bromine, chlorine, fluorine), or is a leaving group (e.g., methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluenesulfonate), and the like; and,

[0033] Ring A, Ring B, Ring C, L, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, o, P are as defined above.

[0034] Definitions

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References to techniques employed herein are intended to refer to the techniques as commonly understood in the art, including variations thereto or substitutions therefor that would be apparent to those of skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate a better understanding of the present application.

[0036] The terms "comprising," "including," "having," "containing," or "involving," and any variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps, although other unrecited elements or method steps are not necessarily present (i.e., these terms also cover the terms "consisting essentially of" and "consisting of").

[0037] As used herein, the term "alkyl" defines a linear or branched saturated aliphatic hydrocarbon. In some embodiments, an 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" refer to linear or branched groups having 1-10 carbon atoms, 1-6 carbon atoms, and 1-4 carbon atoms, respectively (e.g., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, neopentyl, or n-hexyl), which are optionally substituted with one or more (such as 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 (i.e., methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl) having from 1 to 4 carbon atoms.

[0038] As used herein, the term "heteroalkyl" refers to a skeletal chain of atoms comprised of one or more atoms, other than carbon, independently selected from oxygen, nitrogen, sulfur, phosphorus, or a combination thereof, in a backbone of carbon atoms of an alkyl group. Numerical ranges for heteroalkyl groups (e.g., C 2-6 heteroalkyl) refers to the number of carbons in the chain, in this example, including 2-6 carbon atoms. For example, a -CH2OCH2CH3group is referred to as a C3heteroalkyl, and a -CH2OCH2CH2NHCH3group is referred to as a C4heteroalkyl. Attachment to the rest of the molecule can be through a heteroatom or a carbon atom in the heteroalkyl chain.

[0039] As used herein, the term "haloalkyl" refers to an alkyl group substituted with one or more (such as 1 to 3) same or different halogen atoms, the term "C 1-8 haloalkyl," "C 1-6 haloalkyl," and "C 1-4 haloalkyl" refer to haloalkyl groups 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, and the like.

[0040] As used herein, the term "hydroxyalkyl" refers to a group formed by the substitution of one or more hydrogen atoms in an alkyl group with one or more hydroxyl groups, such as C 1-10 hydroxyalkyl, C 1-6 hydroxyalkyl, or C 1-4 hydroxyalkyl, examples of which include, but are not limited to, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, -CH(OH)CH3, and the like.

[0041] As used herein, the term "alkoxy" means -O-alkyl, where alkyl is as defined above, such as 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, propyloxy, isopropyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, t-butyloxy, pentyloxy, hexyloxy, and the like, optionally substituted with one or more (such as 1 to 3) same or different substituents. As the term "haloalkoxy" refers to the substitution of one or more (such as 1 to 3) hydrogen atoms of said alkoxy group with one or more (such as 1 to 3) same or different halogen atoms.

[0042] As used herein, the term "fused ring" or "fused ring" refers to a ring system formed from two or more cyclic structures sharing two adjacent atoms with each other.

[0043] As used herein, the term "spirocyclic" refers to a ring system formed from two or more cyclic structures sharing one ring atom with each other.

[0044] As used herein, the term "bridged ring" refers to a ring system formed from two or more cyclic structures sharing two non-adjacent atoms with each other.

[0045] 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 monocycloalkyl groups (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and the like) and bicycloalkyl groups, including spirocyclic, fused (or annelated) or bridged ring systems (i.e., spirocycloalkyl, fused (or annelated) cycloalkyl, and bridged cycloalkyl groups such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, and the like). In the present application, a cycloalkyl group is optionally substituted with one or more (such as 1 to 3) substituents, which are the same or different. A carbon atom on a cycloalkyl group is optionally substituted with an oxo group (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-forming carbon atoms, for example, C 3-6 cycloalkyl, which can be a monocycloalkyl group, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, or a bicycloalkyl group, for example, C 5-8 spirocycloalkyl, C 5-8 bridged cycloalkyl, C 5-8 fused cycloalkyl, C 5-6 spirocycloalkyl, C 5-6 bridged cycloalkyl, or C 5-6 fused cycloalkyl.

[0046] As used herein, the term "cycloalkoxy" means -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.

[0047] As used herein, the term "heterocyclic group" or "heterocycle" refers to an aliphatic monocyclic or polycyclic (e.g., fused, spirocyclic, or bridged) group having two 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, said heteroatoms including, but not limited to, oxygen, nitrogen, sulfur, and silicon atoms, wherein the carbon atoms and heteroatoms on said heterocyclic group are optionally substituted with oxo groups (e.g., forming C=O, S(=O) or S(=O)2), or optionally with one or more (such as 1 to 3) independently selected from halogens and C 1-3 Alkyl substituents. A "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 tetrahydrofuran, piperidine, morpholine, tetrahydropyran, piperazine, etc. 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, etc. As used herein, the term "3-10 membered heterocyclic group" refers to a heterocyclic group containing 3-10 ring atoms, including but not limited to 4-10 membered heterocyclic groups, 4-9 membered heterocyclic groups, 4-8 membered heterocyclic groups, 4-7 membered heterocyclic groups, 5-6 membered heterocyclic groups, 3-8 membered heterocyclic groups, 3-7 membered heterocyclic groups, 4-7 membered nitrogen-containing heterocyclic groups, 4-7 membered oxygen-containing heterocyclic groups, 4-7 membered sulfur-containing heterocyclic groups, 5-6 membered nitrogen-containing heterocyclic groups, 5-6 membered oxygen-containing heterocyclic groups, 5-6 membered sulfur-containing heterocyclic groups, etc., wherein each of the "nitrogen-containing heterocyclic group," "oxygen-containing heterocyclic group," and "sulfur-containing heterocyclic group" optionally also contains one or more other heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 3-10 membered heterocyclic groups include, but are not limited to, ethylene oxide, aziridinyl, aziridine, oxobutyl, tetrahydrofuranyl, pyrrolylyl, pyrrolidone (e.g., ... ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, dihydrofuranyl, dihydropyrrolyl, dihydrothienyl, and dihydropyranyl. As used herein, the term "3-8 membered heterocyclyl" means a heterocyclyl group 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, and the like, each of which optionally further contains one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 3-8 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl (e.g., ), imidazolidinyl, pyrazolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, trithianyl, dihydrofuranyl, dihydropyrrolyl, dihydrothienyl, and dihydropyranyl. As used herein, the term "3-8 membered heterocyclyl" means a heterocyclyl group 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, and the like, each of which optionally further contains one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples of 3-8 membered heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, pyrrolidinonyl (e.g.,

[0048] In the present application, a heterocyclyl group can form a fused ring structure with a heterocyclyl group or a cycloalkyl group, and the point of attachment of the fused ring structure to other groups can be on either the heterocyclyl group or the cycloalkyl group. Thus, the heterocyclyl groups of the present application also include, but are not limited to, heterocyclyl fused heterocyclyl, heterocyclyl fused cycloalkyl, mono-heterocyclyl fused mono-heterocyclyl, mono-heterocyclyl fused mono-cycloalkyl, e.g., 3-7 membered (mono)heterocyclyl fused 3-7 membered (mono)heterocyclyl, 3-7 membered (mono)heterocyclyl fused (mono)cycloalkyl, 3-7 membered (mono)heterocyclyl fused C 4-6 Examples of (mono)cycloalkyl groups include, but are not limited to, pyrrolidinyl fused cyclopropyl, cyclopentyl fused aziridinyl, pyrrolidinyl fused cyclobutyl, pyrrolidinyl fused pyrrolidinyl, pyrrolidinyl fused piperidinyl, pyrrolidinyl fused piperazinyl, piperidinyl fused morpholinyl, In the present application, a heterocyclyl group also includes bridged heterocyclyl and spirocyclyl groups.

[0049] 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 non-adjacent ring atoms, 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, and the like, e.g., etc. The "nitrogen-containing bridged heterocycle", "oxygen-containing bridged heterocycle", "sulfur-containing bridged heterocycle" optionally further contains one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur.

[0050] 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 from two or more saturated rings sharing one 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, and the like, for example The "nitrogen-containing spiroheterocycle", "oxygen-containing spiroheterocycle", "sulfur-containing spiroheterocycle" optionally further contains one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. The term "6-10 membered nitrogen-containing spiroheterocyclyl" refers to a spiroheterocyclyl group containing a total of 6-10 ring atoms and at least one of which is a nitrogen atom.

[0051] Examples of groups resulting from the fusion of a heterocyclyl group with an aryl group include, but are not limited to:

[0052] As used herein, the term "aryl", "phenyl", or "aromatic ring" refers to an all-carbon monocyclic or fused polycyclic ring system that has a conjugated pi-electron system. As used herein, the term "C 6-14 aryl (aromatic ring)", "C 6-10 aryl (aromatic ring)" means an aryl (aromatic ring) containing 6-14 carbon atoms, 6 to 10 carbon atoms, preferably phenyl (benzene ring) or naphthyl (naphthalene ring). The aryl group is optionally substituted with one or more (such as 1 to 3) same or different substituents (e.g., halogen, OH, CN, NO2, C1-C6 alkyl, etc.).

[0053] As used herein, the term "heteroaryl" or "heteroaromatic ring" refers to a monocyclic or polycyclic aromatic group containing one or more same 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 additionally in each case can be benzo-fused. The heteroatoms can be oxygen, nitrogen, or sulfur. The carbon atoms and heteroatoms on the heteroaryl group are optionally substituted with oxo groups (e.g., forming C=O, S(=O), or S(=O)2).

[0054] As used herein, the terms "5-14 membered heteroaryl" or "5-14 membered heteroaromatic ring", "5-10 membered heteroaryl" or "5-10 membered heteroaromatic ring" mean a heteroaryl (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 heteroaryls, 5-14 membered oxygen-containing heteroaryls, 5-14 membered sulfur-containing heteroaryls, 5-10 membered nitrogen-containing heteroaryls, 5-10 membered oxygen-containing heteroaryls, 5-10 membered sulfur-containing heteroaryls, 5-6 membered nitrogen-containing heteroaryls, 5-6 membered oxygen-containing heteroaryls, 5-6 membered sulfur-containing heteroaryls, and the like. The "nitrogen-containing heteroaryls", "oxygen-containing heteroaryls", and "sulfur-containing heteroaryls" each optionally contain one or more additional heteroatoms independently selected from oxygen, nitrogen, and sulfur. Examples include, but are not limited to, thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl, and the like, or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and the like, as well as 5-14 membered, 5-10 membered fused ring groups containing these groups.

[0055] In the present application, a heteroaryl (e.g., a mono-heteroaryl) can share two adjacent atoms with an aryl (e.g., a monocyclic aryl, e.g., phenyl), a heterocyclyl (e.g., a mono-heterocyclyl), a cycloalkyl (e.g., a monocycloalkyl), or another heteroaryl (e.g., another mono-heteroaryl) to form a fused ring structure, which can be at either heteroaromatic ring or other ring, including but not limited to (mono)heteroaryl fused (mono)heteroaryl, (mono)heteroaryl fused (mono)cycloaryl, (mono)heteroaryl fused (mono)heterocyclyl, and (mono)heteroaryl fused (mono)cycloalkyl, e.g., 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heteroaryl, 5-6 membered (mono)heteroaryl fused phenyl, 5-6 membered (mono)heteroaryl fused 5-6 membered (mono)heterocyclyl, or 5-6 membered (mono)heteroaryl fused C 4-6 (monocycloalkyl), e.g., 5-6 membered heteroaryl fused cyclobutyl, 5-6 membered heteroaryl fused cyclopentyl, or 5-6 membered heteroaryl fused cyclohexyl, examples of which include, but are not limited to, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzimidazole, quinolinyl, isoquinolinyl, and the like.

[0056] As used herein, the term "halo" or "halogen" group is defined to include F, Cl, Br, or I.

[0057] The term "substituted" means that one or more (e.g., one, two, three, four, five, six) hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, 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.

[0058] If a substituent is described as "optionally substituted" with one or more of a list of substituents, then the substituent can be (1) unsubstituted or (2) substituted with one or more of the listed substituents. If a carbon of a substituent is described as optionally substituted with one or more of a list of substituents, then one or more hydrogens on the carbon (to the extent there are any hydrogens present) can be replaced with independently selected optional substituents, alone or in combination. If a nitrogen of a substituent is described as optionally substituted with one or more of a list of substituents, then one or more hydrogens on the nitrogen (to the extent there are any hydrogens present) can each be replaced with an independently selected optional substituent.

[0059] If a substituent is described as "independently selected from" a group, then each substituent is selected independently of the other(s). Thus, each substituent can be the same or different from the other (other) substituent(s).

[0060] As used herein, the term "one or more" means 1 or more than 1, e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10, under reasonable conditions.

[0061] Unless indicated, as used herein, the point of attachment of a substituent can be from any suitable position of the substituent.

[0062] When a bond to a substituent is shown as a dashed line passing through a bond that connects two atoms in a ring, then such substituent can be bonded to either atom in the ring that can be substituted.

[0063] The present application also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the present application 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 usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the present application include, but are not limited to, isotopes of hydrogen, such as deuterium ( 2 H), tritium ( 3 H)); isotopes of carbon, such as 11 C, 13 C and 14 C); isotopes of chlorine, such as 36 Cl); isotopes of fluorine, such as 18 F); isotopes of iodine, such as 123 I and 125 I); isotopes of nitrogen, such as13 N and 15 Oxygen isotopes (e.g. 15 O, 17 O and 18 O); phosphorus isotopes (e.g. 32 P); and sulfur isotopes (e.g. 35 S). Certain isotopically-labeled compounds of the application (for example, those incorporating a radioactive isotope) are useful in drug and / or substrate tissue distribution studies (e.g., assays). The radioactive isotopes tritium, i.e., 3 H), and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready detection. Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of the application can generally be prepared by carrying out the procedures disclosed in the

[0064] The term "stereoisomers" denotes isomers having the same molecular formula but different structures, resulting from a difference in the arrangement of atoms or groups in space. In compounds with one or more asymmetric centers, racemates of the compounds, single enanti (or optical) isomers, and mixtures of enantiomeric or optical isomers can be present. Particular individual molecules can also exist as geometric isomers (cis / trans). Similarly, compounds of the application can exist as mixtures of two or more structurally distinct forms in rapid equilibrium (often referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers, and the like. For example, a nitroso-oxime can exist in the following tautomeric forms in equilibrium in solution:

[0065] It is understood that the scope of the application encompasses all such isomers or mixtures thereof in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%).

[0066] Solid lines (—), solid wedges or dashed wedges Chemical bonds of the compounds of the present application are depicted. The use of a solid line to depict a bond to an asymmetric carbon atom is intended to indicate all possible stereoisomers at that carbon atom (e.g., a particular enantiomer, a racemic mixture, etc.). The use of a solid or dashed wedge to depict a bond to an asymmetric carbon atom is intended to indicate that the depicted stereoisomer is present. When present in a racemic mixture, the solid and dashed wedges are used to define the relative stereochemistry, not the absolute stereochemistry. Unless otherwise indicated, the compounds of the present application are intended to exist in the form of stereoisomers, which include 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 application can exhibit more than one type of isomerism, and consist of mixtures thereof (e.g., racemic mixtures and diastereomeric pairs).

[0067] A wavy line as used herein Indicates that the bond configuration is not certain, e.g., can represent either the R or S configuration; as a wavy line Placed on a bond Indicates that the bond is a connecting bond to another atom, which bond can be a single or double bond. When When placed on a ring, indicates the point of attachment on the ring.

[0068] The present application encompasses all possible crystalline forms or polymorphs of the compounds of the present application, which can be a single polymorph or a mixture of more than one polymorph in any ratio.

[0069] Co-crystals refer to the combination of a pharmaceutically active molecule with other physiologically acceptable acid, base, salt, non-ionized compound molecules in the same crystal lattice by hydrogen bonding, π-π stacking, van der Waals forces and other non-covalent bonds.

[0070] It is also to be understood that certain compounds of the present application can exist in free form for treatment, or as appropriate, in the form of a pharmaceutically acceptable derivative thereof. In the present application, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites, or prodrugs, which upon administration to a patient in need thereof, are capable of providing (directly or indirectly) a compound of the present application or a metabolite or residue thereof. Accordingly, as used herein, reference to a "compound of the present application" is intended to encompass also the various derivative forms of the compound.

[0071] Pharmaceutically acceptable salts of the compounds of the present application include both acid and base addition salts. For example, hexafluorophosphate, meglumine salts, and the like. A review of suitable salts is given in Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, 2002).

[0072] As used herein, the term "ester" means an ester derived from the various generic compounds of the present application, which includes physiologically hydrolysable esters (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the compounds of the present application). The compounds of the present application can also be esters themselves.

[0073] The compounds of the present application can exist in the form of solvates (preferably hydrates), wherein the compound of the present application contains as a structural element of the crystal lattice of the compound a polar solvent, in particular, for example, water, methanol or ethanol. The amount of polar solvent, in particular water, can be present in stoichiometric or non-stoichiometric amounts.

[0074] One skilled in the art will appreciate that not all nitrogen-containing heterocycles are capable of forming N-oxides, as nitrogen requires an available lone pair of electrons to oxidize to an oxide. One skilled in the art will recognize nitrogen-containing heterocycles capable of forming N-oxides. One skilled in the art will also recognize that tertiary amines are capable of forming N-oxides. Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art, including but not limited to oxidation of heterocycles and tertiary amines with peroxy acids such as peroxyacetic acid and meta-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl hydroperoxides such as tert-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane. These methods for preparing N-oxides have been extensively described and reviewed in the literature, see for example: T. L. Gilchrist, Comprehensive Organic Synthesis, vol. 7, pp 748-750; A. R. Katritzky and A. J. Boulton, Eds., Academic Press; and G. W. H. Cheeseman and E. S. G. Werstiuk, Advances in Heterocyclic Chemistry, vol. 22, pp 390-392, A. R. Katritzky and A. J. Boulton, Eds., Academic Press.

[0075] Metabolites of the compounds of the present application, i.e., species derived from the compounds of the present application in vivo, are also within the scope of the present application. Such products can result, for example, from oxidation, reduction, hydrolysis, am idation, deam idation, esterification, enzymatic cleavage, and the like. Thus, the present application includes metabolites of compounds of the present application, including those produced by the ingestion of the compounds of the present application by a mammal.

[0076] The present application further includes within its scope prodrugs of the compounds of the present application, which are certain derivatives of the compounds of the present application which can have little or no pharmacological activity themselves but, upon administration, are converted into compounds of the present application having the desired activity, for example, by hydrolytic cleavage. Such prodrugs are typically functional derivatives of the compounds of the present application which are readily converted to the desired therapeutic agent in vivo. For additional information on prodrugs, see "Pro-drugs as Novel Delivery Systems", Vol. 14, of the A.C.S. Symposium Series (T. Higuchi and V. Stella). Prodrugs of the present application can be prepared by replacing appropriate functionalities present in the compounds of the present application 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).

[0077] The present application also encompasses compounds of the present application containing protecting groups. During any of the processes for preparation of the compounds of the present application, it can be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned, as well as to protect the compound of the present application itself, thus forming a chemically protected form of the compound of the present application. This can be achieved by means of conventional protecting groups, such as those described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which is hereby incorporated by reference. The protecting groups can be removed at a suitable subsequent stage using methods known from the art.

[0078] The term "about" refers to ± 10% of the indicated value, preferably ± 5%, more preferably ± 2%.

[0079] This application is in no way limited to the methods and materials described herein. In the event of any inconsistency between one or more of the incorporated documents, patents, and similar materials (including but not limited to defined terms, term application, described techniques, etc.) and the description of the present application, the description of the present application and the accompanying compound structural formulae shall control. In the present application, in the event of any inconsistency between a chemical name and a chemical structural formula, the chemical structural formula shall control.

[0080] Compound

[0081] In some embodiments, the present application provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof:

[0082] wherein:

[0083] A ring is selected from a 5-14 membered heteroaromatic ring and C 6-14 aromatic ring;

[0084] R 1 , R 3 , R 4 , R 5 each 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 heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl and 5-10 membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl, or heteroaryl being optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 ; or

[0085] two R 4 groups are taken together with the carbon atom to which they are attached to form a 3-6 membered cycloalkyl group, which cycloalkyl group is optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 5 groups; 9

[0086] and R 1 may also be absent;

[0087] R 7 , R 8 are each independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl, each of which alkyl, cycloalkyl, heterocyclyl is optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 groups; or,

[0088] R 7 , R 8 are taken together with the N atom to which they are attached to form a 3-8 membered heterocyclyl group, which heterocyclyl group is optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 groups;

[0089] R 9 are each independently, at each occurrence, selected from the group consisting of H, deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 , -COCH3, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 heteroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, each of which alkyl, alkoxy, heteroalkyl, cycloalkyl, cycloalkoxy, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 7 groups; 8 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C​​3-8 Substitution of cycloalkoxy groups and 3-8 membered heterocyclic groups;

[0090] Ring B is selected from 4-8 membered carbon rings, 4-8 membered heterocycles, 6-10 membered aromatic rings, and 5-10 membered heteroaromatic rings;

[0091] The C ring is selected from 5-8 membered carbon rings, 5-8 membered heterocycles, or 5-10 membered heteroaromatic rings;

[0092] L is selected from C, CR a and N;

[0093] R a Selected from hydrogen, deuterium, hydroxyl, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclic groups;

[0094] R 2 For -PR 6 ;

[0095] P represents a single bond, a double bond, and C represents a C bond. 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-14-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, C 6-10 Aryl, 5-14 heteroaryl, -R 7 -(C=O)-N(R 8 )-、-N(R 8 )-(C=O)-R 7 - The alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R 9 replace;

[0096] R 6 Selected from missing, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14The aryl group, wherein the alkyl, cycloalkyl, heterocyclic, aryl, or heteroaryl group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 replace;

[0097] m, n, and o are each independently selected from 0, 1, 2, 3, 4, 5, or 6.

[0098] In some embodiments, the compound of formula I provided by the present invention is not... (2,4-Dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azacyclobutane-3-yl)-8,9,10,10a-tetrahydropyridin[2,3-a]indolazine-7(5H)-one).

[0099] In some embodiments, the compound of formula I provided by the present invention is not...

[0100] In some embodiments, in the compound of formula I provided by the present invention, when P is selected from methylene, R 6 When selected from nitrogen-containing heterocyclic butanes, R 9 Not trifluoromethylpyridinyl; or,

[0101] When P is selected from a single bond, R 6 Not cyclopropyl; or, when P is selected from cyclopropyl, R 6 Not missing or H.

[0102] In some embodiments, the Formula I compounds provided by the present invention do not contain compounds 1-323.

[0103] In some embodiments, in the compounds of formula I provided by the present invention, ring A is selected from 5-14 membered heteroaromatic rings and C... 6-14 Aromatic rings;

[0104] R 1 R 3 R 4 R 5 Each time it appears, it is independently selected 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 group, -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 groups, C 3-8 Cycloalkoxy, C 6-10 Aryl and 5-10 heteroaryl groups, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, cycloalkoxy, aryl, or heteroaryl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or

[0105] Two R atoms bonded to the same carbon atom 4 Or two Rs 5 Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group, wherein the cycloalkyl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R... 9 replace;

[0106] Furthermore, R 1 It can also be missing;

[0107] R 7 R 8 Each is independently selected from H and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-8 Cycloalkyl and 3-8 membered heterocyclic groups, wherein each of the alkyl, cycloalkyl, and heterocyclic groups is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R groups. 9 Replace; or,

[0108] R 9 Each time it appears, it is independently selected from deuterium, tritium, halogen, -OH, -CN, oxo, and -NR. 7 R 8 -COCH3, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 Alkyl thio, C 1-6 Haloalkylthio, C 2-6 Heteroalkyl, C 3-8 cycloalkyl, C 3-8 Cycloalkoxy, 3-8 membered heterocyclic groups, C 6-10aryl and 5-14 membered heteroaryl, each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 7 R 8 , -COC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy and 3-8 membered heterocyclyl;

[0109] B ring is selected from partially unsaturated 4-8 membered carbocyclic ring, partially unsaturated 4-8 membered heterocyclic ring, 4-8 membered aromatic ring and 4-8 membered heteroaromatic ring;

[0110] C ring is selected from 5-8 membered carbocyclic ring, 5-8 membered heterocyclic ring or 5-8 membered heteroaromatic ring;

[0111] L is selected from C, CR a and N;

[0112] R a is selected from hydrogen, hydroxyl, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl;

[0113] R 2 is -P-R 6 ;

[0114] P is a single bond, a double bond, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and C 3-8 cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, C 6-10 aryl and 3-8 membered heterocyclyl, 5-14 membered heteroaryl and C 3-8 cycloalkyl, C 6-10 aryl and 5-14 membered heteroaryl, each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 ;

[0115] R 6 is selected from absence, C 1-10 alkyl, C 3-10cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and C 3-8 cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl, C 6-10 aryl and 3-8 membered heterocyclyl, 5-14 membered heteroaryl and C 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14 aryl, each of said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 substituents;

[0116] each of m, n, o is independently selected from 0, 1, 2, 3, 4, 5 or 6.

[0117] In certain embodiments, the present application provides compounds of Formula I wherein the A ring is selected from a phenyl ring and a 5-10 membered heteroaromatic ring.

[0118] In certain embodiments, the present application provides compounds of Formula I wherein the A ring is selected from a phenyl 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.

[0119] In certain embodiments, the present application provides compounds of Formula I wherein the A ring is selected from a pyridine, pyrrole, furan, thiophene, benzene, quinoline, indole, pyridopyrrole, pyrimidine, pyrrolopyridine, pyrazolopyridine, imidazopyridine, triazolopyridine, pyrazine and pyridazine ring.

[0120] In certain embodiments, the present application provides compounds of Formula I wherein the A ring is selected from a phenyl ring and a 5-9 membered heteroaromatic ring.

[0121] In certain embodiments, the present application provides compounds of Formula I wherein the A ring is selected from a phenyl 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.

[0122] In certain embodiments, the present application provides compounds of Formula I wherein the A ring is selected from a 5-6 membered nitrogen-containing heteroaromatic ring.

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

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

[0125] In certain embodiments, the present application provides compounds of Formula I wherein the A ring is selected from a pyridine ring, a furan ring, a pyrrole, a thiophene, a pyridazine.

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

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

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

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

[0130] In certain embodiments, the present application provides compounds of Formula I wherein R 1 , R 3 are independently selected from hydrogen, deuterium, tritium, oxo, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 , each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl is optionally substituted with one or more R 9 .

[0131] In certain embodiments, the present application provides compounds of Formula I wherein R 1 , R 3 are independently selected from hydrogen, deuterium, tritium, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6hydroxyalkyl, 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, -NR 7 R 8 , each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more R 9 .

[0132] In certain embodiments, the present application provides compounds of Formula I wherein R 1 , R 3 are independently selected from hydrogen, deuterium, tritium, oxo, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -CONR 7 R 8 , -NHCOC 1-6 alkyl, C 3-8 cycloalkyl, and 5-6 membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more R 9 .

[0133] In certain embodiments, the present application provides compounds of Formula I wherein R 1 , R 3 are independently selected from hydrogen, deuterium, tritium, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, -CONR 7 R 8 , -NHCOC 1-6 alkyl, C 3-8 cycloalkyl, and 5-6 membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more R 9 .

[0134] In certain embodiments, the present application provides compounds of Formula I wherein R 1 , R 3 are each independently selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, 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 heterocyclyl, -NHC 1-4 alkyl, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more R 9 ;

[0135] R 7 , R 8 are each independently selected from H, C 1-4 alkyl.

[0136] In certain embodiments, the present application provides compounds of Formula I wherein R 1 , R 3 are each independently selected from hydrogen, hydroxyl, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, C 2-4 alkenyl, C 2-4 alkynyl, -CONR 7 R 8 , -NHCOC 1-4 alkyl, C 3-5 cycloalkyl and 5-6 membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more R 9 ;

[0137] R 7 , R 8 are each independently selected from H, C 1-4 alkyl.

[0138] In certain embodiments, the present application provides compounds of Formula I wherein R 1 , R 3independently selected from oxo (=0), CH3, CH2CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, methoxy, -NH-CH3, vinyl, N-heterocyclobutyl CH2OH,

[0139] In certain embodiments, the present application provides compounds of formula I wherein R 1 , R 3 are independently selected from CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, vinyl, CH2OH, CH2CH3, -OCH3,

[0140] In certain embodiments, the present application provides compounds of formula I wherein R 1 , R 3 are independently selected from CH3, F, Cl, Br, cyano, CHF2, CF3, ethynyl, vinyl, CH2OH,

[0141] In certain embodiments, the present application provides compounds of formula I wherein the B ring is selected from 4-8 membered carbocyclic ring, 4-8 membered heterocyclic ring, C 6-10 aromatic ring and 5-10 membered heteroaromatic ring.

[0142] In certain embodiments, the present application provides compounds of formula I wherein the B ring is selected from 4-8 membered carbocyclic ring, 4-8 membered heterocyclic ring, 6-8 membered aromatic ring and 5-10 membered heteroaromatic ring.

[0143] For the case that the B ring of the present application is selected from partially unsaturated 4-8 membered carbocyclic ring and partially unsaturated 4-8 membered heterocyclic ring, since the A ring is aromatic, the bond formed between the two atoms of the B ring which are shared with the A ring must be unsaturated bond, thus the B ring is limited to partially unsaturated 4-8 membered carbocyclic ring and partially unsaturated 4-8 membered heterocyclic ring, and the bond at other positions of the B ring can be either saturated or unsaturated.

[0144] In certain embodiments, the present application provides compounds of formula I wherein the B ring is selected from 5-7 membered partially unsaturated heterocyclic ring, 5-7 membered partially unsaturated carbocyclic ring, 5-6 membered heteroaromatic ring and benzene ring.

[0145] In certain embodiments, the present application provides compounds of formula I wherein the B ring is selected from 5-6 membered partially unsaturated heterocyclic ring, 5-6 membered heteroaromatic ring and benzene ring.

[0146] In certain embodiments, the compounds of Formula I provided herein have a B ring selected from the group consisting of a benzene ring, a dihydropyrrole, a tetrahydropyrrole, a pyrrole, a pyridine, a cyclohexene, a cyclopentene, a dihydrofuran ring, and a tetrahydropyridine.

[0147] In certain embodiments, the compounds of Formula I provided herein have a B ring selected from the group consisting of a benzene ring, a dihydropyrrole, a pyrrole, a pyridine, a cyclohexene, a cyclopentene, and a dihydrofuran ring.

[0148] In certain embodiments, the compounds of Formula I provided herein have a B ring selected from the group consisting of a benzene ring, a dihydropyrrole, a pyrrole, a pyridine, a cyclohexene, a cyclopentene, and a dihydrofuran ring.

[0149] In certain embodiments, the compounds of Formula I provided herein have a B ring selected from the group consisting of

[0150] In certain embodiments, the compounds of Formula I provided herein have a B ring selected from the group consisting of

[0151] In certain embodiments, the compounds of Formula I provided herein have a B ring selected from the group consisting of

[0152] In certain embodiments, the compounds of Formula I provided herein have a B ring selected from the group consisting of 5 each occurrence is independently selected from the group consisting of hydrogen, deuterium, tritium, OR 7 , oxo, 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, -HCOC 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, 3-8 membered heterocyclyl, and C 3-8cycloalkoxy, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heterocyclyl, or cycloalkoxy is optionally substituted with one or more (as in 1, 2, 3, 4, 5, 6) R 9 substituted.

[0153] In certain embodiments, the present application provides compounds of Formula I wherein R 5 is independently selected from the group consisting of hydrogen, deuterium, tritium, oxo, hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkoxy, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl is optionally substituted with one or more R 9 ; or,

[0154] two R 5 together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl, said cycloalkyl is optionally substituted with one or more R 9 .

[0155] In certain embodiments, the present application provides compounds of Formula I wherein R 5 is independently selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, and C 1-6 hydroxyalkoxy, each of said alkyl, alkoxy is optionally substituted with one or more R 9 ; or,

[0156] two R 5 together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl, said cycloalkyl is optionally substituted with one or more R 9 .

[0157] In certain embodiments, the present application provides compounds of Formula I wherein R 5 is independently selected from the group consisting of hydrogen, deuterium, tritium, oxo, hydroxyl, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 1-4 hydroxyalkoxy, each of said alkyl, alkoxy is optionally substituted with one or more R 9 ; or,

[0158] two R 5 together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl group, which is optionally substituted with one or more R 9

[0159] In certain embodiments, the present application provides a compound of Formula I, wherein R 5 is independently selected from the group consisting of hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and C 1-4 hydroxyalkoxy, said alkyl, alkoxy groups are optionally substituted with one or more R 9 ; or,

[0160] two R 5 together with the carbon atom to which they are attached form a 3-5 membered cycloalkyl group, which is optionally substituted with one or more R 9

[0161] In certain embodiments, the present application provides a compound of Formula I, wherein R 5 is independently selected from the group consisting of H, CH3, oxo (=0), F, Cl, Br, CHF2, and CF3; or two R 5 together with the carbon atom to which they are attached form a cyclopropyl group.

