Tricyclic compounds, processes for their preparation and uses thereof

Abstract

The application discloses a kind of three annelated compounds, its preparation method and purposes, the three annelated compounds have as shown in structure of formula I, it can be used to treat a variety of mental diseases and neurodegenerative diseases such as schizophrenia, depression, Parkinson's disease etc.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of tri-cyclic compound, its preparation method and use. BACKGROUND

[0002] Monoamine G-protein coupled receptors (GPCRs), such as dopamine receptors, 5-hydroxytryptamine (5-HT) receptors, etc., are associated with various mental and neurodegenerative diseases, such as schizophrenia, depression, Parkinson's disease, etc. Accordingly, most of the anti-mental and neurodegenerative disease drugs exert their effects by regulating the functions of monoamine GPCRs such as dopamine receptors, 5-hydroxytryptamine receptors, etc.

[0003] There are five subtypes of dopamine receptors (D1-5), among which D1 and D5 are D1-type receptors, mainly coupled with G s proteins, and after activation, the intracellular cyclic adenosine monophosphate (cAMP) level is increased; D2, D3 and D4 are D2-type receptors, mainly coupled with G i proteins, and after activation, the intracellular cAMP level is decreased. Abnormalities in the dopaminergic signaling pathway are associated with various diseases such as schizophrenia, Parkinson's disease, etc. Small molecule antagonists or partial agonists targeting dopamine D2 receptors are effective antipsychotic drugs, and the main action targets of drugs such as haloperidol, olanzapine, risperidone, aripiprazole, cariprazine, etc. are dopamine D2 receptors. Dopamine D3 receptors, which belong to the same subfamily as D2, are also important targets of many antipsychotic drugs (such as cariprazine), and highly selective D3 receptor antagonists or partial agonists also have the potential to treat drug addiction.

[0004] Among the five subtypes of dopamine receptors, the D2 receptor has been most extensively and deeply studied. According to the intrinsic activity of dopamine D2 receptor ligands, they can be divided into agonists, antagonists or partial agonists, etc. Clinical drugs such as pramipexole, ropinirole, rotigotine, etc. are agonists of dopamine D2 receptors, which activate dopamine D2 receptors to exert therapeutic effects and are used for the treatment of diseases such as Parkinson's disease and restless leg syndrome. Non-classical antipsychotic drugs such as haloperidol, olanzapine, risperidone, etc. are antagonists of dopamine D2 receptors, which antagonize D2 receptors to exert their effects. The latest generation of antipsychotic drugs, i.e. aripiprazole, brexpiprazole and cariprazine, are partial agonists of dopamine D2 receptors, which can stabilize the dopaminergic signal and are also known as dopamine stabilizers.

[0005] It is worth mentioning that most of the currently known dopamine D2 antagonists and partial agonists have the disadvantage of poor selectivity. For drugs targeting dopamine D2 receptors, the effects of the compounds on other targets can affect the efficacy and side effects of the drugs. For example, for dopamine D2 receptor antagonists, the antagonistic effect of the drug on 5-HT 2A receptors can improve the extrapyramidal side effects of the compound, in which case the antagonistic effect of 5-HT 2A receptors is beneficial. In fact, 5-HT 2A is also another important target of antipsychotic drugs, and is a major target of multi-target “atypical” antipsychotic drugs. The relative strength of the affinity of antipsychotic drugs for 5-HT 2A receptors and dopamine D2 receptors is an important basis for distinguishing “typical” and “atypical” drugs. However, the effects on many other targets, such as the antagonistic effect on histamine H1, the antagonistic effect on 5-HT 2C receptors, and the off-target effects of drugs on cholinergic receptors and adrenergic receptors, are the reasons why most current antipsychotic drugs have many side effects, such as causing weight gain, inducing diabetes, etc. The off-target inhibition of cholinergic activity by some drugs is also a possible cause of further deterioration of cognitive function in patients.

[0006] Recent studies have shown that the antagonistic effect of 5-HT 2A receptors is not necessary for the antipsychotic activity of dopamine D2 receptor partial agonists. D2 receptor partial agonists with reduced 5-HT 2A receptor antagonism have better efficacy in improving the negative symptoms and cognitive function of schizophrenia (Chen et al., Nat Neurosci 2022, 25, 39-49).

[0007] Another target closely related to the treatment of mental illnesses such as schizophrenia is the serotonin 5-HT 1A receptor. 5-HT 1A receptor agonists show good clinical application prospects in the treatment of depression, anxiety, and improvement of negative symptoms and cognitive function in patients with schizophrenia. For dopamine D2 receptor antagonists, the agonistic or partial agonistic effect of the drug on 5-HT 1A receptors can also improve the extrapyramidal side effects of the drug. Atypical antipsychotic drugs such as aripiprazole, brexpiprazole, and cariprazine all have 5-HT 1APartial agonist effect of the receptor. Tandospirone for treating generalized anxiety state, gepirone with antidepressant and anxiolytic effect, buspirone for treating anxiety-related symptoms, ipsapirone with antidepressant and anxiolytic effect, etc., all have 5-HT 1A Pharmacological effect of receptor agonist. 5-HT 1A Receptor agonist Flibanserin was approved by the US FDA in 2015 for the treatment of female sexual desire. 5-HT 1A Receptor agonist or partial agonist is an important direction for the development of new drugs for the treatment of schizophrenia, depression, anxiety, etc.

[0008] Therefore, the development of small molecule compounds with new functional characteristics and selectivity for dopamine D2 receptor, 5-HT 1A Receptor, etc. Monoamine GPCR has the potential to obtain new antipsychotic drugs, enhance efficacy and reduce related side effects. SUMMARY

[0009] In order to overcome the above problems in the prior art, the present application provides a kind of tri-cyclic compound, its preparation method and purposes. The compound of the present application can be used for the treatment of various mental diseases and neurodegenerative diseases such as schizophrenia, depression, Parkinson's disease, etc.

[0010] The present application provides a compound represented by formula I, or a pharmaceutically acceptable salt, isotope derivative, enantiomer, diastereoisomer, tautomer or solvate thereof,

[0011]

[0012] Wherein,

[0013] X is N, O, NR a Or CR b ;

[0014] Y is C or N;

[0015] Is a double bond or a single bond;

[0016] R a And R b Each independently is H or C1-C6 alkyl;

[0017] L is -(CR c R d ) m - or -(CR c R d ) n1-CH=CH-(CR c R d ) n2 -;

[0018] R c and R d each independently is H or C1-C6 alkyl;

[0019] m, n1and n2each independently is 1, 2, 3, 4, 5 or 6;

[0020] M is absent, -O- or -NH-C(O)-;

[0021] Ring Q is a saturated or partially unsaturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring or an 8-11 membered bicyclic fused ring; one ring in said 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;

[0022] R1is C1-C6 alkyl or haloC1-C6 alkyl;

[0023] R2each independently is F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkyl or haloC1-C6 alkoxy;

[0024] R3each independently is F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, haloC1-C6 alkyl, haloC1-C6 alkoxy, -NH-C(O)R e or -NH-S(O)2R e ;

[0025] or, two R3form a 3-8 membered cycloalkyl ring with the atom to which they are attached;

[0026] R e is C1-C6 alkyl, -NH2, -NHR g , -NR f R g or 5-6 membered heteroaryl;

[0027] R f and R g each independently is C1-C6 alkyl;

[0028] R4is oxo (=O);

[0029] p, q and r each independently is 0, 1, 2, 3 or 4;

[0030] the number of heteroatoms in the heterocyclic ring, the heteroaryl ring and the heteroaryl group is independently 1, 2 or 3, each of the heteroatoms being independently N, O or S.

[0031] In some embodiments, R a and R b are H.

[0032] In some embodiments, R c and R d are H.

[0033] In some embodiments, m is 2, 3 or 4.

[0034] In some embodiments, m is 1.

[0035] In some embodiments, n1 and n2 are 1.

[0036] In some embodiments, L is -(CH2)2-, -(CH2)3-, -(CH2)4- or -(CH2)-CH=CH-(CH2)-.

[0037] In some embodiments, L is -(CH2)-.

[0038] In some embodiments, in M, -NH-C(O)- is attached to L via the N atom.

[0039] In some embodiments, each R1 is independently C1-C6 alkyl, such as methyl, ethyl or isopropyl.

[0040] In some embodiments, each R3 is independently F, Cl, Br, I, hydroxyl, C1-C6 alkyl, -NH-C(O)R e or -NH-S(O)2R e ; preferably, each R3 is independently C1-C6 alkyl or -NH-C(O)R e .

[0041] In some embodiments, p is 0.

[0042] In some embodiments, ring Q is attached to M via a C atom.

[0043] In some embodiments, in ring Q, the 3-8 membered carbocyclic ring is a 4, 5, 6 or 7 membered carbocyclic ring.

[0044] In some embodiments, in ring Q, the 3-8 membered heterocyclic ring is a 6 membered heterocyclic ring.

[0045] In some embodiments, in ring Q, the heteroatom in the 3-8 membered heterocyclic ring is N or O, such as a N atom.

[0046] In some embodiments, in ring Q, the 6-10 membered aromatic ring is a benzene ring.

[0047] In some embodiments, in ring Q, the 5-10 membered heteroaromatic ring has 1 or 2 heteroatoms.

[0048] In some embodiments, in ring Q, the 8-11 membered bicyclic fused ring has one ring that is a saturated or partially unsaturated 5-7 membered heterocyclic ring and the other ring that is a benzene ring or a 5-6 membered heteroaromatic ring, wherein the number of heteroatoms in each of the 5-7 membered heterocyclic ring and the 5-6 membered heteroaromatic ring is independently 1 or 2, and the heteroatoms are N.

[0049] In some embodiments, ring Q is (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ),

[0050] (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ), (e.g. ) or (e.g. ).

[0051] In some embodiments, is

[0052] In some embodiments, is

[0053] In some embodiments, q is 0, 1 or 2.

[0054] In some embodiments, r is 0, 1 or 2.

[0055] In some embodiments, is

[0056] wherein R 3-1 is R3, R 3-2 is H or R3, and q and R3 are as defined in any of the embodiments of the application.

[0057] In some embodiments, wherein R 3-1 is each independently -NH-C(O)R e or -NH-S(O)2R e .

[0058] In some embodiments, is In some embodiments, wherein R 3-1 is hydroxy.

[0059] In some embodiments, is For example In some embodiments, wherein R 3-1 is each independently -NH-C(O)R e or -NH-S(O)2R.

[0060] In some embodiments, wherein R 3-1 is each independently -NH-C(O)R e or -NH-S(O)2R e .

[0061] In some embodiments, R 3-1 is each independently F, Cl, Br, I, hydroxy, C1-C6 alkyl or C1-C6 alkoxy.

[0062] In some embodiments, is In some embodiments, In some embodiments,

[0063] In some embodiments, In some embodiments,

[0064]

[0065] In some embodiments, In some embodiments,

[0066] In some embodiments, In some embodiments,

[0067] Scheme (1): In some embodiments,

[0068]

[0069] Scheme (2): In some embodiments,

[0070]

[0071] Scheme (3): In some embodiments,

[0072]

[0073] Scheme (4): In some embodiments,

[0074] Scheme (5): In some embodiments,

[0075] Scheme (6): In some embodiments,

[0076] In some embodiments, L is -(CR c R d )-, M is absent.

[0077] In some embodiments, L is -(CR c R d )2-, M is absent or -NH-C(O)-.

[0078] In some embodiments, L is -(CR c R d )3-, M is -O-.

[0079] In some embodiments, L is -(CR c R d )3-, M is absent.

[0080] In some embodiments, L is -(CR c R d )4-, M is -O-.

[0081] In some embodiments, L is -(CR c R d )4-, M is absent.

[0082] In some embodiments, L is -(CR c R d )-CH=CH-(CR c R d )-, M is -O-.

[0083] In some embodiments, in ring Q, the 3-8 membered carbocyclic ring is a 5-8 membered carbocyclic ring, preferably a 5-7 membered carbocyclic ring, for example a 6-7 membered carbocyclic ring.

[0084] In some embodiments, in ring Q, the 3-8 membered heterocyclic ring is a nitrogen containing 6 membered heterocyclic ring, for example piperidine;

[0085] In some embodiments, in ring Q, the 5-10 membered heteroaromatic ring is

[0086] In some embodiments, in ring Q, the 8-11 membered bicyclic fused ring is an 8-10 membered bicyclic fused ring.

[0087] In some embodiments, in ring Q, the 8-11 membered bicyclic fused ring, one of the rings is a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the 5-7 membered heterocyclic ring contains at most one N atom or at most one O atom.

[0088] In some embodiments, in ring Q, the 8-11 membered bicyclic fused ring, one of the rings is a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the 5-7 membered heterocyclic ring contains at most one N atom or at most one O atom.

[0089] In some embodiments, L is -(CR c R d )2-, in ring Q, the saturated or partially unsaturated 5-7 membered heterocyclic ring in the 8-11 membered bicyclic fused ring contains at most one N.

[0090] In some embodiments, L is -(CR c R d )4-; M is -O-; and the benzene ring or 5-6 membered heteroaromatic ring in the 8-11 membered bicyclic fused ring is a 5-6 membered aromatic heterocycle.

[0091] In some embodiments, ring Q is a saturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or an 8-11 membered bicyclic fused ring; one ring in the 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring.

[0092] In some embodiments, ring Q is a saturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a phenyl group, a 5-10 membered heteroaromatic ring, or an 8-10 membered bicyclic fused ring; one ring in the 8-10 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring.

[0093] In some embodiments, the compound of Formula I has any one of the following structures:

[0094]

[0095] wherein each variable is defined according to any one of the embodiments described herein.

[0096] In some embodiments, the compound is according to any one of the following embodiments:

[0097] Embodiment (1):

[0098] X is N, O, NR a or CR b ;

[0099] Y is C or N;

[0100] L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -;

[0101] R c and R d are each independently H;

[0102] m is 1, 2, 3, or 4;

[0103] n1and n2are 1;

[0104] P is 0;

[0105] r is 0, 1, or 2;

[0106] q is 0, 1, or 2;

[0107] M is absent, -O-, or -NH-C(O)-;

[0108] Ring Q is a saturated 3-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or an 8-11 membered bicyclic fused ring; one ring in the 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;

[0109] R1is C1-C6alkyl;

[0110] R3is each independently F, Cl, Br, I, hydroxyl, C1-C6alkyl, -NH-C(O)R e , or -NH-S(O)2R e ; preferably, R3is each independently hydroxyl, C1-C6alkyl, -NH-C(O)R e , or -NH-S(O)2R e ; alternatively, two R3form a 3-8 membered cycloalkyl with the atom to which they are attached;

[0111] R e is C1-C6alkyl, -NH2, -NHR g , -NR f R g , or 5-6 membered heteroaryl;

[0112] R f and R g are each independently C1-C6alkyl;

[0113] R4is oxo (=O);

[0114] the number of heteroatoms in the heterocyclic ring, heteroaromatic ring, and heteroaryl group is each independently 1, 2, or 3, and the heteroatoms are each independently N, O, or S.

[0115] Scheme (2):

[0116] L is -(CR c R d ) m - or -(CR c Rd ) n1 -CH=CH-(CR c R d ) n2 -;

[0117] R c and R d Each is independently represented by H;

[0118] m can be 1, 2, 3, or 4;

[0119] n1 and n2 are both 1;

[0120] P is 0;

[0121] r is 0, 1, or 2;

[0122] q is 0, 1, or 2;

[0123] M is non-existent, -O-, or -NH-C(O)-;

[0124] Ring Q is a saturated 3-8 membered carbon ring, a saturated or partially unsaturated 3-8 membered heterocycle, a phenyl ring, a 5-10 membered heteroaromatic ring, or an 8-10 membered bicyclic fused ring; one ring of the 8-10 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-6 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocycle in the saturated or partially unsaturated 5-6 membered heterocycle of the 8-10 membered bicyclic fused ring contains one oxygen atom, one nitrogen atom, two nitrogen atoms, or one oxygen atom and one nitrogen atom;

[0125] R1 is a C1-C6 alkyl group;

[0126] R3 is a hydroxyl group, a C1-C6 alkyl group, or a -NH-C(O)R group. e or -NH-S(O)2R e Alternatively, the two R3 atoms and the atoms attached to them form a 3-8 cycloalkyl group;

[0127] R e C1-C6 alkyl, -NH2, -NHR g -NR f R g Or 5-6 yuan of heteroaryl compounds;

[0128] R f and R g Each is independently a C1-C6 alkyl group;

[0129] R4 is an oxometalate (=O);

[0130] the number of heteroatoms in the heterocyclic ring, the heteroaromatic ring and the heteroaryl group is independently 1, 2 or 3, each of the heteroatoms being independently N, O or S;

[0131] Scheme (3):

[0132] X is N or O;

[0133] Y is C;

[0134] P is 0;

[0135] r is 0, 1 or 2;

[0136] q is 0, 1 or 2;

[0137] L is -(CR c R d ) m -; R c and R d are each independently H; m is 2, 3 or 4;

[0138] when m is 2, M is absent or -NH-C(O)-, and ring Q is a saturated 5-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a phenyl group, a 5-10 membered heteroaromatic ring or an 8-11 membered bicyclic fused ring; one ring of the 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;

[0139] when m is 3, M is absent; and ring Q is a partially unsaturated 3-8 membered heterocyclic ring or an 8-11 membered bicyclic fused ring; one ring of the 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring;

[0140] when m is 4, M is -O-, and ring Q is an 8-11 membered bicyclic fused ring; one ring of the 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a 5-6 membered heteroaromatic ring;

[0141] or when m is 4, M is absent;

[0142] R1 is C1-C6 alkyl;

[0143] R3 is each independently F, Cl, Br, I, C1-C6 alkyl or -NH-C(O)R e ; preferably, R3 is each independently F, Cl, Br, I, C1-C6 alkyl or -NH-C(O)R e ; alternatively, two R3 form a 3-8 membered cycloalkyl group with the atom to which they are attached;

[0144] Re C1-C6alkyl, -NH2, -NHR g , -NR f R g or 5-6 membered heteroaryl;

[0145] R f and R g each independently is C1-C6alkyl;

[0146] R4is oxo (=0);

[0147] the number of heteroatoms in the heterocyclic, heteroaromatic and heteroaryl rings is independently 1, 2 or 3, and each of the heteroatoms is independently N, O or S;

[0148] the 5-7 membered heterocyclic ring in the saturated or partially unsaturated 5-7 membered heterocyclic ring in the 8-11 membered bicyclic fused ring contains one oxygen atom, one nitrogen atom, two oxygen atoms, or one oxygen atom and one nitrogen atom;

[0149] Scheme (4):

[0150] X is N or O;

[0151] Y is C;

[0152] P is 0;

[0153] r is 0, 1 or 2;

[0154] q is 0, 1 or 2;

[0155] L is -(CR c R d ) m -; R c and R d each independently is H; m is 2, 3 or 4;

[0156] when m is 2, M is absent or -NH-C(O)-, and ring Q is a saturated 5-8 membered carbocyclic ring, a saturated or partially unsaturated 3-8 membered heterocyclic ring, a phenyl ring, a 5-10 membered heteroaromatic ring, or an 8-10 membered bicyclic fused ring; one ring in the 8-10 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbocyclic ring, or a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring;

[0157] when m is 3, M is absent, and ring Q is a partially unsaturated 3-8 membered heterocyclic ring or an 8-10 membered bicyclic fused ring; one ring in the 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring;

[0158] M is -O-; ring Q is an 8-10 membered bicyclic fused ring; one ring of said 8-10 membered bicyclic fused ring is a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a 5-6 membered heteroaromatic ring;

[0159] or M is absent; ring Q is a saturated or partially unsaturated 3-8 membered heterocyclic ring or an 8-10 membered bicyclic fused ring; one ring of said 8-6 membered bicyclic fused ring is a saturated or partially unsaturated 5-6 membered heterocyclic ring, and the other ring is a benzene ring;

[0160] R1 is C1-C6 alkyl;

[0161] R3 is each independently C1-C6 alkyl, -NH-C(O)R e ; or, two R3 together with the atom to which they are attached form a 3-8 membered cycloalkyl;

[0162] R e is C1-C6 alkyl, -NH2, -NHR g , -NR f R g or 5-6 membered heteroaryl;

[0163] R f and R g are each independently C1-C6 alkyl;

[0164] R4 is oxo (=O);

[0165] the number of heteroatoms in said heterocyclic ring, heteroaromatic ring and heteroaryl is each independently 1, 2 or 3, and said heteroatoms are each independently N, O or S;

[0166] the 5-6 membered heterocyclic ring in the saturated or partially unsaturated 5-6 membered heterocyclic ring in said 8-10 membered bicyclic fused ring contains one oxygen atom, one nitrogen atom, or one oxygen atom and one nitrogen atom;

[0167] Scheme (5):

[0168] X is O; Y is C; P is 0;

[0169] L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 1, 2, 3 or 4;

[0170] L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 - when n1 and n2 are 1, M is -O-, and ring Q is

[0171] L is -(CR c R d ) m - when m is 1, M is absent, ring Q is a saturated 6-membered carbocyclic ring, and R3 is hydroxy;

[0172] L is -(CR c R d ) m - when m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 3-8 membered carbocyclic ring, hexahydropyridine, thiophene, phenyl, and each R3 is independently C1-C6 alkyl, -NH-C(O)R e , R e is C1-C6 alkyl;

[0173] L is -(CR c R d ) m - when m is 3, M is -O-, and ring Q is

[0174] L is -(CR c R d ) m - when m is 4, M is -O- or absent, and ring Q is hexahydropyridine,

[0175] when ring Q is hexahydropyridine, each R3 is independently C1-C6 alkyl;

[0176] when ring Q is , q is 0;

[0177] R1 is C1-C6 alkyl;

[0178] Scheme (6):

[0179] X is N; Y is C; P is 0;

[0180] L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR cR d ) n2 -;R c and R d Each is independently represented by H; m is 2 or 3;

[0181] L is -(CR) c R d ) m When m is 2, M does not exist, ring Q is a saturated 5-7 membered carbon ring, and R3 is independently -NH-C(O)R. e R e It is a C1-C6 alkyl group;

[0182] L is -(CR) c R d ) m When m is 3, M is -O-, and the ring Q is q is 0;

[0183] R1 is a methyl group;

[0184] Option (7):

[0185] X is C; Y is N; P is 0;

[0186] L is -(CR) c R d ) m -or-(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 -;R c and R d Each is independently represented by H; m is 3 or 4;

[0187] L is -(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 When n1 and n2 are 1, M is -O-, and ring Q is

[0188] L is -(CR) c R d ) m When m is 3, M is -O-, and the ring Q is

[0189] L is -(CR) c R d ) m When m is 4, M is -O-, and the ring Q is

[0190] Scheme (8):

[0191] X is O; Y is C; P is 0;

[0192] L is -(CR c R d ) m -; R c and R d are each independently H; m is 2 or 4;

[0193] L is -(CR c R d ) m -; m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 6-7 membered carbocyclic ring, phenyl, an 8-11 membered bicyclic fused ring; one ring of said 8-11 membered bicyclic fused ring is a saturated 5-7 membered heterocyclic ring, the other ring is a 5-6 membered heteroaromatic ring; said 5-6 membered heteroaromatic ring contains one or two nitrogen atoms;

[0194] L is -(CR c R d ) m -; m is 4, M is absent or -O-;

[0195] L is -(CR c R d ) m -; m is 4, M is absent, ring Q is a partially unsaturated 6 membered heterocyclic ring or

[0196] when ring Q is a partially unsaturated 6 membered heterocyclic ring, the heteroatoms in said partially unsaturated 6 membered heterocyclic ring are nitrogen atoms, the number of heteroatoms is independently 1, 2 or 3;

[0197] L is -(CR c R d ) m -; m is 4, M is -O-, ring Q is a partially unsaturated 6 membered heterocyclic ring or

[0198] R3is each independently F, C1-C6 alkyl, -NH-C(O)R e , R e is C1-C6 alkyl.

[0199] Scheme (9):

[0200] X is O; Y is C; P is 0;

[0201] L is -(CR c R d) m - or -(CR c R d ) n1 - CH=CH- (CR c R d ) n2 - ; R c and R d each independently is H; m is 2 or 4;

[0202] L is -(CR c R d ) n1 - CH=CH- (CR c R d ) n2 - ; n1 and n2 are 1, M is -O-, ring Q is

[0203] L is -(CR c R d ) m - ; m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 4-6 membered carbocyclic ring, thiophene, phenyl, R3each independently is C1-C6 alkyl, -NH-C(O)R e , R e is C1-C6 alkyl;

[0204] L is -(CR c R d ) m - ; m is 4, M is -O- or absent, ring Q is hexahydropyridine, q is 0;

[0205] R1is C1-C6 alkyl;

[0206] Scheme (10):

[0207] X is N; Y is C; P is 0;

[0208] L is -(CR c R d ) m - ; R c and R d each independently is H; m is 2 or 3;

[0209] L is -(CR c R d ) m - ; m is 2, M is absent, ring Q is a saturated 6 membered carbocyclic ring, R3each independently is -NH-C(O)R e , R e is C1-C6 alkyl;

[0210] L is -(CR c R d ) m -; when m is 3, M is -O-, and ring Q is q is 0;

[0211] R1is methyl;

[0212] Scheme (11):

[0213] X is C; Y is N; P is 0;

[0214] L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d are each independently H; m is 3 or 4;

[0215] L is -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; when n1 and n2 are 1, M is -O-, and ring Q is

[0216] L is -(CR c R d ) m -; when m is 3, M is -O-, and ring Q is L is -(CR c R d ) m -; when m is 4, M is -O-, and ring Q is In some embodiments, the compound of Formula I has any one of the following structures:

[0217]

[0218]

[0219]

[0220] The present invention also provides a method for preparing the compound shown in Formula I, comprising the following steps: in a solvent (e.g., a mixed solvent of N,N-dimethylformamide and water), the compound shown in Formula II and the compound shown in Formula III (e.g., under the action of DIPEA) undergo the following coupling reaction to obtain the compound shown in Formula I;

[0221]

[0222] Wherein, Hal is a halogen (e.g., Br); the definitions of other variables are as described in any embodiment of the present invention.

[0223] The present invention also provides a pharmaceutical composition comprising a compound of Formula I as described above, or a pharmaceutically acceptable salt, isotope derivative, enantiomer, diastereomer, tautomer, or solvate thereof, and a pharmaceutically acceptable excipient.

[0224] The present invention also provides the use of the pharmaceutical composition described above in the preparation of a medicament for treating mental illness or neurodegenerative diseases.

[0225] The present invention also provides the use of the compound of Formula I as described above, or a pharmaceutically acceptable salt, isotope derivative, enantiomer, diastereomer, tautomer or solvate thereof, in the preparation of a medicament for treating mental illness or neurodegenerative diseases.

[0226] In some implementations, the mental illness or neurodegenerative disease is schizophrenia, depression, or Parkinson's disease.

[0227] Terminology Definition

[0228] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0229] In this invention, the term "substitution" or "substituent" means that a hydrogen atom in a group is replaced by a specified group. When the substitution position is not specified, substitution can occur at any position, but only if a stable or chemically viable chemical is formed is it permitted. Examples are given below: The structure indicates that the hydrogen atoms on ring A are replaced by m R1 atoms. Furthermore, when ring A is a bicyclic fused ring, either ring in the bicyclic ring can be substituted; for example, unless otherwise specified, The structure indicates that hydrogen atoms on ring A1 and / or ring A2 are replaced by m R1 atoms.

[0230] When any variable (e.g., R) occurs more than one time in a compound, its definition in each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is substituted with 0-2 R, then said group can optionally be substituted with up to two R groups, and at each occurrence R is selected independently. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0231] When the number of a linking group is zero, it means that the linking group is a single bond, for example, the structure formed when L is zero in A-L-Z.

[0232] In the present application, the term "alkyl" refers to a saturated straight or branched chain monovalent hydrocarbon radical. C1-C6 alkyl means an alkyl group having 1-6 carbon atoms, which is preferably C1-C4 alkyl, for example, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, or t-butyl.

[0233] In the present application, the term "haloalkyl" refers to a radical in which one or more (e.g., 2, 3, 4, 5, or 6) hydrogen atoms of an alkyl group are replaced with a halogen, wherein each halogen is independently F, Cl, Br, or I. HaloC1-C6 alkyl means a C1-C6 alkyl group substituted with one or more halogens, wherein C1-C6 alkyl is as previously described.

[0234] In the present application, the term "alkoxy" refers to -O-alkyl, wherein alkyl is as previously described. C1-C6 alkoxy means -O-(C1-C6 alkyl), wherein C1-C6 alkyl is as previously described.

[0235] In the present application, the term "carbocyclyl" refers to a saturated, partially unsaturated, or aromatic monocyclic or polycyclic (e.g., fused, spiro, or bridged) ring radical formed only of carbon atoms. In a saturated carbocyclyl, every carbon atom in the ring is saturated, examples of saturated carbocyclyl include, but are not limited to In an aromatic carbocyclyl, every ring is aromatic, examples of aromatic carbocyclyl include, but are not limited to In a partially unsaturated carbocyclyl, at least one carbon atom in the ring is saturated and at least one carbon atom is unsaturated, examples of partially unsaturated carbocyclyl include, but are not limited to A 3-8 membered carbocyclyl can be specifically a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclyl.

[0236] In the present application, the term "heterocycle" refers to a saturated, partially unsaturated, or aromatic monocyclic or polycyclic (e.g., fused, spiro, or bridged) ring system formed from carbon atoms and at least one heteroatom, wherein the heteroatom is independently selected from N, O, and S. In a saturated heterocycle, each atom in the ring is saturated, examples of saturated heterocycles include, but are not limited to In an aromatic heterocycle, each ring is aromatic, examples of aromatic heterocycles include, but are not limited to In a partially unsaturated heterocycle, at least one atom in the ring is saturated and at least one atom is unsaturated, examples of partially unsaturated heterocycles include, but are not limited to

[0237] A 3-8 membered heterocycle can be specifically a 3, 4, 5, 6, 7, or 8 membered heterocycle. A 5-7 membered heterocycle can be specifically a 5, 6, or 7 membered heterocycle.

