A fused pyrimidine ring compound, pharmaceutical composition and use thereof

Abstract

A fused pyrimidine ring compound, a pharmaceutical composition, and its applications. A compound having the formula (I), its stereoisomer, its N-oxide, or a pharmaceutically acceptable salt thereof. The compound has regulatory activity against muscarinic M4 receptors, exhibits improved pharmacodynamic / pharmacokinetic properties, and can be used to treat M4-mediated diseases and disorders.

Description

A fused pyrimidine ring compound, pharmaceutical composition and application thereof

[0001] This application claims priority to Chinese Patent Application No. 2023118228736 filed on December 27, 2023, Chinese Patent Application No. 2024109743874 filed on July 19, 2024, and Chinese Patent Application No. 2024118368685 filed on December 12, 2024. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present application relates to the field of medical technology, and in particular to a fused pyrimidine ring compound, a pharmaceutical composition and applications thereof. Background Art

[0003] Muscarinic acetylcholine receptors (mAChRs) are class I GPCRs composed of seven transmembrane segments, including an extracellular N-terminus, an intracellular C-terminus, and a large intracellular segment between helices 5 and 6. mAChRs were first cloned and sequenced by Kubo et al. in 1986. They are encoded by genes CHRM1 to CHRM5, which give rise to five functionally defined subtypes, M1-M5. M4 is widely expressed in the striatum, caudate nucleus, and putamen, and is co-expressed with dopamine receptors in striatal projection neurons, where it regulates dopamine release and inhibits dopamine D1 receptor function. M4 has emerged as a promising target for treating cognitive and behavioral deficits in neurodegenerative and neuropsychiatric disorders.

[0004] PAMs (positive allosteric modulations, PAMs) are a class of allosteric agonists that do not directly activate receptors. Instead, they bind to allosteric sites, increasing the receptor's affinity for acetylcholine at the orthosteric binding site, thereby enhancing the receptor's response to acetylcholine. Furthermore, allosteric agonists do not cause receptor downregulation, likely because they do not bind to the same site as classical agonists. This advantage can effectively avoid receptor desensitization that is easily caused by classical agonists (Xie Kankan et al., Research Progress on Muscarinic Receptor Expression in Schizophrenia, Neurological Diseases and Mental Health, 2021, Vol. 21, No. 5). Highly subtype-selective PAMs have attracted much attention because they can avoid the adverse effects of activation of surrounding mAChRs. Currently, PAMs targeting various subtypes, especially PAMs targeting M4, have shown potential in antipsychotic and cognitive improvement in preclinical studies (Gould RW, et al. Cognitive enhancement and antipsychotic-like activity following repeated dosing with the selective M4 PAM VU0467154[J]. Neuropharmacology, 2018, 128: 492-502.).

[0005] Currently, only one M4-selective PAM is in clinical development: Emraclidine (CVL-231), a selective positive allosteric modulator (PAM) of the M4 muscarinic receptor developed by Cerevel Therapeutics for the potential oral treatment of psychiatric disorders, including schizophrenia and Alzheimer's disease psychosis. In addition, Vanderbilt University has been committed to the research and development of M4 PAMs since 2013. In the past decade, it has launched a variety of PAMs active molecules targeting M4, such as VU0467154, VU0152099, VU0152100, etc., but they are currently in the preclinical research stage; the currently disclosed patent applications for selective positive allosteric modulators of M4 muscarinic receptors include WO2018002760A1, WO2018234953A1, WO2013126856A1, WO2014035829A1, WO2017223290A1, WO2019113179A1, WO2018035444A1, WO2023064588A1, WO2023141511A1, etc.

[0006] In summary, although there is sufficient literature and drug development information demonstrating that PAMs targeting the M4 muscarinic receptor may provide a new therapeutic approach for cognitive and behavioral deficits in neurodegenerative and neuropsychiatric diseases, no PAMs targeting the M4 muscarinic receptor have yet been successfully marketed. Therefore, there is still a widespread demand in this field for selective positive allosteric modulators of the M4 muscarinic receptor with high subtype selectivity, good efficacy, and high safety. Summary of the Invention

[0007] The present invention provides a fused pyrimidine ring compound, a pharmaceutical composition comprising the compound, and uses thereof. The compound has regulatory activity on muscarinic M4 receptors, has better pharmacodynamics / pharmacokinetic properties, and can be used to treat diseases and disorders mediated by M4.

[0008] To this end, the present invention adopts the following technical solutions:

[0009] In one aspect, the present application provides a compound represented by formula (I), its stereoisomers, its N-oxides or pharmaceutically acceptable salts thereof:

[0010] wherein ring A is selected from C 6-10 aryl and 5- to 10-membered heteroaryl;

[0011] R1 and R2 are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a 、-NR b C(O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more R d replace;

[0012] R3 is independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2Ra 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0013] R a 、R b and R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl and -(CH2)p-C3-C6 cycloalkyl are optionally replaced by one or more R d replace;

[0014] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0015] n is an integer of 0, 1, 2, 3, 4, 5, 6 or 7;

[0016] p is an integer of 1, 2 or 3;

[0017] L1, L2, S1 and S2 are each independently selected from a single bond and -(CR e R f ) m -, where R e and R f Each is independently selected from hydrogen, deuterium, chlorine and C1-C6 alkyl, m is an integer of 1, 2, 3 or 4, and it is provided that L1 and L2 are not single bonds at the same time, and S1 and S2 are not single bonds at the same time;

[0018] M is selected from a single bond, -O- and -CR e R f -, where R e and R fare independently selected from hydrogen, deuterium, chlorine and C1-C6 alkyl, and it is provided that when M is selected from a single bond, L1 is -CH2-, L2 is -CH2-, and the ring formed by S1 and S2 is

[0019] In one embodiment, the compound represented by formula (I) is not any of the following compounds:

[0020] In one embodiment, R1 is hydrogen or halogen;

[0021] R2 is hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group.

[0022] In one embodiment, the C 6-10 Aryl groups independently may be phenyl or naphthyl, preferably phenyl.

[0023] In one embodiment, the 5- to 10-membered heteroaryl group may independently be a 5- to 6-membered heteroaryl group.

[0024] In one embodiment, the heteroatom in the 5- to 10-membered heteroaryl group may independently be N, O or S, and the number of heteroatoms may be 1, 2 or 3; preferably, the heteroatom in the 5- to 10-membered heteroaryl group may be N, and the number of heteroatoms may be 1 or 2.

[0025] In one embodiment, the 5- to 10-membered heteroaryl groups may independently be monocyclic or polycyclic; the polycyclic rings may be fused rings; the polycyclic rings may be bicyclic or tricyclic.

[0026] In one embodiment, the 5- to 10-membered heteroaryl group may independently be pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, quinolyl or isoquinolyl; preferably pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl or isoquinolyl; more preferably

[0027] In one embodiment, the halogen may independently be fluorine, chlorine, bromine or iodine.

[0028] In one embodiment, the C1-C6 alkyl group can independently be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.

[0029] In one embodiment, the C1-C6 haloalkyl group can independently be a C1-C6 alkyl group substituted by one or more halogens, preferably a C1-C3 alkyl group substituted by one or more halogens, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3, preferably -CF3.

[0030] In one embodiment, the C3-C6 cycloalkyl group may independently be cyclopropyl, cyclobutyl, cyclopentyl or cyclopropyl, preferably cyclopropyl.

[0031] In one embodiment, the heteroatoms in the 4- to 7-membered heterocyclic group may independently be N, O or S, and the number of heteroatoms may be 1, 2 or 3; preferably, the heteroatoms in the 4- to 7-membered heterocyclic group may be N or O, and the number of heteroatoms may be 1 or 2;

[0032] In one embodiment, the 4- to 7-membered heterocyclyl group may independently be a 5- to 6-membered heterocyclyl group.

[0033] In one embodiment, the 4 to 7 membered heterocyclic groups independently can be Preferably

[0034] In one embodiment, the 4- to 7-membered heterocycle is a 4-membered heterocyclic group; preferably, the heteroatom of the 4-membered heterocyclic group may be N, and the number of heteroatoms may be 1.

[0035] In one embodiment, the 4 to 7 membered heterocyclic groups independently can be Preferably

[0036] In one embodiment, the C1-C6 alkoxy group can independently be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

[0037] Ring A

[0038] In one embodiment, Ring A is C 6-10In another embodiment, ring A is a 5- to 10-membered heteroaryl group; in another embodiment, ring A is phenyl or a 5- to 6-membered heteroaryl group; in another embodiment, ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1-3 N, O, or S heteroatoms; in another embodiment, ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl, quinolyl, or isoquinolyl; in another embodiment, ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl, or isoquinolyl; in another embodiment, ring A is phenyl or pyridyl.

[0039] R1 and R2

[0040] In one embodiment, R1 and R2 are each independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a 、-NR b C(O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more R d substituted; in another embodiment, R1 and R2 are each independently hydrogen; in another embodiment, R1 and R2 are each independently halogen; in another embodiment, R1 and R2 are each independently cyano; in another embodiment, R1 and R2 are each independently nitro; in another embodiment, R1 and R2 are each independently -OR a In another embodiment, R1 and R2 are each independently -SR a In another embodiment, R1 and R2 are each independently -S(O)2R a In another embodiment, R1 and R2 are each independently -C(O)OR a In another embodiment, R1 and R2 are each independently -NR b Rc In another embodiment, R1 and R2 are each independently -S(O)2NR b R c In another embodiment, R1 and R2 are each independently -NR b S(O)2R a In another embodiment, R1 and R2 are each independently -NR b C(O)R a In another embodiment, R1 and R2 are each independently C1-C6 alkyl; In another embodiment, R1 and R2 are each independently C1-C6 haloalkyl; In another embodiment, R1 and R2 are each independently C3-C6 cycloalkyl; In another embodiment, R1 and R2 are each independently -(CH2)p-C3-C6 cycloalkyl; In another embodiment, R1 and R2 are each independently 4 to 7 membered heterocyclyl, wherein the 4 to 7 membered heterocyclyl contains 1-3 N, O or S heteroatoms; In another embodiment, the C1-C6 alkyl, C3-C6 cycloalkyl, 4 to 7 membered heterocyclyl in R1 and R2 are optionally replaced by one or more R d replace.

[0041] In another embodiment, R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c 、-S(O)2NR b R c , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more R d In another embodiment, R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 haloalkyl and 4 to 7 membered heterocyclic groups, wherein the C1-C6 alkyl and 4 to 7 membered heterocyclic groups are optionally replaced by one or more R dsubstituted, wherein the 4 to 7 membered heterocyclyl contains 1-3 N, O or S heteroatoms; in another embodiment, R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2, -N(CH3)2,

[0042] In another embodiment, R1 and R2 are each independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group, wherein the 4 to 7 membered heterocyclic group is optionally replaced by one or more R d replace;

[0043] More preferably, R1 and R2 are each independently -H, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, -NHCH3, -N(CH3)2, -N(CH2CH3)2,

[0044] In another embodiment, R1 and R2 are each independently hydrogen, halogen, -OR a 、-NR b R c 、-NR b C(O)R a , C1-C6 alkyl or 4 to 7 membered heterocyclic group; preferably, R1 and R2 are each independently -OCH3, -OH, -NH2, Preferably

[0045] In one embodiment, R1 is hydrogen, halogen or C1-C6 alkyl, preferably hydrogen or halogen, more preferably H or Cl.

[0046] In one embodiment, R2 is hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group, preferably hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2, more preferably hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2, further preferably hydrogen, Cl or -N(CH3)2.

[0047] In one embodiment, R2 is hydrogen, halogen, -OR a、-NR b R c 、-NR b C(O)R a , C1-C6 alkyl or 4 to 7 membered heterocyclic group, wherein the 4 to 7 membered heterocyclic group is optionally substituted by one or more R d Substitution; preferably, R2 is -NHCH3, -N(CH2CH3)2, -OCH3, -OH, -NH2, Better, R2 is

[0048] In one embodiment, each R3 is independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d substituted; in another embodiment, each R3 is independently hydrogen; in another embodiment, each R3 is independently halogen; in another embodiment, each R3 is independently -OR a In another embodiment, each R3 is independently -S(O)2R a In another embodiment, each R3 is independently -C(O)R a In another embodiment, each R3 is independently -S(O)2R a In another embodiment, each R3 is independently -C(O)OR a In another embodiment, each R3 is independently -NR b R c In another embodiment, each R3 is independently -C(O)NR b R cIn another embodiment, each R3 is independently -S(O)2NR b R c In another embodiment, each R3 is independently -NR b S(O)2R a In another embodiment, R3 is each independently C1-C6 alkyl; in another embodiment, R3 is each independently C1-C6 haloalkyl; in another embodiment, R3 is each independently C3-C6 cycloalkyl; in another embodiment, R3 is each independently -(CH2)p-C3-C6 cycloalkyl; in another embodiment, the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl in each R3 are optionally replaced by one or more R d replace.

[0049] In one embodiment, each R3 is independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d In another embodiment, R3 is independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R dIn another embodiment, each R3 is independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -S(O)2CF3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2, and -N(CH3)2. In one embodiment, each R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, such as F, methyl, methoxy, -S(O)2CF3 or -CF3;

[0050] More preferably, R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl, such as F, -S(O)2CF3 or -CF3.

[0051] In one embodiment, each R3 is independently hydrogen, halogen, cyano, nitro, -OR a 、-S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl.

[0052] n

[0053] In one embodiment, n is an integer of 0, 1, 2, 3, 4, 5, 6, or 7; in another embodiment, n is 0; in another embodiment, n is 1; in another embodiment, n is 2; in another embodiment, n is 3; in another embodiment, n is 4; in another embodiment, n is 5; in another embodiment, p is n; in another embodiment, n is 7.

[0054] In one embodiment, n is 0, 1, 2 or 3, preferably 1 or 2, more preferably 2.

[0055] L1 and L2

[0056] In one embodiment, L1 and L2 are each independently selected from a single bond and -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 1, 2, 3 and 4, and L1 and L2 are not single bonds at the same time; in another embodiment, L1 is a single bond, L2 is selected from -(CR e R f ) m -, where Re and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2, 3 and 4; in another embodiment, L1 is a single bond, L2 is selected from -(CH2) m -, m is an integer selected from 2 and 3; in another embodiment, L2 is a single bond, L1 is selected from -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2, 3 and 4; in another embodiment, L2 is a single bond, L1 is selected from -(CH2) m -, m is an integer selected from 2 and 3; in another embodiment, L1 is -CR e R f -, L2 is selected from -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2 and 3; in another embodiment, L1 is -CH2-, L2 is selected from -(CH2) m -, m is an integer selected from 2 and 3; in another embodiment, L2 is -CR e R f -, L1 is selected from -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2 and 3; in another embodiment, L2 is -CH2-, L1 is selected from -(CH2) m -, m is an integer selected from 2 and 3;

[0057] In one embodiment, L1 is -CH2- or -(CH2)2-, preferably -CH2-;

[0058] In one embodiment, L2 is -CH2- or -(CH2)2-, preferably -CH2-.

[0059] S1 and S2

[0060] In one embodiment, S1 and S2 are each independently selected from a single bond and -(CR e R f ) m -, where Re and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 1, 2, 3 and 4, and it is provided that S1 and S2 are not single bonds at the same time; in another embodiment, S1 is a single bond, S2 is selected from -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2, 3 and 4; in another embodiment, S1 is a single bond, S2 is selected from -(CH2) m -, m is an integer selected from 2 and 3; in another embodiment, S2 is a single bond, S1 is selected from -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2, 3 and 4; in another embodiment, S2 is a single bond, S1 is selected from -(CH2) m -, m is an integer selected from 2 and 3; in another embodiment, S1 is -CR e R f -, S2 is selected from -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2 and 3; in another embodiment, S1 is -CH2-, S2 is selected from -(CH2) m -, m is an integer selected from 2 and 3; in another embodiment, S2 is -CR e R f -, S1 is selected from -(CR e R f ) m -, where R e and R f are each independently selected from -H, -D, -Cl, -F and -CH3, m is an integer selected from 2 and 3; in another embodiment, S2 is -CH2-, S1 is selected from -(CH2) m -, m is an integer selected from 2 and 3;

[0061] In one embodiment, S1 is -CD2-, -CH2- or -(CH2)2-, preferably -CH2- or -(CH2)2-, more preferably -CH2-;

[0062] In one embodiment, S2 is -CD2-, -CH2-, or -(CH2)2-, preferably -CH2- or -(CH2)2-, more preferably -CH2-.

[0063] M

[0064] In one embodiment, M is selected from a single bond, -O- and -CR e R f -, where R e and R f Each is independently selected from -H, -D, -F and -CH3, and it is provided that when M is a single bond, L1 is -CH2-, L2 is -CH2-, and the ring formed by S1 and S2 is In another embodiment, M is a single bond, and it is provided that when M is a single bond, L1 is -CH2-, L2 is -CH2-, and the ring formed by S1 and S2 is In another embodiment, M is -O-; in another embodiment, M is -CR e R f -, where R e and R f are each independently selected from -H, -D, -F and -CH3; in another embodiment, M is -CH2-;

[0065] In one embodiment, M is a single bond or -CR e R f -, where R e and R f are independently selected from hydrogen, deuterium, chlorine and C1-C6 alkyl; when M is selected from a single bond, L1 is -CH2-, L2 is -CH2-, and the ring formed by S1 and S2 is

[0066] In one embodiment, M is -CR e R f -, where R e and R f are each independently selected from hydrogen, deuterium, F and methyl.

[0067] In one embodiment, R a 、R b and R c Each independently represents hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl, wherein the C1-C6 alkyl is optionally replaced by one or more R d replace;

[0068] Preferably, R a 、R b and R cEach independently represents hydrogen, C1-C6 alkyl or C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally replaced by one or more R d replace;

[0069] More preferably, R a 、R b and R c Each is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl.

[0070] In one embodiment, R d Each is independently halogen, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy, preferably halogen or C1-C6 alkyl.

[0071] In one embodiment, the fragment Can Preferably More preferably

[0072] In one embodiment, the fragment Can Preferably

[0073] In one embodiment, the fragment Can Preferably

[0074] More preferably More preferably

[0075] In one embodiment, the fragment Can

[0076] In one embodiment, the fragment for In one embodiment, the fragment for In one embodiment, the fragment for In one embodiment, the fragment for

[0077] In one embodiment, the fragment for Preferably

[0078] In a more specific embodiment, the present invention provides a compound of the above formula (I), its stereoisomer, its N-oxide or a pharmaceutically acceptable salt thereof, wherein the compound has the structural characteristics of formula (II):

[0079] wherein each group is as defined above;

[0080] Preferably,

[0081] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms;

[0082] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c 、-S(O)2NR b R c , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more R d replace;

[0083] R3 is independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0084] n is an integer of 0, 1, 2, 3 or 4;

[0085] S1 and S2 are each independently selected from a single bond and -(CR e R f ) m -, where R e and R f Each is independently selected from hydrogen, deuterium, fluorine and methyl, m is an integer of 1, 2 or 3, and it is provided that S1 and S2 are not single bonds at the same time;

[0086] M is selected from a single bond and -CR e R f -, where R e and R f are independently selected from hydrogen, deuterium, fluorine and methyl, and it is provided that when M is selected from a single bond, the ring composed of S1 and S2 is

[0087] R a 、R b and R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkane and -(CH2)p-C3-C6 cycloalkyl, wherein said C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0088] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0089] p is an integer of 1, 2 or 3;

[0090] Preferably,

[0091] Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl or isoquinolyl;

[0092] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a、-NR b R c , C1-C6 alkyl, C1-C6 haloalkyl and 4 to 7 membered heterocyclic groups, wherein the C1-C6 alkyl and 4 to 7 membered heterocyclic groups are optionally replaced by one or more R d substituted, wherein the 4- to 7-membered heterocyclyl contains 1-3 N, O or S heteroatoms;

[0093] R3 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R d replace;

[0094] n is an integer of 0, 1, 2, 3 or 4;

[0095] S1 and S2 are each independently selected from -(CH2) m -, m is an integer selected from 1 and 2, and it is provided that S1 and S2 are not single bonds at the same time;

[0096] M is selected from a single bond and -CH2-, and it is provided that when M is selected from a single bond, the ring formed by S1 and S2 is

[0097] R a 、R b and R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl and -(CH2)p-C3-C6 cycloalkyl are optionally replaced by one or more R d replace;

[0098] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0099] p is an integer of 1, 2 or 3;

[0100] Preferably,

[0101] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 N atoms;

[0102] R1 and R2 are each independently hydrogen, halogen, -NR b Rc , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group, wherein the 4 to 7 membered heterocyclic group is optionally replaced by one or more R d replace;

[0103] R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0104] R a 、R b and R c Each is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0105] R d Each is independently halogen or C1-C6 alkyl;

[0106] n is an integer of 0, 1 or 2;

[0107] M is a single bond or -CH2-; when M is a single bond, the ring formed by S1 and S2 is When M is -CH2-, S1 and S2 are -CH2-;

[0108] Preferably,

[0109] Ring A is phenyl or pyridyl;

[0110] R1 is hydrogen, halogen or C1-C6 alkyl;

[0111] R2 is hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2;

[0112] R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; R a Preferably hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0113] n is an integer of 0, 1 or 2;

[0114] M is a single bond or -CH2-; when M is a single bond, the ring formed by S1 and S2 is When M is -CH2-, S1 and S2 are -CH2-;

[0115] Preferably,

[0116] Ring A is phenyl or pyridyl;

[0117] R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2, -N(CH3)2, R3 is each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -S(O)2CF3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2 and -N(CH3)2;

[0118] n is an integer of 0, 1 or 2;

[0119] S1 and S2 are each independently selected from -(CH2) m -, m is an integer selected from 1 and 2, and it is provided that S1 and S2 are not single bonds at the same time;

[0120] M is selected from a single bond and -CH2-, and it is provided that when M is selected from a single bond, the ring formed by S1 and S2 is

[0121] In a more specific embodiment, the present invention provides a compound of the above formula (I), its stereoisomer, its N-oxide or a pharmaceutically acceptable salt thereof, wherein the compound has the structural characteristics of formula (III):

[0122] wherein each group is as defined above;

[0123] Preferably,

[0124] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms;

[0125] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c 、-S(O)2NR b R c , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more Rd replace;

[0126] R3 is independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0127] n is an integer of 0, 1, 2, 3 or 4;

[0128] R a 、R b 、R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0129] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0130] p is an integer of 1, 2 or 3;

[0131] Preferably,

[0132] Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl or isoquinolyl;

[0133] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NRb R c , C1-C6 alkyl, C1-C6 haloalkyl and 4 to 7 membered heterocyclic groups, wherein the C1-C6 alkyl and 4 to 7 membered heterocyclic groups are optionally replaced by one or more R d substituted, wherein the 4- to 7-membered heterocyclyl contains 1-3 N, O or S heteroatoms;

[0134] R3 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R d replace;

[0135] n is an integer of 0, 1, 2, 3 or 4;

[0136] R a 、R b 、R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl and -(CH2)p-C3-C6 cycloalkyl are optionally replaced by one or more R d replace;

[0137] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0138] p is an integer of 1, 2 or 3;

[0139] Preferably,

[0140] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 N atoms;

[0141] R1 and R2 are each independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group, wherein the 4 to 7 membered heterocyclic group is optionally replaced by one or more R d replace;

[0142] R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0143] R a 、R b and R c Each is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0144] R d Each is independently halogen or C1-C6 alkyl;

[0145] n is an integer of 0, 1 or 2;

[0146] Preferably,

[0147] Ring A is phenyl or pyridyl;

[0148] R1 is hydrogen, halogen or C1-C6 alkyl;

[0149] R2 is hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2;

[0150] R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; R a Preferably hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0151] n is an integer of 0, 1 or 2;

[0152] Preferably,

[0153] Ring A is phenyl or pyridyl;

[0154] R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2, -N(CH3)2,

[0155] R3 is each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -S(O)2CF3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2 and -N(CH3)2;

[0156] n is an integer of 0, 1 or 2.

[0157] In a preferred embodiment, the present invention provides a compound of the above formula (I), its stereoisomer, its N-oxide or a pharmaceutically acceptable salt thereof, wherein the compound has the structural characteristics of formula (IV):

[0158] wherein each group is as defined above;

[0159] Preferably,

[0160] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms;

[0161] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c 、-S(O)2NR b R c , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more R d replace;

[0162] R3 is independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0163] n is an integer of 0, 1, 2, 3 or 4;

[0164] R a 、Rb 、R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0165] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0166] p is an integer of 1, 2 or 3;

[0167] Preferably,

[0168] Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl or isoquinolyl;

[0169] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 haloalkyl and 4 to 7 membered heterocyclic groups, wherein the C1-C6 alkyl and 4 to 7 membered heterocyclic groups are optionally replaced by one or more R d substituted, wherein the 4- to 7-membered heterocyclyl contains 1-3 N, O or S heteroatoms;

[0170] R3 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R d replace;

[0171] n is an integer of 0, 1, 2, 3 or 4;

[0172] R a 、R b 、R cEach independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl and -(CH2)p-C3-C6 cycloalkyl are optionally replaced by one or more R d replace;

[0173] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0174] p is an integer of 1, 2 or 3;

[0175] Preferably,

[0176] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 N atoms;

[0177] R1 and R2 are each independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group, wherein the 4 to 7 membered heterocyclic group is optionally replaced by one or more R d replace;

[0178] R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0179] R a 、R b and R c Each is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0180] R d Each is independently halogen or C1-C6 alkyl;

[0181] n is an integer of 0, 1 or 2;

[0182] Preferably,

[0183] Ring A is phenyl or pyridyl;

[0184] R1 is hydrogen, halogen or C1-C6 alkyl;

[0185] R2 is hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2;

[0186] R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; R aPreferably hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0187] n is an integer of 0, 1 or 2;

[0188] Preferably,

[0189] Ring A is phenyl or pyridyl;

[0190] R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2, -N(CH3)2, R3 is each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -S(O)2CF3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2 and -N(CH3)2;

[0191] n is an integer of 0, 1 or 2.

[0192] In a preferred embodiment, the present invention provides a compound of formula (I), a stereoisomer thereof, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structural characteristics of formula (V):

[0193] wherein each group is as defined above;

[0194] Preferably,

[0195] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms;

[0196] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c 、-S(O)2NR b R c , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more R dreplace;

[0197] R3 is independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0198] n is an integer of 0, 1, 2, 3 or 4;

[0199] R a 、R b 、R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0200] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0201] p is an integer of 1, 2 or 3;

[0202] Preferably,

[0203] Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl or isoquinolyl;

[0204] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b Rc , C1-C6 alkyl, C1-C6 haloalkyl and 4 to 7 membered heterocyclic groups, wherein the C1-C6 alkyl and 4 to 7 membered heterocyclic groups are optionally replaced by one or more R d substituted, wherein the 4- to 7-membered heterocyclyl contains 1-3 N, O or S heteroatoms;

[0205] R3 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R d replace;

[0206] n is an integer of 0, 1, 2, 3 or 4;

[0207] R a 、R b 、R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl and -(CH2)p-C3-C6 cycloalkyl are optionally replaced by one or more R d replace;

[0208] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0209] p is an integer of 1, 2 or 3;

[0210] Preferably,

[0211] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 N atoms;

[0212] R1 and R2 are each independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group, wherein the 4 to 7 membered heterocyclic group is optionally replaced by one or more R d replace;

[0213] R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0214] R a 、R b and R c Each is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0215] R d Each is independently halogen or C1-C6 alkyl;

[0216] n is an integer of 0, 1 or 2;

[0217] Preferably,

[0218] Ring A is phenyl or pyridyl;

[0219] R1 is hydrogen, halogen or C1-C6 alkyl;

[0220] R2 is hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2;

[0221] R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; R a Preferably hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0222] n is an integer of 0, 1 or 2;

[0223] Preferably,

[0224] Ring A is phenyl or pyridyl;

[0225] R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2, -N(CH3)2,

[0226] R3 is each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -S(O)2CF3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2 and -N(CH3)2;

[0227] n is an integer of 0, 1 or 2.