[0162] In certain embodiments, the present application provides a compound of Formula I, wherein R 5 is independently selected from the group consisting of H, CH3, F, Cl, Br, CHF2, CF3; or two R 5 together with the carbon atom to which they are attached form a cyclopropyl group.

[0163] In certain embodiments, the present application provides a compound of Formula I, wherein the C ring is selected from a 5-7 membered carbocyclic ring, a 5-8 membered heterocyclic ring (e.g., a nitrogen-containing heterocyclic ring or a Si-containing heterocyclic ring), or a 5-8 membered heteroaromatic ring (e.g., a nitrogen-containing heteroaromatic ring).

[0164] In certain embodiments, the present application provides a compound of Formula I, wherein the C ring is selected from

[0165] In certain embodiments, the present application provides a compound of Formula I, wherein the C ring is selected from

[0166] In certain embodiments, the present application provides a compound of Formula I, wherein the C ring is selected from​​

[0167] In certain embodiments, the present application provides compounds of Formula I wherein R 4 is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkoxy, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl being optionally substituted with one or more R 9 ; or,

[0168] two R 4 , together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl, said cycloalkyl being optionally substituted with one or more R 9 .

[0169] In certain embodiments, the present application provides compounds of Formula I wherein R 4 is independently selected from hydrogen, deuterium, tritium, hydroxyl, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 1-4 hydroxyalkoxy, each of said alkyl, alkoxy being optionally substituted with one or more R 9 ; or,

[0170] two R 4 , together with the carbon atom to which they are attached, form a 3-5 membered cycloalkyl, said cycloalkyl being optionally substituted with one or more R 9 .

[0171] In certain embodiments, the present application provides compounds of Formula I wherein R 4 is 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 they are attached, form a cyclopropyl.

[0172] In certain embodiments, the present application provides compounds of Formula I wherein R 4 is independently selected from H, CH3, F, Cl, Br, CHF2, CF3; or two R 4 , together with the carbon atom to which they are attached, form a cyclopropyl.

[0173] In certain embodiments, the present application provides a compound of formula I that is a compound of formula II:

[0174] wherein ring A, ring C, R 1 , R 2 , R 3 , R 4 , L, m, n are as defined above for compounds of formula I;

[0175] represents Z 1 , X 1 , X 2 , Z 2 , X 3 , X 4 between any two adjacent symbols can be a single or double bond, provided that both adjacent bonds are not double bonds;

[0176] X 1 , X 2 are each independently selected from C, N;

[0177] X 3 , X 4 are each independently selected from C, N and CR 5a ;

[0178] Z 1 , Z 2 are 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 -;

[0179] R 5a and R 5b are as defined above for R 5 in compounds of formula I;

[0180] Z 3 is selected from -O-, -S- and -NR 5a ;

[0181] q is selected from 1 or 2.

[0182] In certain embodiments, the present application provides a compound of Formula II that is a compound of Formula III:

[0183] wherein, 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 a compound of Formula II.

[0184] In certain embodiments, the present application provides a compound of Formula III wherein,

[0185] Z 1 is selected from CR 5a R 5b and CR 5a ;

[0186] X 1 and X 2 are selected from C;

[0187] X 3 is selected from CR 5a or C;

[0188] X 4 is selected from N.

[0189] In certain embodiments, the present application provides a compound of Formula III wherein,

[0190] Z 1 is selected from -CR 5a R 5b -;

[0191] X 1 , X 2 are selected from C;

[0192] X 3 , X 4 are selected from CR 5a R 5b .

[0193] In certain embodiments, the present application provides a compound of Formula III wherein,

[0194] Z 1 is selected from O;

[0195] X 1 , X2 selected from C;

[0196] X 3 , X 4 selected from -CR 5a R 5b -.

[0197] In certain embodiments, the present application provides a compound of Formula III wherein

[0198] Z 1 selected from NR 5a ;

[0199] X 1 , X 2 selected from C;

[0200] X 3 , X 4 selected from CR 5a .

[0201] In certain embodiments, the present application provides a compound of Formula III wherein

[0202] Z 1 selected from S;

[0203] X 1 , X 2 selected from C;

[0204] X 3 , X 4 selected from CR 5a .

[0205] In certain embodiments, the present application provides a compound of Formula III wherein

[0206] Z 1 selected from NR 5a and S;

[0207] X 1 , X 2 , X 3 , X 4 selected from C.

[0208] In certain embodiments, the present application provides a compound of Formula III wherein

[0209] Z 1 selected from SiR 5a R 5b ;

[0210] X 1 , X 2 selected from C;

[0211] X 3 , X4 selected from CR 5a .

[0212] In certain embodiments, the present application provides a compound of Formula III, wherein

[0213] Z 1 selected from CR 5a and N;

[0214] X 1 , X 2 , X 3 selected from C;

[0215] X 4 selected from N.

[0216] In certain embodiments, the present application provides a compound of Formula III, wherein

[0217] Z 1 selected from CR 5a ;

[0218] X 1 , X 2 , X 4 selected from C;

[0219] X 3 selected from N.

[0220] In certain embodiments, the present application provides a compound of Formula III, wherein

[0221] Z 1 selected from CR 5a ;

[0222] X 1 selected from N;

[0223] X 2 , X 3 , X 4 selected from C.

[0224] In certain embodiments, the present application provides a compound of Formula III, wherein

[0225] Z 1 selected from N;

[0226] X 1 , X 4 selected from C;

[0227] X 2 , X 3 selected from C and N.

[0228] In certain embodiments, the present application provides a compound of Formula II is a compound of Formula IV:

[0229] wherein 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.

[0230] In certain embodiments, the present application provides a compound of formula IV, wherein Z 1 is selected from CR 5a ; X 1 , X 2 , X 4 is selected from C; X 3 is selected from N.

[0231] In certain embodiments, the present application provides a compound of formula II, wherein Z 1 is absent; Z 2 is selected from CR 5a ; X 1 , X 2 , X 3 is selected from C; X 4 is selected from N.

[0232] In certain embodiments, the present application provides a compound of formula II, wherein Z 1 , Z 2 is selected from -CR 5a R 5b -, -C(=O)-, CR 5a , -O-, -S-, N, -NR 7 -; X 1 , X 2 is selected from C and N; X 3 , X 4 is selected from C, CR 5a and N.

[0233] In certain embodiments, the present application provides a compound of formula II, which is a compound of formula V:

[0234] wherein 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.

[0235] Z 1 , Z 2 is selected from CR5a R 5b , CR 5a , NR 5a , N, O and S;

[0236] X 1 , X 2 is selected from C;

[0237] X 3 , X 4 is selected from C, CR 5a or N.

[0238] In certain embodiments, the present application provides a compound of formula I which is a compound of formula VI:

[0239] wherein, ring A, ring C, R 1 , R 2 , R 3 , L, m are as defined above for a compound of formula I;

[0240] represents Z 1 , X 1 , X 2 , Z 2 , X 3 , X 4 between any two adjacent symbols in ring B can be a single or a double bond, provided that two adjacent bonds are not simultaneously double bonds;

[0241] X 1 , X 2 are each independently selected from C, N;

[0242] X 3 , X 4 are each independently selected from C, N and CR 5a ;

[0243] Z 1 , Z 2 are 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 -;

[0244] R 5a and R 5b are as defined above for R 5 in the compounds of formula I;

[0245] Z 3 is selected from -0-, -S- and -NR 7 ;

[0246] Y is selected from a single bond, -(CR 4a R 4b ) p -(CR 4a R 4b )-, CR 4a , -C(=0)-, C, -0-, -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 -;

[0247] R 4a and R 4b are as defined above for R 4 in the compounds of formula I;

[0248] p is selected from 0, 1 or 2;

[0249] q is selected from 1 or 2.

[0250] In certain embodiments, the present application provides compounds of formula VI wherein Y is selected from -(CR 4a R 4b ) p -(CR 4a R 4b )-, -C(=0)-, -CR 4a =CR 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 1-6alkyl, C 1-6 haloalkyl, or, R 4a and R 4b together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl.

[0251] In certain embodiments, the present application 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-.

[0252] In certain embodiments, the present application provides compounds of Formula II, Formula VI, wherein

[0253] Z 1 is selected from a single bond, -CR 5a R 5b -, CR 5a , -O-, -S-, N, -NR 5a -, -SiR 5a R 5b -;

[0254] Z 2 is selected from a single bond, -CR 5a R 5b -, CR 5a , N, -NR 7 -, -SiR 5a R 5b -.

[0255] In certain embodiments, the present application provides compounds of Formula II, Formula VI, wherein

[0256] Z 1 is selected from -CR 5a R 5b -, CR 5a , -O-, -S-, N, -NR 5a -, -SiR 5a R 5b -;

[0257] Z 2 is selected from a single bond;

[0258] X 1 , X 2 is selected from C and N;

[0259] X 3 and X 4 are each independently selected from C, N, and CR5a .

[0260] In certain embodiments, the present application provides a compound of Formula I, selected from the group consisting of a group of Formula 1, Formula 2 or Formula 3:

[0261] wherein, in the group of Formula 1,

[0262] 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;

[0263] Z 1 , X 1 , X 2 , Z 2 , X 3 , X 4 as defined above for the compound of Formula II or the compound of Formula VI;

[0264] Y as defined above for the compound of Formula VI;

[0265] Y 1 is selected from the group consisting of absence, C, N and CR 3 ;

[0266] Y 2 , Y 3 , Y 4 are each independently selected from the group consisting of C, N, CR 3 , NR 3 , O and S;

[0267] wherein, in the group of Formula 2,

[0268] 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;

[0269] Z 1 , X 3 , X 4 as defined above for the compound of Formula II or the compound of Formula VI;

[0270] Y as defined above for the compound of Formula VI;

[0271] X 1 , X 2 , Y 2 , Y 3 are each independently selected from the group consisting of C and N;

[0272] Y4 , Y 6 , Y 7 , Y 8 each independently is selected from C, N, CR 3 , NR 3 , O and S;

[0273] Y 5 is selected from the group consisting of a deletion, C, N, CR 3 , NR 3 , O and S;

[0274] wherein the group represented by formula 3 is selected from the group consisting of:

[0275] R 1 , R 3 , R 5 , L, m, o are defined as above for a compound of formula I or a compound of formula VI;

[0276] Z 1 , X 3 , X 4 are defined as above for a compound of formula II or a compound of formula VI;

[0277] Y is defined as above for a compound of formula VI;

[0278] X 1 , X 2 , Y 1 , Y 2 each independently is selected from C and N;

[0279] Y 3 , Y 4 each independently is selected from CR 3 and N;

[0280] Y 5 , Y 6 , Y 7 each independently is selected from C, N, CR 3 , NR 3 , O and S.

[0281] In certain embodiments, the present application provides a compound of formula I, wherein the group represented by formula 1 is selected from the group consisting of:

[0282] wherein R 1 , R 3 , R 5 , Z 1 , X 1 , X 2 , X 3 , X 4 , Y 1 , Y2 , Y 3 , Y 4 , Y, L, m, o are as defined above for the group of formula 1.

[0283] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0284] wherein 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.

[0285] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0286] wherein 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 is not missing.

[0287] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0288] wherein R 1 , R 3 , R 5 , L, n, o are as defined above for the compounds of formula I, the group of formula 1; R 4 , n are as defined above for the compounds of formula I; p is 0, 1 or 2.

[0289] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0290] wherein R 1 , R 3 , R 5 , L, n, o are defined as above for the compounds of formula I, the groups of formula 1 ; R 4 , n are defined as above for the compounds of formula I; p is 0, 1 or 2.

[0291] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0292] wherein R 1 , R 3 , R 4 , R 5 , n, o are defined as above for the compounds of formula I or the groups of formula 1 ;

[0293] Z 1 is defined as above for the compounds of formula VI or the groups of formula 1 ; preferably, Z 1 is selected from -CR 5a R 5b -, CR 5a , -O-, -S-, N, NR 7 and SiR 5a R 5b .

[0294] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0295] wherein R 1 , R 3 , R 4 , R 5 , n, o are defined as above for the compounds of formula I or the groups of formula 1 ; Z 1 is defined as above for the compounds of formula VI or the groups of formula 1 ; preferably, Z 1 is selected from -CR 5a R 5b -, CR 5a , -O-, -S-, N, NR 7 and SiR 5a R 5b .

[0296] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0297] wherein,

[0298] R1 , R 3 , R 5 , o are as defined above for the group of formula 1 ;

[0299] R 4 , n are as defined above for the compound of formula I;

[0300] or, R 4 is as defined above for R 4a , R 4b in formula VI, R 5 is as defined above for R 5a , R 5b in formula VI;

[0301] Y 1 is selected from CH and N;

[0302] Z 1 is selected from CR 5a , N, NR 5a , O and S;

[0303] X 1 , X 2 , X 3 , X 4 is selected from C and N;

[0304] and, Z 1 , X 1 , X 2 , X 3 , X 4 are not simultaneously C.

[0305] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0306] wherein,

[0307] R 1 , R 3 , R 5 , n, o are as defined above for the group of formula 1 ;

[0308] R 4 , n are as defined above for the compound of formula I;

[0309] or, R 4 is as defined above for R 4a , R 4b in formula VI, R 5 is as defined above for R 5a , R 5b in formula VI;

[0310] Y 2 , Y4 CR 3 , -O-, -S-, N and NR 3 , and Y 2 , Y 4 are not simultaneously CR 3 .

[0311] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 1 is selected from:

[0312] wherein,

[0313] R 1 , R 5 , o are as defined above for the group of formula 1 ;

[0314] p is 0, 1, 2;

[0315] R 4 , n are as defined above for the compound of formula I;

[0316] or, R 4 is as defined above for R 4a , R 4b in formula VI, R 5 is as defined above for R 5a , R 5b in formula VI;

[0317] Y 2 is selected from -O-, -S-, N and NR 3 ;

[0318] Z 1 , Z 2 are selected from C, CR 5a and N.

[0319] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 2 is selected from formula 2-1 :

[0320] wherein, 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, o are as defined above for the group of formula 2.

[0321] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 2 is selected from:

[0322] wherein R 1 , R 5 , o are as defined above for the group of formula 2;

[0323] R 4 , n are as defined above for the compound of formula I;

[0324] or R 4 is as defined above for R 4a , R 4b in formula VI, R 5 is as defined above for R 5a , R 5b in formula VI;

[0325] Y 5 , Y 6 , Y 7 , Y 8 are selected from CR 3 and N.

[0326] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 3 is selected from the group of formula 3-1:

[0327] wherein,

[0328] 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, o are as defined above for the group of formula 3.

[0329] In certain embodiments, the present application provides compounds of formula I wherein the group of formula 3 is selected from:

[0330] wherein,

[0331] R 1 , R 5 , o are as defined above for the group of formula 3;

[0332] p is 0, 1, 2;

[0333] R 4 , n are as defined above for compounds of formula I;

[0334] or, R 4 is as defined above for R 4a in formula VI, R 4b is as defined above for R 5 in formula VI, R 5a is as defined above for R 5b in formula VI;

[0335] Y 5 , Y 6 , Y 7 are each independently selected from CR 3 and N.

[0336] In certain embodiments, the present application provides compounds of formula I wherein is selected from:

[0337] In certain embodiments, the present application provides compounds of formula I wherein is selected from:

[0338] In certain embodiments, the present application provides compounds of formula I wherein is selected from:

[0339] In certain embodiments, the present application provides compounds of formula I wherein is selected from:

[0340] In certain embodiments, the present application provides compounds of formula I wherein is selected from:

[0341] In certain embodiments, the present application provides compounds of formula I wherein L is selected from CR4a and N.

[0342] In certain embodiments, the present application provides compounds of Formula I wherein L is selected from CH and N.

[0343] In certain embodiments, the present application 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 heterocyclyl, C 6-10 aryl and C 3-8 cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, C 6-10 aryl and 3-8 membered heterocyclyl, 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 -, said C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and C 3-8 cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, C 6-10 aryl and 3-8 membered heterocyclyl, 5-14 membered heteroaryl and C 3-8 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 substituents.

[0344] In certain embodiments, the present application 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 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl and C 3-6 cycloalkyl and C6 aryl and C 3-6 cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl each optionally substituted with one or more R 9 substituents.

[0345] In certain embodiments, the present application provides compounds of Formula I wherein P is selected from a single bond, a double bond, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, said cycloalkyl or heterocyclyl each optionally substituted with one or more R 9substituted.

[0346] In certain embodiments, the present application 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 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and C6 aryl and C 3-6 cycloalkyl and C6 aryl and C 3-6 cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl each being optionally substituted with one or more R 9 substituted.

[0347] In certain embodiments, the present application provides compounds of Formula I wherein P is selected from -C 1-4 alkyl-(C=O)-NH-, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl and C6 aryl and C 3-6 cycloalkyl and C6 aryl and C 3-6 cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl each being optionally substituted with one or more R 9 substituted.

[0348] In certain embodiments, the present application provides compounds of Formula I wherein P is selected from C 3-6 cycloalkyl and 3-6 membered heterocyclyl, said cycloalkyl or heterocyclyl each being optionally substituted with one or more R 9 substituted.

[0349] In certain embodiments, the present application 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, said alkyl, cycloalkyl or heterocyclyl each being optionally substituted with one or more R 9 substituted.

[0350] In certain embodiments, the present application 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 1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and benzocyclopentanyl, said alkyl, cycloalkyl, benzocyclopentanyl or heterocyclyl each being optionally substituted with one or more R9 replace.

[0351] In some embodiments, in the compound of formula I provided by the present invention, P is selected from single bonds, double bonds, and -C bonds. 1-3 Alkyl-(C=O)-NH-, methylene, C 1-3 Halogenated alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azacyclobutyl, pyrrolidinyl, piperidinyl, piperazine, and benzocyclopentyl, wherein each of the alkyl, cycloalkyl, benzocyclopentyl, or heterocyclic group is optionally oxidized by one or more R groups. 9 Substitution; preferably, P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, pyrrolidinyl, piperidinyl, piperazine, wherein each of the cycloalkyl or heterocyclic groups is optionally replaced by one or more R 9 replace.

[0352] In some embodiments, in the compound of formula I provided by the present invention, P is selected from single bonds, double bonds, methylene groups, etc. Cyclobutyl,

[0353] Alternatively, P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CF3、

[0354] In some embodiments, in the compound of formula I provided by the present invention, P is selected from... Cyclobutyl,

[0355] In some embodiments, in the compound of formula I provided by the present invention, P is a single bond.

[0356] In some embodiments, in the compound of formula I provided by the present invention, R 6 Selected from missing, H, C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, C 6-10 aryl 3-8 membered heterocyclic, 5-14 membered heteroaryl 3-8 membered heterocyclic 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14 Aryl, the C 1-10 Alkyl, C 3-10 Cycloalkyl, 3-10 membered heterocyclic groups, C 6-10 Aryl benzo[C] 3-8 Cycloalkyl, 5-10-membered heteroaryl and 3-8-membered heterocyclic, C6-10 aryl and C 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14 each R 9 is independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, -ORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)N(Rb)2, -NRaS(O)2Rb, -SRa, -S(O)Rb, -S(O)2Rb, -S(O)2N(Ra)2, -CN, and -NO2, wherein each Rais independently H or alkyl, and each Rbis independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, or aryl, and each R

[0357] In certain embodiments, the present application provides a compound of Formula I, wherein R 6 is absent, and P is C 1-6 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, or C 6- aryl and C 3-6 cycloalkyl, each R 9 is independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, -ORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)N(Rb)2, -NRaS(O)2Rb, -SRa, -S(O)Rb, -S(O)2Rb, -S(O)2N(Ra)2, -CN, and -NO2, wherein each Rais independently H or alkyl, and each Rbis independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, or aryl, and each R

[0358] In certain embodiments, the present application provides a compound of Formula I, wherein R 6 is absent, and P is C 1-4 haloalkyl, cycloalkyl, heterocyclyl, or aryl, each R is independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, -ORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)N(Rb)2, -NRaS(O)2Rb, -SRa, -S(O)Rb, -S(O)2Rb, -S(O)2N(Ra)2, -CN, and -NO2, wherein each Rais independently H or alkyl, and each Rbis independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, or aryl, and each R 9 is independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, -ORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)N(Rb)2, -NRaS(O)2Rb, -SRa, -S(O)Rb, -S(O)2Rb, -S(O)2N(Ra)2, -CN, and -NO2, wherein each Rais independently H or alkyl, and each Rbis independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, or aryl, and each R

[0359] In certain embodiments, the present application provides a compound of Formula I, wherein R 6 is absent, and P is cycloalkyl, cycloalkyl, -CH2CF3,

[0360] In certain embodiments, the present application provides a compound of Formula I, wherein R 6 is absent, and P is cycloalkyl, cycloalkyl, heterocyclyl, or aryl, each R 9 is independently selected from the group consisting of halo, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, -ORa, -C(O)Ra, -C(O)ORa, -C(O)N(Ra)2, -NRaC(O)Rb, -NRaC(O)ORb, -NRaC(O)N(Rb)2, -NRaS(O)2Rb, -SRa, -S(O)Rb, -S(O)2Rb, -S(O)2N(Ra)2, -CN, and -NO2, wherein each Rais independently H or alkyl, and each Rbis independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, or aryl, and each R

[0361] In certain embodiments, the present application provides a compound of Formula I, wherein R

[0362] wherein E 1 , E 2 are independently selected from the group consisting of C, CH2, CH, N, NH, O, and S;

[0363] m1is selected from 0, 1, 2, 3, 4, 5, or 6;

[0364] 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 5 , R 6 , R 9 , L, m, n, o are as defined above for compounds of Formula I, Formula II, Formula VI.

[0367] In certain embodiments, the compounds of Formula VII are compounds of Formula VII-1, 1 , R 3 , R 4 , R 6 , R 9 , L, m, n, o are as defined above for compounds of Formula I, Formula II, Formula VI.

[0368] In certain embodiments, the compounds of Formula VII are compounds of Formula VII-1, 1 , R 3 , R 4 , R 6 , R 9 , L, m, and n are as defined above for compounds of Formula I, Formula II, Formula VI.

[0369] In certain embodiments, the compounds of Formula VII are compounds of Formula VII-1, 1 , E 2 is independently selected from C, CH, N, O, and S.

[0370] In certain embodiments, the present application provides compounds of Formula I are compounds of Formula VII-1,

[0371] wherein m2 is selected from 0, 1, 2, or 3;

[0372] m3 is selected from 1, 2, or 3;

[0373] Ring A, Ring B, Ring C, R 1 , R 3 , R 4 , R 5 , R 6 , R 9 , L, m, n, o are as defined above for compounds of Formula I, Formula II, Formula VI, and m1 is as defined in Formula VII.

[0374] In certain embodiments, the compounds of Formula VII-1 are compounds of Formula VII-1-1, 1 , R 3 , R4 6 9 L, m, n, o are as defined above for compounds of formula I, formula II, formula VI.

[0375] In certain embodiments, in the compound of formula VII-1, ring A, ring B, ring C, R 1 3 4 6 9 L, m, and n are as defined above for compounds of formula I, formula II, formula VI.

[0376] In certain embodiments, in the compound of formula VII-1, m1 is selected from 0 and 1, and m2 and m3 are both 1.

[0377] In certain embodiments, the present application provides a compound of formula I is a compound of formula VII-2,

[0378] wherein m2 is selected from 0, 1, 2, or 3;

[0379] m3 is selected from 1, 2, or 3;

[0380] ring A, ring B, ring C, R 1 3 4 5 6 9 L, m, n, o are as defined above for compounds of formula I, formula II, formula VI, and m1 is as defined in formula VII.

[0381] In certain embodiments, in the compound of formula VII-2, ring A, ring B, ring C, R 1 3 4 6 9 L, m, n, o are as defined above for compounds of formula I, formula II, formula VI.

[0382] In certain embodiments, in the compound of formula VII-2, ring A, ring B, ring C, R 1 3 4 6 9 L, m, and n are as defined above for compounds of formula I, formula II, formula VI.

[0383] In certain embodiments, the present application provides a compound of formula I is a compound of formula VIII, ​​​​​​​​​​​​​​​​​​​

[0384] wherein E 1 , E 2 is independently selected from C, CH2, CH, N, NH, O, S;

[0385] m1is selected from 0, 1, 2, 3, 4, 5, or 6;

[0386] m2is selected from 0, 1, 2, or 3;

[0387] m3is selected from 1, 2, or 3;

[0388] Ring A, Ring B, Ring C, R 1 , R 3 , R 4 , R 5 , R 9 , L, m, n, o are as defined above for compounds of Formula I, Formula II, Formula VI.

[0389] 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, n, o are as defined above for compounds of Formula I, Formula II, Formula VI.

[0390] 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 compounds of Formula I, Formula II, Formula VI.

[0391] In certain embodiments, E 1 , E 2 is independently selected from C, CH, N, O, and S.

[0392] In certain embodiments, the present application provides a compound of Formula I is a compound of Formula VIII-1,

[0393] wherein,

[0394] m1is selected from 0, 1, 2, 3, 4, 5, or 6;

[0395] m2is selected from 0, 1, 2, or 3;

[0396] m3is selected from 1, 2, or 3;

[0397] Ring A, Ring B, Ring C, R 1 , R 3 , R 4 , R5 R 9 L, m, n, o are as defined above for compounds of formula I, formula II, formula VI.

[0398] 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, n, o are as defined above for compounds of formula I, formula II, formula VI.

[0399] 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 compounds of formula I, formula II, formula VI.

[0400] In certain embodiments, the present application provides a compound of formula I is a compound of formula VIII-2,

[0401] 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;

[0402] ring A, ring B, ring C, R 1 R 3 R 4 R 5 R 9 L, m, n, o are as defined above for compounds of formula I, formula II, formula VI.

[0403] 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, n, o are as defined above for compounds of formula I, formula II, formula VI.

[0404] 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 compounds of formula I, formula II, formula VI.

[0405] In certain embodiments, the present application provides a compound of formula I wherein R 6 is absent or is selected from 3-10 membered heterocyclyl, 5-14 membered heteroaryl, and C 6-14aryl, each of said aryl or heteroaryl groups being optionally substituted with one or more R 9 substituted.

[0406] In certain embodiments, the present application provides a compound of Formula I wherein R 6 is selected from wherein G 1 , G 2 , G 3 , G 4 , G 5 is each independently selected from CH and N, represents a single or double bond.

[0407] In certain embodiments, the present application provides a compound of Formula I wherein R 6 is selected from absent, 3-8 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 aryl, C 1-6 alkyl, C 1-6 haloalkyl, each of said alkyl, heterocyclyl, aryl or heteroaryl groups being optionally substituted with one or more R 9 substituted.

[0408] In certain embodiments, the present application provides a compound of Formula I wherein R 6 is selected from 5-10 membered heteroaryl and C 6-10 aryl, each of said aryl or heteroaryl groups being optionally substituted with one or more R 9 substituted.

[0409] In certain embodiments, the present application provides a compound of Formula I wherein R 6 is selected from 5-6 membered nitrogen-containing heteroaryl and phenyl, each of said aryl or heteroaryl groups being optionally substituted with one or more R 9 substituted.

[0410] In certain embodiments, the present application provides a compound of Formula I wherein R 6 is selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl, thienyl, and benzoimidazolyl, each of said phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl, thienyl, and benzoimidazolyl being optionally substituted with one or more R 9 substituted.

[0411] In certain embodiments, the present application provides a compound of Formula I wherein R 6selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl, and benzimidazolyl, each of which is optionally substituted with one or more R 9 substituted.

[0412] In certain embodiments, the present application provides compounds of Formula I wherein R 6 selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidazolyl, thiadiazolyl, piperidinyl, thiazolyl, and benzimidazolyl, each of which is optionally substituted with one or more R 9 substituted.

[0413] In certain embodiments, the present application provides compounds of Formula I wherein R 6 wherein G 1 , G 2 , G 3 , G 4 , G 5 each is independently selected from CH and N.

[0414] In certain embodiments, the present application provides compounds of Formula I wherein R 6

[0415] In certain embodiments, the present application provides compounds of Formula I wherein R 6

[0416] In certain embodiments, the present application provides compounds of Formula I wherein R 9 each is independently selected from the group consisting of hydrogen, deuterium, halogen, C 1-4 alkyl, -CN, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 halocycloalkoxy, -NH2, -NH(CH2CH3), -N(CH3)2, C 1-4 haloalkylthio, C 3-6 cycloalkyl, and 5-6 membered heteroaryl, said 5-6 membered heteroaryl is optionally substituted with C 1-4 alkyl, C 1-4 haloalkyl.

[0417] In certain embodiments, the present application provides compounds of Formula I wherein R 9 ​​​each independently selected from hydrogen, deuterium, F, Cl, Br, CH3, -CN, -CHF2, -CF3, -CHF2, -OCH3, -OCHF2, trifluoromethyloxy, -OCH2CF3, -OCH(CH3)CF3, -NH2, -NH(CH2CH3), -N(CH3)2, -SCF3, cyclopropyl,

[0418] In certain embodiments, the present application provides compounds of Formula I wherein R 6 is selected from the group consisting of deletion, -CH3, -CH2CF3, and -CH2CH3.

[0419] In certain embodiments, the present application provides compounds of Formula I wherein R 6 is selected from the group consisting of

[0420] In certain embodiments, the present application provides compounds of Formula I wherein R 6 is selected from the group consisting of deletion, -CH3, -CH2CF3, and -CH2CH3.

[0421] In certain embodiments, the present application provides compounds of Formula I wherein R 6 is selected from the group consisting of

[0422] In certain embodiments, the present application provides compounds of Formula I wherein R 6 is selected from the group consisting of

[0423] In certain embodiments, the present application provides compounds of Formula I wherein R 6 is selected from the group consisting of -CH3, -CH2CF3, and -CH2CH3.

[0424] In certain embodiments, the present application provides compounds of Formula I wherein R 6 is selected from the group consisting of

[0425] In certain embodiments, the present application provides compounds of Formula I wherein R 9 each is independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -NR 7 R 8 , CN, C 3-8 cycloalkyl, C 1-6 haloalkylthio, C 1-6 haloalkoxy and 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted with one or more substituents selected from C 1-6 alkyl.

[0426] In certain embodiments, the present application provides compounds of Formula I wherein R 9 each is 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,

[0427] In certain embodiments, the present application provides compounds of Formula I wherein R 9 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, -NR 7 R 8 , CN, C 3-6 cycloalkyl, C 1-6 haloalkylthio and C 1-6 haloalkoxy.

[0428] In certain embodiments, the present application provides compounds of Formula I wherein R 9 is selected from hydrogen, halogen, -CN, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 haloalkyl, C 1-6 haloalkylthio, C 1-6 alkoxy and -NR 7 R 8 .

[0429] In certain embodiments, the present application provides compounds of Formula I wherein R 9H, F, CHF2, CF3, CH3, -OCH3, and NH2.

[0430] In certain embodiments, the present application provides compounds of formula I wherein R 9 H, F, CHF2, CF3, CH3, -OCH3, and NH2.

[0431] The compounds of the present application have an EC50for muscarinic receptor M4 positive allosteric modulatory activity of 50 from 1 to 10,000 nM, preferably < 1,000 nM, further preferably < 200 nM, more preferably < 100 nM.

[0432] In some embodiments, the compounds of the present application include, but are not limited to:

[0433] In the above compounds of formula I of the present application, the groups of all embodiments can be suitably selected in any combination to result in different general ranges or specific embodiments. These ranges and embodiments are all within the present application. The present application encompasses compounds resulting from any combination of the various embodiments.

[0434] Methods of preparation

[0435] The compounds of the present application can be prepared by any method known in the art. Reagents and starting materials are readily available to one of ordinary skill in the art. Individual isomers, enantiomers, and diastereomers can be separated or resolved 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. Eliel and S. H. Wilen).

[0436] In certain embodiments, the present application provides a first method of preparing a compound of Formula I, comprising the steps of:

[0437] reacting a compound of Formula I-A 2 with a compound of Formula R 2 to form a compound of Formula I;

[0438] wherein X is hydroxyl, halogen (e.g., iodo, bromo, chloro, fluoro), or a leaving group (e.g., methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluenesulfonate), and the like; and the compound I-A is bonded to R 2 through position L'; and reacting the compound of Formula I-A

[0439] ring A, ring B, ring C, L, R 1 , R 2 , R 3 , R 4 , R 5 , m, n, o are as defined above.

[0440] In some embodiments of the present application, the present application provides a method of preparing a compound of Formula I, wherein L is C, or CR a , R 2 , and X is hydroxyl, halogen (e.g., iodo, bromo, chloro, fluoro), or a leaving group (e.g., methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluenesulfonate), and the like; and the compound I-A is bonded to R 2 through position L'; and reacting the compound of Formula I-A

[0441] 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 SF, DIPEA, TEA, and the like. 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, and the like. The reaction is carried out at a suitable temperature, for example, at -78 °C to 150 °C.