[0238] In the present application, the term "aromatic ring" refers to a carbocyclic ring that is aromatic, wherein each ring is aromatic. A 6-10 membered aromatic ring can be specifically a benzene ring or a naphthalene ring.

[0239] In the present application, the term "heteroaromatic ring" refers to a heterocyclic ring that is aromatic, wherein each ring is aromatic. Examples of heteroaromatic rings include, but are not limited to A 5-10 membered heteroaromatic ring can be specifically a 5, 6, 7, 8, 9, or 10 membered heteroaromatic ring.

[0240] In the present application, the term "bicyclic fused ring" refers to a fused ring composed of two monocyclic rings, the connection site to other structures can be located on either monocyclic ring. An 8-11 membered bicyclic fused ring can be specifically an 8, 9, 10, or 11 membered bicyclic fused ring.

[0241] In the present application, the term "cycloalkyl" refers to a monovalent hydrocarbon group that is a monocyclic or polycyclic (e.g., fused, spiro, or bridged) ring system, wherein each carbon atom is saturated. A 3-8 membered cycloalkyl can be specifically a 3, 4, 5, 6, 7, or 8 membered cycloalkyl, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc. Specific examples of cycloalkyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,

[0242] The compounds of the present application and their structures are also meant to include all isomeric (including stereoisomeric and tautomeric, where stereoisomeric, for example, enantiomeric, diastereomeric, geometric (zig and zag isomers) and conformational isomers) forms. They can be defined in terms of absolute stereochemistry designated by the (+) or (-) configuration in its structure and as (R)- or (S)- or, as (D)- or (L)- for amino acids, where the term "absolute stereochemistry" is used herein to refer to the absolute configuration of an enantiomeric or diastereomeric compound structure and the term "configuration" is used herein to refer to the relative stereochemistry of a diastereomeric, geometric, or conformational isomeric compound structure. The present application includes all such possible isomers, as well as, their racemic, enantiomerically enriched or pure, and optionally, atropisomeric forms. Optical (+) and (-), (R)- and (S)-, and (R,R)- / (R,S)- / (S,S)- or (D)- and (L)- isomers can be prepared using chiral starting materials, chiral reagents in a chiral synthesis, chiral resolution, or can be resolved using conventional techniques, for example, but not limited to, high pressure liquid chromatography (HPLC) resolution using a chiral column. When the compounds described herein contain olefinic double bonds, other geometric isomers can also be present. Unless otherwise specified, all geometric isomeric forms of compounds described herein are within the scope of the present application. In the chemical structures depicted herein, the bond " / " is not intended to indicate a specific configuration, i.e., if a configuration isomerism exists in a chemical structure, the bond " / " can be either or or both configurations and are included. Also, all tautomeric forms are included.

[0243] In the present application, the term "tautomers" refers to the movement of a proton from one atom of a molecule to another position in the same molecule. The present application includes tautomers of any of the compounds described.

[0244] In the present application, the term "isotopic derivatives" refers to compounds which differ only in the composition of one or more atoms. For example, compounds of the present application having the structure, except for the replacement of hydrogen by "deuterium" or "tritium," or the replacement of a fluorine by 18 F-fluorine label 18 F isotope or the replacement of a carbon by 11 C-, 13 C-, or 14 C-enriched carbon 11 C-, 13 C-, or 14 C-carbon label; 11 C-, 13 C-, or 14 C-isotope are within the scope of the present application. Such compounds can be useful as, for example, analytical tools or probes in biological assays, or can be used as in vivo diagnostic imaging tracers for disease, or as tracers for pharmacokinetic, pharmacodynamic, or receptor studies. In the present application, the isotopic derivatives are, for example, deuterium substitutions.

[0245] In the present application, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) which does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, i.e., the substance can be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0246] In the present application, the term "pharmaceutically acceptable salt" means a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with the compound which retains the biological activity of the compound. The organic acid can be any of the various organic acids conventionally used in the art to form salts, preferably one or more of methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid and salicylic acid. The inorganic acid can be any of the various inorganic acids conventionally used in the art to form salts, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid. The organic base can be any of the various organic bases conventionally used in the art to form salts, preferably one or more of pyridines, imidazoles, pyrazines, indoles, purines, tertiary amines and anilines. The tertiary amine organic base is preferably triethylamine and / or N,N-diisopropylethylamine. The aniline organic base is preferably N,N-dimethylaniline. The pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine. The inorganic base can be any of the various inorganic bases conventionally used in the art to form salts, preferably one or more of alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, potassium bicarbonate and sodium bicarbonate. The alkali metal hydride is preferably sodium hydride and / or potassium hydride. The alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. The alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide.

[0247] In the present application, the term "solvate" means a substance formed from a compound or its salt with a suitable solvent. The solvent is preferably water or an organic solvent.

[0248] In the present application, the term "patient" includes any animal, preferably a mammal, more preferably a human.

[0249] The above-mentioned preferred conditions can be combined in any manner, based on common general knowledge in the art, to obtain preferred embodiments of the present application.

[0250] The reagents and materials used in the present application are commercially available.

[0251] The present application has positive progress effects in that the compounds of the present application have excellent pharmaceutical effects on various mental diseases and neurodegenerative diseases such as schizophrenia, depression, Parkinson's disease, etc., and thus can be used as effective drugs for treating the above-mentioned diseases. DETAILED DESCRIPTION

[0252] The present application is further illustrated by the following examples without thereby limiting the present application to the scope of the examples. The experimental methods in the following examples, for which specific conditions are not mentioned, are selected according to the conventional methods and conditions, or according to the instructions of the commercial products.

[0253] The reaction in the following examples overnight is 12-18 hours.

[0254] Example 1: Preparation of compound 7-(4-(8-methoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)butoxy)-quinolin-2(1H)-one (I-A1)

[0255]

[0256] Step 1: Synthesis of LRQ-04-148 according to patent WO2006064355A2. 1 H NMR (800 MHz, CDCl3) δ 7.66 (s, 1H), 7.23 (t, J = 7.9 Hz, 1H), 7.18-7.15 (m, 1H), 6.89-6.85 (m, 1H), 4.02 (s, 3H), 3.75 (d, J = 1.2 Hz, 2H). HRMS (ESI) C 11 H 10 NO2 + [M+H] + Calculated: 188.0706, Found: 188.0702.

[0257] Step 2: Synthesis of LRQ-04-149 according to patent WO2006064355A2. 1 H NMR (800 MHz, CDCl3) δ 7.64 (s, 1H), 7.25-7.20 (m, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.84-6.79 (m, 1H), 3.99 (s, 3H), 3.30 (t, J = 7.1 Hz, 2H), 3.21-3.18 (m, 2H). HRMS (ESI) C 11 H 14 NO2 + [M+H] + Calculated: 192.1019, Found: 192.1019.

[0258] Step 3: LRQ-04-149 (500 mg, 2.62 mmol) and Et3N (796 mg, 7.86 mmol) were dissolved in dichloromethane (10 mL), then (Boc)20 (714 mg, 3.27 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, dichloromethane (20 mL*3) was used for extraction, saturated brine was used for washing, and anhydrous sodium sulfate was used for drying. The solvent was removed by reduced pressure evaporation to obtain white solid LRQ-04-150, which was directly used in the next step without purification. HRMS (ESI) C 16 H 22 NO4 + [M+H] + Calcd: 292.1543, Found: 292.1549.

[0259] Step 4: LRQ-04-150 and para-toluenesulfonic acid (25 mg, 0.13 mmol) were dissolved in toluene (10 mL), then paraformaldehyde (157 mg, 5.24 mmol) was added, and the reaction was allowed to proceed at reflux overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, ethyl acetate (20 mL*3) was used for extraction, saturated brine was used for washing, and anhydrous sodium sulfate was used for drying. The solvent was removed by reduced pressure evaporation to obtain white solid LRQ-04-151, which was directly used in the next step without purification. HRMS (ESI) C 17 H 22 NO4 + [M+H] + Calcd: 304.1543, Found: 304.1545.

[0260] Step 5: LRQ-04-151 was dissolved in 4M hydrogen chloride in dioxane solution (8 mL), and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the solvent was removed by reduced pressure evaporation, and the residue was dissolved in ethyl ether (8 mL). After stirring at room temperature for 15 minutes, suction filtration was performed, the filter residue was washed with ethyl ether, and drying was performed under reduced pressure to obtain white solid LRQ-04-153 (202 mg, 38% yield for three steps). 1 H NMR (800 MHz, MeOH-d4) δ 7.22 (t, J = 7.9 Hz, 1H), 7.16-7.11 (m, 1H), 6.97-6.93 (m, 1H), 4.45 (s, 2H), 3.97 (s, 3H), 3.61 (t, J = 6.0 Hz, 2H), 3.07-3.01 (m, 2H). 13C NMR (201 MHz, MeOH-d4) δ 146.92, 145.61, 145.53, 129.59, 125.35, 112.87, 112.35, 108.77, 56.60, 43.13, 41.95, 19.03. HRMS (ESI) C 12 H 14 NO2 + [M+H] + Calcd: 204.1019, Found: 204.1016.

[0261] Step 6: LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)quinolin-2(lH)-one (218 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (119 mg, yield 58%). 1 H NMR (800 MHz, MeOH-d4) δ 7.79-7.71 (m, 1H), 7.45 (d, J = 8.6 Hz, 1H), 7.14-7.07 (m, 1H), 7.01 (d, J = 7.5 Hz, 1H), 6.85-6.72 (m, 3H), 6.46-6.39 (m, 1H), 4.07 (t, J = 5.5 Hz, 2H), 3.96 (s, 3H), 3.71 (s, 2H), 2.96-2.83 (m, 2H), 2.78-2.66 (m, 4H), 1.94-1.76 (m, 4H). 13 CNMR (201 MHz, MeOH-d4) δ 165.02, 161.97, 150.89, 145.68, 144.26, 141.87, 140.60, 129.93, 129.73, 123.88, 117.73, 114.93, 113.27, 112.28, 111.75, 106.83, 99.26, 68.39, 57.53, 56.36, 50.83, 50.39, 27.48, 24.04, 20.90. HRMS (ESI) C 25 H 27 N2O4 + [M+H] + Calcd: 419.1965, Found: 419.1971. HPLC: 99.54% (λ = 254 nm, t R= 11.18 min).

[0262] Example 2: Preparation of compound 7-(4-(8-methoxy-3,4-dihydrobenzo[f]pyran-2(lH)- yl)butyloxy)-3,4-dihydroquinolin-2(lH)-one (I-A2)

[0263]

[0264] After LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(lH)-one (220 mg, 0.74 mmol) were added in turn, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a white solid (113 mg, yield 55%). 1 H NMR (800 MHz, CDC13) δ 8.77 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.05 - 6.97 (m, 2H), 6.76 (d, J = 7.9 Hz, 1H), 6.53 - 6.48 (m, 1H), 6.39 - 6.34 (m, 1H), 3.99 (s, 3H), 3.95 (t, J = 6.1 Hz, 2H), 3.72 (s, 2H), 2.90 - 2.83 (m, 4H), 2.73 (t, J = 5.4 Hz, 2H), 2.71 - 2.66 (m, 2H), 2.62 - 2.58 (m, 2H), 1.87 - 1.80 (m, 2H), 1.80 - 1.74 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 172.24, 158.70, 151.21, 145.25, 143.72, 138.28, 129.74, 128.66, 123.30, 115.78, 111.86, 111.30, 108.86, 106.03, 102.36, 67.89, 57.04, 56.10, 50.43, 50.11, 31.16, 27.17, 24.64, 23.93, 20.87. HRMS (ESI) C 25 H 29 N2O4 + [M+H] + Calcd: 421.2122, Found: 421.2123. HPLC: 97.33% (λ = 254 nm, t R= 11.25 min).

[0265] Example 3: Preparation of compound 6-(4-(8-methoxy-3,4-dihydrobenzofuran[2,3- c]pyridin-2(lH)-yl)butoxy)indolin-2-one (I-A3)

[0266]

[0267] Step 1: LRQ-05-62 (0.25 g, 0.74 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), LRQ-04-153 (100 mg, 0.49 mmol) were added successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (46 mg, yield 23%). 1 HNMR (800 MHz, CDC13) δ 8.47 (s, 1H), 7.11-7.07 (m, 1H), 6.55-6.50 (m, 1H), 6.47 (d, J = 1.6 Hz, 1H), 3.97 (t, J = 6.0 Hz, 2H), 3.52-3.45 (m, 4H), 2.09-2.04 (m, 2H), 1.96-1.90 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 178.61, 159.29, 143.59, 125.28, 117.21, 107.92, 97.74, 67.30, 35.78, 33.52, 29.57, 27.98. HRMS (ESI) C 12 H 15 BrNO2 + [M+H] + Calcd: 284.0281, Found: 284.0289.

[0268] Step 2: LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), LRQ-05-62 (209 mg, 0.74 mmol) were added successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (46 mg, yield 23%). 1H NMR (800 MHz, CDC13) δ 7.72 (s, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.07 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 6.54 - 6.50 (m, 1H), 6.43 (d, J = 2.0 Hz, 1H), 4.03 - 3.95 (m, 5H), 3.76 (s, 2H), 3.46 - 3.40 (m, 2H), 2.96 - 2.90 (m, 2H), 2.80 - 2.70 (m, 4H), 1.88 - 1.84 (m, 2H), 1.83 - 1.80 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 175.12, 159.33, 148.50, 145.32, 143.85, 143.56, 129.93, 125.24, 123.49, 117.14, 111.87, 111.37, 107.81, 106.23, 97.75, 67.96, 57.42, 56.16, 50.42, 49.87, 35.69, 29.83, 27.11, 20.50. HRMS (ESI) C 24 H 27 N2O4 + [M+H] + Calcd: 407.1965, Found: 407.1966. HPLC: 96.65% (λ = 254 nm, t R = 11.28 min).

[0269] Example 4: Preparation of compound 7-(4-(8-methoxy-3,4-dihydrobenzo[2,3-c]pyridin-2(lH)- yl)butoxy)-l-methylquinolin-2(lH)-one (I-A4)

[0270]

[0271] Step 1: 7-hydroxy-l-methylquinolin-2(lH)-one (2.55 g, 14.55 mmol) was dissolved in DMF (40 mL), then K2CO3 (2.1 g, 14.55 mmol), 1,4-dibromobutane (9.42 g, 43.65 mmol) were added successively, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain yellow solid LRQ-05-59 (2.16 g, yield 48%). 1H NMR (800 MHz, CDC13) δ 7.59 (d, J = 9.4 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 6.82 - 6.79 (m, 1H), 6.79 - 6.76 (m, 1H), 6.55 (d, J = 9.4 Hz, 1H), 4.13 - 4.06 (m, 2H), 3.68 (s, 3H), 3.54 - 3.24 (m, 2H), 2.13 - 2.04 (m, 2H), 2.03 - 1.94 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 162.89, 161.21, 141.85, 138.85, 130.23, 118.69, 115.11, 110.00, 99.42, 67.21, 33.39, 30.19, 29.63, 27.94. HRMS (ESI) C 14 H 17 BrNO2 + [M+H] + Calculated: 310.0437, Found: 310.0441.

[0272] Step 2: LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), LRQ-05-59 (228 mg, 0.74 mmol) and reaction at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (108 mg, yield 51%). 1 H NMR (800 MHz, CDC13) δ 7.59 (d, J = 9.4 Hz, 1H), 7.45 (d, J = 8.5 Hz, 1H), 6.82 - 6.79 (m, 1H), 6.79 - 6.76 (m, 1H), 6.55 (d, J = 9.4 Hz, 1H), 4.13 - 4.06 (m, 2H), 3.68 (s, 3H), 3.54 - 3.24 (m, 2H), 2.13 - 2.04 (m, 2H), 2.03 - 1.94 (m, 2H). 13CNMR (201MHz, CDCl3) δ162.87,161.33,151.12,145.25,143.71,141.76,138.83,130.14,129.68,123.34,118.44,114. 95,111.85,111.27,110.05,106.02,99.36,68.10,56.97,56.09,50.51,50.06,29.55,27.19,23.89,20.88.HRMS(ESI)C 26 H 29 N2O4 + [M+H] + Calculated value: 433.2122, Measured value: 433.2125. HPLC: 97.65% (λ=254nm, t R =12.43min).

[0273] Example 5: Preparation of compound 7-(4-(8-methoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)butoxy)-2H-benzopyran-2-one (I-A5)

[0274]

[0275] Step 1: Dissolve 7-hydroxycoumarin (2.36 g, 14.55 mmol) in DMF (40 mL), then add K2CO3 (2.1 g, 14.55 mmol) and 1,4-dibromobutane (9.42 g, 43.65 mmol) sequentially, and react overnight at room temperature. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (50 mL * 3), wash with saturated brine, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to give a white solid LRQ-05-40 (2.37 g, yield 55%). 1 H NMR(800MHz, CDCl3)δ7.63(d,J=9.4Hz,1H),7.38–7.34(m,1H),6.84–6.81(m,1H),6.79(d,J=2.3Hz,1H), 6.24(d,J=9.4Hz,1H),4.05(t,J=6.1Hz,2H),3.49(t,J=6.6Hz,2H),2.11–2.05(m,2H),2.02–1.96(m,2H). 13C NMR (201 MHz, CDC13) δ 162.20, 161.30, 156.02, 143.50, 128.90, 113.28, 112.99, 112.71, 101.50, 67.66, 33.31, 29.44, 27.79. HRMS (ESI) C 13 H 14 BrO3 + [M+H] + Calcd: 297.0121, Found: 297.0429.

[0276] Step 2: LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), LRQ-05-40 (219 mg, 0.74 mmol) and reaction at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a white solid (117 mg, yield 57%). 1 H NMR (800 MHz, CDC13) δ 7.60 (d, J = 9.4 Hz, 1H), 7.33 (d, J = 8.6 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.04-7.00 (m, 1H), 6.84-6.80 (m, 1H), 6.79 (d, J = 2.1 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.24-6.19 (m, 1H), 4.06 (t, J = 6.2 Hz, 2H), 3.99

[0277] (s, 3H), 3.72 (s, 2H), 2.89 (t, J = 5.3 Hz, 2H), 2.77-2.67 (m, 4H), 1.93-1.85 (m, 2H), 1.84-1.73 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 162.20, 161.30, 156.02, 143.50, 128.90, 113.28, 112.99, 112.71, 101.50, 67.66, 33.31, 29.44, 27.79. HRMS (ESI) C 25 H 26 NO5 +[M+H] + Calculated: 420.1805, Found: 420.1807. HPLC: 96.57% (λ = 254 nm, t R = 11.40 min).

[0278] Example 6: Preparation of compound 8-methoxy-2-(4-(quinolin-7-yloxy)butyl)-1,2,3,4- tetrahydrobenzo[f]pyrrole[2,3-c]pyridine (I-A6)

[0279]

[0280] Step 1: After 7-hydroxyquinoline (2.11 g, 14.55 mmol) was dissolved in DMF (40 mL), K2CO3 (2.1 g, 14.55 mmol), 1,4-dibromobutane (9.42 g, 43.65 mmol) were added successively, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain yellow solid LRQ-05-52 (2.52 g, yield 62%). 1 H NMR (800 MHz, CDC13) δ 8.82 (d, J = 2.8 Hz, 1H), 8.07 (d, J = 8.0 Hz, 1H), 7.74 - 7.66 (m, 1H), 7.40 (d, J = 1.9 Hz, 1H), 7.27 - 7.25 (m, 1H), 7.23 - 7.16 (m, 1H), 4.15 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.6 Hz, 2H), 2.16 - 2.06 (m, 2H), 2.06 - 1.98 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 160.04, 150.57, 149.90, 135.92, 128.96, 123.68, 120.15, 119.11, 107.95, 67.23, 33.47, 29.65, 27.88. HRMS (ESI) C 13 H 15 BrNO + [M+H] + Calculated: 280.0332, Found: 280.0339.

[0281] Step 2: LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), LRQ-05-52 (206 mg, 0.74 mmol) and reaction at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (110 mg, yield 56%). 1 H NMR (800 MHz, CDC13) δ 8.81 - 8.75 (m, 1H), 8.06 - 7.99 (m, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.39 (d, J = 2.2 Hz, 1H), 7.24 - 7.20 (m, 1H), 7.20 - 7.15 (m, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.76 - 6.71 (m, 1H), 4.14 (t, J = 6.3 Hz, 2H), 3.97 (s, 3H), 3.70 (s, 2H), 2.85 (t, J = 5.6 Hz, 2H), 2.71 (t, J = 5.5 Hz, 2H), 2.70 - 2.67 (m, 2H), 1.95 - 1.88 (m, 2H), 1.85 - 1.78 (m, 2H). 13 CNMR (201 MHz, CDC13) δ 160.11, 151.31, 150.45, 149.88, 145.20, 143.67, 135.79, 129.74, 128.83, 123.53, 123.21, 120.14, 118.93, 111.83, 111.26, 107.84, 105.96, 67.88, 57.07, 56.05, 50.41, 50.15, 26.98, 24.03, 20.90. HRMS (ESI) C 25 H 27 N2O3 + [M+H] + Calcd: 403.2016, Found: 403.2011. HPLC: 96.75% (λ = 254 nm, t R = 10.06 min).

[0282] Example 7: Preparation of compound 2-(4-(benzo[d]thiazol-5-yloxy)butyl)-8- methoxy-1,2,3,4-tetrahydrobenfo[2,3-c]pyridine (I-A7)

[0283]

[0284] Step 1 : LRQ-04-02 (2.96 g, yield 72%) was obtained as colorless oil after 5-hydroxybenzothiazole (2.20 g, 14.55 mmol) was dissolved in DMF (40 mL), followed by the addition of K2CO3 (2.1 g, 14.55 mmol), 1,4-dibromobutane (9.42 g, 43.65 mmol) successively, and the reaction was allowed to proceed at room temperature overnight. After the completion of the reaction, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction, followed by washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain LRQ-04-02 (2.96 g, yield 72%) as colorless oil. 1 HNMR (800 MHz, CDC13) δ 8.97 (s, 1H), 7.81-7.78 (m, 1H), 7.61-7.57 (m, 1H), 7.10-7.06 (m, 1H), 4.09 (t, J = 6.1 Hz, 2H), 3.50 (t, J = 6.7 Hz, 2H), 2.14-2.06 (m, 2H), 2.03-1.97 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 158.37, 155.11, 154.72, 125.74, 122.19, 116.52, 106.55, 67.44, 33.52, 29.64, 27.98. HRMS (ESI) C 11 H 13 BrNOS + [M+H] + Calcd: 285.9896, Found: 285.9897.

[0285] Step 2: LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), LRQ-04-02 (210 mg, 0.74 mmol) successively, and the reaction was allowed to proceed at 100 °C overnight. After the completion of the reaction, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction, followed by washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (92 mg, yield 46%). 1H NMR (800 MHz, CDC13) δ 8.96 (s, 1H), 7.80 - 7.76 (m, 1H), 7.59 (d, J = 2.3 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.11 - 7.06 (m, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.10 (t, J = 6.2 Hz, 2H), 4.00 (s, 3H), 3.78 (s, 2H), 2.97 - 2.90 (m, 2H), 2.80 - 2.72 (m, 4H), 1.95 - 1.89 (m, 2H), 1.89 - 1.82 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 158.48, 155.04, 154.74, 145.31, 143.83, 129.67, 125.61, 123.38, 122.14, 116.57, 111.88, 111.35, 111.30, 106.56, 106.16, 68.12, 56.92, 56.15, 50.40, 50.03, 27.12, 23.91, 20.68. HRMS (ESI) C 23 H 25 N2O3S + [M+H] + Calcd: 409.1580, Found: 409.1587. HPLC: 95.00% (λ = 254 nm, t R = 11.37 min).

[0286] Example 8: Preparation of compound 7-(3-(8-methoxy-3,4-dihydrobenzo[2,3-c]pyridin-2(lH)- yl)propoxy)quinolin-2(lH)-one (I-A8)

[0287]

[0288] After LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)quinolin-2(lH)-one (208 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (48 mg, yield 24%). 1H NMR (800 MHz, CDC13) δ 11.84 (s, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.43 (d, J = 9.3 Hz, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.84 - 6.80 (m, 2H), 6.77 (d, J = 7.9 Hz, 1H), 6.52 (d, J = 9.4 Hz, 1H), 4.17 (t, J = 6.1 Hz, 2H), 4.00 (s, 3H), 3.74 (s, 2H), 2.90 (t, J = 5.5 Hz, 2H), 2.83 (t, J = 7.2 Hz, 2H), 2.78 - 2.73 (m, 2H), 2.14 - 2.08 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 164.85, 161.44, 145.32, 143.78, 140.93, 140.41, 139.38, 129.85, 129.21, 123.32, 118.18, 114.35, 112.56, 111.97, 111.36, 106.05, 99.25, 66.58, 56.17, 54.06, 50.62, 50.35, 27.38, 21.05. HRMS (ESI) C 24 H 25 N2O4 + [M+H] + Calcd: 405.1809, Found: 405.1811. HPLC: 97.28% (λ = 254 nm, t R = 11.56 min).

[0289] Example 9: Preparation of compound 7-(3-(8-methoxy-3,4-dihydrobenzo[2,3-c]pyrrol-2(lH)-yl)propoxy)-3,4-dihydroquinolin-2(lH)-one (I-A9)

[0290]

[0291] LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(lH)-one (209 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (46 mg, yield 23%).1 H NMR (800 MHz, CDC13) δ 8.08 (s, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.05 - 7.02 (m, 2H), 6.77 (d, J = 7.9 Hz, 1H), 6.55 - 6.51 (m, 1H), 6.35 - 6.32 (m, 1H), 4.03 (t, J = 6.2 Hz, 2H), 4.00 (s, 3H), 3.72 (s, 2H), 2.91 - 2.86 (m, 5H), 2.80 (t, J = 7.2 Hz, 2H), 2.73 (t, J = 5.3 Hz, 2H), 2.63 - 2.59 (m, 2H), 2.11 - 1.98 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 171.83, 158.73, 151.45, 145.31, 143.76, 138.23, 129.83, 128.80, 123.33, 115.95, 111.94, 111.34, 108.81, 106.03, 102.38, 66.36, 56.15, 54.08, 50.59, 50.31, 31.23, 27.46, 24.73, 21.04. HRMS (ESI) C 24 H 27 N2O4 + [M+H] + Calcd: 407.1965, Found: 407.1958. HPLC: 96.06% (λ = 254 nm, t R = 11.55 min).

[0292] Example 10: Preparation of compound (E)-7-((4-(8-methoxy-3,4- dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)but-2-en-l-yl)oxy)quinolin-2(lH)-one (I-A10)

[0293]

[0294] After LRQ-04-153 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), (E)-7-(4-bromobut-2-en-l-yl)oxy)quinolin-2(lH)-one (217 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (150 mg, yield 74%).1 H NMR (800 MHz, CDC13) δ 12.27 (s, 1H), 7.70 (d, J = 9.4 Hz, 1H), 7.43 (d, J = 8.6 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.85 (s, 1H), 6.84 - 6.79 (m, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.55 (d, J = 9.4 Hz, 1H), 6.08 - 6.01 (m, 1H), 5.98 - 5.91 (m, 1H), 4.71 - 4.61 (m, 2H), 3.99 (s, 3H), 3.72 (s, 2H), 3.33 (d, J = 6.4 Hz, 2H), 2.91 - 2.84 (m, 2H), 2.72 (t, J = 5.2 Hz, 2H). 13 C NMR (201 MHz, CDC13) δ 165.02, 160.92, 151.36, 145.30, 143.76, 140.86, 140.45, 131.59, 129.82, 129.20, 128.14, 123.29, 118.29, 114.45, 112.89, 111.88, 111.33, 106.05, 99.44, 68.51, 59.02, 56.15, 50.17, 50.02, 20.95. HRMS (ESI) C 25 H 25 N2O4 + [M+H] + Calcd: 417.1809, Found: 417.1811. HPLC: 99.16% (λ = 254 nm, t R = 11.76 min).

[0295] Example 11: Preparation of compound N-(trans-4-(2-(8-methoxy-3,4- dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)cyclohexyl)acetamide (I-A11)

[0296]

[0297] Step 1: NaOH (62 mg, 1.56 mmol) was dissolved in H2O (10 mL), then K2CO3 (440 mg, 3.16 mmol), trans-(N-BOC-4-aminocyclohexyl)acetic acid (200 mg, 0.78 mmol) and benzyl bromide (540 mg, 3.16 mmol) were added successively, and the reaction was refluxed for 3 h. After the reaction was completed, it was cooled to room temperature, extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to obtain white solid LRQ-04-11 (220 mg, yield 83%). 1 H NMR (800 MHz, CDC13) δ 7.38 - 7.30 (m, 5H), 5.10 (s, 2H), 4.37 (s, 1H), 3.42 - 3.29 (m, 1H), 2.24 (d, J = 6.8 Hz, 2H), 2.03 - 1.92 (m, 2H), 1.82 - 1.70 (m, 3H), 1.43 (s, 9H), 1.16 - 1.00 (m, 4H). 13 C NMR (201 MHz, CDC13) δ 172.79, 155.33, 136.15, 128.68 (2C), 128.33, 128.30 (2C), 79.22, 66.25, 49.58, 41.52, 34.18 (2C), 33.25, 31.71 (2C), 28.56 (3C). HRMS (ESI) C 20 H 29 NO4Na + [M+H] + Calcd: 370.1989, Found: 370.1988.