[0228] In a preferred embodiment, the present invention provides a compound of the above formula (I), its stereoisomer, its N-oxide or a pharmaceutically acceptable salt thereof, wherein the compound has the structural characteristics of formula (VI):

[0229] wherein each group is as defined above;

[0230] Preferably,

[0231] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1-3 N, O or S heteroatoms;

[0232] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c 、-S(O)2NR b R c , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl, wherein the C1-C6 alkyl C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4 to 7 membered heterocyclyl are optionally substituted by one or more R d replace;

[0233] R3 is independently selected from hydrogen, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0234] n is an integer of 0, 1, 2, 3 or 4;

[0235] R a 、Rb 、R c Each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d replace;

[0236] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0237] p is an integer of 1, 2 or 3;

[0238] Preferably,

[0239] Ring A is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolyl or isoquinolyl;

[0240] R1 and R2 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 haloalkyl and 4 to 7 membered heterocyclic groups, wherein the C1-C6 alkyl and 4 to 7 membered heterocyclic groups are optionally replaced by one or more R d substituted, wherein the 4- to 7-membered heterocyclyl contains 1-3 N, O or S heteroatoms;

[0241] R3 are each independently selected from hydrogen, halogen, -OR a 、-SR a 、-S(O)2R a 、-C(O)OR a 、-NR b R c , C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R d replace;

[0242] n is an integer of 0, 1, 2, 3 or 4;

[0243] R a 、R b 、R cEach independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl and -(CH2)p-C3-C6 cycloalkyl are optionally replaced by one or more R d replace;

[0244] R d Each is independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy;

[0245] p is an integer of 1, 2 or 3;

[0246] Preferably,

[0247] Ring A is phenyl or a 5- to 6-membered heteroaryl group containing 1, 2 or 3 N atoms;

[0248] R1 and R2 are each independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group, wherein the 4 to 7 membered heterocyclic group is optionally replaced by one or more R d replace;

[0249] R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl;

[0250] R a 、R b and R c Each is independently hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0251] R d Each is independently halogen or C1-C6 alkyl;

[0252] n is an integer of 0, 1 or 2;

[0253] Preferably,

[0254] Ring A is phenyl or pyridyl;

[0255] R1 is hydrogen, halogen or C1-C6 alkyl;

[0256] R2 is hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2;

[0257] R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; R aPreferably hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0258] n is an integer of 0, 1 or 2;

[0259] Preferably,

[0260] Ring A is phenyl or pyridyl;

[0261] R1 and R2 are each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2, -N(CH3)2, R3 is each independently selected from -H, -F, -Cl, -Br, -OH, -CH3, -CH2CH3, -CF3, -OCH3, -SCH3, -S(O)2CH3, -S(O)2CF3, -C(O)OH, -C(O)OCH3, -C(O)OCH2CH3, -NHCH3, -N(CH3)2 and -N(CH3)2;

[0262] n is an integer of 0, 1 or 2.

[0263] In a preferred embodiment, the present invention provides a compound of the above formula (I), a stereoisomer thereof, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, wherein the compound has the structural characteristics of formula (VII):

[0264] wherein each group is as defined above;

[0265] Preferably,

[0266] R1 is H or Cl;

[0267] R2 is H, Cl or -N(CH3)2;

[0268] R1 and R2 are not H at the same time;

[0269] R3 is each independently H, F or -CF3; R3 is not H at the same time.

[0270] In a preferred embodiment, the compound has the structural characteristics of formula (III):

[0271] Ring A is phenyl or pyridyl;

[0272] R1 is hydrogen or halogen;

[0273] R2 is hydrogen, halogen, -NR bR c , C1-C6 alkyl, C1-C6 haloalkyl or 4 to 7 membered heterocyclic group;

[0274] R3 is independently hydrogen, halogen, cyano, nitro, -OR a 、-S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, preferably hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl;

[0275] R b and R c Each is independently hydrogen or C1-C6 alkyl;

[0276] R a is hydrogen, C1-C6 alkyl or C1-C6 haloalkyl;

[0277] n is an integer of 0, 1 or 2.

[0278] In a preferred embodiment, the compound represented by formula (I) has the structural characteristics of formula (III):

[0279] Wherein, R1 is H or halogen, preferably H or Cl;

[0280] R2 is H, halogen, -NR b R c or a 4- to 7-membered heterocyclic group, preferably -NR b R c or a 4- to 7-membered heterocyclic group;

[0281] R b and R c Each is independently hydrogen or C1-C6 alkyl;

[0282] snippet for Preferably More preferably

[0283] In a preferred embodiment, the compound represented by formula (I) has the structural characteristics of formula (III):

[0284] in,

[0285] R1 is H or Cl;

[0286] R2 is hydrogen, halogen, -NR b R c, C1-C6 alkyl or 4 to 7 membered heterocyclic group; the heteroatom in the 4 to 7 membered heterocyclic group may be N or O, and the number of heteroatoms may be 1 or 2;

[0287] R b and R c Each is independently hydrogen or C1-C6 alkyl;

[0288] R3 is each independently F, -S(O)2CF3 or -CF3;

[0289] n is 2;

[0290] Ring A is

[0291] In a preferred embodiment, the compound represented by formula (I) has the structural characteristics of formula (III):

[0292] in,

[0293] R1 is H or Cl;

[0294] R2 is H, Cl, -N(CH3)2 or a 4- to 7-membered heterocyclic group; the heteroatom in the 4- to 7-membered heterocyclic group may be N or O, and the number of heteroatoms may be 1 or 2;

[0295] snippet for

[0296] In a preferred embodiment, the compound represented by formula (I) has the structural characteristics of formula (III):

[0297] in,

[0298] R1 is H or Cl;

[0299] R2 is H, Cl or

[0300] snippet for

[0301] In a preferred embodiment, the compound represented by formula (I) has the structural characteristics of formula (III):

[0302] Wherein, R1 is H or halogen, preferably H or Cl;

[0303] R2 is H, halogen, -NR b R c or a 4- to 7-membered heterocyclic group, preferably -NR b Rc or a 4- to 7-membered heterocyclic group; the heteroatom in the 4- to 7-membered heterocyclic group is N or O, and the number of heteroatoms is 1 or 2;

[0304] R b and R c Each is independently hydrogen or C1-C6 alkyl;

[0305] snippet for

[0306] In a preferred embodiment, the compound represented by formula (I) has the structural characteristics of formula (III):

[0307] Wherein, R1 is H or Cl;

[0308] R2 is -N(CH3)2- or

[0309] snippet for

[0310] Preferred compounds of the present invention include, but are not limited to, the following compounds, their stereoisomers, their N-oxides, or pharmaceutically acceptable salts thereof:

[0311] In another aspect, the present invention provides a compound of formula (IX) or a compound of formula (VIII),

[0312] Wherein, R1, R2, R3, L1, L2, M, S1, S2, A and n are as defined above.

[0313] In another aspect, the present invention also provides any intermediate described in the present invention.

[0314] In another aspect, the present invention provides a method for preparing the compound of formula (I), its stereoisomers, its N-oxide or pharmaceutically acceptable salt according to any one of the first aspects of the present application, the preparation method comprising the following steps:

[0315] The intermediate of formula (VIII) or its salt and the intermediate of formula (IX) are reacted in the presence of an amide condensing agent to obtain a compound of formula (I);

[0316] Here, the groups R1, R2, R3, L1, L2, M, S1, S2, A and n in the intermediate formula (VIII) and the intermediate formula (IX) are defined the same as in formula (I);

[0317] The amide condensation agent is a carbodiimide condensation agent, an onium salt condensation agent or an organic phosphorus condensation agent.

[0318] The preparation conditions may be conventional conditions for such reactions in the art.

[0319] In a preferred embodiment, the salt is a hydrochloride, a sulfate or a trifluoroformate;

[0320] In a preferred embodiment, the amide condensation agent is TCFH and NMI.

[0321] In a preferred embodiment, the preparation may further include an organic solvent, which may be a nitrile solvent, such as acetonitrile.

[0322] In a preferred embodiment, the molar ratio of the intermediate formula (VIII) to the intermediate formula (IX) is 1:(0.5-2), preferably 1:1.

[0323] In a preferred embodiment, when the amide condensing agents are TCFH and NMI, the molar ratio of the intermediate of formula (VIII) to TCFH is 1:(1-2), preferably 1:1.2.

[0324] In a preferred embodiment, when the amide condensation agents are TCFH and NMI, the molar ratio of the intermediate of formula (VIII) to NMI is 1:(2-5), preferably 1:3.5.

[0325] In one embodiment, the reaction temperature of the preparation method is 0-60°C, preferably 10-30°C.

[0326] In one embodiment, the reaction time of the preparation method is such that no product is generated, for example, 2 to 10 hours, and for example, 4 hours.

[0327] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, a stereoisomer thereof, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutical excipient. In a specific embodiment, the compound of the present invention is provided in a therapeutically effective amount. In a specific embodiment, the compound of the present invention is provided in a prophylactic effective amount.

[0328] In another aspect, the present invention provides a use of a compound of the present invention, its stereoisomer, its N-oxide or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing diseases and / or disorders mediated by M4.

[0329] In one embodiment, the diseases and / or disorders mediated by M4 include but are not limited to Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis, or atherosclerosis.

[0330] In another aspect, the present invention provides a use of a compound of the present invention, a stereoisomer thereof, an N-oxide thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and / or preventing a disease and / or disorder;

[0331] Such diseases and / or disorders include, but are not limited to, Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive impairment, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis, or atherosclerosis.

[0332] In another aspect, the present invention provides a method for treating diseases and / or disorders mediated by M4, comprising the step of administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, its stereoisomer, its N-oxide or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

[0333] In one embodiment, the diseases and / or disorders mediated by M4 include but are not limited to Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver disease, hepatitis, or atherosclerosis.

[0334] The following definitions are provided for the terms used to describe the present invention in the specification and claims of this application. For specific terms, if the meaning defined in this application is inconsistent with the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail. If not defined in this application, the term shall have the meaning commonly understood by those skilled in the art.

[0335] The names of the compounds in this application correspond to their structural formulas. When the names of the compounds are inconsistent with the structural formulas, the structural formulas shall prevail, or the names of the compounds can be inferred based on the specific circumstances of the present invention and the knowledge of those skilled in the art.

[0336] As used herein, numerical ranges such as 0 to 10, 1-6, 1-3, etc., defined in substituents indicate integers within the range, such as 1-6 is 1, 2, 3, 4, 5, or 6.

[0337] The term "plurality" refers to 2, 3, 4, 5, 6, 7, 8, 9, 10 or more, preferably 2, 3 or 4.

[0338] “C 6-10 "Aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having 6-10 ring carbon atoms and zero heteroatoms. In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C10 aryl"; e.g., naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, C6 aryl is particularly preferred.

[0339] "5 to 10 membered heteroaryl" refers to a group of 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having annular carbon atoms and 1-4 annular heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings. In some embodiments, 5 to 6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having annular carbon atoms and 1-4 annular heteroatoms.

[0340] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepine, oxepinyl, and thiepine. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0341] "Halogen" refers to a fluorine, chlorine, bromine or iodine atom.

[0342] "Alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.

[0343] “C 1- "C6 alkyl" refers to a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, also known as "lower alkyl". Examples of the alkyl group include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, sec-butyl, isobutyl, n-pentyl, 3-pentyl, pentyl, neopentyl, 3-methyl-2-butyl, tert-pentyl and n-hexyl. The alkyl group in the present application is preferably C 1- C3 alkyl.

[0344] “C 1- C6 haloalkyl" refers to the above-mentioned "C 1- C6 alkyl" is substituted by one or more halogen groups. In some embodiments, C 1- C3 haloalkyl is particularly preferred. Exemplary haloalkyl groups include, but are not limited to: -CF3, -CH2F, -CHF2, -CH F CH2F, -CH2CHF2, -CF2CF3, -CCl3, -CH2Cl, -CHCl2, etc.

[0345] “C1- C6 alkoxy" refers to a group -OR, where R is C 1- C6 alkyl. In some embodiments, C 1- C3 alkoxy is particularly preferred. Specific alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0346] “C 3- C6 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon group having 3 to 6 ring carbon atoms and zero heteroatoms. In some embodiments, C 3- C5 cycloalkyl is preferred, and C3 cycloalkyl is more preferred. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0347] "4- to 7-membered heterocyclyl" refers to a group of a 4- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus and silicon, preferably nitrogen, oxygen or sulfur, and the number of heteroatoms is 1, 2 or 3. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. In some embodiments, a 3- to 6-membered heterocyclyl is particularly preferred, which is a 3- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; more preferably a 5- to 6-membered heterocyclyl is a 5- to 6-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. Exemplary heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, piperidinyl, tetrahydropyranyl, dihydropyridinyl, piperazinyl, morpholinyl, dithianyl, dioxanyl, and the like.

[0348] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0349] "Pharmaceutically acceptable salts" refer to pharmaceutically acceptable organic or inorganic salts, as defined above, of the compounds of the present invention, which possess the desired pharmacological activity. Such salts include acid addition salts formed with inorganic or organic acids. Pharmaceutically acceptable salts also include base addition salts, which may be formed in the presence of acidic protons capable of reacting with inorganic or organic bases.

[0350] The term "optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the term "optionally substituted with one or more substituents" means that the atom may or may not be substituted. When substituted, it means that any one or more hydrogen atoms on the specified atom are replaced by a substituent.

[0351] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 1-2 Rs, the group may be optionally substituted with up to two Rs, with each occurrence of R being an independent choice. Furthermore, combinations of substituents and / or their variants are permissible only if such combinations result in stable compounds.

[0352] "Cyano" refers to -CN.

[0353] "Nitro" refers to -NO2.

[0354] "Amino" refers to -NH2.

[0355] "Hydroxyl" refers to -OH.

[0356] The term "therapeutically effective amount" refers to an amount administered to a patient that is sufficient to effectively treat a disease. The therapeutically effective amount will vary depending on the type of compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted by those skilled in the art as appropriate.

[0357] The term "pharmaceutical excipients" refers to all substances contained in pharmaceutical preparations other than the active pharmaceutical ingredient (API). These substances are generally classified into two categories: excipients and additives. For details, see the Pharmacopoeia of the People's Republic of China (2020 Edition) and the Handbook of Pharmaceutical Excipients (Paul J Sheskey, Bruno C Hancock, Gary P Moss, David J Goldfarb, 2020, 9th Edition).

[0358] The term "treat" refers to eliminating the cause or alleviating the symptoms of a disease.

[0359] The term "prevent" refers to reducing the risk of developing a disease.

[0360] The term "patient" refers to any animal, typically a mammal, such as a human, that needs to be treated or prevented. Mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, and the like.

[0361] Other features and advantages of the present application will be described in the following description, and in part will become apparent from the description, or will be understood by practicing the present application. Other advantages of the present application can be realized and obtained by the solutions described in the description.

[0362] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention.

[0363] The reagents and raw materials used in the present invention are commercially available.

[0364] The positive progress of the present invention is that the fused pyrimidine ring compound and the pharmaceutical composition containing the compound and the use thereof have regulatory activity on the muscarinic M4 receptor, have better pharmacodynamics / pharmacokinetic properties, and can be used to treat diseases and disorders mediated by M4. DETAILED DESCRIPTION

[0365] The following examples are provided to illustrate the present invention and its beneficial effects in detail, with the aim of helping readers better understand the essence and features of the present invention and not to limit the scope of the present invention. The following examples are provided only to illustrate the present invention and should not be construed as limiting the scope of the present invention.

[0366] The structures of the compounds were confirmed by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶. NMR measurements were performed using a Bruker Avance Neo 400 MHz NMR spectrometer in deuterated dimethyl sulfoxide (DMSO-d₆) and deuterated chloroform (CDCl₃), with tetramethylsilane (TMS) as the internal standard.

[0367] LCMS was determined using Waters ACQUITY UPLC.

[0368] High performance liquid chromatography (HPLC) was performed on a Thermo UltiMate 3000 liquid chromatograph using a Venusil ASB C18 (4.6*250 mm, 5 μm) column.

[0369] The thin layer chromatography silica gel plate used was West Asia Reagent GF254 silica gel plate.

[0370] Column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0371] The known starting materials of the present application can be synthesized by methods known in the art, or can be purchased from reagent companies such as Aladdin, Bidex Pharmaceuticals, and WuXi AppTec.

[0372] The abbreviations used herein have the following meanings:

[0373] HPLC: High Performance Liquid Chromatography

[0374] LCMS: Liquid chromatography-mass spectrometry

[0375] TLC: Thin layer chromatography

[0376] 1 H NMR: hydrogen nuclear magnetic resonance spectroscopy

[0377] TCFH: N,N,N',N'-Tetramethylchloroformamidine hexafluorophosphate

[0378] NMI: N-methylimidazole

[0379] BINAP: 1,1'-binaphthyl-2,2'-diyl (diphenylphosphine)

[0380] (Pd2(dba)3: tris(dibenzylideneacetone)dipalladium(0)

[0381] DIPEA: N,N-diisopropylethylamine

[0382] EtOH: ethanol

[0383] Intermediate P1

[0384] {1-[2-(Trifluoromethyl)pyridin-4-yl]azetidin-3-yl}acetic acid (Intermediate P1)

[0385] Step 1: Synthesis of methyl azetidin-3-yl acetate hydrochloride (P1_2)

[0386] Under ice-cooling, 4N hydrochloric acid / ethanol (10 ml) was added dropwise to a solution of intermediate P1_1 (5 g, 21.8 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and concentrated to obtain intermediate P1_2 as a colorless, transparent oil (3.51 g, yield: 97.43%, purity: HPLC>98%). ESI-MS m / z: 130.1 [M+H] + .

[0387] Step 2: Synthesis of methyl {1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}acetate (P1_4)

[0388] The intermediate P1_2 (2.08 mmol, 1.0 eq, 271 mg), the intermediate P1_3 (5.21 mmol, 2.5 eq, 592 mg), and BINAP (0.83 mmol, 0.4 eq, 288 mg) were added to a reaction flask, and toluene (10 ml) was added to dissolve and stir, and then Cs2CO3 (10.4 mmol, 5.0 eq, 1.85 g) was added and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.42 mmol, 0.2 eq, 205 mg) was added and the reaction was kept at 70°C for 16 min. Hours, LCMS detection reaction to P1_2 reaction complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify the intermediate P1_4 as a colorless transparent oil (518mg, yield: 90.69%, purity: HPLC>83%). ESI-MS m / z: 275.1[M+H] + .

[0389] Step 3: Synthesis of {1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}acetic acid (P1)

[0390] Intermediate P1_4 (1.88 mmol, 518 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 hours. LCMS confirmed that the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P1 as a white solid powder (127 mg, yield: 25.83%, purity: HPLC>90%). ESI-MS m / z: 261.1 [M+H] + .

[0391] Intermediate P2

[0392] [1-(2,3-Difluoropyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P2)

[0393] Step 1: Synthesis of methyl [1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]acetate (P2_2)

[0394] The intermediate P1_2 (3.88 mmol, 1.0 eq, 640 mg), P2_1 (4.86 mmol, 1.25 eq, 0.94 g), and BINAP (0.19 mmol, 0.05 eq, 120 mg) were added to a reaction flask, and toluene (10 ml) was added to dissolve and stir. Then, cesium carbonate (9.7 mmol, 2.5 eq, 3160 mg) was added and heated in an oil bath at 70°C. After the temperature rose, (Pd2(dba)3 (0.10 mmol, 0.025 eq, 89 mg) was added and the reaction was kept at 70°C for 8 hours. LCMS detected that P1_2 disappeared. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (20 ml) and washed with ethyl acetate (3 x 40 mL). The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to obtain the intermediate P2_2 as a colorless, transparent oil (425 mg, yield: 45.12%, purity: HPLC>90%). ESI-MS m / z: 243.1 [M+H] + .

[0395] Step 2: Synthesis of [1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]acetic acid (P2)

[0396] Intermediate P2_2 (1.76 mmol, 425 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. Stirring was continued at room temperature for 10 hours. LCMS analysis revealed the disappearance of P2_2. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. A white solid powder precipitated. After standing for 10 minutes, it was filtered and washed thoroughly with purified water (10 ml, three times). The filter cake was then dried at 40°C to obtain intermediate P2 as a white solid powder (336 mg, yield: 83.91%, purity: HPLC>90%). ESI-MS m / z: 229.1 [M+H] + .

[0397] Intermediate P3

[0398] [1-(Pyridin-2-yl)azetidin-3-yl]acetic acid (Intermediate P3)

[0399] Step 1: Synthesis of [1-(pyridin-2-yl)azetidin-3-yl]acetate (P3_2)

[0400] The intermediate P1_2 (3.88mmol, 1.0eq, 500mg), P3_1 (9.71mmol, 2.5eq, 1.53g), BINAP (1.55mmol, 0.4eq, 965mg) were added to a reaction flask, toluene (10ml) was added to dissolve and stir, and then cesium carbonate (19.4mmol, 5.0eq, 6.32g) was added, and heated in an oil bath at 70°C. After the temperature rose, (Pd2(dba)3 (0.78mmol, 0.2eq, 714mg) was added, and the reaction was kept at 70°C for 8 hours. LCMS detected that P1_2 disappeared. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (20ml) and washed with ethyl acetate (3x The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to obtain the intermediate P3_2 as a colorless, transparent oil (650 mg, yield: 81.41%, purity: HPLC>90%). ESI-MS m / z: 207.1 [M+H] + .

[0401] Step 2: Synthesis of [1-(pyridin-2-yl)azetidin-3-yl]acetic acid (P3)

[0402] Intermediate P3_2 (3.17 mmol, 650 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. Stirring was continued at room temperature for 10 hours. LCMS analysis indicated that the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P3 as a white solid powder (541 mg, yield: 89.30%, purity: HPLC>90%). ESI-MS m / z: 193.1 [M+H] + .

[0403] Intermediate P4

[0404] 2-(1-(4-(trifluoromethyl)sulfonyl)phenyl)azetidin-3-yl)acetic acid (Intermediate P4)

[0405] Step 1: Synthesis of methyl 2-(1-(4-(trifluoromethyl)sulfonyl)phenyl)azetidin-3-yl)acetate (P4_1)

[0406] The intermediate P1_2 (1.94mmol, 1.0eq, 322mg), the intermediate P4_1 (3.88mmol, 2.0eq, 1.12g), and BINAP (0.78mmol, 0.4eq, 268mg) were added to a reaction flask, and toluene (5ml) was added to dissolve and stir, and then cesium carbonate (9.7mmol, 5.0eq, 1.72g) was added, and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.39mmol, 0.2eq, 191mg) was added, and the reaction was maintained at 70°C. Heat for 8 hours, LCMS monitoring reaction completion. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x10ml) and extracted with ethyl acetate (3x50ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify P4_2 as a colorless, transparent oil. (376mg, yield: 57.57%, purity: HPLC>90%). ESI-MS m / z: 338.1[M+H] + .

[0407] Step 2: Synthesis of 2-(1-(4-(trifluoromethyl)sulfonyl)phenyl)azetidin-3-yl)acetic acid (Intermediate P4)

[0408] Intermediate P4_2 (1.12 mmol, 376 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. The solution was stirred at room temperature for 10 hours. LCMS monitored the reaction to be complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and then further dried in a vacuum oven to obtain intermediate P4 as a white solid powder (217 mg, yield: 60.22%, purity: HPLC>90%). ESI-MS m / z: 323.04 [M+H] + .

[0409] Intermediate P5

[0410] [1-(3-Fluoropyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P5)

[0411] Step 1: Synthesis of [1-(3-fluoropyridin-4-yl)azetidin-3-yl]acetate (P5_2)

[0412] The intermediate P1_2 (3.88mmol, 1.0eq, 0.64g), P5_1 (4.86mmol, 1.25eq, 0.85g), and BINAP (0.19mmol, 0.05eq, 120mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then cesium carbonate (9.7mmol, 2.5eq, 3.16g) was added, and heated in an oil bath at 70℃. After the temperature rose, (Pd2(dba)3 (0.10mmol, 0.025eq, 8 9mg), the reaction was heated at 70 ° C for 8 hours, and the reaction was monitored by LCMS. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (20ml) and extracted with ethyl acetate (3x30ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent cyclohexane / ethyl acetate, gradient 10: 1 to 1: 1) was used to obtain P5_2, 819mg of colorless transparent oil. ESI-MS m / z: 225.1[M+H] + .

[0413] Step 2: Synthesis of [1-(3-fluoropyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P5)

[0414] P5_2 (1.0 eq, 431 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. Stirring was continued at room temperature for 10 h. The reaction was monitored for completion by LCMS. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. A white solid powder precipitated. After standing for 10 min, it was filtered and washed thoroughly with purified water (10 ml, three times). The filter cake was then dried at 40°C to obtain P5 as a white solid powder (375 mg, yield: 83.25%, purity: HPLC>90%). ESI-MS m / z: 211.1 [M+H] + .

[0415] Intermediate P6

[0416] [1-(3,5-Difluoropyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P6)

[0417] Step 1: Synthesis of methyl [1-(3,5-difluoropyridin-4-yl)azetidin-3-yl]acetate (P6_2)

[0418] The intermediate P1_2 (3.88 mmol, 1.0 eq, 0.64 g), P6_1 (4.86 mmol, 1.25 eq, 0.94 g), and BINAP (0.19 mmol, 0.05 eq, 120 mg) were added to a reaction flask, and toluene (10 ml) was added for dissolution and stirring. Then, cesium carbonate (9.7 mmol, 2.5 eq, 3.16 g) was added and heated in an oil bath at 70°C. After the temperature rose, (Pd2(dba)3 (0.10 mmol, 0.025 eq, 89 mg) was added and the reaction was kept at 70°C for 8 hours. The reaction was completed after LCMS monitoring. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (20 ml) and washed with ethyl acetate (3 x 10% ethanol). The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) afforded P6_2, 425 mg of a colorless, transparent oil. ESI-MS m / z: 243.1 [M+H] + .

[0419] Step 2: Synthesis of [1-(3,5-difluoropyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P6)

[0420] P6_2 (1.0 eq, 425 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. Stirring was continued at room temperature for 10 h. The reaction was monitored for completion by LCMS. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. A white solid powder precipitated. After standing for 10 min, it was filtered and washed thoroughly with purified water (10 ml, three times). The filter cake was then dried at 40°C to obtain P6 as a white solid powder (336 mg, yield: 83.91%, purity: HPLC>90%). ESI-MS m / z: 229.1.1 [M+H] + .

[0421] Intermediate P7

[0422] (3S)-1-[2-(Trifluoromethyl)pyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (Intermediate P7)

[0423] Step 1: Synthesis of (3S)-tetrahydropyrrole-3-methyl carboxylate (P7_2)

[0424] Under ice-cooling, 4N hydrochloric acid / ethanol (1.5 ml) was added dropwise to a solution of intermediate P7_1 (0.5 g, 21.8 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and concentrated to obtain intermediate P1_2 as a colorless, transparent oil (292 mg, yield: 81.05%, purity: HPLC>98%). ESI-MS m / z: 130.1 [M+H] + .

[0425] Step 2: Synthesis of (3S)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydropyrrole-3-carboxylic acid methyl ester (P7_3)

[0426] The intermediate P7_2 (1.77mmol, 1.0eq, 292mg), the intermediate P1_3 (5.21mmol, 3.0eq, 592mg), and BINAP (0.09mmol, 0.05eq, 29mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then Cs2CO3 (8.85mmol, 5.0eq, 2.89g) was added, and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.04mmol, 0.025eq, 21mg) was added, and the reaction was kept at 70°C and heated for 16 minutes. Hours, LCMS detection reaction to P7_2 reaction complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify the intermediate P7_3 as a colorless transparent oil (428mg, yield: 88.43%, purity: HPLC>90%). ESI-MS m / z: 275.1[M+H] + .

[0427] Step 3: Synthesis of (3S)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (P7)

[0428] Intermediate P1_4 (1.56 mmol, 428 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 hours. LCMS confirmed the complete reaction of P7_3. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P7 as a white solid powder (352 mg, yield: 78.04%, purity: HPLC>90%). ESI-MS m / z: 261.1 [M+H] + .

[0429] Intermediate P8

[0430] (3R)-1-[2-(Trifluoromethyl)pyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (Intermediate P8)

[0431] Step 1: Synthesis of (3R)-tetrahydropyrrole-3-methyl carboxylate (P8_2)

[0432] Under ice-cooling, 4N hydrochloric acid / ethanol (1.5 ml) was added dropwise to a solution of intermediate P7_1 (0.5 g, 21.8 mmol) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and concentrated to obtain intermediate P1_2 as a colorless, transparent oil (304 mg, yield: 84.38%, purity: HPLC>98%). ESI-MS m / z: 130.1 [M+H] + .

[0433] Step 2: Synthesis of (3R)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydropyrrole-3-carboxylic acid methyl ester (P8_3)

[0434] The intermediate P8_2 (1.84mmol, 1.0eq, 304mg), the intermediate P1_3 (5.50mmol, 3.0eq, 628mg), and BINAP (0.09mmol, 0.05eq, 29mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then Cs2CO3 (9.2mmol, 5.0eq, 3.0g) was added and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.04mmol, 0.025eq, 21mg) was added and the reaction was kept at 70°C for 16 hours. When LCMS detected that the reaction was complete until P8_2. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify the intermediate P8_3 as a colorless transparent oil (392mg, yield: 77.65%, purity: HPLC>90%). ESI-MS m / z: 275.1[M+H] + .

[0435] Step 3: Synthesis of (3R)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (P8)

[0436] Intermediate P1_4 (1.43 mmol, 392 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 hours. LCMS confirmed that the reaction was complete until P8_3 was fully reacted. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P8 as a white solid powder (331 mg, yield: 88.98%, purity: HPLC>90%). ESI-MS m / z: 261.1 [M+H] + .

[0437] Intermediate P9

[0438] [1-(2-Methoxypyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P9)

[0439] Step 1: Synthesis of [1-(2-methoxypyridin-4-yl)azetidin-3-yl]acetate (P9_2)

[0440] The intermediate P1_2 (3.88mmol, 1.0eq, 0.64g), P9_1 (4.86mmol, 1.25eq, 0.92g), BINAP (0.19mmol, 0.05eq, 120mg) were added to a reaction flask, toluene (10ml) was added to dissolve and stir, and then cesium carbonate (9.7mmol, 2.5eq, 3.16g) was added, and heated in an oil bath at 70°C. After the temperature rose, (Pd2(dba)3 (0.10mmol, 0.025eq, 89mg) was added, and the reaction was kept at 70°C for 8 hours. The reaction was completed after LCMS monitoring. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (20ml) and washed with ethyl acetate (3x The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient from 10:1 to 1:1) afforded P9_2 as a colorless, transparent oil (480 mg, yield: 53%). ESI-MS m / z: 237.1 [M+H] + .