[0442] 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 selected from palladium catalysts (e.g., palladium acetate, palladium chloride, and the like), metal rhodium catalysts, metal ruthenium catalysts, nickel catalysts, and the like. The metal coupling reaction can be carried out under literature conditions or similar conditions thereof.

[0443] In some embodiments of the present application, the method of preparing a compound of Formula I of the present application, wherein L is N, a compound of Formula I-A 2 The chemical bond is preferably constructed by an addition reaction or a metal coupling reaction.

[0444] 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, and the like. 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, and the like. The reaction is carried out at a suitable temperature, for example, at -78 °C to 150 °C.

[0445] The metal coupling reaction is preferably an Ullmann coupling reaction, a Buchwald-Hartwig coupling reaction, and a Chan-Lam coupling reaction.

[0446] 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.

[0447] 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.

[0448] the Chan-Lam coupling reaction, compound R 2 X in -X is a boronic acid or boronic ester. The Chan-Lam coupling reaction is performed under oxygen or air conditions. The Chan-Lam coupling reaction is performed under basic conditions. The Chan-Lam coupling reaction is preferably performed in the presence of a catalyst. The catalyst is preferably a copper catalyst.

[0449] In certain embodiments, the present application provides a second method of preparing a compound of Formula I, comprising the steps of:

[0450] reacting a compound of Formula I-B 2 with a compound R

[0451] wherein X is hydroxyl, halogen (e.g., iodo, bromo, chloro, fluoro), or a leaving group (e.g., methyl sulfonate, ethyl sulfonate, phenyl sulfonate, p-toluenesulfonate), and the like;

[0452] 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.

[0453] In some embodiments of the present application, the method of preparing a compound of Formula I of the present application, a compound of Formula I-B 6 The chemical bond is preferably constructed by an addition reaction or a metal coupling reaction.

[0454] The addition reaction is preferably performed in the presence of a suitable base. The base can be selected from NaH, NaOH, LDA, LiHDMS, n-BuLi, K2CO3, Cs2CO3, CSF, DIPEA, TEA, and the like. The addition reaction is preferably performed in a suitable solvent. The solvent can be selected from THF, 1,4-dioxane, DMF, DMSO, NMP, acetonitrile, and the like. The reaction is performed at a suitable temperature, for example, at -78 °C to 150 °C.

[0455] The metal coupling reaction is preferably an Ullmann coupling reaction, a Buchwald-Hartwig coupling reaction, and a Chan-Lam coupling reaction.

[0456] 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.

[0457] 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.

[0458] The Chan-Lam coupling reaction, compound R 2 X in -X is preferably a boronic acid or boronic ester. The Chan-Lam coupling reaction is preferably carried out under oxygen or air conditions. The Chan-Lam coupling reaction is preferably carried out under basic conditions. The Chan-Lam coupling reaction is preferably carried out in the presence of a catalyst, which is preferably a copper catalyst.

[0459] It will be appreciated by those skilled in the art that, depending on the structure of the desired product, one or more of the above preparation methods can be omitted, and the order of the reaction steps can be appropriately adjusted, and protection / deprotection reaction steps can be added or omitted, as necessary.

[0460] Pharmaceutical compositions, formulations, and methods of treatment

[0461] In some embodiments, the present application provides a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, and one or more pharmaceutically acceptable carriers.

[0462] In some embodiments, the present application provides a pharmaceutical formulation comprising a prophylactically or therapeutically effective amount of a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer, or isotopically-labeled compound thereof, and one or more pharmaceutically acceptable carriers. The pharmaceutical formulation is preferably a solid formulation, a semi-solid formulation, a liquid formulation, or a gaseous formulation.

[0463] In some embodiments, the pharmaceutical composition or pharmaceutical formulation can further comprise one or more additional therapeutic agents.

[0464] In some embodiments, the pharmaceutical composition or pharmaceutical preparation is preferably administered by oral, intravenous, intra-arterial, subcutaneous, intraperitoneal, intramuscular, or transdermal routes.

[0465] In some embodiments, the present application provides use of a compound of the present application 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 application, or a pharmaceutical preparation of the present application, in the manufacture of a medicament for preventing or treating a M4-mediated disease or condition.

[0466] In some embodiments, the present application provides use of a compound of the present application 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 application, or a pharmaceutical preparation of the present application, in the manufacture of a medicament for modulating (preferably positively allosteric modulating) M4 activity.

[0467] In some embodiments, the present application provides a compound of the present application 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 application, or a pharmaceutical preparation of the present application, for use in preventing or treating a M4-mediated disease or condition.

[0468] In some embodiments, the present application provides a method of preventing or treating a M4-mediated disease or condition, comprising administering to an individual in need thereof an effective amount of a compound of the present application 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 application, or a pharmaceutical preparation of the present application.

[0469] In some embodiments, the M4-mediated disease or condition comprises Alzheimer’s disease, schizophrenia, psychosis, Parkinson’s disease, pain, addiction, Huntington’s disease, sleep disorders, cognitive impairment (e.g., mild cognitive impairment, age-related mild cognitive impairment, and amnestic mild cognitive impairment), movement disorders, dry mouth, pulmonary arterial hypertension, chronic obstructive pulmonary disease (COPD), asthma, urinary incontinence, glaucoma, Trisomy 21 (Down syndrome), cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

[0470] 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.

[0471] The EC50value of the positive allosteric modulation activity of the compounds of the present application on the muscarinic acetylcholine receptor M4 50 at 1 to 10000 nM, preferably

[0472] ≤ 1000 nM, further preferred ≤ 200 nM, more preferred ≤ 100 nM.

[0473] A "pharmaceutically acceptable carrier" in the present application means a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered, and which is suitable for use with humans and / or other animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio as in the ordinary medical judgment.

[0474] Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of this application include, but are not limited to, sterile aqueous solutions or dispersions. Examples of suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences (1990).

[0475] The pharmaceutical compositions of the present application can act systemically and / or topically. To this end, they can be administered by suitable routes.

[0476] For these administration routes, the pharmaceutical compositions of the present application can be administered in suitable dosage forms.

[0477] The term "effective amount" as used herein means that amount of a compound which will relieve to some extent one or more of the symptoms of the disorder being treated.

[0478] Dosage regimens can be adjusted to provide the optimum 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 exigencies of the therapeutic situation. It is important that dosage values be taken as being typical of the conditions under which treatment is carried out, and that dosage values can vary according to the type and severity of the condition being treated. It is further to be understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.

[0479] The amount of a compound of the present application administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the judgment of the prescribing physician. In general, an effective dosage in the range of about 0.0001 to about 50 mg per kg body weight per day is used. In some instances, dosage levels less than the lower range above can be sufficient, while in other cases still larger doses up to the upper level stated can be employed, provided they are first divided into several small doses for administration throughout the day.

[0480] The compounds of the present application can be present in the pharmaceutical composition or pharmaceutical formulation in an amount or dosage of about 0.01 mg to about 1000 mg.

[0481] The term "treating" as used herein, 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, unless otherwise indicated.

[0482] "Individual" as used herein includes a human or non-human animal. Exemplary human individuals include a human individual (referred to as a patient) suffering from a disease (e.g., a disease described herein) or a normal individual. "Non-human animals" in the present application include all vertebrates, e.g., non-mammals (e.g., birds, amphibians, reptiles) and mammals, e.g., non-human primates, domestic animals, and / or laboratory animals (e.g., sheep, dogs, cats, cows, pigs, etc.).

[0483] In some embodiments, the pharmaceutical composition or pharmaceutical formulation of the present application can 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 method of treatment of the present application can further comprise administering one or more additional therapeutic or prophylactic agents (e.g., other drugs for treating M4-mediated diseases or conditions). DETAILED DESCRIPTION

[0484] EMBODIMENTS

[0485] The present application is further described in connection with the following examples, which are provided not to limit the scope of the application.

[0486] Abbreviations used herein have the following meanings:

[0487] The compounds of the present application were isolated and purified by preparative TLC, silica gel column chromatography, Prep-HPLC and / or flash column chromatography, and their structures were confirmed by 1H NMR and / or MS. Reaction monitoring was carried out using TLC or LC-MS.

[0488] 1 H NMR spectra were recorded on a Bruker superconducting nuclear magnetic resonance spectrometer (model AVANCE III HD 400 MHz).

[0489] LC / MS was carried out using Agilent 1260 Infinity / Agilent 6120 Quadrupole.

[0490] TLC was carried out using silica gel GF 254 as the stationary phase.

[0491] Column chromatography was generally carried out using 200-300 mesh silica gel (Qingdao Marine) as the stationary phase.

[0492] Flash column chromatography was carried out using a Biotage flash column chromatograph.

[0493] Prep-HPLC was carried out using Agilent 1260 and Waters 2489.

[0494] Microwave reactions were carried out using a Biotage Initiator microwave reactor.

[0495] In the following examples, the temperature of the reaction was room temperature (15-30 °C) unless otherwise specified.

[0496] The reagents used in the present application were purchased from Acros Organics, Aldrich Chemical Company, or companies such as TCI Chemicals.

[0497] Synthetic Examples:

[0498] Synthesis of Intermediate 1: 2,4-dimethyl-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[l,2- a]pyrazin-6(7H)-one (Int-1)

[0499] Step one: Synthesis of ethyl 4,6-dimethyl-lH-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound Int-1-2)

[0500] Ethyl 5-amino-lH-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] + .

[0501] Step two: synthesis of ethyl 1-(2-((tert-butoxycarbonyl)amino)ethyl)-4,6-dimethyl- lH-pyrrolo[2,3-b]pyridine-2-carboxylate (compound Int-1-3)

[0502] 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 sequentially added. The mixed solution was heated to 80 °C and stirred overnight, and then cooled to room temperature. Water was added to the solution, and extraction was performed with ethyl acetate. The organic phase was dried with 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] + .

[0503] Step three: synthesis of 2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[l,2-a]pyrazin- 6(7H)-one (compound Int-1)

[0504] 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. Stirring was performed at room temperature for 0.5 hours, and the reaction was confirmed to be complete by LCMS. Concentration was performed under reduced pressure. The obtained compound was dissolved in 20 mL of anhydrous methanol, and anhydrous potassium carbonate (2.41 g, 17.43 mmol) was added. Stirring was performed at room temperature for 8 hours, and concentration was performed under reduced pressure. Purification was performed 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 (400 MHz, CDC13) δ 7.39 (s, 1H), 6.87 (s, 1H), 6.50 (s, 1H), 4.61 - 4.53 (m, 2H), 3.84 (t, J = 7.0 Hz, 2H), 2.68 (s, 3H), 2.61 (s, 3H).

[0505] Synthesis of intermediate 2: 2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one

[0506] Step one: Synthesis of (E)-ethyl 3-(3-cyano-4,6-dimethylpyridin-2-yl)acrylate (Compound Int-2-2)

[0507] To a round bottom flask was added compound 2-chloro-4,6-dimethylnicotinonitrile (10 g, 60.02 mmol), 1,4-dioxane (100 mL), water (10 mL), followed by (E)-ethyl 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), Pd(dppf)2Cl2(4.39 g, 6.00 mmol). After nitrogen replacement, the temperature was raised to 110 °C and stirred for 12 hours. LCMS detected that the reaction was complete, the temperature was returned to room temperature, 1,4-dioxane was removed under reduced pressure, water was added, dichloromethane was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and 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] + .

[0508] Step two: 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)

[0509] To a round-bottom flask was added compound (E)-3-(3-cyano-4,6-dimethylpyridin-2- yl)acrylic acid ethyl ester (6.2 g, 26.93 mmol), 5% sodium hydroxide aqueous solution 60 mL, and the mixture was stirred at 60 °C for 4 h, then the temperature was increased to 100 °C and the reaction was continued for another 4 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, and the pH was adjusted to 6-7 with acid in an ice bath. The product (2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7- yl)acetic acid) was purified by C18 reverse-phase flash column chromatography (3.8 g, 17.25 mmol), MS [ESI]: m / z = 221.1, [M+H] + .

[0510] Step Three: Synthesis of 2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7- yl)acetamide (compound Int-2-4)

[0511] To a round-bottom flask was added compound (E)-3-(3-cyano-4,6-dimethylpyridin-2- yl)acrylic acid ethyl ester (6.2 g, 26.93 mmol), 5% sodium hydroxide aqueous solution 60 mL, and the mixture was stirred at 60 °C for 4 h, then the temperature was increased to 100 °C and the reaction was continued for another 4 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, and the pH was adjusted to 6-7 with acid in an ice bath. The product (2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7- yl)acetic acid) was purified by C18 reverse-phase flash column chromatography (3.8 g, 17.25 mmol), MS [ESI]: m / z = 221.1, [M+H] + .

[0512] Step four: synthesis of 2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7- yl)ethan-1 -amine (Compound Int-2-5) Into a round-bottom flask was placed 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), anhydrous tetrahydrofuran (30 mL), and the flask was purged with nitrogen three times. Borane tetrahydrofuran complex (82.10 mmol, 10 eq) was slowly added under ice-bath cooling, and the addition was completed. The reaction was continued at 70 °C for 24 h. LCMS detection showed that the reaction was complete. The reaction was quenched with methanol (100 mL) under ice-bath cooling. After no gas was released, 4 M hydrochloric acid (50 mL) was added, and the reaction was stirred at 60 °C overnight. The reaction was cooled to room temperature, and NaOH aqueous solution was added to adjust the pH to 7-8 under ice-bath cooling. The reaction was concentrated under reduced pressure, and 2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethan-1 -amine (0.8 g, 4.18 mmol) was obtained by C18 reverse-phase flash column chromatography. MS [ESI]: m / z = 192.1, [M+H]+. + .

[0513] Step five: 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)

[0514] Into a round-bottom flask was placed 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), and the reaction was stirred at room temperature for 2 h. The reaction was continued at 70 °C for 48 h. LCMS detection showed that the reaction was complete. The reaction was concentrated under reduced pressure, and 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) was obtained by C18 reverse-phase flash column chromatography. MS [ESI]: m / z = 218.1, [M+H]+.

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

[0516] Step one: Synthesis of methyl 4-((4-oxopentan-2-ylidene)amino)thiophene-2-carboxylate (Compound Int-3-2)

[0517] To a round-bottom flask was added 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). The temperature was raised to 80 °C and stirring was continued for 16 h. The reaction was cooled to room temperature and quenched with saturated brine, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound Int-3-2 (6.2 g, 25.8 mmol). MS (ESI): m / z = 240.1, [M+H] + .

[0518] Step two: Synthesis of methyl 5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-3)

[0519] To a round-bottom flask was added compound Int-3-2 (6.2 g, 25.8 mmol), polyphosphoric acid (50 mL). The temperature was raised to 130 °C and stirring was continued for 5 h. LCMS showed the reaction was completed, the reaction was diluted with water (500 mL) while hot and the pH was adjusted to neutral, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound Int-3-3 (3.5 g, 16.1 mmol). MS (ESI): m / z = 222.1, [M+H] + .

[0520] Step three: Synthesis of methyl 3-bromo-5,7-dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-4)

[0521] To a round-bottom flask was added compound Int-3-3 (3.5 g, 16.1 mmol), trifluoroacetic acid / concentrated sulfuric acid (20 mL, 4:1), NBS (5.7 mg, 32.2 mmol) was added slowly under vigorous stirring, stirring was continued at room temperature for 24 h. LCMS showed the reaction was completed, the reaction was diluted with ice water slowly and the pH was adjusted to neutral, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give compound Int-3-4 (1.5 g, 5.1 mmol). MS (ESI): m / z = 300.1, [M+H] + .

[0522] Step four: Synthesis of methyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-5,7- dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-5)

[0523] Into a round bottom flask was placed compound Int-3-4 (1.5 g, 5.1 mmol), toluene (90 mL), water (30 mL), followed by (2-((tert-butoxycarbonyl)amino)ethyl)potassium trifluoroborate (2.5 g, 10.2 mmol), cesium carbonate (4.9 g, 15.3 mmol), Ruphos (700 mg, 1.5 mmol), Pd(OAc)2 (115 mg, 0.51 mmol). After nitrogen purging for three times, the temperature was raised to 80 °C and stirred for 16 h. LCMS showed the reaction was complete, the reaction was cooled to room temperature, toluene was removed by reduced pressure, water was added, and the mixture was extracted with dichloromethane for three times, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure. Compound Int-3-5 (501 mg, 1.3 mmol) was obtained by column chromatography. MS (ESI): m / z = 365.1, [M+H] + .

[0524] Step five: Synthesis of trifluoroacetate salt of methyl 3-(2-aminoethyl)-5,7- dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound Int-3-6)

[0525] Into a round bottom flask was placed compound Int-3-5 (501 mg, 1.3 mmol), dichloromethane / trifluoroacetic acid (10 mL, 4:1). The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete, the reaction was concentrated by reduced pressure to give compound Int-3-6 (337 mg, 1.28 mmol). MS (ESI): m / z = 265.1, [M+H] + .

[0526] Step six: Synthesis of 2,4-dimethyl-8,9-dihydrothieno[3,2-b:5,4-c']dipyridin-6(7H)- one (Compound Int-3)

[0527] Into a round bottom flask was placed compound Int-3-6 (337 mg, 1.28 mmol), anhydrous methanol (10 mL), potassium carbonate (345 mg, 2.5 mmol). The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete, saturated aqueous ammonium chloride solution was added to quench, methanol was removed by reduced pressure, the residue was added water, and the mixture was extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated by reduced pressure. Compound Int-3 (255 mg, 1.1 mmol) was obtained by column chromatography. MS (ESI): m / z = 233.1, [M+H] + .

[0528] Synthesis of intermediate 4: 7-(azetidin-3-yl)-2,4-dimethyl-8,9-dihydrothieno[3,2- b:5,4-c']dipyridine-6(7H)-one

[0529] Step one: 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)

[0530] Into a round-bottom flask was added 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), dichloromethane (50 mL). Stirring at room temperature for 2 hours. LCMS detection reaction was complete, saturated aqueous ammonium chloride solution was added to quench, dichloromethane extraction 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography to give compound Int-4-1 (2.0 g, 4.77 mmol). MS (ESI): m / z = 420.3, [M+H] + .

[0531] Step two: Synthesis of tert-butyl 3-(2,4-dimethyl-6-oxo-8,9-dihydrothieno[3,2-b:5,4-']dipyridin- 7(6H)-yl)azetidine-1-carboxylate (Compound Int-4-2)

[0532] Into a round-bottom flask was added compound Int-4-1 (2.0 g, 4.77 mmol), potassium carbonate (1.97 g, 14.31 mmol), methanol (30 ml). Stirring at room temperature for 2 hours. LCMS detection reaction was complete, filtered, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by column chromatography to give compound Int-4-2 (1.6 g, 4.13 mmol). MS (ESI): m / z = 389.2, [M+H] + .

[0533] Step three: Synthesis of 7-(azetidin-3-yl)-2,4-dimethyl-8,9-dihydrothieno[3,2-b:5,4- c']dipyridine-6(7H)-one (Compound Int-4)

[0534] To a round bottom flask was added compound Int-4-2 (1.6 g, 4.13 mmol), dichloromethane (20 mL), trifluoroacetic acid (5 mL), stirred at room temperature for 4 hours. LCMS detected that the reaction was complete, concentrated under reduced pressure, purified by basic prep-HPLC to give the title compound Int-4 (500 mg, 1.74 mmol). MS (ESI): m / z = 288.5, [M+H] + .

[0535] Synthesis of intermediate 5: 8-(azetidin-3-yl)-2,4-dimethyl-8,9,10,10a- tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one

[0536] Step one: synthesis of 3-(2-(2,4-dimethyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-7-yl)acetamido)azetidine-1-carboxylate benzyl ester (compound Int-5-01)

[0537] To a round bottom flask was 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), N-methylimidazole (7.46 g, 90.8 mmol), stirred at room temperature for 10 minutes, then added 3-aminoazetidine-1-carboxylate benzyl ester (7.02 g, 34.1 mmol) and continued to react for 12 hours, LCMS detected that the reaction was complete, purified by C18 reverse phase flash column chromatography to give compound Int-5-01 (6.5 g, 15.9 mmol), MS (ESI): m / z = 409.1, [M+H] + .

[0538] Step two: synthesis of 3-((2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7- yl)ethyl)amino)azetidine-1-carboxylate benzyl ester (compound Int-5-02)

[0539] To a round-bottom flask, was added compound Int-5-01 (6.5 g, 15.9 mmol), anhydrous tetrahydrofuran (100 mL), after nitrogen replacement, borane tetrahydrofuran complex (159.1 mmol) was slowly added under ice-bath, after the addition was completed, the temperature was increased to 70 °C and the reaction was continued for 10 hours. LCMS detection showed that the reaction was complete, the temperature was returned to room temperature, methanol (200 mL) was added to quench the reaction under ice-bath, after no gas was released, it was rotary evaporated, 50 mL of methanol was added for dissolution, 4M hydrochloric acid (100 mL) was added, the temperature was increased to 60 °C and stirred overnight, the temperature was cooled to room temperature, NaOH aqueous solution was added to adjust the pH to 7-8, dichloromethane was extracted for 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by C18 reverse phase flash column chromatography to obtain compound Int-5-02 (5 g, 13.14 mmol), MS (ESI): m / z = 381.1, [M+H] + .

[0540] Step three: 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-carboxylic acid benzyl ester (compound Int-5-03)

[0541] To a round-bottom flask, was added compound Int-5-02 (5 g, 13.14 mmol), anhydrous tetrahydrofuran (50 mL), triethylamine (1.6 g, 15.7 mmol), N,N'-carbonyldiimidazole (2.13 g, 13.14 mmol), the reaction was carried out at room temperature for 2 hours, then the temperature was increased 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 silica gel column preparation to obtain compound Int-5-03 (3 g, 7.38 mmol), MS (ESI): m / z = 407.1, [M+H] + .

[0542] Step four: 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)

[0543] To a round-bottom flask, was added compound Int-5-03 (3 g, 7.38 mmol), methanol (30 mL), palladium hydroxide (5.18 g, 36.9 mmol), the reaction was carried out at room temperature for 4 hours, LCMS detection showed that the reaction was complete, the reaction liquid was filtered through diatomite, washed with methanol, the filtrate was concentrated under reduced pressure, and purified by silica gel column preparation to obtain Int-5 (1.9 g, 6.98 mmol), MS (ESI): m / z = 273.1, [M+H] + .

[0544] Synthesis of intermediate 6: 2-(6-(tert-butoxy carbonyl)-2,4-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-7-yl)acetic acid (Int-6)

[0545] Step one: Synthesis of (2-chloro-4,6-dimethylpyridin-3-yl)methanamine (compound Int-6-2)

[0546] Into a round bottom flask was added compound Int-6-1 (5 g, 30.01 mmol), anhydrous tetrahydrofuran (50 mL), and the flask was purged with nitrogen three times. Then borane tetrahydrofuran complex (61.1 mmol) was slowly added under ice bath, and the reaction was continued at 70 °C for 6 hours. The reaction was complete by LCMS detection, and the reaction was quenched with methanol (50 mL) under ice bath. After no gas was released, 4M hydrochloric acid (30 mL) was added, and the reaction was continued at 60 °C for 6 hours. The reaction was cooled to room temperature, and NaOH aqueous solution was added to adjust the pH to 7-8 under ice bath. The organic phase was dried with 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] + .

[0547] Step two: Synthesis of tert-butyl ((2-chloro-4,6-dimethylpyridin-3-yl)methyl)carbamate (compound Int-6-3)

[0548] Into a round bottom flask was added compound Int-6-2 (4.2 g, 24.61 mmol), dichloromethane (50 mL), and triethylamine (3.74 g, 36.92 mmol). The reaction was continued at room temperature for half an hour, and di-tert-butyl dicarbonate (6.45 g, 29.54 mmol) was added. The reaction was continued for 2 hours. The reaction was complete by LCMS detection, and the reaction was concentrated under reduced pressure. The crude product was purified by column chromatography to obtain compound Int-6-3 (5.6 g, 20.68 mmol), MS (ESI): m / z = 271.1, [M+H] + .

[0549] Step three: 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)

[0550] To a round bottom flask was added compound Int-6-3 (5.6 g, 20.68 mmol), DMF (60 mL), water (6 mL), followed by (E)-2-(ethoxycarbonyl)vinylboron pinacol ester (7.01 g, 31.02 mmol), cesium carbonate (13.48 g, 41.37 mmol), cataCXium APd G3 (1.51 g, 2.07 mmol). After nitrogen purging, the temperature was raised to 110 °C and stirred for 36 h. LCMS indicated the reaction was complete, the reaction was allowed to cool 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] + .

[0551] Step Four: 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)

[0552] To a round bottom flask was added compound Int-6-4 (3.8 g, 11.36 mmol), methanol (20 mL), water (5 mL), NaOH (681 mg, 17.04 mmol), and the reaction was stirred at 60 °C for 4 h. LCMS indicated the reaction was complete, the reaction was allowed to cool to room temperature, and the pH was adjusted to 6-7 with acid in an ice bath. The product was purified by C18 reverse phase prep purification to give compound Int-6 (2.8 g, 9.14 mmol), MS (ESI): m / z = 307.1, [M+H] + .

[0553] 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)

[0554] Step One: Synthesis of (2,5-dichloro-4,6-dimethylpyridin-3-yl)methanamine (Compound Int 7-2)

[0555] Into a four-necked flask was placed compound Int 7-1 (300 g, 1.49 mol), tetrahydrofuran (500 mL), then temperature was controlled to 0 °C, borane tetrahydrofuran complex (1 M, 3.51 mol, 3.51 L) was added dropwise slowly, after the addition was completed, the temperature was raised to 60 °C, and stirred for 14 hours. TLC (PE:EA = 2:1) detection reaction was complete, cooling to 0 °C, to the reaction solution was slowly added methanol 300 mL while stirring, after the addition was completed, stirred for one hour, reduced pressure concentration, to obtain compound Int 7-2 (300 g, crude).

[0556] Step two: synthesis of tert-butyl ((2,5-dichloro-4,6-dimethylpyridin-3- yl)methyl)carbamate (compound Int 7-3)

[0557] Into a four-necked flask was placed compound Int 7-2 (300 g, crude), triethylamine (320 g, 3.16 mol), dichloromethane (800 mL), then temperature was controlled to 0 °C, di-tert-butyl dicarbonate (405 g, 1.86 mol) was added dropwise slowly, after the addition was completed, the temperature was raised to 25 °C, and stirred for 2 hours. TLC (n-heptane: ethyl acetate = 2:1) detection reaction was complete, reduced pressure concentration, to obtain crude product, the crude product was slurried with (n-heptane: ethyl acetate = 10:1), and filtered to obtain compound Int 7-3 (390 g, 1.28 mol).

[0558] Step three: 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)

[0559] Into a four-necked flask was placed compound Int 7-3 (65 g, 212.98 mmol), dimethylbutyldiglycolic acid 2-(ethoxycarbonyl)vinyl ester (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). After nitrogen replacement for three times, the temperature was raised to 110 °C, and stirred for 15 hours. TLC (n-heptane: ethyl acetate = 3:1) detection reaction was complete, saturated sodium chloride solution 500 mL was added to quench the reaction, ethyl acetate 1500 mL was added for extraction, the organic phase was washed with sodium chloride solution 300 mL*2, the organic phase was dried over anhydrous sodium sulfate, and reduced pressure concentration, the title compound Int 7 (53 g, 143.69 mmol) was obtained by silica gel column chromatography purification.

[0560] MS (ESI): m / z = 369.1 [M+H] +

[0561] 1 H NMR (400 MHz, DMSO-d6) δ 5.04 (s, 1H), 4.62 (d, J = 8.0 Hz, 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).

[0562] Synthesis of Intermediate 8: tert-butyl 7-(2-ethoxy-2-oxoethyl)-2,4-dimethyl- 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Int 8)

[0563] Step one: Synthesis of (2-chloro-4,6-dimethylpyridin-3-yl)methanamine (Compound Int 8-2)

[0564] Into a four-necked flask was placed compound Int 8-1 (300 g, 1.80 mol), tetrahydrofuran (500 mL), then temperature was controlled to 0 °C, borane tetrahydrofuran complex (1 M, 4.5 mol, 4.5 L) was added dropwise slowly, after the addition was completed, the temperature was raised to 60 °C, and stirred for 14 hours. TLC (PE:EA = 2:1) detection reaction was complete, the temperature was lowered to 0 °C, 300 mL of methanol was added to the reaction solution slowly while stirring, after the addition was completed, it was stirred for one hour, and concentrated under reduced pressure to obtain compound Int 8-2 (300 g, crude product).

[0565] Step two: Synthesis of tert-butyl (2-chloro-4,6-dimethylpyridin-3-yl)methyl)carbamate (Compound Int 8-3)

[0566] Into a three-necked flask was placed compound Int 8-2 (300 g, crude product), triethylamine (266.9 g, 2.64 mol), dichloromethane (1000 mL), then temperature was controlled to 0 °C, BOC-anhydride (460.5 g, 2.11 mol) was added dropwise slowly, after the addition was completed, the temperature was raised to 25 °C, and stirred for 2 hours. TLC (n-heptane: ethyl acetate = 2:1) detection reaction was complete, concentrated under reduced pressure to obtain crude product, the crude product was slurried with (n-heptane: ethyl acetate = 10:1), and filtered to obtain compound Int 8-3 (425 g, 1.28 mol).

[0567] Step three: 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)

[0568] To a three-necked flask was added compound Int 8-3 (60 g, 221.60 mmol), dimethylbutanediol 2-(ethoxycarbonyl)vinylacetate (75.15 g, 332.40 mmol), [n- butyldi(1-adamantyl)phosphine]methanesulfonic acid (2-amino-1,1'- biphenyl-2-yl)palladium(II) (16.1 g, 22.2 mmol), cesium carbonate (144.40 g, 443.20 mmol), N,N-dimethylformamide (600 mL) and water (100 mL). After nitrogen replacement, the temperature was raised to 110 °C and stirred for 18 hours. TLC (n-heptane: ethyl acetate = 3:1) detection showed that the reaction was complete, saturated sodium chloride solution was added for quenching, ethyl acetate was used for extraction, the organic phase was washed with saturated sodium chloride solution, the organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the title compound Int 8 (15 g, 44.85 mmol) was obtained by silica gel column chromatography. MS (ESI): m / z = 335.2 [M+H] + .

[0569] Synthesis of intermediate 9: 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3- yl)acetic acid (Int 9)

[0570] Step one: Synthesis of methyl 2-(azetidin-3-yl)acetate (compound Int 9-2)

[0571] To a single-necked flask was added compound Int 9-1 (5 g, 21.81 mmol), dichloromethane (10 mL), followed by trifluoroacetic acid (5 mL), and stirred at room temperature for 3 hours. LCMS detection showed that the reaction was complete, and the compound Int 9-2 (5.0 g, crude, trifluoroacetate salt) was obtained by concentration under reduced pressure. MS (ESI): m / z = 130.2 [M+H] + .

[0572] Step two: Synthesis of methyl 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3- yl)acetate (compound Int 9-3)

[0573] Into a single necked flask was placed 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), 4-chloro-2-(trifluoromethyl)pyridine (4.12 g, 22.71 mmol), then warmed to 80 °C, stirred for 15 h. LCMS showed the reaction was complete, quenched with saturated sodium chloride solution, extracted with ethyl acetate, washed the organic phase with saturated sodium chloride solution, dried the organic phase over anhydrous sodium sulfate, concentrated under reduced pressure, purified by silica gel column chromatography to give the title compound Int 9-3 (5 g, 18.23 mmol). MS (ESI): m / z = 275.1 [M+H] + .

[0574] Step three: Synthesis of 2-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)acetic acid (compound Int 9)

[0575] Into a single necked flask was placed 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), stirred at 25 °C for 2 h. TLC (n-heptane: ethyl acetate = 2:1) showed the reaction was complete, concentrated the methanol under reduced pressure, adjusted the pH = 6 with 1M hydrochloric acid, filtered to give the title compound Int 9 (3.75 g, 14.41 mmol).

[0576] Intermediate 10: Synthesis of benzyl 3-(2-(tert-butoxy)-2-oxoethyl)azetidine-1-carboxylate (Int 10)

[0577] Step one: Synthesis of benzyl 3-(2-(tert-butoxy)-2-oxoethyl)azetidine-1-carboxylate (compound Int 10-3)

[0578] Into a three necked flask was placed compound Int 10-2 (17.21 g, 68.22 mmol, 16.02 mL), tetrahydrofuran 200 mL, cooled to -10 °C under nitrogen protection, added sodium hydride (3.12 g, 77.97 mmol) in portions, stirred at 0 °C for 1 h, then added compound Int 10-1 (10 g, 48.73 mmol), stirred at 25 °C for 3 h under nitrogen protection. TLC (n-heptane: ethyl acetate = 3:1) showed the reaction was complete, quenched with saturated ammonium chloride solution 300 mL, extracted with ethyl acetate 300 mL, concentrated under reduced pressure, purified by silica gel column chromatography to give the title compound Int 10-3 (11 g, 36.26 mmol). MS (ESI): m / z = 629.3, [2M+Na]+ .