[0298] Step 2: LRQ-04-11 (200 mg, 0.63 mmol) was dissolved in THF (10 mL), and the reaction was cooled to -10 °C after being replaced with nitrogen for three times. DIBAL-H (1.9 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction was warmed to 0 °C and reacted for 6 h. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (5 mL) was added, followed by stirring at room temperature for 1 h. Ethyl acetate (20 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure to obtain white solid LRQ-04-12-Boc, which was directly used in the next step without purification. HRMS (ESI) C 13 H 26 NO3 + [M+H] + Calcd: 244.1907, Found: 244.1910.

[0299] Step 3: LRQ-04-12-Boc was dissolved in DCM (10 mL) and cooled to 0 °C, then carbon tetrabromide (500 mg, 1.41 mmol) and triphenylphosphine (500 mg, 1.88 mmol) were added successively. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (20 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain white solid LRQ-04-152-Boc (113 mg, yield 59%). 1 H NMR (800 MHz, CDC13) δ 3.45 - 3.39 (m, 2H), 3.39 - 3.33 (m, 1H), 2.04 - 1.95 (m, 2H), 1.81 - 1.72 (m, 4H), 1.50 - 1.37 (m, 10H), 1.14 - 1.06 (m, 2H), 1.06 - 0.97 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 155.37, 79.22, 49.88, 39.68, 35.38, 33.33 (2C), 31.87, 31.30 (2C), 28.58 (3C). HRMS (ESI) C 13 H 25 BrNO2 + [M+H] + Calcd: 306.1063, Found: 306.1066.

[0300] Step 4: LRQ-04-152-Boc (113 mg, 0.38 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, then trifluoroacetic acid (1 mL) was added and the reaction was allowed to proceed for 2 hours. After the reaction was completed, the solvent was removed by reduced pressure evaporation to obtain colorless oily liquid LRQ-04-12-NH2, which was directly used in the next step without purification. HRMS (ESI) C8H 17 BrN + [M+H] + Calcd: 206.0539, Found: 206.0541.

[0301] Step 5: LRQ-04-12-NH2 was dissolved in DCM (10 mL), then triethylamine (115 mg, 1.14 mmol) and acetyl chloride (33 mg, 0.42 mmol) were added successively, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, dichloromethane (20 mL*3) was used for extraction, saturated brine was used for washing, and anhydrous sodium sulfate was used for drying. After the solvent was removed under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain yellow solid LRQ-05-70 (43 mg, yield 46%). 1 HNMR (800 MHz, CDC13) δ 5.48-5.27 (m, 1H), 3.74-3.64 (m, 1H), 3.42 (t, J = 7.0 Hz, 2H), 2.01-1.96 (m, 2H), 1.94 (s, 3H), 1.80-1.73 (m, 4H), 1.48-1.41 (m, 1H), 1.14-1.08 (m, 2H), 1.08-1.01 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 169.34, 48.63, 39.59, 35.29, 32.97 (2C), 31.86, 31.17 (2C), 23.70. HRMS (ESI) C 10 H 19 BrNO + [M+H] + Calcd: 248.0645, Found: 248.0638.

[0302] Step 6: LRQ-04-153 (24 mg, 0.12 mmol) was dissolved in DMF (8 mL), then DIPEA (45 mg, 0.35 mmol), LRQ-05-70 (42 mg, 0.17 mmol) were added successively, and the reaction was allowed to proceed at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, ethyl acetate (50 mL*3) was used for extraction, saturated brine was used for washing, and anhydrous sodium sulfate was used for drying. After the solvent was removed under reduced pressure, the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain yellow solid (20 mg, yield 44%). 1H NMR (800 MHz, CDC13) δ 7.12 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.79 - 6.71 (m, 1H), 5.37 (d, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.74 - 3.62 (m, 3H), 2.83 (t, J = 5.5 Hz, 2H), 2.71 (t, J = 5.4 Hz, 2H), 2.65 - 2.58 (m, 2H), 2.01 - 1.94 (m, 2H), 1.93 (s, 3H), 1.81 - 1.74 (m, 2H), 1.53 - 1.46 (m, 2H), 1.31 - 1.26 (m, 1H), 1.11 - 1.04 (m, 4H). 13 CNMR (201 MHz, CDC13) δ 169.35, 151.31, 145.26, 143.72, 129.78, 123.29, 111.86, 111.30, 106.02, 56.12, 55.31, 50.46, 50.23, 48.73, 35.26, 34.36, 33.15 (2C), 31.95 (2C), 23.67, 20.89. HRMS (ESI) C 22 H 31 N2O3 + [M+H] + Calcd: 371.2329, Found: 371.2333. HPLC: 96.63% (l = 254 nm, t R = 10.56 min).

[0303] Example 12: Preparation of compound 3-(trans-4-(2-(8-methoxy-3,4- dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)cyclohexyl)-l,l-dimethylurea (I-A12)

[0304]

[0305] Step 1: LRQ-04-12-NH2 was dissolved in DCM (10 mL), then triethylamine (115 mg, 1.14 mmol) and dimethylcarbamoyl chloride (45 mg, 0.42 mmol) were added successively, and the reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, dichloromethane (20 mL*3) was extracted, saturated brine was washed, and anhydrous sodium sulfate was dried. The solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain yellow solid LRQ-04-152 (42 mg, yield 40%). 1H NMR (800 MHz, CDC13) δ 4.14 (s, 1H), 3.61 - 3.53 (m, 1H), 3.43 (t, J = 7.0 Hz, 2H), 2.87 (s, 6H), 2.06 - 1.97 (m, 2H), 1.80 - 1.71 (m, 4H), 1.48 - 1.39 (m, 1H), 1.14 - 0.99 (m, 4H). 13 CNMR (201 MHz, CDC13) δ 157.92, 49.84, 39.67, 36.27 (2C), 35.46, 33.88 (2C), 32.01, 31.39 (2C). HRMS (ESI) C 11 H 22 BrN2O + [M+H] + Calculated: 277.0910, Found: 277.0911.

[0306] Step 2: LRQ-04-153 (24 mg, 0.12 mmol) was dissolved in DMF (8 mL), then DIPEA (45 mg, 0.35 mmol), LRQ-04-152 (47 mg, 0.17 mmol) were added successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (17 mg, yield 35%). 1 H NMR (800 MHz, CDC13) δ 7.11 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.77 - 6.73 (m, 1H), 4.13 (d, J = 7.5 Hz, 1H), 3.98 (s, 3H), 3.67 (s, 2H), 3.60 - 3.52 (m, 1H), 2.86 (s, 6H), 2.84 (t, J = 5.5 Hz, 2H), 2.74 - 2.67 (m, 2H), 2.66 - 2.58 (m, 2H), 2.02 - 1.98 (m, 2H), 1.80 - 1.76 (m, 2H), 1.54 - 1.46 (m, 2H), 1.30 - 1.25 (m, 1H), 1.11 - 1.04 (m, 4H). 13C NMR (201 MHz, CDC13) δ 157.94, 151.31, 145.26, 143.73, 129.79, 123.27, 111.86, 111.30, 106.01, 56.12, 55.41, 50.45, 50.24, 49.93, 36.24 (2C), 35.45, 34.39, 34.07 (2C), 32.17 (2C), 20.89. HRMS (ESI) C 23 H 34 N3O3 + [M+H] + Calcd: 400.2595, Found: 400.2608. HPLC: 98.43% (l = 254 nm, t R = 10.65 min).

[0307] Example 13: Preparation of compound N-(trans-4-(2-(8-methoxy-3,4- dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)cyclohexyl)methanesulfonamide (I-A13)

[0308]

[0309] Step 1: LRQ-04-12-NH2 was dissolved in DCM (10 mL), then triethylamine (115 mg, 1.14 mmol) and methylsulfonyl chloride (48 mg, 0.42 mmol) were added successively, and the reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, dichloromethane (20 mL*3) was extracted, saturated brine was washed, and anhydrous sodium sulfate was dried. After the solvent was removed under reduced pressure, the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain white solid LRQ-05-71 (53 mg, yield 49%). 1 H NMR (800 MHz, CDC13) δ 4.33 - 4.22 (m, 1H), 3.42 (t, J = 7.0 Hz, 2H), 3.30 - 3.20 (m, 1H), 2.97 (s, 3H), 2.11 - 2.01 (m, 2H), 1.85 - 1.79 (m, 2H), 1.78 - 1.71 (m, 2H), 1.52 - 1.40 (m, 1H), 1.34 - 1.19 (m, 2H), 1.11 - 0.96 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 53.26, 42.37, 39.42, 34.97, 34.25 (2C), 31.60, 31.20 (2C). HRMS (ESI) C9H 19 BrNO2S + [M+H]+ Calculated: 284.0314, Found: 284.0317.

[0310] Step 2: LRQ-04-153 (24 mg, 0.12 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (45 mg, 0.35 mmol), LRQ-05-71 (48 mg, 0.17 mmol) at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (19 mg, yield 38%). 1 H NMR (800 MHz, CDC13) δ 7.15 (t, J = 7.8 Hz, 1H), 7.05-7.02 (m, 1H), 6.80-6.76 (m, 1H), 4.36-4.26 (m, 1H), 4.00 (s, 3H), 3.82 (s, 2H), 3.29-3.18 (m, 1H), 3.03-2.93 (m, 5H), 2.83-2.77 (m, 2H), 2.76-2.70 (m, 2H), 2.09-2.02 (m, 2H), 1.85-1.77 (m, 2H), 1.59-1.51 (m, 2H), 1.31-1.28 (m, 1H), 1.25-1.20 (m, 2H), 1.12-1.02 (m, 2H). 13 CNMR (201 MHz, CDC13) δ 151.31, 145.34, 143.91, 129.40, 123.57, 111.83, 111.38, 106.37, 56.17, 54.75, 53.28, 50.29, 49.70, 42.26, 34.82, 34.35 (2C), 33.53, 31.91 (2C), 20.20. HRMS (ESI) C 21 H 31 N2O4S + [M+H] + Calculated: 407.1999, Found: 407.1996. HPLC: 99.02% (λ = 254 nm, t R = 10.85 min).

[0311] Example 14: Preparation of compound N-(2-(8-methoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide (I-A14)

[0312]

[0313] Step 1: LRQ-04-153 (340 mg, 1.67 mmol) and DIPEA (1.3 g, 10.02 mmol) were dissolved in DMF (10 mL), and then N-Boc-2-bromoethylamine (561 mg, 2.51 mmol) was added. The reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain yellow solid LRQ-05-116 (200 mg, yield 35%). 1 H NMR (800 MHz, CDCl3) δ 7.14 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.00 (s, 3H), 3.70 (s, 2H), 3.37-3.27 (m, 2H), 2.90-2.84 (m, 2H), 2.78-2.69 (m, 4H), 1.44 (s, 9H). HRMS (ESI) C 19 H 27 N2O4 + [M+H] + Calcd: 347.1965, Found: 347.1963.

[0314] Step 2: LRQ-05-116 (70 mg, 0.20 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, and then trifluoroacetic acid (1 mL) was added. The reaction was carried out for 2 hours. After the reaction was completed, the solvent was removed by reduced pressure evaporation to obtain a colorless oily liquid, which was dissolved in dichloromethane (10 mL), and then DIPEA (155 mg, 1.20 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (44 mg, 0.30 mmol) were added. The reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and dichloromethane (20 mL*3) was extracted with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain white solid (48 mg, yield 77%). 1H NMR (800 MHz, CDC13) δ 7.15 (t, J = 7.8 Hz, 1H), 7.06-7.02 (m, 1H), 6.81-6.74 (m, 1H), 6.18-6.09 (m, 1H), 4.07-3.92 (m, 5H), 3.70 (s, 2H), 3.48-3.42 (m, 2H), 3.42-3.34 (m, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.3 Hz, 2H), 2.36-2.29 (m, 1H), 1.83-1.76 (m, 2H), 1.75-1.70 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 174.47, 150.99, 145.36, 143.75, 129.65, 123.49, 111.97, 111.31, 106.19, 67.41 (2C), 56.17, 55.46, 50.15, 50.04, 42.30, 36.44, 29.43 (2C), 20.97. HRMS (ESI) C 20 H 27 N2O4 + [M+H] + Calculated: 359.1965, Found: 359.1962. HPLC: 98.69% (λ = 254 nm, t R = 11.69 min).

[0315] Example 15: Preparation of compound 4,4-difluoro-N-(2-(8-methoxy-3,4- dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)cyclohexane-l-carboxamide (I-A15)

[0316]

[0317] LRQ-05-116 (70 mg, 0.20 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, then trifluoroacetic acid (1 mL) was added and the reaction was allowed to proceed for 2 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to obtain a colorless oily liquid, which was dissolved in dichloromethane (10 mL), DIPEA (155 mg, 1.20 mmol) and 4,4-difluorocyclohexanecarbonyl chloride (68 mg, 0.30 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain a white solid (43 mg, yield 63%). 1H NMR (800 MHz, CDC13) δ 7.15 (t, J = 7.8 Hz, 1H), 7.06 - 7.01 (m, 1H), 6.79 (d, J = 7.9 Hz, 1H), 6.17 - 6.07 (m, 1H), 4.00 (s, 3H), 3.70 (s, 2H), 3.47 - 3.39 (m, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.76 (t, J = 5.9 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 2.21 - 2.11 (m, 3H), 1.94 - 1.87 (m, 2H), 1.86 - 1.79 (m, 2H), 1.76 - 1.65 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 174.23, 150.98, 145.37, 143.76, 129.64, 123.51, 122.79 (t, J = 449.2 Hz), 111.97, 111.32, 106.20, 56.17, 55.44, 50.14, 50.06, 42.88, 36.47, 32.98 (t, J = 25.2 Hz) (2C), 26.07, 26.02, 20.97. HRMS (ESI) C 21 H 27 F2N2O3 + [M+H] + Calcd: 393.1984, Found: 393.1979. HPLC: 99.04% (λ = 254 nm, t R = 11.88 min).

[0318] Example 16: Preparation of compound 7-(4-(8-ethoxy-3,4-dihydrobenzo[2,3-c]pyridine-2(lH)- yl)butoxy)quinolin-2(lH)-one (I-A16)

[0319]

[0320] Step 1: After 2-(7-hydroxybenzofuran-3-yl)acetic acid methyl ester (2.0 g, 9.70 mmol) and K2CO3 (1.3 g, 9.70 mmol) were dissolved in DMF (10 mL), iodoethane (4.54 g, 29.10 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to obtain colorless oily liquid LRQ-05-125 (2.2 g, yield 97%). 1H NMR (800 MHz, CDC13) δ 7.63 (s, 1H), 7.19 - 7.10 (m, 2H), 6.83 - 6.79 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.72 (s, 3H), 3.70 (s, 2H), 1.51 (t, J = 7.0 Hz, 3H). HRMS (ESI) C 13 H 15 O4 + [M+H] + Calculated: 235.0965, Found: 235.0964.

[0321] Step 2: LRQ-05-125 (2.2 g, 9.40 mmol) was dissolved in THF (10 mL), after nitrogen replacement for three times, the reaction solution was cooled to -10 °C, DIBAL-H (28.2 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction solution was warmed to 0 °C for 6 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (80 mL) was added, followed by stirring at room temperature for 1 hour, ethyl acetate (50 mL*3) was extracted, saturated brine was washed, anhydrous sodium sulfate was dried, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain LRQ-05-127 (1.5 g, yield 77%) as a light yellow oily liquid. 1 H NMR (800 MHz, CDC13) δ 7.63 (s, 1H), 7.19 - 7.10 (m, 2H), 6.83 - 6.79 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.72 (s, 3H), 3.70 (s, 2H), 1.51 (t, J = 7.0 Hz, 3H). HRMS (ESI) C 12 H 15 O3 + [M+H] + Calculated: 207.1016, Found: 207.1013.

[0322] Step 3: LRQ-05-127 (1.5 g, 7.28 mmol), triphenylphosphine (2.86 g, 10.92 mmol) and phthalimide (1.61 g, 10.92 mmol) were dissolved in tetrahydrofuran (50 mL), cooled to 0 °C, and then DEAD (1.90 g, 10.92 mmol) was added. Then the reaction solution was warmed to room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, ethyl acetate (50 mL*3) was extracted, saturated brine was washed, anhydrous sodium sulfate was dried, and then the solvent was removed by reduced pressure evaporation to obtain LRQ-05-129 as a light yellow oily liquid. HRMS (ESI) C 20 H18 NO4 + [M+H] + Calcd: 336.1230, Found: 336.1224.

[0323] Step 4: LRQ-05-129 was dissolved in a mixture of methanol (80 mL) and dichloromethane (20 mL), then hydrazine hydrate (911 mg, 18.2 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the solvent was removed by reduced pressure evaporation to obtain a light yellow oily liquid LRQ-05-131, which was directly used in the next step without purification. HRMS (ESI) C 12 H 16 NO2 + [M+H] + Calcd: 206.1176, Found: 206.1182.

[0324] Step 5: LRQ-05-131 and Et3N (2.21 g, 21.84 mmol) were dissolved in dichloromethane (10 mL), then (Boc)20 (1.99 g, 9.10 mmol) was added, and the reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, dichloromethane (20 mL*3) was extracted, saturated brine was washed, and anhydrous sodium sulfate was dried, and then the solvent was removed by reduced pressure evaporation to obtain a light yellow oily liquid LRQ-05-133, which was directly used in the next step without purification. HRMS (ESI) C 17 H 24 NO4 + [M+H] + Calcd: 306.1700, Found: 306.1703.

[0325] Step 6: LRQ-05-133 and para-toluenesulfonic acid (88 mg, 0.51 mmol) were dissolved in toluene (20 mL), then para-toluenesulfonic acid (88 mg, 0.51 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, ethyl acetate (20 mL*3) was extracted, saturated brine was washed, and anhydrous sodium sulfate was dried, and then the solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to obtain a light yellow oily liquid LRQ-05-135 (750 mg, 33% yield for four steps). 1HNMR (800 MHz, CDC13) δ 7.13 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 6.80-6.76 (m, 1H), 4.62 (s, 2H), 4.30-4.20 (m, 2H), 3.81-3.66 (m, 2H), 2.78-2.65 (m, 2H), 1.49 (s, 9H), 1.28 (t, J = 6.0 Hz, 3H). HRMS (ESI) C 18 H 24 NO4 + [M+H] + Calculated: 318.1700, Found: 318.1701.

[0326] Step 7: LRQ-05-135 (750 mg, 2.36 mmol) was dissolved in 4 M hydrogen chloride in dioxane (10 mL) and stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in diethyl ether (8 mL), stirred at room temperature for 15 minutes, and then suction filtered. The filter residue was washed with diethyl ether and dried under reduced pressure to obtain white solid LRQ-05-137 (436 mg, yield 85%). 1 HNMR (800 MHz, CDC13) δ 7.13 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 6.9 Hz, 1H), 6.80-6.76 (m, 1H), 4.62 (s, 2H), 4.30-4.20 (m, 2H), 3.81-3.66 (m, 2H), 2.78-2.65 (m, 2H), 1.49 (s, 9H), 1.28 (t, J = 6.0 Hz, 3H). HRMS (ESI) C 13 H 16 NO2 + [M+H] + Calculated: 218.1176, Found: 218.1182.

[0327] Step 8: LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), and then DIPEA (178 mg, 1.38 mmol) and 7-(4-bromobutoxy)quinolin-2(1H)-one (103 mg, 0.35 mmol) were sequentially added. The mixture was stirred at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain an orange-yellow solid (47 mg, yield 47%). 1H NMR (800 MHz, CDC13) δ 7.74 - 7.68 (m, 1H), 7.46 - 7.40 (m, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.83 - 6.78 (m, 2H), 6.76 (d, J = 7.9 Hz, 1H), 6.53 (d, J = 9.4 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 4.11 (t, J = 6.2 Hz, 2H), 3.74 (s, 2H), 2.94 - 2.86 (m, 2H), 2.79 - 2.67 (m, 4H), 1.93 - 1.88 (m, 2H), 1.86 - 1.79 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 164.86, 161.49, 150.69, 145.73, 144.59, 140.92, 140.44, 131.36, 129.19, 123.29, 118.13, 114.29, 112.69, 111.89, 111.20, 107.21, 99.08, 68.19, 64.56, 50.52, 50.27, 49.71, 32.94, 29.84, 27.15, 15.09. HRMS (ESI) C 26 H 29 N2O4 + [M+H] + Calcd: 433.2122, Found: 433.2124. HPLC: 97.89% (λ = 254 nm, t R = 12.44 min).

[0328] Example 17: Preparation of compound 3-(trans-4-(2-(8-ethoxy-3,4- dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)cyclohexyl)-l,l-dimethylurea (I-A17)

[0329]

[0330] After LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), DIPEA (178 mg, 1.38 mmol), LRQ-04-152 (94 mg, 0.35 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain yellow solid I (11 mg, yield 12%).1 H NMR (800 MHz, CDC13) δ 7.10 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.77 - 6.73 (m, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.69 (s, 2H), 3.61 - 3.53 (m, 1H), 2.87 (s, 6H), 2.86 - 2.82 (m, 2H), 2.75 - 2.70 (m, 2H), 2.65 - 2.61 (m, 2H), 2.02 - 2.00 (m, 2H), 1.81 - 1.76 (m, 2H), 1.53 - 1.48 (m, 5H), 1.31 - 1.28 (m, 1H), 1.10 - 1.05 (m, 4H). HRMS (ESI) C 24 H 36 N3O3 + [M+H] + Calcd: 414.2751, Found: 414.2748. HPLC: 97.97% (λ = 254 nm, t R = 12.47 min).

[0331] Example 18: Preparation of compound 7-(4-(8-isopropoxy-3,4-dihydrobenzo[2,3- c]pyrindin-2(lH)-yl)butoxy)quinolin-2(lH)-one (I-A18)

[0332]

[0333] Step 1: After 2-(7-hydroxybenzofuran-3-yl)acetic acid methyl ester (2.0 g, 9.70 mmol) and K2CO3 (1.3 g, 9.70 mmol) were dissolved in DMF (10 mL), 2-bromopropane (3.58 g, 29.10 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to obtain colorless oily liquid LRQ-05-126 (2.3 g, yield 98%). 1 H NMR (800 MHz, CDC13) δ 7.10 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.77 - 6.73 (m, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.69 (s, 2H), 3.61 - 3.53 (m, 1H), 2.87 (s, 6H), 2.86 - 2.82 (m, 2H), 2.75 - 2.70 (m, 2H), 2.65 - 2.61 (m, 2H), 2.02 - 2.00 (m, 2H), 1.81 - 1.76 (m, 2H), 1.53 - 1.48 (m, 5H), 1.31 - 1.28 (m, 1H), 1.10 - 1.05 (m, 4H). HRMS (ESI) C 14 H 17 O4 + [M+H] +Calculated: 249.1121, Found: 249.1115.

[0334] Step 2: LRQ-05-126 (2.3 g, 9.50 mmol) was dissolved in THF (10 mL), and after nitrogen replacement for three times, the reaction solution was cooled to -10 °C, and DIBAL-H (28.5 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction solution was warmed to 0 °C for 6 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (80 mL) was added, followed by stirring at room temperature for 1 hour, extraction with ethyl acetate (50 mL*3), washing with saturated brine, drying over anhydrous sodium sulfate, and then removing the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain white solid LRQ-05-128 (1.6 g, yield 77%). 1 H NMR (800 MHz, CDCl3) δ 7.51 (s, 1H), 7.14 (d, J = 4.4 Hz, 2H), 6.85-6.81 (m, 1H), 4.83-4.75 (m, 1H), 3.94-3.89 (m, 2H), 2.96-2.90 (m, 2H), 1.43 (d, J = 6.1 Hz, 6H). HRMS (ESI) C 13 H 17 O3 + [M+H] + Calculated: 221.1172, Found: 221.1171.

[0335] Step 3: LRQ-05-128 (1.6 g, 7.32 mmol), triphenylphosphine (2.88 g, 10.97 mmol) and phthalimide (1.61 g, 10.97 mmol) were dissolved in tetrahydrofuran (50 mL), cooled to 0 °C, and then DEAD (1.91 g, 10.97 mmol) was added. Then the reaction solution was warmed to room temperature for overnight reaction. After the reaction was completed, water (10 mL) was added for dilution, extraction with ethyl acetate (50 mL*3), washing with saturated brine, drying over anhydrous sodium sulfate, and then removing the solvent under reduced pressure to obtain white solid LRQ-05-130, which was directly used in the next step without purification. HRMS (ESI) C 21 H 20 NO4 + [M+H] + Calculated: 350.1387, Found: 350.1388.

[0336] Step 4: LRQ-05-130 was dissolved in a mixture of methanol (80 mL) and dichloromethane (20 mL), then hydrazine hydrate (916 mg, 18.3 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the solvent was removed by reduced pressure evaporation to obtain orange-yellow solid LRQ-05-132, which was directly used in the next step without purification. HRMS (ESI) C 13 H 18 NO2 + [M+H] + Calcd: 220.1332, Found: 220.1336.

[0337] Step 5: LRQ-05-132 and Et3N (2.22 g, 21.96 mmol) were dissolved in dichloromethane (10 mL), then (Boc)20 (2.00 g, 9.15 mmol) was added, and the reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, dichloromethane (20 mL*3) was extracted, saturated brine was washed, and anhydrous sodium sulfate was dried. The solvent was removed by reduced pressure evaporation to obtain light yellow oily liquid LRQ-05-134, which was directly used in the next step without purification. HRMS (ESI) C 18 H 26 NO4 + [M+H] + Calcd: 320.1856, Found: 320.1858.

[0338] Step 6: LRQ-05-134 and para-toluenesulfonic acid (88 mg, 0.51 mmol) were dissolved in toluene (20 mL), then para-toluenesulfonic acid (88 mg, 0.51 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, ethyl acetate (20 mL*3) was extracted, saturated brine was washed, and anhydrous sodium sulfate was dried. The solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to obtain light yellow oily liquid LRQ-05-136 (890 mg, 37% yield for four steps). 1 HNMR (800 MHz, CDCl3) δ 7.12 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.82-6.79 (m, 1H), 4.83-4.75 (m, 1H), 4.62 (s, 2H), 3.80-3.66 (m, 2H), 2.77-2.62 (m, 2H), 1.49 (s, 10H), 1.43 (d, J = 6.1 Hz, 6H). HRMS (ESI) C 19 H 26 NO4 + [M+H] +Calculated: 332.1856, Found: 332.1849.

[0339] Step 7: LRQ-05-136 (890 mg, 2.69 mmol) was dissolved in 4 M hydrogen chloride in dioxane (10 mL) and stirred at room temperature overnight. After the reaction was completed, the solvent was removed under reduced pressure, and the residue was dissolved in diethyl ether (8 mL) and stirred at room temperature for 15 minutes. The mixture was filtered, and the filter residue was washed with diethyl ether and dried under reduced pressure to obtain white solid LRQ-05-138 (577 mg, yield 83%). 1 HNMR (800 MHz, CDC13) δ 7.11 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 7.9 Hz, 1H), 4.80 - 4.75 (m, 1H), 4.07 (s, 2H), 3.25 - 3.17 (m, 2H), 2.78 - 2.69 (m, 2H), 1.42 (d, J = 6.1 Hz, 6H). HRMS (ESI) C 14 H 18 NO2 + [M+H] + Calculated: 232.1332, Found: 232.1334.

[0340] Step 8: LRQ-05-138 (50 mg, 0.22 mmol) was dissolved in DMF (8 mL), and then DIPEA (171 mg, 1.32 mmol) and 7-(4-bromobutoxy)quinolin-2(1H)-one (97 mg, 0.33 mmol) were sequentially added. The mixture was stirred at 100°C overnight. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain an orange-yellow solid (42 mg, yield 44%). 1 HNMR (800 MHz, CDC13) δ 7.71 (d, J = 9.4 Hz, 1H), 7.43 (d, J = 9.0 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.82 - 6.75 (m, 3H), 6.53 (d, J = 9.4 Hz, 1H), 4.82 - 4.73 (m, 1H), 4.15 - 4.05 (m, 2H), 3.75 (s, 2H), 2.96 - 2.85 (m, 2H), 2.78 - 2.67 (m, 4H), 1.93 - 1.86 (m, 2H), 1.86 - 1.78 (m, 2H), 1.42 (d, J = 6.1 Hz, 6H). 13C NMR (201 MHz, CDC13) δ 164.88, 161.48, 146.94, 144.82, 143.48, 140.93, 140.45, 129.39, 129.19, 123.27, 118.13, 114.30, 112.69, 111.86, 111.26, 109.57, 99.09, 71.50, 68.19, 57.00, 50.53, 50.27, 29.85, 27.13, 23.99, 22.37 (2C). HRMS (ESI) C 27 H 31 N2O4 + [M+H] + Calcd: 447.2278, Found: 447.2273. HPLC: 97.68% (l=254 nm, t R = 12.45 min).

[0341] Example 19: Preparation of compound 3-(trans-4-(2-(8-isopropoxy-3,4- dihydrobenzo[f]pyran-2(lH)-yl)ethyl)cyclohexyl)-l,l-dimethylurea (I-A19)

[0342]

[0343] LRQ-05-138 (50 mg, 0.22 mmol) was dissolved in DMF (8 mL), then DIPEA (171 mg, 1.32 mmol), LRQ-04-152 (89 mg, 0.33 mmol) were added successively, and the mixture was reacted at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (22 mg, yield 24%). 1H NMR (800 MHz, CDC13) δ 7.09 (t, J = 7.8 Hz, 1H), 7.01 - 6.98 (m, 1H), 6.79 - 6.74 (m, 1H), 4.83 - 4.72 (m, 1H), 3.68 (s, 2H), 3.62 - 3.51 (m, 1H), 2.86 (s, 6H), 2.85 - 2.81 (m, 2H), 2.74 - 2.68 (m, 2H), 2.66 - 2.58 (m, 2H), 2.02 - 1.99 (m, 2H), 1.81 - 1.76 (m, 2H), 1.53 - 1.47 (m, 2H), 1.40 (d, J = 6.1 Hz, 6H), 1.28 (s, 1H), 1.09 - 1.05 (m, 4H). HRMS (ESI) C 25 H 38 N3O3 + [M+H] + Calcd: 428.2908, Found: 428.2901. HPLC: 97.43% (λ = 254 nm, t R = 12.47 min).