[0441] Step 2: Synthesis of [1-(2-methoxypyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P9)

[0442] P9_2 (1.0 eq, 480 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. The solution was stirred at room temperature for 10 h. LCMS monitored the reaction for completeness. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. A white solid powder precipitated. After standing for 10 min, it was filtered and washed thoroughly with purified water (10 ml, three times). The filter cake was dried at 40°C to obtain P9 as a white solid powder (405 mg, yield: 89.67%, purity: HPLC>90%). ESI-MS m / z: 223.1 [M+H] + .

[0443] Intermediate P10

[0444] [1-(2-Methylpyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P10)

[0445] Step 1: Synthesis of [1-(2-methylpyridin-4-yl)azetidin-3-yl]acetate (P10_2)

[0446] The intermediate P1_2 (3.88mmol, 1.0eq, 0.64g), P10_1 (4.86mmol, 1.25eq, 0.85g), BINAP (0.19mmol, 0.05eq, 120mg) were added to a reaction flask, toluene (10ml) was added to dissolve and stir, and then cesium carbonate (9.7mmol, 2.5eq, 3.16g) was added, and heated in an oil bath at 70°C. After the temperature rose, (Pd2(dba)3 (0.10mmol, 0.025eq, 89mg) was added, and the reaction was kept at 70°C for 8 hours. The reaction was completed after LCMS monitoring. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (20ml) and washed with ethyl acetate (3x The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to obtain P10_2 as a colorless, transparent oil (1.02 g, yield: 71.39%). ESI-MS m / z: 221.1 [M+H] + .

[0447] Step 2: Synthesis of [1-(2-methylpyridin-4-yl)azetidin-3-yl]acetic acid (Intermediate P10)

[0448] P10_2 (1.0 eq, 1.02 g) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. Stirring was continued at room temperature for 10 h. The reaction was monitored for completion by LCMS. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. A white solid powder precipitated. After standing for 10 min, it was filtered and washed thoroughly with purified water (10 ml, three times). The filter cake was then dried at 40°C to obtain P10 as a white solid powder (377 mg, yield: 66.72%, purity: HPLC>90%). ESI-MS m / z: 207.1 [M+H] + .

[0449] Intermediate P11

[0450] 2-(1-(6-methylpyridazin-3-yl)azetidin-3-yl)acetic acid (Intermediate P11)

[0451] Step 1: Synthesis of methyl 2-(1-(6-methylpyridazin-3-yl)azetidin-3-yl)acetate (P11_2)

[0452] The intermediate P1_2 (3.88mmol, 1.0eq, 0.64g), P11_1 (4.86mmol, 1.25eq, 0.85g), BINAP (0.19mmol, 0.05eq, 120mg) were added to a reaction flask, toluene (10ml) was added to dissolve and stir, and then cesium carbonate (9.7mmol, 2.5eq, 3.16g) was added, and heated in an oil bath at 70°C. After the temperature rose, (Pd2(dba)3 (0.10mmol, 0.025eq, 89mg) was added, and the reaction was kept at 70°C for 8 hours. The reaction was completed after LCMS monitoring. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (20ml) and washed with ethyl acetate (3x The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to obtain P11_2 as a colorless, transparent oil (350 mg, yield: 41.01%, purity: HPLC>90%). ESI-MS m / z: 221.1 [M+H] + .

[0453] Step 2: Synthesis of 2-(1-(6-methylpyridazin-3-yl)azetidin-3-yl)acetic acid (Intermediate P11)

[0454] P11_2 (1.58 mmol, 1.0 eq, 350 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the solution to pH 13. The solution was stirred at room temperature for 10 h. LCMS monitored the reaction to be complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. A white solid powder precipitated. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain P11 as a white solid powder (276 mg, yield: 84.22%, purity: HPLC>90%). ESI-MS m / z: 207.1 [M+H] + .

[0455] Intermediate P12

[0456] (3R)-1-[2-Methoxypyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (Intermediate P12)

[0457] Step 1: Synthesis of (3R)-1-[2-methoxypyridin-4-yl]tetrahydropyrrole-3-carboxylic acid methyl ester (P12_2)

[0458] The intermediate P8_2 (3.03mmol, 1.0eq, 500mg), the intermediate P12_1 (3.03mmol, 1.0eq, 567mg), and BINAP (0.15mmol, 0.05eq, 48mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then Cs2CO3 (9.09mmol, 3.0eq, 1.71g) was added, and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.08mmol, 0.025eq, 42mg) was added, and the reaction was kept at 70°C and heated for 16 seconds. Hours, LCMS detection reaction to P12_1 reaction complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify the intermediate P12_2 as a colorless transparent oil (491mg, yield: 68.79%, purity: HPLC>90%). ESI-MS m / z: 237.1[M+H] + .

[0459] Step 2: Synthesis of (3R)-1-[2-methoxypyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (P12)

[0460] Intermediate P1_4 (2.08 mmol, 491 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 hours. LCMS analysis confirmed the complete reaction of P12_2. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P12 as a white solid powder (329 mg, yield: 71.34%, purity: HPLC>90%). ESI-MS m / z: 223.1 [M+H] + .

[0461] Intermediate P13

[0462] (R)-1-(4-(Trifluoromethyl)sulfonyl)phenyl)pyrrolidine-3-carboxylic acid (Intermediate P13)

[0463] Step 1: Synthesis of (R)-1-(4-(trifluoromethyl)sulfonyl)phenyl)pyrrolidine-3-carboxylic acid methyl ester (P13_3)

[0464] The intermediate P8_2 (1.51mmol, 1.0eq, 250mg), the intermediate P13_1 (3.03mmol, 2.0eq, 436mg), and BINAP (0.08mmol, 0.05eq, 24mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then Cs2CO3 (4.55mmol, 3.0eq, 860mg) was added and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.04mmol, 0.025eq, 11mg) was added and the reaction was heated at 70°C for 16 min. Hours, LCMS detection reaction to P8_2 reaction complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify the intermediate P13_2 as a colorless transparent oil (388mg, yield: 75.99%, purity: HPLC>90%). ESI-MS m / z: 338.1[M+H] + .

[0465] Step 2: Synthesis of (R)-1-(4-(trifluoromethyl)sulfonyl)phenyl)pyrrolidine-3-carboxylic acid (P13)

[0466] Intermediate P13_2 (1.15 mmol, 388 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to around 13. Stirring was continued at room temperature for 10 hours. LCMS analysis indicated that the reaction of P13_2 was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P13 as a white solid powder (185 mg, yield: 49.85%, purity: HPLC>90%). ESI-MS m / z: 324.1 [M+H] + .

[0467] Intermediate P14

[0468] (3R)-1-[2-Methylpyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (Intermediate P14)

[0469] Step 1: Synthesis of (3R)-1-[2-methylpyridin-4-yl]tetrahydropyrrole-3-carboxylic acid methyl ester (P14_2)

[0470] The intermediate P8_2 (3.03mmol, 1.0eq, 500mg), the intermediate P14_1 (3.03mmol, 1.0eq, 528mg), and BINAP (0.15mmol, 0.05eq, 48mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then Cs2CO3 (9.09mmol, 3.0eq, 1.71g) was added, and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.08mmol, 0.025eq, 42mg) was added, and the reaction was kept at 70°C and heated for 16 seconds. Hours, LCMS detection reaction to P14_1 reaction complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify the intermediate P14_2 as a colorless transparent oil (564mg, yield: 84.22%, purity: HPLC>90%). ESI-MS m / z: 221.1[M+H] + .

[0471] Step 2: Synthesis of (3R)-1-[2-methylpyridin-4-yl]tetrahydropyrrole-3-carboxylic acid (P14)

[0472] Intermediate P14_2 (2.55 mmol, 564 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 hours. LCMS analysis confirmed that the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P14 as a white solid powder (387 mg, yield: 73.26%, purity: HPLC>90%). ESI-MS m / z: 207.1 [M+H] + .

[0473] Intermediate P15

[0474] (3R)-1-(6,7-Dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl)tetrahydropyrrole-3-carboxylic acid (Intermediate P15)

[0475] Step 1: Synthesis of (3R)-1-(6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl)tetrahydropyrrole-3-carboxylic acid methyl ester (P15_2)

[0476] Intermediate P8_2 (3.03mmol, 1.0eq, 500mg), intermediate P15_1 (3.03mmol, 1.0eq, 600mg), and BINAP (0.15mmol, 0.05eq, 48mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then Cs2CO3 (9.09mmol, 3.0eq, 1.71g) was added, and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.08mmol, 0.025eq, 42mg) was added, and the reaction was kept at 70°C and heated for 16 seconds. Hours, LCMS detection reaction to P15_1 reaction was complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to purify the intermediate P15_2 as a colorless transparent oil (416mg, yield: 55.85%, purity: HPLC>90%). ESI-MS m / z: 247.1[M+H] + .

[0477] Step 2: Synthesis of (3R)-1-(6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl)tetrahydropyrrole-3-carboxylic acid (P15)

[0478] Intermediate P15_2 (1.68 mmol, 416 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 hours. LCMS analysis confirmed that the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P15 as a white solid powder (282 mg, yield: 72.65%, purity: HPLC>90%). ESI-MS m / z: 233.1 [M+H] + .

[0479] Intermediate P16

[0480] (3R)-1-(6,7-Dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl)tetrahydropyrrole-3-carboxylic acid (Intermediate P16)

[0481] Step 1: Synthesis of (3R)-1-(6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl)tetrahydropyrrole-3-carboxylic acid methyl ester (P16_2)

[0482] The intermediate P8_2 (3.03mmol, 1.0eq, 500mg), the intermediate P16_1 (3.03mmol, 1.0eq, 528mg), and BINAP (0.15mmol, 0.05eq, 48mg) were added to a reaction flask, and toluene (10ml) was added to dissolve and stir, and then Cs2CO3 (9.09mmol, 3.0eq, 1.71g) was added and heated in an oil bath at 70°C. After the temperature rose, Pd2(dba)3 (0.08mmol, 0.025eq, 42mg) was added and the reaction was kept heated at 70°C. After 16 hours, LCMS detection showed that the reaction was complete until P16_1 was reacted. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3x20ml) and extracted with ethyl acetate (3x100ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (2x10ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: cyclohexane / ethyl acetate, gradient 10:1 to 1:1) was used to obtain intermediate P16_2 as a colorless, transparent oil (374mg, yield: 55.59%, purity: HPLC>90%). MS m / z=222.1[M+H] + .

[0483] Step 2: Synthesis of (3R)-1-(6,7-dihydro-5H-cyclopenta[1,2-b]pyridin-3-yl)tetrahydropyrrole-3-carboxylic acid (P16)

[0484] Intermediate P16_2 (1.69 mmol, 374 mg) was dissolved in methanol (4.0 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 hours. LCMS analysis confirmed that the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to 5. The solution was concentrated under reduced pressure to dryness and further dried in a vacuum oven to obtain intermediate P16 as a white solid powder (251 mg, yield: 71.65%, purity: HPLC>90%). ESI-MS m / z: 208.1 [M+H] + .

[0485] Intermediate M1

[0486] 2,4-Dichloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine trifluoroacetate (Intermediate M1)

[0487] Trifluoroacetic acid (2 ml) was added dropwise to a solution of intermediate M1_1 (0.36 mmol, 0.1 g) in dichloromethane (5 ml), and the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated and concentrated to obtain M1 as colorless, transparent crystals (101 mg, yield: 96.33%, purity: HPLC>98%). ESI-MS m / z: 190.0 [M+H] + .

[0488] Intermediate M6

[0489] 4-(2-Chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine hydrochloride (Intermediate M6)

[0490] Step 1: Synthesis of tert-butyl 2-chloro-4-morpholinyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidine-6-carboxylate (Intermediate M6_2)

[0491] M1_1 (200 mg, 0.69 mmol, 1 eq) was added to a reaction flask, and 2 mL of 2-isopropanol was added with stirring to dissolve. M6_1 (54 mg, 0.62 mmol, 0.9 eq) and N,N-diisopropylethylamine (DIPEA, 178 mg, 1.38 mmol, 2 eq) were then added sequentially. The mixture was evacuated, replaced with nitrogen three times, and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated, washed three times with saturated ammonium chloride solution, and extracted three times with EA. The organic phase was concentrated and purified by flash column chromatography (PE / EA system, 18% EA) to obtain M6_2 (185 mg, yield: 79%, purity: HPLC>90%) as a white solid. ESI-MS m / z: 341.3 [M+H] + .

[0492] Step 2: Synthesis of 4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)morpholine hydrochloride (Intermediate M6)

[0493] M6_2 (185 mg, 0.54 mmol, 1.0 eq) was added to a reaction flask, and EtOH (2 mL) was added and stirred to dissolve. Hydrochloric acid in ethanol (2 mL) was added dropwise at room temperature. Stirring was continued at room temperature for 2 h, and a white solid gradually precipitated. After completion of the reaction, the product was filtered to obtain a filter cake, M6 (95 mg, yield: 73%, purity: HPLC>90%). ESI-MS m / z: 241.3 [M+H] + .

[0494] Intermediate M7

[0495] 2-Chloro-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M7)

[0496] Step 1: Synthesis of tert-butyl 2-chloro-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine-6-carboxylate (Intermediate M7_2)

[0497] M1_1 (800 mg, 2.76 mmol, 1 eq) was added to a reaction flask, and 2 mL of 2-isopropanol was added with stirring to dissolve. M7_1 (248 mg, 2.48 mmol, 0.9 eq) and N,N-diisopropylethylamine (DIPEA, 711 mg, 5.51 mmol, 2 eq) were then added sequentially. The mixture was evacuated, replaced with nitrogen three times, and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated, washed three times with saturated ammonium chloride solution, and extracted three times with EA. The organic phase was concentrated and purified by flash column chromatography (PE / EA system, 18% EA) to obtain compound M7_2 (794 mg, yield: 82%, purity: HPLC>90%) as a white solid. ESI-MS m / z: 354.3 [M+H] + .

[0498] Step 2: 2-chloro-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M3)

[0499] M7_2 (160 mg, 0.45 mmol, 1.0 eq) was added to a reaction flask, and EtOH (2 mL) was added with stirring to dissolve. Hydrochloric acid in ethanol (2 mL) was added dropwise at room temperature. Stirring was continued at room temperature for 2 h, and a white solid gradually precipitated. After completion of the reaction, as monitored by TLC, filtration afforded the product, M7 (25 mg, yield: 43.18%, purity: HPLC>90%), as a white solid. ESI-MS m / z: 254.3 [M+H] + .

[0500] Intermediate M8

[0501] 4-(4-Methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M8)

[0502] Step 1: Synthesis of tert-butyl 4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine-6-carboxylate (Intermediate M8_2)

[0503] M8_1 (800 mg, 3.12 mmol, 1 eq) was added to a reaction flask, and 8 mL of 2-isopropanol was added with stirring to dissolve. M7_1 (280 mg, 2.84 mmol, 0.9 eq) and N,N-diisopropylethylamine (DIPEA, 800 mg, 6.24 mmol, 2 eq) were then added sequentially. The mixture was evacuated, replaced with nitrogen three times, and stirred at room temperature for 2 h. After completion of the reaction, the reaction solution was concentrated, washed three times with saturated ammonium chloride solution, and extracted three times with EA. The organic phase was concentrated and purified by flash column chromatography (PE / EA system, 18% EA) to obtain compound M8_2 (240 mg, yield: 24%, purity: HPLC>90%) as a white solid. ESI-MS m / z: 320.3 [M+H] + .

[0504] Step 2: 4-(4-Methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M8)

[0505] M8_2 (240 mg, 0.75 mmol, 1.0 eq) was added to a reaction flask, and EtOH (2 mL) was added and stirred to dissolve. Hydrochloric acid in ethanol (2 mL) was added dropwise at room temperature. Stirring was continued at room temperature for 2 h, and a white solid gradually precipitated. After completion of the reaction, the product was filtered to obtain a filter cake, M8 (140 mg, yield: 85%, purity: HPLC>90%). ESI-MS m / z: 220.2 [M+H] + .

[0506] Intermediate M9

[0507] 4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M9)

[0508] Step 1: Synthesis of tert-butyl 4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine-6-carboxylate (Intermediate M9_2)

[0509] M8_1 (100 mg, 0.39 mmol, 1 eq) was added to a reaction flask, and 2 mL of 2-isopropanol was added with stirring to dissolve. M9_1 (64 mg, 0.78 mmol, 2 eq) and N,N-diisopropylethylamine (DIPEA, 152 mg, 1.17 mmol, 3 eq) were then added sequentially. The mixture was evacuated, replaced with nitrogen three times, and heated to 60°C with stirring for 4 h. TLC confirmed the reaction was complete. The product precipitated upon cooling to room temperature. Filtering afforded the filter cake, M9_2 (60 mg, yield: 58%, purity: HPLC >90%), as a white solid. ESI-MS m / z: 265.35 [M+H]+ .

[0510] Step 2: 4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M9)

[0511] M9_2 (60 mg, 0.23 mmol, 1.0 eq) was added to a reaction flask, and EtOH (2 mL) was added and stirred to dissolve. Hydrochloric acid in ethanol (2 mL) was added dropwise at room temperature. Stirring was continued at room temperature for 2 h, and a white solid gradually precipitated. After completion of the reaction, the product was filtered to obtain a filter cake, M9 (45 mg, yield: 100%, purity: HPLC>90%). ESI-MS m / z: 165.26 [M+H] + .

[0512] Intermediate M10

[0513] 2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M10)

[0514] Step 1: Synthesis of tert-butyl 2-chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine-6-carboxylate (Intermediate M10_1)

[0515] M1_1 (100 mg, 0.34 mmol, 1 eq) was added to a reaction flask, and 2 mL of 2-isopropanol was added with stirring to dissolve. M9_1 (56 mg, 0.68 mmol, 2 eq) and N,N-diisopropylethylamine (DIPEA, 133 mg, 1.03 mmol, 3 eq) were then added sequentially. The mixture was evacuated, replaced with nitrogen three times, and heated to 60°C with stirring for 6 h. The reaction was monitored for completion by TLC. Purification by column chromatography (PE / EA system, 20% EA) afforded M10_1 (84 mg, yield: 82%, purity: HPLC >90%) as a white solid. ESI-MS m / z: 299.35 [M+H] + .

[0516] Step 2: 2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M10)

[0517] M10_1 (40 mg, 0.13 mmol, 1.0 eq) was added to a reaction flask, and EtOH (2 mL) was added and stirred to dissolve. Hydrochloric acid in ethanol (2 mL) was added dropwise at room temperature. Stirring was continued at room temperature for 2 h, and a white solid gradually precipitated. After completion of the reaction, TLC monitoring was performed and filtration was performed to obtain the filter cake, which was the product, M10 (30 mg, yield: 97%, purity: HPLC>90%). ESI-MS m / z: 199.29 [M+H] + .

[0518] Intermediate M11

[0519] 2-Chloro-4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M11)

[0520] Step 1: Synthesis of tert-butyl 2-chloro-4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine-6-carboxylate (Intermediate M11_2)

[0521] M1_1 (500 mg, 1.67 mmol, 1 eq) was added to a reaction flask and dissolved in a mixture of ethyl acetate (1 ml) and methanol (1 ml). M11_1 (225 mg, 3.34 mmol, 2 eq) and N,N-diisopropylethylamine (DIPEA, 647 mg, 5.01 mmol, 3 eq) were then added sequentially. The atmosphere was evacuated and replaced with nitrogen three times, and stirred at room temperature for 6 h. The reaction was monitored for completion by TLC. Purification by column chromatography (PE / EA system, 13% EA) afforded M11_2 (341 mg, yield: 72%, purity: HPLC >90%) as a white solid. ESI-MS m / z: 285.34 [M+H] + .

[0522] Step 2: 2-Chloro-4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M11)

[0523] M11_2 (200 mg, 0.70 mmol, 1.0 eq) was added to a reaction flask, and EtOH (2 mL) was added and stirred to dissolve. Hydrochloric acid in ethanol (2 mL) was added dropwise at room temperature. Stirring was continued at room temperature for 2 h, and a white solid gradually precipitated. After completion of the reaction, TLC monitoring was performed, and filtration was performed to obtain the filter cake, which was the product, M11 (150 mg, yield: 97%, purity: HPLC>90%). ESI-MS m / z: 185.29 [M+H] + .

[0524] Intermediate M12

[0525] 4-(Methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M12)

[0526] Step 1: Synthesis of tert-butyl 4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine-6-carboxylate (Intermediate M12_1)

[0527] M8_1 (100 mg, 0.39 mmol, 1 eq) was added to a reaction flask, and 2 mL of 2-isopropanol was added with stirring to dissolve. M11_1 (53 mg, 0.78 mmol, 2 eq) and N,N-diisopropylethylamine (DIPEA, 152 mg, 1.17 mmol, 3 eq) were then added sequentially. The mixture was evacuated, replaced with nitrogen three times, and heated to 60°C with stirring for 4 h. TLC confirmed the reaction was complete. The product precipitated upon cooling to room temperature. Filtration afforded the filter cake, M12_1 (67 mg, yield: 69%, purity: HPLC >90%), as a white solid. ESI-MS m / z: 251.36 [M+H] + .

[0528] Step 2: 4-(Methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidine hydrochloride (Intermediate M12)

[0529] M12_1 (67 mg, 0.36 mmol, 1.0 eq) was added to a reaction flask, and EtOH (2 mL) was added and stirred to dissolve. Hydrochloric acid in ethanol (2 mL) was added dropwise at room temperature. Stirring was continued at room temperature for 2 h, and a white solid gradually precipitated. After completion of the reaction, TLC monitoring was performed, and filtration afforded the product, M12 (27 mg, yield: 55%, purity: HPLC>90%), as a filter cake. ESI-MS m / z: 151.39 [M+H] + .

[0530] Example 1

[0531] 1-(2,4-Dichloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 1)

[0532] Weigh the intermediate P1 (0.12mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NMI (0.42mmol, 3.5eq, 34mg) and stir to dissolve for 15 minutes. Weigh the intermediate M1 (0.12mmol, 1.0eq, 34mg), add and stir to dissolve. Add TCFH (0.13mmol, 1.1eq, 36mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was dropped into purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10ml, three times) and dried at 40°C to obtain yellow solid compound 1 (14mg, yield: 28.19%, purity: HPLC>98%). ESI-MS m / z: 432.1[M+H] + .

[0533] Example 2

[0534] 1-(2-Chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 2)

[0535] Weigh the intermediate P1 (0.12mmol, 1.0eq, 30mg), add analytical grade acetonitrile (2ml) and stir to dissolve, add NMI (0.42mmol, 3.5eq, 34mg) and stir to dissolve for 15 minutes. Weigh the intermediate M2 (0.12mmol, 1.0eq, 21mg), add and stir to dissolve. Add TCFH (0.13mmol, 1.1eq, 36mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then thoroughly washed with purified water (10ml, three times) and dried at 40°C to obtain a yellow solid compound (28mg, yield: 61.19%, purity: HPLC>98%). ESI-MS m / z: 398.1[M+H] + . 1H NMR (400MHz, DMSO-d6) δ8.79–8.74(m,1H),8.20(d,J=5.7Hz,1H),6.70(d,J=2.2Hz,1H),6.52(dd,J=5.7,2.3Hz,1H),4.89(td,J=2.5,1.2Hz ,2H),4.66(dd,J=15.8,1.7Hz,2H),4.17(t,J=8.2Hz,2H),3.70(ddd,J=8.3,5.7,2.0Hz,2H),3.20–3.06(m,1H),2.85(dd,J=7.7,3.5Hz,2H).

[0536] Example 3

[0537] 1-(2-Chloro-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 3)

[0538] Intermediate P1 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytically pure acetonitrile (2 ml) with stirring and dissolving. NMI (0.42 mmol, 3.5 eq, 34 mg) was added and stirred and dissolved for 15 minutes. Intermediate M3 hydrochloride (0.12 mmol, 1.0 eq, 21 mg) was weighed and added and stirred and dissolved. TCFH (0.13 mmol, 1.1 eq, 36 mg) was added and stirred and dissolved. Stirred at room temperature for 4 hours. The reaction solution was added dropwise to purified water (20 ml), then extracted with dichloromethane (20 ml). The organic phase was dried over sodium sulfate and evaporated to a droplet-free state. Column chromatography (SiO2, eluent: dichloromethane / methanol, gradient 1:0 to 15:1) gave compound 3 as a colorless, transparent oil (12 mg, yield: 26.61%, yield: HPLC>98%). ESI-MS m / z:392.30[M+H] + .

[0539] Example 4

[0540] 1-(2-Chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 4)

[0541] Weigh the intermediate P2 (0.13mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NMI (0.46mmol, 3.5eq, 38mg) and stir to dissolve for 15 minutes. Weigh the intermediate M2 (0.13mmol, 1.0eq, 25mg), add and stir to dissolve. Add TCFH (0.14mmol, 1.1eq, 39mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was dropped into purified water (10ml) for crystallization, and then filtered after standing for 10 minutes. The filter cake was then washed thoroughly with purified water (10ml, three times) and dried at 40°C to obtain compound 4 as a white solid powder (36mg, yield: 74.78%, purity: HPLC>98%). ESI-MS m / z: 366.24[M+H] + . 1 H NMR (400MHz, CDCl3) δ8.67–8.56(m,1H),7.57(dd,J=16.3,5.5Hz,1H),6.15(t,J=5.7Hz,1H),4.91(q,J=1.7Hz,1H),4.88–4 .79(m,3H),4.43(td,J=8.3,2.3Hz,2H),3.90(ddt,J=9.3,6.2,3.1Hz,2H),3.34–3.21(m,1H),2.84(dd,J=7.8,2.4Hz,2H).

[0542] Example 5

[0543] 1-(2,4-Dichloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 5)

[0544] Weigh the intermediate P2 (0.13mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NM1 (0.46mmol, 3.5eq, 38mg) and stir to dissolve for 15 minutes. Weigh the intermediate M1 (0.13mmol, 1.0eq, 29mg), add and stir to dissolve. Add TCFH (0.14mmol, 1.1eq, 39mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was dropped into purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then thoroughly washed with purified water (10ml, three times) and dried at 40°C to obtain compound 5 as a white solid powder (18mg, yield: 34.20%, purity: HPLC>98%). ESI-MS m / z: 400.16[M+H] + .1 H NMR (400MHz, CDCl3) δ7.60(d,J=5.6Hz,1H),6.16(t,J=5.7Hz,1H),4.88(p,J=2.4,1.9Hz,3H),4.84(d,J=2.2 Hz,1H),4.43(td,J=8.2,2.2Hz,2H),3.94–3.86(m,2H),3.29(p,J=6.5Hz,1H),2.84(dd,J=15.5,7.7Hz,2H).

[0545] Example 6

[0546] 2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]-1-(6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)ethan-1-one (Compound 6)

[0547] Weigh the intermediate P2 (0.13mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NM1 (0.46mmol, 3.5eq, 38mg) and stir to dissolve for 15 minutes. Weigh the intermediate M4 (0.13mmol, 1.0eq, 20mg), add and stir to dissolve. Add TCFH (0.14mmol, 1.1eq, 39mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was dropped into purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10ml, three times) and dried at 40°C to obtain compound 6 as a white solid powder (25mg, yield: 57.48%, purity: HPLC>98%). ESI-MS m / z: 332.25[M+H] + . 1 H NMR (400MHz, CDCl3) δ9.17(d,J=5.7Hz,1H),8.78–8.69(m,1H),7.56(d,J=5.6Hz,1H),6.14(t,J=5.7Hz,1H),4.95–4.90(m,1H),4.89– 4.80 (m, 3H), 4.41 (td, J = 8.3, 2.3Hz, 2H), 3.89 (dtd, J = 7.8, 5.3, 2.2Hz, 2H), 3.28 (tdd, J = 10.4, 7.9, 4.0Hz, 1H), 2.84 (d, J = 7.7Hz, 2H).