[0579] 1 H NMR (400 MHz, DMSO-d6) δ 7.38 - 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).

[0580] Step two: synthesis of 3-(2-(tert-butoxy)-2-oxoethyl)azetidine-1-carboxylate benzyl ester (compound Int 10)

[0581] To a single-neck flask was added 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), after nitrogen replacement for three times, the temperature was raised to 90 °C, and stirred for 14 hours. TLC (n-heptane: ethyl acetate = 3:1) detection reaction was complete, 200 mL of aqueous solution was added to quench the reaction, 300 mL of ethyl acetate was added for extraction, concentrated under reduced pressure, and the title compound Int 10 (5.3 g, 17.36 mmol) was obtained by silica gel column chromatography. MS (ESI): m / z = 250.2, [M-56] + .

[0582] 1 H NMR (400 MHz, DMSO-d6) δ 7.38 - 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).

[0583] Example 1: synthesis of 2,4-dimethyl-8-(1-methyl-1H-pyrazol-4-yl)-8,9,10,10a- tetrahydropyrrolo[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (compound 324)

[0584] To the reaction vessel was placed compound Int-2 (30 mg, 138.08 µmol), 1,4-dioxane (1 mL), followed by 4-iodo-1-methyl-1H-pyrazole (43 mg, 207.12 µmol), copper iodide (2.6 mg, 13.81 µmol), dimethyl ethylenediamine (2.4 mg, 27.62 µmol), potassium carbonate (38.2 mg, 165.69 µmol). After purging with nitrogen, the temperature was increased to 110 °C and stirred for 12 h. The reaction was checked by LCMS and upon completion, it was allowed to cool 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] + . 1 H-NMR (400 MHz, CDCl3) δ 7.78 (s, 1H), 7.41 (s, 1H), 6.86 (s, 1H), 4.91 (d, J = 15.2 Hz, 1H), 4.78 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 3.81 (s, 3H), 3.76 - 3.60 (m, 2H), 2.67 (d, J = 15.2 Hz, 1H), 2.47 (s, 3H), 2.21 (s, 3H), 1.88 - 1.77 (m, 1H).

[0585] Example 2: 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)

[0586] Step one: 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)

[0587] To the reaction vessel was placed compound Int-2 (200 mg, 920.51 µmol), 1,4-dioxane (5 mL), followed by 4-iodopyridine (283.0 mg, 1.38 mmol), copper iodide (35.1 mg, 184.1 µmol), dimethyl ethylenediamine (36.5 mg, 411.2 µmol), potassium carbonate (254.4 mg, 1.84 mmol). After purging with nitrogen, the temperature was increased to 110 °C and stirred for 12 h. The reaction was checked by LCMS and upon completion, it was allowed to cool 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 Prep-HPLC purification.

[0588] MS (ESI): m / z = 295.1, [M+H]+. 1 H NMR (400 MHz, CDC13) δ 8.44 (d, J = 5.2 Hz, 2H), 7.42 (d, J = 5.2 Hz, 2H), 6.87 (s, 1H), 4.95 (d, J = 15.2 Hz, 1H), 4.79 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 15.2 Hz, 1H), 4.04 - 3.65 (m, 2H), 2.77 (d, J = 13.2 Hz, 1H), 2.47 (s, 3H), 2.22 (s, 3H), 2.12 - 1.74 (m, 1H).

[0589] Step two: Chiral isomer resolution

[0590] Compound 21 (85 mg, 288.76 umol) was resolved by column ChiralGel DH 7 pm with mobile phase n-hexane - absolute ethanol - triethylamine (85: 15: 1) to give compound 21a (30 mg) and compound 21b (25 mg), the retention time of compound 21a was 28.239 min, the retention time of compound 21b was 43.468 min.

[0591] Example 3: Synthesis of 2,4-dimethyl-7-(2-(trifluoromethyl)pyridin-4-yl)- 8,9-dihydropyrrolo[3',2':4,5]pyrrolo[l,2-a]pyrazin-6(7H)-one (Compound 112)

[0592] Compound Int-1 (20 mg, 92.91 umol) was dissolved in 1 mL dry 1,4-dioxane, 4-bromo-2-(trifluoromethyl)pyridine (21 mg, 92.91 umol), anhydrous potassium carbonate (25.7 mg, 185.83 umol), copper(I) iodide (17.7 mg, 92.91 umol), DMEDA (16.4 mg, 185.83 umol) were added in turn, replaced with nitrogen, and stirred at 110 °C for 8 hours. LCMS detection showed that the reaction was complete, filtered with diatomite, and concentrated to give a crude product, which was purified by Prep-HPLC to give the title compound 112 (7.8 mg, 21.65 umol), MS (ESI): m / z = 361.3, [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.74 (d, J = 5.6 Hz, 1H), 7.84 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 5.6, 2.0 Hz, 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).

[0593] Referring to the synthetic method of Example 3, the following compound can be synthesized:

[0594] Example 14: 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)

[0595] Step one: Synthesis of (E)-ethyl 3-(3-cyano-4,6-dimethylpyridin-2-yl)acrylate (Compound 25-2)

[0596] To a round bottom flask was added compound 2-chloro-4,6-dimethylnicotinonitrile (Int-2-1, 5 g, 30.01 mmol), 1,4-dioxane (50 mL), water (5 mL), followed by (Z)-(4-ethoxy-4-oxo-2-buten-2-yl)pinacol boronate (10.81 g, 45.02 mmol), potassium carbonate (8.3 g, 60.02 mmol), Pd(dppf)2Cl2(2.20 g, 3.00 mmol). After replaced with nitrogen, the temperature was raised to 110 °C and stirred for 12 hours. LCMS detection showed the reaction was complete, the reaction was cooled to room temperature, 1,4-dioxane was removed by reduced pressure concentration, water was added, dichloromethane was used to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated by reduced pressure, and the title compound (4.1 g, 16.78 mmol) was obtained by column chromatography, MS (ESI): m / z = 245.1, [M+H] + .

[0597] Step two: 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)

[0598] To a round-bottom flask was added compound 25-2 (2 g, 8.19 mmol), 5% sodium hydroxide aqueous solution 20 mL, and the mixture was stirred at 60 °C for 4 h, then the temperature was increased to 100 °C and the reaction was continued for another 4 h. LCMS detection showed that the reaction was complete. After the reaction mixture was cooled to room temperature, acid was added to adjust the pH to 6-7. The mixture was purified by C18 prep-HPLC to give compound 25-3 (1.2 g, 5.12 mmol), MS (ESI): m / z = 235.1, [M+H] + .

[0599] Step three: 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)

[0600] To a round-bottom flask was added compound 25-3 (0.5 g, 2.13 mmol), DMF (5 mL), TCFH (1.2 g, 4.27 mmol), N-methylimidazole (0.70 g, 8.54 mmol), and the mixture was stirred at room temperature for 10 min. Then 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (0.69 g, 3.2 mmol) was added and the reaction was continued for another 6 h. LCMS detection showed that the reaction was complete. The mixture was purified by reverse phase prep-HPLC to give compound 25-5 (0.68 g, 1.57 mmol), MS (ESI): m / z = 434.1, [M+H] + .

[0601] Step four: 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)azetidin-3-amine (compound 25-6)

[0602] To a round-bottom flask was added compound 25-5 (0.68 g, 1.57 mmol), anhydrous tetrahydrofuran (5 mL), and the mixture was replaced with nitrogen three times. Then borane tetrahydrofuran complex (15.7 mmol) was slowly added under ice bath. After the addition was completed, the temperature was increased to 70 °C and the reaction was continued for another 24 h. LCMS detection showed that the reaction was complete. The mixture was cooled to room temperature, and methanol (50 mL) was added to quench the reaction under ice bath. After no gas was released, 4 M hydrochloric acid (10 mL) was added and the mixture was stirred at 60 °C overnight. The mixture was cooled to room temperature and NaOH aqueous solution was added to adjust the pH to 7-8 under ice bath. The mixture was extracted with dichloromethane and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and purified by C18 prep-HPLC to give compound 25-6 (0.35 g, 0.86 mmol), MS (ESI): m / z = 406.1, [M+H] + .

[0603] Step five: synthesis of 2,4,12,4,10-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)

[0604] To a round bottom flask was added compound 25-6 (0.1 g, 0.24 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (37.4 mg, 0.37 mmol), N,N'-carbonyldiimidazole (47.9 mg, 0.29 mmol), reacted at room temperature for half an hour, then heated to 70 °C for 12 hours, LCMS detected that the reaction was complete, returned to room temperature, concentrated under reduced pressure, and the title compound (60 mg, 0.13 mmol) was obtained by Prep-HPLC preparation purification.

[0605] MS (ESI): m / z = 432.1, [M+H] + , 1 H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 5.6 Hz, 1H), 6.82 (s, 1H), 6.56 (d, J = 2.0 Hz, 1H), 6.31 (dd, J = 5.6, 2.0 Hz, 1H), 5.49 - 5.24 (m, 1H), 4.84 (d, J = 15.2 Hz, 1H), 4.42 (d, J = 15.2 Hz, 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).

[0606] Example 15: synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-8,9-dihydrothieno[3,2- b:5,4-c']dipyridin-6(7H)-one (Compound 154)

[0607] Into a round bottom flask was added compound Int-3 (255 mg, 1.1 mmol), 1,4-dioxane (20 mL), 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 purging, the temperature was raised to 95 °C and stirred for 16 h. LCMS showed the reaction was complete. The reaction was cooled 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 give the title compound (34 mg, 0.11 mmol).

[0608] MS (ESI): m / z = 310.1, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.65 (s, 2H), 7.51 (d, J = 5.2 Hz, 2H), 7.12 (s, 1H), 4.27 (t, J = 6.8 Hz, 2H), 3.45 (t, J = 6.8 Hz, 2H), 2.70 (s, 3H), 2.59 (s, 3H).

[0609] Example 16: Synthesis of 2,4,9-trimethyl-7-(pyridin-4-yl)-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[l,2-a]pyrazin-6(7H)-one (Compound 327)

[0610] Step one: Synthesis of ethyl l-(l-((tert-butoxycarbonyl)amino)propan-2-yl)-4,6-dimethyl-lH-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 27-02)

[0611] Compound Int-1-2 (1.75 g, 8.02 mmol) was dissolved in 20 mL DMF, followed by the addition of 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). The mixture solution was heated to 80 °C and stirred overnight. The solution was cooled to room temperature. Water was added, and the mixture was extracted with ethyl acetate three times. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel column chromatography gave compound 27-02 (1.26 g, 3.49 mmol), MS (ESI): m / z = 376.2, [M+H] + .

[0612] Step two: synthesis of 2,4,9-trimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[l,2- a]pyrazin-6(7H)-one (compound 27-03)

[0613] Firstly, compound 27-02 (1.26 g, 3.49 mmol) was dissolved in 20 mL DCM, and 4 mL trifluoroacetic acid was added. It was stirred at room temperature for 0.5 hours, LCMS detection showed that the reaction was complete, and it was concentrated under reduced pressure. The obtained crude compound was dissolved in 20 mL anhydrous methanol, and anhydrous potassium carbonate (2.41 g, 17.43 mmol) was added. It 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] + .

[0614] Step three: synthesis of 2,4,9-trimethyl-7-(pyridin-4-yl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[l,2- a]pyrazin-6(7H)-one (compound 327)

[0615] Compound 27-03 (20 mg, 87.23 μmol) was dissolved in 1 mL dry 1,4-dioxane, and 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), DMEDA (15.6 mg, 174.46 μmol) were added in turn, replaced with nitrogen, and stirred at 110°C for 8 hours. LCMS detection showed that the reaction was complete, filtered with diatomite, and the filtrate was concentrated to obtain a crude product. The crude product was prepared by Prep-HPLC to obtain the title compound 327 (7.8 mg, 19.17 μmol).

[0616] MS (ESI): m / z = 307.3, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 6.4 Hz, 2H), 7.58 (dd, J = 4.8, 1.6 Hz, 2H), 7.30 (s, 1H), 6.95 (s, 1H), 4.74 - 4.62 (m, 1H), 4.51 (qd, J = 13.2, 3.2 Hz, 2H), 2.55 (s, 3H), 2.54 (s, 3H), 1.26 (d, J = 6.4 Hz, 3H).

[0617] Example 17: Synthesis of 3-chloro-2,4-dimethyl-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 329)

[0618] Step one: Synthesis of 5-chloro-2-hydroxy-4,6-dimethylnicotinonitrile (Compound 29-02)

[0619] To a round-bottom flask was added compound 2-hydroxy-4,6-dimethylnicotinic acid nitrile (6 g, 40.50 mmol), acetonitrile (100 mL), and chlorosulfonyl chloride (8.20 g, 60.74 mmol) was added dropwise slowly at 0 °C. LCMS showed the reaction was complete, the reaction was quenched by water, the pH was adjusted to 7-8, dichloromethane was used to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 29-02 (7 g, 38.33 mmol), MS (ESI): m / z = 183.1, [M+H] + .

[0620] Step two: Synthesis of 2-bromo-5-chloro-4,6-dimethylnicotinonitrile (Compound 29-03)

[0621] To a round-bottom flask was added compound 29-02 (7 g, 38.33 mmol), toluene (100 mL), and phosphorus oxybromide (16.48 g, 57.50 mmol) was added slowly at room temperature, followed by heating to 110 °C for 6 hours. LCMS showed the reaction was complete, the reaction was quenched by water, the pH was adjusted to 7-8, dichloromethane was used to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain compound 29-03 (7.5 g, 30.55 mmol), MS (ESI): m / z = 246.1, [M+H] + .

[0622] Step three: Synthesis of (2-bromo-5-chloro-4,6-dimethylpyridin-3-yl)methanamine (Compound 29-04)

[0623] Into a round-bottom flask was added compound 29-03 (7.5 g, 30.55 mmol), anhydrous tetrahydrofuran (50 mL), and the flask was purged with nitrogen three times. Then borane tetrahydrofuran complex (61.1 mmol) was slowly added under ice-bath cooling, and the reaction was continued at 70 °C for 6 h after the addition was completed. The reaction was determined to be complete by LCMS, and the reaction was quenched by the addition of methanol (50 mL) under ice-bath cooling. After no gas was released, 4 M hydrochloric acid (30 mL) was added, and the reaction was continued at 60 °C for 6 h. After the reaction mixture was cooled to room temperature, NaOH aqueous solution was added to adjust the pH to 7-8 under ice-bath cooling. 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] + .

[0624] Step four: Synthesis of tert-butyl (2-bromo-5-chloro-6-methylpyridin-3- yl)methylcarbamate (compound 29-05)

[0625] Into a round-bottom flask was added 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), and the reaction was continued at room temperature for half an hour. Then di-tert-butyl dicarbonate (5.25 g, 24.04 mmol) was added, and the reaction was continued for 2 h. The reaction was determined to be complete by LCMS, and the reaction 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] + .

[0626] Step five: Synthesis of (E)-ethyl 3-(3-(((tert-butoxycarbonyl)amino)methyl)-5- chloro-4,6-dimethylpyridin-2-yl)acrylate (compound 29-06)

[0627] To a round-bottom flask was added compound 29-05 (4 g, 11.92 mmol), 1,4-dioxane (40 mL), water (4 mL), followed by (E)-2-(ethoxycarbonyl)vinyl boronic acid pinacol ester (1.77 g, 17.88 mmol), potassium carbonate (3.29 g, 23.84 mmol), Pd(dppf)2Cl2(0.87 g, 1.19 mmol). After nitrogen replacement, the temperature was raised to 110 °C and stirred for 12 h. LCMS showed the reaction was complete. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure. 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 29-06 (2.8 g, 11.92 mmol), MS (ESI): m / z = 369.1, [M+H] + .

[0628] Step six: 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)

[0629] To a round-bottom flask was added compound 29-06 (2.8 g, 11.92 mmol), 5% sodium hydroxide aqueous solution 30 mL, and the mixture was stirred at 60 °C for 4 h. The temperature was then raised to 100 °C and the reaction was continued for another 4 h. LCMS showed the reaction was complete. After cooling to room temperature, the pH was adjusted to 6-7 with acid in an ice bath. The product was purified by C18 reverse-phase preparative purification to give compound 29-07 (1.8 g, 5.28 mmol), MS (ESI): m / z = 341.1, [M+H] + .

[0630] Step seven: 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)

[0631] To a round-bottom flask was added compound 29-07 (1 g, 2.93 mmol), DMF (20 mL), TCFH (1.65 g, 5.87 mmol), N-methylimidazole (0.96 g, 11.74 mmol), and the mixture was stirred at room temperature for 10 min. Then 1-(2-(trifluoromethyl)pyridin-4- yl)azetidin-3-amine (0.95 g, 4.40 mmol) was added and the reaction was continued for another 6 h. LCMS showed the reaction was complete. The product was purified by reverse-phase preparative purification to give the target compound 29-08 (1.2 g, 2.93 mmol), MS (ESI): m / z = 541.1, [M+H] + .

[0632] Step eight: 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)

[0633] To a round bottom flask was added compound 29-08 (1.2 g, 2.93 mmol), DCM (10 mL), 12 N hydrochloric acid solution was added slowly dropwise at room temperature, the reaction was carried out for 4 hours. LCMS detected that the reaction was complete, concentrated and dried to obtain the crude product compound 29-09 (0.7 g, 1.59 mmol), MS (ESI): m / z = 441.1, [M+H] + .

[0634] Step nine: 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)

[0635] To a round bottom flask was added compound 29-09 (0.7 g, 1.59 mmol), anhydrous tetrahydrofuran (10 mL), after nitrogen replacement, borane tetrahydrofuran complex (3.2 mmol) was slowly added under ice bath, and the temperature was raised to 70°C for further reaction for 6 hours. LCMS detected that the reaction was complete, and the temperature was restored to room temperature. Methanol (5 mL) was added to quench the reaction under ice bath. After no gas was released, 4M hydrochloric acid (2 mL) was added, and the temperature was raised to 60°C for reaction for 2 hours. The temperature was cooled to room temperature, and NaOH aqueous solution was added to adjust the pH to 7-8 under ice bath. Dichloromethane was used for extraction, and the organic phase was dried with anhydrous sodium sulfate. Filtration and reduced pressure concentration gave the crude product compound 29-10 (0.42 g, 0.98 mmol), MS (ESI): m / z = 427.1, [M+H] + .

[0636] Step ten: synthesis of 3-chloro-2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4- yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrrolo[2',3':3,4]pyrrolo[1,2-c]pyrimidin- 7(5H)-one (Compound 329)

[0637] To a round bottom flask was added compound 29-10 (0.1 g, 0.98 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (35.6 mg, 0.35 mmol), N,N'-carbonyldiimidazole (45.6 mg, 0.28 mmol), and the reaction was allowed to proceed at room temperature for half an hour, then the temperature was raised to 70 °C and the reaction was allowed to proceed for 12 hours. The reaction was monitored by LCMS and was found to be complete. The reaction was allowed to cool to room temperature and was concentrated under reduced pressure. The resulting residue was purified by Prep-HPLC to afford the title compound (56 mg, 0.12 mmol).

[0638] MS (ESI): m / z = 452.1, [M+H] + , 1 H-NMR (400 MHz, CDC13) δ 8.32 (d, J = 5.6 Hz, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.38 (dd, J = 5.6, 2.0 Hz, 1H), 5.51 - 5.33 (m, 1H), 4.96 (d, J = 15.2 Hz, 1H), 4.76 (d, J = 11.2 Hz, 1H), 4.55 (d, J = 15.2 Hz, 1H), 4.30 - 4.20 (m, 3H), 4.04 (dd, J = 8.4, 5.6 Hz, 1H), 3.66 - 3.51 (m, 2H), 2.90 - 2.64 (m, 1H), 2.64 (s, 3H), 2.33 (s, 3H), 1.74 - 1.69 (m, 1H).

[0639] Step eleven: Chiral resolution (compound 329a and compound 329b)

[0640] Compound 329 (873 mg, 1.93 mmol) synthesized by the above method was resolved by chiral column using the following method: Compound 329 (873 mg, 1.93 mmol) was dissolved in mobile phase at room temperature, the sample concentration was 1 mg / ml, and was filtered with 0.45 pm organic filter membrane; the column type was Unichiral CNZ-5H, size: 20 mm I.D. x 250 mm L, mobile phase was n-hexane-absolute ethanol (60:40), column temperature was 30 °C, flow rate was 25 ml / min, detection wavelength was 254 nm, and 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 column resolution. The chiral analysis conditions were as follows: Chiralpak® AD-H, n-hexane-absolute ethanol-triethylamine (85:15:1), column temperature was 35 °C, flow rate was 1.0 mL, and detection wavelength was 260 nm.

[0641] Compound 329a: MS (ESI): m / z = 452.1, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.31 (d, J = 5.6 Hz, 1H), 6.62 (d, J = 2.2 Hz, 1H), 6.38 (dd, J = 5.6, 2.0 Hz, 1H), 5.47 - 5.37 (m, 1H), 4.96 (d, J = 15.2 Hz, 1H), 4.79 - 4.73 (m, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.31 - 4.19 (m, 3H), 4.06 (dd, J = 8.4, 5.6 Hz, 1H), 3.60 (dd, J = 8.8, 2.8 Hz, 2H), 2.75 - 2.66 (m, 1H), 2.64 (s, 3H), 2.33 (s, 3H), 1.78 - 1.64 (m, 1H).

[0642] Compound 329b: MS (ESI): m / z = 452.1, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.32 (d, J = 5.6 Hz, 1H), 6.62 (d, J = 2.0 Hz, 1H), 6.39 (dd, J = 5.6, 2.0 Hz, 1H), 5.46 - 5.37 (m, 1H), 4.96 (d, J = 15.2 Hz, 1H), 4.76 (d, J = 11.2 Hz, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.32 - 4.20 (m, 3H), 4.06 (dd, J = 8.4, 5.6 Hz, 1H), 3.63 - 3.55 (m, 2H), 2.75 - 2.67 (m, 1H), 2.64 (s, 3H), 2.33 (s, 3H), 1.78 - 1.65 (m, 1H).

[0643] Example 18: 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)

[0644] Step one: Synthesis of (2-chloro-6-methyl-4-(trifluoromethyl)pyridin-3-yl)methanamine (Compound 30-02)

[0645] Into a round-bottom flask, was placed compound 30-01 (2 g, 9.07 mmol), anhydrous tetrahydrofuran (50 mL), and the flask was purged with nitrogen three times. Then borane tetrahydrofuran complex (19.95 mmol) was slowly added under ice-bath cooling. After the addition was completed, the reaction mixture was warmed to 70 °C and stirred for 6 h. The reaction was monitored by LCMS and was determined to be complete. The reaction mixture was cooled to room temperature, and methanol (50 mL) was added to quench the reaction. After no gas was released, 4 M hydrochloric acid (30 mL) was added, and the reaction mixture was warmed to 60 °C and stirred for 6 h. The reaction mixture was cooled to room temperature, 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 give the crude product compound 30-02 (1.4 g, 6.23 mmol), MS (ESI): m / z = 225.1, [M+H] + .

[0646] Step two: synthesis of tert-butyl (2-chloro-6-methyl-4-(trifluoromethyl)pyridin-3- yl)methyl)carbamate (compound 30-03)

[0647] Into a round-bottom flask, was placed 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). The reaction mixture was stirred at room temperature for 0.5 h, and di-tert-butyl dicarbonate (1.63 g, 7.48 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by LCMS and was determined to be complete. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to give compound 30-03 (1.2 g, 3.7 mmol), MS (ESI): m / z = 325.1, [M+H] + .

[0648] Step three: synthesis of (E)-ethyl 3-(3-(((tert-butoxycarbonyl)amino)methyl)-6-methyl-4- (trifluoromethyl)pyridin-2-yl)acrylate (compound 30-04)

[0649] To a round-bottom flask was added compound 30-03 (1.2 g, 3.7 mmol), 1,4-dioxane (10 mL), water (1 mL), followed by (E)-2-(ethoxycarbonyl)vinyl boronic acid pinacol ester (0.54 g, 5.54 mmol), potassium carbonate (1.02 g, 7.39 mmol), Pd(dppf)2Cl2(0.27 g, 0.36 mmol). After nitrogen replacement, the temperature was raised to 110 °C and stirred for 12 h. LCMS showed the reaction was complete. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure. 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 residue was purified by column chromatography to give compound 30-04 (0.8 g, 2.06 mmol), MS (ESI): m / z = 389.1, [M+H] + .

[0650] Step four: 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)

[0651] To a round-bottom flask was added compound 30-04 (0.8 g, 2.06 mmol), 5% sodium hydroxide aqueous solution 10 mL, and the mixture was stirred at 60 °C for 4 h. The temperature was then raised to 100 °C and the reaction was continued for another 4 h. LCMS showed the reaction was complete. After cooling to room temperature, the pH was adjusted to 6-7 with acid in an ice bath. The mixture was purified by C18 reverse-phase flash chromatography to give compound 30-05 (0.6 g, 1.67 mmol), MS (ESI): m / z = 361.1, [M+H] + .

[0652] Step five: 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)

[0653] To a round-bottom flask was added compound 30-05 (0.6 g, 1.67 mmol), DMF (5 mL), TCFH (0.934 g, 3.33 mmol), N-methylimidazole (0.54 g, 6.66 mmol), and the mixture was stirred at room temperature for 10 min. Then 1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-amine (0.54 g, 2.5 mmol) was added and the reaction was continued for another 6 h. LCMS showed the reaction was complete. The mixture was purified by reverse-phase flash chromatography to give compound 30-06 (0.7 g, 1.25 mmol), MS (ESI): m / z = 560.3, [M+H] + .

[0654] Step six: 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)

[0655] To a round bottom flask was added compound 30-06 (0.7 g, 1.25 mmol), DCM (10 mL), 12 N hydrochloric acid solution was added slowly dropwise at room temperature, the reaction was carried out for 4 hours. LCMS detected that the reaction was complete, concentrated and dried to obtain the crude product 30-07 (0.62 g, 1.35 mmol), MS (ESI): m / z = 460.3, [M+H] + .

[0656] Step seven: 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)azetidine-3-amine (compound 30-08)

[0657] To a round bottom flask was added compound 30-07 (0.62 g, 1.35 mmol), anhydrous tetrahydrofuran (10 mL), after nitrogen replacement, borane tetrahydrofuran complex (3.2 mmol) was slowly added under ice bath, and the temperature was increased to 70 °C to continue the reaction for 6 hours. LCMS detected that the reaction was complete, and the temperature was restored to room temperature. Methanol (5 mL) was added to quench the reaction under ice bath. After no gas was released, 4 M hydrochloric acid (2 mL) was added, and the temperature was increased to 60 °C to react for 2 hours. The temperature was cooled to room temperature, and NaOH aqueous solution was added to adjust the pH to 7-8 under ice bath. Dichloromethane was extracted, and the organic phase was dried with anhydrous sodium sulfate. Filtration and reduced pressure concentration obtained the crude product compound 30-08 (0.42 g, 0.94 mmol), MS (ESI): m / z = 446.1, [M+H] + .

[0658] Step eight: 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)

[0659] To a round bottom flask was added compound 30-08 (0.10 g, 0.22 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (34.08 mg, 0.33 mmol), N,N'-carbonyldiimidazole (43.6 mg, 0.27 mmol), reaction at room temperature for half an hour, then heated to 70 °C for 12 hours, LCMS detection reaction was complete, restore to room temperature, reduced pressure concentration, by Prep-HPLC preparation purification to get the target compound 330 (60 mg, 0.12 mmol).

[0660] MS (ESI): m / z = 472.2, [M+H] + . 1 H-NMR (400 MHz, CDC13) δ 8.32 (d, J = 5.6 Hz, 1H), 7.31 (s, 1H), 6.63 (d, J = 2.0 Hz, 1H), 6.40 (dd, J = 5.6, 2.0 Hz, 1H), 5.56 - 5.36 (m, 1H), 5.19 (d, J = 16.0 Hz, 1H), 4.81 (d, J = 11.2 Hz, 1H), 4.69 (d, J = 16.0 Hz, 1H), 4.38 - 4.21 (m, 3H), 4.09 (dd, J = 8.4, 5.6 Hz, 1H), 3.66 - 3.62 (m, 2H), 2.87 - 2.69 (m, 1H), 2.66 (s, 3H) 1.84 - 1.70 (m, 1H).

[0661] Example 19: 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)

[0662] Step one: 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)

[0663] A round-bottom flask was charged with compound tert-butyl (2-bromo-5-chloro-4,6-dimethylpyridin-3-yl)methylcarbamate (29-05) (1 g, 2.86 mmol), 1,4-dioxane (10 mL), followed by acrylonitrile (227.6 mg, 4.29 mmol), potassium acetate (561.4 mg, 5.72 mmol), palladium chloride (50.7 mg, 0.28 mmol), BINAP (356.2 mg, 0.57 mmol). After nitrogen substitution, the temperature was raised to 130 °C and stirred for 12 h. LCMS showed the reaction was complete. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure. 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 residue was purified by silica gel column chromatography to give the target compound 31-01 (420 mg, 1.31 mmol), MS (ESI): m / z = 322.2, [M+H] + .

[0664] Step two: 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)

[0665] A round-bottom flask was charged with compound 31-01 (420 mg, 1.31 mmol), methanol (5 mL), Raney nickel (42 mg). After hydrogen substitution, the temperature was raised to 60 °C and stirred for 6 h. LCMS showed the reaction was complete. After cooling to room temperature, the reaction mixture was filtered and washed with methanol. The filtrate was concentrated and dried to give the crude product 31-02 (310 mg, 0.95 mmol), MS (ESI): m / z = 326.2, [M+H] + .

[0666] Step three: 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)

[0667] A round-bottom flask was charged with compound 31-02 (310 mg, 0.95 mmol), DCM (5 mL), 12 N hydrochloric acid solution (1 mL) was added dropwise slowly at room temperature. The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The pH was adjusted to 7-8 by adding 2 N aqueous sodium hydroxide solution. The mixture was concentrated and purified by C18 reverse phase preparation to give compound 31-03 (150 mg, 0.66 mmol), MS (ESI): m / z = 226.2, [M+H]+.

[0668] Step four: 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)

[0669] To a round bottom flask was added compound 31-03 (150 mg, 0.66 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (100.9 mg, 0.99 mmol), N,N'-carbonyldiimidazole (107.8 mg, 0.66 mmol), reaction at room temperature for half an hour, then heated to 60 °C for 6 hours, LCMS detection reaction was complete, restore to room temperature, reduced pressure concentration, purified by C18 reversed phase preparation to obtain compound 31-04 (108 mg, 0.42 mmol), MS (ESI): m / z = 252.2, [M+H]+.

[0670] Step five: synthesis of 3-chloro-2,4-dimethyl-8-(pyridin-4-yl)-8,9,10,10- tetrahydropyrrolo[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (compound 331)

[0671] To a Schlenk flask was added compound 31-04 (108 mg, 0.39 mmol), 1,4- dioxane (2 mL), followed by 4-iodopyridine (122.2 mg, 0.59 mmol), cuprous iodide (7.6 mg, 39.7 μmol), dimethyl ethylenediamine (7 mg, 79.46 μmol), potassium carbonate (164.7 mg, 1.19 mmol). After nitrogen replacement, heated to 110 °C and stirred. LCMS detection reaction was complete, restore to room temperature, filter with diatomite, washed with dichloromethane, reduced pressure concentration, purified by Prep-HPLC preparation to obtain target compound 331 (40 mg, 0.12 mmol).

[0672] MS (ESI): m / z = 329.2, [M+H]+. 1 H NMR (400 MHz, CDCl3) δ 8.53 (s, 2H), 7.54 (s, 2H), 5.05 (d, J = 15.2 Hz, 1H), 4.87 (d, J = 11.6 Hz, 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).

[0673] Example 20: synthesis of 7,9-dimethyl-2-(pyridin-4-yl)-3,4-dihydroimidazo[1,2- a:4,5-c']dipyridin-1(2H)-one (compound 194)

[0674] Step one: Synthesis of ethyl 6, 8-dimethylimidazo[l,2-a]pyridine-2-carboxylate (compound 35-03)

[0675] Into a round-bottom flask was added compound 35-01 (5.0 g, 40.9 mmol), 35-02 (8.4 g, 42.2 mmol), 1,4-dioxane (100 mL), sodium bicarbonate (6.9 g, 81.9 mmol). The temperature was raised to 100 °C and stirring was continued for 16 hours. The reaction was cooled to room temperature and quenched with dilute hydrochloric acid, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the title compound 35-03 (7.1 g, 32.3 mmol). MS (ESI): m / z = 219.1, [M+H] + .