[0344] Example 20: Preparation of compound 7-(2-(8-methoxy-3,4-dihydrobenzo[2,3-c]pyridin-2(lH)-yl)butyl)quinolin-2(lH)-one (I-A20) (IHCH-5219)

[0345]

[0346] Step 1, 3-aminobenzoic acid methyl ester (1.00 g, 5.17 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, then pyridine (818 mg, 10.34 mmol) and cinnamoyl chloride (1.29 g, 7.76 mmol) were added successively, and the reaction was allowed to proceed overnight at room temperature. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was added for extraction, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure to obtain orange-yellow oily liquid LRQ-06-95, which was directly used in the next step without further purification. HRMS (ESI) C 20 H 22 NO3 + [M+H]+Calcd: 324.1594, Found: 324.1597.

[0347] Step 2, LRQ-06-95 was dissolved in chlorobenzene (20 mL), after nitrogen was replaced for three times, aluminum chloride (3.45 g, 25.85 mmol) was added, the reaction was heated to 95 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain LRQ-06-96 (780 mg, two-step reaction yield 61%) as a light yellow solid. 1 H NMR (800 MHz, CDC13) δ 7.81 (d, J = 9.3 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.22 (s, 1H), 7.10-7.07 (m, 1H), 6.69 (d, J = 9.4 Hz, 1H), 3.68 (s, 3H), 2.79-2.73 (m, 2H), 2.36 (t, J = 7.4 Hz, 2H), 2.03-1.99 (m, 2H). HRMS (ESI) C 14 H 16 NO3 + [M+H]+calcd: 246.1125, found: 246.1119.

[0348] Step 3, LRQ-06-96 (780 mg, 3.18 mmol) was dissolved in THF (20 mL), after nitrogen was replaced for three times, the reaction solution was cooled to -10 °C, DIBAL-H (10 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction solution was warmed to 0 ℃ The reaction was carried out for 6 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (10 mL) was added, followed by stirring at room temperature for 1 hour, extraction with ethyl acetate (20 mL*3), washing with saturated brine, drying over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain LRQ-06-97 as a yellow oily liquid. HRMS (ESI) C 13 H 16 NO2 + [M+H]+calcd: 218.1176, found: 218.1178.

[0349] Step 4, LRQ-06-97 was dissolved in DCM (10 mL) and cooled to 0 °C, then carbon tetrabromide (1.58 g, 4.77 mmol) and triphenylphosphine (1.67 g, 6.36 mmol) were added successively. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (20 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to obtain LRQ-06-98 (45 mg, 5% yield for two steps) as a light yellow solid. 1 H NMR (600 MHz, MeOH-d4) δ 7.89 (d, J = 9.4 Hz, 1H), 7.58 (d, J = 8.1 Hz, 1H), 7.26 (s, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.64 (d, J = 9.4 Hz, 1H), 3.49 (t, J = 6.7 Hz, 2H), 2.89 (t, J = 7.9 Hz, 2H), 1.97 - 1.92 (m, 2H), 1.83 - 1.77 (m, 2H). HRMS (ESI) C 13 H 15 BrNO + [M+H]+calcd: 280.0332, found: 280.0328.

[0350] Step 5, LRQ-04-153 (21 mg, 0.10 mmol) was dissolved in DMF (8 mL), then DIPEA (84 mg, 0.65 mmol) and LRQ-06-98 (45 mg, 0.16 mmol) were added successively. The reaction was allowed to proceed at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (13 mg, 32% yield). 1 H NMR (800 MHz, CDCl3) δ 12.16 (s, 1H), 7.76 (d, J = 9.4 Hz, 1H), 7.51 - 7.41 (m, 1H), 7.22 (s, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.06 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.80 - 6.72 (m, 1H), 6.70 - 6.58 (m, 1H), 3.99 (s, 3H), 3.68 (s, 2H), 2.88 - 2.80 (m, 2H), 2.79 - 2.70 (m, 4H), 2.67 - 2.59 (m, 2H), 1.78 - 1.69 (m, 2H), 1.68 - 1.58 (m, 2H) 13CNMR (201 MHz, CDC13) δ 164.78, 151.38, 146.11, 145.27, 143.74, 141.00, 138.78, 129.81, 127.82, 123.69, 123.28, 120.44, 118.29, 115.57, 111.89, 111.33, 105.97, 57.38, 56.12, 50.58, 50.24, 36.03, 29.22, 27.10, 20.97. HRMS (ESI) C 25 H 27 N2O3 + [M+H]+calcd: 403.2016, found: 403.2011. HPLC: 98.65% (l=254 nm, t R =11.68 min).

[0351] Example 21: Preparation of compound 1-((8-methoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(lH)- yl)methyl)cyclohexan-l-ol (I-A21) (IHCH-5228)

[0352]

[0353] LRQ-04-153 (50 mg, 0.25 mmol) was dissolved in absolute ethanol (10 mL), after the addition of methylene cyclohexane oxide (138 mg, 1.25 mmol), the reaction was heated to 60 °C overnight. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a white solid (32 mg, yield 42%). 1 H NMR (800 MHz, CDC13) δ 7.14 (t, J = 7.8 Hz, 1H), 7.07 - 7.02 (m, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.00 (s, 3H), 3.87 (s, 2H), 3.07 - 2.95 (m, 2H), 2.78 - 2.68 (m, 2H), 2.57 (s, 2H), 1.69 - 1.62 (m, 2H), 1.61 - 1.53 (m, 3H), 1.50 - 1.42 (m, 2H), 1.39 - 1.32 (m, 2H), 1.30 - 1.23 (m, 1H). 13C NMR (201 MHz, CDC13) δ 151.46, 145.34, 143.65, 129.73, 123.40, 112.07, 111.31, 106.09, 70.73, 66.18, 56.15, 52.80, 52.74, 36.61 (2C), 26.00, 22.25 (2C), 21.96. HRMS (ESI) C 19 H 26 NO3 + [M+H] + Calcd: 316.1907, Found: 316.1908. HPLC: 97.68% (l=254 nm, t R = 11.41 min).

[0354] Example 22: Preparation of compound 2-(4-(8-methoxy-3,4-dihydrobenzofuran[2,3- c]pyridin-2(lH)-yl)butyl)-4-methyl-l,2,4-triazine-3,5(2H,4H)-dione (I-A22) (IHCH-5201)

[0355]

[0356] Step 1, 4-methyl-2H-[l,2,4]triazine-3,5-dione (2.25 g, 17.70 mmol) was dissolved in DMF (20 mL), then NaH (0.85 g, 21.24 mmol) was added, followed by 1,4-dibromobutane (11.46 g, 53.10 mmol), and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction, followed by saturated brine washing, drying over anhydrous sodium sulfate, and removal of the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain a light yellow oily liquid LRQ-06-15 (2.19 g, yield 47%). 1 H NMR (800 MHz, CDC13) δ 7.39 (s, 1H), 4.01 (t, J = 6.7 Hz, 2H), 3.43 (t, J = 6.3 Hz, 2H), 3.33 (s, 3H), 1.96 - 1.84 (m, 4H). HRMS (ESI) C8H 13 BrN3O2 + [M+H]+Calcd: 262.0186, Found: 262.0188.

[0357] Step 2, LRQ-04-153 (50 mg, 0.25 mmol) was dissolved in DMF (8 mL) and then DIPEA (191 mg, 1.48 mmol), LRQ-06-15 (97 mg, 0.37 mmol) were added successively. The reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (31 mg, yield 33%). 1 H NMR (800 MHz, CDC13) δ 7.39 (s, 1H), 7.13 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.78-6.74 (m, 1H), 4.06-4.01 (m, 2H), 3.99 (s, 3H), 3.69 (s, 2H), 3.33 (s, 3H), 2.89-2.81 (m, 2H), 2.77-2.70 (m, 2H), 2.69-2.62 (m, 2H), 1.88-1.80 (m, 2H), 1.69-1.62 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 156.32, 151.16, 148.96, 145.29, 143.75, 133.90, 129.75, 123.33, 111.89, 111.32, 106.03, 56.84, 56.14, 51.74, 50.49, 50.19, 27.10, 26.18, 24.36, 20.93. HRMS (ESI) C 20 H 25 N4O4 + [M+H]+calcd: 385.1870, found: 385.1865. HPLC: 98.02% (λ = 254 nm, t R = 10.85 min).

[0358] Example 23: Preparation of compound 2-(3-(8-methoxy-3,4-dihydrobenzo[2,3-c]pyrrol-2(lH)-yl)propyl)-4-methyl-l,2,4-triazine-3,5(2H,4H)-dione (I-A23) (IHCH-5202)

[0359]

[0360] Step 1, LRQ-06-28 (1.78 g, 41% yield) was obtained as colorless oil after LRQ-04- 152 (2.25 g, 17.70 mmol) was dissolved in DMF (20 mL) and then NaH (0.85 g, 21.24 mmol), 1,3-dibromopropane (11.25 g, 53.10 mmol) were added successively, and the reaction was carried out at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain LRQ-06-28 (1.78 g, 41% yield) as colorless oil. 1 H NMR (800 MHz, CDC13) δ 7.41 (s, 1H), 4.04 (t, J = 6.6 Hz, 2H), 3.43 (t, J = 6.2 Hz, 2H), 3.20 (s, 3H), 1.91 - 1.82 (m, 2H). HRMS (ESI) C7H 11 BrN3O2 + [M+H]+calcd: 248.0029, found: 248.0031.

[0361] Step 2, LRQ-06-28 (91 mg, 0.37 mmol) was added successively after LRQ-04-153 (50 mg, 0.25 mmol) was dissolved in DMF (8 mL), and then DIPEA (191 mg, 1.48 mmol) was added at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (35 mg, 38% yield). 1 H NMR (800 MHz, CDC13) δ 7.37 (s, 1H), 7.12 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 4.13 - 4.06 (m, 2H), 3.99 (s, 3H), 3.66 (s, 2H), 3.26 (s, 3H), 2.86 - 2.77 (m, 2H), 2.71 - 2.66 (m, 4H), 2.07 - 1.99 (m, 2H). 13CNMR(201MHz,CDCl3)δ156.31,151.20,149.02,145.25,143.68,133.79,129.69,123.33,11 1.80,111.30,106.01,56.11,54.38,50.48,50.24,50.18,26.98,25.87,20.97.HRMS(ESI)C 19 H 23 N4O4 + [M+H]+ Calculated value: 371.1714, Measured value: 371.1712. HPLC: 96.59% (λ=254nm, t R =10.54min).

[0362] Example 24: Preparation of compound 1-(2-(-methoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (I-A24) (IHCH-5223)

[0363]

[0364] LRQ-04-153 (50 mg, 0.25 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (191 mg, 1.48 mmol) and 1-(2-bromoethyl)-1,3-dihydro-2H-benzimidazol-2-one (92 mg, 0.38 mmol). The mixture was reacted overnight at 100 °C. After the reaction was complete, the mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to give a pale yellow solid (35 mg, yield 42%). 1 H NMR(800MHz, CDCl3)δ9.72(s,1H),7.13(t,J=7.8Hz,1H),7.10–7.06(m,2H),7.06–7.03(m,2H),7.03–7.00(m,1H ),6.76(d,J=7.9Hz,1H),4.12(t,J=6.9Hz,2H),3.99(s,3H),3.83(s,2H),3.04–2.92(m,4H),2.77–2.68(m,2H). 13C NMR (201 MHz, CDC13) δ 155.57, 149.30, 145.29, 143.72, 130.41, 129.75, 128.07, 123.34, 121.68, 121.48, 111.96, 111.34, 109.80, 107.97, 106.07, 56.16, 54.67, 50.52, 50.36, 39.17, 20.90. HRMS (ESI) C 21 H 22 N3O3 + [M+H]+calcd: 364.1656, found: 364.1657. HPLC: 95.01% (l=254 nm, t R = 11.84 min).

[0365] Example 25: Preparation of compound 7-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)butyl)quinolin-2(lH)-one (I-A25) (IHCH-5225)

[0366]

[0367] LRQ-05-137 (22 mg, 0.10 mmol) was dissolved in DMF (8 mL), then DIPEA (84 mg, 0.65 mmol), LRQ-06-98 (45 mg, 0.16 mmol) were added successively, and the mixture was reacted at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (10 mg, yield 23%). 1 H NMR (800 MHz, CDC13) δ 12.06 (s, 1H), 7.74 (d, J = 9.4 Hz, 1H), 7.48 - 7.42 (m, 1H), 7.26 (s, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.05 - 7.02 (m, 1H), 7.00 (d, J = 7.6 Hz, 1H), 6.77 - 6.71 (m, 1H), 6.62 (d, J = 9.4 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 3.78 (s, 2H), 2.98 - 2.89 (m, 2H), 2.79 - 2.67 (m, 6H), 1.75 - 1.67 (m, 4H), 1.48 (t, J = 7.0 Hz, 3H). 13C NMR (201 MHz, CDC13) δ 164.55, 145.86, 144.55, 143.97, 142.25, 140.93, 138.77, 129.63, 127.80, 123.63, 123.36, 120.43, 118.26, 115.53, 111.81, 111.18, 107.27, 64.51, 57.04, 50.50, 49.95, 35.85, 29.00, 26.63, 20.47, 15.03. HRMS (ESI) C 26 H 29 N2O3 + [M+H]+calcd: 417.2173, found: 417.2177. HPLC: 98.08% (l=254 nm, t R = 11.69 min).

[0368] Example 26: Preparation of compound 7-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)propyl)quinolin-2(lH)-one (I-A26) (IHCH-5218)

[0369]

[0370] Step 1, methyl 3-aminophenylalanate (1.00 g, 5.58 mmol) was dissolved in dichloromethane (10 mL), after cooling to 0 °C, pyridine (883 mg, 11.16 mmol) and cinnamoyl chloride (1.39 g, 8.37 mmol) were added successively, and the reaction was allowed to warm to room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction, and saturated brine was used for washing. After drying over anhydrous sodium sulfate, the solvent was removed by evaporation under reduced pressure to obtain colorless oily liquid LRQ-06-89, which was directly used in the next step without purification. HRMS (ESI) C 19 H 20 NO3 + [M+H]+calcd: 310.1438, found: 310.1438.

[0371] Step 2, LRQ-06-89 was dissolved in chlorobenzene (20 mL), and after being replaced with nitrogen for three times, aluminum chloride (3.72 g, 27.90 mmol) was added, and the temperature was increased to 95 °C for 3 hours. After the reaction was completed, the reaction solution was cooled to 0 °C, diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain white solid LRQ-06-90 (954 mg, two-step reaction yield 74%). 1 H NMR (800 MHz, CDC13) δ 7.82 (d, J = 9.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.14-7.11 (m, 1H), 6.70 (d, J = 9.3 Hz, 1H), 3.70 (s, 3H), 2.83-2.77 (m, 2H), 2.66 (t, J = 7.4 Hz, 2H) HRMS (ESI) C 13 H 14 NO3 + [M+H]+calcd: 232.0968, found: 232.0966.

[0372] Step 3, LRQ-06-90 (520 mg, 2.25 mmol) was dissolved in THF (20 mL), and after being replaced with nitrogen for three times, the reaction solution was cooled to -10 °C, and DIBAL-H (7 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction solution was warmed to 0 °C for 6 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (10 mL) was added, followed by stirring at room temperature for 1 hour, extraction with ethyl acetate (20 mL*3), washing with saturated brine, drying over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation to obtain light yellow solid LRQ-06-91, which was directly used in the next step without purification. HRMS (ESI) C 12 H 14 NO2 + [M+H] + calcd: 204.1019, found: 204.1024.

[0373] Step 4, LRQ-06-91 was dissolved in DCM (10 mL) and cooled to 0 °C, and carbon tetrabromide (1.12 g, 3.38 mmol) and triphenylphosphine (1.18 g, 4.50 mmol) were added in turn. The reaction was carried out at room temperature overnight. After the reaction was completed, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to obtain white solid LRQ-06-92 (370 mg, two-step reaction yield 62%).1 H NMR (600 MHz, CDC13) δ 7.86 (d, J = 9.3 Hz, 1H) 7.58 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.14 (d, J = 7.9 Hz, 1H), 6.75 (d, J = 9.3 Hz, 1H), 3.41 (t, J = 6.5 Hz, 2H), 2.93 - 2.86 (m, 2H), 2.23 - 2.20 (m, 2H). HRMS (ESI) C 12 H 13 BrNO + [M+H]+ calculated: 266.0175, found: 266.0169.

[0374] Step 5, LRQ-05-137 (40 mg, 0.18 mmol) was dissolved in DMF (8 mL) and DIPEA (140 mg, 1.08 mmol), LRQ-06-92 (72 mg, 0.27 mmol) were added successively. The reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted. After washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (22 mg, yield 30%). 1 H NMR (800 MHz, CDC13) δ 12.62 (s, 1H), 7.78 (d, J = 9.4 Hz, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.28 (s, 1H), 7.12 - 7.06 (m, 2H), 7.03 - 7.00 (m, 1H), 6.78 - 6.73 (m, 1H), 6.68 (d, J = 9.4 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.69 (s, 2H), 2.87 - 2.80 (m, 2H), 2.80 - 2.77 (m, 2H), 2.74 - 2.70 (m, 2H), 2.66 - 2.59 (m, 2H), 2.00 - 1.91 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 164.99, 151.43, 145.76, 144.54, 143.88, 140.99, 138.84, 129.93, 127.81, 123.66, 123.22, 120.42, 118.33, 115.73, 111.88, 111.16, 107.10, 64.50, 56.68, 50.52, 50.28, 33.70, 29.02, 21.01, 15.06. HRMS (ESI) C 25 H27 N2O3 + [M+H]+calcd: 403.2016, found: 403.2017. HPLC: 97.83% (l=254 nm, t R = 11.70 min).

[0375] Example 27: Preparation of compound 7-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)quinolin-2(lH)-one (I-A27) (IHCH-5217)

[0376]

[0377] Step 1, Methyl 3-aminobenzenepropanoate (1.00 g, 6.05 mmol) was dissolved in dichloromethane (10 mL), cooled to 0 °C, and then pyridine (957 mg, 12.10 mmol) and cinnamoyl chloride (1.52 g, 9.08 mmol) were added successively. The reaction mixture was warmed to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (50 mL*3). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure to give brown-yellow oily liquid LRQ-06-82, which was used directly in the next step without further purification. HRMS (ESI) C 18 H 18 NO3 + [M+H]+calcd: 296.1281, found: 296.1288.

[0378] Step 2, LRQ-06-82 was dissolved in chlorobenzene (20 mL), and then aluminum trichloride (4.03 g, 30.25 mmol) was added after the solution was replaced with nitrogen three times. The reaction mixture was warmed to 95 °C and stirred for 3 h. After the reaction was completed, the reaction mixture was cooled to 0 °C and diluted with water (10 mL). The mixture was extracted with ethyl acetate (20 mL*3), and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1:1) to give LRQ-06-84 as a light yellow solid (604 mg, 46% for two steps). 1 H NMR (800 MHz, CDC13) δ 7.81 (d, J = 9.4 Hz, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.32 (s, 1H), 7.18 - 7.15 (m, 1H), 6.71 (d, J = 9.4 Hz, 1H), 3.74 (s, 2H), 3.71 (s, 3H). HRMS (ESI) C 12 H 12 NO3 +[M+H]+calcd: 218.0812, found: 218.0813.

[0379] Step 3, LRQ-06-84 (560 mg, 2.57 mmol) was dissolved in THF (20 mL), and the reaction solution was cooled to -10 °C after nitrogen replacement for three times. Then DIBAL-H (8 mL, 1.0 M tetrahydrofuran solution) was added. The reaction solution was then warmed to 0 °C for 6 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (10 mL) was added, followed by stirring at room temperature for 1 hour, extraction with ethyl acetate (20 mL*3), washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure to obtain a light yellow solid LRQ-06-85, which was directly used in the next step without purification. HRMS (ESI) C 11 H 12 NO2 + [M+H]+calcd: 190.0863, found: 190.0865.

[0380] Step 4, LRQ-06-85 was dissolved in DCM (10 mL) and cooled to 0 °C, and carbon tetrabromide (1.28 g, 3.86 mmol) and triphenylphosphine (1.35 g, 5.14 mmol) were added in turn. The reaction was carried out at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, extraction was performed with ethyl acetate (20 mL*3), washing was performed with saturated brine, drying was performed over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain white solid LRQ-06-86 (300 mg, two-step reaction yield 46%). 1 H NMR (600 MHz, CDCl3) δ 7.88 (d, J = 9.4 Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 7.26 (s, 1H), 7.16 (d, J = 7.9 Hz, 1H), 6.76 (d, J = 9.4 Hz, 1H), 3.63 (t, J = 7.3 Hz, 2H), 3.29 (t, J = 7.3 Hz, 2H). HRMS (ESI) C 11 H 11 BrNO + [M+H]+calcd: 252.0019, found: 252.0013.

[0381] Step 5, LRQ-05-137 (40 mg, 0.18 mmol) was dissolved in DMF (8 mL) and then DIPEA (140 mg, 1.08 mmol), LRQ-06-86 (68 mg, 0.27 mmol) were added successively. The reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (14 mg, yield 20%). 1 H NMR (800 MHz, CDC13) δ 12.20 (s, 1H), 7.79 - 7.70 (m, 1H), 7.46 (d, J = 7.9 Hz, 1H), 7.24 (s, 1H), 7.11 (t, J = 7.7 Hz, 2H), 7.02 (d, J = 7.7 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 6.68 - 6.61 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.81 (s, 2H), 3.04 - 2.97 (m, 2H), 2.97 - 2.90 (m, 4H), 2.79 - 2.73 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 164.68, 151.13, 144.58, 143.94, 143.65, 140.90, 138.74, 129.86, 127.94, 123.92, 123.30, 120.68, 118.49, 115.91, 111.94, 111.20, 107.18, 64.53, 58.75, 50.57, 50.21, 34.30, 20.95, 15.08. HRMS (ESI) C 24 H 25 N2O3 + [M+H]+calcd: 389.1860, found: 389.1865. HPLC: 95.13% (λ = 254 nm, t R = 11.68 min).

[0382] Example 28: Preparation of compound 1-((8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)- yl)methyl)cyclohexan-l-ol (I-A28) (IHCH-5232)

[0383]

[0384] LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in absolute ethanol (10 mL), and after the addition of methylene cyclohexane oxide (128 mg, 1.15 mmol), the reaction was warmed to 60 °C overnight. After the completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a white solid (29 mg, yield 38%). 1 H NMR (800 MHz, CDC13) δ 7.12 (t, J = 7.8 Hz, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.79 - 6.75 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.87 (s, 2H), 3.06 - 2.94 (m, 2H), 2.76 - 2.68 (m, 2H), 2.56 (s, 2H), 1.71 - 1.63 (m, 2H), 1.63 - 1.53 (m, 3H), 1.51 (t, J = 7.0 Hz, 3H), 1.49 - 1.42 (m, 2H), 1.39 - 1.34 (m, 2H), 1.30 - 1.23 (m, 1H). 13 C NMR (201 MHz, CDC13) δ 148.08, 144.63, 143.82, 129.85, 123.36, 112.07, 111.15, 107.18, 70.72, 64.53, 55.72, 52.85, 52.82, 36.63 (2C), 26.02, 22.28 (2C), 21.97, 15.07. HRMS (ESI) C 20 H 28 NO3 + [M+H] + Calculated: 330.2064, Found: 330.2069. HPLC: 97.60% (λ = 254 nm, t R = 11.58 min).

[0385] Example 29: Preparation of compound 7-(4-(8-ethoxy-3,4-dihydrobenzo[f]pyran-2(lH)- yl)butyloxy)-l,8-naphthyridin-2(lH)-one (IHCH-5213) (I-A29)

[0386]

[0387] Step 1, cool concentrated sulfuric acid (6 mL) to 0 °C, then add 2-amino-7-hydroxy-1,8- naphthyridine (1.00 g, 6.21 mmol) and sodium nitrite (684 mg, 9.92 mmol) successively, and then warm to room temperature and continue to react for 15 min. After the reaction is completed, pour into ice water, adjust pH to 8 with saturated aqueous sodium bicarbonate solution, extract with ethyl acetate (50 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure to obtain a gray-brown solid LRQ-06-64, which is directly used in the next step without purification. HRMS (ESI) C8H7N2O2 + [M+H]+calcd: 163.0502, found: 163.0507.

[0388] Step 2, dissolve LRQ-06-64 in DMF (20 mL), then add K2CO3 (858 mg, 6.21 mmol) and 1,4-dibromobutane (2.68 g, 12.42 mmol) successively, and then react at room temperature overnight. After the reaction is completed, dilute with water (10 mL), extract with ethyl acetate (50 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to obtain a red-brown solid LRQ-06-65 (202 mg, 11% yield for two steps). 1 HNMR (800 MHz, CDCl3) δ 10.09 (s, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 9.4 Hz, 1H), 6.59 (d, J = 8.4 Hz, 1H), 6.55 (d, J = 9.4 Hz, 1H), 4.41 (t, J = 6.3 Hz, 2H), 3.49 (t, J = 6.7 Hz, 2H), 2.09-2.01 (m, 2H), 1.99-1.92 (m, 2H). HRMS (ESI) C 12 H 14 BrN2O2 + [M+H]+calcd: 297.0233, found: 297.0237.

[0389] Step 3, dissolve LRQ-05-137 (50 mg, 0.23 mmol) in DMF (8 mL), then add DIPEA (178 mg, 1.38 mmol) and LRQ-06-65 (104 mg, 0.35 mmol) successively, and then react at 100 °C overnight. After the reaction is completed, dilute with water (10 mL), extract with ethyl acetate (50 mL*3), wash with saturated brine, dry over anhydrous sodium sulfate, and then evaporate the solvent under reduced pressure. Purify the residue by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (10 mg, 10% yield).1 H NMR (800 MHz, CDC13) δ 9.82 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 9.4 Hz, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.77 - 6.73 (m, 1H), 6.58 (d, J = 8.4 Hz, 1H), 6.52 (d, J = 9.4 Hz, 1H), 4.43 - 4.36 (m, 2H), 4.24 (q, J = 7.0 Hz, 2H), 3.72 (s, 2H), 2.92 - 2.84 (m, 2H), 2.75 - 2.71 (m, 2H), 2.71 - 2.65 (m, 2H), 1.91 - 1.82 (m, 2H), 1.82 - 1.75 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 164.86, 163.87, 151.28, 148.53, 144.55, 143.89, 139.31, 138.45, 129.87, 123.27, 119.18, 111.85, 111.17, 108.77, 107.52, 107.11, 66.69, 64.51, 57.06, 50.54, 50.19, 26.87, 24.02, 20.90, 15.07. HRMS (ESI) C 25 H 28 N3O4 + [M+H]+calcd: 434.2074, found: 434.2071. HPLC: 95.39% (l=254 nm, t R = 12.05 min).

[0390] Example 30: Preparation of compound 6-(4-(8-ethoxy-3,4-dihydrobenzo[f]pyran-2(lH)- yl)butyloxy)-2H-benzo[b][l,4]oxazin-3(4H)-one (IHCH-5194) (I-A30)

[0391]

[0392] Step 1, 6-hydroxy-2H-1, 4-benzoxazin-3(4H)-one (0.3 g, 1.77 mmol) was dissolved in DMF (10 mL), then K2CO3(0.25 g, 1.77 mmol), 1, 4-dibromobutane (1.15 g, 5.31 mmol) were added successively, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:2) to obtain yellow solid LRQ-05-61 (0.20 g, yield 38%). 1 H NMR (800 MHz, CDC13) δ 7.72 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 6.53-6.46 (m, 1H), 6.37-6.32 (m, 1H), 4.56 (s, 2H), 3.94 (t, J = 6.1 Hz, 2H), 3.48 (t, J = 6.6 Hz, 2H), 2.09-2.01 (m, 2H), 1.96-1.88 (m, 2H). HRMS (ESI) C 12 H 15 BrNO3 + [M+H]+calcd: 300.0230, found: 300.0233.

[0393] Step 2, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), LRQ-05-61 (105 mg, 0.35 mmol) were added successively, and the reaction was allowed to proceed at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain orange solid (31 mg, yield 31%). 1H NMR (800 MHz, CDC13) δ 8.62 (s, 1H), 7.11 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.86 (d, J = 8.8 Hz, 1H), 6.78 - 6.74 (m, 1H), 6.51 - 6.47 (m, 1H), 6.37 (d, J = 2.6 Hz, 1H), 4.54 (s, 2H), 4.25 (q, J = 6.9 Hz, 2H), 3.97 - 3.89 (m, 2H), 3.73 (s, 2H), 2.92 - 2.84 (m, 2H), 2.76 - 2.72 (m, 2H), 2.72 - 2.65 (m, 2H), 1.87 - 1.81 (m, 2H), 1.81 - 1.75 (m, 2H), 1.51 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 166.46, 154.82, 151.21, 144.59, 143.94, 137.71, 129.85, 126.94, 123.33, 117.32, 111.88, 111.18, 109.53, 107.19, 102.92, 68.41, 67.57, 64.55, 57.00, 50.53, 50.17, 27.22, 23.97, 20.84, 15.07. HRMS (ESI) C 25 H 29 N2O5 + [M+H]+calcd: 437.2071, found: 437.2072. HPLC: 96.67% (λ = 254 nm, t R = 11.92 min).