[0548] Example 7

[0549] 2-[1-(Pyridin-2-yl)azetidin-3-yl]-1-(5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl)ethan-1-one (Compound 7)

[0550] Intermediate P3 (0.16 mmol, 1.0 eq, 30 mg) was weighed and dissolved in analytically pure acetonitrile (2 ml). NMI (0.54 mmol, 3.5 eq, 45 mg) was added and stirred for 15 minutes. Intermediate M5 free base (0.16 mmol, 1.0 eq, 21 mg) was weighed and added and dissolved. TCFH (0.17 mmol, 1.1 eq, 48 mg) was added and dissolved. The mixture was stirred at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 minutes, it was filtered and the filter cake was washed thoroughly with purified water (10 ml, three times) and dried at 40°C to obtain a yellow solid. Compound 7 was purified by column chromatography (SiO2, eluent: dichloromethane / methanol, gradient 1:0 to 80:1) to obtain compound 7 as a colorless, transparent oil (35.4 mg, yield: 72.64%, purity: HPLC>95%). ESI-MS m / z:310.27[M+H] + . 1 H NMR

[0551] Example 8

[0552] 1-(2-chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-(1-{4-[dioxy-(trifluoromethyl)-λ 6 -thio]phenyl}azetidin-3-yl)ethan-1-one (Compound 8)

[0553] Weigh the intermediate P4 (0.09mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NMI (0.31mmol, 3.5eq, 25mg) and stir to dissolve for 15 minutes. Weigh the intermediate M2 (0.09mmol, 1.0eq, 17mg), add and stir to dissolve. Add TCFH (0.10mmol, 1.1eq, 28mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was dropped into purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10ml, three times) and dried at 40°C to obtain compound 8 as a yellow solid (10.6mg, yield: 24.83%, purity: HPLC>95%). ESI-MS m / z: 461.29[M+H] + . 1H NMR (400MHz, CDCl3) δ8.74–8.53(m,1H),7.88–7.69(m,2H),6.49–6.29(m,2H),4.97–4.74(m,4H),4.34(t, J=8.4Hz, 2H), 3.81 (dt, J=8.7, 6.0Hz, 2H), 3.34 (tdt, J=10.5, 7.7, 3.7Hz, 1H), 2.84 (dd, J=7.6, 1.9Hz, 2H).

[0554] Example 9

[0555] 1-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(3-fluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 9)

[0556] P5 (0.14 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) with stirring and dissolving. NM1 (0.49 mmol, 3.5 eq, 40 mg) was added and stirred and dissolved for 15 min. M2 (0.14 mmol, 1.0 eq, 27 mg) was weighed and added and stirred and dissolved. TCFH (0.15 mmol, 1.1 eq, 42 mg) was added and stirred and dissolved. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 9 (25 mg, yield: 50.52%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 348.29 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.79(d,J=13.3Hz,1H),8.54(d,J=6.8Hz,1H),8.15(d,J=6.8Hz,1H),6.76(dd,J=8.6,6.8Hz,1H ), 4.89 (d, J = 2.3Hz, 2H), 4.67 (s, 1H), 4.64 (s, 1H), 4.53 (s, 2H), 4.11 (s, 2H), 3.19–3.14 (m, 1H), 2.90 (t, J = 6.8Hz, 2H).

[0557] Example 10

[0558] 1-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(3,5-difluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 10)

[0559] P6 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NM1 (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M2 (0.13 mmol, 1.0 eq, 25 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 10 (19 mg, yield: 39.63%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 366.36 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.77(d,J=8.9Hz,1H),8.08(d,J=1.4Hz,2H),4.90–4.87(m,2H),4.65(d,J=17.3 Hz,2H),4.44(tt,J=8.4,2.7Hz,2H),4.06–3.99(m,2H),3.10–3.03(m,1H),2.85(dd,J=7.7,4.0Hz,2H).

[0560] Example 11

[0561] 1-(2-Chloro-4-morpholinyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidin-6-yl)2-(1-(2,3-difluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 11)

[0562] P2 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytically pure acetonitrile (2 ml) and stirred to dissolve. NM1 (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M6 (0.13 mmol, 1.0 eq, 36 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 11 (21 mg, yield: 35.54%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 451.33 [M+H] + .1 H NMR (600MHz, DMSO-d6) δ7.58(d,J=5.3Hz,1H),6.43(q,J=5.4Hz,1H),4.98(s,1H),4.76(s,1H),4.66(s,1H),4.40(s,1H) ,4.31–4.27(m,2H),3.84(s,2H),3.66(dt,J=15.3,5.0Hz,8H),3.09(s,1H),2.87(d,J=7.7Hz,1H),2.83(d,J=7.7Hz,1H).

[0563] Example 12

[0564] 1-(2-Chloro-4-(4-methylpiperazin-1-yl)-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(2,3-difluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 12)

[0565] P2 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytically pure acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M7 (0.13 mmol, 1.0 eq, 38 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 12 as a white solid powder (25 mg, yield: 41.22%, purity: HPLC>95%). ESI-MS m / z: 464.50 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ7.58 (dd, J=5.7, 2.1Hz, 1H), 6.42 (q, J=5.8Hz, 1H), 4. 97(d,J=2.1Hz,1H),4.74(t,J=2.1Hz,1H),4.65(t,J=2.0Hz,1H),4.39(d,J=2. 1Hz,1H),4.33–4.25(m,2H),3.84(t,J=6.8Hz,2H),3.67–3.62(m,4H),3.08(s, 1H), 2.88 (d, J = 7.7Hz, 1H), 2.82 (d, J = 7.7Hz, 1H), 2.39 (td, J = 5.0, 2.7Hz, 4H).

[0566] Example 13

[0567] 1-(2-Chloro-4-morpholinyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidin-6-yl)2-(1-(3-fluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 13)

[0568] P5 (0.14 mmol, 1.0 eq, 30 mg) was weighed and added to analytically pure acetonitrile (2 ml) and stirred to dissolve. NMI (0.49 mmol, 3.5 eq, 40 mg) was added and stirred to dissolve for 15 min. M6 (0.14 mmol, 1.0 eq, 40 mg) was weighed and added and stirred to dissolve. TCFH (0.15 mmol, 1.1 eq, 42 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40 ° C to obtain compound 13 as a white solid powder (18 mg, yield: 28.98%, purity: HPLC>95%). ESI-MS m / z: 433.50 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.10(s,1H),7.98(d,J=5.4Hz,1H),6.47(dt,J=9.7,4.9Hz,1H),4.98(s,1H),4.76(s,1H),4.66(s,1H) ,4.40(s,1H),4.22(q,J=7.9Hz,2H),3.76(s,2H),3.69–3.62(m,8H),3.07(s,1H),2.86(d,J=7.7Hz,1H),2.82(d,J=7.7Hz,1H).

[0569] Example 14

[0570] 1-(2-Chloro-4-morpholinyl-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidin-6-yl)2-(1-(3,5-difluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 14)

[0571] P6 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M6 (0.13 mmol, 1.0 eq, 36 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 14 (21 mg, yield: 35.69%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 451.33 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.07(d,J=2.5Hz,2H),4.97(s,1H),4.75(s,1H),4.65(s,1H),4.48–4.42(m,2H),4.41(d,J=12.8Hz,1H),4 .01(dp,J=11.1,3.7,3.1Hz,2H),3.66(dq,J=15.5,5.2Hz,8H),3.07(p,J=7.3Hz,1H),2.87(d,J=7.6Hz,1H),2.82(d,J=7.7Hz,1H).

[0572] Example 15

[0573] 1-(2-Chloro-4-(4-methylpiperazin-1-yl)-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(3-fluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 15)

[0574] P5 (0.14 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.49 mmol, 3.5 eq, 40 mg) was added and stirred to dissolve for 15 min. M7 (0.14 mmol, 1.0 eq, 40 mg) was weighed and added and stirred to dissolve. TCFH (0.15 mmol, 1.1 eq, 42 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 15 as a white solid powder (31 mg, yield: 48.89%, purity: HPLC>95%). ESI-MS m / z: 446.47 [M+H]+ . 1 H NMR(600MHz,DMSO-d6)δ8.10(dd,J=4.6,2.5Hz,1H),8.00–7.96(m,1H),6.47(dt,J=8.3,5.2 Hz,1H),4.97(t,J=2.1Hz,1H),4.74(t,J=2.0Hz,1H),4.65(t,J=1.9Hz,1H),4.39(d,J=2.1Hz ,1H),4.22(qd,J=8.0,2.1Hz,2H),3.77(ddd,J=8.0,5.7,1.9Hz,2H),3.64(dd,J=9.4,5.3Hz ,4H),3.10–3.03(m,1H),2.87(d,J=7.7Hz,1H),2.81(d,J=7.7Hz,1H),2.39(t,J=5.1Hz,4H).

[0575] Example 16

[0576] 1-(2-Chloro-4-(4-methylpiperazin-1-yl)-5,7-dihydro-6-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(3,5-difluoropyridin-4-yl)azetidin-3-yl)ethan-1-one (Compound 16)

[0577] P6 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M7 (0.13 mmol, 1.0 eq, 38 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 16 (26 mg, yield: 42.77%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 464.44 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.09–8.06(m,2H),4.96(d,J=2.5Hz,1H),4.73(s,1H),4.66–4.62(m,1H),4.48–4.40(m,2H),4.38(s,1H),4.02(d dd,J=8.8,5.9,2.8Hz,2H),3.64(q,J=5.3Hz,4H),3.10–3.04(m,1H),2.88(d,J=7.6Hz,1H),2.81(d,J=7.6Hz,1H),2.39(q,J=4.6Hz,4H).

[0578] Example 17

[0579] 1-(2-Chloro-4-morpholinyl-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 17)

[0580] Weigh the intermediate P1 (0.12mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NMI (0.42mmol, 3.5eq, 34mg) and stir to dissolve for 15 minutes. Weigh the intermediate M6 (0.12mmol, 1.0eq, 32mg), add and stir to dissolve. Add TCFH (0.13mmol, 1.1eq, 36mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10ml, three times) and dried at 40°C to obtain yellow solid compound 17 (17mg, yield: 30.50%, purity: HPLC>98%). ESI-MS m / z: 483.45[M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.21 (dd, J=5.7, 1.5Hz, 1H), 6.71 (dd, J=4.2, 2.3Hz, 1H) ,6.53(ddd,J=6.0,3.8,2.3Hz,1H),4.98(t,J=2.1Hz,1H),4.76(t,J=2.0Hz,1H), 4.66(t,J=2.0Hz,1H),4.40(d,J=2.1Hz,1H),4.16(q,J=8.0Hz,2H),3.71–3.62( m, 8H), 3.11 (td, J = 7.8, 5.8Hz, 1H), 2.86 (d, J = 7.7Hz, 2H), 2.82 (d, J = 7.7Hz, 2H).

[0581] Example 18

[0582] 1-(2-Chloro-4-methylpiperazinyl-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 18)

[0583] Weigh the intermediate P1 (0.12mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NMI (0.42mmol, 3.5eq, 34mg) and stir to dissolve for 15 minutes. Weigh the intermediate M7 (0.12mmol, 1.0eq, 34mg), add and stir to dissolve. Add TCFH (0.13mmol, 1.1eq, 36mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution is added dropwise to purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake is then thoroughly washed with purified water (10ml, three times) and dried at 40°C to obtain yellow solid compound 18 (31mg, yield: 48.35%, purity: HPLC>95%). ESI-MS m / z: 496.34[M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.21(dd,J=5.7,1.7Hz,1H),6.71(dd,J=5.1,2.3Hz,1H),6.5 3(td,J=5.2,2.3Hz,1H),4.97(t,J=2.1Hz,1H),4.74(t,J=2.0Hz,1H),4.65(t,J=2.0 Hz,1H),4.39(d,J=2.0Hz,1H),4.16(q,J=8.1Hz,2H),3.71–3.62(m,4H),3.10(tt,J= 11.9, 4.0Hz, 1H), 2.87 (d, J = 7.7Hz, 1H), 2.81 (d, J = 7.7Hz, 1H), 2.39 (t, J = 5.0Hz, 4H).

[0584] Example 19

[0585] [2-Chloro-4-(1,4-oxazepan-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl][(3S)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydro-1H-pyrrol-3-yl]methanone (Compound 19)

[0586] P7 (0.12 mmol, 1.0 eq, 30 mg) was weighed, analytical grade acetonitrile (2 ml) was added and stirred to dissolve, NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M6 (0.12 mmol, 1.0 eq, 32 mg) was weighed, added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve, and stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain white solid compound 19 (27 mg, yield: 36.37%, purity: HPLC>95%). ESI-MS m / z: 483.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.22(t,J=5.2Hz,1H),6.86(dd,J=6.2,2.0Hz,1H),6.69(dd,J=5.8,2.1Hz,1H),5.1 7–5.02(m,1H),4.88–4.75(m,2H),4.44(s,1H),3.74–3.65(m,8H),3.63–3.37(m,5H),2.34–2.09(m,2H).

[0587] Example 20

[0588] [2-Chloro-4-(1,4-oxazepan-4-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl][(3R)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydro-1H-pyrrol-3-yl]methanone (Compound 20)

[0589] Weigh P8 (0.12 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.46 mmol, 3.5 eq, 38 mg) and stir to dissolve for 15 min. Weigh M6 (0.12 mmol, 1.0 eq, 32 mg), add and stir to dissolve. Add TCFH (0.14 mmol, 1.1 eq, 39 mg) and stir to dissolve, and stir at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain white solid compound 20 (14 mg, yield: 19.25%, purity: HPLC> 95%). ESI-MS m / z: 483.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.22(t,J=5.2Hz,1H),6.86(dd,J=6.3,2.2Hz,1H),6.69(dd,J=5.8,2.2Hz,1H),5.1 7–5.04(m,1H),4.88–4.71(m,2H),4.44(s,1H),3.74–3.62(m,8H),3.64–3.36(m,5H),2.33–2.11(m,2H).

[0590] Example 21

[0591] [2-Chloro-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl][(3S)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydro-1H-pyrrol-3-yl]methanone (Compound 21)

[0592] Weigh P7 (0.12 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.46 mmol, 3.5 eq, 38 mg) and stir to dissolve for 15 min. Weigh M7 (0.12 mmol, 1.0 eq, 33 mg), add and stir to dissolve. Add TCFH (0.14 mmol, 1.1 eq, 39 mg) and stir to dissolve, and stir at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain white solid compound 21 (22 mg, yield: 34.03%, purity: HPLC>95%). ESI-MS m / z: 496.34 [M+H] + .

[0593] Example 22

[0594] [2-Chloro-4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl][(3R)-1-[2-(trifluoromethyl)pyridin-4-yl]tetrahydro-1H-pyrrol-3-yl]methanone (Compound 22)

[0595] P7 (0.12 mmol, 1.0 eq, 30 mg) was weighed, analytical grade acetonitrile (2 ml) was added and stirred to dissolve, NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M8 (0.12 mmol, 1.0 eq, 33 mg) was weighed, added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve, and stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain white solid compound 22 (12 mg, yield: 16.23%, purity: HPLC>95%). ESI-MS m / z: 496.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.27–8.08(m,1H),6.86(dd,J=4.5,2.3Hz,1H),6.69(dd,J=5.8,2.1Hz,1H),5.16– 5.05(m,1H),4.88–4.71(m,2H),4.43(s,1H),3.74–3.40(m,9H),2.43–2.34(m,4H),2.33–2.10(m,5H).

[0596] Example 23

[0597] 1-(2-Chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-[1-(2-methoxypyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 23)

[0598] P9 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M2 (0.13 mmol, 1.0 eq, 25 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40 ° C to obtain compound 23 as a white solid powder (26 mg, yield: 53.83%, purity: HPLC>95%). ESI-MS m / z: 360.36 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.77(d,J=6.8Hz,1H),7.76(d,J=5.9Hz,1H),6.09(dd,J=5.9,1.7Hz,1H),5.68(s,1H),4.88(d,J=12.4Hz, 2H),4.65(d,J=17.4Hz,2H),4.12–4.02(m,2H),3.78(s,3H),3.66–3.53(m,2H),3.15–2.94(m,1H),2.83(dd,J=7.6,4.0Hz,2H).

[0599] Example 24

[0600] 1-(2-Chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-[1-(2-methylpyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 24)

[0601] Weigh P10 (0.13 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve. Add NMI (0.46 mmol, 3.5 eq, 38 mg) and stir to dissolve for 15 min. Weigh M2 (0.13 mmol, 1.0 eq, 25 mg), add and stir to dissolve. Add TCFH (0.14 mmol, 1.1 eq, 39 mg) and stir to dissolve. Stir at room temperature for 4 h. The reaction solution is added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it is filtered and then washed with purified water (10 ml, three times). The filter cake is dried at 40 ° C to obtain compound 24 (28 mg, yield: 64.09%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 344.33 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.78(d,J=11.0Hz,1H),8.10–8.04(m,1H),6.55–6.50(m,2H),4.89(s,2H),4.66(d,J =17.4Hz,2H),4.33(t,J=7.8Hz,2H),3.89(s,2H),3.20–3.10(m,1H),2.88(t,J=7.2Hz,2H),2.43(s,3H).

[0602] Example 25

[0603] 1-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)-2-(1-(6-methylpyridazin-3-yl)azetidin-3-yl)ethan-1-one (Compound 25)

[0604] Weigh P11 (0.13 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve. Add NMI (0.46 mmol, 3.5 eq, 38 mg) and stir to dissolve for 15 min. Weigh M2 (0.13 mmol, 1.0 eq, 25 mg), add and stir to dissolve. Add TCFH (0.14 mmol, 1.1 eq, 39 mg) and stir to dissolve. Stir at room temperature for 4 h. The reaction solution is added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it is filtered and then thoroughly washed with purified water (10 ml, three times). The filter cake is dried at 40 ° C to obtain white solid powder compound 25 (35 mg, yield: 69.86%, purity: HPLC>95%). ESI-MS m / z: 345.33 [M+H] + . 1H NMR (600MHz, DMSO) δ8.77(d,J=4.5Hz,1H),7.24(d,J=9.1Hz,1H),6.73(d,J=9.0Hz,1H),4.90(d,J=2.9Hz,2H),4.66(d,J=17. 0Hz, 2H), 4.15 (t, J = 8.0Hz, 2H), 3.72–3.66 (m, 2H), 3.18–3.01 (m, 1H), 2.84 (dd, J = 7.6, 3.9Hz, 2H), 2.41 (s, 3H), 1.23 (s, 1H).

[0605] Example 26

[0606] 1-[2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2-methylpyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 26)

[0607] P10 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytically pure acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M10 (0.13 mmol, 1.0 eq, 26 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 26 (27 mg, yield: 48.26%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 387.32 [M+H] + . 1 H NMR(600MHz,DMSO)δ8.07(d,J=7.8Hz,1H),6.53–6.48(m,2H),5.12–4.83(m,2H),4.67–4.35(m,2H),4.34 –4.27(m,2H),3.86(dd,J=9.3,5.8Hz,2H),3.18–3.10(m,7H),2.86(dd,J=22.7,7.7Hz,2H),2.41(s,3H).

[0608] Example 27

[0609] 2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]-1-[4-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 27)

[0610] P2 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M8 (0.12 mmol, 1.0 eq, 33 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 27 (35 mg, yield: 62%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 430.32 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.52(s,1H),7.59(dt,J=7.9,3.9Hz,1H),6.47–6.39(m,1H),5.02(s,1H),4.81(s,1H),4.71(s,1H),4.44(s, 1H), 4.31 (dd, J=19.0, 9.6Hz, 2H), 3.87–3.83 (m, 2H), 3.78 (s, 4H), 3.19–3.08 (m, 5H), 2.88 (dd, J=20.0, 7.7Hz, 2H), 2.71 (s, 3H).

[0611] Example 28

[0612] 2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]-1-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 28)

[0613] P2 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M9 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 28 (48 mg, yield: 89%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 375.30 [M+H] + . 1 H NMR(600MHz,DMSO)δ8.39(s,1H),7.58(d,J=5.6Hz,1H),6.45–6.38(m,1H),5.12(s,1H),4.89(s,1H),4.64(s,1H),4.3 9(s,1H),4.32–4.26(m,2H),3.85(t,J=6.3Hz,2H),3.17–3.13(m,6H),3.09(tt,J=21.6,6.9Hz,1H),2.91–2.80(m,2H).

[0614] Example 29

[0615] 1-[2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 29)

[0616] P2 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M10 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 29 (42 mg, yield: 85.35%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 409.22 [M+H] + . 1H NMR (600MHz, DMSO) δ7.58(d,J=5.6Hz,1H),6.43(td,J=5.9,3.0Hz,1H),5.10(s,1H),4.86(s,1H),4.63(s,1H),4.38( s,1H),4.33–4.25(m,2H),3.90–3.77(m,2H),3.15(d,J=2.7Hz,6H),3.11–3.06(m,1H),2.84(dd,J=27.5,7.7Hz,2H).

[0617] Example 30

[0618] (2-Chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)[(3R)-1-(2-methoxypyridin-4-yl)tetrahydro-1H-pyrrol-3-yl]methanone (Compound 30)

[0619] Weigh P12 (0.14 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.49 mmol, 3.5 eq, 40 mg) and stir to dissolve for 15 min. Weigh M2 (0.14 mmol, 1.0 eq, 27 mg), add and stir to dissolve. Add TCFH (0.16 mmol, 1.1 eq, 45 mg) and stir to dissolve, and stir at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain white solid compound 30 (24 mg, yield: 50.53%, purity: HPLC>95%). ESI-MS m / z: 360.40 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.78(d,J=6.2Hz,1H),7.78(d,J=6.2Hz,1H),6.30(d,J=6.0Hz,1H),5.85(s,1H),5.76(s,2H) ,5.11–4.96(m,2H),4.69(d,J=16.2Hz,2H),3.81(s,3H),3.65–3.57(m,1H),3.53–3.46(m,2H),2.34–2.07(m,2H).

[0620] Example 31

[0621] 1-[2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2-methoxypyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 31)

[0622] P9 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M10 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 31 (31 mg, yield: 57.32%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 403.32 [M+H] + . 1 H NMR (600MHz, DMSO) δ7.74(d,J=5.8Hz,1H),6.06(d,J=5.8Hz,1H),5.62(s,1H),5.09(s,1H),4.86(s,1H),4.63(s,1H),4.3 8(s,1H),4.06–3.99(m,2H),3.74(s,3H),3.58–3.53(m,2H),3.15(s,6H),3.08–3.01(m,1H),2.80(dd,J=25.9,7.7Hz,2H).

[0623] Example 32

[0624] 1-[2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(6-methyl-1,2-diazepin-3-yl)azetidin-3-yl]ethan-1-one (Compound 32)

[0625] Weigh P11 (0.13 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve. Add NMI (0.46 mmol, 3.5 eq, 38 mg) and stir to dissolve for 15 min. Weigh M10 (0.13 mmol, 1.0 eq, 30 mg), add and stir to dissolve. Add TCFH (0.14 mmol, 1.1 eq, 39 mg) and stir to dissolve. Stir at room temperature for 4 h. The reaction solution is added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it is filtered and then washed thoroughly with purified water (10 ml, three times). The filter cake is dried at 40°C to obtain compound 32 (13 mg, yield: 23.29%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 388.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ7.24(dd,J=9.1,0.8Hz,1H),6.72(dd,J=9.0,2.5Hz,1H),5.10(s,1H),4.87(s,1H),4.64(s,1H),4.38(s,1 H),4.14(td,J=8.0,4.5Hz,2H),3.72–3.65(m,2H),3.15(s,6H),3.11–3.04(m,1H),2.82(dd,J=26.0,7.7Hz,2H),2.41(s,3H).

[0626] Example 33

[0627] 1-[2-Chloro-4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3-fluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 33)

[0628] P5 (0.14 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.49 mmol, 3.5 eq, 40 mg) was added and stirred to dissolve for 15 min. M11 (0.14 mmol, 1.0 eq, 32 mg) was weighed and added and stirred to dissolve. TCFH (0.15 mmol, 1.1 eq, 42 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 33 as a white solid powder (38 mg, yield: 48.89%, purity: HPLC>95%). ESI-MS m / z: 377.34 [M+H] + .1 H NMR (600MHz, DMSO) δ8.10(d,J=4.5Hz,1H),7.98(d,J=5.3Hz,1H),7.91–7.83(m,1H),6.47(dd,J=8.3,5.4Hz,1H),4.63(s,1H),4.56(s,1H),4 .56(s,1H),4.37(dd,J=20.7,6.5Hz,2H),4.26–4.19(m,2H),3.81–3.72(m,2H),3.12–3.01(m,1H),2.85(d,J=4.4Hz,3H),2.82–2.71(m,2H).

[0629] Example 34

[0630] 1-[2-Chloro-4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3,5-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 34)

[0631] P6 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M11 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 34 (35 mg, yield: 67.51%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 395.44 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.10–8.05(m,2H),7.90–7.81(m,1H),4.63(s,1H),4.56(s,1H),4.47–4.42(m,2H),4.38 (d,J=21.3Hz,2H),4.06–3.99(m,2H),3.12–3.00(m,1H),2.85(d,J=4.8Hz,3H),2.80(dd,J=7.6,3.9Hz,2H).

[0632] Example 35

[0633] 1-[2-Chloro-4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 35)

[0634] P2 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M11 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 35 (29 mg, yield: 55.94%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 395.44 [M+H] + . 1 H NMR (600MHz, DMSO) δ7.90–7.79(m,1H),7.58(d,J=5.6Hz,1H),6.44–6.39(m,1H),4.64(s,1H),4.57(s,1H),4.40(s,1H), 4.36(s,1H),4.32–4.26(m,2H),3.87–3.79(m,2H),3.13–3.04(m,1H),2.85(d,J=4.7Hz,3H),2.81(dd,J=7.6,4.3Hz,2H).

[0635] Example 36

[0636] 1-[2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-(1-{4-[dioxyylidene(trifluoromethyl)-λ6-thio]phenyl}azetidin-3-yl)ethan-1-one (Compound 36)

[0637] Weigh the intermediate P4 (0.09mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NMI (0.31mmol, 3.5eq, 25mg) and stir to dissolve for 15 minutes. Weigh the intermediate M10 (0.09mmol, 1.0eq, 29mg), add and stir to dissolve. Add TCFH (0.10mmol, 1.1eq, 28mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then thoroughly washed with purified water (10ml, three times) and dried at 40°C to obtain compound 36 as a yellow solid (40mg, yield: 85.54%, purity: HPLC>95%). ESI-MS m / z: 504.3[M+H] + . 1 H NMR (600MHz, DMSO) δ7.72(d,J=8.7Hz,2H),6.58(dd,J=9.1,2.2Hz,2H),5.10(s,1H),4.87(s,1H),4.64(s,1H),4.39( s,1H),4.27–4.18(m,2H),3.76(dd,J=8.5,5.8Hz,2H),3.15(s,6H),3.13–3.07(m,1H),2.86(dd,J=23.9,7.7Hz,2H).

[0638] Example 37

[0639] 1-[2-Chloro-4-(methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-(1-{4-[dioxyylidene(trifluoromethyl)-λ6-thio]phenyl}azetidin-3-yl)ethan-1-one (Compound 37)

[0640] Weigh the intermediate P4 (0.09mmol, 1.0eq, 30mg), add analytically pure acetonitrile (2ml) and stir to dissolve, add NMI (0.31mmol, 3.5eq, 25mg) and stir to dissolve for 15 minutes. Weigh the intermediate M11 (0.09mmol, 1.0eq, 28mg), add and stir to dissolve. Add TCFH (0.10mmol, 1.1eq, 28mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10ml, three times) and dried at 40°C to obtain compound 37 as a yellow solid (27mg, yield: 59.32%, purity: HPLC>95%). ESI-MS m / z: 490.34[M+H] + .1 H NMR (600MHz, DMSO) δ7.91–7.82(m,1H),7.72(dd,J=9.0,2.8Hz,2H),6.58(d,J=9.0Hz,2H),4.64(s,1H),4.57 (s,1H),4.39(d,J=20.6Hz,2H),4.27–4.18(m,2H),3.80–3.72(m,2H),3.17–3.04(m,1H),2.89–2.80(m,5H).

[0641] Example 38

[0642] (R)-(2-Chloro-4-(dimethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(4-((trifluoromethyl)sulfonyl)phenyl)pyrrolidin-3-yl)methanone (Compound 38)

[0643] Weigh the intermediate P13 (0.09 mmol, 1.0 eq, 30 mg), add analytically pure acetonitrile (2 ml) and stir to dissolve, add NMI (0.31 mmol, 3.5 eq, 25 mg) and stir to dissolve for 15 minutes. Weigh the intermediate M10 (0.09 mmol, 1.0 eq, 29 mg), add and stir to dissolve. Add TCFH (0.10 mmol, 1.1 eq, 28 mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain compound 38 as a yellow solid (37 mg, yield: 79.28%, purity: HPLC> 95%). ESI-MS m / z: 504.3 [M+H] + . 1 H NMR (600MHz, DMSO) δ7.75 (dd, J=9.1, 3.9Hz, 2H), 6.85–6.77 (m, 2H), 5.23 (q, J=13.3Hz, 1H), 4.91 (s, 1H), 4.80 ( q,J=15.8Hz,1H),4.42(s,1H),3.79–3.67(m,1H),3.64–3.43(m,4H),3.16(d,J=10.3Hz,6H),2.38–2.11(m,2H).

[0644] Example 39

[0645] (R)-(2-Chloro-4-(methylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(4-((trifluoromethyl)sulfonyl)phenyl)pyrrolidin-3-yl)methanone (Compound 39)

[0646] Weigh the intermediate P13 (0.09 mmol, 1.0 eq, 30 mg), add analytically pure acetonitrile (2 ml) and stir to dissolve, add NMI (0.31 mmol, 3.5 eq, 25 mg) and stir to dissolve for 15 minutes. Weigh the intermediate M11 (0.09 mmol, 1.0 eq, 28 mg), add and stir to dissolve. Add TCFH (0.10 mmol, 1.1 eq, 28 mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain compound 39 as a yellow solid (32 mg, yield: 70.53%, purity: HPLC> 95%). ESI-MS m / z: 490.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ7.97–7.79(m,1H),7.79–7.71(m,2H),6.82(dd,J=9.1,3.3Hz,2H),4.87–4.6 1(m,2H),4.45(s,1H),4.41(s,1H),3.76–3.39(m,5H),2.85(d,J=4.4Hz,3H),2.36–2.14(m,2H).