[0676] Step two: Synthesis of ethyl 3-bromo-6, 8-dimethylimidazo[l,2-a]pyridine-2-carboxylate (compound 35-04)

[0677] Into a round-bottom flask was added compound 35-03 (7.1 g, 32.3 mmol), DCM (100 mL), NBS (5.7 g, 32.2 mmol) was slowly added with stirring, and stirring was continued at room temperature for 5 hours. The reaction was detected by LCMS to be complete, water was added to quench the reaction, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 35-04 (4.1 g, 13.6 mmol). MS (ESI): m / z = 297.1, [M+H] + .

[0678] Step three: Synthesis of ethyl 3-(2-((tert-butoxycarbonyl)amino)ethyl)-6, 8-dimethylimidazo[l,2-a]pyridine-2-carboxylate (compound 35-05)

[0679] Into a round bottom flask was added compound 35-04 (1.5 g, 5.1 mmol), toluene (90 mL), water (30 mL), followed by (2-((tert-butoxycarbonyl)amino)ethyl)potassium trifluoroborate (2.5 g, 10.2 mmol), cesium carbonate (4.9 g, 15.3 mmol), Ruphos (700 mg, 1.5 mmol), Pd(OAc)2 (115 mg, 0.51 mmol). After nitrogen purging, the temperature was raised to 80 °C and stirred for 16 h. LCMS showed the reaction was complete. The reaction was cooled 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. The title compound 35-05 (202 mg, 0.56 mmol) was obtained by column chromatography. MS (ESI): m / z = 365.1, [M+H] + .

[0680] Step four: synthesis of ethyl 3-(2-aminoethyl)-6,8-dimethylimidazo[l,2- a]pyridine-2-carboxylate (compound 35-06)

[0681] Into a round bottom flask was added compound 35-05 (202 mg, 0.56 mmol), dichloromethane / trifluoroacetic acid (10 mL, 4: 1). The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. The reaction 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] + .

[0682] Step five: synthesis of 7,9-dimethyl-3,4-dihydroimidazo[l,2-a:4,5-c']dipyridin-l(2H)-one (compound 35-07)

[0683] Into a round bottom flask was added compound 35-06 (143 mg, 0.55 mmol), anhydrous methanol (10 mL), potassium carbonate (150 mg, 1.1 mmol). The reaction was stirred at room temperature for 2 h. LCMS showed the reaction was complete. Saturated aqueous ammonium chloride solution was added to quench the reaction. The methanol was removed by concentration under reduced pressure. The residue was added with water and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound 35-07 (105 mg, 0.49 mmol) was obtained by column chromatography. MS (ESI): m / z = 216.1, [M+H] + .

[0684] Step six: synthesis of 7,9-dimethyl-2-(pyridin-4-yl)-3,4-dihydroimidazo[l,2- a:4,5-c']dipyridin-l(2H)-one (compound 194)

[0685] To a round bottom flask was added compound 35-07 (105 mg, 0.49 mmol), 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 copper iodide (60 mg, 0.3 mmol). After nitrogen purging, the temperature was raised to 95 °C and stirred for 16 hours. LCMS showed the reaction was complete, the reaction was cooled to room temperature, 1,4-dioxane was removed under reduced pressure, water was added, dichloromethane was used to extract, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by Prep-HPLC to give the title compound 194 (23 mg, 0.08 mmol). MS (ESI): m / z = 293.1, [M+H] + , 1 H NMR (400 MHz, CD3OD) d 8.77 (s, 2H), 8.10 (s, 1H), 7.65 (s, 2H), 7.12 (s, 1H), 4.35 (t, J = 6.6 Hz, 2H), 3.40 (t, J = 6.6 Hz, 2H), 2.65 (s, 3H), 2.35 (s, 3H).

[0686] Example 21: Synthesis of 2,4-dimethyl-8-((S)-tetrahydrofuran-3-yl)-8,9,10,10a- tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (Compound 335)

[0687] Step one: 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)

[0688] To a round bottom flask was added compound Int-2-3 (0.5 g, 2.27 mmol), DMF (10 mL), TCFH (1.27 g, 4.54 mmol), N-methylimidazole (0.74 g, 9.08 mmol), the reaction was continued for 10 minutes at room temperature, then (S)-tetrahydrofuran-3-amine (0.29 g, 3.41 mmol) was added and the reaction was continued for 2 hours. LCMS showed the reaction was complete, and the product was purified by reverse phase preparation to give compound 36-01 (0.48 g, 1.66 mmol), MS (ESI): m / z = 290.1, [M+H] + .

[0689] 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)

[0690] To a round-bottom flask was added compound 36-01 (0.48 g, 1.66 mmol), anhydrous tetrahydrofuran (10 mL), and borane tetrahydrofuran complex (16.6 mmol) was slowly added under nitrogen replacement at ice bath, and the reaction was continued at 70 °C for 24 h. The reaction was complete by LCMS detection, and the reaction was quenched with methanol (20 mL) at ice bath. After no gas was released, 4M hydrochloric acid was added, and the reaction was stirred at 60 °C overnight. The reaction was cooled to room temperature, and NaOH aqueous solution was added to adjust the pH to 7-8 at ice bath. The reaction 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, and its MS (ESI): m / z = 262.1, [M+H] + .

[0691] Step 3: Synthesis of 2,4-dimethyl-8-((S)-tetrahydrofuran-3-yl)-8,9,10,10a- tetrahydropyrrolo[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 335)

[0692] To a round-bottom flask was added 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) was added at room temperature for 2 h, and the reaction was continued at 70 °C for 48 h. The reaction was complete by LCMS detection, and the reaction was concentrated under reduced pressure. Compound 335 (58 mg, 0.20 mmol) was obtained by reverse phase preparative purification.

[0693] MS (ESI): m / z = 288.2, [M+H] + . 1H-NMR (400 MHz, CDC13), δ 6.89 (s, 1H), 5.43-5.15 (m, 1H), 4.95 (d, J = 15.2 Hz, 1H), 4.81-4.62 (m, 1H), 4.51 (d, J = 15.2 Hz, 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).

[0694] Referring to the synthetic method of Example 21, the following compound can be synthesized:

[0695] Example 27: Synthesis of 2,4-dimethyl-8-((R)-tetrahydrofuran-3-yl)-8,9,10,10a- tetrahydropyrimido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 336)

[0696] Step one: Synthesis of 2,4-dimethyl-7-(2-oxo-2-(((R)-tetrahydrofuran-3-yl)amino)ethyl)- 5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (Compound 37-03)

[0697] Into a round-bottom flask was added 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), DMF (5 mL), stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, water was added to quench the reaction, DCM was extracted, reduced pressure concentration, purified by silica gel column chromatography to obtain compound 37-03 (245.6 mg, 0.65 mmol). MS [ESI]: m / z = 376.2, [M+H] + .

[0698] Step two: Synthesis of 2,4-dimethyl-7-(2-(R)-tetrahydrofuran-3-yl)amino)ethyl)-5,7- dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (Compound 37-04)

[0699] To a round-bottom flask was added compound 37-03 (245.6 mg, 0.65 mmol), borane tetrahydrofuran complex (5 mL), THF (5 ml), 60 °C stirring for 2 hours. LCMS detection of the reaction was complete, the reaction was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, the crude product was subjected to the next step reaction (205.3 mg, 0.57 mmol). MS [ESI]: m / z = 362.2, [M+H] + .

[0700] Step three: 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)

[0701] To a round-bottom flask was added compound 37-04 (205.3 mg, 0.57 mmol), 12 N HCl (2 mL), THF (5 mL), stirring at room temperature for 2 hours. LCMS detection of the reaction was complete, the pH was adjusted to 7 by adding aqueous sodium hydroxide solution, extracted with dichloromethane, concentrated under reduced pressure, the crude product was subjected to the next step reaction (142.4 mg, 0.54 mmol). MS [ESI]: m / z = 262.2, [M+H] + .

[0702] Step four: synthesis of 2,4-dimethyl-8-((R)-tetrahydrofuran-3-yl)-8,9,10,10a- tetrahydropyrimido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (compound 336)

[0703] To a round-bottom flask was added compound 37-05 (50.0 mg, 0.19 mmol), CDI (37.2 mg, 0.23 mmol), TEA (19.4 mg, 0.19 mmol), 90 °C heating stirring overnight. LCMS detection of the reaction was complete, filtered, concentrated under reduced pressure, the crude product was purified by Prep-HPLC to give the title compound 336 (30.4 mg, 0.11 mmol).

[0704] MS (ESI): m / z = 288.2, [M+H] + . 1H NMR (400 MHz, CDC13) δ 6.88 (s, 1H), 5.35 - 5.14 (m, 1H), 4.94 (d, J = 15.0 Hz, 1H), 4.75 - 4.63 (m, 1H), 4.49 (d, J = 15.0 Hz, 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).

[0705] Example 28: Synthesis of 7-(pyridin-4-yl)-2,4-bis(trifluoromethyl)-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[l,2-a]pyrazin-6(7H)-one (Compound 338)

[0706] Step one: Synthesis of ethyl 4,6-bis(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridine-2- carboxylate (Compound 39-01)

[0707] Into a round-bottom flask was added compound Int-1-1 (500 mg, 3.24 mmol), absolute ethanol (2 mL), 1,1,1,5,5,5-hexafluoropentane-2,4-dione (1.35 g, 6.49 mmol, 918.08 uL) and 12 N HC1 (1 mL). The temperature was raised to 80 °C and stirring was continued for 16 h. The reaction was cooled to room temperature and quenched with saturated brine, extracted with ethyl acetate 3 times, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography to give the title compound 39-01 (350 mg, 1.07 mmol). MS (ESI): m / z = 327.0, [M+H]+.

[0708] Step two: Synthesis of ethyl l-(2-((tert-butoxycarbonyl)amino)ethyl)-4,6- bis(trifluoromethyl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 39-02)

[0709] Into a round-bottom flask, was placed compound 39-01 (300 mg, 919.70 µmol), solvent DMF, potassium iodide (152.67 mg, 919.70 µmol, 48.93 µL), cesium carbonate (599.31 mg, 1.84 mmol). The temperature was raised to 80 °C and stirring was continued for 3 h. The reaction was cooled to room temperature and quenched with saturated brine, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 39-02 (280 mg, 596.54 µmol). MS (ESI): m / z = 470.1, [M+H]+.

[0710] Step three: Synthesis of ethyl 1-(2-aminoethyl)-4,6-bis(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (compound 39-03)

[0711] Into a round-bottom flask, was placed compound 39-02 (280 mg, 596.54 µmol), dichloromethane / trifluoroacetic acid (10 mL, 4:1). The reaction was stirred at room temperature for 2 h. The reaction was complete by LCMS detection, and the reaction was concentrated under reduced pressure to give the crude compound 39-03 (273 mg, 739.31 µmol). MS (ESI): m / z = 370.0, [M+H]+.

[0712] Step four: Synthesis of 2,4-bis(trifluoromethyl)-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (compound 39-04)

[0713] Into a round-bottom flask, was placed crude compound 39-03 (270 mg, 731.19 µmol), anhydrous methanol (10 mL), potassium carbonate (707.38 mg, 5.12 mmol). The reaction was stirred at room temperature for 3 h. The reaction was complete by LCMS detection, and saturated aqueous ammonium chloride solution was added to quench, the methanol was removed by concentration under reduced pressure, the residue was added water, extracted with ethyl acetate, the organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the title compound 39-04 (200 mg, 618.82 µmol). MS (ESI): m / z = 324.0, [M+H]+.

[0714] Step five: 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)

[0715] Into a round-bottom flask, was placed compound 39-04 (20 mg, 61.88 µmol), 1,4-dioxane (1 mL), 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 copper iodide (11.8 mg, 61.88 µmol). After nitrogen substitution, the temperature was raised to 95 °C and stirred for 16 h. LCMS showed the reaction went to completion. The reaction was cooled down to room temperature, 1,4-dioxane was removed under reduced pressure, 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 gave title compound 338 (13 mg, 32.48 µmol).

[0716] MS (ESI): m / z = 401.0, [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.60 (d, J = 5.4 Hz, 2H), 7.88 (s, 1H), 7.65 (dd, J = 4.8, 1.4 Hz, 2H), 7.49 - 7.41 (m, 1H), 4.76 (dd, J = 6.6, 4.9 Hz, 2H), 4.46 (dd, J = 6.6, 4.9 Hz, 2H).

[0717] Example 29: Synthesis of 7-cyclopropyl-2,4-dimethyl-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 342)

[0718] Step one: Synthesis of ethyl 1-(2-bromoethyl)-4,6-dimethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (Compound 44-02)

[0719] Compound Int-1-2 (100 mg, 458.19 µmmol) was dissolved in 2 mL DMF, sodium hydride (32 mg, 1.37 mmol) was added under ice-bath, after stirred for 20 min, 1,2-dibromoethane (103 mg, 549.83 µmol) was added, the mixture was heated at 80 °C for 12 h. LCMS showed the reaction went to completion. The reaction was quenched with water, and purified by silica gel column to give compound 44-02 (66 mg, 202.95 µmol), MS (ESI): m / z = 325.1, [M+H] + .

[0720] Step 2: Synthesis of 7-cyclopropyl-2,4-dimethyl-8,9-dihydropyrido[3',2':4,5]pyrrolo[l,2- a]pyrazin-6(7H)-one (Compound 342)

[0721] Compound 44-02 (66 mg, 202.95 umol) was dissolved in 2 mL of acetonitrile, anhydrous potassium carbonate (70 mg, 507.38 umol) and cyclopropylamine (58 mg, 1.01 mmol) were added successively, heated to 60 °C, and reacted for 18 h. LCMS detection showed that the reaction was complete, and the target compound 342 (10.8 mg, 42.30 umol) was obtained by Prep-HLPC purification.

[0722] MS (ESI): m / z 256.1, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 7.20 (s, 1H), 6.81 (s, 1H), 4.37 (dd, J = 6.6, 5.0 Hz, 2H), 3.78 (dd, J = 6.6, 5.0 Hz, 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).

[0723] Example 30: Synthesis of 7-(bicyclo[l. l. l]pentan-l-yl)-2,4-dimethyl-8,9- dihydropyrido[3',2':4,5]pyrrolo[l,2-a]pyrazin-6(7H)-one (Compound 344)

[0724] Step 1: Synthesis of 4,6-dimethyl-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Compound 46-01)

[0725] Ethyl 4,6-dimethyl-lH-pyrrolo[2,3-b]pyridine-2-carboxylate (120 mg, 549.83 umol) was added to a 25 mL reaction flask, anhydrous ethanol 3 mL was added, and stirred at room temperature. Sodium hydroxide (55 mg, 1.38 mmol) was weighed and dissolved in 1 mL of water, and slowly added to the reaction flask, and the substrate was gradually dissolved. Stirring at room temperature for 3 h. TLC monitoring showed that the reaction was complete, adjusted to pH about 6 with IN HCl, extracted with ethyl acetate, and concentrated to give 104 mg of crude product.

[0726] Step 2: Synthesis of N-(bicyclo[l. l. l]pentan-l-yl)-4,6-dimethyl-lH-pyrrolo[2,3-b]pyridine- 2-carboxamide (Compound 46-03)

[0727] 4,6-dimethyl-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (104 mg, 546.80 pmol) was dissolved in DMF (3 mL), HATU (208 mg, 546.80 pmol) and DIPEA (66.4 mg, 656.16 pmol) were added, stirred at room temperature for 10 min, then bicyclo[l.l.l]pentan-l-amine hydrochloride (78.5 mg, 656.16 pmol) was added, stirred at room temperature for 3 h. LC-MS monitoring showed that the raw material was completely reacted, after removing DMF by concentration, ethyl acetate extraction, the organic phase was concentrated, and C18 reverse phase column chromatography gave compound 46-03 (29 mg, 113.6 pmol). MS (ESI): m / z = 256.1, [M+H + ]。

[0728] Step three: synthesis of 7-(bicyclo[l. l. l]pentan- l-yl)-2,4-dimethyl-8,9- dihydropyrrolo[3',2':4,5]pyrrolo[l,2-a]pyrazin-6(7H)-one (compound 344)

[0729] Compound 46-03 (26 mg, 101.84 pmol) was dissolved in DMF (2 mL) in a 50 mL reaction bottle, NaH (4.5 mg, 112.02 pmol) was reacted at 0 °C for 30 min, 1,2-dibromoethane (21.0 mg, 112.02 pmol) was dissolved in DMF (2 mL), added to the reaction bottle, and reacted at room temperature for 2 h. LC-MS monitoring showed a small amount of product and significant remaining raw material. Stir at room temperature overnight, supplement with NaH (4.5 mg, 112.02 pmol). React at 80 °C for 16 h, the product increased. Continue heating, the product did not change significantly. Remove DMF by concentration, extract with ethyl acetate, concentrate the organic phase to get the crude product, separate the crude product by Prep-HPLC to get compound 344 (2.2 mg, 7.82 pmol).

[0730] MS (ESI): m / z = 282.1, [M+H + ], 1 H NMR (400 MHz, CDC13) δ 7.16 (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 = 1.2 Hz, 1H).

[0731] Example 31: Synthesis of 2-(2,4-dimethyl-6-oxo-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-7(6H)-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide (Compound 347)

[0732] Step one: Synthesis of 2-bromo-N-(1-methyl-1H-pyrazol-4-yl)acetamide (Compound 49-03)

[0733] Compound 49-01 (1 g, 7.49 mmol) was dissolved in 10 mL DCM, triethylamine (833.3 mg, 8.23 mmol) and compound 49-02 (1.18 g, 7.49 mmol) were added, stirred at room temperature for 2 hours under nitrogen protection, LC-MS monitoring reaction completion. Silica gel column chromatography purification gave compound 49-03 (530 mg, 2.43 mmol), MS (ESI): m / z = 218.1, [M+H] + .

[0734] Step two: Synthesis of 2-(2,4-dimethyl-6-oxo-8,9-dihydropyrido[3',2':4,5]pyrrolo[1,2- a]pyrazin-7(6H)-yl)-N-(1-methyl-1H-pyrazol-4-yl)acetamide (Compound 347)

[0735] Compound Int-1 (20 mg, 92.91 umol) was dissolved in 1 mL DMF, NaH (7 mg, 278.74 mmol) was added at 0 °C, stirred at room temperature for 0.5 hours, compound 49-03 (20.3 mg, 92.91 umol) was added, stirred at room temperature for 8 h, LC-MS monitoring reaction completion. Quench with water, extracted with ethyl acetate, the organic phase was dried and concentrated to give the crude product, which was purified by Prep-HPLC to give compound 347 (9.1 mg, 25.82 umol).

[0736] MS (ESI): m / z = 353.1, [M+H] + . 1 H NMR (400 MHz, CDCl3) d 8.60 (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 = 5.6 Hz, 2H), 3.84 (s, 3H), 2.64 (s, 3H), 2.53 (s, 3H).

[0737] Example 32: Synthesis of 2,4-dimethyl-7-(2,2,2-trifluoroethyl)-8,9-dihydrothieno[3,2- b:5,4-c']dipyridin-6(7H)-one (Compound 348)

[0738] To a round bottom flask was added 2,4-dimethyl-8,9-dihydrothieno[3,2-b:5,4-c']dipyridin-6(7H)- one (Compound Int-3) (100 mg, 0.43 mmol), DMF (2 mL), NaH (20 mg, 0.52 mmol) and stirred for 10 min under ice bath condition. Then 2,2,2-trifluoroethyl triflate (100 mg, 0.43 mmol) was added slowly drop wise, brought to room temperature and stirring was continued for 2 h. LCMS showed complete consumption of the substrate and reaction was complete. It was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by Prep-HPLC to get the title compound 348 (27 mg, 0.086 mmol).

[0739] MS (ESI): m / z = 315.2, [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.30 (s, 1H), 4.35 (q, J = 9.2 Hz, 2H), 3.98 (t, J = 6.8 Hz, 2H), 3.31 (d, J = 6.8 Hz, 2H), 2.69 (s, 3H), 2.62 (s, 3H).

[0740] Following the procedure of Example 32, the following compounds were synthesized:

[0741] Example 35: Synthesis of 2,4-dimethyl-7-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9- dihydrothieno[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound 156)

[0742] 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). It was heated to 90 °C and stirred for 2 h. LCMS showed complete consumption of the starting material and reaction was complete. It was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate, organic phase was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure and purified by Prep-HPLC to get the title compound (42 mg, 0.097 mmol).

[0743] MS (ESI): m / z = 432.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (d, J = 5.8 Hz, 1H), 7.27 (s, 1H), 6.81 (d, J = 2.2 Hz, 1H), 6.62 (dd, J = 5.8, 2.2 Hz, 1H), 5.55 - 5.37 (m, 1H), 4.34 (t, J = 8.8 Hz, 2H), 4.23 (dd, J = 9.4, 5.6 Hz, 2H), 3.90 (t, J = 6.8 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.59 (s, 3H), 2.53 (s, 3H).

[0744] Example 36: Synthesis of 7-(1-(1,3,4-thiadiazol-2-yl)azetidin-3-yl)-2,4-dimethyl- 8,9-dihydrothiopheno[3,2-b:5,4-c']dipyridine-6(7H)-one (Compound 351)

[0745] To a round bottom flask was added Intermediate Int-4 (315 mg, 1.1 mmol), 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 copper(I) iodide (110 mg, 0.55 mmol). After nitrogen purging, the temperature was raised to 95 °C and stirred for 16 h. LCMS showed the reaction was complete. The reaction was allowed to cool 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 give the title compound 351 (5.2 mg, 0.014 mmol).

[0746] MS (ESI): m / z = 432.2, [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.62 (s, 1H), 7.16 (s, 1H), 5.45 - 5.35 (m, 1H), 4.44 - 4.31 (m, 4H), 3.90 (t, J = 6.8 Hz, 2H), 3.24 (s, 2H), 2.56 (s, 3H), 2.49 (s, 3H).

[0747] Example 37: Synthesis of 7-(2,3-dihydro-lH-inden-2-yl)-2,4-dimethyl-8,9- dihydrothieno[3,2-b:5,4-c']dipyridine-6(7H)-one (Compound 352)

[0748] Step one: Synthesis of methyl 3-(2-((2,3-dihydro-lH-inden-2-yl)amino)ethyl)-5,7- dimethylthieno[3,2-b]pyridine-2-carboxylate (Compound 55-01)

[0749] Into a round-bottom flask, was placed compound Int-3-6 (337 mg, 1.28 mmol), 2- indanone (253 mg, 1.92 mmol), sodium triacetoxyborohydride (852 mg, 3.84 mmol), dichloromethane (10 mL). Stirred at room temperature for 2 hours. LCMS showed the reaction was complete, quenched by saturated aqueous ammonium chloride solution, extracted by dichloromethane, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, purified by silica gel column chromatography to give the title compound 55-01 (145 mg, 0.38 mmol). MS (ESI): m / z = 380.2, [M+H] + .

[0750] Step two: Synthesis of 2,4-dimethyl-7-(pyridin-4-yl)-8,9-dihydrothieno[3,2- b:5,4-c']dipyridine-6(7H)-one (Compound 352)

[0751] Into a round-bottom flask, was placed compound 55-01 (145 mg, 0.38 mmol), potassium carbonate (212 mg, 1.54 mmol), methanol (10 ml). Stirred at room temperature for 2 hours. LCMS showed the reaction was complete, filtered, purified by Prep-HPLC to give the title compound 352 (17 mg, 0.049 mmol).

[0752] MS (ESI): m / z = 349.3, [M+H] + . 1 H NMR (400 MHz, CD3OD) d 7.17 - 7.13 (m, 3H), 7.09 - 7.07 (m, 2H), 5.52 - 5.45 (m, 1H), 3.55 (t, J = 6.8 Hz, 2H), 3.18 (d, J = 8.4 Hz, 2H), 3.11 - 3.01 (m, 4H), 2.54 (s, 3H), 2.48 (s, 3H).

[0753] Example 38: Synthesis of 2,4-dimethyl-7-(1-(pyrimidin-5-yl)azetidin-3-yl)- 8,9-dihydrothieno[3,2-b:5,4-c']dipyrimidin-6(7H)-one (Compound 353)

[0754] Into a round bottom flask was placed intermediate Int-4 (100 mg, 0.35 mmol), 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 purging, the temperature was raised to 95 °C and stirred for 5 h. LCMS showed the reaction was complete. The reaction was allowed to cool 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 title compound 353 (5.2 mg, 0.014 mmol) was purified by Prep-HPLC.

[0755] MS (ESI): m / z = 366.2, [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.54 (s, 1H), 8.11 (s, 2H), 7.24 (s, 1H), 5.50 (tt, J = 7.8, 5.6 Hz, 1H), 4.39 (t, J = 8.2 Hz, 2H), 4.24 (dd, J = 8.4, 5.6 Hz, 2H), 4.02 (t, J = 6.8 Hz, 2H), 3.32 (d, J = 2.2 Hz, 2H), 2.65 (s, 3H), 2.58 (s, 3H).

[0756] Referring to the synthetic method of Example 38, the following compounds can be synthesized:

[0757] Example 45: Synthesis of 3-chloro-8-(3,3-difluorocyclobutyl)-2,4-dimethyl-8,9,10,10- tetrahydropyrrolo[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 357)

[0758] Step one: Synthesis of (2,5-dichloro-4,6-dimethylpyridin-3-yl)methanamine (Compound 60-02)

[0759] Into a round bottom flask was added compound 2,5-dichloro-4,6-dimethylnicotinonitrile (7.5 g, 30.55 mmol), anhydrous tetrahydrofuran (50 mL), nitrogen was replaced for three times, then borane tetrahydrofuran complex (61.1 mmol) was slowly added under ice bath, after the addition was completed, the temperature was increased to 70 °C and the reaction was continued for 6 hours. LCMS detection showed that the reaction was complete, the temperature was restored to room temperature, methanol (50 mL) was added under ice bath to quench the reaction, after there was no gas emission, 4M hydrochloric acid (30 mL) was added, the temperature was increased to 60 °C and the reaction was continued for 6 hours, the temperature was cooled to room temperature, NaOH aqueous solution was added under ice bath to adjust the pH to 7-8, dichloromethane was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 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] + .

[0760] Step two: synthesis of tert-butyl (2,5-dichloro-4,6-dimethylpyridin-3- yl)methyl)carbamate (compound 60-03)

[0761] Into a round bottom flask was added compound (2,5-dichloro-4,6-dimethylpyridin-3- yl)methanamine (5 g, 20.04 mmol), dichloromethane (50 mL), triethylamine (3.04 g, 30.06 mmol), DMAP (489.5 mg, 4.01 mmol), the reaction was carried out at room temperature for half an hour, then di-tert-butyl dicarbonate (5.25 g, 24.04 mmol) was added and the reaction was continued for 2 hours. LCMS detection showed that the reaction was complete, the temperature was reduced to room temperature, and the reaction was quenched with methanol (50 mL) under ice bath. After there was no gas emission, 4M hydrochloric acid (30 mL) was added, the temperature was increased to 60 °C and the reaction was continued for 6 hours, the temperature was cooled to room temperature, NaOH aqueous solution was added under ice bath to adjust the pH to 7-8, dichloromethane was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 60-03 (5.6 g, 16.69 mmol), MS (ESI): m / z = 305.1, [M+H] + .

[0762] Step three: synthesis of (E)-ethyl 3-(3-(((tert-butoxycarbonyl)amino)methyl)-5-chloro-4,6- dimethylpyridin-2-yl)acrylate (compound 60-05)

[0763] To a round-bottom flask was added compound 60-03 (4 g, 11.92 mmol), 1,4-dioxane (40 mL), water (4 mL), followed by (E)-2-(ethoxycarbonyl)vinyl boronic acid pinacol ester (1.77 g, 17.88 mmol), potassium carbonate (3.29 g, 23.84 mmol), Pd(dppf)2Cl2(0.87 g, 1.19 mmol). After nitrogen replacement, the temperature was raised to 110 °C and stirred for 12 h. LCMS showed the reaction was complete. After cooling to room temperature, 1,4-dioxane was removed under reduced pressure. 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. Compound 60-05 (2.8 g, 11.92 mmol) was obtained by column chromatography, MS (ESI): m / z = 369.1, [M+H] + .

[0764] Step Four: 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)

[0765] To a round-bottom flask was added compound 60-05 (2.8 g, 11.92 mmol), 5% sodium hydroxide aqueous solution 30 mL, and the mixture was stirred at 60 °C for 4 h. The temperature was raised to 100 °C and the reaction was continued for another 4 h. LCMS showed the reaction was complete. After cooling to room temperature, the pH was adjusted to 6-7 with acid in an ice bath. Compound 60-06 (1.8 g, 5.28 mmol) was obtained by C18 reverse-phase flash chromatography, MS (ESI): m / z = 341.1, [M+H] + .

[0766] Step Five: 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)

[0767] To a round-bottom flask was added compound 60-06 (1 g, 2.93 mmol), DMF (20 mL), TCFH (1.65 g, 5.87 mmol), N-methylimidazole (0.96 g, 11.74 mmol), and the mixture was stirred at room temperature for 10 min. 3,3-Difluorocyclobutane-1-amine (0.95 g, 4.40 mmol) was added and the reaction was continued for another 6 h. LCMS showed the reaction was complete. Compound 60-08 (1.2 g, 2.93 mmol) was obtained by C18 reverse-phase flash chromatography, MS (ESI): m / z = 430.1, [M+H] + .

[0768] Step six: 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)

[0769] To a round-bottom flask was added compound 60-08 (0.7 g, 1.59 mmol), anhydrous tetrahydrofuran (10 mL), and the flask was purged with nitrogen three times. Borane tetrahydrofuran complex (3.2 mmol) was slowly added under ice-bath cooling, and the addition was completed. The temperature was increased to 70 °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 methanol (5 mL) was added to quench the reaction under ice-bath cooling. After no gas was released, Pd / C was added, and the temperature was increased to 60 °C for stirring for 2 hours. Filtration and concentration under reduced pressure gave crude product 60-09 (0.42 g, 0.98 mmol), MS (ESI): m / z = 316.1, [M+H] + .

[0770] Step seven: 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)

[0771] To a round-bottom flask was added compound 60-09 (1.2 g, 2.93 mmol), DCM (10 mL), and 12 N hydrochloric acid solution was slowly added dropwise at room temperature. The reaction was carried out for 4 hours. LCMS detection showed that the reaction was complete. NaOH aqueous solution was added to adjust the pH to 7-8, dichloromethane was added for extraction, the organic phase was dried over anhydrous sodium sulfate, and concentration and drying under reduced pressure gave crude product compound 60-10 (0.7 g, 1.59 mmol), MS (ESI): m / z = 330.1, [M+H] + .

[0772] Step eight: 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)

[0773] To a round-bottom flask was added compound 60-10 (0.1 g, 0.98 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (35.6 mg, 0.35 mmol), N,N'-carbonyldiimidazole (45.6 mg, 0.28 mmol), and the reaction was carried out at room temperature for half an hour. The temperature was increased 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 concentration under reduced pressure gave the target compound 357 (56 mg, 0.12 mmol), which was purified by Prep-HPLC.

[0774] MS (ESI): m / z = 342.1, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 4.93 (d, J = 15.2 Hz, 1H), 4.81 - 4.67 (m, 2H), 4.52 (d, J = 15.2 Hz, 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).

[0775] Referring to the synthetic method of Example 45, the following compound can be synthesized:

[0776] Example 49: Synthesis of 7-((1H-pyrazol-4-yl)methyl)-2,4-dimethyl-8,9- dihydrothiopheno[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound 362)

[0777] Step one: Synthesis of methyl (1H-pyrazol-4-yl)trifluoromethanesulfonate (Compound 65-02)

[0778] Into a round-bottom flask was added compound 65-01 (1.0 g, 10.2 mmol), dichloromethane (100 mL), triethylamine (2.1 g, 20.4 mmol), placed in an ice water bath, slowly added trifluoromethanesulfonic anhydride (2.8 g, 10.2 mmol) dropwise with stirring, and stirred at room temperature for 2 hours. LCMS showed that the reaction was complete, the reaction solution was quenched with saturated brine, the organic phase was separated, the aqueous phase was extracted with dichloromethane, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The title compound 65-02 (1.4 g, 6.3 mmol) was obtained by column chromatography. MS (ESI): m / z = 230.2, [M+H] + .

[0779] Step two: Synthesis of 7-((1H-pyrazol-4-yl)methyl)-2,4-dimethyl-8,9- dihydrothiopheno[3,2-b:5,4-c']dipyridin-6(7H)-one (Compound 362)

[0780] To a round bottom flask was added compound Int-3 (100 mg, 0.43 mmol), DMF (2 mL), NaH (20 mg, 0.52 mmol) and stirred for 10 min under ice bath condition. Then (1H-pyrazol-4-yl)methyl trifluoromethanesulfonate (99 mg, 0.43 mmol) was added slowly drop wise, brought to room temperature and stirring was continued for 2 h. LCMS showed complete consumption of the substrate and reaction was complete. It was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The title compound 362 (16 mg, 0.051 mmol) was obtained by purification on Prep-HPLC. MS (ESI): m / z = 312.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.61 (s, 2H), 7.24 (s, 1H), 4.57 (s, 2H), 3.67 (t, J = 7.2 Hz, 2H), 3.10 (t, J = 7.2 Hz, 2H), 2.57 (s, 3H), 2.52 (s, 3H).