[0394] Example 31: Preparation of compound 2-(3-(benzo[d][l,3]dioxol-5-yloxy)propyl)-8- ethoxy-l,2,3,4-tetrahydrobenzo[f]pyrrolo[2,3-c]pyridine (IHCH-5193)

[0395]

[0396] Step 1, LRQ-05-51 (90 mg, 0.35 mmol) was added to a solution of LRQ-05-137 (50 mg, 0.23 mmol) in DMF (8 mL) and the mixture was stirred at 100 °C overnight. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (50 mL*3). The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 1:10) to give a white solid (39 mg, yield 42%). 1 H NMR (800 MHz, CDC13) δ 6.70 (d, J = 8.4 Hz, 1H), 6.51-6.49 (m, 1H), 6.35-6.31 (m, 1H), 5.92 (s, 2H), 4.03 (t, J = 5.8 Hz, 2H), 3.62-3.55 (m, 2H), 2.31-2.24 (m, 2H). HRMS (ESI) C 10 H 12 BrO3 + [M+H]+calcd: 258.9964, found: 258.9970.

[0397] Step 2, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (178 mg, 1.38 mmol), LRQ-05-51 (90 mg, 0.35 mmol), and the mixture was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction. After being washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the residue was purified by column chromatography on silica gel (methanol / dichloromethane = 1:10) to give a white solid (39 mg, yield 42%). 1 H NMR (800 MHz, CDC13) δ 6.70 (d, J = 8.4 Hz, 1H), 6.51-6.49 (m, 1H), 6.35-6.31 (m, 1H), 5.92 (s, 2H), 4.03 (t, J = 5.8 Hz, 2H), 3.62-3.55 (m, 2H), 2.31-2.24 (m, 2H). HRMS (ESI) C 13C NMR (201 MHz, CDC13) δ 154.59, 151.31, 148.33, 144.56, 143.91, 141.68, 129.89, 123.25, 111.87, 111.16, 108.03, 107.13, 105.79, 101.19, 98.21, 67.07, 64.51, 54.13, 50.56, 50.34, 27.49, 20.95, 15.06. HRMS (ESI) C 23 H 26 NO5 + [M+H]+calcd: 396.1805, found: 396.1800. HPLC: 97.98% (l=254 nm, t R =12.72 min).

[0398] Example 32: Preparation of compound N-(2-(8-ethoxy-3,4-dihydrobenzo[f]pyran-2(lH)- yl)ethyl)cycloheptanecarboxamide (IHCH-5215)

[0399]

[0400] LRQ-06-67 (70 mg, 0.19 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, then trifluoroacetic acid (1 mL) was added and the reaction was allowed to proceed for 2 hours. After the reaction was completed, the solvent was removed by evaporation under reduced pressure to obtain a colorless oily liquid, which was dissolved in dichloromethane (10 mL), DIPEA (150 mg, 1.16 mmol) and cycloheptanecarbonyl chloride (46 mg, 0.28 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with dichloromethane (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain a light yellow solid (35 mg, yield 47%). 1H NMR (800 MHz, CDC13) δ 7.13 (t, J = 7.8 Hz, 1H), 7.05 - 7.02 (m, 1H), 6.80 - 6.75 (m, 1H), 6.11 (s, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.74 (s, 2H), 3.46 - 3.39 (m, 2H), 2.93 - 2.85 (m, 2H), 2.80 - 2.76 (m, 2H), 2.76 - 2.71 (m, 2H), 2.25 - 2.18 (m, 1H), 1.89 - 1.83 (m, 2H), 1.78 - 1.71 (m, 2H), 1.68 - 1.62 (m, 2H), 1.58 - 1.49 (m, 7H), 1.46 - 1.40 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 177.64, 152.38, 144.64, 143.95, 129.69, 123.46, 111.92, 111.17, 107.32, 64.57, 55.61, 50.15, 50.06, 47.56, 36.35, 31.83 (2C), 28.24 (2C), 26.72 (2C), 20.74, 15.07. HRMS (ESI) C 23 H 33 N2O3 + [M+H] + Calculated: 385.2486, Found: 385.2487. HPLC: 96.48% (λ = 254 nm, t R = 13.09 min).

[0401] Example 33: Preparation of compound N-(2-(8-ethoxy-3,4-dihydrobenzo[f]pyran-2(lH)- yl)ethyl)cyclopentanecarboxamide (IHCH-5214)

[0402]

[0403] LRQ-06-67 (70 mg, 0.19 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. After the addition of trifluoroacetic acid (1 mL), the reaction was allowed to proceed for 2 h. After the completion of the reaction, the solvent was removed under reduced pressure to obtain a colorless oily liquid, which was dissolved in DCM (10 mL). DIPEA (150 mg, 1.16 mmol) and cyclopentylcarbonyl chloride (40 mg, 0.28 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the completion of the reaction, the reaction mixture was diluted with saturated aqueous NaHC03solution (10 mL) and extracted with DCM (20 mL*3). The organic layer was washed with saturated brine, dried over anhydrous Na2S04, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1:1) to obtain a yellow solid (20 mg, yield 29%). 1 H NMR (800 MHz, CDC13) δ 7.12 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.4 Hz, 1H), 6.79 - 6.74 (m, 1H), 6.18 (s, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.71 (s, 2H), 3.47 - 3.40 (m, 2H), 2.90 - 2.84 (m, 2H), 2.78 - 2.73 (m, 2H), 2.73 - 2.68 (m, 2H), 2.54 - 2.46 (m, 1H), 1.87 - 1.79 (m, 2H), 1.77 - 1.67 (m, 4H), 1.59 - 1.52 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 176.56, 150.83, 144.59, 143.89, 129.70, 123.38, 111.88, 111.13, 107.25, 64.53, 55.56, 50.12, 50.01, 45.94, 36.51, 30.58 (2C), 25.99 (2C), 20.77, 15.03. HRMS (ESI) C 21 H 29 N2O3 + [M+H] + Calcd: 357.2173, Found: 357.2170. HPLC: 96.44% (λ = 254 nm, t R = 12.37 min).

[0404] Example 34: Preparation of compound 3-(3-(2-(8-ethoxy-3,4-dihydrobenzo[2,3-c]pyridine-2(lH)-yl)ethyl)cyclobutyl)-l,l-dimethylurea (l-A34) (IHCH-5195)

[0405]

[0406] Step 1, tert-Butyl 3-oxocyclobutylcarbamate (2.00 g, 10.80 mmol) was dissolved in DCM (10 mL), then methoxyformylmethylene triphenylphosphonium (4.33 g, 12.96 mmol) was added, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain LRQ-05-148 (2.22 g, yield 85%) as a yellow solid. 1 H NMR (600 MHz, CDC13) δ 5.70 (s, 1H), 4.81 (s, 1H), 4.31-4.15 (m, 1H), 3.69 (s, 3H), 3.62-3.47 (m, 1H), 3.26-3.11 (m, 1H), 3.00-2.84 (m, 1H), 2.79-2.65 (m, 1H), 1.45 (s, 9H). HRMS (ESI) C 12 H 20 NO4 + [M+H]+calcd: 242.1387, found: 242.1384.

[0407] Step 2, LRQ-05-148 (2.00 g, 8.30 mmol) was dissolved in anhydrous methanol (20 mL), then 10% palladium-carbon was added, and the reaction was allowed to proceed at room temperature overnight after hydrogen replacement three times and hydrogen was introduced. After the reaction was completed, the filtrate was obtained by evaporation under reduced pressure, and LRQ-05-149 was obtained as a white solid without purification and was directly used in the next step. HRMS (ESI) C 12 H 22 NO4 + [M+H]+calcd: 244.1543, found: 244.1546.

[0408] Step 3, LRQ-05-149 was dissolved in THF (20 mL), and the reaction was allowed to proceed at -10°C after nitrogen replacement three times, then DIBAL-H (25 mL, 1.0M tetrahydrofuran solution) was added. Then the reaction was allowed to proceed at 0°C for 6 hours. After the reaction was completed, saturated potassium sodium tartrate aqueous solution (10 mL) was added, followed by stirring at room temperature for 1 hour, extraction with ethyl acetate (20 mL*3), washing with saturated brine, drying with anhydrous sodium sulfate, and evaporation under reduced pressure to obtain LRQ-05-150 as a light yellow oily liquid without purification and was directly used in the next step. HRMS (ESI) C 11 H 12 NO3 + [M+H]+calcd: 216.1594, found: 216.1589.

[0409] Step 4, LRQ-05-150 was dissolved in DCM (10 mL) and cooled to 0 °C, then carbon tetrabromide (2.79 g, 8.41 mmol) and triphenylphosphine (2.94 g, 11.21 mmol) were added successively. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (20 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate) to obtain white solid LRQ-06-03 (1.38 g, 60% yield for three steps). 1 H NMR (600 MHz, CDC13) δ 4.25 - 4.07 (m, 1H), 3.36 - 3.27 (m, 2H), 2.56 - 1.86 (m, 7H), 1.44 - 1.39 (m, 9H). HRMS (ESI) C 11 H 20 BrNO2Na + [M+H]+calcd: 300.0570, found: 300.0575.

[0410] Step 5, LRQ-06-03 (250 mg, 1.41 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, then trifluoroacetic acid (1 mL) was added. The reaction was allowed to proceed for 2 hours. After the reaction was completed, the solvent was removed by reduced pressure evaporation to obtain yellowish oil LRQ-06-03-NH2. The product was used directly in the next step without further purification. HRMS (ESI) C6H 13 BrN + [M+H]+calcd: 178.0226, found: 178.0227.

[0411] Step 6, LRQ-06-03-NH2 was dissolved in DCM (10 mL), then triethylamine (428 mg, 4.23 mmol) and dimethylaminomethyl chloride (182 mg, 1.69 mmol) were added successively. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and dichloromethane (20 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain yellowish oil LRQ-06-04 (132 mg, 59% yield for two steps). 1 H NMR (600 MHz, CDC13) δ 4.23 - 4.07 (m, 1H), 3.39 - 3.24 (m, 2H), 2.94 - 2.83 (m, 6H), 2.61 - 1.90 (m, 7H). HRMS (ESI) C9H 18 BrN2O +[M+H]+calcd: 249.0597, found: 249.0600.

[0412] Step 7, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), LRQ-06-04 (87 mg, 0.35 mmol) were added successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, the mixture was diluted with water (10 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain an orange solid (38 mg, yield 42%). 1 H NMR (800 MHz, CDC13) δ 7.12 - 7.08 (m, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 4.52 - 4.40 (m, 1H), 4.26 - 4.21 (m, 2H), 3.69 (s, 2H), 2.89 - 2.86 (m, 6H), 2.86 - 2.82 (m, 2H), 2.74 - 2.69 (m, 2H), 2.54 - 2.51 (m, 2H), 2.35 - 1.60 (m, 7H), 1.50 (t, J = 7.0 Hz, 3H). HRMS (ESI) C 22 H 32 N3O3 + [M+H]+calcd: 386.2438, found: 386.2431. HPLC: 95.46% (λ = 254 nm, t R = 11.55 min).

[0413] Example 35: Preparation of compound N-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)benzamide (IHCH-5212)

[0414]

[0415] LRQ-06-67 (70 mg, 0.19 mmol) was dissolved in DCM (10 mL), cooled to 0 °C, and reacted with trifluoroacetic acid (1 mL) for 2 hours. After the reaction was complete, the solvent was removed under reduced pressure, yielding a colorless oily liquid. This liquid was then dissolved in dichloromethane (10 mL), and DIPEA (150 mg, 1.16 mmol) and benzoyl chloride (40 mg, 0.28 mmol) were added. The mixture was reacted overnight at room temperature. After the reaction was complete, the mixture was diluted with saturated sodium bicarbonate aqueous solution (10 mL), extracted with dichloromethane (20 mL * 3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give a pale yellow solid (10 mg, yield 14%). 1 H NMR(800MHz,MeOH-d4)δ8.31(s,1H),7.88–7.80(m,2H),7.51(t,J=7.4Hz,1H),7.47–7.39(m,2H),7.11(t,J=7.8Hz,1H),7.03(d,J=7.7Hz,1H),6.85 –6.79(m,1H),4.20(q,J=7.0Hz,2H),3.93(s,2H),3.72–3.63(m,2H),3.12 –3.06(m,2H),3.04–2.98(m,2H),2.83–2.75(m,2H),1.43(t,J=7.0Hz,3H). 13 C NMR(201MHz,MeOH-d4)δ170.41,150.46,145.88,145.45,135.38,132.75,130.57,129.55(2C),128.2 9(2C),124.62,112.80,112.15,109.11,65.63,57.18,51.56,50.74,38.01,21.03,15.26.HRMS(ESI)C 22 H 25 N2O3 + [M+H] + Calculated value: 365.1860, Measured value: 365.1863. HPLC: 96.03% (λ=254nm, t R =12.20min).

[0416] Example 36: Preparation of compound N-(2-(8-ethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(1H)-yl)ethyl)thiophene-2-carboxamide (I-A36) (IHCH-5211)

[0417]

[0418] Step 1 : LRQ-05-137 (320 mg, 1.48 mmol) was dissolved in DMF (10 mL), followed by the addition of DIPEA (1.15 g, 8.88 mmol) and N-Boc-2-bromoethylamine (498 mg, 2.22 mmol) successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 : 1) to obtain LRQ-06-67 (293 mg, yield 55%) as a yellow solid. 1 H NMR (800 MHz, CDC13) δ 8.02 (s, 1H), 7.15-7.09 (m, 1H), 7.05-7.00 (m, 1H), 6.81-6.74 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.77 (s, 2H), 3.42-3.27 (m, 2H), 2.99-2.92 (m, 2H), 2.84-2.71 (m, 4H), 1.51 (t, J = 7.0 Hz, 3H), 1.44 (s, 9H). HRMS (ESI) C 20 H 29 N2O4 + [M+H] + Calcd: 361.2122, Found: 361.2120.

[0419] Step 2: LRQ-06-67 (70 mg, 0.19 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. After the addition of trifluoroacetic acid (1 mL), the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by reduced pressure evaporation to obtain a colorless oily liquid, which was dissolved in dichloromethane (10 mL). DIPEA (150 mg, 1.16 mmol) and 2-thiophenecarbonyl chloride (42 mg, 0.28 mmol) were added, and the mixture was stirred at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and dichloromethane (20 mL*3) was added for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 : 1) to obtain a light yellow solid (14 mg, yield 19%). 1H NMR (800 MHz, MeOH-d4) δ 8.32 (s, 1H), 7.69-7.66 (m, 1H), 7.64-7.61 (m, 1H), 7.13-7.08 (m, 2H), 7.03 (d, J = 7.7 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 4.20 (q, J = 7.0 Hz, 2H), 3.92 (s, 2H), 3.68-3.61 (m, 2H), 3.10-3.04 (m, 2H), 3.01-2.96 (m, 2H), 2.81-2.75 (m, 2H), 1.43 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, MeOH-d4) δ 164.67, 150.40, 145.87, 145.44, 139.94, 131.76, 130.55, 129.76, 128.80, 124.63, 112.80, 112.15, 109.11, 65.63, 57.22, 51.55, 50.71, 37.85, 21.00, 15.27. HRMS (ESI) C 20 H 23 N2O3S + [M+H] + Calcd: 371.1424, Found: 371.1430. HPLC: 96.23% (λ = 254 nm, t R = 12.02 min).

[0420] Example 37: Preparation of compound 2-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)-3,4-dihydroisoquinolin-l(2H)-one (I-A37) (IHCH-5198)

[0421]

[0422] Step 1, 3,4-dihydroisoquinolin-l(2H)-one (526 mg, 3.57 mmol) was dissolved in toluene (10 mL) and cooled to 0 °C, NaH (167 mg, 4.18 mmol) was added, and the reaction was refluxed for 1 h. Then the reaction was cooled to room temperature, methyl bromoacetate (639 mg, 4.18 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (20 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain a light yellow oily liquid LRQ-06-23 (746 mg, yield 95%). 1H NMR (800 MHz, CDC13) δ 8.01 - 7.96 (m, 1H), 7.37 - 7.31 (m, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.26 (s, 2H), 3.66 (s, 3H), 3.57 (t, J = 6.7 Hz, 2H), 2.99 - 2.93 (m, 2H). HRMS (ESI) C 12 H 14 NO3 + [M+H]+calcd: 220.0968, found: 220.0972.

[0423] Step 2, LRQ-06-23 (526 mg, 2.40 mmol) was dissolved in THF (10 mL), and after three times of nitrogen replacement, the reaction solution was cooled to -10 °C, and DIBAL-H (7 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction solution was warmed to 0 °C and reacted for 6 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (10 mL) was added, followed by stirring at room temperature for 1 hour, extraction with ethyl acetate (20 mL*3), washing with saturated brine, drying over anhydrous sodium sulfate, and then removing the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-24, which was directly used in the next step without purification. HRMS (ESI) C 11 H 14 NO2 + [M+H]+calcd: 192.1019, found: 192.1015.

[0424] Step 3, LRQ-06-24 was dissolved in DCM (10 mL) and cooled to 0 °C, and carbon tetrabromide (1.19 g, 3.60 mmol) and triphenylphosphine (1.26 g, 4.80 mmol) were added in turn, and the reaction was carried out at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, extraction was performed with ethyl acetate (20 mL*3), washing was performed with saturated brine, drying was performed over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain yellow solid LRQ-06-22 (255 mg, two-step reaction yield 42%). 1 H NMR (800 MHz, CDC13) δ 8.01 - 7.96 (m, 1H), 7.37 - 7.31 (m, 1H), 7.25 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.6 Hz, 1H), 4.26 (s, 2H), 3.66 (s, 3H), 3.57 (t, J = 6.7 Hz, 2H), 2.99 - 2.93 (m, 2H). HRMS (ESI) C 11 H 13 BrNO +[M+H]+calcd: 254.0175, found: 254.0179.

[0425] Step 4, LRQ-05-137 (40 mg, 0.19 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), LRQ-06-22 (74 mg, 0.29 mmol) were added successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (15 mg, yield 21%). 1 H NMR (800 MHz, MeOH-d4) δ 7.94 - 7.90 (m, 1H), 7.46 - 7.40 (m, 1H), 7.35 - 7.29 (m, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.11 - 7.06 (m, 1H), 7.03 - 6.99 (m, 1H), 6.81 - 6.77 (m, 1H), 4.21 (q, J = 7.0 Hz, 2H), 3.87 - 3.78 (m, 4H), 3.70 - 3.61 (m, 2H), 3.04 - 2.99 (m, 2H), 2.99 - 2.96 (m, 2H), 2.96 - 2.90 (m, 2H), 2.77 - 2.69 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, MeOH-d4) δ 166.61, 151.61, 145.73, 145.26, 140.05, 133.10, 130.79, 130.12, 128.61, 128.21, 127.91, 124.36, 112.75, 112.05, 108.87, 65.59, 55.49, 51.46, 51.06, 47.81, 46.02, 28.81, 21.49, 15.28. HRMS (ESI) C 24 H 27 N2O3 + [M+H]+calcd: 391.2016, found: 391.2011. HPLC: 98.96% (λ = 254 nm, t R = 11.33 min).

[0426] Example 38: Preparation of compound 2-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)-6-methyl-3,4-trihydro-2,7-naphthyridin-l(2H)-one (IHCH-5199)

[0427]

[0428] Step 1, 4-Chloro-6-methylnicotinic acid methyl ester (4.03 g, 21.78 mmol), tributylvinyltin (10.36 g, 32.67 mmol) and tetrakis(triphenylphosphine)palladium (1.76 g, 1.52 mmol) were dissolved in toluene (10 mL) and 1,4-dioxane (10 mL), after nitrogen replacement for three times, the reaction was heated to 90 °C overnight. After the reaction was completed, it was diluted with saturated aqueous sodium bicarbonate solution (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to obtain orange-yellow oily liquid LRQ-06-05 (3.2 g, yield 83%). 1 H NMR (800 MHz, CDCl3) δ 8.99 (s, 1H), 7.55-7.47 (m, 1H), 7.32 (s, 1H), 5.84 (d, J = 17.5 Hz, 1H), 5.53 (d, J = 11.0 Hz, 1H), 3.92 (s, 3H), 2.61 (s, 3H). HRMS (ESI) C 10 H 12 NO2 + [M+H]+calcd: 178.0863, found: 178.0868.

[0429] Step 2, LRQ-06-05 (3.20 g, 18.08 mmol) was mixed with 50 ml of ammonia (50 mL, 7.0 M methanol solution) in a sealed tube, and the reaction was stirred at 100 °C overnight. After the reaction was completed, the solvent was removed under reduced pressure to obtain pink solid LRQ-06-06, which was directly used in the next step without purification. HRMS (ESI) C9H 11 N2O + [M+H]+calcd: 163.0866, found: 163.0869.

[0430] Step 3, LRQ-06-06 was dissolved in toluene (10 mL) and cooled to 0 °C, NaH (844 mg, 21.17 mmol) was added, and the reaction was refluxed for 1 h. Then the reaction was cooled to room temperature, methyl bromoacetate (3.23 g, 21.17 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain LRQ-06-25 (3.72 g, 88% yield for two steps) as a yellow solid. 1 H NMR (800 MHz, CDC13) δ 9.09 (s, 1H), 7.02 (s, 1H), 4.34 (s, 2H), 3.76 (s, 3H), 3.67 (t, J = 6.6 Hz, 2H), 3.03 (t, J = 6.6 Hz, 2H), 2.60 (s, 3H). HRMS (ESI) C 12 H 15 N2O3 + [M+H]+calcd: 235.1077, found: 235.1082.

[0431] Step 4, LRQ-06-25 (600 mg, 2.56 mmol) was dissolved in THF (10 mL), and the reaction was cooled to -10 °C after being replaced with nitrogen three times. DIBAL-H (8 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction was warmed to 0 °C and reacted for 6 h. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (10 mL) was added, followed by stirring at room temperature for 1 h. The reaction was extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation to obtain LRQ-06-26 as a light yellow oily liquid. The product was directly used in the next step without purification. HRMS (ESI) C 11 H 15 N2O2 + [M+H]+calcd: 207.1128, found: 207.1130.

[0432] Step 5, LRQ-06-26 was dissolved in DCM (10 mL) and cooled to 0 °C. Carbon tetrabromide (1.27 g, 3.84 mmol) and triphenylphosphine (1.34 g, 5.12 mmol) were added in sequence, and the reaction was stirred at room temperature overnight. After the reaction was completed, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain LRQ-06-27 (206 mg, 30% yield for two steps) as a yellow solid. 1H NMR(800MHz,MeOH-d4)δ8.95(s,1H),7.76(s,1H),3.83(t,J=6.6Hz,2H),3.80(t, J=5.5Hz,2H),3.73–3.69(m,2H),3.28(t,J=6.6Hz,2H),2.76(s,3H).HRMS(ESI)C 11 H 14 BrN2O + [M+H]+ Calculated value: 269.0284, Measured value: 269.0283.

[0433] Step 6: Dissolve LRQ-05-137 (50 mg, 0.23 mmol) in DMF (8 mL), then add DIPEA (191 mg, 1.48 mmol) and LRQ-06-27 (94 mg, 0.35 mmol) sequentially, and react overnight at 100 °C. After the reaction is complete, dilute with water (10 mL), extract with ethyl acetate (50 mL * 3), wash with saturated brine, dry with anhydrous sodium sulfate, remove the solvent under reduced pressure, and purify the residue by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (27 mg, yield 29%). 1 H NMR (800MHz, CDCl3) δ9.07(s,1H),7.11(t,J=7.8Hz,1H),7.02(d,J=7.7Hz,1H),6.96(s,1H),6.77(d,J=7.9Hz,1H),4.27–4.21(m,2H ),3.88–3.76(m,4H),3.69–3.62(m,2H),3.03–2.96(m,2H),2.95–2.90(m,4H),2.77–2.70(m,2H),2.56(s,3H),1.50(t,J=7.0Hz,3H). 13 C NMR (201MHz, CDCl3) δ163.36,161.52,150.69,149.22,147.00,144.54,143.86,129.70,123.34,122.65,121.0 6,111.89,111.14,107.24,64.51,54.78,50.55,50.30,46.56,45.26,27.66,24.62,20.81,15.01.HRMS(ESI)C 24 H 28 N3O3 + [M+H]+ Calculated value: 406.2125, Measured value: 406.2121. HPLC: 95.82% (λ=254nm, t R= 11.88 min).

[0434] Example 39: Preparation of compound 5-(2-(8-ethoxy-3,4-dihydrobenzo[2,3-c]pyrrol-2(lH)-yl)ethyl)- 2,3-dimethyl-2,5,6,7-tetrahydro-4H-pyrazolo[4,3-c]pyridin-4-one (IHCH-5216)

[0435]

[0436] Step 1, methyl 3-bromo-l,5-dimethyl-lH-pyrazole-4-carboxylate (0.46 g, 2.04 mmol), potassium 2((tert-butoxycarbonyl)amino)ethyl trifluoroborate (0.76 g, 3.04 mmol), cesium carbonate (1.64 g, 5.06 mmol) and [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll) dichloromethane complex (0.16 g, 0.18 mmol) were dissolved in toluene (16 mL) and water (8 mL), after nitrogen replacement for three times, the reaction was heated to 100 °C for 3 hours. After the reaction was completed, water (10 mL) was added for dilution, ethyl acetate (20 mL*3) was extracted, saturated brine was washed, anhydrous sodium sulfate was dried, and the solvent was removed by reduced pressure to obtain orange-yellow oily liquid LRQ-06-71, which was directly used in the next step without purification. HRMS (ESI) C 14 H 24 N3O4 + [M+H]+calcd for C9H9N3O4: 223.0701, found: 223.0701.

[0437] Step 2, LRQ-06-71 was dissolved in DCM (10 mL) and cooled to 0 °C, then trifluoroacetic acid (1 mL) was added and the reaction was carried out for 2 hours. After the reaction was completed, the solvent was removed by reduced pressure to obtain light yellow oily liquid LRQ-06-71-NH2, which was directly used in the next step without purification. HRMS (ESI) C9H 16 N3O2 + [M+H]+calcd for C9H9N3O4: 223.0701, found: 223.0701.

[0438] Step 3, LRQ-06-71-NH2 was dissolved in methanol (10 mL), then sodium methoxide (2 mL, 5.0 M methanol solution) was added and the reaction was carried out at room temperature for 0.5 hours. After the reaction was completed, the solvent was removed by reduced pressure, then water (10 mL) was added for dilution, dichloromethane (20 mL*3) was extracted, and water was washed. After anhydrous sodium sulfate was dried, the solvent was removed by reduced pressure to obtain light yellow solid LRQ-06-72, which was directly used in the next step without purification. HRMS (ESI) C8H 12 N3O +[M+H]+calcd: 166.0975, found: 166.0969.

[0439] Step 4, LRQ-06-72 was dissolved in toluene (10 mL) and cooled to 0 °C, NaH (94 mg, 2.36 mmol) was added, and the reaction was refluxed for 1 h. Then the reaction was cooled to room temperature, ethyl bromoacetate (394 mg, 2.36 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give LRQ-06-75 (220 mg, 43% yield for four steps) as a light yellow solid. 1 H NMR (800 MHz, CDCl3) δ 4.24 (s, 2H), 4.20 (q, J = 7.1 Hz, 2H), 3.79-3.73 (m, 3H), 3.67-3.62 (m, 2H), 3.00-2.91 (m, 2H), 2.56-2.50 (m, 3H), 1.28 (t, J = 7.1 Hz, 3H). HRMS (ESI) C 12 H 18 N3O3 + [M+H]+calcd: 252.1343, found: 252.1341.

[0440] Step 5, LRQ-06-75 (220 mg, 0.87 mmol) was dissolved in THF (5 mL), and the reaction was cooled to -10 °C after being replaced with nitrogen three times. DIBAL-H (3 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction was warmed to 0 °C and reacted for 6 h. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (10 mL) was added, followed by stirring at room temperature for 1 h. The reaction was extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure to give LRQ-06-77 as a light yellow oily liquid. The product was directly used in the next step without purification. HRMS (ESI) C 10 H 16 N3O2 + [M+H]+calcd: 210.1237, found: 210.1238.

[0441] Step 6, LRQ-06-77 was dissolved in DCM (10 mL) and cooled to 0 °C, then carbon tetrabromide (432 mg, 1.31 mmol) and triphenylphosphine (456 mg, 1.74 mmol) were added successively. The reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (20 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain yellow solid LRQ-06-78 (40 mg, 17% yield for two steps). 1 H NMR (600 MHz, CDC13) δ 3.87 (t, J = 6.4 Hz, 2H), 3.83 (s, 3H), 3.72 (t, J = 6.6 Hz, 2H), 3.57 (t, J = 6.4 Hz, 2H), 2.99 (t, J = 6.5 Hz, 2H), 2.55 (s, 3H). HRMS (ESI) C 10 H 15 BrN3O + [M+H]+calcd: 272.0393, found: 272.0391.

[0442] Step 7, LRQ-05-137 (22 mg, 0.10 mmol) was dissolved in DMF (8 mL), then DIPEA (78 mg, 0.60 mmol), LRQ-06-78 (40 mg, 0.15 mmol) were added successively. The reaction was allowed to proceed at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain red-brown solid (6 mg, 14% yield). 1 H NMR (800 MHz, CDC13) δ 7.11 (t, J = 7.8 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.78-6.73 (m, 1H), 4.25 (q, J = 7.0 Hz, 2H), 3.79 (s, 2H), 3.74 (s, 3H), 3.72-3.69 (m, 2H), 3.65-3.62 (m, 2H), 2.97-2.91 (m, 2H), 2.88-2.83 (m, 4H), 2.73-2.71 (m, 2H), 2.53 (s, 3H), 1.50 (t, J = 7.0 Hz, 3H). HRMS (ESI) C 23 H 29 N4O3 + [M+H]+calcd: 409.2234, found: 409.2237. HPLC: 95.42% (λ = 254 nm, t R= 12.10 min).