[0647] Example 40

[0648] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-(1-{4-[dioxyylidene(trifluoromethyl)-λ6-thio]phenyl}azetidin-3-yl)ethan-1-one (Compound 40)

[0649] Weigh the intermediate P4 (0.09 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.31 mmol, 3.5 eq, 25 mg) and stir to dissolve for 15 minutes. Weigh the intermediate M9 (0.09 mmol, 1.0 eq, 18 mg), add and stir to dissolve. Add TCFH (0.10 mmol, 1.1 eq, 28 mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain compound 40 as a yellow solid (27 mg, yield: 62.04%, purity: HPLC> 95%). ESI-MS m / z: 470.34 [M+H] + . 1 H NMR(600MHz,DMSO)δ8.39(s,1H),7.75–7.67(m,2H),6.58(dd,J=9.0,1.8Hz,2H),5.13(s,1H),4.90(s,1H),4.64(s,1 H),4.39(s,1H),4.27–4.17(m,2H),3.80–3.72(m,2H),3.15(s,6H),3.14–3.09(m,1H),2.87(dd,J=20.3,7.7Hz,2H).

[0650] Example 41

[0651] (R)-(4-(Dimethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(4-((trifluoromethyl)sulfonyl)phenyl)pyrrolidin-3-yl)methanone (Compound 41)

[0652] Weigh the intermediate P13 (0.09 mmol, 1.0 eq, 30 mg), add analytically pure acetonitrile (2 ml) and stir to dissolve, add NMI (0.31 mmol, 3.5 eq, 25 mg) and stir to dissolve for 15 minutes. Weigh the intermediate M9 (0.09 mmol, 1.0 eq, 18 mg), add and stir to dissolve. Add TCFH (0.10 mmol, 1.1 eq, 28 mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40 ° C to obtain compound 41 as a yellow solid (28 mg, yield: 64.34%, purity: HPLC> 95%). ESI-MS m / z: 470.34 [M+H] + . 1H NMR (600MHz, DMSO) δ8.41(s,1H),7.75(d,J=9.1Hz,2H),6.82(d,J=7.5Hz,2H),5.26(q,J=13.3Hz,1H),4.94(s, 1H), 4.80 (q, J = 15.4Hz, 1H), 4.43 (s, 1H), 3.79–3.70 (m, 1H), 3.65–3.43 (m, 4H), 3.15 (s, 6H), 2.42–2.13 (m, 2H).

[0653] Example 42

[0654] 1-[4-(Methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3-fluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 42)

[0655] P5 (0.14 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.49 mmol, 3.5 eq, 40 mg) was added and stirred to dissolve for 15 min. M12 (0.14 mmol, 1.0 eq, 27 mg) was weighed and added and stirred to dissolve. TCFH (0.15 mmol, 1.1 eq, 42 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 42 (35 mg, yield: 71.76%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 343.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.52–8.40(m,2H),8.13(dd,J=6.5,3.3Hz,1H),6.78–6.69(m,1H),4.63(d,J=29.8Hz,2H),4.56– 4.45(m,2H),4.44–4.34(m,2H),4.12–4.01(m,2H),3.22–3.12(m,1H),2.88(dd,J=9.5,4.0Hz,3H),2.86–2.69(m,2H).

[0656] Example 43

[0657] 1-[4-(Methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3,5-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 43)

[0658] P6 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M12 (0.12 mmol, 1.0 eq, 24 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 43 as a white solid powder (30 mg, yield: 63.33%, purity: HPLC>95%). ESI-MS m / z: 361.21 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.44(d,J=8.6Hz,1H),8.14–8.08(m,2H),7.25–6.99(m,1H),4.63(d,J=33.1Hz,2H),4.47(t,J= 8.3Hz, 2H), 4.41 (d, J = 13.3Hz, 2H), 4.04 (t, J = 6.5Hz, 2H), 3.13–3.03 (m, 1H), 2.91–2.85 (m, 3H), 2.85–2.81 (m, 2H).

[0659] Example 44

[0660] 1-[4-(Methylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 44)

[0661] P2 (0.12 mmol, 1.0 eq, 30 mg) was weighed and added to analytical grade acetonitrile (2 ml) and stirred to dissolve. NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred to dissolve for 15 min. M12 (0.12 mmol, 1.0 eq, 24 mg) was weighed and added and stirred to dissolve. TCFH (0.14 mmol, 1.1 eq, 39 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40°C to obtain compound 44 (28 mg, yield: 58.95%, purity: HPLC>95%) as a white solid powder. ESI-MS m / z: 361.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.40 (s, 1H), 7.61–7.56 (m, 1H), 7.44–7.26 (m, 1H), 6.43 (t, J = 5.9Hz, 1H), 4.62 (d, J = 29.0Hz, 2H), 4. 41(s,2H),4.30(t,J=8.0Hz,2H),3.85(t,J=6.5Hz,2H),3.16–3.02(m,1H),2.87(t,J=4.7Hz,3H),2.83(t,J=7.8Hz,2H).

[0662] Example 45

[0663] (2-Chloro-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)[(3R)-1-(2-methylpyridin-4-yl)tetrahydro-1H-pyrrol-3-yl]methanone (Compound 45)

[0664] Weigh P14 (0.14 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.49 mmol, 3.5 eq, 40 mg) and stir to dissolve for 15 min. Weigh M2 (0.14 mmol, 1.0 eq, 27 mg), add and stir to dissolve. Add TCFH (0.16 mmol, 1.1 eq, 45 mg) and stir to dissolve, and stir at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40°C to obtain white solid compound 45 (17 mg, yield: 33.23%, purity: HPLC>95%). ESI-MS m / z: 344.44 [M+H] + . 1H NMR(600MHz,DMSO)δ8.82–8.76(m,1H),8.19–8.10(m,1H),6.83–6.71(m,2H),5.11–4.95(m,2H),4.6 9(d,J=15.9Hz,2H),3.81–3.54(m,4H),2.56–2.53(m,1H),2.47(d,J=4.1Hz,3H),2.39–2.16(m,2H).

[0665] Example 46

[0666] (R)-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)pyrrolidin-3-yl)methanone (Compound 46)

[0667] P15 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytically pure acetonitrile (2 ml) and stirred to dissolve. NMI (0.49 mmol, 3.5 eq, 40 mg) was added and stirred to dissolve for 15 min. M2 (0.13 mmol, 1.0 eq, 25 mg) was weighed and added and stirred to dissolve. TCFH (0.16 mmol, 1.1 eq, 45 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40 ° C to obtain white solid compound 46 (14 mg, yield: 24.56%, purity: HPLC>95%). ESI-MS m / z: 370.42 [M+H] + . 1 H NMR(600MHz,DMSO)δ8.78(d,J=5.8Hz,1H),7.71(d,J=2.4Hz,1H),7.05(s,1H),5.11–4.97(m,2H),4 .69(d,J=16.0Hz,2H),3.62–3.37(m,5H),2.88–2.81(m,3H),2.33–2.12(m,2H),2.08–2.01(m,2H).

[0668] Example 47

[0669] (R)-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(6-methylpyridazin-3-yl)pyrrolidin-3-yl)methanone (Compound 47)

[0670] Weigh P16 (0.14 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.49 mmol, 3.5 eq, 40 mg) and stir to dissolve for 15 min. Weigh M2 (0.14 mmol, 1.0 eq, 27 mg), add and stir to dissolve. Add TCFH (0.16 mmol, 1.1 eq, 45 mg) and stir to dissolve, and stir at room temperature for 4 h. The reaction solution is added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake is then washed thoroughly with purified water (10 ml, three times) and dried at 40°C to obtain white solid compound 47 (14 mg, yield: 28.08%, purity: HPLC>95%). ESI-MS m / z: 345.42 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.77(d,J=3.2Hz,1H),7.24(d,J=9.2Hz,1H),6.84(d,J=9.2Hz,1H),5.10–4.98(m,2H),4.69(d,J=1 6.3Hz,2H),3.79–3.72(m,1H),3.61–3.55(m,2H),3.51–3.46(m,2H),2.42(s,3H),2.33–2.26(m,1H),2.21–2.15(m,1H).

[0671] Example 48

[0672] (2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)[(3R)-1-(2-methoxypyridin-4-yl)tetrahydro-1H-pyrrol-3-yl]methanone (Compound 48)

[0673] Weigh P12 (0.13 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.46 mmol, 3.5 eq, 48 mg) and stir to dissolve for 15 min. Weigh M10 (0.13 mmol, 1.0 eq, 30 mg), add and stir to dissolve. Add TCFH (0.15 mmol, 1.1 eq, 42 mg) and stir to dissolve, and stir at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 min, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40°C to obtain white solid compound 48 (14 mg, yield: 25.92%, purity: HPLC>95%). ESI-MS m / z: 403.49 [M+H] + . 1H NMR (600MHz, DMSO) δ7.85(d,J=6.9Hz,1H),6.51–6.39(m,1H),6.07(d,J=5.3Hz,1H),3.96(d,J=3.2Hz,3H),3.78– 3.70(m,1H),3.65–3.57(m,2H),3.54–3.45(m,2H),3.16(d,J=10.8Hz,6H),2.38–2.23(m,1H),2.23–2.10(m,1H).

[0674] Example 49

[0675] (R)-(2-Chloro-4-(dimethylamino)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(6,7-dihydro-5H-cyclopentadienyl[b]pyridin-3-yl)pyrrolidin-3-yl)methanone (Compound 49)

[0676] P15 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added to analytically pure acetonitrile (2 ml) and stirred to dissolve. NMI (0.49 mmol, 3.5 eq, 40 mg) was added and stirred to dissolve for 15 min. M10 (0.13 mmol, 1.0 eq, 30 mg) was weighed and added and stirred to dissolve. TCFH (0.16 mmol, 1.1 eq, 45 mg) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 min, it was filtered and the filter cake was thoroughly washed with purified water (10 ml, three times) and dried at 40 ° C to obtain white solid compound 49 (13 mg, yield: 24.52%, purity: HPLC>95%). ESI-MS m / z: 413.52 [M+H] + . 1 H NMR (600MHz, DMSO) δ7.74(s,1H),7.19(s,1H),5.23(q,J=13.4Hz,1H),4.90(s,1H),4.79(q,J=15.8Hz,1H),4.42(s,1H),3 .68–3.37(m,5H),3.16(d,J=10.8Hz,6H),2.90(t,J=7.3Hz,4H),2.35–2.25(m,1H),2.21–2.12(m,1H),2.12–2.04(m,2H).

[0677] Example 50

[0678] (R)-(2-Chloro-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidin-6-yl)(1-(4-((trifluoromethyl)sulfonyl)phenyl)pyrrolidin-3-yl)methanone (Compound 50)

[0679] Weigh the intermediate P13 (0.09 mmol, 1.0 eq, 30 mg), add analytical grade acetonitrile (2 ml) and stir to dissolve, add NMI (0.31 mmol, 3.5 eq, 25 mg) and stir to dissolve for 15 minutes. Weigh the intermediate M2 (0.09 mmol, 1.0 eq, 17 mg), add and stir to dissolve. Add TCFH (0.10 mmol, 1.1 eq, 28 mg) and stir to dissolve, and stir at room temperature for 4 hours. The reaction solution was added dropwise to purified water (10 ml) for crystallization, allowed to stand for 10 minutes, and then filtered. The filter cake was then washed thoroughly with purified water (10 ml, three times) and dried at 40°C to obtain compound 50 as a yellow solid (39 mg, yield: 91.37%, purity: HPLC>95%). ESI-MS m / z: 461.34 [M+H] + . 1 H NMR (600MHz, DMSO) δ8.78(d,J=7.8Hz,1H),7.75(d,J=8.9Hz,2H),6.82(d,J=9.1Hz,2H),5.12–4.97 (m,2H),4.70(d,J=16.1Hz,2H),3.72(dd,J=10.1,7.7Hz,1H),3.64–3.43(m,4H),2.42–2.14(m,2H).

[0680] Example 51

[0681] 1-{4-[Cyclopropyl(methyl)amino]-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl}-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 51)

[0682] Synthesis of Intermediate M13_1: 4-chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) was added to a reaction flask, 2-isopropanol (2 mL) was added and stirred to dissolve, N-methylcyclopropylamine hydrochloride (168 mg, 1.56 mmol) and N,N-diisopropylethylamine (302 mg, 2.34 mmol) were added sequentially, and the mixture was evacuated, replaced with nitrogen three times, and stirred at 60°C for 4 h. After completion of the reaction as monitored by TLC, the reaction solution was concentrated, ethyl acetate (20 mL) was added, and then washed with saturated ammonium chloride solution (20 mL x 3). The organic phase was concentrated to obtain 180 mg of a crude white solid (79.65% yield), which was used directly in the next step. ESI-MS m / z: 291.14 [M+H] + .

[0683] Synthesis of Intermediate M13: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of Intermediate M13_1 (180 mg, 0.62 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtration and drying afforded 120 mg of a white solid in an 85.41% yield. ESI-MS m / z: 191.25 [M+H] + .

[0684] Synthesis of the final product, Compound 51: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M13 (30 mg, 0.13 mmol) was weighed and added and dissolved with stirring. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 27 mg of white solid powder, Compound 51, with a yield of 51.24%. ESI-MS m / z: 401.26 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.44(s,1H),7.58(d,J=5.6Hz,1H),6.42(t,J=5.9Hz,1H),5.21(s,1H),5.01(d,J=2.5Hz,1H),4.69–4.66(m,1H),4.42(s, 1H),4.29(t,J=8.6Hz,2H),3.88–3.83(m,2H),3.08(d,J=2.4Hz,5H),2.8 5(dd,J=18.7,7.7Hz,2H),0.91(dt,J=6.9,3.4Hz,1H),0.87–0.77(m,3H).

[0685] Example 52

[0686] 1-{4-[Cyclopropyl(ethyl)amino]-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl}-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 52)

[0687] Synthesis of Intermediate M14_1: 4-Chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) was added to a reaction flask, 2-isopropanol (2 mL) was added and stirred to dissolve, N-ethyl-cyclopropylamine hydrochloride (189 mg, 1.56 mmol) and N,N-diisopropylethylamine (302 mg, 2.34 mmol) were added sequentially, and the mixture was evacuated, replaced with nitrogen three times, and stirred at 60°C for 4 h. After completion of the reaction as monitored by TLC, the reaction solution was concentrated, ethyl acetate (20 mL) was added, and the mixture was washed with saturated ammonium chloride solution (20 mL x 3). The organic phase was concentrated to obtain 190 mg of a crude white solid, which was directly used in the next step. Yield: 80.17%. ESI-MS m / z: 305.13 [M+H] + .

[0688] Synthesis of Intermediate M14: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of Intermediate M14_1 (190 mg, 0.63 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtration and drying afforded 140 mg of a white solid in a 93.33% yield. ESI-MS m / z: 205.28 [M+H] + .

[0689] Synthesis of the final product, Compound 52: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M14 (31 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 24 mg of white solid powder, Compound 52, with a yield of 43.89%. ESI-MS m / z: 415.26 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.44(s,1H),7.58(d,J=5.6Hz,1H),6.42(t,J=5.9Hz,1H),5.21(s,1H) ,5.00(s,1H),4.67(t,J=1.7Hz,1H),4.42(s,1H),4.32–4.26(m,2H),3.85(t,J=6.8Hz,2H),3. 65(qd,J=6.9,4.6Hz,2H),3.12–3.01(m,2H),2.87(d,J=7.7Hz,1H),2.84(d,J=7.7Hz,1H),1.0 9(td,J=7.0,3.4Hz,3H),0.94(h,J=5.0Hz,1H),0.88–0.84(m,1H),0.82(dt,J=6.5,3.4Hz,2H).

[0690] Example 53

[0691] 1-[4-(Dicyclopropylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 53)

[0692] Synthesis of Intermediate M15_1: 4-chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) was added to a reaction flask, 2-isopropanol (2 mL) was added and stirred to dissolve, followed by the addition of dicyclopropylamine hydrochloride (208 mg, 1.56 mmol) and N,N-diisopropylethylamine (302 mg, 2.34 mmol). The mixture was then evacuated, replaced with nitrogen three times, and stirred at 60°C for 4 h. After completion of the reaction, as monitored by TLC, the reaction solution was concentrated, ethyl acetate (20 mL) was added, and the mixture was washed with saturated ammonium chloride solution (20 mL x 3). The organic phase was concentrated to yield 200 mg of a crude white solid, which was used directly in the next step with a yield of 81.14%. ESI-MS m / z: 317.20 [M+H]. + .

[0693] Synthesis of Intermediate M15: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of M15_1 (200 mg, 0.63 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtered and dried to obtain 150 mg of a white solid in a 94.22% yield. ESI-MS m / z: 217.27 [M+H] + .

[0694] Synthesis of the final product Compound 53: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M15 (33 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 29 mg of white solid powder Compound 53, with a yield of 51.67%. ESI-MS m / z: 427.26 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.49(s,1H),7.58(d,J=5.6Hz,1H),6.45–6.39(m,1H), 5.10(s,1H),4.89(d,J=2.5Hz,1H),4.70–4.67(m,1H),4.44(s,1H),4.29(t,J= 8.3Hz,2H),3.85(t,J=7.0Hz,2H),3.09(dtd,J=15.7,7.9,2.0Hz,1H),2.85(tt ,J=7.4,3.2Hz,4H),0.86(dtd,J=27.2,7.0,5.0Hz,4H),0.70(h,J=4.7Hz,4H).

[0695] Example 54

[0696] 1-[4-(azetidin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3-fluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 54)

[0697] Synthesis of Intermediate M16_1: 4-chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol, 1 eq) was added to a reaction flask. 2 mL of 2-isopropanol was added and stirred to dissolve. Azetidine hydrochloride (146 mg, 1.56 mmol, 2 eq) and N,N-diisopropylethylamine (303 mg, 2.35 mmol, 3 eq) were then added sequentially. The mixture was evacuated, replaced with nitrogen three times, and stirred at room temperature for 4 h. After completion of the reaction, the reaction mixture was concentrated, ethyl acetate (20 ml) was added, and then washed with saturated ammonium chloride solution (20 ml x 3). The organic phase was concentrated to yield 200 mg of a crude white solid, which was used directly in the next step with a yield of 92.59%. ESI-MS m / z: 277.41 [M+H]. + .

[0698] Synthesis of Intermediate M16: A 4M hydrochloric acid / dioxane solution (2 mL) was added dropwise to a solution of Intermediate M16_1 (200 mg, 0.72 mmol, 1 eq) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtration and drying afforded 150 mg of a white solid in a 98.04% yield. ESI-MS m / z: 177.22 [M+H] + .

[0699] Synthesis of the final product, Compound 54: Intermediate P5 (30 mg, 0.14 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (40 mg, 0.49 mmol) was added and stirred for 15 min. M16 (30 mg, 0.14 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (42 mg, 0.15 mmol) were added sequentially and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 33 mg of white solid powder, Compound 54, with a yield of 62.77%. ESI-MS m / z: 185.18 [M / 2+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.37(d,J=2.7Hz,1H),8.10(dd,J=4.6,2.3Hz,1H),8.00 –7.96(m,1H),6.47(ddd,J=8.7,5.4,3.9Hz,1H),4.88(d,J=2.1Hz,1H),4.66–4. 61(m,2H),4.38(d,J=2.1Hz,1H),4.26–4.17(m,6H),3.77(t,J=7.2Hz,2H),3.07 (ttd,J=8.6,5.8,3.1Hz,1H),2.83(t,J=7.1Hz,2H),2.34(pd,J=7.5,4.9Hz,2H).

[0700] Example 55

[0701] 1-[4-(azetidin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3,5-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 55)

[0702] Synthesis of the final product, Compound 55: Intermediate P6 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. M16 (27 mg, 0.13 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) were added sequentially and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 41 mg of a white solid powder, with a yield of 80.99%. ESI-MS m / z: 194.17 [M / 2+H] + .1 H NMR(600MHz,DMSO-d6)1H NMR (600MHz, DMSO-d6) δ8.37(d,J=2.4Hz,1H),8.07(m,J=2.7,1.3Hz,2H),4.88(d,J=2.4Hz,1H),4.67–4.61(m,2H),4.44(m,J=8.2,5.8,3.0 Hz,2H),4.38(d,J=2.1Hz,1H),4.20(s,4H),4.02(m,J=8.5,5.5,2.5Hz,2H),3.11–3.03(m,1H),2.83(t,J=7.5Hz,2H),2.34(h,J=7.6Hz,2H).

[0703] Example 56

[0704] 1-[4-(azetidin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 56)

[0705] Synthesis of the final product Compound 56: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. M16 (27 mg, 0.12 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) were added in sequence and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40 ° C to obtain 7 mg of white solid powder Compound 56, with a yield of 13.78%. ESI-MS m / z: 387.33 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.37(s,1H),7.58(d,J=5.5Hz,1H),6.42(dd,J=9.9,5.7Hz,1H),4.88(s,1H),4.65(s,1H),4.63(s,1H), 4.38(s,1H),4.32–4.26(m,2H),4.26–4.07(m,4H),3.92–3.77(m,2H),3.22–2.95(m,1H),2.89–2.79(m,2H),2.40–2.27(m,2H).

[0706] Example 57

[0707] 2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]-1-[4-(tetrahydro-1H-pyrrol-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 57)

[0708] Synthesis of Intermediate M17_1: 4-Chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) was added to a reaction flask, 2-isopropanol (2 mL) was added and stirred to dissolve, tetrahydropyrrole (110 mg, 1.56 mmol) and N,N-diisopropylethylamine (302 mg, 2.34 mmol) were added sequentially, and the mixture was evacuated, replaced with nitrogen three times, and stirred at 60°C for 4 h. After completion of the reaction as monitored by TLC, the reaction solution was concentrated, ethyl acetate (20 mL) was added, and the mixture was washed with saturated ammonium chloride solution (20 mL x 3). The organic phase was concentrated to obtain 210 mg of a crude white solid in a yield of 92.33%. This product was directly used in the next step. ESI-MS m / z: 291.20 [M+H] + .

[0709] Synthesis of Intermediate M17: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of M17_1 (210 mg, 0.72 mmol) in dichloromethane (5 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtration and drying afforded 150 mg of a white solid in a 91.57% yield. ESI-MS m / z: 191.27 [M+H] + .

[0710] Synthesis of the final product, Compound 57: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. M17 (29 mg, 0.13 mmol) and N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) were added sequentially and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 35 mg of white solid powder, Compound 57, with a yield of 66.50%. ESI-MS m / z: 401.21 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.36(d,J=1.5Hz,1H),7.58(dd,J=5.5,1.8Hz,1H),6 .42(td,J=5.9,1.8Hz,1H),5.13(s,1H),4.89(s,1H),4.64(t,J=2.1Hz,1H),4 .39(d,J=2.1Hz,1H),4.29(d,J=10.3Hz,2H),3.85(t,J=7.5Hz,2H),3.62(s, 4H), 3.09 (dt, J=13.2, 7.3Hz, 1H), 2.85 (dd, J=16.1, 7.7Hz, 2H), 1.90 (s, 4H).

[0711] Example 58

[0712] 2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]-1-(4-methoxy-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)ethan-1-one (Compound 58)

[0713] Synthesis of Intermediate M18_1: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of tert-butyl 4-chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylate (200 mg, 0.78 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtration and drying afforded 119 mg of a white solid in a 79.24% yield. ESI-MS m / z: 155.99 [M+H]. + .

[0714] Synthesis of Intermediate M18: Intermediate M18_1 (119 mg, 0.62 mmol) was added to a reaction flask, and methanol (2 mL) was added and stirred to dissolve. Sodium methoxide (270 mg, 5 mmol) was then added and the temperature was raised to 60°C and stirred for 3 h. After completion of the reaction as monitored by TLC and LCMS, the reaction solution was concentrated, DCM (20 mL) was added, and then washed with saturated brine (20 mL x 3). The organic phase was concentrated to obtain 80 mg of a crude white solid, with a yield of 85.45%. This was directly used in the next step. ESI-MS m / z: 152.06 [M+H] + .

[0715] Synthesis of the final product, Compound 58: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M18 (20 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 12 mg of white solid powder, Compound 58, with a yield of 25.26%. ESI-MS m / z: 362.19 [M+H] + . 1 H NMR(600MHz, DMSO-d6)δ8.76(s,1H),7.58(d,J=5.6Hz,1H),6.43(t,J=5.9Hz,1H),4.83(t,J=2.0Hz,1H),4.80(s,1H),4.59–4.55(m,1H),4.5 4(s,1H), 4.30(t,J=8.2Hz,2H), 4.00(d,J=2.5Hz,3H), 3.85(t,J=6.6Hz,2H), 3.09(ddd,J=14.2,8.4,6.3Hz,1H), 2.86(dd,J=7.7,3.5Hz,2H).

[0716] Example 59

[0717] 2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]-1-(4-hydroxy-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)ethan-1-one (Compound 59)

[0718] Synthesis of Intermediate M19_1: 4-Chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) was added to a reaction flask, and methanol (2 mL) was added and stirred to dissolve. Sodium methoxide (337 mg, 6.24 mmol) was then added and the temperature was raised to 60°C and stirred for 3 h. After completion of the reaction as monitored by TLC and LCMS, the reaction solution was concentrated, DCM (20 mL) was added, and the solution was washed with saturated brine (20 mL x 3). The organic phase was concentrated to obtain 169 mg of a crude white solid, with a yield of 86.22%. This product was directly used in the next step. ESI-MS m / z: 252.20 [M+H] + .

[0719] Synthesis of Intermediate M19: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of Intermediate M19_1 (169 mg, 0.67 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtration and drying afforded 109 mg of a white solid in a 93.71% yield. ESI-MS m / z: 138.12 [M+H] + .

[0720] Synthesis of the final product, Compound 59: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M19 (23 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 32 mg of white solid powder, Compound 59, with a yield of 70.09%. ESI-MS m / z: 348.13 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ12.72(s,1H),8.22(s,1H),7.58(d,J=5.6Hz,1H),6.42(td,J=5.9,1.4Hz,1H),4.69(t,J=2.9Hz,1H),4.62(t,J=2.9Hz ,1H),4.44(t,J=2.9Hz,1H),4.37(t,J=2.8Hz,1H),4.28(d,J=8.5Hz,2H),3.84(q,J=7.2,6.0Hz,2H),3.12–3.04(m,1H),2.82(t,J=8.2Hz,2H).

[0721] Example 60

[0722] 1-[4-(Diethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 60)

[0723] Synthesis of Intermediate M20_1: 4-chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) was added to a reaction flask, 2-isopropanol (2 mL) was added and stirred to dissolve, followed by the addition of diethylamine hydrochloride (170 mg, 1.56 mmol) and N,N-diisopropylethylamine (302 mg, 2.34 mmol). The mixture was then evacuated, replaced with nitrogen three times, and stirred at 60°C for 4 h. After completion of the reaction as monitored by TLC, the reaction mixture was concentrated, ethyl acetate (20 mL) was added, and the mixture was washed with saturated ammonium chloride solution (20 mL x 3). The organic phase was concentrated to yield 160 mg of a crude white solid, in a yield of 70.17%. ESI-MS m / z: 293.23 [M+H]. + .

[0724] Synthesis of Intermediate M20: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of Intermediate M20_1 (160 mg, 0.55 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtration and drying afforded 120 mg of a white solid in a 95.69% yield. ESI-MS m / z: 193.22 [M+H] + .

[0725] Synthesis of the final product, Compound 60: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M20 (30 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 25 mg of white solid powder, Compound 60, with a yield of 45.56%. ESI-MS m / z: 403.21 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.39(d,J=1.6Hz,1H),7.58(d,J=5.6Hz,1H),6.43(td,J =5.9,3.6Hz,1H),4.99(s,1H),4.78(s,1H),4.63(s,1H),4.38(s,1H),4.29(dd,J =11.0,4.9Hz,2H),3.85(t,J=7.3Hz,2H),3.51(dq,J=9.6,6.4,5.1Hz,4H),3.12– 3.07 (m, 1H), 2.89 (d, J = 7.7Hz, 1H), 2.84 (d, J = 7.7Hz, 1H), 1.15 (q, J = 7.0Hz, 6H).

[0726] Example 61

[0727] 1-(4-Amino-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl)-2-[1-(2,3-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 61)

[0728] Synthesis of Intermediate M21_1: 4-chloro-5H-pyrrolo[3,4-D]pyrimidine-6(7H)-carboxylic acid tert-butyl ester (200 mg, 0.78 mmol) was added to a 10 mL microwave reaction vial. Ethanol (5 mL) was added and stirred to dissolve. 2 mL of aqueous ammonia was then added. The microwave vial was sealed and placed in a microwave reactor at 150°C for 30 min. TLC and LCMS monitoring indicated the reaction was complete. The reaction solution was concentrated to yield 170 mg of the crude product as a white solid, with a yield of 92.39%. ESI-MS m / z: 237.32 [M+H]. + .