[0781] Example 50: Synthesis of 2,4-dimethyl-7-(2-methylpyridin-4-yl)-5- (trifluoromethyl)-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (Compound 363)

[0782] Step one: Synthesis of 5-iodo-2,4-dimethyl-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[1,2- a]pyrazin-6(7H)-one (Compound 66-01)

[0783] Compound Int-1 (100 mg, 464 μmol) was dissolved in 2 mL ACN, NIS (105 mg, 464 μmol) was added and stirred at room temperature for 3 h. LC-MS showed complete reaction and compound 66-01 (140 mg, 41 μmol) was obtained by purification on silica gel column, MS (ESI): m / z = 342.1, [M+H] + .

[0784] Step two: Synthesis of 2,4-dimethyl-5-(trifluoromethyl)-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[1,2- a]pyrazin-6(7H)-one (Compound 66-02)

[0785] Compound 66-01 (140 mg, 410 μmol) was dissolved in 2 mL DMF, methyl fluorosulfonyl difluoroacetate (158 mg, 820 μmol), cuprous iodide (235 mg, 1.23 mmol) were added successively, protected by nitrogen, warmed to 80 °C for 10 hours. LC-MS detection showed the reaction was complete, and compound 66-02 (58 mg, 205 μmol) was obtained by silica gel column purification, MS (ESI): m / z = 284.1, [M+H] + .

[0786] Step three: Synthesis of 2,4-dimethyl-7-(2-methylpyridin-4-yl)-5- (trifluoromethyl)-8,9-dihydropyrrolo[3',2':4,5]pyrrolo[1,2-a]pyrazin-6(7H)-one (363)

[0787] Compound 66-02 (58 mg, 205 μmol) was dissolved in 1 mL dry 1,4-dioxane, 4-bromo-2-methylpyridine (53 mg, 307 μmol), anhydrous potassium carbonate (57 mg, 409 μmol), cuprous iodide (39 mg, 205 μmol), DMEDA (36 mg, 409 μmol) were added successively, replaced by nitrogen, warmed to 110 °C and stirred for 8 hours. LCMS detection showed the reaction was complete, and compound 363 (13.8 mg, 36.86 μmol) was obtained by filtration on silica gel and column chromatography, MS (ESI): m / z = 375.3, [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.54 (d, J = 5.6 Hz, 1H), 7.38 (s, 1H), 7.22 (d, J = 4.2 Hz, 1H), 6.98 (s, 1H), 4.69-4.57 (m, 2H), 4.30-4.20 (m, 2H), 2.65 (d, J = 2.2 Hz, 3H), 2.63 (s, 3H), 2.60 (s, 3H).

[0788] Example 51: Synthesis of 2,4-dimethyl-8-(1-(2-methylpyridin-4-yl)azetidin-3-yl)- 8,9,10,10a-tetrahydropyrrolo[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 11)

[0789] To a Schlenk flask was added compound Int-5 (50 mg, 183.59 umol), 1,4-dioxane (2 mL), followed by 4-bromo-2-methylpyridine (37.9 mg, 220.3 umol), Ruphos Pd G3 (14.78 mg, 18.36 umol), Ruphos (25.7 mg, 55.08 umol), cesium carbonate (179.45 mg, 550.76 umol). After nitrogen substitution, it was warmed to 90 °C and stirred for 12 h. LCMS showed the reaction was complete. It was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, and purified by Prep-HPLC to give compound 11 (22.3 mg, 60.53 umol).

[0790] MS (ESI): m / z = 364.2, [M+H] + . 1 H-NMR (400 MHz, CDC13) δ 8.14 (d, J = 6.4 Hz, 1H), 6.92 (s, 1H), 6.23 (dd, J = 6.4, 2.4 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 5.42 - 5.22 (m, 1H), 4.92 (d, J = 15.2 Hz, 1H), 4.76 (d, J = 9.6 Hz, 1H), 4.52 (d, J = 15.2 Hz, 1H), 4.41 - 4.27 (m, 3H), 4.18 (dd, J = 9.6, 5.6 Hz, 1H), 3.76 - 3.47 (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).

[0791] Referring to the synthetic method of Example 51, the following compounds can be synthesized:

[0792] Example 105: Synthesis of 2,4-dimethyl-8-(l-(3-methyl-l,2,4-thiadiazol-5-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)- one (Compound 365)

[0793] To the flask was added compound Int-5 (50 mg, 183.59 umol), 1,4-dioxane (2 mL), followed by 5-chloro-3-methyl-l,2,4-thiadiazole (29.6 mg, 220.3 umol), cesium fluoride (33.5 mg, 220.3 umol), triethylamine (28 mg, 220.3 umol) sequentially, warmed to 90 °C and stirred for 12 h. The reaction was complete by LCMS, allowed to come to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure and purified by Prep-HPLC to get compound 365 (27.2 mg, 72.88 umol).

[0794] MS (ESI): m / z = 371.2, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 6.92 (s, 1H), 5.61 - 5.43 (m, 1H), 4.93 (d, J = 15.2 Hz, 1H), 4.78 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 15.2 Hz, 1H), 4.43 - 4.30 (m, 3H), 4.19 (dd, J = 9.2, 5.6 Hz, 1H), 3.70 - 3.53 (m, 2H), 2.76 (d, J = 12.0 Hz, 1H), 2.53 (s, 3H), 2.43 (s, 3H), 2.26 (s, 3H), 1.81 - 1.63 (m, 1H).

[0795] Referring to the method of synthesis of Example 105, the following compounds can be synthesized:

[0796] Example 112: Synthesis of 8-(l-(2-cyclopropyl-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (Compound 371)

[0797] Step 1: Synthesis of 8-(l-(2-chloro-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4- dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (Compound 75-01)

[0798] To a sealed tube was added compound Int-5 (50 mg, 183.59 µmol), 1,4-dioxane (2 mL), followed by 2,4-dichloro-5-fluoropyrimidine (36 mg, 220.3 µmol), cesium fluoride (33.5 mg, 220.3 µmol), triethylamine (28 mg, 220.3 µmol), warmed to 90 °C, stirred for 12 h. LCMS showed the reaction was complete, allowed to warm to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by silica gel column chromatography to afford compound 75-01 (62 mg, 153.90 µmol). MS (ESI): m / z = 403.1, [M+H] + .

[0799] Step 2: Synthesis of 8-(l-(2-cyclopropyl-5-fluoropyrimidin-4-yl)azetidin-3-yl)-2,4- dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (Compound 371)

[0800] To a Schlenk tube was added compound 75-01 (62 mg, 153.90 µmol), 1,4-dioxane (2 mL), water (0.2 mL), followed by cyclopropylboronic acid (19.2 mg, 223.4 µmol), Pd(dppf)2Cl2 (12.2 mg, 14.89 µmol), potassium carbonate (61.8 mg, 446.81 µmol). After replaced with nitrogen, warmed to 90 °C, stirred for 12 h. LCMS showed the reaction was complete, allowed to warm to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by Prep-HPLC to afford compound 371 (35.2 mg, 85.68 µmol).

[0801] MS (ESI): m / z = 409.1, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 4.4 Hz 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, 2.8 Hz, 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).

[0802] Chiral resolution:

[0803] Compound 371 (580 mg) was resolved by chiral column to give compound 371a (264.9 mg) and compound 371b (262.9 mg) using UniChiral YMC-CMD-5H column with n-hexane - absolute ethanol (60:40) as mobile phase.

[0804] Compound 371a: Retention time RT = 14.409 min, LC-MS: m / z = 409.2 [M+H] + , 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 4.4 Hz 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, 2.8 Hz, 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).

[0805] Compound 371b: Retention time RT = 16.052 min, LC-MS: m / z = 409.2 [M+H] + , 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 4.4 Hz, 1H), 7.01 (s, 1H), 5.24 - 5.18 (m, 1H), 4.76 (d, J = 15.2 Hz, 1H), 4.71 (d, J = 12.0 Hz, 1H), 4.42 - 4.30 (m, 4H), 4.25 (d, J = 6.0 Hz, 1H), 3.61 - 3.54 (m, 2H), 2.52 (d, J = 4.0 Hz, 1H), 2.43 (s, 3H), 2.23 (s, 3H), 1.98 - 1.92 (m, 1H), 1.62 - 1.54 (m, 1H), 0.89 - 0.84 (m, 4H).

[0806] Example 113: 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)

[0807] Step one: 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

[0808] To a sealed tube was added compound 2,4-dimethyl-8,9,10,10a- tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (50 mg, 183.59 pmol), 1,4- dioxane (2 mL), followed by 2,4-dichloropyrimidine (32.8 mg, 220.3 pmol), cesium fluoride (33.5 mg, 220.3 pmol), triethylamine (28 mg, 220.3 pmol), warmed to 90 °C, stirred for 12 h. LCMS showed the reaction was complete, allowed to cool to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by reverse phase prep to give compound 86-01 (42 mg, 109.13 pmol), MS (ESI): m / z = 385.1, [M+H] + .

[0809] Step two: synthesis of 8-(l-(2-(ethylamino)pyrimidin-4-yl)azetidin-3-yl)-2,4- dimethyl-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (compound 380) and 8-(l-(2-(dimethylamino)pyrimidin-4-yl)azetidin-3-yl)-2,4-dimethyl- 8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (compound 381)

[0810] To the microwave tube was added compound 86-01 (42 mg, 109.13 μmol), N,N- dimethylacetamide (2 mL), followed by ethylamine (5.9 mg, 130.9 μmol), cesium fluoride (19.9 mg, 130.9 μmol), triethylamine (13.2 mg, 130.9 μmol) sequentially. The microwave condition was set at 130 °C, power: 400 W, and the reaction was allowed to proceed for 3 h. LCMS indicated the reaction was complete, the reaction was allowed to cool to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, and the crude was purified by Prep-HPLC to give compound 380 (8.1 mg, 20.33 μmol) and compound 381 (12.2 mg, 31.0 μmol).

[0811] Compound 380: MS (ESI): m / z = 394.2, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 5.6 Hz, 1H), 7.01 (s, 1H), 6.53 (t, J = 5.6 Hz, 1H), 5.63 (d, J = 5.6 Hz, 1H), 5.25 - 5.09 (m, 1H), 4.85 - 4.66 (m, 2H), 4.39 (d, J = 14.8 Hz, 1H), 4.15 - 4.04 (m, 3H), 3.96 (dd, J = 9.0, 5.6 Hz, 1H), 3.62 - 3.49 (m, 2H), 3.22 (q, J = 7.2 Hz, 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 = 7.2 Hz, 3H).

[0812] Compound 381: MS (ESI): m / z = 394.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 5.6 Hz, 1H), 7.01 (s, 1H), 5.65 (d, J = 5.6 Hz, 1H), 5.26 - 5.12 (m, 1H), 4.76 (d, J = 15.2 Hz, 1H), 4.71 (d, J = 11.2 Hz, 1H), 4.39 (d, J = 15.2 Hz, 1H), 4.19 - 4.07 (m, 3H), 3.98 (dd, J = 9.2, 5.6 Hz, 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).

[0813] Example 114: 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)

[0814] Step one: 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)

[0815] Into a Schlenk, was added compound Int-5 (50 mg, 183.59 umol), 1,4-dioxane (2 mL), followed by 2-fluoro-4-iodopyridine (49.13 mg, 220.3 umol), Ruphos Pd G3 (14.78 mg, 18.36 umol), Ruphos (25.7 mg, 55.08 umol), cesium carbonate (179.45 mg, 550.76 umol). After nitrogen substitution, it was warmed to 90 °C and stirred for 12 h. LCMS showed the reaction was completed. It was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure. Purification by Prep-HPLC afforded compound 13 (27.2 mg, 74.03 umol).

[0816] MS (ESI): m / z = 368.2, [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 5.6 Hz, 1H), 7.01 (s, 1H), 6.32 (dt, J = 5.6, 2.0 Hz, 1H), 6.01 (d, J = 2.0 Hz, 1H), 5.27 - 5.18 (m, 1H), 4.77 (d, J = 15.2 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.40 (d, J = 15.2 Hz, 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).

[0817] Step two: chiral resolution

[0818] Compound 13 (3.0 g, 8.16 mmol) was resolved by column CHIRALPAK AS (30*250 mm 5 pm) (Daicel) with mobile phase carbon dioxide: methanol (65:35) to give compound 13a (1.1 g) and compound 13b (1.1 g), the retention time of compound 13a was 31.618 min, and the retention time of compound 13b was 41.429 min.

[0819] Compound 13a: MS [ESI]: m / z = 368.2, [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 5.6 Hz, 1H), 6.88 (s, 1H), 6.10 (dt, J = 5.6, 1.6 Hz, 1H), 5.75 (d, J = 1.6 Hz, 1H), 5.36 (d, J = 5.6 Hz, 1H), 4.88 (d, J = 15.2 Hz, 1H), 4.71 (s, 1H), 4.46 (d, J = 15.2 Hz, 1H), 4.21 - 4.04 (m, 3H), 3.91 (dd, J = 8.4, 5.6 Hz, 1H), 3.59 - 3.50 (m, 2H), 2.74 (d, J = 11.2 Hz, 1H), 2.49 (s, 3H), 2.21 (s, 3H), 1.72 - 1.57 (m, 1H).

[0820] Compound 13b: MS [ESI]: m / z = 368.2, [M+H] + . 1H NMR (400 MHz, CDC13) δ 7.85 (d, J = 5.8 Hz, 1H), 6.95 (s, 1H), 6.21 - 6.16 (m, 1H), 5.82 (d, J = 2.0 Hz, 1H), 5.46 - 5.35 (m, 1H), 4.95 (d, J = 15.2, 1H), 4.81 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 15.2 Hz, 1H), 4.26 - 4.13 (m, 3H), 3.99 (dd, J = 8.4, 5.6 Hz, 1H), 3.68 - 3.55 (m, 2H), 2.83 (d, J = 12.0 Hz, 1H), 2.57 (s, 3H), 2.27 (s, 3H), 1.78 - 1.58 (m, 1H).

[0821] Example 115: 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)

[0822] Step one: Synthesis of 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-carboxylic acid tert-butyl ester (Compound 89-01)

[0823] To a round bottom flask was added compound 29-07 (3.0 g, 8.8 mmol), benzyl 3- aminoazetidine-1-carboxylate (2.2 g, 10.56 mmol), NMI (2.9 g, 35.29 mmol), TCFH (4.94 g, 17.61 mmol), DMF (25 mL), stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, the reaction was quenched by the addition of water, extracted by DCM, concentrated under reduced pressure, purified by column chromatography to give compound 89-01 (3.6 g, 6.80 mmol). MS [ESI]: m / z = 529.2, [M+H] + .

[0824] Step two: Synthesis of 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-carboxylic acid tert-butyl ester (Compound 89-02)

[0825] To a round-bottom flask was added compound 89-01 (3.6 g, 6.80 mmol), borane tetrahydrofuran complex (25 mL), THF (25 ml), 60 °C stirring for 2 hours. LCMS detected that the reaction was complete, methanol was added to quench the reaction, reduced pressure concentration, the crude product was subjected to the next reaction (3.3 g, 6.41 mmol). MS [ESI]: m / z = 515.2, [M+H] + .

[0826] 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)

[0827] To a round-bottom flask was added compound 89-02 crude (3.6 g, 6.80 mmol), HCl / 1,4-dioxane (10 mL), stirring at room temperature for 2 hours. LCMS detected that the reaction was complete, sodium hydroxide aqueous solution was added to adjust the pH to 7, dichloromethane was extracted, reduced pressure concentration, the crude product was subjected to the next reaction (2.74 g, 6.6 mmol). MS [ESI]: m / z = 415.2, [M+H] + .

[0828] Step four: synthesis of benzyl 3-(3-chloro-2,4-dimethyl-7-oxo-5,9,10,10a-tetrahydro pyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-8(7H)-yl)azetidine-1-carboxylate (compound 89-04)

[0829] To a round-bottom flask was added compound 89-03 crude (2.74 g, 6.6 mmol), TEA (0.79 g, 7.81 mmol), CDI (0.94 g, 6.51 mmol), 90 °C heating stirring overnight. LCMS detected that the reaction was complete, filtration, reduced pressure concentration, purification by column chromatography to obtain compound 89-04 (2.4 g, 5.44 mmol).

[0830] MS [ESI]: m / z = 441.2, [M+H] + .

[0831] Step five: synthesis of 3-(3-chloro-2,4-dimethyl-7-oxo-5,9,10,10a-tetrahydro pyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-8(7H)-yl)azetidin-1-amine (compound 89-05)

[0832] To a round bottom flask was added compound 89-04 (2.4 g, 5.44 mmol), MeOH (20 mL), palladium hydroxide (480 mg, 20 wt%), stirred at room temperature under H2atmosphere overnight. LCMS showed the reaction was complete, filtered, concentrated under reduced pressure, purified by column chromatography to give compound 89-05 (0.81 g, 2.61 mmol). MS [ESI]: m / z = 307.2, [M+H] + .

[0833] Step six: 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)

[0834] To a round bottom flask was added compound 89-05 (25.0 mg, 0.082 mmol), 2,2,2- trifluoroethyl trifluoromethanesulfonate (28.4 mg, 0.12 mmol), DMF (3 mL), stirred at room temperature overnight. LCMS showed the reaction was complete, purified by Prep-HPLC to give the title compound (15.2 mg, 0.038 mmol). MS [ESI]: m / z = 389.1, [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 4.94 - 4.85 (m, 2H), 4.71 (dd, J = 11.2, 2.0 Hz, 1H), 4.50 (d, J = 15.2 Hz, 1H), 3.84 - 3.67 (m, 2H), 3.61 - 3.56 (m, 1H), 3.54 - 3.44 (m, 2H), 3.38 (t, J = 7.2 Hz, 1H), 3.04 (q, J = 9.2 Hz, 2H), 2.68 - 2.64 (m, 1H), 2.62 (s, 3H), 2.31 (s, 3H), 1.71 - 1.61 (m, 1H).

[0835] Example 116: 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)

[0836] To a round-bottom flask was added compound 89-05 (25.0 mg, 0.082 mmol), DCM (3 mL), aqueous formaldehyde (6.8 mg, 0.12 mmol), sodium borohydride (34.54 mg, 0.016 mmol), stirred at room temperature overnight. LCMS showed the reaction was complete, purified by pre-HPLC to give compound 384 (10.5 mg, 0.038 mmol). MS [ESI]: m / z = 321.1, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 4.92 (d, J = 15.2 Hz, 1H), 4.76 - 4.60 (m, 4H), 4.53 (d, J = 15.2 Hz, 1H), 4.29 (s, 1H), 3.57 (td, J = 12.0, 3.6 Hz, 1H), 3.33 (dd, J = 11.2, 4.4 Hz, 1H), 3.03 (s, 3H), 2.62 (s, 3H), 2.32 - 1.96 (m, 2H), 1.76 - 1.64 (m, 1H).

[0837] Example 117: Synthesis of 3-chloro-2,4-dimethyl-8-(l-(2-(trifluoromethyl)pyridin-4- yl)pyrrolidin-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)- one (Compound 385)

[0838] Step one: Synthesis of tert-butyl (l-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3- yl)carbamate (Compound 91-02)

[0839] To a round-bottom flask was added tert-butyl pyrrolidin-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), dioxane (10 ml), stirred at 90 °C under nitrogen protection overnight. LCMS showed the reaction was complete, quenched by water, extracted by DCM, concentrated under reduced pressure, purified by column chromatography to give compound 91-02 (1.52 g, 4.59 mmol). MS [ESI]: m / z = 332.2, [M+H] + .

[0840] Step two: Synthesis of l-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-amine (Compound 91-03)

[0841] To a round-bottom flask was added compound 91-02 (1.52 g, 4.59 mmol), HC1 (2 ml), DCM / MeOH (10:1, 10 ml), stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, added aqueous sodium hydroxide solution to adjust pH to 7, dichloromethane extraction, reduced pressure concentration, the crude product was used in the next step reaction (1.0 g, 4.32 mmol). MS [ESI]: m / z = 232.2, [M+H] + .

[0842] Step three: 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-pyrrolo[3,4- b]pyridine-6-carboxylate (compound 91-04)

[0843] To a round-bottom flask was added compound 91-03 crude (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), DMF (10 ml), stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, added water to quench the reaction, DCM extraction, reduced pressure concentration, purified by column chromatography to obtain compound 91-04 (452.4 mg, 0.82 mmol). MS [ESI]: m / z = 553.2, [M+H] + .

[0844] Step four: 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)

[0845] To a round-bottom flask was added compound 91-04 (452.4 mg, 0.82 mmol), borane tetrahydrofuran complex (5 ml), THF (5 ml), stirred at 60°C for 2 hours. LCMS detected that the reaction was complete, added water to quench the reaction, ethyl acetate extraction, reduced pressure concentration, the crude product was used in the next step reaction (421.5 mg, 0.78 mmol). MS [ESI]: m / z = 540.2, [M+H] + .

[0846] Step five: Synthesis of N-(2-(3-chloro-2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-7-yl)ethyl)-l-(2-(trifluoromethyl)pyridin-4-yl)pyrrolidin-3-amine (Compound 91-06)

[0847] To a round-bottom flask was added compound 91-05 crude (421.5 mg, 0.78 mmol), HC1 (2 ml), THF (5 ml), stirred at room temperature for 2 hours. LCMS detected that the reaction was complete, added sodium hydroxide aqueous solution to adjust pH to 7, dichloromethane extraction, reduced pressure concentration, crude product for next step reaction (323.2 mg, 0.73 mmol). MS [ESI]: m / z = 240.2, [M+H] + .

[0848] Step six: Synthesis of 3-chloro-2,4-dimethyl-8-(l-(2-(trifluoromethyl)pyridin-4- yl)pyrrolidin-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)- one (Compound 385)

[0849] To a round-bottom flask was added compound 91-06 crude (50.0 mg, 0.11 mmol), CDI (18.4 mg, 0.11 mmol), TEA (13.8 mg, 0.14 mmol), heated and stirred at 90 °C overnight. LCMS detected that the reaction was complete, filtered, reduced pressure concentration, purified by Prep-HPLC to obtain compound 385 (23.2 mg, 0.049 mmol). MS [ESI]: m / z = 466.2, [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.29 (t, J = 5.6 Hz, 1H), 6.74 (dd, J = 7.2, 2.4 Hz, 1H), 6.52 - 6.33 (m, 1H), 5.37 - 5.14 (m, 1H), 5.04 - 4.89 (m, 1H), 4.81 - 4.66 (m, 1H), 4.54 (d, J = 15.2 Hz, 1H), 3.68 - 3.50 (m, 2H), 3.50 - 3.15 (m, 4H), 2.66 (dd, J = 13.6, 3.0 Hz, 1H), 2.62 (s, 3H), 2.32 (s, 3H), 2.31 - 2.11 (m, 2H), 1.73 - 1.57 (m, 1H).

[0850] Example 118: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2,3-a]indolizine-7(5H)-one (Compound 63)

[0851] Step one: Synthesis of tert-butyl 7-(2-hydroxyethyl)-2,4-dimethyl-5,7-dihydro-6H- pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 93-1)

[0852] Into a three-necked flask was placed Int-8 (4.0 g, 13.1 mmol), tetrahydrofuran (20 ml), replaced by nitrogen, cooled to zero, added lithium aluminum hydride (600 mg, 15.7 mmol), the reaction solution was slowly warmed, stirred for 1 hour. TLC (n-heptane: ethyl acetate = 3:1) detected that the reaction was complete, the reaction solution was temperature controlled, water, 15% sodium hydroxide aqueous solution was added slowly dropwise respectively, 10 g of anhydrous sodium sulfate was added, stirred, suction filtered, the filtrate was concentrated under reduced pressure to obtain the title compound 93-1 (3.8 g, 12.8 mmol). MS [ESI]: m / z = 293.2 [M+H] + .

[0853] Step two: Synthesis of 2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethan-1-ol (Compound 93-2)

[0854] Into a 100 mL single-necked flask was added compound 93-1 (3.8 g, 12.8 mmol), hydrochloric acid dioxane solution (4.0 M, 15 mL), stirred at 25 °C, LCMS detected that the reaction was complete, concentrated under reduced pressure to obtain the title compound 93-2 (2.4 g, crude). MS [ESI]: m / z = 193.2 [M+H] + .

[0855] Step three: 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)

[0856] 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-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (5.7 g, 15.0 mmol), N,N-diisopropyl ethylamine (4.8 g, 37.8 mmol), dichloromethane (20 mL), stirred at 25 °C for 1 h, then compound 93-2 (2.4 g, 12.7 mmol) was added, LCMS showed the reaction was complete, then saturated sodium chloride solution was added to quench, extracted, concentrated under reduced pressure, 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] + .

[0857] Step four: 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)

[0858] To a single necked flask was added imidazole (0.78 g, 11.5 mmol), triphenyl phosphine (3.0 g, 11.5 mmol), iodine (2.19 g, 8.6 mmol), dichloromethane (20 ml), stirred at 25 °C for 30 min, then compound 93-3 was added, stirred at 25 °C for 15 h, then saturated sodium sulfite solution was added to quench, extracted, concentrated under reduced pressure, purified by normal phase column chromatography to give the title compound 93-4 (1.5 g, 2.8 mmol). MS [ESI]: m / z = 545.2 [M+H] + .

[0859] Step five: synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrrolo[2,3-a]indolizine-7(5H)-one (compound 63)

[0860] To a three necked flask was added compound 93-4 (0.15 g, 0.27 mmol), tetrahydrofuran (10 mL), replaced with nitrogen for three times, then potassium tert-butoxide tetrahydrofuran solution (1 M, 0.81 mmol, 0.82 mL) was added dropwise under ice bath, stirred at 25 °C for 2 h, LCMS showed the reaction was complete, then saturated sodium chloride solution was added to quench, extracted, concentrated under reduced pressure, purified by Prep-HPLC to give the title compound 63 (50.2 mg, 0.12 mmol).

[0861] MS [ESI]: m / z = 417.2 [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.21 (dd, J = 5.6, 2.8 Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 6.52 (dd, J = 6.0, 2.4 Hz, 1H), 6.39 - 6.10 (m, 1H), 5.12 - 4.82 (m, 1H), 4.78 - 4.58 (m, 1H), 4.48 - 4.28 (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).

[0862] Compound 63 was chiral separated using a Unichiral CNZ-5H column with n-hexane - absolute ethanol (50:50) as mobile phase to give 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), compound 63d (9.4 mg, RT = 33.09 min).

[0863] Compound 63a

[0864] 1 H NMR (400 MHz, CDC13) δ 8.21 (dd, J = 5.6, 2.8 Hz, 1H), 6.85 (d, J = 5.2 Hz, 1H), 6.52 (dd, J = 6.0, 2.4 Hz, 1H), 6.39 - 6.10 (m, 1H), 5.12 - 4.82 (m, 1H), 4.78 - 4.58 (m, 1H), 4.48 - 4.28 (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).

[0865] Compound 63b

[0866] 1H 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).

[0867] Compound 63c

[0868] 1 H 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).

[0869] Compound 63d

[0870] 1 H 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).

[0871] Example 119: 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]indolizine-7(5H)-one (Compound 84)

[0872] Step one: 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)

[0873] Into a three-necked flask was placed compound Int 7 (16 g, 43.38 mmol), tetrahydrofuran 200 mL, nitrogen was replaced after cooling to zero, then lithium aluminum hydride (1.98 g, 52.05 mmol) was added, the reaction solution was slowly warmed to 0 °C, stirring. TLC (n-heptane: ethyl acetate = 3:1) detection reaction was complete, the reaction solution was controlled to 0 °C, sodium hydroxide aqueous solution was slowly added respectively, 30 g of anhydrous sodium sulfate was added, stirring, suction filtration, the filtrate was concentrated under reduced pressure to give compound 94-1 (14 g, 42.84 mmol).

[0874] Step two: 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)

[0875] Into a three-necked flask was placed imidazole (4.37 g, 64.26 mmol), triphenylphosphine (16.85 g, 64.26 mmol), dichloromethane (300 mL), controlled to 0 °C, stirring, then iodine (16.31 g, 64.26 mmol) was added, stirring, then compound 94-1 (14 g, 42.84 mmol) was added, the reaction solution was slowly warmed to 25 °C. TLC detection reaction was complete, saturated sodium bisulfite solution was added to quench, extraction, concentrated under reduced pressure, purified by silica gel column chromatography to give compound 94-2 (12 g, 27.48 mmol).

[0876] Step three: 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)

[0877] Into a three-necked flask was placed compound 94-2 (3.72 g, 8.51 mmol), Int 10 (2 g, 6.55 mmol), tetrahydrofuran (30 mL), and the mixture was cooled to -30 °C. Lithium bis(trimethylsilyl)amide (1 M, 10.48 mmol, 10.48 mL) was added slowly dropwise, and the reaction mixture was allowed to warm to 25 °C slowly. The reaction was monitored by LCMS. When the reaction was completed, the reaction was quenched by the addition of saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 94-3 (1.2 g, 1.95 mmol). MS [ESI]: m / z = 614.3, [M+H] + .

[0878] Step Four: 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)

[0879] Into a single-necked flask was placed compound 94-3 (1.2 g, 1.95 mmol), dichloromethane (6 mL), and trifluoroacetic acid (3 mL) was added slowly. The reaction mixture was stirred at 25 °C. The reaction was monitored by LCMS. When the reaction was completed, the reaction was concentrated under reduced pressure to give compound 94-4 (850 mg, 1.86 mmol). MS [ESI]: m / z = 458.2, [M+H] + .

[0880] Step Five: Synthesis of 3-(3-chloro-2,4-dimethyl-7-oxo-5,7,8,9,10,10- hexahydropyrrolo[2,3-a]indolizin-8-yl)azetidine-1-carboxylate benzyl ester (Compound 94-5)

[0881] Into a single-necked flask was placed compound 94-4 (850 mg, 1.86 mmol), N,N- diisopropylethylamine (1.2 g, 9.28 mmol), N,N-dimethylacetamide (30 mL), and the mixture was stirred. (7-Azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.28 g, 3.34 mmol) was added. The reaction mixture was stirred at 25 °C. The reaction was monitored by LCMS. When the reaction was completed, the reaction was quenched by the addition of saturated sodium chloride solution. The mixture was extracted and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to give compound 94-5 (500 mg, 1.14 mmol). MS [ESI]: m / z = 440.2, [M+H] + .

[0882] Step Six: Synthesis of 8-(azetidin-3-yl)-3-chloro-2,4-dimethyl-8,9,10,10- tetrahydropyrrolo[2,3-a]indolizin-7(5H)-one (Compound 94-6)

[0883] Into a 100 mL single necked flask, was placed compound 94-5 (500 mg, 1.14 mmol), methanol (5 mL), tetrahydrofuran (5 mL), purged with nitrogen three times, then palladium on carbon (240 mg) was added. LCMS showed the reaction was complete, suction filtered, the filtrate was concentrated under reduced pressure to give the title compound 94-6 (300 mg, 981.03 pmol, crude). MS [ESI]: m / z = 306.1, [M+H] + .

[0884] Step seven: 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]indolizine-7(5H)-one (compound 84)

[0885] Into a 100 mL single necked flask, was placed 94-6 (300 mg, 981.03 pmol, crude), N- methylpyrrolidone (5 mL), 4-chloro-2-(trifluoromethyl)pyridine (214 mg, 1.18 mmol), cesium fluoride (298.04 mg, 1.96 mmol) was added. The reaction was stirred at 90 °C for 12 h. LCMS showed the reaction was complete, 10 mL of saturated sodium chloride solution was added, 30 mL of ethyl acetate was added to extract, concentrated under reduced pressure, purified by Prep-HPLC to give compound 84 (51 mg, 113.11 pmol).

[0886] MS [ESI]: m / z = 451.1, [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.21 (dd, J = 5.6, 2.8 Hz, 1H), 6.72 (t, J = 2.8 Hz, 1H), 6.56 - 6.53 (m, 1H), 4.96 - 4.77 (m, 2H), 4.50 - 4.36 (m, 1H), 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).

[0887] Chiral resolution (compound 84a, 84b, 84c and 84d)

[0888] Compound 84 was resolved using a chiral column type Unichiral CNZ-5H with mobile phase n-hexane - absolute ethanol (50:50) to obtain compound 84a (5.5 mg, RT = 32.25 min), compound 84b (7.2 mg, RT = 39.32 min), compound 84c (6.1 mg, RT = 26.80 min), compound 84d (7.5 mg, RT = 54.38 min).