[0443] Example 40: Preparation of compound 2-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine- 1 -one (LRQ-06-49) Preparation of compound 2-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)-2,3,4,5-tetrahydro-lH-benzo[c]azepine- 1 -one (LRQ-06-49)

[0444]

[0445] Step 1, LRQ-06-49 (1.00 g, 4.30 mmol) was dissolved in THF (20 mL), and the reaction solution was cooled to -10 °C after being replaced with nitrogen three times. Then, DIBAL-H (13 mL, 1.0 M tetrahydrofuran solution) was added. The reaction solution was warmed to 0 °C and reacted for 6 hours. After the reaction was completed, saturated potassium sodium tartrate aqueous solution (10 mL) was added, followed by stirring at room temperature for 1 hour. Ethyl acetate (20 mL*3) was extracted, and saturated brine was washed. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a light yellow solid LRQ-06-52, which was directly used in the next step without purification. Step 1, LRQ-06-49 (1.00 g, 4.30 mmol) was dissolved in THF (20 mL), and the reaction solution was cooled to -10 °C after being replaced with nitrogen three times. Then, DIBAL-H (13 mL, 1.0 M tetrahydrofuran solution) was added. The reaction solution was warmed to 0 °C and reacted for 6 hours. After the reaction was completed, saturated potassium sodium tartrate aqueous solution (10 mL) was added, followed by stirring at room temperature for 1 hour. Ethyl acetate (20 mL*3) was extracted, and saturated brine was washed. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a light yellow solid LRQ-06-52, which was directly used in the next step without purification. 1 HNMR (800 MHz, CDC13) δ 7.71-7.67 (m, 1H), 7.41-7.37 (m, 1H), 7.35-7.30 (m, 1H), 7.18-7.14 (m, 1H), 4.36 (s, 2H), 3.77 (s, 3H), 3.33-2.25 (m, 2H), 2.94-2.84 (m, 2H), 2.16-2.00 (m, 2H). HRMS (ESI) C 13 H 16 NO3 + [M+H]+ calculated: 234.1125, found: 234.1127.

[0446] Step 1, LRQ-06-49 (1.00 g, 4.30 mmol) was dissolved in THF (20 mL), and the reaction solution was cooled to -10 °C after being replaced with nitrogen three times. Then, DIBAL-H (13 mL, 1.0 M tetrahydrofuran solution) was added. The reaction solution was warmed to 0 °C and reacted for 6 hours. After the reaction was completed, saturated potassium sodium tartrate aqueous solution (10 mL) was added, followed by stirring at room temperature for 1 hour. Ethyl acetate (20 mL*3) was extracted, and saturated brine was washed. After drying with anhydrous sodium sulfate, the solvent was removed under reduced pressure to obtain a light yellow solid LRQ-06-52, which was directly used in the next step without purification. 12 H 16 NO2+ [M+H]+calcd for C9H9BrN2O2: 268.0332, found: 268.0334.

[0447] Step 3, LRQ-06-52 was dissolved in DCM (10 mL) and cooled to 0 °C, then carbon tetrabromide (2.14 g, 6.45 mmol) and triphenylphosphine (2.26 g, 8.60 mmol) were added successively, and the reaction was allowed to proceed at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (20 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate) to obtain LRQ-06-54 (69 mg, 6% yield for two steps) as a yellowish oil. 1 HNMR (600 MHz, CDC13) δ 7.70-7.64 (m, 1H), 7.41-7.36 (m, 1H), 7.36-7.30 (m, 1H), 7.15 (d, J = 7.3 Hz, 1H), 4.01-3.92 (m, 2H), 3.69-3.60 (m, 2H), 3.37-3.26 (m, 2H), 2.88-2.79 (m, 2H), 2.15-2.02 (m, 2H). HRMS (ESI) C 12 H 15 BrNO + [M+H]+calcd for C9H9BrN2O2: 268.0332, found: 268.0334.

[0448] Step 4, LRQ-05-137 (40 mg, 0.19 mmol) was dissolved in DMF (8 mL), and then DIPEA (178 mg, 1.38 mmol) and LRQ-06-54 (69 mg, 0.28 mmol) were added successively, and the reaction was allowed to proceed at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (17 mg, 23% yield). 1H NMR (800 MHz, CDC13) δ 7.65 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.14 - 7.08 (m, 2H), 7.02 (d, J = 7.7 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.84 - 3.80 (m, 2H), 3.79 (s, 2H), 3.24 (t, J = 6.4 Hz, 2H), 2.97 - 2.92 (m, 2H), 2.92 - 2.87 (m, 2H), 2.79 - 2.75 (m, 2H), 2.75 - 2.69 (m, 2H), 2.05 - 1.98 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 CNMR (201 MHz, CDC13) δ 171.29, 151.23, 144.56, 143.86, 137.68, 136.37, 130.82, 129.87, 128.57, 128.27, 126.96, 123.27, 111.95, 111.16, 107.12, 64.51, 55.78, 50.66, 50.36, 47.37, 45.72, 30.38, 30.32, 21.03, 15.05. HRMS (ESI) C 25 H 29 N2O3 + [M+H]+calcd: 405.2173, found: 405.2180. HPLC: 96.07% (A = 254 nm, t R = 12.48 min).

[0449] Example 41: Preparation of compound 5-(2-(8-ethoxy-3,4-dihydrobenzo[f]pyran-2(lH)- yl)ethyl)-l-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(lH)-one (IHCH-5210)

[0450]

[0451] ​Step 1, LRQ-06-56 was dissolved in toluene (10 mL) and cooled to 0 °C, then NaH (368 mg, 9.20 mmol) was added, and the reaction was refluxed for 1 h. Then the reaction was cooled to room temperature, methyl bromoacetate (1.41 g, 9.20 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give LRQ-06-57 (909 mg, 49% yield over two steps) as a light yellow solid. 13 N2O + [M+H]+calcd for C9H

[0452] Step 1, LRQ-06-56 was dissolved in toluene (10 mL) and cooled to 0 °C, then NaH (368 mg, 9.20 mmol) was added, and the reaction was refluxed for 1 h. Then the reaction was cooled to room temperature, methyl bromoacetate (1.41 g, 9.20 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to give LRQ-06-57 (909 mg, 49% yield over two steps) as a light yellow solid. 1 H NMR (800 MHz, CDC13) δ 6.70 (d, J = 3.0 Hz, 1H), 6.57-6.54 (m, 1H), 4.33 (s, 2H), 3.73 (s, 3H), 3.54-3.48 (m, 5H), 2.83-2.78 (m, 2H), 2.27-2.18 (m, 2H). HRMS (ESI) C 12 H 17 N2O3 + [M+H]+calcd for C9H

[0453] Step 3, LRQ-06-57 (400 mg, 1.69 mmol) was dissolved in THF (20 mL), and after three times of nitrogen replacement, the reaction solution was cooled to -10 °C, and DIBAL-H (5 mL, 1.0 M tetrahydrofuran solution) was added. Then the reaction solution was warmed to 0 °C and reacted for 6 hours. After the reaction was completed, saturated aqueous potassium sodium tartrate solution (10 mL) was added, followed by stirring at room temperature for 1 hour, extraction with ethyl acetate (20 mL*3), washing with saturated brine, drying over anhydrous sodium sulfate, and then removing the solvent under reduced pressure to obtain a light yellow oily liquid LRQ-06-58. Without purification, it was directly used in the next step reaction. HRMS (ESI) C 11 H 17 N2O2 + [M+H]+calcd: 209.1285, found: 209.1287.

[0454] Step 4, LRQ-06-58 was dissolved in DCM (10 mL) and cooled to 0 °C, and carbon tetrabromide (841 mg, 2.54 mmol) and triphenylphosphine (887 mg, 3.38 mmol) were added in turn. The reaction was carried out at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, extraction was performed with ethyl acetate (20 mL*3), washing was performed with saturated brine, drying was performed over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate) to obtain black solid LRQ-06-59 (200 mg, two-step reaction yield 44%). 1 H NMR (800 MHz, MeOH-d4) δ 6.88-6.85 (m, 1H), 6.59 (d, J = 3.2 Hz, 1H), 4.94-4.89 (m, 2H), 4.26-4.21 (m, 2H), 3.87-3.83 (m, 2H), 3.66 (s, 3H), 3.13-3.05 (m, 2H), 2.33-2.24 (m, 2H). HRMS (ESI) C 11 H 16 BrN2O + [M+H]+calcd: 271.0441, found: 271.0441.

[0455] Step 5, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), and then DIPEA (191 mg, 1.48 mmol), LRQ-06-59 (95 mg, 0.35 mmol) were added in turn. The reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, extraction was performed with ethyl acetate (50 mL*3), washing was performed with saturated brine, drying was performed over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (48 mg, yield 51%). 1H NMR (800 MHz, CDC13) δ 7.10 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.67 (d, J = 2.9 Hz, 1H), 6.56 - 6.52 (m, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.80 - 3.73 (m, 4H), 3.50 - 3.43 (m, 5H), 2.97 - 2.90 (m, 2H), 2.86 - 2.81 (m, 2H), 2.77 - 2.73 (m, 2H), 2.73 - 2.66 (m, 2H), 2.14 - 2.07 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 CNMR (201 MHz, CDC13) δ 166.22, 151.34, 144.54, 143.86, 133.06, 129.93, 123.24, 121.57, 117.23, 111.95, 111.17, 110.79, 107.14, 64.54, 55.46, 50.69, 50.32, 49.26, 47.45, 34.16, 26.60, 26.45, 21.01, 15.06. HRMS (ESI) C 24 H 30 N3O3 + [M+H]+calcd: 408.2282, found: 408.2279. HPLC: 96.12% (l = 254 nm, t R = 12.07 min).

[0456] Example 42: Preparation of compound 5-(2-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)ethyl)-l-methyl-5,6,7,8-tetrahydropyrazolo[4,3-c]azepin-4(lH)-one (IHCH-5207)

[0457]

[0458] Step 1, 1-methyl-l,5,6,7-tetrahydro-4H-indazol-4-one (1.00 g, 6.66 mmol), sodium acetate (1.05 g, 4.20 mmol), and hydroxylamine hydrochloride (0.21 g, 0.25 mmol) were dissolved in anhydrous ethanol (16 mL), and the reaction was heated to 60 °C overnight. After the reaction was completed, the reaction mixture was filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain white solid LRQ-06-47-1, which was directly used in the next step without purification. HRMS (ESI) C8H 12 N3O​+ [M+H]+calcd: 166.0975, found: 166.0977.

[0459] Step 2, LRQ-06-47-1 and triethylamine (2.02 g, 19.98 mmol) were dissolved in DCM (20 mL), p-toluenesulfonyl chloride (1.46 g, 7.66 mmol) was added, and the reaction was refluxed for 0.5 h. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The yellow solid was dissolved in trifluoroacetic acid (5 mL), and the reaction was refluxed for 0.5 h. After the reaction was completed, the solvent was removed by reduced pressure evaporation, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, dichloromethane (50 mL*3) was extracted, and water was washed. After drying over anhydrous sodium sulfate, the solvent was removed by reduced pressure evaporation to obtain yellow solid LRQ-04-47, which was directly used in the next step without purification. HRMS (ESI) C8H 12 N3O + [M+H]+calcd: 166.0975, found: 166.0975.

[0460] Step 3, LRQ-04-47 was dissolved in toluene (10 mL) and cooled to 0 °C, NaH (311 mg, 7.79 mmol) was added, and the reaction was refluxed for 1 h. Then the reaction liquid was cooled to room temperature, methyl bromoacetate (1.19 g, 7.79 mmol) was added, and the reaction was refluxed overnight. After the reaction was completed, water (10 mL) was added for dilution, ethyl acetate (20 mL*3) was extracted, and saturated brine was washed. After drying over anhydrous sodium sulfate, the solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain yellow solid LRQ-06-50 (620 mg, 39% yield for three steps). 1 H NMR (800 MHz, CDCl3) δ 8.16 (s, 1H), 4.71 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 2.71 (t, J = 6.2 Hz, 2H), 2.55-2.45 (m, 2H), 2.08-1.98 (m, 2H) HRMS (ESI) C 11 H 16 N3O3 + [M+H]+calcd: 238.1186, found: 238.1187.

[0461] Step 4, LRQ-06-50 (600 mg, 2.53 mmol) was dissolved in THF (5 mL), and the reaction solution was cooled to -10 °C after being replaced with nitrogen for three times. Then DIBAL-H (8 mL, 1.0 M in tetrahydrofuran) was added. The reaction solution was then warmed to 0 °C for 6 h. After the reaction was completed, saturated aqueous potassium sodium tartrate (10 mL) was added, followed by stirring at room temperature for 1 h. The reaction mixture was extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation to obtain a light yellow solid LRQ-06-53. The product was used directly in the next step without further purification. HRMS (ESI) C 10 H 16 N3O2 + [M+H]+calcd: 210.1237, found: 210.1242.

[0462] Step 5, LRQ-06-53 was dissolved in DCM (10 mL) and cooled to 0 °C. Carbon tetrabromide (1.26 g, 3.79 mmol) and triphenylphosphine (1.33 g, 5.06 mmol) were added successively. The reaction was stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added to dilute the reaction mixture, which was extracted with ethyl acetate (20 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain LRQ-06-55 (261 mg, 38% yield for two steps) as a colorless oily liquid. 1 H NMR (800 MHz, MeOH-d4) δ 8.03 (s, 1H), 5.03-4.97 (m, 2H), 4.31-4.25 (m, 2H), 3.92-3.90 (m, 2H), 3.89 (s, 3H), 3.20-3.15 (m, 2H), 2.34-2.27 (m, 2H). HRMS (ESI) C 10 H 15 BrN3O + [M+H]+calcd: 272.0393, found: 272.0397.

[0463] Step 6, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), and then DIPEA (191 mg, 1.48 mmol) and LRQ-06-55 (93 mg, 0.35 mmol) were added successively. The reaction was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added to dilute the reaction mixture, which was extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (29 mg, 31% yield). 1H NMR (800 MHz, CDC13) δ 7.97 - 7.94 (m, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.03 - 6.99 (m, 1H), 6.76 (d, J = 7.9 Hz, 1H), 4.27 - 4.21 (m, 2H), 3.78 - 3.73 (m, 7H), 3.52 - 3.47 (m, 2H), 2.96 - 2.91 (m, 2H), 2.87 - 2.82 (m, 2H), 2.82 - 2.76 (m, 2H), 2.74 - 2.69 (m, 2H), 2.16 - 2.12 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 164.25, 151.44, 144.57, 143.88, 142.11, 140.80, 129.81, 123.34, 116.31, 111.95, 111.17, 107.20, 64.54, 55.23, 50.64, 50.28, 49.29, 47.17, 36.68, 26.00, 25.79, 20.89, 15.05. HRMS (ESI) C 23 H 29 N4O3 + [M+H]+calcd: 409.2234, found: 409.2238. HPLC: 95.13% (λ = 254 nm, t R = 12.08 min).

[0464] Example 43: Preparation of compound 2-(4-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)butyl)-4-methyl-l,2,4-triazine-3,5(2H,4H)-dione (I-A43) (IHCH-5196)

[0465]

[0466] After LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), DIPEA (178 mg, 1.38 mmol), LRQ-06-15 (92 mg, 0.35 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (52 mg, yield 56%). 1H NMR (800 MHz, CDC13) δ 7.38 (s, 1H), 7.10 (t, J = 7.8 Hz, 1H), 7.01 (d, J = 7.7 Hz, 1H), 6.79 - 6.71 (m, 1H), 4.24 (q, J = 7.0 Hz, 2H), 4.04 - 4.00 (m, 2H), 3.69 (s, 2H), 3.33 (s, 3H), 2.86 - 2.81 (m, 2H), 2.74 - 2.69 (m, 2H), 2.67 - 2.62 (m, 2H), 1.87 - 1.78 (m, 2H), 1.67 - 1.60 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 156.31, 151.21, 148.94, 144.56, 143.90, 133.88, 129.85, 123.26, 111.84, 111.14, 107.14, 64.51, 56.83, 51.76, 50.54, 50.27, 27.08, 26.18, 24.41, 20.93, 15.06. HRMS (ESI) C 21 H 27 N4O4 + [M+H]+calcd: 399.2027, found: 399.2023. HPLC: 98.26% (λ = 254 nm, t R = 11.67 min).

[0467] Example 44: Preparation of compound 2-(3-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)propyl)-4-methyl-l,2,4-triazine-3,5(2H,4H)-dione (I-A44) (IHCH-5197)

[0468]

[0469] Step 1, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), LRQ-06-28 (86 mg, 0.35 mmol) were added successively, and the mixture was reacted at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (10 mg, yield 11%). 1H NMR (800 MHz, MeOH-d4) δ 7.41 (s, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.02 - 6.99 (m, 1H), 6.81 (d, J = 7.8 Hz, 1H), 4.21 (q, J = 7.0 Hz, 2H), 4.12 - 4.06 (m, 2H), 3.68 (s, 2H), 3.19 (s, 3H), 2.90 - 2.82 (m, 2H), 2.78 - 2.72 (m, 2H), 2.72 - 2.66 (m, 2H), 2.09 - 2.03 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H). 13 CNMR (201 MHz, MeOH-d4) δ 158.04, 151.64, 150.58, 145.84, 145.36, 134.97, 130.80, 124.46, 112.76, 112.09, 108.96, 65.64, 55.68, 51.42, 51.31, 50.92, 27.04, 26.36, 21.60, 15.28. HRMS (ESI) C 20 H 25 N4O4 + [M+H]+calcd: 385.1870, found: 385.1864. HPLC: 98.94% (λ = 254 nm, t R = 11.81 min).

[0470] Example 45: Preparation of compound 1-(4-(8-ethoxy-3,4-dihydrobenofuran[2,3-c]pyridin-2(lH)-yl)butyl)-4,4-dimethylpiperidine-2,6-dione (I-A45) (IHCH-5191)

[0471]

[0472] Step 1, after 3,3-dimethyl glutarimide (1.00 g, 7.08 mmol) was dissolved in DMF (10 mL), K2CO3(0.98 g, 7.08 mmol), 1,4-dibromobutane (4.59 g, 21.25 mmol) were added successively, and the reaction was carried out at room temperature overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to obtain a light yellow oily liquid LRQ-05-54 (1.60 g, yield 82%). 1HNMR (800 MHz, CDC13) δ 3.79 (t, J = 7.3 Hz, 2H), 3.41 (t, J = 6.7 Hz, 2H), 2.50 (s, 4H), 1.88 - 1.81 (m, 2H), 1.71 - 1.64 (m, 2H), 1.07 (s, 6H). HRMS (ESI) C 11 H 19 BrNO2 + [M+H]+calcd: 276.0594, found: 276.0590.

[0473] Step 2, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), LRQ-05-54 (97 mg, 0.35 mmol) were added successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a light yellow solid (60 mg, yield 63%). 1 H NMR (800 MHz, MeOH-d4) δ 7.12 (t, J = 7.8 Hz, 1H), 7.07 - 7.01 (m, 1H), 6.84 (d, J = 7.9 Hz, 1H), 4.22 (q, J = 7.0 Hz, 2H), 3.84 (s, 2H), 3.83 - 3.79 (m, 2H), 3.07 - 2.99 (m, 2H), 2.84 - 2.75 (m, 4H), 2.56 (s, 4H), 1.72 - 1.62 (m, 2H), 1.62 - 1.54 (m, 2H), 1.44 (t, J = 7.0 Hz, 3H), 1.06 (s, 6H). 13 CNMR (201 MHz, MeOH-d4) δ 174.20 (2C), 146.78, 146.02, 145.80, 129.72, 125.16, 112.75, 112.31, 109.67, 65.65, 57.23, 51.60, 49.91, 46.81 (2C), 39.43, 30.00, 27.69 (2C), 26.22, 23.44, 19.65, 15.23. HRMS (ESI) C 24 H 33 N2O4 + [M+H]+calcd: 413.2435, found: 413.2433. HPLC: 98.10% (λ = 254 nm, t R = 12.32 min).

[0474] Example 46: Preparation of compound 8-(4-(8-ethoxy-3,4-dihydrobenzofuran[2,3- c]pyridin-2(lH)-yl)butyl)-8-azaspiro[4.5]decane-7,9-dione (I-A46) (IHCH-5192)

[0475]

[0476] Step 1, LRQ-05-55 (1.60 g, 5.98 mmol) was dissolved in DMF (10 mL), then K2CO3 (0.83 g, 5.98 mmol) and 1,4-dibromobutane (3.87 g, 17.94 mmol) were added successively, and the mixture was stirred at room temperature overnight. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:4) to give LRQ-05-137 (1.60 g, yield 88%) as a yellow oil. 1 H NMR (800 MHz, CDC13) δ 3.79 (t, J = 7.3 Hz, 2H), 3.41 (t, J = 6.7 Hz, 2H), 2.59 (s, 4H), 1.87-1.78 (m, 2H), 1.74-1.63 (m, 6H), 1.52-1.43 (m, 4H). HRMS (ESI) C 13 H 21 BrNO2 + [M+H]+calcd: 302.0750, found: 302.0752.

[0477] Step 2, LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol) and LRQ-05-55 (110 mg, 0.35 mmol) were added successively, and the mixture was stirred at 100 °C overnight. After the reaction was completed, the reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (50 mL*3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to give a yellow solid (42 mg, yield 41%). 1HNMR (800 MHz, MeOH-d4) δ 7.17 (t, J = 7.9 Hz, 1H), 7.12 - 7.06 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.31 (s, 2H), 4.22 (q, J = 7.0 Hz, 2H), 3.84 - 3.78 (m, 2H), 3.50 - 3.44 (m, 2H), 3.23 - 3.18 (m, 2H), 3.00 - 2.95 (m, 2H), 2.64 (s, 4H), 1.81 - 1.74 (m, 2H), 1.74 - 1.68 (m, 4H), 1.65 - 1.59 (m, 2H), 1.53 - 1.47 (m, 4H), 1.44 (t, J = 7.0 Hz, 3H). 13 CNMR (201 MHz, MeOH-d4) δ 174.46 (2C), 146.85, 146.04, 145.83, 129.74, 125.15, 112.75, 112.30, 109.67, 65.66, 57.25, 51.61, 49.93, 45.39 (2C), 40.61, 39.48, 38.40 (2C), 26.26, 25.15 (2C), 23.44, 19.68, 15.23. HRMS (ESI) C 26 H 35 N2O4 + [M+H]+calcd: 439.2591, found: 439.2587. HPLC: 97.68% (λ = 254 nm, t R = 12.64 min).

[0478] Example 47: Preparation of compound 1-(2-(-ethoxy-3,4-dihydrobenzofuran[2,3-c]pyridin-2(lH)-yl)ethyl)-l,3-dihydro-2H-benzo[d]imidazol-2-one (I-A47) (IHCH-5224)

[0479]

[0480] LRQ-05-137 (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), 1-(2-bromoethyl)-1,3-dihydro-2H-benzimidazol-2-one (84 mg, 0.35 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (27 mg, yield 31%). 1 H NMR (800 MHz, CDC13) δ 9.68 (s, 1H), 7.14-7.03 (m, 5H), 7.00 (d, J = 7.7 Hz, 1H), 6.76 (d, J = 7.9 Hz, 1H), 4.25 (q, J = 7.0 Hz, 2H), 4.15-4.09 (m, 2H), 3.85 (s, 2H), 3.04-2.95 (m, 4H), 2.75-2.69 (m, 2H), 1.50 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDC13) δ 155.54, 150.23, 144.58, 143.92, 130.40, 129.81, 128.05, 123.32, 121.69, 121.50, 111.92, 111.19, 109.80, 108.00, 107.25, 64.56, 54.61, 50.55, 50.37, 39.14, 20.81, 15.08. HRMS (ESI) C 22 H 24 N3O3 + [M+H]+calcd: 378.1812, found: 378.1815. HPLC: 96.61% (λ = 254 nm, t R = 11.84 min).

[0481] Example 48: Preparation of compound 7-(4-(8-methoxy-1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)butoxy)quinolin-2(1H)-one (I-B1)

[0482]

[0483] Steps 1, 2, 3: The synthesis method of LRQ-04-165-Me is the same as that of patent US 5631265 A 19970520, and LRQ-04-165-Me is a yellow solid (17% yield for three steps). 1H NMR (800 MHz, MeOH-d4) δ 7.05 (d, J = 7.9 Hz, 1H), 6.97 (t, J = 7.8 Hz, 1H), 6.69 - 6.66 (m, 1H), 4.34 (s, 2H), 3.94 (s, 3H), 3.51 - 3.47 (m, 2H), 3.02 - 2.99 (m, 2H). HRMS (ESI) C 12 H 15 N2O + [M+H] + Calculated: 203.1179, Found: 203.1185.

[0484] Step 4: LRQ-04-165-Me (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)quinolin-2(lH)-one (218 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (72 mg, yield 35%). 1 H NMR (800 MHz, MeOH-d4) δ 7.88 (d, J = 9.4 Hz, 1H), 7.56 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.90 - 6.87 (m, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.66 (d, J = 7.6 Hz, 1H), 6.44 (d, J = 9.4 Hz, 1H), 4.21 (s, 2H), 4.16 (t, J = 5.9 Hz, 2H), 3.94 (s, 3H), 3.42 - 3.35 (m, 2H), 3.18 - 3.11 (m, 2H), 3.00 (t, J = 5.8 Hz, 2H), 2.03 - 1.98 (m, 2H), 1.98 - 1.92 (m, 2H). 13 C NMR (201 MHz, MeOH-d4) δ 163.98, 161.27, 147.76, 146.20, 140.61, 132.22, 131.32, 128.54, 125.51, 121.31, 117.88, 117.00, 113.53, 111.82, 107.15, 103.71, 100.27, 69.10, 56.84, 55.84, 52.40, 50.43, 27.21, 22.62, 19.84. HRMS (ESI) C25 H 28 N3O3 + [M+H] + Calculated: 418.2125, Found: 418.2126. HPLC: 97.90% (l = 254 nm, t R = 11.51 min).

[0485] Example 49: Preparation of compound 7-(4-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)butoxy)quinolin-2(1H)-one (I-B2)

[0486]

[0487] Step 1, 2, 3: LRQ-04-165-Et was synthesized with 2-ethoxyphenylhydrazine as raw material, and the synthesis method was the same as that of patent US 5631265A 19970520. LRQ-04-165-Et was a yellow solid (16% yield for three steps). 1 H NMR (800 MHz, MeOH-d4) d 7.01 (d, J = 7.8 Hz, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 7.6 Hz, 1H), 4.18 (q, J = 7.0 Hz, 2H), 4.13 (s, 2H), 3.30 - 3.24 (m, 2H), 2.89 - 2.82 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H). HRMS (ESI) C 13 H 17 N2O + [M+H] + Calculated: 217.1335, Found: 217.1337.

[0488] Step 4: LRQ-04-165-Et (105 mg, 0.49 mmol) was dissolved in DMF (8 mL), and then DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)quinolin-2(1H)-one (218 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, and then saturated brine was washed, and then anhydrous sodium sulfate was dried, and then the solvent was removed by reduced pressure evaporation, and then the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (36 mg, yield 17%). 1H NMR (800 MHz, MeOH-d4) δ 7.88 (d, J = 9.4 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.90 - 6.87 (m, 1H), 6.86 (d, J = 2.3 Hz, 1H), 6.67 (d, J = 7.6 Hz, 1H), 6.44 (d, J = 9.4 Hz, 1H), 4.42 - 4.29 (m, 2H), 4.20 - 4.16 (m, 4H), 3.58 - 3.44 (m, 2H), 3.35 - 3.32 (m, 1H), 3.08 - 3.02 (m, 2H), 2.08 - 2.02 (m, 2H), 1.99 - 1.94 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, MeOH-d4) δ 163.68, 160.60, 146.94, 141.94, 140.79, 131.12, 129.86, 126.99, 125.49, 121.26, 116.30, 115.24, 111.71, 107.11, 104.68, 104.49, 100.22, 68.98, 64.75, 56.89, 52.42, 50.45, 27.20, 22.60, 19.85, 15.31. HRMS (ESI) C 26 H 30 N3O3 + [M+H] + Calcd: 432.2282, Found: 432.2284. HPLC: 97.97% (λ = 254 nm, t R = 11.06 min).

[0489] Example 50: Preparation of compound 7-(3-(8-methoxy-l,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)propoxy)quinolin-2(lH)-one (I-B3)

[0490]

[0491] After LRQ-04-165-Me (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)quinolin-2(1H)-one (208 mg, 0.74 mmol) were added sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (98 mg, yield 50%). 1 H NMR (800 MHz, MeOH-d4) δ 7.78 (d, J = 9.4 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.85-6.82 (m, 1H), 6.80 (d, J = 1.9 Hz, 1H), 6.62-6.58 (m, 1H), 6.43 (d, J = 9.3 Hz, 1H), 4.13 (t, J = 5.9 Hz, 2H), 3.92 (s, 3H), 3.85 (s, 2H), 3.02 (s, 2H), 2.94-2.90 (m, 2H), 2.89-2.84 (m, 2H), 2.21-2.14 (m, 2H). 13 C NMR (201 MHz, MeOH-d4) δ 165.07, 161.63, 145.22, 141.96, 141.35, 134.23, 129.88, 128.79, 127.34, 120.01, 117.95, 116.83, 113.25, 111.31, 107.91, 102.36, 99.37, 66.92, 55.62, 54.80, 51.77, 50.82, 27.04, 21.36. HRMS (ESI) C 24 H 26 N3O3 + [M+H] + Calcd: 404.1969, Found: 404.1970. HPLC: 99.24% (λ = 254 nm, t R = 11.88 min).