[0729] Synthesis of Intermediate M21: A 4M hydrochloric acid / dioxane solution (2 ml) was added dropwise to a solution of Intermediate M21_1 (170 mg, 0.72 mmol) in dichloromethane (1 ml). The reaction mixture was stirred at room temperature for 4 hours. A white solid precipitated, as monitored by LCMS and TLC. The reaction was complete. Filtered and dried to obtain 100 mg of a white solid in an 80.45% yield. ESI-MS m / z: 137.09 [M+H] + .

[0730] Synthesis of the final product, Compound 61: Intermediate P2 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M21 (23 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 17 mg of white solid powder, Compound 61, with a yield of 37.40%. ESI-MS m / z: 347.18 [M+H] + .

[0731] Example 62

[0732] 1-[4-(azetidin-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 62)

[0733] Intermediate P1 (56 mg, 0.22 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (37 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M16 (47 mg, 0.22 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (67 mg, 0.24 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40 ° C to obtain 36 mg of light pink solid powder compound 62, with a yield of 39.99%. ESI-MS m / z: 210.19 [M / 2+H] + . 1H NMR (600MHz, DMSO-d6) δ8.37 (d, J=3.0Hz, 1H), 8.21 (dd, J=5.7, 1.8Hz, 1H), 6.71 (dd, J= 3.8,2.2Hz,1H),6.53(dt,J=5.8,2.9Hz,1H),4.88(d,J=2.6Hz,1H),4.67–4.62(m,2H),4 .39(d,J=2.0Hz,1H),4.20(s,4H),4.16(td,J=8.2,5.8Hz,2H),3.69(dd,J=8.4,5.7Hz, 2H), 3.14–3.06 (m, 1H), 2.83 (dd, J=7.7, 4.3Hz, 2H), 2.34 (tdd, J=10.3, 7.6, 4.9Hz, 2H).

[0734] Example 63

[0735] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3-fluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 63)

[0736] Intermediate P5 (30 mg, 0.14 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (40 mg, 0.49 mmol) was added and stirred for 15 min. Intermediate M9 (28 mg, 0.14 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (42 mg, 0.15 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml) and extracted with 10 ml of dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, and spun down to dryness. The mixture was then purified by column chromatography (eluent f: methanol / dichloromethane, gradient 1:80 to 1:40) to obtain 28 mg of compound 63, with a yield of 55.00%. ESI-MS m / z: 179.22 [M / 2+H]. + . 1 H NMR (600 MHz, DMSO) δ

[0737] Example 64

[0738] 4-(3-{2-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-oxyylideneethyl}azetidin-1-yl)-3-fluoropyridine-2-carbonitrile (Compound 64)

[0739] Synthesis of intermediate P17_2: Intermediate P1_2 (0.64 g, 3.88 mmol), 3-fluoro-4-iodopyridine-2-carbonitrile (1.20 g, 4.86 mmol), and 1,1'-binaphthyl-2,2'-diyl (diphenylphosphine) (120 mg, 0.19 mmol) were added to a reaction flask, toluene (10 ml) was added to dissolve and stir, and then cesium carbonate (3.16 g, 9.7 mmol) was added. The mixture was heated in an oil bath at 70°C. After the temperature rose, tris(dibenzylideneacetone)dipalladium(0) (89 mg, 0.10 mmol) was added. The reaction was maintained at 70°C and heated for 8 hours. LCMS monitoring showed that the reaction was complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3 x 20 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, cyclohexane / ethyl acetate, gradient 10:1 to 1:1) afforded 375 mg of a yellow, transparent oil in a yield of 38.82%. ESI-MS m / z: 250.20 [M+H] + .

[0740] Synthesis of Intermediate P17: P17_2 (375 mg, 1.51 mmol) was dissolved in methanol (10.0 ml) with stirring. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 h. LCMS monitoring indicated that the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 5. A yellow solid powder precipitated. After standing for 10 min, the mixture was filtered and washed with purified water (10 ml x 3). The filter cake was then dried at 40°C to yield 145 mg of a yellow solid powder (40.97% yield). ESI-MS m / z: 236.13 [M+H]. + .

[0741] Synthesis of the final product, compound 64: Intermediate P17 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M9 (26 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 7 mg of white solid powder, compound 64, with a yield of 14.39%. ESI-MS m / z: 382.21 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.39(s,1H),8.07(d,J=5.4Hz,1H),6.73(ddd,J=8.2,5.5,2.7Hz,1H),5.12(s,1H),4.90(s,1H),4.64(s,1H),4 .39(s,1H),4.33(s,2H),3.88(s,2H),3.15(d,J=2.3Hz,6H),2.88(d,J=7.7Hz,1H),2.84(d,J=7.7Hz,1H),2.00(dt,J=12.2,7.6Hz,1H).

[0742] Example 65

[0743] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-{1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 65)

[0744] Intermediate M9 (122 mg, 0.61 mmol), intermediate P1 (158 mg, 0.61 mmol), and N-methylimidazole (175 mg, 2.13 mmol) were placed in a round-bottom flask and stirred with 5 mL of acetonitrile. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188 mg, 0.67 mmol) was added and allowed to react at room temperature for 6 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1) to obtain 30 mg of the final product, compound 65, as a yellow powder in a yield of 12.15%. ESI-MS m / z: 407.25 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.39(d,J=1.8Hz,1H),8.21(d,J=5.7Hz,1H),6.71(d,J=2.3 Hz,1H),6.53(dt,J=5.3,2.3Hz,1H),5.12(s,J=2.2Hz,1H),4.90(s,1H),4.64(s,J= 2.0Hz, 1H), 4.39 (s, J=2.5Hz, 1H), 4.17 (m, J=8.2, 5.4Hz, 2H), 3.69 (m, J=8.4, 5.6Hz ,2H),3.15(s,6H),3.12–3.08(m,1H),2.87(d,J=7.7Hz,1H),2.83(d,J=7.7Hz,1H).

[0745] Example 66

[0746] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(5-fluoro-6-methylpyridin-2-yl)azetidin-3-yl]ethan-1-one (Compound 66)

[0747] Synthesis of Intermediate P18_2: Intermediate P1_2 (361 mg, 2.19 mmol), 2-bromo-5-fluoro-6-methylpyridine (621 mg, 3.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.79 g, 5.48 mmol) were placed in a round-bottom flask. 15 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 15 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 1.12 g of crude intermediate P18_2, which was directly used in the next step. LCMS (ESI) m / z = 239.24 [M+H] + .

[0748] Synthesis of Intermediate P18: The crude intermediate P18_2 (1.12 g) was placed in a flask, 5 mL of methanol was added, and 1 M sodium hydroxide solution was slowly added dropwise to the flask to adjust the pH to 13-14. The reaction was allowed to proceed at room temperature for 2 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and dichloromethane (60 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1 M dilute hydrochloric acid. The solution was then lyophilized to obtain 820 mg of intermediate P18 containing sodium chloride as a brownish-yellow solid. ESI-MS m / z: 225.26 [M+H] + .

[0749] Synthesis of the final product, Compound 66: 500 mg of the salt-containing intermediate P18 was placed in a round-bottom flask, acetonitrile (3 mL x 3) was added, and ultrasonic filtration was performed. To the filtrate, intermediate M9 (122 mg, 0.61 mmol) and N-methylimidazole (175 mg, 2.14 mmol) were added and stirred evenly. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188 mg, 0.67 mmol) was weighed and added to the reaction solution. The reaction was allowed to react at room temperature for 3 h. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then purified by column chromatography (eluent: methanol / dichloromethane, gradient 1:60 to 1:40) to obtain 38 mg of the final product, Compound 66, as a white viscous liquid, with a yield of 16.81%. ESI-MS m / z:371.30[M+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.48–7.23(m,1H),6.19(m,J=8.9,2.5 Hz,1H),5.11(s,1H),4.89(s,1H),4.63(s,J=2.7Hz,1H),4.38(s,1H),4.04 (m,J=7.9,5.0Hz,2H),3.58(m,J=8.4,5.7,3.4Hz,2H),3.14(s,6H),3.05–2 .97(m,1H),2.83–2.80(m,1H),2.77(d,J=7.7Hz,1H),2.26(d,J=2.9Hz,3H).

[0750] Example 67

[0751] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(2-fluoro-6-methylpyridin-2-yl)azetidin-3-yl]ethan-1-one (Compound 67)

[0752] Synthesis of intermediate P19_2: Intermediate P1_2 (361 mg, 2.19 mmol), 2-bromo-3-fluoro-6-methylpyridine (621 mg, 3.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.79 g, 5.48 mmol) were placed in a round-bottom flask. 15 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 12 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 1.16 g of crude intermediate P19_2, a brownish-yellow viscous liquid, which was directly used in the next reaction. ESI-MS m / z: 239.21 [M+H] +

[0753] Synthesis of intermediate P19: Take the crude intermediate P19_2 (1.16g) in a flask, add 5mL of methanol and stir, and slowly add 1mol / L sodium hydroxide to the flask to adjust the pH of the solution to 13-14. The reaction is carried out at room temperature for 1.5h. LCMS monitoring shows that the reaction is complete. The reaction solution is concentrated in vacuo, and the residue is extracted with 60mL of water and dichloromethane (60mLx3). The organic phase is discarded, and the aqueous phase is adjusted to pH 5 with 1mol / L dilute hydrochloric acid. The solution is freeze-dried to obtain 950mg of intermediate P19 containing sodium chloride as a yellow solid. ESI-MS m / z: 225.26[M+H] + .

[0754] Synthesis of the final product, Compound 67: 500 mg of the salt-containing intermediate P19 was placed in a round-bottom flask, acetonitrile (3 mL x 3) was added, and ultrasonic filtration was performed. To the filtrate, intermediate M9 (122 mg, 0.61 mmol) and N-methylimidazole (175 mg, 2.14 mmol) were added and stirred evenly. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188 mg, 0.67 mmol) was weighed and added to the reaction solution. The reaction was allowed to react at room temperature for 3.5 hours. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was added to 50 mL of water and stirred. A white solid precipitated. The residue was filtered with suction, and the filter cake was dried to obtain 23 mg of the final product, Compound 67, as a white solid, in a yield of 10.18%. ESI-MS m / z: 371.29 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),7.25(m,J=12.5,7.9,2.0Hz,1H),6.64–6 .34(d,1H),5.12(s,1H),4.89(s,1H),4.64(s,J=2.5Hz,1H),4.38(s,1H),4.1 7(m,J=7.9,4.8,1.9Hz,2H),3.74(m,J=7.6,4.0Hz,2H),3.14(s,6H),3.03(m, J=14.0,7.4Hz,1H),2.83(d,J=7.7Hz,1H),2.79(d,J=7.7Hz,1H),2.27(s,3H).

[0755] Example 68

[0756] 4-(3-{2-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-oxyylideneethyl}azetidin-1-yl)-2-(trifluoromethyl)benzene-1-carbonitrile (Compound 68)

[0757] Synthesis of Intermediate P20_2: Intermediate P1_2 (361 mg, 2.19 mmol), 2-trifluoromethyl-4-bromobenzonitrile (547 mg, 2.19 mmol), tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.78 g, 5.46 mmol) were placed in a round-bottom flask. 15 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 12 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 1 g of crude intermediate P20_2, which was directly used in the next step. ESI-MS m / z: 299.07 [M+H] + .

[0758] Synthesis of intermediate P20: Take the crude intermediate P20_2 (1g) in a round-bottom flask, add 7mL of methanol and stir, and slowly add 1mol / L sodium hydroxide to the flask to adjust the pH of the solution to 13-14. React at room temperature for 2h. LCMS monitoring shows that the reaction is complete. The reaction solution is concentrated in vacuo, and the residue is extracted with 60mL of water and dichloromethane (60mLx3). The organic phase is discarded, and the aqueous phase is adjusted to pH 5 with 1mol / L dilute hydrochloric acid. Dichloromethane (30mLx3) is added for extraction. The organic phase is collected and dried to obtain 221mg of intermediate P20 as a yellow viscous liquid. ESI-MS m / z: 285.06[M+H] + .

[0759] Synthesis of the final product, Compound 68: Intermediate P20 (221 mg, 0.78 mmol), intermediate M9 (128 mg, 0.64 mmol), and N-methylimidazole (224 mg, 2.73 mmol) were mixed in a round-bottom flask. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (240 mg, 0.86 mmol) was added to the reaction mixture and allowed to react at room temperature for 3 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and 3 times of dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. Purification by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1) afforded 30 mg of the final product, Compound 68, in a yield of 10.85%. ESI-MS m / z: 431.29 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.39(s,1H),7.77(d,J=8.6Hz,1H),6.75(s,1H),6.66(d,J=8.6Hz,1H),5.12(s,1H),4.90(s,1 H),4.64(s,1H),4.39(s,1H),4.26–4.16(m,2H),3.77–3.69(m,2H),3.15(s,6H),3.13–3.05(m,1H),2.90–2.79(m,2H).

[0760] Example 69

[0761] 4-(3-{2-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-oxyylideneethyl}azetidin-1-yl)-2,3,5,6-tetrafluorobenzene-1-carbonitrile (Compound 69)

[0762] Synthesis of Intermediate P21_2: Intermediate P1_2 (361 mg, 2.19 mmol), 2.3.4.5.6-pentafluorobenzonitrile (594 mg, 2.84 mmol), triethylamine (266 mg, 2.63 mmol), and 7 mL of DMSO were placed in a flask and reacted at 40°C for 10 h. LCMS monitoring confirmed the reaction was complete. After completion, the reaction solution was extracted with 30 mL of dichloromethane and water (50 mL x 3). The organic phase was spin-dried to give 452 mg of crude intermediate P21_2. ESI-MS m / z: 303.08 [M+H] +

[0763] Synthesis of intermediate P21: The crude intermediate P21_2 (452 ​​mg) was placed in a round-bottom flask, 5 mL of methanol was added and stirred, and 1 mol / L sodium hydroxide was slowly added dropwise to the flask to adjust the pH of the solution to 13-14. The reaction was allowed to proceed at room temperature for 2 h. LCMS monitoring confirmed the completion of the reaction. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and dichloromethane (60 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1 mol / L dilute hydrochloric acid. Dichloromethane (30 mL x 3) was then added for extraction. The organic phase was collected and dried to obtain 121 mg of intermediate P21. ESI-MS m / z: 321.11 [M+CH3OH+H] +

[0764] Synthesis of the final product, Compound 69: Intermediate M9 (42 mg, 0.21 mmol), intermediate P21 (69 mg, 0.21 mmol), and N-methylimidazole (121 mg, 1.47 mmol) were mixed in a round-bottom flask. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (130 mg, 0.46 mmol) was added to the reaction mixture and allowed to react at room temperature for 2 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and 3 times of dichloromethane (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1) to obtain 40 mg of the final product, Compound 69, in a yield of 43.55%. ESI-MS m / z: 435.23 [M+H] + . 1 H NMR (600MHz, DMSO-d6) δ8.38(s,1H),5.11(s,1H),4.88(s,1H),4.63(s,J=1.8Hz,1H),4.56(m,J=7.3Hz,2H),4. 38(s,J=2.3Hz,1H), 4.15(m,J=7.5Hz,2H), 3.14(m,J=5.6Hz,7H), 2.87(d,J=7.6Hz,1H), 2.84(d,J=7.7Hz,1H).

[0765] Example 70 and Example 71

[0766] 2-(3-{2-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-oxyylideneethyl}azetidin-1-yl)-2,3-difluorobenzene-1-carbonitrile (Compound 70)

[0767] 4-(3-{2-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-oxyylideneethyl}azetidin-1-yl)-3,4-difluorobenzene-1-carbonitrile (Compound 71)

[0768] Synthesis of Intermediates P22_21 and P22_22: Intermediate P1_2 (361 mg, 2.19 mmol), 2,3,4-trifluorobenzonitrile (447 mg, 2.84 mmol), triethylamine (266 mg, 2.63 mmol), and 7 mL of DMSO were placed in a flask and reacted at 40°C for 9 h. LCMS monitoring confirmed the reaction was complete. After completion, the reaction solution was extracted with 30 mL of dichloromethane and water (50 mL x 3). The organic phase was spin-dried to obtain 438 mg of a crude mixture of intermediates P22_21 and P22_22. ESI-MS m / z: 267.11 [M+H] + .

[0769] Synthesis of intermediate P22: A crude mixture of intermediates P22_21 and P22_22 (438 mg) was placed in a round-bottom flask, 5 mL of methanol was added and stirred, and 1 mol / L sodium hydroxide was slowly added dropwise to the flask to adjust the pH of the solution to 13-14. The reaction was allowed to proceed at room temperature for 2 h. LCMS monitoring confirmed that the reaction was complete. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and dichloromethane (60 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1 mol / L dilute hydrochloric acid. Dichloromethane (30 mL x 3) was then added for extraction. The organic phase was collected and dried to obtain 150 mg of a mixture of intermediates P221 and P222. ESI-MS m / z: 253.09 [M+H] + .

[0770] Synthesis of the final products, Compound 70 and Compound 71: A mixture of intermediates P221 and P222 (150 mg, 0.59 mmol), intermediate M9 (118 mg, 0.59 mmol), and N-methylimidazole (171 mg, 2.08 mmol) were stirred in a round-bottom flask. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (184 mg, 0.65 mmol) was added to the reaction mixture and allowed to react at room temperature for 1 h. LCMS confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. Purification by thin-layer chromatography (developing solvent: ethyl acetate:methanol = 20:1) afforded 20 mg of the final product, Compound 70, as a white solid in an 8.44% yield. ESI-MS m / z: 399.20 [M+H] + .1 H NMR (600 MHz, DMSO-d6) δ 8.38 (s, 1H), 7.43 (ddd, J = 8.6, 20.8, 1.8 Hz, 1H), 6.39 (dt, J = 8.9, 5.2 Hz, 1H), 5.12 (s, 1H), 4.89 (s, 1H), 4.64 (s, 1H), 4.39 (s, 1H), 4.33–4.27 (m, 2H), 3.89–3.78 (m, 2H), 3.15 (d, J = 2.4 Hz, 6H), 3.13–3.07 (m, 1H), 2.87 (d, J = 7.7 Hz, 1H), 2.84 (d, J = 7.6 Hz, 1H). 21 mg of the final product, compound 71, was obtained as a white solid in a yield of 8.45%. ESI-MS m / z:399.20[M+H] + . 1 H NMR(600MHz,DMSO-d6)1H NMR (600MHz, DMSO) δ8.39(s,1H),7.37(ddd,J=8.3,5.6,2.2Hz,1H),6.74(ddd,J=9.3,6.9,2.4Hz,1H),5.12(s,1H),4.90(s,1H),4.64( s,1H),4.57–4.50(m,2H),4.39(s,1H),4.15–4.06(m,2H),3.15(d,6H),3.10–3.02(m,1H),2.89(d,J=7.7Hz,1H),2.85(d,J=7.7Hz,1H).

[0771] Example 72

[0772] 2-[1-(2,3-difluorophenyl)azetidin-3-yl]-1-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 72)

[0773] Synthesis of intermediate P23_2: Intermediate P1_2 (363 mg, 2.19 mmol), 1-bromo-2,3-difluorobenzene (633 mg, 3.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.79 g, 5.48 mmol) were placed in a round-bottom flask. 15 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 15 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 2.1 g of crude intermediate P23_2, which was directly used in the next step. ESI-MS m / z: 242.24 [M+H] + .

[0774] Synthesis of intermediate P23: Take the crude intermediate P23_2 (2.1g) in a flask, add 5mL of methanol and stir, and slowly add 1mol / L sodium hydroxide to the flask to adjust the pH of the solution to 13-14. React at room temperature for 2h. LCMS monitoring shows that the reaction is complete. The reaction solution is concentrated in vacuo, and the residue is extracted with 60mL of water and dichloromethane (60mLx3). The organic phase is discarded, and the aqueous phase is adjusted to pH 5 with 1mol / L dilute hydrochloric acid. After freeze-drying in a freeze dryer, 60mL of water and dichloromethane (60mLx3) are added to dissolve, wash, filter, and concentrate to obtain 311mg of intermediate P23 containing sodium chloride. ESI-MS m / z: 228.26[M+H] + .

[0775] Synthesis of the final product, Compound 72: Intermediate M9 (86 mg, 0.43 mmol), intermediate P23 (97 mg, 0.43 mmol), and N-methylimidazole (122 mg, 1.49 mmol) were placed in a flask and stirred with 5 mL of acetonitrile. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (132 mg, 0.47 mmol) was added and allowed to react at room temperature for 2 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1) to obtain 30 mg of the final product, Compound 72, as a yellow viscous liquid in an 18.87% yield. ESI-MS m / z: 374.25 [M+H] + . 1H NMR (600MHz, Methanol-d4) δ8.35 (s, 1H), 6.91 (tdd, J = 8.1, 5.5, 1.8Hz, 1H), 6.57–6 .50(m,1H),6.32–6.27(m,1H),5.17(d,J=2.0Hz,1H),5.01–4.94(m,1H),4.69(t,J=1 .8Hz,1H),4.52(d,J=2.0Hz,1H),4.18(tt,J=7.8,2.4Hz,2H),3.71(ddd,J=7.7,5.7 ,1.9Hz,2H),3.23(d,J=4.1Hz,6H),3.17–3.09(m,1H),2.89(dd,J=27.1,7.7Hz,2H).

[0776] Example 73

[0777] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3-fluoro-5-methylpyridin-2-yl)azetidin-3-yl]ethan-1-one (Compound 73)

[0778] Synthesis of intermediate P24_2: Intermediate P1_2 (361 mg, 2.19 mmol), 2-bromo-3-fluoro-5-methylpyridine (621 mg, 3.29 mmol), tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.79 g, 5.48 mmol) were placed in a round-bottom flask. 15 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 15 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 1 g of crude intermediate P24_2, which was directly used in the next reaction. ESI-MS m / z: 239.24 [M+H] + .

[0779] Synthesis of Intermediate P24: 1 g of crude intermediate P24_2 was placed in a flask, 5 mL of methanol was added, and 1 mol / L sodium hydroxide was slowly added dropwise to the flask to adjust the pH to 13-14. The reaction was allowed to proceed at room temperature for 2 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and dichloromethane (60 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1 mol / L dilute hydrochloric acid. The product was then freeze-dried to yield 850 mg of intermediate P24 containing sodium chloride. ESI-MS m / z: 225.26 [M+H] + .

[0780] Synthesis of the final product, Compound 73: 500 mg of the salt-containing intermediate P24 was placed in a round-bottom flask, added to acetonitrile (3 mL x 3), and ultrasonically filtered. To the filtrate, intermediate M9 (122 mg, 0.61 mmol) and N-methylimidazole (175 mg, 2.14 mmol) were added and stirred thoroughly. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188 mg, 0.67 mmol) was added to the reaction mixture and allowed to react at room temperature for 3 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by column chromatography (eluent: methanol / dichloromethane, gradient 1:100) to obtain 30 mg of the final product, Compound 73, as a white solid in a yield of 13.72%. ESI-MS m / z: 371.27 [M+H]. + . 1 H NMR(600MHz, DMSO-d6)δ8.38(s,1H),7.74(s,1H),7.27(d,J=13.2,2.0Hz,1H),5.12(s,1H),4.89(s,1H),4.74–4.56(m,1H),4.38(s, 1H),4.20–4.05(m,2H),3.78–3.61(m,2H),3.14(s,6H),3.07–2.99(m,1H),2.83(d,J=7.6Hz,1H),2.79(d,J=7.6Hz,1H),2.15(s,3H).

[0781] Example 74

[0782] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-{1-[1-nitro-2-(trifluoromethyl)phenyl-4-yl]azetidin-3-yl}ethan-1-one (Compound 74)

[0783] Synthesis of Intermediate P25_2: Intermediate P1_2 (361 mg, 2.19 mmol), 4-bromo-2-(trifluoromethyl)nitrobenzene (886 mg, 3.28 mmol), tris(dibenzylideneacetone)dipalladium(0) (50 mg, 0.05 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.78 g, 5.47 mmol) were placed in a round-bottom flask. 15 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 12 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 1.20 g of crude intermediate P25_2, which was directly used in the next step. ESI-MS m / z: 319.14 [M+H] + .

[0784] Synthesis of Intermediate P25: 1.2 g of crude intermediate P25_2 was placed in a flask, 5 mL of methanol was added, and 1 mol / L sodium hydroxide was slowly added dropwise to the flask to adjust the pH to 13-14. The reaction was allowed to proceed at room temperature for 2 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and dichloromethane (60 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1 mol / L dilute hydrochloric acid. The product was then lyophilized in a freeze dryer to yield 650 mg of intermediate P25 containing sodium chloride. ESI-MS m / z: 305.08 [M+H] + .

[0785] Synthesis of the final product, Compound 74: 650 mg of the salt-containing intermediate P25 was placed in a round-bottom flask, acetonitrile (3 mL x 3) was added, and ultrasonic filtration was performed. To the filtrate, intermediate M9 (122 mg, 0.61 mmol) and N-methylimidazole (175 mg, 2.14 mmol) were added and stirred evenly. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (188 mg, 0.67 mmol) was weighed and added to the reaction solution. The reaction was allowed to react at room temperature for 3 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. After purification by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1), the final product, Compound 74 (supplemented mass), was obtained as a yellow viscous liquid in a yield of 10.91%. ESI-MS m / z:451.19[M+H] +. 1H NMR (600MHz, DMSO-d6) δ8.39(d,J=2.7Hz,1H),8.08(d,J=9.1Hz,1H),20.72(t,J=2.4Hz,1H),20.65(dt,J=9.2,2.5Hz,1H),5.13(s,1H),4. 90(s,1H),4.65(s,1H),4.40(s,1H),4.32–4.20(m,2H),3.85–3.74(m,2H),3.17–3.12(m,7H),2.88(d,J=7.8Hz,1H),2.85(d,J=7.7Hz,1H).

[0786] Example 75

[0787] 2-[1-(5,6-difluoropyridin-3-yl)azetidin-3-yl]-1-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 75)

[0788] Synthesis of intermediate P26_2: Intermediate P1_2 (200 mg, 1.21 mmol), 5-bromo-2,3-difluoropyridine (350 mg, 1.81 mmol), cesium carbonate (1.18 g, 3.62 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (57 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (62 mg, 0.06 mmol) were added to a 50 ml reaction flask, toluene (5 mL) was added, the mixture was vacuumed, nitrogen purged three times, and stirred at 90 ° C for 8 h. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated, the residue was diluted with water (3x20 ml), and extracted with ethyl acetate (3x100 ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: petroleum ether / ethyl acetate, 9%) afforded a yellow, transparent oil (170 mg, yield: 58.10%). ESI-MS m / z: 243.17 [M+H] + .

[0789] Synthesis of intermediate P26: Intermediate P26_2 (80 mg, 0.33 mmol) was dissolved in methanol (4 ml) and stirred. 1 M sodium hydroxide solution was added dropwise to adjust the pH of the reaction solution to around 13. The reaction was stirred at room temperature for 3 h. TLC and LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated to remove methanol from the system. The aqueous phase was washed with DCM (3 x 20 ml) to remove organic impurities and then the pH was adjusted to around 5 with 1 M dilute hydrochloric acid. The solution was concentrated under reduced pressure to dryness and the concentrate was further dried in a vacuum drying oven to obtain a yellow solid powder, 150 mg. ESI-MS m / z: 229.13 [M+H] + .

[0790] Synthesis of Compound 75: 150 mg of intermediate P26 was added to acetonitrile (2 ml), sonicated, and filtered. N-methylimidazole (60 mg, 0.73 mmol) was added to the filtrate and stirred to dissolve for 15 min. Intermediate M9 (70 mg, 0.35 mmol) was then weighed and added to dissolve with stirring. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (110 mg, 0.38 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The mixture was washed thoroughly with purified water (10 ml, three times). The filter cake was purified by HPLC (acetonitrile / water, 50:50) to obtain 10 mg of a light yellow solid powder, yield: 9.25%, HPLC purity: 96.90%. ESI-MS m / z: 375.27 [M+H] + . 1 H NMR(600MHz,DMSO)δ8.38(s,1H),7.16(s,2H),5.12(s,1H),4.89(s,1H),4.64(s,1H),4.38(s,1H),4.05(d,J =4.1Hz, 2H), 3.57 (t, J = 6.5Hz, 2H), 3.15 (s, 6H), 3.07 (dd, J = 13.2, 7.4Hz, 1H), 2.83 (dd, J = 22.9, 7.7Hz, 2H).

[0791] Example 76

[0792] 2-[1-(5-Bromo-3-fluoropyridin-2-yl)azetidin-3-yl]-1-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 76)

[0793] Synthesis of intermediate P27_2: Intermediate P1_2 (200 mg, 1.21 mmol), 5-bromo-2,3-difluoropyridine (350 mg, 1.81 mmol), cesium carbonate (1.18 g, 3.62 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (48 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (51 mg, 0.05 mmol) were added to a 50 ml reaction flask, 1,4-dioxane (5 mL) was added, the mixture was vacuumed, nitrogen purged three times, and stirred at 90 ° C for 8 h. After the reaction was completed by LCMS monitoring, the reaction solution was concentrated, the residue was diluted with water (3x20 ml), and extracted with ethyl acetate (3x100 ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: PE / EA, 9% EA) afforded 150 mg of a yellow transparent oil, yield: 40.92%. ESI-MS m / z: 303.04 [M+H] + ,305.05[M+2+H] + .