[0889] Compound 84a:

[0890] 1 H NMR (400 MHz, CD3OD) δ 8.15 (d, J = 5.6 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 6.52 (dd, J = 5.6, 2.4 Hz, 1H), 5.03 (d, J = 15.6 Hz, 1H), 4.84 - 4.80 (m, 1H), 4.46 (d, J = 16.0 Hz, 1H), 4.25 (t, J = 8.4 Hz, 1H), 4.20 - 4.18 (m, 2H), 3.96 (dd, J = 8.4, 6.4 Hz, 1H), 3.24 - 3.13 (m, 1H), 2.81 - 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).

[0891] Compound 84b:

[0892] 1 H NMR (400 MHz, CD3OD) δ 8.14 (d, J = 6.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.51 (dd, J = 6.0, 2.0 Hz, 1H), 4.91 - 4.87 (m, 2H), 4.56 (d, J = 15.6 Hz, 1H), 4.31 (t, J = 8.4 Hz, 1H), 4.20 (t, J = 8.4 Hz, 1H), 3.96 (dd, J = 8.4, 6.0 Hz, 1H), 3.87 (dd, J = 8.4, 6.0 Hz, 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).

[0893] Compound 84c:

[0894] 1H NMR (400 MHz, CD3OD) δ 8.14 (d, J = 5.6 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 5.6, 2.0 Hz, 1H), 5.03 (d, J = 15.6 Hz, 1H), 4.84 - 4.80 (m, 1H), 4.46 (d, J = 15.6 Hz, 1H), 4.25 (t, J = 8.4 Hz, 1H), 4.20 - 4.16 (m, 2H), 3.96 (dd, J = 8.4, 6.4 Hz, 1H), 3.24 - 3.16 (m, 1H), 2.81 - 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).

[0895] Compound 84d:

[0896] 1 H NMR (400 MHz, CD3OD) δ 8.14 (d, J = 5.6 Hz, 1H), 6.72 (d, J = 2.0 Hz, 1H), 6.52 (dd, J = 5.6, 2.0 Hz, 1H), 5.03 (d, J = 15.6 Hz, 1H), 4.84 - 4.80 (m, 1H), 4.46 (d, J = 15.6 Hz, 1H), 4.25 (t, J = 8.4 Hz, 1H), 4.20 - 4.16 (m, 2H), 3.96 (dd, J = 8.4, 6.4 Hz, 1H), 3.24 - 3.16 (m, 1H), 2.81 - 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).

[0897] Example 120: Preparation of compounds 94-5A, 94-5B, 94-5C and 94-5D

[0898] The compound 94-5 obtained from Example 119 was resolved to obtain compound 94-5A (RT = 1.19 min), compound 94-5B (RT = 1.29 min), compound 94-5C (RT = 1.76 min), compound 94-5D (RT = 2.08 min). Resolution conditions: column type CHIRALCEL OJ-3 (4.6*100 mm), mobile phase anhydrous ethanol (30%), column temperature 35 °C, flow rate 2 mL / min.

[0899] Compound 94-5A: 1H NMR (400 MHz, DMSO) δ 7.39 - 7.29 (m, 5H), 5.03 (s, 2H), 4.92 (d, J = 16.0 Hz, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.36 (d, J = 16.0 Hz, 1H), 4.12 - 3.81 (m, 4H), 2.93 - 2.83 (m, 1H), 2.61 - 2.53 (m, 4H), 2.46 - 2.41 (m, 1H), 2.30 (s, 3H), 2.11 (d, J = 9.3 Hz, 1H), 1.57 - 1.41 (m, 2H).

[0900] Compound 94-5B: 1 H NMR (400 MHz, DMSO) δ 7.39 - 7.23 (m, 5H), 5.02 (s, 2H), 4.83-4.76 (m, 2H), 4.46 (d, J = 15.6 Hz, 1H), 4.15 - 3.95 (m, 2H), 3.85-3.65 (m, 2H), 2.81 - 2.67 (m, 2H), 2.55 (s, 3H), 2.37 - 2.30 (m, 4H), 2.14 - 2.05 (m, 1H), 1.53 - 1.41 (m, 1H), 1.38 - 1.27 (m, 1H).

[0901] Compound 94-5C: 1 H NMR (400 MHz, DMSO) δ 7.39 - 7.29 (m, 5H), 5.03 (s, 2H), 4.92 (d, J = 16.0 Hz, 1H), 4.75 (d, J = 10.8 Hz, 1H), 4.36 (d, J = 16.0 Hz, 1H), 4.12 - 3.81 (m, 4H), 2.93 - 2.83 (m, 1H), 2.61 - 2.53 (m, 4H), 2.46 - 2.41 (m, 1H), 2.30 (s, 3H), 2.11 (d, J = 9.3 Hz, 1H), 1.57 - 1.41 (m, 2H).

[0902] Compound 94-5D: 1 H NMR (400 MHz, DMSO) δ 7.39 - 7.23 (m, 5H), 5.02 (s, 2H), 4.83-4.76 (m, 2H), 4.46 (d, J = 15.6 Hz, 1H), 4.15 - 3.95 (m, 2H), 3.85-3.65 (m, 2H), 2.81 - 2.67 (m, 2H), 2.55 (s, 3H), 2.37 - 2.30 (m, 4H), 2.14 - 2.05 (m, 1H), 1.53 - 1.41 (m, 1H), 1.38 - 1.27 (m, 1H).

[0903] Example 121: Synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrrolo[2,3-a]indolizine-7(5H)-one-8-deuterium (Compound 499)

[0904] Step one: 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)

[0905] Into a single-neck flask was placed 2-(1-(tert-butoxycarbonyl)azetidin-3-yl)acetic acid (10.35 g, 48.09 mmol), (7-azobenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (23.90 g, 62.52 mmol), N,N-diisopropyl ethylamine (31.08 g, 240.47 mmol), dichloromethane (300 ml), stirred at 25 °C, added compound 93-2 (11 g, 48.09 mmol, hydrochloride), stirred at room temperature, LCMS detected that the reaction was complete, added saturated sodium chloride solution to quench, extracted with dichloromethane, concentrated under reduced pressure, normal phase column chromatography to obtain the title compound 95-1 (23 g, crude). MS [ESI]: m / z = 390.2 [M+H] + .

[0906] Step two: 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)

[0907] Into a single-neck flask was placed compound 95-1 (23 g, crude), triphenylphosphine (17.78 g, 67.78 mmol), dichloromethane (300 ml), controlled to 0 °C under nitrogen protection, added N-bromosuccinimide (12.06 g, 67.78 mmol), stirred at 0 °C for 3 hours, TLC detected that the reaction was complete, added saturated sodium bisulfite solution to quench, extracted with dichloromethane, concentrated under reduced pressure to obtain compound 95-2 (30 g, crude). MS [ESI]: m / z = 452.1 [M+H] + .

[0908] Step three: Synthesis of tert-butyl 3-(2,4-dimethyl-7-oxo-5,7,8,9,10,10-hexahydropyrrolo[2,3-a]indolizine-8-yl)azetidine-1-carboxylate (Compound 95-3)

[0909] Into a three-necked flask was placed compound 95-2 (30 g, crude), tetrahydrofuran (200 ml), nitrogen replacement, cooling to -70 °C, stirring, slowly dropping sodium bis(trimethylsilyl)amide (1 M, 60.79 mmol, 60.79 mL), slowly warming and stirring again, LCMS detection of complete reaction, adding saturated ammonium chloride solution for quenching, ethyl acetate extraction, reduced pressure concentration, normal phase column chromatography to obtain compound 95-3 (6.3 g, 16.96 mmol). MS [ESI]: m / z = 372.2, [M+H] + .

[0910] Step four: synthesis of tert-butyl 3-(2,4-dimethyl-7-oxo-5,7,8,9,10,10- hexahydropyrido[2,3-a]indolizine-8-yl-8-deuterium)azetidine-1-carboxylate (compound 95-4)

[0911] Into a three-necked flask was placed compound 95-3 (1 g, 2.69 mmol), tetrahydrofuran (20 ml), nitrogen replacement, cooling to zero and stirring, slowly dropping sodium bis(trimethylsilyl)amide (2 M, 4.04 mmol, 2.02 mL), stirring and adding deuterated methanol (485.45 mg, 13.46 mmol), adding saturated ammonium chloride solution for quenching, ethyl acetate extraction, reduced pressure concentration, normal phase column chromatography to obtain the title compound 95-4 (360 mg, 966.50 µmol). MS [ESI]: m / z = 373.2 [M+H] + .

[0912] Step five: 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)

[0913] Into a single-necked flask was placed compound 95-4 (360 mg, 966.50 µmol), dichloromethane (10 mL), slowly adding trifluoroacetic acid (3 mL) with stirring, stirring the reaction solution at 25 °C for 16 hours. LCMS detection of complete reaction, reduced pressure concentration to obtain compound 95-5 (350 mg, 908.20 µmol, trifluoroacetic acid salt). MS [ESI]: m / z = 273.2 [M+H] + .

[0914] Step six: synthesis of 2,4-dimethyl-8-(1-(2-(trifluoromethyl)pyridin-4-yl)azetidin-3-yl)-8,9,10,10-tetrahydropyrido[2,3-a]indolizine-7(5H)-one-8-deuterium (compound 499)

[0915] To a single-neck flask was added 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). The reaction was heated to 100 °C and stirred for 3 h. LCMS showed the reaction was complete. The reaction was diluted with 10 mL of saturated sodium chloride solution and extracted with 30 mL of ethyl acetate. The organic layer was concentrated under reduced pressure and purified by Prep-HPLC to give the title compound 499 (27 mg, 60.69 μmol).

[0916] MS [ESI]: m / z = 418.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.28 (dd, J = 6.4, 2.4 Hz, 1H), 6.97 (d, J = 6.0 Hz, 1H), 6.59 (dd, J = 6.0, 2.4 Hz, 1H), 6.37 - 6.33 (m, 1H), 5.08 (d, J = 16.0 Hz, 0.5H), 4.92 (d, J = 16.0 Hz, 0.5H), 4.87 - 4.77 (m, 1H), 4.51 (d, J = 16.0 Hz, 0.5H), 4.40 (d, J = 16.0 Hz, 0.5H), 4.34 (t, J = 8.4 Hz, 0.5H), 4.28 (d, J = 8.4 Hz, 0.5H), 4.22 - 4.14 (m, 1.5H), 3.97 (dd, J = 8.4, 6.0 Hz, 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).

[0917] Example 122: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azetidin-3-yl)-2,4- dimethyl-8,9,10,10-tetrahydropyrido[2,3-a]indolizine-7(5H)-one (Compound 507A)

[0918] Step one: Compound 95-3 was separated by column Unichiral CNZ-5H with mobile phase of n-hexane-absolute ethanol (50:50 and 80:20) to give compound 95-3A (520 mg, RT = 9.37 min), compound 95-3B (500 mg, RT = 11.91 min), compound 95-3C (550 mg, RT = 15.18 min), compound 95-3D (550 mg, RT = 16.26 min).

[0919] Step two: Synthesis of 8-(azetidin-3-yl)-2,4-dimethyl-8,9,10,10-tetrahydropyrido[2,3- a] indolizine-7(5H)-one (compound 507A-1)

[0920] Into a single-neck flask was added 95-3D (550 mg, 1.48 mmol), dichloromethane (5 mL), trifluoroacetic acid (2 mL) was added slowly under stirring, the reaction solution was stirred at 25 °C for 5 hours. LCMS detection showed that the reaction was complete, and the compound 507A-1 (720 mg, crude product) was obtained by concentration under reduced pressure.

[0921] Step three: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-4-yl)azetidin-3-yl)-2,4-dimethyl- 8,9,10,10-tetrahydropyrido[2,3-a]indolizine-7(5H)-one (compound 507A)

[0922] Into a single-neck flask was 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'-biphenylyl) palladium (II) (31 mg, 36.85 μmol), 2-fluoro-4-iodo-6-methylpyridine (131 mg, 552.78 μmol), nitrogen was replaced, and the reaction solution was stirred at 90 °C for 12 hours. LCMS detection showed that the reaction was complete, saturated sodium chloride solution was added, ethyl acetate was extracted, concentrated under reduced pressure, and the title compound 507A (9.7 mg, 25.50 μmol) was obtained by Prep-HPLC purification.

[0923] MS [ESI]: m / z = 381.2 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.08 (s, 1H), 6.13 (s, 1H), 5.74 (d, J = 1.6 Hz, 1H), 4.87-4.83 (m, 2H), 4.53 (d, J = 15.2 Hz, 1H), 4.24 (t, J = 8.4 Hz, 1H), 4.12 (t, J = 8.4 Hz, 1H), 3.88 (dd, J = 8.8, 6.0 Hz, 1H), 3.80 (dd, J = 8.0, 6.0 Hz, 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).

[0924] Referring to the synthesis of Example 122, the following compound can be synthesized:

[0925] Example 129: Synthesis of 8-(1-(2-fluoro-6-methylpyridin-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 507B)

[0926] Referring to the synthesis of Example 122, the following compound can be synthesized:

[0927] Example 137: 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)

[0928] Step One: 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)

[0929] Int-5 (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL) were added to a Schlenk flask, 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 purging with nitrogen, the mixture was heated to 90 °C and stirred for 12 hours. The reaction was confirmed to be complete by LCMS. The mixture was then allowed to return to room temperature, filtered through diatomaceous earth, washed with dichloromethane, concentrated under reduced pressure, and purified by Prep-HPLC to obtain compound 442 (22.2 mg, 60.42 μmol).

[0930] MS[ESI]: m / z = 368.2, [M+H] + NMR: 1 H 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).

[0931] Step 2: Chiral splitting

[0932] Compound 442 (300 mg) was resolved 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 min, and the retention time of compound 442b was 7.142 min.

[0933] Compound 442a: MS [ESI]: m / z = 368.2, [M+H] + , 1H NMR (400 MHz, CDC13) δ 7.88 (d, J = 2.0 Hz, 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, 2.0 Hz, 1H), 4.82 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 15.2 Hz, 1H), 4.27 - 4.18 (m, 2H), 4.13 (dd, J = 8.0, 5.6 Hz, 1H), 3.95 (dd, J = 8.0, 5.6 Hz, 1H), 3.67 - 3.56 (m, 2H), 2.84 (d, J = 11.2 Hz, 1H), 2.58 (s, 3H), 2.29 (s, 3H), 1.80 - 1.66 (m, 1H).

[0934] Compound 442b: MS [ESI]: m / z = 368.2, [M+H] + , 1 H NMR (400 MHz, CDC13) δ 7.88 (d, J = 2.0 Hz, 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 = 11.2 Hz, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.27 - 4.18 (m, 2H), 4.13 (dd, J = 8.0, 6.0 Hz, 1H), 3.96 (dd, J = 8.0, 5.6 Hz, 1H), 3.67 - 3.54 (m, 2H), 2.83 (d, J = 11.2 Hz, 1H), 2.55 (s, 3H), 2.30 (s, 3H), 1.80 - 1.64 (m, 1H).

[0935] Example 138: 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)

[0936] Step one: Synthesis of tert-butyl (1-(2-bromo-5-fluoropyrimidin-4-yl)azetidin-3-yl)carbamate (Compound 111-2)

[0937] To a Schlenk flask was added compound 111-1 (5 g, 29.03 mmol), 1,4-dioxane (50 mL), 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), cesium carbonate (18.92 g, 58.06 mmol). After nitrogen substitution, the temperature was raised and stirred for 12 hours. LCMS detection showed the reaction was complete, the temperature was returned to room temperature, filtered through celite, washed with dichloromethane, concentrated under reduced pressure, and purified by column chromatography to obtain compound 111-2 (6.2 g, 17.86 mmol), MS [ESI]: m / z = 348.2, [M+H] + .

[0938] Step two: synthesis of tert-butyl (1-(5-fluoro-2-(methoxy(methyl)carbamoyl)pyrimidin-4- yl)azetidin-3-yl)carbamate (compound 111-3)

[0939] To a Schlenk flask was added compound 111-2 (6.2 g, 17.86 mmol), DMF (50 mL), followed by Pd(dppf)2Cl2(1.31 g, 1.79 mmol), N,O-dimethylhydroxylamine hydrochloride (2.09 g, 21.43 mmol), cesium carbonate (11.64 g, 58.06 mmol), followed by carbon monoxide substitution, the temperature was raised to 90 °C, and stirred for 12 hours. LCMS detection showed the reaction was complete, the temperature was returned to room temperature, filtered through celite, washed with dichloromethane, concentrated under reduced pressure, and purified by column chromatography to obtain compound 111-3 (3.5 g, 9.85 mmol), MS [ESI]: m / z = 356.2, [M+H] + .

[0940] Step three: synthesis of tert-butyl (1-(5-fluoro-2-formylpyrimidin-4-yl)azetidin-3- yl)carbamate (compound 111-4)

[0941] Into a round-bottom flask, was placed compound 111-3 (3.5 g, 9.85 mmol), THF (30 mL), replaced with N2, moved to -20 °C, slowly added DIBAL-H (2.1 g, 14.77 mmol), then slowly warmed to room temperature and stirred for 4 h. LCMS detected that the reaction was complete, slowly added HCl (15 mL, 1 N) at 0 °C to quench the reaction, then added NaOH (15 mL, 1 N) to pH = 7, the mixture was extracted with EA. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 111-4 (1.2 g, 4.05 mmol) was obtained by column chromatography for preparation and purification, MS [ESI]: m / z = 297.2, [M+H] + .

[0942] Step four: synthesis of tert-butyl (1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)azetidin-3- yl)carbamate (compound 111-5)

[0943] Into a round-bottom flask, was placed compound 111-4 (1.2 g, 4.05 mmol), DCM (10 mL), replaced with N2 three times, moved to an ice bath, slowly added DAST (1.96 g, 12.15 mmol), then slowly warmed to room temperature and stirred for 12 h. LCMS detected that the reaction was complete, added saturated NaHCO3 to quench the reaction, adjusted to pH = 7, then extracted with EA, the combined organic layers were washed with saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Compound 111-5 (800 mg, 2.51 mmol) was obtained by column chromatography for preparation and purification, MS [ESI]: m / z = 319.2, [M+H] + .

[0944] Step five: synthesis of 1-(2-(difluoromethyl)-5-fluoropyrimidin-4-yl)azetidin-3-amine (compound 111-6)

[0945] Into a round-bottom flask, was placed compound 111-5 (800 mg, 2.51 mmol), DCM (10 mL), slowly added 4N HCl / 1,4-dioxane solution, reacted at room temperature for 4 h, LCMS detected that the reaction was complete, the reaction liquid was concentrated and dried to give compound 111-6 (600 mg), MS [ESI]: m / z = 219.2, [M+H] + .

[0946] Step six: synthesis of tert-butyl 7-(2-hydroxyethyl)-2,4-dimethyl-5,7-dihydropyrrolo[3,4- b]pyridine-6-carboxylate (compound 111-7)

[0947] Into a round-bottom flask was added compound Int-6-4 (5 g, 14.95 mmol), THF (100 mL), LAH (5 g, 14.95 mmol) was added slowly at -78 °C, stirred at -78 °C for 0.5 h. Then heated to 25 °C and stirred for 4 h. LCMS showed the reaction was complete, NH4CI (50 mL) was added slowly 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 give a residue, which was purified by column chromatography to afford compound 111-7 (3.8 g, 13.00 mmol), MS [ESI]: m / z = 293.2, [M+H] + .

[0948] Step seven: synthesis of tert-butyl 2,4-dimethyl-7-(2-oxoethyl)-5,7-dihydropyrrolo[3,4- b]pyridine-6-carboxylate (compound 111-8)

[0949] Into a three-necked round-bottom flask was added compound oxalyl chloride (3.30 g, 25.99 mmol), DCM (20 mL), replaced with nitrogen, DMSO (4.06 g, 51.99 mmol) was added slowly dropwise at -70 °C, after the addition was completed, 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 h, LCMS showed the reaction was complete, then TEA (7.89 g, 77.98 mmol) was added dropwise, the mixture was heated slowly to 25 °C and stirred for 2 h. The reaction mixture was added to H2O and extracted with EA. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography gave compound 111-8 (2.2 g, 7.58 mmol), MS [ESI]: m / z = 291.2, [M+H] + .

[0950] Step eight: 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)

[0951] To a round-bottom flask was added compound 111-8 (300 mg, 1.03 mmol), DCM (5 mL), 111-6 (315.7 mg, 1.24 mmol), AcOH, and the reaction was stirred for 15 min before NaBH(OAc)3 (328 mg, 1.55 mmol) was added. The reaction was stirred at 25 °C for 4 h. LCMS showed the reaction was complete, quenched with saturated brine, and then extracted with EA. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by column chromatography to give compound 111-9 (400 mg, 812.1 µmol). MS [ESI]: m / z = 493.2, [M+H] + .

[0952] Step Nine: 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)azetidine-3-amine (Compound 111-10)

[0953] To a round-bottom flask was added compound 111-9 (400 mg, 812.1 µmol), DCM (10 mL), and 5 mL of 4N HCl / 1,4-dioxane solution was added dropwise slowly. The reaction was stirred at room temperature for 4 h. LCMS showed the reaction was complete, the reaction was concentrated and dried, adjusted to pH = 7 with saturated NaHCO3, and then extracted with EA. 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] + .

[0954] Step Ten: 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)

[0955] To a sealed tube was added 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). The reaction was stirred at elevated temperature. LCMS showed the reaction was complete, and compound 497 (31 mg, 74.1 µmol) was obtained by Prep-HPLC purification. MS [ESI]: m / z = 419.2, [M+H] + .

[0956] NMR:1 H NMR (400 MHz, CDC13) δ 8.00 (d, J = 4.0 Hz, 1H), 6.87 (s, 1H), 6.33 (t, J = 54.8 Hz, 1H), 5.36 (t, J = 6.4 Hz, 1H), 4.87 (d, J = 15.2 Hz, 1H), 4.72 (d, J = 11.6 Hz, 1H), 4.46 (d, J = 15.2 Hz, 4H), 4.35 - 4.22 (m, 1H), 3.55 (dd, J = 8.8, 2.8 Hz, 2H), 2.71 (s, 1H), 2.48 (s, 3H), 2.21 (s, 3H), 1.73 - 1.63 (m, 1H).

[0957] Example 139: Synthesis of 8-(1-(5-fluoro-6-deuterp yridin-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)

[0958] Step one: Synthesis of 3-bromo-5-fluoro-6-deuterp yridine (Compound 112-2)

[0959] Into a three-necked round-bottom flask was added compound 2,5-dibromo-3- fluoropyridine (1 g, 3.92 mmol), THF (10 mL), purged with nitrogen, slowly added Turbo reagent (0.68 g, 4.71 mmol) at -70 °C, after the addition, slowly warmed to 0 °C, then added heavy water dropwise, continued to react for 4 hours, LCMS detected that the reaction was complete, the reaction mixture was quenched with saturated ammonium chloride, extracted with ethyl acetate. The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure to give a residue. Purification by column chromatography gave compound 112-2 (0.52 g, 2.94 mmol), MS [ESI]: m / z = 178.2, [M+H] + .

[0960] Step two: Synthesis of 8-(1-(5-fluoro-6-deuterp yridin-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)

[0961] To a Schlenk tube was added compound Int-5 (50 mg, 183.59 umol), 1,4-dioxane (2 mL), followed by compound 112-2 (38.99 mg, 220.3 umol), Ruphos Pd G3 (14.78 mg, 18.36 umol), Ruphos (25.7 mg, 55.08 umol), cesium carbonate (179.45 mg, 550.76 umol). After nitrogen purging, the temperature was increased to 90 °C and stirred for 12 h. LCMS showed the reaction was complete, cooled down to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by Prep-HPLC to give compound 498 (32.1 mg, 86.85 umol).

[0962] MS (ESI): m / z = 369.2, [M+H] + . 1 H NMR (400 MHz, DMSO) 1 H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.18 (d, J = 11.6 Hz, 1H), 6.96 (s, 1H), 5.48 - 5.36 (m, 1H), 4.97 (d, J = 14.8 Hz, 1H), 4.89 - 4.77 (m, 1H), 4.64 - 4.42 (m, 3H), 4.37 (s, 1H), 4.19 (s, 1H), 3.76 - 3.55 (m, 2H), 2.85 (s, 1H), 2.59 (s, 3H), 2.30 (s, 3H), 1.78 - 1.70 (m, 1H).

[0963] Example 140: Synthesis of 3-chloro-8-(1-(6-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 500)

[0964] Into a round bottom flask was added compound 89-05 (500 mg, 1.63 mmol), 1,4-dioxane (10 mL), followed by 2-fluoro-5-bromo-pyridine (430.2 mg, 2.45 mmol), Ruphos Pd G3 (136.3 mg, 163.00 µmol), RuPhos (76.05 mg, 163.00 µmol), cesium carbonate (1.06 g, 3.26 mmol). After nitrogen purging, the temperature was raised to 90 °C and stirred for 12 h. LCMS showed the reaction was complete, the reaction was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by silica gel column chromatography to give compound 500 (204.4 mg, 508.63 µmol), MS [ESI]: m / z = 402.1, [M+H] + .

[0965] Chiral resolution (compound 500a and compound 500b)

[0966] Compound 500 (204.4 mg, 508.63 µmol) was resolved using Unichiral YMC-CMD-5H column, mobile phase: methanol (100%) to give compound 500a (96.7 mg, RT = 11.217 min) and compound 500b (100.9 mg, RT = 13.141 min).

[0967] Compound 500a: MS [ESI]: m / z = 402.1, [M+H] + , 1 H NMR (400 MHz, CDCl3) d 7.42 – 7.37 (m, 1H), 6.93 – 6.87 (m, 1H), 6.79 (dd, J = 8.8, 3.0 Hz, 1H), 5.43 – 5.33 (m, 1H), 4.96 (d, J = 15.2 Hz, 1H), 4.80 – 4.71 (m, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.23 – 4.14 (m, 2H), 4.04 (dd, J = 7.6, 5.8 Hz, 1H), 3.87 (dd, J = 7.6, 5.8 Hz, 1H), 3.72 – 3.65 (m, 1H), 3.64 – 3.53 (m, 1H), 2.71 (d, J = 12.8 Hz, 1H), 2.64 (s, 3H), 2.33 (s, 3H), 1.77 – 1.64 (m, 1H).

[0968] Compound 500b: MS [ESI]: m / z = 402.1, [M+H] + , 1H NMR (400 MHz, CDC13) δ 7.41 - 7.38 (m, 1H), 6.92 - 6.87 (m, 1H), 6.79 (dd, J = 8.8, 3.0 Hz, 1H), 5.42 - 5.35 (m, 1H), 4.96 (d, J = 15.2 Hz, 1H), 4.75 (d, J = 11.2 Hz, 1H), 4.54 (d, J = 15.2 Hz, 1H), 4.21 - 4.15 (m, 2H), 4.04 (dd, J = 7.8, 5.8 Hz, 1H), 3.87 (dd, J = 7.6, 5.8 Hz, 1H), 3.72 - 3.66 (m, 1H), 3.62 - 3.55 (m, 1H), 2.72 - 2.66 (m, 1H), 2.63 (s, 3H), 2.33 (s, 3H), 1.76 - 1.69 (m, 1H).

[0969] Example 141 : Synthesis of 2,4-dimethyl-8-(l-(6-methylpyridazin-4-yl)azetidin-3-yl)- 8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (Compound 396)

[0970] To a Schlenk flask was added compound 395, followed by trimethylboroxine (24.46 mg, 194.8 μmol), Pd(dppf)2Cl2(9.51 mg, 12.99 μmol), cesium carbonate (76.34 mg, 259.8 μmol), 1,4-dioxane (2 mL), water (0.2 mL). After nitrogen substitution, the temperature was raised to 110 °C and stirred for 12 hours. LCMS detection showed the reaction was complete, the reaction was recovered to room temperature, filtered by celite, washed by dichloromethane, concentrated under reduced pressure, and compound 396 (15.2 mg, 41.16 μmol) was obtained by reverse phase preparation purification.

[0971] MS [ESI]: m / z = 365.2, [M+H] + NMR: 1H NMR (400 MHz, CDC13) δ 8.27 (d, J = 2.4 Hz, 1H), 6.92 (s, 1H), 6.23 (d, J = 2.4 Hz, 1H), 5.42 - 5.31 (m, 1H), 4.92 (d, J = 15.2 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 15.2 Hz, 1H), 4.36 - 4.33 (m, 3H), 4.23 - 4.12 (m, 1H), 3.67 - 3.50 (m, 2H), 2.80 - 2.70 (m, 1H), 2.60 (s, 3H), 2.53 (s, 3H), 2.27 (s, 3H), 1.79 - 1.66 (m, 1H).

[0972] Example 142: Synthesis of 8-(1-(5,6-difluoropyridin-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 459)

[0973] Step one: Synthesis of 2,3-difluoropyridine-5-boronic acid pinacol ester (Compound 134-02)

[0974] Into a Schlenk, compound 5-bromo-2,3-difluoropyridine (1 g, 5.16 mmol), 1,4-dioxane (15 mL) was charged, followed by pinacol diboronic acid (1.96 g, 7.73 mmol), Pd(dppf)2Cl2(377.21 mg, 515.5 μmol), potassium acetate (1.01 g, 10.31 mmol). After nitrogen substitution, the temperature was raised to 90 °C and stirred for 12 h. TLC detection showed the reaction was complete, the temperature was returned to room temperature, filtered through celite, washed with dichloromethane, concentrated under reduced pressure, and purified by reverse phase prep to give Compound 134-02 (560 mg, 2.32 mmol).

[0975] Step two: Synthesis of 8-(1-(5,6-difluoropyridin-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 459)

[0976] To a Schlenk flask was added Int-5 (50 mg, 129.91 μmol), followed by 2,3-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (66.38 mg, 275.3 μmol), copper acetate (66.6 mg, 367.1 μmol), triethylamine (37.16 mg, 367.18 μmol), dichloromethane (2 mL). After oxygen was replaced, it was stirred at room temperature for 12 hours. LCMS detection showed that the reaction was complete, and it was restored to room temperature, filtered with celite, washed with dichloromethane, concentrated under reduced pressure, and purified by Prep-HPLC to obtain compound 459 (14.2 mg, 36.84 μmol).

[0977] MS [ESI]: m / z = 386.1, [M+H] + . NMR: 1 H NMR (400 MHz, CDC13) δ 7.13 (t, J = 2.4 Hz, 1H), 6.95 (s, 1H), 6.70 - 6.61 (m, 1H), 5.45 - 5.30 (m, 1H), 4.95 (d, J = 15.2 Hz, 1H), 4.81 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 15.2 Hz, 1H), 4.25 - 4.15 (m, 2H), 4.07 (dd, J = 8.0, 6.0 Hz, 1H), 3.90 (dd, J = 8.0, 6.0 Hz, 1H), 3.68 - 3.55 (m, 2H), 2.81 (s, 1H), 2.57 (s, 3H), 2.29 (s, 3H), 1.79 - 1.70 (m, 1H).

[0978] Step three: chiral resolution

[0979] Compound 459 (300 mg) obtained by the synthetic method of step two was resolved by chiral column using column type Unichiral YMC-CMD-5H, mobile phase anhydrous ethanol (100%), column temperature 30 °C, flow rate 25 ml / min to obtain compound 459a (132 mg) and compound 459b (122 mg). The retention time of compound 459a was 5.731 min, and the retention time of compound 459b was 7.085 min.

[0980] Compound 459a: MS [ESI]: m / z = 386.1, [M+H] + , 1H NMR (400 MHz, CDC13) δ 7.13 (t, J = 2.4 Hz, 1H), 6.94 (s, 1H), 6.71 - 6.61 (m, 1H), 5.43 - 5.32 (m, 1H), 4.94 (d, J = 15.2 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 15.2 Hz, 1H), 4.25 - 4.15 (m, 2H), 4.08 (dd, J = 8.0, 6.0 Hz, 1H), 3.90 (dd, J = 8.0, 6.0 Hz, 1H), 3.68 - 3.55 (m, 2H), 2.79 (s, 1H), 2.56 (s, 3H), 2.28 (s, 3H), 1.80 - 1.67 (m, 1H).

[0981] Compound 459b: MS [ESI]: m / z = 386.1, [M+H] + , 1 H NMR (400 MHz, CDC13) δ 7.13 (t, J = 2.4 Hz, 1H), 6.94 (s, 1H), 6.71 - 6.61 (m, 1H), 5.43 - 5.32 (m, 1H), 4.94 (d, J = 15.2 Hz, 1H), 4.80 (d, J = 11.2 Hz, 1H), 4.53 (d, J = 15.2 Hz, 1H), 4.25 - 4.15 (m, 2H), 4.08 (dd, J = 8.0, 6.0 Hz, 1H), 3.90 (dd, J = 8.0, 6.0 Hz, 1H), 3.68 - 3.55 (m, 2H), 2.79 (s, 1H), 2.56 (s, 3H), 2.28 (s, 3H), 1.80 - 1.67 (m, 1H).