[0492] Example 51: Preparation of compound 7-(3-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propoxy)quinolin-2(1H)-one (I-B4)

[0493]

[0494] After LRQ-04-165-Et (105 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)quinolin-2(1H)-one (208 mg, 0.74 mmol) were added sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted. After saturated brine washing, anhydrous sodium sulfate drying, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (98 mg, yield 48%). 1 H NMR (800 MHz, MeOH-d4) δ 7.75 (d, J = 9.4 Hz, 1H), 7.46 (d, J = 8.7 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.92 (t, J = 7.8 Hz, 1H), 6.83-6.80 (m, 1H), 6.78 (d, J = 2.2 Hz, 1H), 6.58 (d, J = 7.7 Hz, 1H), 6.43 (d, J = 9.4 Hz, 1H), 4.19-4.14 (m, 2H), 4.11 (t, J = 6.1 Hz, 2H), 3.83 (s, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.92-2.87 (m, 2H), 2.86 (t, J = 5.8 Hz, 2H), 2.21-2.10 (m, 2H), 1.45 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, MeOH-d4) δ 164.87, 161.75, 145.78, 141.75, 140.52, 133.40, 129.69, 128.67, 127.12, 119.89, 117.84, 114.91, 113.11, 111.11, 107.85, 103.28, 99.21, 66.79, 64.12, 54.53, 51.51, 50.64, 26.91, 21.18, 15.15. HRMS (ESI) C 25 H 28 N3O3 + [M+H] + Calcd: 418.2125, Found: 418.2124. HPLC: 96.54% (λ = 254 nm, t R = 12.22 min).

[0495] Example 52: Preparation of compound 7-(3-(8-methoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (I-B5)

[0496]

[0497] After LRQ-04-165-Me (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(lH)-one (209 mg, 0.74 mmol) were added sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was added for extraction. After saturated brine was washed, anhydrous sodium sulfate was added for drying, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (75 mg, yield 38%). 1 H NMR (800 MHz, MeOH-d4) δ 7.04 (d, J = 7.8 Hz, 1H), 7.00 (d, J = 8.3 Hz, 1H), 6.95 (t, J = 7.8 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 6.51 - 6.47 (m, 1H), 6.38 (d, J = 2.3 Hz, 1H), 3.99 (t, J = 6.0 Hz, 2H), 3.91 (s, 3H), 3.87 (s, 2H), 3.03 (t, J = 5.4 Hz, 2H), 2.92 - 2.88 (m, 2H), 2.87 (t, J = 5.6 Hz, 2H), 2.84 (t, J = 7.6 Hz, 2H), 2.56 - 2.49 (m, 2H), 2.14 - 2.06 (m, 2H). 13 C NMR (201 MHz, MeOH-d4) δ 172.96, 158.67, 146.41, 138.49, 136.51, 128.89, 128.38, 126.80, 119.89, 116.31, 111.13, 109.23, 105.43, 102.57, 102.24, 66.38, 55.53, 54.33, 51.30, 50.39, 31.15, 26.74, 24.68, 20.79. HRMS (ESI) C 24 H 28 N3O3 + [M+H] + Calcd: 406.2125, Found: 406.2123. HPLC: 96.96% (λ = 254 nm, t R = 12.32 min).

[0498] Example 53: Preparation of compound 7-(3-(8-ethoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4- b]indol-2-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (I-B6)

[0499]

[0500] LRQ-04-165-Et (105 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(1H)-one (209 mg, 0.74 mmol) sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, followed by washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (84 mg, yield 41%). 1 H NMR (800 MHz, CDCl3) δ 8.18 (s, 1H), 8.09 (s, 1H), 7.07 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.98 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H), 6.54-6.50 (m, 1H), 6.33-6.29 (m, 1H), 4.19 (q, J = 7.0 Hz, 2H), 4.02 (t, J = 6.3 Hz, 2H), 3.76 (s, 2H), 2.93 (t, J = 5.4 Hz, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 5.5 Hz, 2H), 2.81 (t, J = 7.2 Hz, 2H), 2.62-2.58 (m, 2H), 2.10-2.05 (m, 2H), 1.46 (t, J = 7.0 Hz, 3H). 13 C NMR (201 MHz, CDCl3) δ 171.78, 158.69, 145.27, 138.24, 136.41, 128.78, 128.56, 126.55, 122.29, 119.92, 115.92, 110.94, 108.90, 102.89, 102.29, 66.44, 63.73, 54.11, 51.18, 50.51, 31.23, 29.84, 27.26, 24.72, 15.19. HRMS (ESI) C 25 H 30 N3O3 + [M+H] +Calculated: 420.2282, Found: 420.2283. HPLC: 99.77% (λ = 254 nm, t R = 12.32 min).

[0501] Example 54: Preparation of compound 3-(trans-4-(2-(8-methoxy-1,3,4,9-tetrahydro- 2H-pyrido[3,4-b]indol-2-yl)ethyl)cyclohexyl)-1,1-dimethylurea (I-B7)

[0502]

[0503] LRQ-04-165-Me (24 mg, 0.12 mmol) was dissolved in DMF (8 mL), then DIPEA (45 mg, 0.35 mmol), LRQ-04-152 (47 mg, 0.17 mmol) were added successively, and the mixture was reacted at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a white solid (13 mg, yield 27%). 1 H NMR (800 MHz, MeOH-d4) δ 7.03 - 6.98 (m, 1H), 6.91 (t, J = 7.8 Hz, 1H), 6.62 (d, J = 7.7 Hz, 1H), 3.93 (s, 3H), 3.84 - 3.74 (m, 2H), 3.54 - 3.46 (m, 1H), 3.02 - 2.96 (m, 2H), 2.91 - 2.82 (m, 8H), 2.80 - 2.70 (m, 2H), 1.94 - 1.88 (m, 2H), 1.87 - 1.82 (m, 2H), 1.62 - 1.55 (m, 2H), 1.35 - 1.31 (m, 1H), 1.30 - 1.26 (m, 2H), 1.16 - 1.07 (m, 2H). 13 C NMR (201 MHz, MeOH-d4) δ 153.70, 144.70, 134.33, 129.52, 128.07, 120.52, 115.01, 111.67, 108.14, 56.78, 55.75, 52.52, 51.37, 51.18, 36.72, 36.43 (2C), 35.41, 34.29 (2C), 33.35 (2C), 21.71. HRMS (ESI) C 23 H 35 N4O2 + [M+H] +Calculated: 399.2755, Found: 399.2752. HPLC: 97.46% (λ = 254 nm, t R = 11.33 min).

[0504] Example 55: Preparation of compound 3-(trans-4-(2-(8-ethoxy-1,3,4,9-tetrahydro- 2H-pyrido[3,4-b]indol-2-yl)ethyl)cyclohexyl)-1,1-dimethylurea (I-B8)

[0505]

[0506] LRQ-04-165-Et (26 mg, 0.12 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (45 mg, 0.35 mmol), LRQ-04-152 (47 mg, 0.17 mmol) sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, followed by washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a white solid (5 mg, yield 10%). 1 H NMR (800 MHz, CDC13) δ 7.00 (d, J = 7.9 Hz, 1H), 6.94 (t, J = 7.8 Hz, 1H), 6.57 (d, J = 7.7 Hz, 1H), 4.13 (q, J = 7.0 Hz, 2H), 4.01 (s, 2H), 3.56 - 3.49 (m, 1H), 3.14 - 3.06 (m, 2H), 2.92 - 2.87 (m, 2H), 2.85 (s, 6H), 2.82 - 2.74 (m, 2H), 2.00 - 1.91 (m, 2H), 1.74 - 1.66 (m, 2H), 1.63 - 1.53 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H), 1.27 - 1.24 (m, 1H), 1.08 - 0.99 (m, 4H). 13 C NMR (201 MHz, CDC13) δ 157.91, 145.41, 133.63, 127.94, 126.88, 120.03, 110.77, 107.55, 103.26, 63.76, 55.16, 54.20, 50.38, 49.75, 36.24 (2C), 35.21, 33.79 (2C), 31.90 (2C), 29.75, 20.98, 15.07. HRMS (ESI) C 24 H 37 N4O2 + [M+H] +Calculated: 413.2911, Found: 413.2913. HPLC: 97.72% (λ = 254 nm, t R = 11.31 min).

[0507] Example 56: Preparation of compound 1-((8-methoxy-1,3,4,9-tetrahydro-2H-pyrido[3,4-b]indol-2-yl)methyl)cyclohexan-1-ol (IHCH-5229)

[0508]

[0509] LRQ-05-165-Me (50 mg, 0.25 mmol) was dissolved in absolute ethanol (10 mL), after the addition of methylene cyclohexane oxide (138 mg, 1.25 mmol), the reaction was heated to 60 °C overnight. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid IHCH-5229 (5 mg, yield 6%). 1 H NMR (800 MHz, CDC13) δ 8.02 (s, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.65-6.61 (m, 1H), 3.94 (s, 3H), 3.91 (s, 2H), 3.08-3.00 (m, 2H), 2.87-2.79 (m, 2H), 2.59 (s, 2H), 1.70-1.65 (m, 2H), 1.63-1.54 (m, 3H), 1.50-1.45 (m, 2H), 1.40-1.37 (m, 2H), 1.31-1.29 (m, 1H). 13 CNMR (201 MHz, CDC13) δ 146.02, 136.02, 128.45, 126.19, 120.04, 114.41, 111.04, 102.07, 70.64, 66.22, 55.48, 53.53, 53.01, 36.73 (2C), 26.02, 22.28 (2C), 21.13. HRMS (ESI) C 19 H 27 N2O2 + [M+H] + Calculated: 413.2911, Found: 413.2913. HPLC: 97.72% (λ = 254 nm, t R = 11.90 min).

[0510] Example 57: Preparation of compound 3-(3-(2-(8-methoxy-1,3,4,9-tetrahydro- 2H-pyrido[3,4-b]indol-2-yl)ethyl)cyclobutyl)-1,1-dimethylurea (I-B10) (IHCH-5226)

[0511]

[0512] LRQ-05-165-Me (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), LRQ-06-04 (87 mg, 0.35 mmol) were added successively, and the mixture was reacted at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (13 mg, yield 14%). 1 H NMR (800 MHz, CDC13) δ 8.70 (d, J = 67.5 Hz, 1H), 7.09 - 7.01 (m, 1H), 7.01 - 6.93 (m, 1H), 6.62 - 6.57 (m, 1H), 4.64 - 4.57 (m, 1H), 4.39 - 4.09 (m, 1H), 3.95 - 3.86 (m, 3H), 3.82 - 3.74 (m, 2H), 2.98 - 2.90 (m, 2H), 2.89 - 2.84 (m, 6H), 2.84 - 2.78 (m, 2H), 2.61 - 2.53 (m, 2H), 2.52 - 2.43 (m, 1H), 2.22 - 1.83 (m, 3H), 1.84 - 1.76 (m, 1H), 1.77 - 1.69 (m, 1H), 1.49 - 1.41 (m, 1H). HRMS (ESI) C 21 H 31 N4O2 + [M+H]+calcd: 371.2442, found: 371.2443. HPLC: 95.02% (λ = 254 nm, t R = 11.25 min).

[0513] Example 58: Preparation of compound 3-(3-(2-(8-ethoxy-1,3,4,9-tetrahydro-2H- pyrido[3,4-b]indol-2-yl)ethyl)cyclobutyl)-1,1-dimethylurea (I-B11) (IHCH-5227)

[0514]

[0515] LRQ-05-165-Et (50 mg, 0.23 mmol) was dissolved in DMF (8 mL), then DIPEA (178 mg, 1.38 mmol), LRQ-06-04 (87 mg, 0.35 mmol) were added successively, and the mixture was reacted at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (20 mg, yield 23%). 1 H NMR (800 MHz, CDC13) δ 7.01 - 6.97 (m, 1H), 6.96 (t, J = 7.7 Hz, 1H), 6.60 - 6.56 (m, 1H), 5.14 - 4.79 (m, 1H), 4.36 - 4.25 (m, 2H), 4.13 - 4.09 (m, 2H), 3.34 - 3.26 (m, 2H), 3.02 - 2.94 (m, 2H), 2.91 - 2.81 (m, 8H), 2.46 - 2.19 (m, 2H), 2.07 - 2.02 (m, 1H), 2.00 - 1.94 (m, 2H), 1.85 - 1.76 (m, 1H), 1.61 - 1.55 (m, 1H), 1.42 (t, J = 3.5 Hz, 3H). HRMS (ESI) C 22 H 33 N4O2 + [M+H]+calcd: 385.2598, found: 385.2595. HPLC: 95.17% (λ = 254 nm, t R = 11.25 min).

[0516] Example 59: Preparation of compound 7-(4-(9-methoxy-3,4-dihydropyrazin[1,2- a]indol-2(1H)-yl)butoxy)quinolin-2(1H)-one (I-C1)

[0517]

[0518] Step 1-3: The synthesis method of LRQ-05-03 is the same as that of patent WO2004099212A1, and LRQ-05-03 is a red-brown solid (three-step reaction yield 57%). 1H NMR (800 MHz, MeOH-d4) δ 7.03 (t, J = 7.9 Hz, 1H), 6.93 (d, J = 8.2 Hz, 1H), 6.53 (d, J = 7.7 Hz, 1H), 6.26 - 6.21 (m, 1H), 4.14 (s, 2H), 4.04 - 4.00 (m, 2H), 3.90 (s, 3H), 3.31 - 3.30 (m, 2H). HRMS (ESI) C 12 H 15 N2O + [M+H] + Calculated: 203.1179, Found: 203.1174.

[0519] Step 4: LRQ-05-03 (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)quinolin-2(lH)-one (218 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (59 mg, yield 29%). 1 H NMR (800 MHz, CDCl3) δ 12.06 (s, 1H), 7.71 (d, J = 9.4 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.07 (t, J = 7.9 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.84 - 6.77 (m, 2H), 6.59 - 6.46 (m, 2H), 6.30 (s, 1H), 4.11 (t, J = 6.1 Hz, 2H), 4.07 (t, J = 5.5 Hz, 2H), 3.94 (s, 3H), 3.85 (s, 2H), 3.00 (t, J = 5.4 Hz, 2H), 2.65 (t, J = 7.2 Hz, 2H), 1.94 - 1.87 (m, 2H), 1.83 - 1.79 (m, 2H). 13 C NMR (201 MHz, MeOH-d4) δ 164.55, 161.52, 152.95, 141.40, 140.14, 137.62, 132.17, 129.35, 121.75, 118.69, 117.57, 114.48, 112.88, 102.48, 100.31, 98.92, 94.21, 68.04, 57.33, 55.42, 51.48, 50.59, 41.76, 27.06, 23.57. HRMS (ESI) C25 H 28 N3O3 + [M+H] + Calculated: 418.2125, Found: 418.2120. HPLC: 97.08% (l=254 nm, t R = 11.84 min).

[0520] Example 60: Preparation of compound 7-(4-(9-methoxy-3,4-dihydropyrazin[1,2- a]indol-2(1H)-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (I-C2)

[0521]

[0522] After LRQ-05-03 (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (220 mg, 0.74 mmol) were added in turn, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a red-brown solid (64 mg, yield 31%). 1 H NMR (800 MHz, CDC13) δ 8.04 (s, 1H), 7.07 (t, J = 7.9 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.55 - 6.49 (m, 2H), 6.32 - 6.27 (m, 2H), 4.06 (t, J = 5.6 Hz, 2H), 4.00 - 3.91 (m, 5H), 3.83 (s, 2H), 2.98 (t, J = 5.6 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.66 - 2.55 (m, 4H), 1.89 - 1.81 (m, 2H), 1.80 - 1.74 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 171.76, 158.77, 153.07, 138.26, 137.59, 132.91, 128.81, 121.51, 118.79, 115.91, 108.82, 102.35, 102.34, 100.20, 93.92, 67.97, 57.38, 55.50, 51.57, 50.71, 42.13, 31.24, 27.21, 24.74, 23.83. HRMS (ESI) C 25H 30 N3O3 + [M+H] + Calculated: 420.2282, Found: 420.2276. HPLC: 96.64% (λ = 254 nm, t R = 11.86 min).

[0523] Example 61: Preparation of compound 7-(3-(9-methoxy-3,4-dihydropyrazin[1,2- a]indol-2(1H)-yl)propoxy)quinolin-2(1H)-one (I-C3)

[0524]

[0525] After LRQ-05-03 (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)quinolin-2(1H)-one (208 mg, 0.74 mmol) were added in turn, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (53 mg, yield 27%). 1 H NMR (800 MHz, MeOH-d4) δ 7.77 (d, J = 9.3 Hz, 1H), 7.48 (d, J = 8.7 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.1 Hz, 1H), 6.89 - 6.83 (m, 1H), 6.81 (d, J = 2.4 Hz, 1H), 6.56 (d, J = 7.7 Hz, 1H), 6.47 (d, J = 9.4 Hz, 1H), 6.28 (s, 3H), 4.16 (t, J = 6.1 Hz, 2H), 4.11 (t, J = 5.7 Hz, 2H), 3.95 (s, 3H), 3.90 (s, 2H), 3.07 (t, J = 5.6 Hz, 2H), 2.82 (t, J = 7.4 Hz, 2H), 2.19 - 2.10 (m, 2H). 13C NMR (201 MHz, MeOH-d4) δ 164.75, 161.64, 153.12, 141.60, 140.33, 137.82, 132.38, 129.54, 121.94, 118.87, 117.72, 114.74, 112.98, 102.66, 100.50, 99.14, 94.34, 66.51, 55.54, 54.55, 51.75, 50.88, 42.02, 26.95. HRMS (ESI) C 24 H 26 N3O3 + [M+H] + Calculated: 404.1969, Found: 404.1972. HPLC: 99.27% (l=254 nm, t R = 11.56 min).

[0526] Example 62: Preparation of compound 7-(3-(9-methoxy-3,4-dihydropyrazin[1,2- a]indol-2(1H)-yl)propoxy)-3,4-dihydroquinolin-2(1H)-one (I-C4)

[0527]

[0528] LRQ-05-03 (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(1H)-one (209 mg, 0.74 mmol) were added successively, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (65 mg, yield 33%). 1H NMR (800 MHz, CDC13) δ 8.26 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.56 - 6.49 (m, 2H), 6.36 - 6.32 (m, 1H), 6.31 (s, 1H), 4.07 (t, J = 5.5 Hz, 2H), 4.03 (t, J = 6.1 Hz, 2H), 3.94 (s, 3H), 3.86 (s, 2H), 3.01 (t, J = 5.3 Hz, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.75 (t, J = 7.0 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.09 - 2.02 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 171.91, 158.69, 153.06, 138.28, 137.56, 132.66, 128.79, 121.59, 118.75, 115.96, 108.77, 102.36, 102.36, 100.19, 94.01, 66.18, 55.49, 54.27, 51.56, 50.79, 42.08, 31.21, 27.12, 24.71. HRMS (ESI) C 24 H 28 N3O3 + [M+H] + Calcd: 406.2125, Found: 406.2131. HPLC: 97.30% (λ = 254 nm, t R = 11.64 min).

[0529] Example 63: Preparation of compound (E)-7-((4-(9-methoxy-3,4- dihydro-pyrazino[1,2-a]indol-2(1H)-yl)but-2-en-1-yl)oxy)quinolin-2(1H)-one (I-C5)

[0530]

[0531] After LRQ-05-03 (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), (E)-7-(4-bromobut-2-en-1-yl)oxy)quinolin-2(1H)-one (217 mg, 0.74 mmol) were added sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted. After saturated brine washing, anhydrous sodium sulfate drying, the solvent was removed under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (47 mg, yield 23%). 1 H NMR (800 MHz, MeOH-d4) δ 7.73-7.70 (m, 1H), 7.44 (d, J = 8.7 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.86 (d, J = 8.1 Hz, 1H), 6.83-6.81 (m, 1H), 6.78 (d, J = 2.3 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 6.44 (d, J = 9.4 Hz, 1H), 6.25-6.23 (m, 1H), 5.99-5.90 (m, 2H), 4.62 (d, J = 4.6 Hz, 2H), 4.03 (t, J = 5.7 Hz, 2H), 3.89 (s, 3H), 3.80 (s, 2H), 3.24 (d, J = 5.5 Hz, 2H), 2.98-2.94 (m, 2H). 13 C NMR (201 MHz, MeOH-d4) δ 164.52, 160.95, 152.97, 141.33, 140.13, 137.65, 132.11, 130.28, 129.41, 129.21, 121.78, 118.70, 117.86, 114.65, 112.98, 102.48, 100.33, 99.38, 94.26, 68.27, 59.34, 55.42, 51.48, 50.22, 41.82. HRMS (ESI) C 25 H 26 N3O3 + [M+H] + Calcd: 416.1969, Found: 416.1971. HPLC: 98.09% (λ = 254 nm, t R = 11.75 min).

[0532] Example 64: Preparation of compound (E)-7-((4-(9-methoxy-3,4-dihydropyrazin[1,2- a]indol-2(1H)-yl)but-2-en-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (I-C6)

[0533]

[0534] After LRQ-05-03 (99 mg, 0.49 mmol) was dissolved in DMF (8 mL), DIPEA (189 mg, 1.47 mmol), (E)-7-(4-bromobut-2-en-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (218 mg, 0.74 mmol) were added sequentially and reacted at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (72 mg, yield 35%). 1 H NMR (800 MHz, CDCl3) δ 8.19 (s, 1H), 7.08 (t, J = 7.9 Hz, 1H), 7.05 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.1 Hz, 1H), 6.57-6.50 (m, 2H), 6.36 (d, J = 2.3 Hz, 1H), 6.28 (s, 1H), 5.98-5.90 (m, 2H), 4.53 (d, J = 4.5 Hz, 2H), 4.06 (t, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.81 (s, 2H), 3.25 (d, J = 5.3 Hz, 2H), 2.98 (t, J = 5.6 Hz, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.65-2.58 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 171.85, 158.22, 153.05, 138.32, 137.58, 132.70, 130.64, 128.96, 128.83, 121.55, 118.75, 116.24, 109.05, 102.65, 102.35, 100.16, 94.02, 68.30, 59.50, 55.48, 51.54, 50.38, 42.12, 31.19, 24.73. HRMS (ESI) C 25 H 28 N3O3 + [M+H] + Calcd: 418.2125, Found: 418.2122. HPLC: 98.74% (λ = 254 nm, t R = 11.84 min).

[0535] Example 65: Preparation of compound 3-(trans-4-(2-(9-methoxy-3,4- dihydro-pyrazino[1,2-a]indol-2(1H)-yl)ethyl)cyclohexyl)-1,1-dimethylurea (I-C7)

[0536]

[0537] LRQ-05-03 (24 mg, 0.12 mmol) was dissolved in DMF (8 mL), then DIPEA (45 mg, 0.35 mmol), LRQ-04-152 (47 mg, 0.17 mmol) were added successively, and the mixture was reacted at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (11 mg, yield 23%). 1 H NMR (800 MHz, CDC13) δ 7.07 (t, J = 7.9 Hz, 1H), 6.93 - 6.85 (m, 1H), 6.55 - 6.48 (m, 1H), 6.29 (s, 1H), 4.06 (t, J = 5.6 Hz, 2H), 3.94 (s, 3H), 3.80 (s, 2H), 3.61 - 3.54 (m, 1H), 2.95 (t, J = 5.6 Hz, 2H), 2.87 (s, 6H), 2.60 - 2.50 (m, 2H), 2.06 - 1.97 (m, 2H), 1.81 - 1.76 (m, 2H), 1.53 - 1.47 (m, 2H), 1.35 - 1.27 (m, 1H), 1.14 - 1.00 (m, 4H). 13 C NMR (201 MHz, CDC13) δ 157.98, 153.06, 137.58, 132.49, 121.46, 118.79, 102.35, 100.18, 93.88, 55.69, 55.50, 51.66, 50.71, 49.98, 42.10, 36.28 (2C), 35.35, 34.22, 34.13 (2C), 32.20 (2C). HRMS (ESI) C 23 H 35 N4O2 + [M+H] + Calculated: 399.2755, Found: 399.2749. HPLC: 96.99% (λ = 254 nm, t R = 11.84 min).

[0538] Example 66: Preparation of compound N-(2-(9-methoxy-3,4-dihydropyrazin[1,2- a]indol-2(1H)-yl)ethyl)tetrahydro-2H-pyran-4-carboxamide (I-C8)

[0539]

[0540] Step 1: LRQ-05-03 (920 mg, 4.55 mmol) and DIPEA (3.53 g, 27.30 mmol) were dissolved in DMF (10 mL), then N-Boc-2-bromoethylamine (561 mg, 2.51 mmol) was added, and the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain a yellow solid (800 mg, yield 51%). 1 H NMR (800 MHz, CDC13) δ 7.09 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.32 (s, 1H), 4.14-4.04 (m, 2H), 3.94 (s, 3H), 3.86 (s, 2H), 3.43-3.26 (m, 2H), 3.14-2.91 (m, 2H), 2.80-2.63 (m, 2H), 1.43 (s, 9H). HRMS (ESI) C 19 H 28 N3O3 + [M+H] + Calcd: 346.2125, Found: 346.2131.

[0541] Step 2: LRQ-05-113 (70 mg, 0.20 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C, then trifluoroacetic acid (1 mL) was added and the reaction was carried out for 2 hours. After the reaction was completed, the solvent was removed by reduced pressure evaporation to obtain a colorless oily liquid, which was dissolved in dichloromethane (10 mL), and then DIPEA (155 mg, 1.20 mmol) and tetrahydro-2H-pyran-4-carbonyl chloride (44 mg, 0.30 mmol) were added, and the reaction was carried out at room temperature overnight. After the reaction was completed, saturated aqueous sodium bicarbonate solution (10 mL) was added for dilution, and dichloromethane (20 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:1) to obtain a yellow solid (43 mg, yield 36%). 1H NMR (800 MHz, CDC13) δ 7.10 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.55 (d, J = 7.7 Hz, 1H), 6.31 (s, 1H), 6.18 - 6.07 (m, 1H), 4.07 (t, J = 5.5 Hz, 2H), 4.00 - 3.95 (m, 2H), 3.94 (s, 3H), 3.83 (s, 2H), 3.49 - 3.42 (m, 2H), 3.40 - 3.32 (m, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 2.34 - 2.27 (m, 1H), 1.82 - 1.74 (m, 2H), 1.72 - 1.66 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 174.56, 153.12, 137.54, 132.26, 121.87, 118.68, 102.33, 100.32, 94.20, 67.36 (2C), 55.94, 55.50, 51.38, 50.35, 42.24, 42.17, 36.11, 29.38 (2C). HRMS (ESI) C 20 H 28 N3O3 + [M+H] + Calculated: 358.2125, Found: 358.2123. HPLC: 97.41% (λ = 254 nm, t R = 11.75 min).

[0542] Example 67: Preparation of compound 4,4-difluoro-N-(2-(9-methoxy-3,4- dihydro-pyrazino[1,2-a]indol-2(1 H)-yl)ethyl)cyclohexane-1 -carboxamide (I-C9)

[0543]

[0544] LRQ-05-116 (70 mg, 0.20 mmol) was dissolved in DCM (10 mL) and cooled to 0 °C. After the addition of trifluoroacetic acid (1 mL), the reaction was allowed to proceed for 2 h. After the completion of the reaction, the solvent was removed under reduced pressure to obtain a colorless oily liquid, which was dissolved in DCM (10 mL). DIPEA (155 mg, 1.20 mmol) and 4,4-difluorocyclohexanecarbonyl chloride (68 mg, 0.30 mmol) were added, and the reaction was allowed to proceed at room temperature overnight. After the completion of the reaction, the reaction mixture was diluted with saturated aqueous NaHC03solution (10 mL) and extracted with DCM (20 mL x 3). The organic layer was washed with saturated brine, dried over anhydrous Na2S04, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1:1) to obtain a yellow solid (91 mg, 73% yield). 1 H NMR (800 MHz, CDC13) δ 7.12 - 7.08 (m, 1H), 6.94 - 6.88 (m, 1H), 6.55 (d, J = 7.7 Hz, 1H), 6.32 (s, 1H), 6.13 - 6.06 (m, 1H), 4.07 (t, J = 5.6 Hz, 2H), 3.95 (s, 3H), 3.83 (s, 2H), 3.48 - 3.42 (m, 2H), 3.00 (t, J = 5.5 Hz, 2H), 2.71 (t, J = 5.8 Hz, 2H), 2.19 - 2.08 (m, 3H), 1.92 - 1.86 (m, 2H), 1.84 - 1.78 (m, 2H), 1.74 - 1.65 (m, 2H). 13 CNMR (201 MHz, CDC13) δ 174.30, 153.13, 137.54, 132.28, 121.91, 121.55 (t, J = 549.9 Hz), 118.67, 102.34, 100.34, 94.19, 55.93, 55.51, 51.39, 50.38, 42.85, 42.21, 36.13, 32.95 (t, J = 25.2 Hz) (2C), 26.05, 26.01. HRMS (ESI) C 21 H 28 F2N3O2 + [M+H] + Calcd: 392.2144, Found: 392.2138. HPLC: 96.36% (λ = 254 nm, t R = 11.90 min).

[0545] Example 68: Preparation of compound 7-(4-(9-ethoxy-3,4-dihydropyrazin[1,2- a]indol-2(1H)-yl)butoxy)quinolin-2(1H)-one (I-C10)

[0546]

[0547] Step 1: 4-methoxyindole-2-carboxylic acid (5.0 g, 26.15 mmol) was dissolved in dichloromethane (50 mL), after nitrogen replacement for three times, the reaction solution was cooled to -78 °C, BBr3(39.2 mL, 2.0 M dichloromethane solution) was added. Then the reaction solution was warmed to room temperature for 6 hours. After the reaction was completed, it was cooled to -30 °C, methanol (5 mL) was added to quench the reaction, followed by stirring at room temperature for 1 hour, diluted with water (30 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain a red-brown oily liquid which was dissolved in ethanol (50 mL), sulfuric acid (0.5 mL) was added, and the reaction was refluxed overnight. After the reaction was completed, the solvent was removed under reduced pressure, diluted with saturated aqueous sodium bicarbonate solution (30 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain a red-brown oily liquid LRQ-05-122, which was directly used in the next step without purification. HRMS (ESI) C 11 H 12 NO3 + [M+H] + Calcd: 206.0812, Found: 206.0814.