[0794] Synthesis of intermediate P27: Intermediate P27_2 (100 mg, 0.33 mmol) was dissolved in methanol (4 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to around 13. The solution was stirred at room temperature for 3 h. TLC and LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated to remove methanol from the system. The aqueous phase was washed with DCM (3 x 20 ml) to remove organic impurities and then the pH was adjusted to around 5 with 1 M dilute hydrochloric acid. The solution was concentrated under reduced pressure to dryness and the concentrate was further dried in a vacuum drying oven to obtain 200 mg of a yellow solid powder. ESI-MS m / z: 289.02 [M+H] + ,291.02[M+2+H] + .

[0795] Synthesis of Compound 76: 200 mg of intermediate P27 was added to a reaction flask, acetonitrile (2 ml) was added, and the mixture was sonicated and filtered. N-methylimidazole (48 mg, 0.58 mmol) was added to the filtrate and stirred for 15 min. Intermediate M9 (55 mg, 0.28 mmol) was weighed and added, stirred and dissolved, and finally N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (85 mg, 0.30 mmol) was added and stirred and dissolved. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The mixture was washed thoroughly with purified water (10 ml, three times). The filter cake was purified by HPLC (acetonitrile / water = 60:40) to obtain 20 mg of a light yellow solid powder (yield: 16.67%), HPLC purity: 92.74%. ESI-MS m / z: 435.17 [M+H] + ,437.18[M+2+H] + . 1 H NMR (600MHz, DMSO) δ8.38(s,1H),8.01(s,1H),7.76(d,J=11.6Hz,1H),5.12(s,1H),4.89(s,1H),4.63(s,1H),4.38(s,1H ), 4.22 (d, J = 7.3Hz, 2H), 3.78 (t, J = 6.9Hz, 2H), 3.14 (s, 6H), 3.06 (dd, J = 13.2, 5.8Hz, 1H), 2.83 (dd, J = 24.2, 7.7Hz, 2H).

[0796] Example 77

[0797] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3-fluoro-4-methylpyridin-2-yl)azetidin-3-yl]ethan-1-one (Compound 77)

[0798] Synthesis of intermediate P28_2: Intermediate P1_2 (200 mg, 1.21 mmol), 2-bromo-3-fluoro-4-methylpyridine (343 mg, 1.81 mmol), cesium carbonate (1.18 g, 3.62 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (57 mg, 0.12 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (62 mg, 0.06 mmol) were added to a 50 ml reaction flask, toluene (5 mL) was added, the mixture was vacuumed, nitrogen purged three times, and stirred at 90 ° C for 8 h. After completion of the reaction, the reaction solution was concentrated by LCMS monitoring, the residue was diluted with water (3x20 ml), and extracted with ethyl acetate (3x100 ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. 200 mg of a yellow transparent oil was obtained, with a yield of 69.44%. ESI-MS m / z: 239.26 [M+H] + .

[0799] Synthesis of intermediate P28: Intermediate P28_2 (200 mg, 0.84 mmol) was dissolved in methanol (4 ml) and stirred. 1 M sodium hydroxide solution was added dropwise to adjust the pH of the reaction solution to around 13. The reaction was stirred at room temperature for 3 h. TLC and LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated to remove methanol from the system. The aqueous phase was washed with DCM (3 x 20 ml) to remove organic impurities and then the pH was adjusted to around 5 with 1 M dilute hydrochloric acid. The solution was concentrated under reduced pressure to dryness and the concentrate was further dried in a vacuum drying oven to obtain 220 mg of a yellow solid powder. ESI-MS m / z: 225.22 [M+H] + .

[0800] Synthesis of Compound 77: 220 mg of intermediate P28 was added to acetonitrile (2 ml), sonicated, and filtered. N-methylimidazole (60 mg, 0.73 mmol) was added to the filtrate and stirred for 15 min. Intermediate M9 (70 mg, 0.35 mmol) was then weighed and dissolved. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (110 mg, 0.38 mmol) was added and stirred for 4 h. The reaction mixture was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The mixture was washed thoroughly with purified water (10 ml, three times). The filter cake was purified by HPLC (mobile phase: acetonitrile:water = 28:72) to obtain 22 mg of a light yellow solid powder, with a yield of 16.97% and an HPLC purity of 93.30%. ESI-MS m / z: 371.36 [M+H] + . 1H NMR (600MHz, DMSO) δ8.38(s,1H),7.74(d,J=4.9Hz,1H),6.56(t,J=4.7Hz,1H),5.12(s,1H),4.89(s,1H),4.64(s,1H),4.39(s,1H),4. 18(dd,J=4.9,1.9Hz,2H), 3.75(dd,J=7.8,6.2Hz,2H), 3.15(s,6H), 3.04(d,J=6.1Hz,1H), 2.82(dd,J=25.0,7.6Hz,2H), 2.16(s,3H).

[0801] Example 78

[0802] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(4-chloro-5-fluoropyridin-2-yl)azetidin-3-yl]ethan-1-one (Compound 78)

[0803] Synthesis of intermediate P29_2: Intermediate P1_2 (200 mg, 1.21 mmol), 2-bromo-4-chloro-5-fluoropyridine (381 mg, 1.81 mmol), cesium carbonate (1.18 g, 3.62 mmol), 2-dicyclohexylphosphine-2', 4', 6'-triisopropylbiphenyl (48 mg, 0.10 mmol), tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (51 mg, 0.05 mmol) were added to a 50 ml reaction flask, toluene (5 mL) was added, the mixture was vacuumed, nitrogen purged three times, and stirred at 90 ° C for 8 h. After completion of the reaction, the reaction solution was concentrated by LCMS monitoring, the residue was diluted with water (3x20 ml), and extracted with ethyl acetate (3x100 ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, eluent: PE / EA, 8% EA) afforded 80 mg of a light yellow transparent oil, with a yield of 25.56%. ESI-MS m / z: 259.15 [M+H] + .

[0804] Synthesis of intermediate P29: Intermediate P29_2 (80 mg, 0.31 mmol) was dissolved in methanol (4 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to around 13. The solution was stirred at room temperature for 3 h. TLC and LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated to remove methanol from the system. The aqueous phase was washed with DCM (3 x 20 ml) to remove organic impurities and then the pH was adjusted to around 5 with 1 M dilute hydrochloric acid. The product was then extracted with DCM (3 x 20 ml), dried over anhydrous sodium sulfate, and concentrated to give 40 mg of a yellow oil with a yield of 52.91%. ESI-MS m / z: 245.13 [M+H] + .

[0805] Synthesis of Compound 78: Intermediate P29 (40 mg, 0.16 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (28 mg, 0.34 mmol) was added and stirred for 15 min. Intermediate M9 (33 mg, 0.16 mmol) was weighed and added and stirred to dissolve. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (50 mg, 0.18 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The mixture was washed thoroughly with purified water (10 ml, three times). The filter cake was dried to obtain 7 mg of a light yellow solid powder, with a yield of 10.99%. ESI-MS m / z: 391.23 [M+H] + . 1 H NMR(600MHz,MeOD)δ8.36(s,1H),7.97(s,1H),6.51(s,1H),5.18(s,1H),4.99(s,1H),4.69(s, 1H),4.53(s,1H),4.19(s,2H),3.73(s,2H),3.23(s,6H),2.92–2.86(m,1H),1.35–1.27(m,2H).

[0806] Example 79

[0807] 1-[2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3,5-difluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 79)

[0808] Intermediate P6 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M10 (30 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 41 mg of white solid powder compound 79, with a yield of 76.18%. ESI-MS m / z: 409.48 [M+H] + .

[0809] Example 80

[0810] 2-[1-(3-Bromo-2-fluoro-6-nitrophenyl)azetidin-3-yl]-1-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 80)

[0811] Synthesis of intermediate P31_2: Intermediate P1_2 (200 mg, 1.21 mmol), intermediate P31_1 (430 mg, 1.81 mmol), cesium carbonate (1.18 g, 3.62 mmol), 2-dicyclohexylphosphine-2',4',6'-triisopropylbiphenyl (57 mg, 0.12 mmol), and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (62 mg, 0.06 mmol) were added to a 50 ml reaction flask. 1,4-dioxane (5 mL) was added and the mixture was evacuated, replaced with nitrogen three times, and stirred at 90 ° C for 8 h. After the reaction was completed, the reaction solution was concentrated and the residue was diluted with water (3x20 ml) and extracted with ethyl acetate (3x100 ml). The combined organic layer was washed with saturated sodium chloride aqueous solution (2x10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was obtained as a yellow transparent oil (200 mg), with a yield of 34.48%. ESI-MS m / z: 347.04 [M+H] + ,349.01[M+2+H] + .

[0812] Synthesis of Intermediate P31: Intermediate P31_2 (200 mg, 0.58 mmol) was dissolved in methanol (4 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. The solution was stirred at room temperature for 3 h. TLC and LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated to remove methanol from the system. The aqueous phase was washed with DCM (3 x 20 ml) to remove organic impurities and then the pH was adjusted to approximately 5 with 1 M dilute hydrochloric acid. The solution was concentrated under reduced pressure to dryness and the concentrate was further dried in a vacuum drying oven to obtain 117 mg of a yellow solid powder in a yield of 60.62%. ESI-MS m / z: 332.96 [M+H] + ,334.93[M+2+H] + .

[0813] Synthesis of Compound 80: Intermediate P31 (117 mg, 0.35 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (60 mg, 0.73 mmol) was added and stirred for 15 min. Intermediate M9 (70 mg, 0.35 mmol) was weighed and added and dissolved with stirring. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (110 mg, 0.38 mmol) was added and dissolved with stirring. The mixture was stirred at room temperature for 4 h. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1) to obtain 16 mg of a light yellow solid powder in a yield of 9.54%. ESI-MS m / z: 479.20 [M+H] + ,481.20[M+2+H] + . 1 H NMR (600MHz, DMSO) δ8.38(s,1H),7.50(d,J=9.0Hz,1H),7.10–6.94(m,1H),5.09(s,1H),4.88(s,1H),4.61(s,1H),4.37(s ,1H),4.24(t,J=8.5Hz,2H),3.77(d,J=3.9Hz,2H),3.14(d,J=3.0Hz,6H),3.03–2.96(m,1H),2.82(dd,J=24.6,7.6Hz,2H).

[0814] Example 81

[0815] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-{2,2,4,4-tetradeuteride-1-[2-(trifluoromethyl)pyridin-4-yl]azetidin-3-yl}ethan-1-one (Compound 81)

[0816] Synthesis of Intermediate P32_2: 4-Bromo-2-(trifluoromethyl)pyridine (1.38 g, 6.11 mmol), 3-hydroxyazetidine hydrochloride (1 g, 9.12 mmol), cesium fluoride (927 mg, 6.11 mmol), and triethylamine (2.40 g, 23.72 mmol) were placed in a 50 mL round-bottom flask. 10 mL of DMSO was added and stirred. The mixture was heated to 90°C under nitrogen for 12 h. LCMS confirmed the reaction was complete. The temperature was lowered, and 50 mL of water was added to the reaction mixture with stirring. A large amount of white solid precipitated. The mixture was filtered and the filter cake was dried in an air drying oven to obtain 1.51 g of a white solid, with a yield of 75.88%. ESI-MS m / z: 219.10 [M+H]. + .

[0817] Synthesis of Intermediate P32_3: Intermediate P32_2 (1 g, 4.59 mmol) and Dess-Martin periodinane (3.9 g, 9.20 mmol, DMP) were placed in a 50 mL round-bottom flask, stirred evenly with 12 mL of dichloromethane, and allowed to react at room temperature for 10 h. LCMS monitoring confirmed the reaction was complete. After completion, 15 mL of dichloromethane and 50 mL of saturated sodium thiosulfate solution were added to the reaction solution and stirred for 30 min. The mixture was allowed to stand for separation, and the organic layer was collected. 50 mL of saturated sodium carbonate was added and stirred for 15 min. The organic layer was separated and dried, then purified by column chromatography (pure DCM) to obtain 700 mg of Intermediate P32_3 as a white powder in a yield of 70.71%. ESI-MS m / z: 249.17 [M+CH3OH+H] + .

[0818] Synthesis of Intermediate P32_4: Intermediate P32_3 (700 mg, 3.24 mmol), potassium tert-butoxide (1.45 g, 12.96 mmol), and 5 mL of deuterated methanol were placed in a 50 mL round-bottom flask and allowed to react at room temperature for 18 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was dropwise added with 1 mol / L hydrochloric acid to adjust the pH to 7 and concentrated in vacuo. The residue was extracted with 50 mL of water and 3 times of dichloromethane (40 mL). The aqueous phase was collected and dried to give 566 mg of Intermediate P32_4 as a white solid (yield 79.41%). ESI-MS m / z: 239.16 [M+H2O+H] + .

[0819] Synthesis of Intermediate P32_5: Intermediate P32_4 (566 mg, 2.57 mmol) and ethoxycarbonylmethylenetriphenylphosphine (896 mg, 2.57 mmol) were placed in a 50 mL round-bottom flask, stirred with 6 mL of dichloromethane, and allowed to react at room temperature for 17 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated in vacuo, and the residue was extracted with water (40 mL x 3) and 50 mL of dichloromethane. The organic phase was collected, dried, and purified by column chromatography (eluent: petroleum ether / ethyl acetate, gradient 100:1) to obtain 456 mg of Intermediate P32_5 as a white solid in a yield of 61.21%. ESI-MS m / z: 291.16 [M+H] + .

[0820] Synthesis of Intermediate P32_6: Intermediate P32_5 (456 mg, 1.57 mmol) and 160 mg of Pd / C were placed in a 50 mL round-bottom flask. 6 mL of dichloromethane was added and stirred. The mixture was allowed to react at room temperature under a hydrogen atmosphere for 19 h. LCMS monitoring confirmed the reaction was complete. The reaction mixture was filtered and the filtrate was dried to yield 176 mg of Intermediate P32_6 in a 38.22% yield. ESI-MS m / z: 293.16 [M+H] + .

[0821] Synthesis of Intermediate P32_7: Intermediate P32_6 (176 mg, 0.60 mmol) and 6 mL of methanol were placed in a round-bottom flask. 1 mol / L NaOH was slowly added dropwise to adjust the pH of the solution to 13-14. The mixture was allowed to react at room temperature for 3 h. LCMS monitoring confirmed the reaction was complete. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and dichloromethane (60 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1 mol / L dilute hydrochloric acid. The product was then lyophilized to yield 600 mg of Intermediate P32_7 containing sodium chloride. ESI-MS m / z: 265.13 [M+H] +

[0822] Synthesis of the final product, Compound 81: 600 mg of the salt-containing intermediate P32_7 was placed in a round-bottom flask, acetonitrile (3 mL x 3) was added, and ultrasonic filtration was performed. To the filtrate, intermediate M9 (80 mg, 0.49 mmol) and N-methylimidazole (140 mg, 1.71 mmol, NMI) were added and stirred evenly. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (150 mg, 0.54 mmol, TCFH) was weighed and added to the reaction solution. The reaction was allowed to react at room temperature for 3 h. LCMS monitoring showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried. After purification by thin-layer chromatography (developing solvent: dichloromethane:methanol = 15:1), 32 mg of the final product, Compound 81, was obtained as an off-white powder in a yield of 22.31%. ESI-MS m / z:205.97[M+H] + / 2. 1 H NMR (600MHz, DMSO-d6) δ8.39(s,J=1.7Hz,1H),8.20(d,J=5.7Hz,1H),6.71(s,J=2.2Hz,1H),6.53(m,J=5.2,2.3Hz,1H),5.12(s,1 H), 4.90 (s, 1H), 4.64 (s, J = 2.6Hz, 1H), 4.39 (s, 1H), 3.15 (s, 6H), 3.11–3.06 (m, 1H), 2.86 (d, J = 7.8Hz, 1H), 2.83 (d, J = 7.7Hz, 1H).

[0823] Example 82

[0824] 1-[4-(Dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-{1-[3-fluoro-5-(trifluoromethyl)pyridin-2-yl]azetidin-3-yl}ethan-1-one (Compound 82)

[0825] Synthesis of Intermediate P33_2: Intermediate P1_2 (0.64 g, 3.88 mmol), 2-bromo-3-fluoro-5-trifluoromethylpyridine (1.18 g, 4.86 mmol), and 1,1'-binaphthyl-2,2'-diyl(diphenylphosphine) (120 mg, 0.19 mmol) were added to a reaction flask. Toluene (10 ml) was added and dissolved with stirring. Cesium carbonate (3.16 g, 9.7 mmol) was then added and heated in an oil bath at 70°C. After the temperature rose, tris(dibenzylideneacetone)dipalladium(0) (89 mg, 0.10 mmol) was added and the reaction was maintained at 70°C for 8 hours. LCMS monitoring indicated that the reaction was complete. Most of the toluene was removed by vacuum concentration, and the residue was diluted with water (3 x 20 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over sodium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, cyclohexane / ethyl acetate, gradient 10:1 to 1:1) afforded 286 mg of a colorless, transparent oil (yield 25.25%). ESI-MS m / z: 293.18 [M+H] + .

[0826] Synthesis of Intermediate P33: Intermediate P33_2 (286 mg, 0.98 mmol) was dissolved in methanol (10.0 ml) with stirring. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. Stirring was continued at room temperature for 10 h. LCMS monitoring indicated that the reaction was complete. 1 M dilute hydrochloric acid was added to the reaction solution to adjust the pH to approximately 5. A white solid powder precipitated. After standing for 10 min, the mixture was filtered and washed with purified water (10 ml x 3). The filter cake was then dried at 40°C to yield 166 mg of a white solid powder, a yield of 60.96%. ESI-MS m / z: 279.16 [M+H] + .

[0827] Synthesis of the final product, Compound 82: Intermediate P33 (36 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M9 (26 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 21 mg of white solid powder, Compound 82, with a yield of 38.16%. ESI-MS m / z: 425.34 [M+H] + . 1H NMR(600MHz,DMSO-d6)δ8.39(d,J=1.4Hz,1H),8.26–8.22(m,1H),7.81(dt,J =12.4,2.5Hz,1H),5.12(t,J=2.1Hz,1H),4.90(s,1H),4.64(d,J=2.0Hz,1H), 4.39(t,J=2.0Hz,1H),4.34(q,J=8.8,8.1Hz,2H),3.91(t,J=7.4Hz,2H),3.1 5(d,J=1.6Hz,6H), 3.10(s,1H), 2.88(d,J=7.7Hz,1H), 2.84(d,J=7.7Hz,1H).

[0828] Example 83

[0829] 2-[1-(3,5-difluoropyridin-4-yl)azetidin-3-yl]-1-[4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]ethan-1-one (Compound 83)

[0830] Intermediate P6 (30 mg, 0.13 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M9 (26 mg, 0.13 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40°C to obtain 34 mg of white solid powder compound 83, with a yield of 70.46%. ESI-MS m / z: 375.39 [M+H] + . 1 H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.09–8.06(m,2H),5.12(d,J=2.0Hz,1H),4.91–4.87(m,1H),4.63(d,J=1.9Hz,1H),4.48–4.40(m,2H) ,4.38(d,J=2.1Hz,1H),4.05–3.99(m,2H),3.15(d,J=4.2Hz,6H),3.07(qd,J=8.1,5.9Hz,1H),2.87(d,J=7.7Hz,1H),2.83(d,J=7.6Hz,1H).

[0831] Example 84

[0832] 1-[2-Chloro-4-(dimethylamino)-6,7-dihydro-5H-pyrrolo[4,3-d]pyrimidin-6-yl]-2-[1-(3-fluoropyridin-4-yl)azetidin-3-yl]ethan-1-one (Compound 84)

[0833] Intermediate P5 (25 mg, 0.12 mmol) was weighed and dissolved in acetonitrile (2 ml). N-methylimidazole (38 mg, 0.46 mmol) was added and stirred for 15 min. Intermediate M10 (27 mg, 0.12 mmol) was weighed and added and stirred to dissolve. N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (39 mg, 0.14 mmol) was added and stirred to dissolve. The mixture was stirred at room temperature for 4 h. The reaction solution was added dropwise to purified water (10 ml), allowed to stand for 10 min, and then filtered. The filter cake was washed with purified water (10 ml x 3) and dried at 40 ° C to obtain 42 mg of white solid powder compound 84, with a yield of 90.46%. ESI-MS m / z: 391.47 [M+H] + . 1 H NMR (600MHz, Methanol-d4) δ8.26(d,J=6.8Hz,1H),8.00(d,J=6.8Hz,1H),6.69(ddd,J=8.8,6.9,2.5Hz,1H),5.13(d,J=2.1Hz,1H),4.95(t,J=1 .9Hz,2H),4.67–4.63(m,2H),4.49(d,J=2.1Hz,1H),3.23(d,J=4.9Hz,7H),2.96(d,J=7.7Hz,1H),2.92(d,J=7.7Hz,2H),2.62(q,J=2.0Hz,1H).

[0834] Example 85

[0835] Synthesis of intermediate P34_2: Intermediate P1_2 (361 mg, 2.19 mmol), 3,5-dichloro-4-iodopyridine (627 mg, 2.29 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (55 mg, 54 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.78 g, 5.46 mmol) were placed in a round-bottom flask. 10 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 16 h. LC-MS monitored the reaction to be complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 1.21 g of crude product, which was directly used in the next step. ESI-MS m / z: 275.11 [M+H] + .

[0836] Synthesis of Intermediate P34: The crude intermediate P34_2 (1 g) was placed in a flask, 5 mL of methanol was added and stirred, and 1 M sodium hydroxide was slowly added dropwise to the flask to adjust the pH of the solution to 13-14. The reaction was allowed to react at room temperature for 2 h. LC-MS monitored the reaction to completion. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and dichloromethane (60 mL x 3). The organic phase was discarded, and the aqueous phase was adjusted to pH 5 with 1 M dilute hydrochloric acid. A white solid precipitated and was filtered. The filter cake was the product and dried to obtain 350 mg of a white powder. ESI-MS m / z: 261.06 [M+H] + .

[0837] Synthesis of Compound 85: Intermediate P34 (100 mg, 0.38 mmol), intermediate M16 (81 mg, 0.38 mmol), and N-methylimidazole (80 mg, 1.33 mmol) were placed in a round-bottom flask and stirred thoroughly with 4 mL of acetonitrile. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (118 mg, 0.42 mmol) was added to the reaction mixture and allowed to react at room temperature for 3 h. LC-MS monitored the reaction for completion. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and 3 times of dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and purified by thin-layer chromatography (developing solvent: methanol / dichloromethane 15:1) to obtain 25 mg of the final product as a white powder in a yield of 15.72%. ESI-MS m / z: 210.27 [M / 2+1]. + . 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=1.6Hz,1H),8.04(d,J=1.5Hz,2H),4.90–4.84(m,1H),4.83–4.74(m,2H),4.67–4.60(m ,2H),4.40–4.36(m,1H),4.36–4.27(m,2H),4.26–4.15(m,4H),2.93–2.85(m,1H),2.84–2.77(m,2H),2.37–2.30(m,2H).

[0838] Example 86

[0839] Synthesis of Intermediate P35_2: Intermediate P1_2 (90 mg, 0.55 mmol), 3,5-dibromo-4-iodopyridine (200 mg, 0.55 mmol), cesium carbonate (450 mg, 1.38 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (32 mg, 0.06 mmol), and tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (28 mg, 0.03 mmol) were added to a 50 ml reaction flask. Anhydrous 1,4-dioxane (3 mL) was added, and the mixture was evacuated, replaced with nitrogen three times, and stirred at 90°C overnight. After completion of the reaction, the reaction solution was concentrated, and the residue was diluted with water (3 x 20 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic layers were washed with saturated aqueous sodium chloride (2 x 10 ml), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (SiO2, eluent: ethyl acetate / petroleum ether, 11%) to afford 90 mg of a yellow, transparent oil in a 44.87% yield. ESI-MS m / z: 362.97 [M+H] + ,364.99[M+2+H] + .

[0840] Synthesis of Intermediate P35: Intermediate P35_2 (90 mg, 0.25 mmol) was dissolved in methanol (2 ml) and stirred. 1 M sodium hydroxide solution was added to adjust the pH of the solution to approximately 13. The solution was stirred at room temperature for 2 h. TLC and LC-MS monitored the reaction for completion. The reaction solution was concentrated to remove methanol from the system. The aqueous phase was washed with DCM (3 x 20 ml) to remove organic impurities and then the pH was adjusted to approximately 5 with 1 M dilute hydrochloric acid. Solids gradually precipitated. The filter cake was filtered and dried to obtain 19 mg of a white solid in a yield of 22.09%. ESI-MS m / z: 348.95 [M+H]. + ,350.94[M+2+H] + .

[0841] Synthesis of Compound 86: Intermediate M16 (12 mg, 0.05 mmol) was weighed and dissolved in analytically pure acetonitrile (2 ml). N-methylimidazole (9 mg, 0.11 mmol) was added and dissolved with stirring for 15 min. Intermediate P35 (19 mg, 0.05 mmol) was weighed and dissolved with stirring. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (17 mg, 0.06 mmol) was added and dissolved with stirring. The mixture was stirred at room temperature for 4 h. After completion of the reaction, solids gradually precipitated. LC-MS monitoring revealed that the reaction solution was filtered and then washed thoroughly with purified water (10 ml, three times). The filter cake was dried to obtain 20 mg of a white solid powder in a yield of 72.54%. ESI-MS m / z: 255.09, 256.00 [M / 2+H] + ;508.99,509.04[M+H] + . 1 H NMR (400MHz, DMSO) δ8.37(d,J=1.8Hz,1H),8.18(d,J=1.4Hz,2H),4.87(s,1H),4.81(t,J=8.2Hz,2H),4.64(d,J=12.4Hz, 2H),4.38(s,1H),4.31(dd,J=8.6,5.5Hz,2H),4.20(s,4H),2.81(d,J=4.9Hz,2H),2.71–2.63(m,1H),2.38–2.31(m,2H).

[0842] Example 87

[0843] Synthesis of Intermediate P36_2: Intermediate P1_2 (361 mg, 2.19 mmol), 3-chloro-4-iodopyridine (547 mg, 2.29 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (49 mg, 48 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63 mg, 0.11 mmol), and cesium carbonate (1.78 g, 5.46 mmol) were placed in a round-bottom flask. 10 mL of toluene was added and stirred evenly. The mixture was placed in a 90°C oil bath and reacted for 15 h. LC-MS monitored the reaction to be complete. The reaction solution was filtered and the filtrate was concentrated in vacuo to obtain 1.16 g of crude product, which was directly used in the next step. LC-MS (ESI) m / z = 241.17 [M+H] + .

[0844] Synthesis of Intermediate P36: 1.12 g of crude intermediate P36_2 was placed in a flask, 5 mL of methanol was added, and the mixture was stirred. 1 M sodium hydroxide was slowly added dropwise to the flask to adjust the pH to 13-14. The reaction was allowed to react at room temperature for 2 h. LC-MS monitored the reaction for completion. The reaction solution was concentrated in vacuo, and the residue was extracted with 60 mL of water and 3 times of dichloromethane (60 mL). The organic phase was discarded, and the aqueous phase was adjusted to a pH of approximately 5 with 1 M dilute hydrochloric acid. The mixture was then concentrated under reduced pressure to yield 1 g of a yellow solid containing sodium chloride. LC-MS (ESI) m / z = 227.15 [M+H] + .

[0845] Synthesis of Example 87: 200 mg of the salt-containing intermediate P36 was placed in a round-bottom flask, added to acetonitrile (3 mL x 3), and ultrasonically filtered. To the filtrate, intermediate M16 (60 mg, 0.28 mmol) and N-methylimidazole (80 mg, 0.98 mmol) were added and stirred thoroughly. Finally, N,N,N',N'-tetramethylchloroformamidine hexafluorophosphate (87 mg, 0.31 mmol) was added to the reaction mixture and allowed to react at room temperature for 3 h. LC-MS monitored the reaction to be complete. The reaction mixture was concentrated under reduced pressure, and the residue was extracted with 50 mL of water and dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried to dryness. Purification by thin-layer chromatography (developing solvent: methanol / dichloromethane 15:1) afforded 23 mg of the final product as a yellow solid in a yield of 21.34%. LC-MS (ESI) m / z = 193.27 [M / 2+1]. 1 H NMR (400MHz, DMSO-d6) δ8.37(d,J=2.2Hz,1H),8.22(s,1H),8.08(d,J=5.9Hz,1H),6.51(d,J=6.0Hz,1H),4.88(d,J=2.3Hz,1H),4. 69-4.60(m,2H),4.51-4.32(m,3H),4.28-4.13(m,4H),4.03-3.91(m,2H),3.08–2.99(m,1H),2.88-2.79(m,2H),2.39-2.29(m,2H).

[0846] Comparative Example 1

[0847] Intermediate P2 (0.13 mmol, 1.0 eq, 30 mg) was weighed and dissolved in analytically pure acetonitrile (2 ml). NMI (0.46 mmol, 3.5 eq, 38 mg) was added and stirred for 15 minutes. Intermediate M13 (0.13 mmol, 1.0 eq, 25 mg) was weighed and dissolved. TCFH (0.14 mmol, 1.1 eq, 54 mg) was added and stirred for 4 hours. The reaction solution was added dropwise to purified water (10 ml) for crystallization. After standing for 10 minutes, it was filtered and the filter cake was washed thoroughly with purified water (10 ml, three times) and dried at 40°C to obtain comparative example compound 1 as a yellow solid (16 mg, yield: 33.55%, purity: HPLC>95%). ESI-MS m / z: 365.1 [M+H]+. 1 H NMR (400MHz, CDCl3) δ7.68–7.58(m,2H),7.32(dd,J=8.1,5.3Hz,1H),6.17(t,J=5.8Hz,1H),4.84(d,J=17.9 Hz, 4H), 4.44 (td, J = 8.3, 2.0Hz, 2H), 3.93 (dd, J = 14.8, 7.0Hz, 2H), 3.37–3.20 (m, 1H), 2.83 (d, J = 7.7Hz, 2H).