[0982] Referring to the synthetic method of Example 142, the following compounds can be synthesized:

[0983] Example 146: Synthesis of 8-(1-(6-fluoropyridin-2-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 464)

[0984] A round-bottomed flask was charged with Int-5 (50 mg, 183.6 µmol), 2,6-difluoropyridine (42.3 mg, 367.2 µmol), cesium carbonate (119.6 mg, 367.2 µmol), DMF (2 mL), and warmed to 80 °C for 8 h. The reaction was monitored to be complete by LCMS, saturated ammonium chloride solution was added, extracted with ethyl acetate, combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound 464 (6.9 mg, 18.78 µmol) was obtained by Prep-HPLC purification.

[0985] MS [ESI]: m / z = 368.2, [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.61 (q, J = 8.0 Hz, 1H), 7.07 (s, 1H), 6.25 (dd, J = 8.0, 2.2 Hz, 1H), 6.21 (dd, J = 8.0, 2.0 Hz, 1H), 5.24 – 5.15 (m, 1H), 4.88 – 4.83 (m, 1H), 4.78 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 14.8 Hz, 1H), 4.28 – 4.19 (m, 3H), 4.07 (dd, J = 8.8, 5.6 Hz, 1H), 3.67 (dd, J = 8.8, 3.0 Hz, 2H), 2.74 – 2.65 (m, 1H), 2.50 (s, 3H), 2.30 (s, 3H), 1.75 – 1.63 (m, 1H).

[0986] Following the same method of synthesis of Reference Example 146, the following compound was synthesized:

[0987] Example 155: Synthesis of 8-(1-(4-fluoro-2-methylpyrimidin-5-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 468)

[0988] Step one: Synthesis of tert-butyl (1-(2-bromo-4-fluoropyrimidin-5-yl)azetidin-3-yl)carbamate (Compound 143-2)

[0989] To a Schlenk flask was added compound 143-1 (1 g, 5.81 mmol), 1,4-dioxane (10 mL), followed by 2,5-dibromo-4-fluoropyrimidine (1.78 g, 6.97 mmol), Ruphos Pd G3 (467.5 mg, 580.6 μmol), Ruphos (270.9 mg, 580.6 μmol), cesium carbonate (3.78 g, 11.61 mmol). After nitrogen substitution, it was warmed to 90 °C and stirred for 12 h. LCMS showed the reaction was complete, it was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by column chromatography to give compound 143-2 (1.3 g, 3.74 mmol), MS [ESI]: m / z = 348.2, [M+H] + .

[0990] Step two: synthesis of tert-butyl (1-(4-fluoro-2-methylpyrimidin-5-yl)azetidin-3- yl)carbamate (compound 143-3)

[0991] To a Schlenk flask was added compound 143-2 (1.3 g, 3.74 mmol), followed by trimethylboroxine (705.0 mg, 5.62 mmol), Pd(dppf)2Cl2 (273.9 mg, 374.4 μmol), cesium carbonate (2.44 g, 7.49 mmol), 1,4-dioxane (10 mL), water (1 mL). After nitrogen substitution, it was warmed to 110 °C and stirred for 12 h. LCMS showed the reaction was complete, it was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, purified by column chromatography to give compound 143-3 (420 mg, 1.49 mmol), MS [ESI]: m / z = 283.2, [M+H] + .

[0992] Step three: synthesis of trifluoroacetate salt of 1-(4-fluoro-2-methylpyrimidin-5- yl)azetidin-3-amine (compound 143-4)

[0993] To a round bottom flask was added compound 143-3 (420 mg, 1.49 mmol), dichloromethane (5 mL), trifluoroacetic acid (1.7 g, 14.9 mmol) was added dropwise slowly under ice bath, the reaction was stirred at room temperature for 6 h. LCMS showed the reaction was complete, concentrated and dried by rotary evaporation to give crude 143-4 (300 mg). MS [ESI]: m / z = 183.2, [M+H] + .

[0994] Step 4: Synthesis of tert-butyl 7-(2-((l-(4-fluoro-2-methylpyrimidin-5-yl)azetidin-3- yl)amino)-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate (Compound 143-5)

[0995] To a round-bottom flask were added compound Int-6 (0.3 g, 979.3 μmol), DMF (3 mL), TCFH (412.1 mg, 1.47 mmol), N-methylimidazole (241.2 mg, 2.94 mmol) sequentially, and the reaction was allowed to proceed at room temperature for 10 min. Then compound 143-4 (300 mg) was added, and the reaction was allowed to proceed for another 6 h. LCMS detection showed that the reaction was complete. Purification by reverse phase preparation gave compound 143-5 (0.32 g, 0.68 mmol). MS [ESI]: m / z = 471.2, [M+H] + .

[0996] Step 5: Synthesis of N-(2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)-l-(4- fluoro-2-methylpyrimidin-5-yl)azetidin-3-amine (Compound 143-6)

[0997] To a round-bottom flask were added compound 143-5 (0.32 g, 0.68 mmol), anhydrous tetrahydrofuran (5 mL), and borane tetrahydrofuran complex (1.4 mmol) sequentially, and the reaction was allowed to proceed at 70 °C for 6 h after nitrogen replacement for 3 times. LCMS detection showed that the reaction was complete. After the reaction was allowed to cool to room temperature, methanol (5 mL) was added to quench the reaction. After no gas was released, 4 M hydrochloric acid (2 mL) was added, and the reaction was allowed to proceed at 60 °C for 2 h. After the reaction was allowed to cool to room temperature, 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 compound 143-6 (0.1 g, 0.28 mmol). MS [ESI]: m / z = 357.1, [M+H] + .

[0998] Step 6: Synthesis of 8-(l-(4-fluoro-2-methylpyrimidin-5-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a- tetrahydropyrido[2',3':3,4]pyrrolo[l,2-c]pyrimidin-7(5H)-one (Compound 468)

[0999] To a round bottom flask was added compound 143-6 (0.1 g, 0.28 mmol), anhydrous tetrahydrofuran (1 mL), triethylamine (34.0 mg, 0.33 mmol), N,N'-carbonyldiimidazole (45.4 mg, 0.28 mmol), after reaction at room temperature for half an hour, continue to react at 70 °C for 12 hours, LCMS detection reaction is complete, restore to room temperature, reduced pressure concentration, purified by reversed phase preparation to obtain compound 468 (60 mg, 0.15 mmol).

[1000] MS [ESI]: m / z = 383.2, [M+H] + , 1 H NMR (400 MHz, CDC13) δ 7.91 (d, J = 4.4 Hz, 1H), 6.92 (s, 1H), 5.48 - 5.37 (m, 1H), 4.94 (dd, J = 15.2, 2.0 Hz, 1H), 4.77 (d, J = 11.2 Hz, 1H), 4.52 (d, J = 15.2 Hz, 4H), 4.34 - 4.24 (m, 1H), 3.67 - 3.59 (m, 2H), 2.75 (dd, J = 12.8, 2.8 Hz, 1H), 2.53 (s, 3H), 2.51 (s, 3H), 2.26 (s, 3H), 1.76 - 1.68 (m, 1H).

[1001] Example 156: Synthesis of 2,4-dimethyl-8-(1-(6-(trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)-8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (Compound 469)

[1002] Step one: Synthesis of 8-(1-(4-bromo-6-(trifluoromethyl)pyridazin-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 144-01)

[1003] Int-5 (140 mg, 514 μmol) was dissolved in 2 mL of 1,4-dioxane, 3,4-dibromo-6- (trifluoromethyl) pyridazine (157 mg, 514 umol), Ruphos (24 mg, 51 umol), Ruphos Pd G3 (43 mg, 51 umol), cesium carbonate (335 mg, 1.03 mmol) were added successively, nitrogen was purged, and the reaction was heated to 90 °C for 12 h. LC-MS was used to monitor the completion of the reaction. Ethyl acetate was used for extraction, and the crude product was purified by normal phase column (eluent: dichloromethane / methanol gradient elution) to give compound 144-01 (130 mg, 262 μmol) at methanol volume ratio from 0 to 5%, MS [ESI]: m / z = 497.1, [M+H]+.

[1004] Step two: synthesis of 2,4-dimethyl-8-(1-(6-(trifluoromethyl)pyridazin-3-yl)azetidin-3-yl)- 8,9,10,10a-tetrahydropyrido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (compound 469)

[1005] Compound 144-01 (130 mg, 262 μmol) was dissolved in 2 mL of anhydrous ethanol, 10% palladium on carbon was added, and the reaction was purged with hydrogen three times. The reaction was stirred at room temperature for 5 h. LC-MS was used to monitor the completion of the reaction. The palladium on carbon was filtered, and the target compound 469 (17.2 mg, 42 μmol) was obtained by reverse phase column (eluent: water / acetonitrile gradient elution). MS [ESI]: m / z = 419.1, [M+H]+. + .

[1006] 1 H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 9.2 Hz, 1H), 6.95 (s, 1H), 6.60 (d, J = 9.2 Hz, 1H), 5.57 - 5.40 (m, 1H), 4.95 (d, J = 15.0 Hz, 1H), 4.81 (d, J = 11.2 Hz, 1H), 4.59 - 4.35 (m, 4H), 4.25 (dd, J = 9.2, 5.8 Hz, 1H), 3.63 (dd, J = 8.8, 2.7 Hz, 2H), 2.83 (d, J = 11.4 Hz, 1H), 2.56 (s, 3H), 2.28 (s, 3H), 1.83 - 1.75 (m, 1H).

[1007] Example 157: synthesis of 8-(1-(6-(difluoromethyl)-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 477)

[1008] Step 1: Synthesis of 5-bromo-3-fluoropyridine-2-carbaldehyde (compound 152-2)

[1009] To a round-bottom flask was added compound 152-1 (5 g, 5.16 mmol), anhydrous tetrahydrofuran (50 mL) under nitrogen protection, DIBAL-H (4.25 g, 29.85 mmol) was added slowly dropwise, and stirred for 4 hours. LCMS detection showed that the reaction was complete, 4M hydrochloric acid (10 mL) was added, and the reaction was continued for 1 hour. After the reaction was restored to room temperature, saturated sodium bicarbonate was added to adjust the pH to 7-8. The mixture was filtered through diatomite, and the filter cake was washed with dichloromethane several times. The organic layer was concentrated under reduced pressure, and purified by silica gel column to obtain compound 152-2 (2.1 g, 10.29 mmol), MS [ESI]: m / z = 204.1, [M+H] + .

[1010] Step 2: Synthesis of 5-bromo-2-(difluoromethyl)-3-fluoropyridine (compound 152-3)

[1011] To a round-bottom flask was added compound 152-2 (2.1 g, 10.29 mmol), anhydrous dichloromethane (20 mL) under nitrogen protection, and DAST (2.49 g, 15.44 mmol) was added slowly dropwise at 0°C. After the addition was completed, the mixture was moved to room temperature and stirred for 12 hours. LCMS detection showed that the reaction was complete, and saturated sodium bicarbonate (20 mL) was added to quench the reaction. The aqueous layer was extracted with dichloromethane, and the combined organic layers were concentrated under reduced pressure. Purification by silica gel column gave compound 152-3 (1.2 g, 5.31 mmol), MS [ESI]: m / z = 226.1, [M+H] + .

[1012] Step 3: Synthesis of 8-(1-(6-(difluoromethyl)-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 477)

[1013] Compound Int-5 (50 mg, 183.59 μmol) and 1,4-dioxane (2 mL) were added to a Schlenk flask, followed by 152-3 (41.8 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). The mixture was purged with nitrogen, heated, and stirred. The reaction was monitored by LCMS until complete. The mixture was then allowed to return to room temperature, filtered through diatomaceous earth, washed with dichloromethane, concentrated under reduced pressure, and purified by reverse-phase chromatography to give compound 477 (23.6 mg, 61.87 μmol).

[1014] MS[ESI]: m / z = 418.2, [M+H] + NMR: 1 H NMR (400MHz, CDCl3) δ7.59 (d, J = 2.0Hz, 1H), 6.97 (s, 1H), 6.57 (d, J = 54.0Hz, 1H),6.38(dd,J=11.6,2.0Hz,1H),5.39–5.23(m,1H),4.92(d,J=15.2Hz,2H), 4.48(d,J=15.2Hz,1H),4.24–4.07(m,3H),3.96(dd,J=8.0,5.6Hz,1H),3.60– 3.49(m,2H),3.01–2.80(m,1H),2.59(s,3H),2.27(s,3H),1.75–1.60(m,1H).

[1015] Example 158: Synthesis of 5-(3-(2,4-dimethyl-7-oxo-5,9,10,10a-tetrahydropyridine[2',3':3,4]pyrrolo[1,2-c]pyrimidin-8(7H)-yl)azacyclobutane-1-yl)pyridazine-3-nitrile (compound 397)

[1016] Step 1: Synthesis of (1-(6-bromopyrazin-4-yl)azacyclobutane-3-yl)tert-butyl carbamate (compound 153-2)

[1017] To a Schlenk flask was added compound 153-1 (1 g, 5.81 mmol), 1,4-dioxane (10 mL), followed by 3,5-dibromopyridazine (1.66 g, 6.97 mmol), Ruphos Pd G3 (467.5 mg, 580.6 µmol), Ruphos (270.9 mg, 580.6 µmol), cesium carbonate (3.78 g, 11.61 mmol). After nitrogen substitution, it was warmed to 90 °C and stirred for 12 h. LCMS showed the reaction was complete. It was cooled to room temperature, filtered over celite, washed with dichloromethane, concentrated under reduced pressure, and purified by column chromatography to give compound 153-2 (1.2 g, 3.74 mmol), MS [ESI]: m / z = 330.2, [M+H] + .

[1018] Step two: Synthesis of 1-(6-bromopyridin-4-yl)azetidin-3-amine (compound 153-3)

[1019] To a round bottom flask was added compound 153-2 (1.2 g, 3.74 mmol), dichloromethane (5 mL), trifluoroacetic acid (1.7 g, 14.9 mmol) was added dropwise slowly under ice bath, and the reaction was stirred at room temperature for 6 h. LCMS showed the reaction was complete. It was concentrated and dried by rotary evaporation to give compound 153-3 (600 mg). MS [ESI]: m / z = 230.2, [M+H] + .

[1020] Step three: Synthesis of 7-(2-((1-(6-bromopyrazin-4-yl)azetidin-3-yl)amino)-2-oxoethyl)-2,4-dimethyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylic acid tert-butyl ester (compound 153-4)

[1021] To a round bottom flask was added compound Int-6 (0.5 g, 1.63 mmol), DCM (5 mL), TCFH (915.8 mg, 3.26 mmol), N-methylimidazole (536.0 mg, 6.53 mmol), and the reaction was stirred at room temperature for 10 min. Then compound 153-3 (600 mg) was added and the reaction was stirred for another 6 h. LCMS showed the reaction was complete. It was purified by reverse phase prep to give compound 153-4 (0.62 g, 1.2 mmol), MS [ESI]: m / z = 518.2, [M+H] + .

[1022] Step four: Synthesis of 1-(6-bromopyridazin-4-yl)-N-(2-(2,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-7-yl)ethyl)azetidin-3-amine (compound 153-5)

[1023] To a round-bottom flask was added compound 153-4 (0.62 g, 1.2 mmol), anhydrous tetrahydrofuran (10 mL), and borane tetrahydrofuran complex (2.4 mmol) after nitrogen replacement, and the mixture was slowly added dropwise while being cooled in an ice bath. After the addition was completed, the mixture was warmed to 70 °C and reacted for 6 h. The reaction was determined to be complete by LCMS. After the mixture was cooled to room temperature, methanol (5 mL) was added to quench the reaction. After no gas was released, 4 M hydrochloric acid (2 mL) was added, and the mixture was warmed to 60 °C and reacted for 2 h. After the mixture was cooled to room temperature, an aqueous NaOH solution was added to adjust the pH to 7-8 while being cooled in an ice bath. The mixture was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 153-5 (0.3 g, 0.74 mmol). MS [ESI]: m / z = 404.1, [M+H] + .

[1024] Step five: synthesis of 8-(1-(6-bromopyridazin-4-yl)azetidin-3-yl)-2,4-dimethyl-8,9,10,10a-tetrahydropyrimido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-7(5H)-one (compound 153-6)

[1025] To a round-bottom flask was added compound 153-5 (0.3 g, 0.74 mmol), anhydrous tetrahydrofuran (3 mL), triethylamine (112.9 mg, 1.12 mmol), and N,N'-carbonyldiimidazole (144.7 mg, 0.89 mmol). After the mixture was reacted at room temperature for half an hour, the mixture was warmed to 70 °C and reacted for 12 h. The reaction was determined to be complete by LCMS. After the mixture was cooled to room temperature, it was concentrated under reduced pressure, and the residue was purified by reverse-phase preparative purification to obtain compound 153-6 (280 mg, 0.66 mmol). MS [ESI]: m / z = 430.2, [M+H] + .

[1026] Step six: synthesis of 5-(3-(2,4-dimethyl-7-oxo-5,9,10,10a-tetrahydropyrimido[2',3':3,4]pyrrolo[1,2-c]pyrimidin-8(7H)-yl)azetidin-1-yl)pyridazine-3-carbonitrile (compound 397)

[1027] To a Schlenk flask was added compound 153-6 (280 mg, 0.66 mmol), zinc cyanide (206.3 mg, 1.96 mmol), zinc powder (21.32 mg, 326.1 µmol), Pd(dppf)2Cl2 (53.26 mg, 65.22 µmol), ...

Claims

1. A compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof: wherein: A ring is selected from a 5-14 membered heteroaromatic ring and C 6-14 aromatic ring; R 1 , R 3 , R 4 , R 5 are each independently at each occurrence selected 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 heterocyclyl, C 3-8 cycloalkoxy, C 6-10 aryl and 5-10 membered heteroaryl, each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, cycloalkoxy, aryl or heteroaryl being optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 ; or Two R atoms bonded to the same carbon atom 4 Or two Rs 5 Together with the carbon atom it is attached to, it forms a 3-6 membered cycloalkyl group, wherein the cycloalkyl group is optionally bounded by one or more (e.g., 1, 2, 3, 4, 5, or 6) R... 9 replace; and R 1 may also be a deletion; R 7 , R 8 each independently is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl and 3-8 membered heterocyclyl, each optionally substituted by one or more (e.g. 1, 2, 3, 4, 5, 6) R 9 ; or, R 7 , R 8 and the N atom to which they are attached together form a 3-8 membered heterocyclyl group, which is optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) R 9 substituents; R 9 are each independently at each occurrence selected from the group consisting of H, deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 , -COCH3, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 heteroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, each optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) substituents each independently selected from the group consisting of halogen, -OH, -CN, -NR 7 R 8 , -COC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy and 3-8 membered heterocyclyl; B ring 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; C ring 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 haloalkyl, C 1-6 hydroxyalkyl, C 3-8 cycloalkyl, and 3-8 membered heterocyclyl; R 2 -P-R 6 ; P is a single bond, a double bond, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and C 3-8 cycloalkyl, 5-14 membered heteroaryl and 3-8 membered heterocyclyl, C 6-10 aryl and 3-8 membered heterocyclyl, 5-14 membered heteroaryl and C 3-8 cycloalkyl, C 6-10 aryl, 5-14 membered heteroaryl, -R 7 -(C=0)-N(R 8 )-, -N(R 8 )-(C=0)-R 7 -, each of said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 substituents; R 6 selected from deletion, H, C 1-10 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl and C 3-8 cycloalkyl, 5-10 membered heteroaryl and 3-8 membered heterocyclyl, C 6-10 aryl and 3-8 membered heterocyclyl, 5-14 membered heteroaryl and C 3-8 cycloalkyl, 5-14 membered heteroaryl and C 6-14 aryl, each of said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl being optionally substituted by one or more (such as 1, 2, 3, 4, 5, 6) R 9 substituents; m, n, o are each independently selected from 0, 1, 2, 3, 4, 5, or 6; The compound of formula I is not compound 1-144, compound 146-323, when P is selected from methylene, R 6 when P is selected from methylene, R 9 is not trifluoromethylpyridyl; or, when P is selected from a single bond, R 6 is not cyclopropyl; or, when P is selected from cyclopropyl, R 6 is not absent or H.

2. The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, A ring is selected from C 6-10 aromatic and 5-10 membered heteroaromatic rings.

3. The compound of any one of claims 1-2 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, A ring is selected from 4. The compound of any one of claims 1-3 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 1 , R 3 is independently selected from hydrogen, deuterium, tritium, oxo, OR 7 , hydroxyl, halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, 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 , each of said alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclyl, heteroaryl is optionally substituted with one or more R 9 .

5. The compound of any one of claims 1-4 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 1 , R 3 is independently selected from oxo (=0), CH3, CH2CH3, F, CI, Br, cyano, CHF2, CF3, ethynyl, methoxy, -NH-CH3, vinyl, N-heterocyclobutyl, CH2OH, 6. The compound of any one of claims 1-5 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, B ring 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 of claim 6 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, B ring is selected from phenyl, dihydropyrrole, tetrahydropyrrole, pyrrole, thiophene, pyrazole, imidazole, pyridine, cyclohexene, cyclopentene, dihydrofuran ring, and tetrahydropyridine.

8. The compound of any one of claims 1-7 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, B ring is selected from 9. The compound of any one of claims 1-8 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 5 Each time it appears, it is independently selected from hydrogen, deuterium, tritium, OR 7 Oxygen, hydroxyl, halogen, cyano, nitro, C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 alkenyl, C 2-6 alkynyl group, -NR 7 R 8 -CONR 7 R 8 -COC 1-6 Alkyl, -HCOC 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, 3-8 membered heterocyclic and C 3-8 Cycloalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, heterocyclic or cycloalkoxy group is optionally surrounded by one or more (e.g., 1, 2, 3, 4, 5, 6) R 9 Replacement; preferably, R 5 Independently selected from hydrogen, deuterium, tritium, hydroxyl, oxo, halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups and C 1-6 hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R 9 Substitution; or, two R atoms bonded to the same carbon atom 5 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

10. The compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-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 Haloalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy groups, C 1-6 hydroxyalkoxy, wherein the alkyl, alkenyl, alkynyl, alkoxy, heteroalkyl, cycloalkyl, heterocyclic, and heteroaryl groups are each optionally surrounded by one or more R 9 Substitution; or, two R atoms bonded to the same carbon atom 4 Together with the carbon atom it is attached to, they form a 3-5 membered cycloalkyl group, which is optionally bonded by one or more R atoms. 9 replace.

11. The compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, C ring is selected from a 5-7 membered carbocyclic ring, a 5-8 membered heterocyclic ring (e.g., a nitrogen-containing heterocyclic ring or a Si-containing heterocyclic ring), or a 5-8 membered heteroaromatic ring (e.g., a nitrogen-containing heteroaromatic ring).

12. The compound of any one of claims 1-11 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, C ring is selected from 13. The compound of any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, The compounds have a structure according to Formula II: wherein, represents Z in ring B 1 , X 1 , X 2 , Z 2 , X 3 , X 4 either of the two adjacent symbols can be a single or double bond, provided that both adjacent bonds are not double bonds; X 1 , X 2 are each independently selected from C, N; X 3 , X 4 are each independently selected from C, N and CR 5a ; Z 1 , Z 2 are 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 are as defined in claim 1 5 ; Z 3 selected from -0-, -S-, and -NR 5a ; q is selected from 1 or 2; L is selected from C, CR a and N, with the remaining groups being as defined in any of claims 1 to 12.

14. The compound of any one of claims 1-13 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, The compounds have a structure according to Formula III: wherein, Z 1 selected from CR 5a R 5b and CR 5a ; X 1 and X 2 is 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 selected 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 is selected from CR 5a and N; X 1 , X 2 and X 3 is selected from C; X 4 is selected from N; or, Z 1 is selected from CR 5a ; X 1 , X 2 and X 4 is selected from C; X 3 is selected from N; or, Z 1 selected from CR 5a ; X 1 selected from N; X 2 , X 3 and X 4 selected from C; 15. The compound of any one of claims 1-14 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, Z 1 selected 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 defined in claim 1 for R 5 , L is selected from C, CR a and N, and the remaining groups are as defined in any of claims 1 to 13. wherein, The compounds have a structure according to Formula IV:

16. The compound of claim 13 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, 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, with the remaining groups being as defined in any of claims 1 to 14. wherein, Z 1 absent; Z 2 selected from CR 5a ; X 1 , X 2 , X 3 selected from C; X 4 selected from N; and ring B is a pyrrole ring.

17. The compound of any one of claims 1-15, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, The compounds have a structure according to Formula V: p is selected from 0, 1, or 2; 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 is 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 of claims 1 to 15.

18. The compound of any one of claims 1-17, 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 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 defined in claim 1 4 R 19. The compound of any one of claims 1-18 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, L is selected from C, CR a and N, with the remaining groups being as defined in any of claims 1 to 15. wherein the group of Formula 1 is Y is selected from the group consisting of -(CR 4a R 4b ) p -(CR 4a R 4b )-, -C(=O)-, -CR 4a =NR 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 the group consisting of hydrogen, C 1-6 alkyl and C 1-6 haloalkyl, or R a and R b together with the carbon atom to which they are attached form a 3-6 membered cycloalkyl.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, a group selected from a group of Formula 1, Formula 2, or Formula 3, wherein the group of Formula 2 is Y 1 selected from the group consisting of deletion, C, N and CR 3 ; Y 2 , Y 3 , Y 4 are each independently selected from the group consisting of C, N, CR 3 , NR 3 , O and S; wherein the group of Formula 3 is X 1 , X 2 , Y 2 , Y 3 are each independently selected from C and N; Y 4 , Y 6 , Y 7 , Y 8 are each independently selected from the group consisting of C, N, CR 3 , NR 3 , O and S; Y 5 independently selected from the group consisting of deletion, C, N, CR 3 , NR 3 , O, and S; 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, X 1 , X 2 , Y 1 , Y 2 are each independently selected from C and N; Y 3 , Y 4 are each independently selected from CR 3 and N; Y 5 , Y 6 , Y 7 are each independently selected from the group consisting of C, N, CR 3 , NR 3 , O and S; each L in said Formula 1, Formula 2 and Formula 3 is independently selected from C, CR a and N, with the remaining groups being as defined in any of claims 1-19. wherein p is selected from 0, 1, or 2; the group represented by formula 1 is selected from the group consisting of: Preferably, the group represented by formula 1 is selected from: wherein Y 1 not missing; More preferably, the group represented by formula 1 is selected from the group consisting of:

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, Preferably, Z 1 selected from -CR 5a R 5b -, CR 5a , -O-, -S-, N, NR 7 and SiR 5a R 5b .

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 represented by formula 1 is selected from the group consisting of: wherein Y 1 is 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 is selected from C and N; and Z is not simultaneously C; and 1 , X is not simultaneously C; and 1 , X is not simultaneously C; and 2 , X is not simultaneously C; and 3 , X is not simultaneously C; and 4 , X is not simultaneously C; and Alternatively, the group represented by formula 1 is selected from: wherein Y 2 , Y 4 is selected from CR 3 , -O-, -S-, N and NR 3 , and Y 2 , Y 4 are not simultaneously CR 3 ; Alternatively, the group represented by formula 1 is selected from: wherein Y 2 is selected from -0-, -S-, N and NR 3 ; Z 1 , Z 2 is selected from C, CR 5a , 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, said group of formula 2 is selected from formula 2-1: Preferably, the group represented by formula 2 is selected from: wherein Y 5 , Y 6 , Y 7 , Y 8 is selected from CR 3 and N. wherein p is 0, 1, 2; the group represented by formula 3 is selected from formula 3-1: Preferably, the group represented by formula 3 is selected from:

25. The compound of any one of claims 1-24 or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, Preferably, Y 5 , Y 6 , Y 7 are each independently selected from CR 3 and N. ​ selected from the group consisting of:

26. The compound of any one of claims 1-25, 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 1-26, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, P is selected from a single bond, a double bond, -C 1-6 alkyl-(C=0)-NR 7 -, -NR 7 -(C=0)-C 1-6 alkyl-, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl and C6aryl and C 3-6 cycloalkyl and C6aryl and C 3-6 cycloalkyl, said alkyl, cycloalkyl, heterocyclyl or aryl each being optionally substituted with one or more R 9 substituents.

28. The compound of any one of claims 1-27, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, P is selected from the group consisting of a bond, a double bond, -C 1-3 alkyl-(C=0)-NH-, methylene, ethylene, propylene, C 1-3 haloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and benzocyclopentanyl, each of which alkyl, cycloalkyl, benzocyclopentanyl, or heterocyclyl is optionally substituted with one or more R 9 substituents.

29. The compound of any one of claims 1-28, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, P is selected from the group consisting of a bond, a double bond, methylene, cyclohexyl, or P is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2CF3, 30. The compound of any one of claims 1-27, 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 VII: wherein E 1 , E 2 is 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 are as defined in any one of claims 1-27.

31. The compound of any one of claims 1-30, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 6 selected from a deletion, 3-10 membered heterocyclyl, 5-14 membered heteroaryl, C 6-14 aryl, C 1-6 alkyl and C 1-6 haloalkyl, each of said alkyl, aryl or heteroaryl groups being optionally substituted with one or more R 9 substituents.

32. The compound of any one of claims 1-31, 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 are each independently at each occurrence selected from the group consisting of H, deuterium, tritium, halogen, -OH, -CN, oxo, -NR 7 R 8 , -COCH3, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 2-6 heteroalkyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, each independently optionally substituted with one or more (such as 1, 2, 3, 4, 5, 6) substituents selected from the group consisting of halogen, -OH, -CN, -NR 7 R 8 , -COC 1-6 alkyl, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-6 cycloalkyl, C 3-8 cycloalkoxy and 3-8 membered heterocyclyl; R is preferably selected from the group consisting of hydrogen, deuterium D, halogen, C 9 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -NR 1-6 R 7 R 8 , CN, C 3-8 cycloalkyl, C 1-6 haloalkylthio, C 1-6 haloalkyloxy and 5-10 membered heteroaryl, said 5-10 membered heteroaryl being optionally substituted by one or more groups selected from C 1-6 alkyl; more preferably, R 9 are each independently at each occurrence selected from the group consisting of H, deuterium D, F, CI, 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 1-31, 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 haloalkyl, C 1-6 alkoxy, -NR 7 R 8 , CN, C 3-8 cycloalkyl, C 3-8 halocycloalkoxy, C 1-6 haloalkylthio, C 1-6 haloalkyloxy and 5-10 membered heteroaryl, which 5-10 membered heteroaryl is optionally substituted by one or more radicals 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 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C 3-6 halocycloalkoxy, -NH2, -NH(CH2CH3), -N(CH3)2, C 1-4 haloalkylthio, C 3-6 cycloalkyl and 5-6 membered heteroaryl, which 5-6 membered heteroaryl is optionally substituted by C 1-4 alkyl, C 1-4 haloalkyl; 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 1-33, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, wherein, R 6 selected from 35. A compound 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 of any one of claims 1-35, 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 of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 36, in the manufacture of a medicament for the prevention or treatment of a muscarinic acetylcholine receptor M4-mediated disease or condition.

38. The use of claim 37, wherein the M4-mediated disease or condition is selected from the group consisting of Alzheimer’s disease, schizophrenia, psychosis, Parkinson’s disease, pain, addiction, Huntington’s disease, sleep disorders, cognitive impairment (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, asthma, urinary incontinence, glaucoma, 21-trisomy Down’s syndrome, cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

39. A compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 36, for use in the prevention or treatment of a muscarinic acetylcholine receptor M4-mediated disease or condition; preferably, the M4-mediated disease or condition is selected from the group consisting of Alzheimer’s disease, schizophrenia, psychosis, Parkinson’s disease, pain, addiction, Huntington’s disease, sleep disorders, cognitive impairment (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, asthma, urinary incontinence, glaucoma, 21-trisomy Down’s syndrome, cerebral amyloid angiopathy, dementia, hereditary cerebral hemorrhage with amyloidosis of the Dutch type, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

40. A method of preventing or treating a muscarinic acetylcholine receptor M4-mediated disease or condition, the method comprising administering to an individual in need thereof an effective amount of a compound of any one of claims 1-35, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically-labeled compound, polymorph, solvate, N-oxide, metabolite, or prodrug thereof, or a pharmaceutical composition of claim 36.

41. The method of claim 40, wherein the M4-mediated disease or condition is selected from the group consisting of Alzheimer’s disease, schizophrenia, psychosis, Parkinson’s disease, pain, addiction, Huntington’s disease, sleep disorders, cognitive impairment (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, asthma, urinary incontinence, glaucoma, 21 trisomy Down syndrome, cerebral amyloid angiopathy, dementia, Dutch-type hereditary amyloid encephalopathy, Creutzfeld-Jakob disease, prion disorders, amyotrophic lateral sclerosis, progressive supranuclear palsy, head trauma, stroke, pancreatitis, inclusion body myositis, other peripheral amyloidosis, diabetes, autism, and atherosclerosis.

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