[0848] Comparative Example 2

[0849] The structure of the compound of Comparative Example 2 is shown below, and it was prepared according to the method of Example 1 (Compound 1) of Patent PCT / CN2023 / 127298.

[0850] Comparative Example 3

[0851] The structure of the compound of Comparative Example 3 is shown below, and it was prepared according to the method of Example 7 (Compound 7) of Patent PCT / CN2023 / 127298.

[0852] CVL-231 (Emraclidine):

[0853] Biological activity test

[0854] Biological Example 1: Testing of the Allosteric Modulatory Activity of the Compounds of the Invention on Acetylcholine-Activated M4 Receptors

[0855] Experimental purpose: Using FLIPR detection technology, we detected the allosteric regulatory effect of the test compound on the intracellular calcium ion release induced by acetylcholine activation of M4 receptor at the cellular level.

[0856] Main experimental materials and sources:

[0857] DMEM (culture medium)—gibco-11965-092

[0858] Fluo-4Direct TM Kit—Invitrogen-F10471

[0859] 384-well poly-lysine-coated cell plate - Greiner-781090

[0860] Vi-cell XR Cell Viability Analyzer - Beckman Coulter

[0861] Compound Preparation ECHO (Acoustic Pipetting System) - Greiner-781280

[0862] Experimental plan:

[0863] 1. Cell preparation: Take Chinese Hamster Ovary cells (CHO) in the logarithmic growth phase that stably express M4 muscarinic acetylcholine receptor (M4mAChR) and culture the cells. Wash with DPBS (Dulbecco's phosphate buffered saline) buffer, add 3mL of EDTA (ethylenediaminetetraacetic acid)-trypsin and place in a 37°C carbon dioxide incubator for digestion. After 1-2 minutes, remove the cells and add culture medium to terminate the digestion. Repeatedly pipette to disperse the cells and then centrifuge to collect the cells. Cells were plated at 10x10 5 The cells were suspended in growth medium at a concentration of 10 cells / ml; 20 μL of the cell suspension (20K / well) was added to each well of a 384-well plate; and the cells were placed in a 37° C., 5% CO 2 incubator overnight.

[0864] 2. FLIPR experiment preparation: prepare probenecid in FLIPR assay buffer; prepare 2X (8 μM) Fluo-4Direct TM The sample was diluted to 10 points with loading buffer (10 mL each). Then 900 nL of compound was transferred to a 384-well compound plate using an ECHO pipetting system.

[0865] 3. Add Fluo-4: Remove the cell plate from the incubator, gently remove the culture medium, and use a pipette to add 20 μL of assay buffer and 20 μL of 2X Fluo-4Direct™ No-Wash Loading Buffer to the 384-well cell culture plate. The final volume in the cell culture plate is 40 μL.

[0866] 4. Incubation: Incubate at 37°C, 5% CO2 for 50 minutes, then incubate at room temperature for 10 minutes.

[0867] 5. Test: Remove the cell plate from the incubator and place it in the FLIPR. Run the FLIPR instrument software and follow the program settings to add 10uL of the experimental buffer solution and read the fluorescence signal. Then add 10μL of the agonist reference compound, read the fluorescence signal, and calculate the EC 20 , prepare 6×EC 20 agonist concentration. Make a 3-fold 10-point serial dilution of the test compound and reference compound using ECHO, and transfer 900 nL to the compound plate. Add 40 μL of FLIPR buffered saline to the compound plate. Run the FLIPR instrument software and, according to the set program, add 10 μL of the test compound and reference compound to the cell plate and read the fluorescence signal. Then add 10 μL of 6×EC 20 concentration of agonist to the cell plate and read the fluorescence signal.

[0868] 6. Experimental Evaluation Methods and Results Analysis: The functional drug screening system FLIPR was used to detect changes in intracellular calcium ion concentration. The maximum activation percentage of calcium flux (% Activity @ Max Dose) was used to determine the in vitro cellular activity of the compounds of this invention. The results are shown in Tables 1 and 2 below.

[0869] Table 1. Allosteric regulation of the compounds of the present invention on acetylcholine-activated M4 receptors

[0870] Table 2. Allosteric regulation of the compounds of the present invention on acetylcholine-activated M4 receptors

[0871] Biological Example 2: Central nervous system excitation inhibitory effect test

[0872] Experimental purpose: To determine the inhibitory effect of the compounds of the present invention on central nervous system excitation in the KM mouse central nervous system excitation model.

[0873] Experimental instrument: Rat and mouse autonomous movement analyzer

[0874] Experimental animals: Male KM mice (purchased from Hunan Slake Jingda Experimental Animal Co., Ltd.) were selected as experimental animals. The weight was 18-20 g when purchased, and the weight was about 21-23 g after two days of adaptation to the breeding environment.

[0875] Experimental animal adaptation process for the experimental environment: After the purchased male KM mice have passed the quarantine, they are adapted to the experimental environment in the animal breeding room for two days. On the third day, a special metal piece is attached to the right foot of the mouse and the mouse is placed in a mouse adaptation cylinder to adapt to the experimental environment for 2-3 days, 1-2 hours a day. The adaptation standard is that 90% of the mice are completely quiet. After the adaptation is completed each day, the fallen metal piece is replaced in time.

[0876] Experimental Methods: Before the formal experiment, KM male mice were placed in an acclimation cylinder for 15-30 minutes. Mice that were lying quietly and safely were selected for the formal experiment. Before the experiment, the locomotor activity analyzer was debugged to ensure the stability of the instrument. The model group was given a subcutaneous injection of the modeling agent (5ml / kg, 10mg / kg morphine hydrochloride injection) on one side of the abdomen to establish the model. The blank control group was not given the modeling agent or any test sample. The test group was first given a subcutaneous injection of 10mg / kg morphine hydrochloride injection on one side of the abdomen to establish the model. At the same time, the drug was administered to the other side of the abdomen according to the provided administration method and dosage. After standing for 15 minutes, the mice were placed in the locomotor activity analyzer and the changes in mouse activity were recorded for 60 minutes.

[0877] Results and Data Processing and Analysis: The efficacy of the test compound was expressed as the percentage inhibition of spontaneous activity (MPE%) in mice. The data were processed using the statistical software Graph Pad 9.0. All statistical analyses were performed using two-tailed analysis, with a statistical level set at P ≤ 0.05. Each indicator was expressed as "mean ± standard error." Based on the obtained results, a sample distribution diagram, a time-dependent curve of spontaneous activity changes, and a graph of spontaneous activity inhibition were plotted and analyzed. The experimental results are shown in Table 3 below:

[0878] Table 3. Efficacy results of each group in the central nervous system excitation model

[0879] *p<0.05, **p<0.01, ***p<0.001, ****p<0.0001 vs. model group, two-way ANOVA statistics

[0880] The compound of the present invention has a significant central nervous system excitation inhibitory effect, and its central nervous system excitation inhibitory effect in vivo is significantly better than that of the control compound, and it still has a good central nervous system excitation inhibitory effect at a lower concentration.

[0881] Biological Example 3: Determination of the inhibitory effect of the compound of the present invention on MK-801-induced fast activity behavior in mice

[0882] 1.1 Experimental Animals and Instruments: 17-19 g SPF-grade male ICR mice were purchased from Hunan Slake Jingda Laboratory Animal Co., Ltd.; the mouse open field test chamber and VisuTrack animal behavior analysis software were purchased from Shanghai Xinruan.

[0883] 1.2 Test samples and solvents

[0884] MK-801: 0.9% NaCl injection (solvent), purchased from Shanghai MacLean Biochemical Technology Co., Ltd.; the compound of this example, CVL231, Comparative Example 1 and Comparative Example 2: 5% DMSO + 30% PEG-400 + 5% Tween-80 + 60% saline (solvent).

[0885] Experimental methods:

[0886] Purchased SPF-grade male ICR mice were acclimated to the housing environment for 3 days. Prior to the experiment, the mice were placed in an open-field chamber for 2-3 hours to reduce their anxiety about the new environment. During the experiment, the animals were grouped by weight and randomly divided into a blank group, a model group, and a treatment group, with 10 mice per group. Detailed dosing information is shown in Table 4 below:

[0887] Table 4. Experimental groups and drug administration information

[0888] The mice were dosed according to the above grouping and dosing information. The drug-treated group was given the corresponding compound by intraperitoneal injection according to the corresponding dosage. The blank group and the model group were given the same volume of solvent by intraperitoneal injection. 15 minutes later, all groups except the blank group were injected with MK-801 (0.3 mg / kg) by intraperitoneal injection. The blank group was injected with the same volume of normal saline. After administration, the mice were immediately placed in the experimental box. The activities of the mice in the experimental box (total movement distance) were automatically recorded by a camera for 30 minutes, and the recorded mouse activities were analyzed and processed using VisuTrack animal behavior analysis software. After the experiment, the experimental results were processed using the statistical software Graph Pad 9.0. All statistical analyses were performed using one-tailed analysis, and the statistical level was set at P ≤ 0.05. Each indicator is expressed as "mean ± standard error". MPE% (Maximum Possible Effect, as a percentage) was calculated based on the results.

[0889] MPE%=(Mean(model)-individual data) / (Mean(model)-Mean(sham))×100%.

[0890] Notes: ① Subtract the values ​​of the sham group to eliminate the influence of background noise on the experiment. ② Mean(model) represents the mean value of the model group; Mean(sham) represents the mean value of the blank control; Individual data: Individual data of the drug-treated group. The experimental results are shown in Table 5 below:

[0891] Table 5. Inhibitory effects of the compounds of the present invention on MK-801-induced rapid activity behavior in mice Note: *p<0.05, **p<0.01, ***p<0.001.

[0892] The above results show that a single intraperitoneal injection of 10 mg / kg of representative compounds 54, 55, 56, 57, 71, 72, and 83 of the present invention significantly inhibited MK-801-induced hyperlocomotion in mice. Furthermore, compound 55 of the present invention significantly inhibited MK-801-induced hyperlocomotion in mice at 3 mg / kg, with an MPE% of 46±6.7*. However, CVL-231, Comparative Example 2, and Comparative Example 3 showed no significant inhibitory effect on MK-801-induced hyperlocomotion at this dose.

[0893] Although the embodiments disclosed in this application are as described above, the contents described are merely embodiments adopted to facilitate understanding of this application and are not intended to limit this application. Any person skilled in the art to which this application belongs may make any modifications and changes in the form and details of the implementation without departing from the spirit and scope disclosed in this application, but the scope of protection of this application shall still be based on the scope defined by the attached claims.

Claims

1. A compound of formula (I), its stereoisomers, its N-oxides or its pharmaceutically acceptable salts: Among them, Ring A is selected from C 6-10 aryl and 5- to 10-membered heteroaryl; R1 and R2 are each independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, -OR a , -SR a , -S(O)2R a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R c , -S(O)2NR b R c , -NR b S(O)2R a , -NR b C(O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl, and 4- to 7-membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl, and 4- to 7-membered heterocyclic group are optionally substituted with one or more R d substituents; Each R3 is independently selected from hydrogen, protium, deuterium, tritium, halogen, cyano, nitro, -OR a 、-SR a 、-S(O)2R a 、-C(O)R a 、-C(O)OR a 、-NR b R c 、-C(O)NR b R c 、-S(O)2NR b R c 、-NR b S(O)2R a 、C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted with one or more R d substituted; R a 、R b and R c each independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted with one or more R d substituents; R d each independently selected from halogen, hydroxy, amino, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and C1-C6 alkoxy; n is an integer of 0, 1, 2, 3, 4, 5, 6 or 7; p is an integer of 1, 2 or 3; L1, L2, S1 and S2 are each independently selected from a single bond and -(CR e R f ) m -, where R e and R f are each independently selected from hydrogen, deuterium, chlorine and C1-C6 alkyl, m is an integer of 1, 2, 3 or 4, and it is stipulated that L1 and L2 are not both single bonds, and S1 and S2 are not both single bonds; M is selected from a single bond, -O-, and -CR e R f -, where R e and R f are each independently selected from hydrogen, deuterium, chlorine, and C1-C6 alkyl, and it is stipulated that when M is selected from a single bond, L1 is -CH2-, L2 is -CH2-, and the ring formed by S1 and S2 is 2. The compound represented by formula (I) as claimed in claim 1, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) The said C 6-10 The aryl group is independently phenyl or naphthyl, preferably phenyl; (2) The 5- to 10-membered heteroaryl is independently a 5- to 6-membered heteroaryl; (3) The heteroatoms in the 5- to 10-membered heteroaryl are independently N, O or S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatom of the 5- to 10-membered heteroaryl is N, and the number of heteroatoms can be 1 or 2; (4) The 5- to 10-membered heteroaryl is independently monocyclic or polycyclic; the polycyclic can be a fused ring; the polycyclic can be bicyclic or tricyclic; (5) The 5- to 10-membered heteroaryl group is independently a pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, pyrrolyl group, pyrazolyl group, imidazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, furyl group, thienyl group, quinolinyl group or isoquinolinyl group; preferably a pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group, quinolinyl group or isoquinolinyl group; more preferably (6) The halogen is independently fluorine, chlorine, bromine or iodine; (7) The C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl; (8) The C1-C6 haloalkyl is independently a C1-C3 alkyl substituted by one or more halogens, such as -CH2F, -CH2Cl, -CHF2, -CHCl2, -CCl3, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3, preferably -CF3; (9) The C3-C6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, preferably cyclopropyl; (10) The heteroatoms in the 4- to 7-membered heterocyclic group are independently N, O or S, and the number of heteroatoms is 1, 2 or 3; preferably, the heteroatoms in the 4- to 7-membered heterocyclic group are N or O, and the number of heteroatoms can be 1 or 2; (11) The 4- to 7-membered heterocyclic group is independently a 5- to 6-membered heterocyclic group; (12) The 4- to 7-membered heterocyclic group is independently Preferably and (13) The C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably methoxy.

3. The compound represented by formula (I) according to claim 1, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) Ring A is phenyl or a 5- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms of N, O or S, preferably phenyl or a 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms of N, O or S, more preferably a 5- to 6-membered heteroaryl containing 1 or 2 N atoms, such as pyridyl; (2) Each of R1 and R2 is independently hydrogen, halogen, cyano, nitro, -OR a , -SR a , -S(O)2R a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R c , -S(O)2NR b R c , -NR b S(O)2R a , -NR b C(O)R a , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl or a 4- to 7-membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4- to 7-membered heterocyclic group are optionally substituted by one or more R d substituted; Preferably, each of R1 and R2 is independently hydrogen, halogen, -OR a , -SR a , -S(O)2R a , -C(O)OR a , -NR b R c , -S(O)2NR b R c , C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl or a 4- to 7-membered heterocyclic group, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, -(CH2)p-C3-C6 cycloalkyl and 4- to 7-membered heterocyclic group are optionally substituted by one or more R d substituents; More preferably, each of R1 and R2 is independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or a 4- to 7-membered heterocyclic group, wherein the 4- to 7-membered heterocyclic group is optionally substituted with one or more R d substituents; More preferably, each of R1 and R2 is independently -H, -F, -Cl, -Br, -CH3, -CH2CH3, -CF3, -NHCH3, -N(CH3)2, -N(CH2CH3)2, (3) Each R3 is independently hydrogen, halogen, cyano, nitro, -OR a , -SR a , -S(O)2R a , -C(O)R a , -C(O)OR a , -NR b R c , -C(O)NR b R c , -S(O)2NR b R c , -NR b S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, C3-C6 cycloalkyl or -(CH2)p-C3-C6 cycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl and -(CH2)p-C3-C6 cycloalkyl are optionally substituted by one or more R d substituted; Preferably, each R3 is independently hydrogen, halogen, -OR a , -SR a , -S(O)2R a , -C(O)OR a , -NR b R c , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, wherein the C1-C6 alkyl is optionally substituted by one or more R d substituted; More preferably, each R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl, such as F, methyl, methoxy, -S(O)2CF3 or -CF3; More preferably, each R3 is independently halogen, -S(O)2R a or C1-C6 haloalkyl, such as F, -S(O)2CF3 or -CF3; (4) n is 0, 1, 2 or 3, preferably 1 or 2, more preferably 2; (5)R a 、R b and R c each independently is hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with one or more R d substituents; Preferably, R a , R b and R c are each independently hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group; (6)R d Each independently is halogen, hydroxy, amino, C1-C6 alkyl, C3-C6 cycloalkyl or C1-C6 alkoxy, preferably halogen or C1-C6 alkyl; (7)L1 and L2 are each independently a single bond or -(CH2) m -; m is 1, 2 or 3; L1 and L2 are not simultaneously a single bond; (8) S1 and S2 are each independently a single bond or -(CH2) m -; m is 1, 2 or 3; S1 and S2 are not simultaneously a single bond; and (9) M is a single bond or -CR e R f -, where R e and R f are each independently selected from hydrogen, deuterium, chlorine, and C1-C6 alkyl; when M is selected from a single bond, L1 is -CH2-, L2 is -CH2-, and the ring formed by S1 and S2 is Preferably, M is -CR e R f -, where R e and R f are each independently selected from hydrogen, deuterium, F, and methyl; More preferably, M is -CH2-.

4. The compound of formula (I) as claimed in claim 1, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) R1 is hydrogen, halogen or C1-C6 alkyl, preferably hydrogen or halogen, more preferably H or Cl; (2) R2 is hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or a 4- to 7-membered heterocyclic group, preferably hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2, more preferably hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2, still more preferably hydrogen, Cl or -N(CH3)2; (3) L1 is -CH2- or -(CH2)2-, preferably -CH2-; (4) L2 is -CH2- or -(CH2)2-, preferably -CH2-; (5) S1 is -CH2- or -(CH2)2-, preferably -CH2-; (6) S2 is -CH2- or -(CH2)2-, preferably -CH2-; (7) Fragment For Preferably and (8) Fragment For Preferably 5. The compound represented by formula (I), its stereoisomers, its N-oxides or its pharmaceutically acceptable salts as claimed in claim 1, characterized in that, The compound represented by formula (I) satisfies one or more of the following conditions: (1) R2 is hydrogen, halogen, -OR a , -NR b R c , -NR b C(O)R a , C1-C6 alkyl or a 4- to 7-membered heterocyclic group, wherein the 4- to 7-membered heterocyclic group is optionally substituted by one or more R d ; preferably, R2 is -NHCH3, -N(CH2CH3)2, -OCH3, -OH, -NH2, Preferably, R2 is (2) Each R3 is independently hydrogen, halogen, cyano, nitro, -OR a , -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; (3) S1 is -CD2-, -CH2- or -(CH2)2-; (4) S2 is -CD2-, -CH2- or -(CH2)2-; and (5)R a 、R b and R c are each independently hydrogen, a C1-C6 alkyl group, a C1-C6 haloalkyl group or a C3-C6 cycloalkyl group, where the C1-C6 alkyl group is optionally substituted with one or more R d substituents.

6. The compound of formula (I) as claimed in claim 1, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, characterized in that, The compound represented by formula (I) satisfies one or both of the following conditions: (1) Fragment For Preferably and (2) Fragment For 7. The compound represented by formula (I) as claimed in claim 1, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, characterized in that, The compound represented by formula (I) satisfies one or both of the following conditions: (1) The 4- to 7-membered heterocycle is a 4-membered heterocyclic group; more preferably, the heteroatom of the 4-membered heterocyclic group is N and the number of heteroatoms is 1; and (2) Fragment For Preferably 8. The compound represented by formula (I), its stereoisomers, its N-oxides or its pharmaceutically acceptable salts according to any one of claims 1-7, characterized in that, The compound represented by formula (I) satisfies one of the following schemes: Scheme 1: The compound represented by the formula (I) has the structural characteristics of the formula (II): Wherein, the definitions of R1, R2, R3, M, S1, S2, A and n are as described in any one of claims 1-7; Scheme 2: The compound represented by formula (I) has the structural feature of formula (III): Wherein, the definitions of R1, R2, R3, A and n are as described in any one of claims 1-7; Scheme 3: The compound represented by formula (I) has the structural feature of formula (IV): Wherein, the definitions of R1, R2, R3, A and n are as described in any one of claims 1-7; Scheme 4: The compound represented by the formula (I) has the structural feature of the formula (V): Wherein, the definitions of R1, R2, R3, A and n are as described in any one of claims 1-7; Scheme 5: The compound represented by formula (I) has the structural feature of formula (VI): Wherein, the definitions of R1, R2, R3, A and n are as described in any one of claims 1-7; Scheme 6: The compound represented by formula (I) has the structural feature of formula (VII): Wherein, the definitions of R1, R2 and R3 are as described in any one of claims 1-7.

9. The compound represented by formula (I), its stereoisomers, its N-oxides or its pharmaceutically acceptable salts according to any one of claims 1-8, characterized in that, The compound represented by formula (I) satisfies one of the following schemes: Scheme 1: The compound represented by the formula (I) has the structural feature of the formula (III): Wherein, Ring A is phenyl or a 5- to 6-membered heteroaryl containing 1, 2 or 3 N atoms; R1 and R2 are each independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or a 4- to 7-membered heterocyclic group, wherein the 4- to 7-membered heterocyclic group is optionally substituted with one or more R d substituents; Each R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; R a 、R b and R c each independently is hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group; R d Each independently is a halogen or a C1-C6 alkyl group; n is an integer of 0, 1 or 2; Scheme 2: The compound represented by formula (I) has the structural feature of formula (III): Wherein, Ring A is phenyl or pyridyl; R1 is hydrogen, halogen or C1-C6 alkyl; R2 is hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2; Each R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; R a is preferably hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group; n is an integer of 0, 1 or 2; Scheme 3: The compound represented by formula (I) has the structural feature of formula (IV): Wherein, Ring A is phenyl or a 5- to 6-membered heteroaryl containing 1, 2 or 3 N atoms; R1 and R2 are each independently hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or a 4- to 7-membered heterocyclic group, where the 4- to 7-membered heterocyclic group is optionally substituted with one or more R d substituents; Each R3 is independently hydrogen, halogen, -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; R a 、R b and R c are each independently hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group; R d Each independently is a halogen or a C1-C6 alkyl group; n is an integer of 0, 1 or 2; Scheme 4: The compound represented by the formula (I) has the structural feature of the formula (IV): Wherein, Ring A is phenyl or pyridyl; R1 is hydrogen, halogen or C1-C6 alkyl; R2 is hydrogen, C1-C6 alkyl, halogen or -N(C1-C6 alkyl)2; Each of R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; R a is preferably hydrogen, C1-C6 alkyl or C1-C6 haloalkyl; n is an integer of 0, 1 or 2; Scheme 5: The compound represented by the formula (I) has the structural feature of the formula (VII): R1 is H or Cl; R2 is H, Cl or -N(CH3)2; R1 and R2 are not both H at the same time; R3 are each independently H, F or -CF3; R3 are not all H at the same time; Scheme 6: The compound represented by the formula (I) has the structural feature of the formula (III): R1 is H or halogen; R2 is -NR b R c or a 4- to 7-membered heterocyclic group; R a and R b each independently selected from hydrogen or C1-C6 alkyl; Fragment For Scheme 7: The compound represented by formula (I) has the structural feature of formula (III): R1 is H or Cl; R2 is -NR b R c or a 4- to 7-membered heterocyclic group; R b and R c each independently selected from hydrogen or C1-C6 alkyl; Fragment For Scheme 8: The compound represented by the formula (I) has the structural feature of the formula (III): Ring A is phenyl or pyridyl; R1 is hydrogen or halogen; R2 is hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or a 4- to 7-membered heterocyclic group; Each R3 is independently hydrogen, halogen, cyano, nitro, -OR a , -S(O)2R a , C1-C6 alkyl, C1-C6 alkoxy or C1-C6 haloalkyl; R a is hydrogen, a C1-C6 alkyl group or a C1-C6 haloalkyl group; n is an integer of 0, 1 or 2; Scheme 9: The compound represented by formula (I) has the structural feature of formula (III): Ring A is phenyl or pyridyl; R1 is hydrogen or halogen; R2 is hydrogen, halogen, -NR b R c , C1-C6 alkyl, C1-C6 haloalkyl or a 4- to 7-membered heterocyclic group; R b and R c each independently selected from hydrogen or C1-C6 alkyl; Each R3 is independently hydrogen, halogen, -S(O)2R a or C1-C6 haloalkyl; n is an integer of 0, 1 or 2; Scheme 10: The compound represented by formula (I) has the structural feature of formula (III): R1 is H or Cl; R2 is hydrogen, halogen, -NR b R c , C1-C6 alkyl or a 4- to 7-membered heterocyclic group; the heteroatom in the 4- to 7-membered heterocyclic group is N or O, and the number of heteroatoms is 1 or 2; R b and R c each independently selected from hydrogen or C1-C6 alkyl; R3 are each independently F, -S(O)2CF3 or -CF3; n is 2; Ring A is Scheme 11: The compound represented by formula (I) has the structural feature of formula (III): R1 is H or Cl; R2 is H, Cl, -N(CH3)2 or a 4- to 7-membered heterocyclic group; the heteroatom in the 4- to 7-membered heterocyclic group is N or O and the number of heteroatoms is 1 or 2; Fragment For Scheme 12: The compound represented by formula (I) has the structural feature of formula (III): R1 is H or Cl; R2 is H, Cl or Fragment For Scheme 13: The compound represented by the formula (I) has the structural feature of the formula (III): Wherein, R1 is H or halogen; R2 is H, halogen, -NR b R c or a 4- to 7-membered heterocyclic group; R b and R c each independently selected from hydrogen or C1-C6 alkyl; Fragment For Scheme 14: The compound represented by formula (I) has the structural feature of formula (III): Wherein, R1 is H or Cl; R2 is -NR b R c or a 4- to 7-membered heterocyclic group; the heteroatom in the 4- to 7-membered heterocyclic group is N or O, and the number of heteroatoms is 1 or 2; R b and R c each independently selected from hydrogen or C1-C6 alkyl; Fragment For Scheme 15: The compound represented by formula (I) has the structural feature of formula (III): Wherein, R1 is H or Cl; R2 is -N(CH3)2- or Fragment For 10. The compound represented by formula (I) according to claim 1, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, characterized in that, The compound represented by the formula (I) is selected from any of the following compounds:

11. A method for preparing a compound of formula (I) as described in any one of claims 1-10, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, said preparation method comprising the following steps: The compound of formula (I) is prepared from the intermediate of formula (VIII) or its salt and the intermediate of formula (IX) in the presence of an amide condensing agent; Among them, R1, R2, R3, L1, L2, M, S1, S2, A and n are defined as described in any one of claims 1-10; The amide condensing agent is a carbodiimide condensing agent, an onium salt condensing agent or an organophosphorus condensing agent; Preferably, the preparation method satisfies one or more of the following conditions: (1) The salt is hydrochloride, sulfate or trifluoromethanesulfonate; (2) The amide condensing agent is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole; (3) The preparation may further include an organic solvent, and the organic solvent is a nitrile solvent, such as acetonitrile; (4) The molar ratio of intermediate formula (VIII) to intermediate formula (IX) is 1:(0.5-2), preferably 1:1; (5) When the amide condensing agent is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole, the molar ratio of intermediate formula (VIII) to N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate is 1:(1-2), preferably 1:1.2; (6) When the amide condensing agent is N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate and N-methylimidazole, the molar ratio of intermediate formula (VIII) to N-methylimidazole is 1:(2-5), preferably 1:3.5; (7) The reaction temperature of the preparation method is 0-60 °C, preferably 10-30 °C; and (8) The reaction time of the preparation method is 2-10 hours, such as 4 hours.

12. A pharmaceutical composition comprising a compound of formula (I) as described in any one of claims 1-10, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, and at least one pharmaceutical excipient.

13. Use of a compound of formula (I) as described in any one of claims 1-10, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, or a pharmaceutical composition as described in claim 12 in the preparation of a drug for treating and / or preventing M4-mediated diseases and / or disorders; Preferably, the M4-mediated diseases and / or disorders include but are not limited to: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver, hepatitis or atherosclerosis.

14. Use of a compound of formula (I) as described in any one of claims 1-10, its stereoisomers, its N-oxides or its pharmaceutically acceptable salts, or a pharmaceutical composition as described in claim 12 in the preparation of a drug for treating and / or preventing diseases and / or disorders; The diseases and / or disorders include, but are not limited to: Alzheimer's disease, schizophrenia or psychosis, pain, addiction, sleep disorders, cognitive disorders, depression, Parkinson's disease, Huntington's disease, movement disorders, pulmonary hypertension, chronic obstructive pulmonary disease, asthma, urinary incontinence, glaucoma, cerebral amyloid angiopathy, dementia, stroke, pancreatitis, peripheral amyloidosis, diabetes, alcoholic liver, hepatitis or atherosclerosis.

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