[0548] Step 2: LRQ-05-122 and K2CO3(3.6 g, 26.15 mmol) were dissolved in DMF (50 mL), then iodoethane (4.49 g, 28.76 mmol) was added, and the reaction was stirred at room temperature overnight. After the reaction was completed, it was diluted with water (20 mL), extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed under reduced pressure to obtain an orange-red oily liquid LRQ-05-123, which was directly used in the next step without purification. HRMS (ESI) C 13 H 16 NO3 + [M+H] + Calcd: 234.1125, Found: 234.1121.

[0549] Step 3: LRQ-05-123, potassium tert-butoxide (6.27 g, 52.30 mmol) was dissolved in DMF (50 mL) and stirred at room temperature for 40 min, then bromoacetonitrile (4.40 g, 39.23 mmol) was added, and the reaction mixture was stirred at 60 °C for 30 min. Then the reaction mixture was cooled to room temperature and stirred overnight. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1:10) to obtain LRQ-05-124 (0.96 g, 13% yield for three steps) as a yellow solid. 1 H NMR (800 MHz, CDC13) δ 7.53 (s, 1H), 7.35 (t, J = 8.1 Hz, 1H), 7.01-6.97 (m, 1H), 6.59 (d, J = 7.8 Hz, 1H), 5.58 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.19 (q, J = 7.0 Hz, 2H), 1.50 (t, J = 7.0 Hz, 3H), 1.42 (t, J = 7.1 Hz, 3H). HRMS (ESI) C 15 H 17 N2O3 + [M+H] + Calcd: 273.1234, Found: 273.1231.

[0550] Step 4: LRQ-05-124 (0.96 g, 3.53 mmol) was dissolved in tetrahydrofuran (10 mL), and then lithium aluminum hydride (536 mg, 14.1 mmol) was added, and the reaction mixture was stirred at reflux for 4 h. After the reaction was completed, the reaction mixture was cooled to 0 °C, quenched with saturated aqueous ammonium chloride solution (5 mL), and then stirred at room temperature for 1 h. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (50 mL*3), washed with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by reduced pressure evaporation to obtain LRQ-05-145 as an orange-yellow solid, which was used directly in the next step without purification. HRMS (ESI) C 13 H 17 N2O + [M+H] + Calcd: 217.1335, Found: 217.1329.

[0551] Step 5: LRQ-05-145 (15 mg, 0.07 mmol) was dissolved in DMF (8 mL), then DIPEA (54 mg, 0.42 mmol), 7-(4-bromobutoxy)quinolin-2(lH)-one (31 mg, 0.11 mmol) were added successively, and the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain an orange-yellow solid (14 mg, yield 47%). 1 H NMR (800 MHz, CDC13) δ 7.73 - 7.68 (m, 1H), 7.42 (d, J = 8.6 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.83 (s, 1H), 6.80 - 6.77 (m, 1H), 6.55 - 6.48 (m, 2H), 6.34 - 6.31 (m, 1H), 4.17 (q, J = 7.0 Hz, 2H), 4.12 - 4.04 (m, 4H), 3.88 (s, 2H), 3.08 - 2.98 (m, 2H), 2.72 - 2.62 (m, 2H), 1.94 - 1.87 (m, 2H), 1.85 - 1.78 (m, 2H), 1.47 (t, J = 7.0 Hz, 3H). HRMS (ESI) C 26 H 30 N3O3 + [M+H] + Calcd: 432.2282, Found: 432.2284. HPLC: 97.54% (λ = 254 nm, t R = 11.84 min).

[0552] Example 69: Preparation of compound 3-(trans-4-(2-(9-ethoxy-3,4- dihydropyrazino[l,2-a]indol-l(7H)-yl)ethyl)cyclohexyl)-l,l-dimethylurea (I-Cll)

[0553]

[0554] Step 1: LRQ-05-145 (25 mg, 0.11 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (85 mg, 0.66 mmol), LRQ-04-152 (47 mg, 0.17 mmol) and reaction at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was used for extraction. After washing with saturated brine, anhydrous sodium sulfate was used for drying, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (17 mg, yield 36%). 1 H NMR (800 MHz, CDC13) δ 7.04 (t, J = 7.9 Hz, 1H), 6.88 (d, J = 8.1 Hz, 1H), 6.52 (d, J = 7.7 Hz, 1H), 6.31 (s, 1H), 4.17 (q, J = 7.0 Hz, 2H), 4.08 - 4.01 (m, 2H), 3.80 (s, 2H), 3.62 - 3.54 (m, 1H), 2.98 - 2.92 (m, 2H), 2.87 (s, 6H), 2.60 - 2.54 (m, 2H), 2.03 - 2.00 (m, 2H), 1.83 - 1.75 (m, 2H), 1.52 - 1.48 (m, 2H), 1.46 (t, J = 7.0 Hz, 3H), 1.31 - 1.29 (m, 1H), 1.10 - 1.06 (m, 4H). HRMS (ESI) C 24 H 37 N4O2 + [M+H] + Calcd: 413.2911, Found: 413.2907. HPLC: 97.84% (λ = 254 nm, t R = 11.82 min).

[0555] Example 70: Preparation of compound 1-((9-methoxy-3,4-dihydropyrazino[l,2- a]indol-2(lH)-yl)methyl)cyclohexan-l-ol (I-C12) (IHCH-5231)

[0556]

[0557] LRQ-05-03 (50 mg, 0.25 mmol) was dissolved in anhydrous ethanol (10 mL), followed by the addition of methylene cyclohexane oxide (138 mg, 1.25 mmol) and reaction at 60 °C overnight. After the reaction was completed, the solvent was removed by reduced pressure evaporation, and the residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (29 mg, yield 37%). 1H NMR (800 MHz, CDC13) δ 7.09 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.30 (s, 1H), 4.07 (t, J = 5.5 Hz, 2H), 4.01 (s, 2H), 3.94 (s, 3H), 3.23 - 3.12 (m, 2H), 2.54 (s, 2H), 1.70 - 1.63 (m, 2H), 1.62 - 1.53 (m, 3H), 1.50 - 1.45 (m, 2H), 1.42 - 1.34 (m, 2H), 1.32 - 1.24 (m, 1H). 13 C NMR (201 MHz, CDC13) δ 153.09, 137.61, 132.35, 121.74, 118.59, 102.34, 100.26, 98.41, 70.90, 66.39, 55.50, 53.93, 53.08, 41.93, 36.51 (2C), 25.98, 22.20 (2C). HRMS (ESI) C 19 H 27 N2O2 + [M+H] + Calcd: 315.2067, Found: 315.2068. HPLC: 98.92% (l = 254 nm, t R = 11.45 min).

[0558] Example 71: Preparation of compound 7-(4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazin-2(lH)-yl)butoxy)quinolin-2(lH)-one (I-D1)

[0559]

[0560] Steps 1, 2, 3, 4, 5, 6: LRQ-05-36 was synthesized from 2-nitro-3-fluoroanisole as starting material, the synthetic method was the same as literature European Journal of Medicinal Chemistry 186 (2020) 111881, LRQ-05-03 was red-brown solid (20% yield for six steps). 1 H NMR (800 MHz, CDC13) δ 7.09 (t, J = 7.9 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 6.30 (s, 1H), 4.07 (t, J = 5.5 Hz, 2H), 4.01 (s, 2H), 3.94 (s, 3H), 3.23 - 3.12 (m, 2H), 2.54 (s, 2H), 1.70 - 1.63 (m, 2H), 1.62 - 1.53 (m, 3H), 1.50 - 1.45 (m, 2H), 1.42 - 1.34 (m, 2H), 1.32 - 1.24 (m, 1H). 13C NMR (201 MHz, CDC13) δ 151.28, 147.47, 135.85, 132.46, 123.14, 103.49, 101.93, 55.87, 44.81, 43.04, 42.72. HRMS (ESI) C 11 H 14 N3O + [M+H] + Calcd: 204.1131, Found: 204.1134.

[0561] Step 7: LRQ-05-36 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)quinolin-2(lH)-one (218 mg, 0.74 mmol) sequentially, and the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (119 mg, yield 58%). 1 H NMR (800 MHz, CDC13) δ 12.07 (s, 1H), 7.69 (d, J = 9.4 Hz, 1H), 7.41 (d, J = 8.7 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.85 (s, 1H), 6.81-6.77 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.54-6.48 (m, 1H), 4.12-4.07 (m, 4H), 4.00 (s, 3H), 3.93 (s, 2H), 3.03 (t, J = 5.5 Hz, 2H), 2.69 (t, J = 7.1 Hz, 2H), 1.93-1.86 (m, 2H), 1.83-1.76 (m, 2H). 13 C NMR (201 MHz, CDC13) δ 164.91, 161.43, 151.24, 148.08, 140.96, 140.44, 135.59, 132.83, 129.16, 122.96, 118.01, 114.31, 112.71, 103.26, 101.95, 99.14, 68.05, 57.15, 55.84, 52.07, 49.78, 42.22, 26.95, 23.62. HRMS (ESI) C 24 H 27 N4O3 + [M+H] +Calculated: 419.2078, Found: 419.2072. HPLC: 95.92% (λ = 254 nm, t R = 12.47 min).

[0562] Example 72: Preparation of compound 7-(4-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2- a]pyrazin-2(1H)-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (I-D2)

[0563]

[0564] LRQ-05-36 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), 7-(4-bromobutoxy)-3,4-dihydroquinolin-2(1H)-one (220 mg, 0.74 mmol) sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, followed by washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (58 mg, yield 28%). 1 H NMR (800 MHz, CDCl3) δ 8.23 (s, 1H), 7.17 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 6.53-6.46 (m, 1H), 6.34 (d, J = 2.0 Hz, 1H), 4.09 (t, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.98-3.93 (m, 4H), 3.03 (t, J = 5.5 Hz, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 7.1 Hz, 2H), 2.61-2.57 (m, 2H), 1.87-1.82 (m, 2H), 1.80-1.74 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 171.83, 158.68, 151.18, 148.00, 138.29, 135.48, 132.87, 128.74, 123.12, 115.91, 108.67, 103.41, 102.41, 101.94, 67.79, 57.13, 55.87, 51.88, 49.76, 42.19, 31.21, 27.02, 24.70, 23.60. HRMS (ESI) C 24 H 29N4O3 + [M+H] + Calculated: 421.2234, Found: 421.2239. HPLC: 96.98% (λ = 254 nm, t R = 12.33 min).

[0565] Example 73: Preparation of compound 7-(3-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[1,2- a]pyrazin-2(1H)-yl)propoxy)quinolin-2(1H)-one (I-D3)

[0566]

[0567] LRQ-05-36 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)quinolin-2(1H)-one (208 mg, 0.74 mmol) sequentially, and the reaction was carried out at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by reduced pressure evaporation. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (61 mg, yield 31%). 1 H NMR (800 MHz, CDCl3) δ 12.19 (s, 1H), 7.71-7.67 (m, 1H), 7.42 (d, J = 8.7 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.86 (d, J = 1.8 Hz, 1H), 6.82-6.78 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.51 (d, J = 9.3 Hz, 1H), 4.15 (t, J = 6.0 Hz, 2H), 4.11 (t, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.96 (s, 2H), 3.06 (t, J = 5.5 Hz, 2H), 2.82 (t, J = 7.0 Hz, 2H), 2.12-2.07 (m, 2H). 13 C NMR (201 MHz, CDCl3) δ 164.95, 161.31, 151.25, 147.94, 140.92, 140.45, 135.58, 132.39, 129.17, 123.02, 118.12, 114.39, 112.54, 103.30, 101.97, 99.30, 66.14, 55.85, 54.09, 52.06, 49.96, 42.21, 26.94. HRMS (ESI) C 23 H25 N4O3 + [M+H] + Calculated: 405.1921, Found: 405.1918. HPLC: 96.89% (λ = 254 nm, t R = 11.48 min).

[0568] Example 74: Preparation of compound 7-(3-(9-methoxy-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazin-2(lH)-yl)propoxy)-3,4-dihydroquinolin-2(lH)-one (I-D4)

[0569]

[0570] LRQ-05-36 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), followed by the addition of DIPEA (189 mg, 1.47 mmol), 7-(3-bromopropoxy)-3,4-dihydroquinolin-2(lH)-one (209 mg, 0.74 mmol) sequentially, and the reaction was carried out at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted, followed by washing with saturated brine, drying over anhydrous sodium sulfate, and removing the solvent under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (74 mg, yield 37%). 1 H NMR (800 MHz, CDC13) δ 7.16 (t, J = 7.9 Hz, 1H), 7.02 (d, J = 8.2 Hz, 1H), 6.95-6.88 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.55-6.48 (m, 1H), 6.35 (s, 1H), 4.10 (t, J = 5.4 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H), 4.00 (s, 3H), 3.93 (s, 2H), 3.04 (t, J = 5.4 Hz, 2H), 2.87 (t, J = 7.4 Hz, 2H), 2.79 (t, J = 7.0 Hz, 2H), 2.60 (t, J = 7.5 Hz, 2H), 2.08-2.00 (m, 2H). 13 CNMR (201 MHz, CDC13) δ 171.84, 158.64, 151.34, 147.96, 138.21, 135.65, 133.02, 128.78, 122.92, 115.97, 108.71, 103.19, 102.33, 101.90, 65.93, 55.82, 54.14, 52.12, 50.02, 42.19, 31.17, 27.07, 24.70. HRMS (ESI) C 23H 27 N4O3 + [M+H] + Calculated: 407.2078, Found: 407.2073. HPLC: 98.49% (λ = 254 nm, t R = 11.55 min).

[0571] Example 75: Preparation of compound (E)-7-((4-(9-methoxy-3,4- dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)but-2-en-1-yl)oxy)-3,4- dihydroquinolin-2(1H)-one (I-D5)

[0572]

[0573] LRQ-05-36 (100 mg, 0.49 mmol) was dissolved in DMF (8 mL), then DIPEA (189 mg, 1.47 mmol), (E)-7-(4-bromobut-2-en-1-yl)oxy)-3,4-dihydroquinolin-2(1H)-one (218 mg, 0.74 mmol) were added successively, and the mixture was reacted at 100 °C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (109 mg, yield 53%). 1 H NMR (800 MHz, CDC13) δ 8.27 (s, 1H), 7.16 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.92 (d, J = 8.0 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 6.56 - 6.51 (m, 1H), 6.36 (d, J = 2.4 Hz, 1H), 5.99 - 5.87 (m, 2H), 4.55 - 4.48 (m, 2H), 4.09 (t, J = 5.5 Hz, 2H), 4.00 (s, 3H), 3.92 (s, 2H), 3.29 (d, J = 5.3 Hz, 2H), 3.02 (t, J = 5.5 Hz, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.64 - 2.56 (m, 2H). 13C NMR (201 MHz, CDC13) δ 171.87, 158.20, 151.36, 147.87, 138.32, 135.68, 133.12, 129.81, 129.40, 128.84, 122.90, 116.25, 109.01, 103.20, 102.63, 101.90, 68.17, 59.10, 55.84, 52.14, 49.31, 42.13, 31.18, 24.72. HRMS (ESI) C 24 H 27 N4O3 + [M+H] + Calcd: 419.2078, Found: 419.2081. HPLC: 98.33% (l = 254 nm, t R = 11.81 min).

[0574] Example 76: Preparation of compound 3-(trans-4-(2-(9-methoxy-3,4- dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)ethyl)cyclohexyl)-1,1-dimethylurea (I-D6)

[0575]

[0576] LRQ-05-36 (24 mg, 0.12 mmol) was dissolved in DMF (8 mL), then DIPEA (45 mg, 0.35 mmol), LRQ-04-152 (47 mg, 0.17 mmol) were added successively, and the mixture was reacted at 100°C overnight. After the reaction was completed, water (10 mL) was added for dilution, and ethyl acetate (50 mL*3) was extracted with saturated brine, dried over anhydrous sodium sulfate, and then the solvent was removed by evaporation under reduced pressure. The residue was separated and purified by silica gel column chromatography (methanol / dichloromethane = 1:10) to obtain a yellow solid (12 mg, yield 25%). 1 H NMR (800 MHz, CDC13) δ 7.16 (t, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 7.9 Hz, 1H), 4.12 (d, J = 7.5 Hz, 1H), 4.10 (t, J = 5.5 Hz, 2H), 4.01 (s, 3H), 3.89 (s, 2H), 3.61 - 3.54 (m, 1H), 3.00 (t, J = 5.5 Hz, 2H), 2.87 (s, 6H), 2.65 - 2.59 (m, 2H), 2.05 - 1.99 (m, 2H), 1.81 - 1.77 (m, 2H), 1.53 - 1.47 (m, 2H), 1.35 - 1.28 (m, 1H), 1.14 - 1.03 (m, 4H). 13C NMR (201 MHz, CDC13) δ 157.97, 151.28, 148.17, 135.65, 132.94, 122.89, 103.21, 101.93, 55.84, 55.44, 52.21, 49.94, 49.79, 42.20, 36.27 (2C), 35.10, 34.07 (2C), 34.03, 32.11 (2C). HRMS (ESI) C 22 H 34 N5O2 + [M+H] + Calcd: 400.2707, Found: 400.2699. HPLC: 97.29% (l=254 nm, t R = 11.14 min).

[0577] Example 77: Preparation of compound 1-((9-methoxy-3,4-dihydrobenzo[4,5]imidazo[l,2- a]pyrazin-2(lH)-yl)methyl)cyclohexan-l-ol (IHCH-5230)

[0578]

[0579] LRQ-05-36 (50 mg, 0.25 mmol) was dissolved in absolute ethanol (10 mL), after the addition of methylene cyclohexane oxide (138 mg, 1.25 mmol), the reaction was heated to 60 °C overnight. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the residue was separated and purified by silica gel column chromatography (methanol / methylene chloride = 1:10) to obtain a white solid (10 mg, yield 13%). 1 H NMR (800 MHz, CDC13) δ 7.16 (t, J = 8.0 Hz, 1H), 6.95 - 6.89 (m, 1H), 6.69 (d, J = 7.9 Hz, 1H), 4.14 - 4.05 (m, 4H), 3.99 (s, 3H), 3.25 - 3.16 (m, 2H), 2.58 (s, 2H), 1.67 - 1.60 (m, 2H), 1.60 - 1.51 (m, 3H), 1.49 - 1.43 (m, 2H), 1.42 - 1.36 (m, 2H), 1.30 - 1.26 (m, 1H). 13 C NMR (201 MHz, CDC13) δ 151.31, 148.03, 135.64, 132.85, 123.01, 103.19, 101.90, 71.27, 66.48, 55.79, 54.53, 52.18, 42.09, 36.25 (2C), 25.90, 22.12 (2C). HRMS (ESI) C 18 H26 N3O2 + [M+H] + Calculated: 316.2020, Found: 316.2025. HPLC: 99.78% (λ = 254 nm, t R = 11.67 min).

[0580] Bioassay Example 1: Test of the affinity of compounds of general formula (I) for the dopamine D2 receptor

[0581] The affinity of the compounds of the application for the dopamine D2 receptor was determined using the method of radioligand competition.

[0582] Experimental procedure:

[0583] First step, preparation of cell membrane fraction containing specific dopamine D2 receptor. 10 cm culture dish was transfected with 10 ng dopamine D2 receptor and 40 μL PEI, 48 hours later, 10 cm culture dish was taken out from the cell room, in which the cultured cells have expressed dopamine D2 receptor. The culture solution was sucked by vacuum pump, 3 mL lysis solution was added to each well, and the cells were placed in 4°C refrigerator for 10 minutes. After the cells were detached, they were transferred to 15 mL centrifuge tube, centrifuged at 1500 rpm for 5 minutes at 4°C, and the supernatant was discarded. The cell pellet was transferred to a tissue homogenizer, and 3 mL lysis solution was added, and the cells were ground until they were broken. Then, the cell suspension was aliquoted into multiple EP tubes, centrifuged at 12000 rpm for 5 min at 4°C, and the supernatant was discarded. The precipitate was the cell membrane fraction containing dopamine D2 receptor.

[0584] Second step, ligand receptor binding experiment on 293T membrane fraction transiently expressing dopamine D2 receptor. First, add standard binding buffer to the cell membrane fraction containing dopamine D2 receptor, and use an electric tissue homogenizer to break and resuspend the cell membrane. Add 30 μL membrane protein suspension to each well of a 96-well plate. Then, add 30 μL of different drugs to the 96-well plate from left to right, ensuring that the final concentration of drugs is 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two replicates for each treatment. Next, add 30 μL of 3 H]-Methylspiperone to each well of the 96-well plate. Incubate at room temperature for 2 hours in the dark. Detect. The machine reads the amount of 3 H]-Methylspiperone bound to the membrane, and after further data processing, the affinity K i value of different compounds for the dopamine D2 receptor is obtained.

[0585] The results are shown in Table 1. The results show that compounds I-A1 to I-D7 have certain affinity activity to dopamine D2 receptors, and the compounds of the present application have certain affinity activity to dopamine D2 receptors.

[0586] Table 1

[0587]

[0588]

[0589] Note: data use [ 3 H]-Methylspiperone (0.3-0.5 nM) as the average K i (pK i ± SEM) of the competition binding experiment of the radioactive ligand.

[0590] Biological test example 2: test of functional activity of compounds on dopamine D2 receptors

[0591] In order to detect the downstream G protein signal pathway mediated by dopamine D2 receptors, on the first day, 6 cm culture dishes were transfected with 1 μg of dopamine D2 receptors, 1 μg of Gα i1 (Gα i1 -Rluc) containing C-terminal Renilla luciferase, 1 μg of G β3 , 1 μg of Gγ9 (Gγ9-GFP) containing C-terminal green fluorescent protein, and 16 μL of PEI. At the same time, in order to detect the downstream β-arrestin2 signal pathway mediated by dopamine D2 receptors, on the first day, 6 cm culture dishes were transfected with 500 μg of dopamine D2 receptors (D2-Rluc) containing C-terminal Renilla luciferase, 500 μg of G protein-coupled receptor kinase 2 (GRK2), 2500 μg of β-arrestin2 (GFP2-ARRB2) containing N-terminal green fluorescent protein, and 14 μL of PEI. On the second day, the confluent cells were digested, and one 96-well plate was plated with the amount of cells of one 6 cm culture dish of confluent cells, 100 μL of culture solution per well. On the third day, drug detection was performed. The 96-well plate was taken out of the cell room to remove the culture solution, 40 μL of substrate coelenterazine 400a (final concentration 5 μM) was added to each well, followed by the addition of 20 μL of different drugs from left to right, to ensure that the final concentration of the drugs decreases from bottom to top, two repeats for each treatment, and finally, machine detection. The machine reads the membrane situation of β-arrestin2 in the cells and the dissociation of G protein trimers, the former represents the activation degree of the downstream β-arrestin2 signal pathway of dopamine D2 receptors, and the latter represents the activation degree of the downstream G protein signal pathway of dopamine D2 receptors, and thus the agonistic effect of various compounds on dopamine D2 receptors can be revealed. The results are shown in Table 2.

[0592] The results show that compounds I-A1 to I-D7 have certain agonistic activity on dopamine D2 receptors.

[0593] Table 2

[0594]

[0595]

[0596]

[0597]

[0598] Note: All data are mean ± SEM (n = 3 independent experiments). 1 EC 50 EC50 is the concentration of a compound that gives a half-maximal response in an experiment. 2 EC50 max % indicates the percentage of the maximal response (EC50) produced by a compound in an experiment relative to the endogenous ligand dopamine. max

[0599] Biological Test Example 3: Test of the affinity of compounds of general formula (I) for 5-hydroxytryptamine 1A (5-HT 1A ) receptors

[0600] The affinity of the compounds of the present application for 5-hydroxytryptamine 1A (5-HT 1A ) receptors was determined using the method of radioligand competition.

[0601] Experimental procedure:

[0602] First step, preparation of cell membrane components containing specific serotonin 1A receptors. 10 cm culture dishes of HEK-293T cells were transfected with 10 μg of serotonin 1A receptors and 40 μL of PEI, and after 48 hours, the 10 cm culture dishes were removed from the incubator, in which the cells cultured had expressed serotonin 1A receptors. The culture medium was aspirated with a vacuum pump, 3 mL of lysis solution was added per dish, and the cells were placed in a 4°C refrigerator for 10 minutes. After the cells were detached, they were transferred to a 15 mL centrifuge tube, and centrifuged at 1500 rpm for 5 minutes in a 4°C centrifuge. The supernatant was discarded. The cell pellet was transferred to a tissue homogenizer, and 3 mL of lysis solution was added, and the cells were ground until they were broken. Then, the cell suspension was aliquoted into multiple EP tubes, and centrifuged at 12000 rpm for 5 min in a 4°C centrifuge, and the supernatant was discarded. The pellet was the cell membrane component containing serotonin 1A receptors.

[0603] ​Second step, ligand binding experiment of 293T membrane component transiently expressing serotonin 1A receptor. First, add standard binding buffer to cell membrane component containing serotonin 1A receptor, and resuspend the cell membrane by electric tissue homogenizer. Add 30 μL membrane protein suspension to each well of 96-well plate. Then, add 30 μL different drugs to 96-well plate from left to right, and ensure that the final concentration of drugs is 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0M, two repeats for each treatment. Then, add 30 μL 3 H]-LSD to each well of 96-well plate. Incubate at room temperature for 2 hours in dark, and then detect. The reading value of instrument reflects the amount of 3 H]-LSD binding to membrane, and the value of Ki of different compounds to serotonin 1A receptor is obtained after further data processing.

[0604] Experimental steps:

[0605] The results are shown in Table 3. The results show that the compound of the present application has strong affinity activity to 5-hydroxytryptamine 1A (5-HT 1A ) receptor.

[0606] Table 3

[0607] Compound Affinity Ki I-A15 5.43 nM I-A22 0.073 nM I-A27 0.64 nM I-A32 2.55 nM I-A41 0.78 nM I-A42 0.42 nM I-A43 0.015 nM Aripiprazole 53.79 nM Cariprazine 9.94 nM

[0608] Biological test example 4: functional activity test of compound to 5-hydroxytryptamine 1A (5-HT 1A ) receptor

[0609] To detect the downstream G protein signal pathway mediated by serotonin 1A receptor, on the first day, 6 cm culture dish with HEK-293T cells was transfected with 1 μg serotonin 1A receptor, 1 μg Gα i1 (Gα i1 -Rluc) containing C-terminal sea anemone luciferase, 1 μg G β3 , 1 μg G γ9 (G γ9 -GFP) containing C-terminal green fluorescent protein, and 16 μL PEI. At the same time, to detect the downstream β-arrestin2 signal pathway mediated by serotonin 1A receptor, on the first day, 6 cm culture dish was transfected with 500 ng serotonin 1A receptor (5HT 1AR-Rluc), 500 ng G protein-coupled receptor kinase 2 (GRK2), 2500 ng β-arrestin2 containing N-terminal green fluorescent protein (GFP2-ARRB2) and 14 μL PEI. The next day, confluent cells were digested and plated in a 96-well plate with a cell density of one 6-cm dish per well in 100 μL medium. On the third day, drug testing was performed. The 96-well plate was taken out of the cell incubator and the medium was removed. Then 40 μL of substrate coelenterazine 400a (final concentration 5 μM) was added to each well, followed by 20 μL of different drugs added from left to right, ensuring that the final drug concentration decreased from bottom to top. Each treatment was performed in duplicate. Finally, the plate was put into the instrument for detection. The instrument readings reflected the membrane translocation of β-arrestin2 and the dissociation of G protein trimer. The former represented the activation degree of the β-arrestin2 signal pathway downstream of the serotonin 1A receptor, and the latter represented the activation degree of the G protein signal pathway downstream of the serotonin 1A receptor. Thus, the agonistic effect of various compounds on the serotonin 1A receptor could be revealed.

[0610] The results are shown in Table 4.

[0611] The results show that the compounds of the present application have moderate to strong agonistic activity on the serotonin 1A (5-HT 1A ) receptor.

[0612] Table 4

[0613]

[0614]

[0615]

[0616] Notes: 1 EC 50 is the concentration of the compound that gives a half-maximal response in the experiment. 2 E max % indicates the percentage of the maximal response (E max ) produced by the compound in the experiment relative to the endogenous ligand 5-hydroxytryptamine.

[0617] Biological Test Example 5: Test of the affinity of the compounds of the present application for the 5-HT 2A receptor

[0618] The affinity of the compounds of the present application for the 5-HT 2A receptor was determined using the method of radioligand competition. First, a cell membrane fraction containing the specific 5-HT 2A receptor was prepared. A 10-cm dish was seeded with 10 ng of 5-HT 2AReceptors and 40 μL PEI for transfection. 48 hours later, 10 cm dishes of cells expressing 5-HT 2A receptors were removed from the cell room. The medium was aspirated with a vacuum pump, and 3 mL lysis buffer was added to each well. The cells were left to stand at 4°C for 10 minutes. After the cells were detached, they were transferred to 15 mL centrifuge tubes and centrifuged at 1500 rpm for 5 minutes at 4°C. The supernatant was discarded. The cell pellets were transferred to a tissue homogenizer, and 3 mL lysis buffer was added. The cells were ground until they were broken. The cell suspension was then aliquoted into EP tubes and centrifuged at 12000 rpm for 5 minutes at 4°C. The supernatant was discarded. The pellets were the cell membrane fractions containing 5-HT 2A receptors. In the second step, the 293T membrane fractions transiently expressing 5-HT 2A receptors were subjected to ligand receptor binding experiments. First, the cell membrane fractions containing 5-HT 2A receptors were added to standard binding buffer, and the cell membranes were broken and resuspended with an electric tissue homogenizer. 30 μL of the membrane protein suspension was added to each well of a 96-well plate. Then, 30 μL of different drugs was added to each well of the 96-well plate from left to right, so that the final concentration of the drugs was 10 -5 M, 10 -6 M, 10 -7 M, 10 -8 M, 10 -9 M, 0 M, with two replicates for each treatment. Next, 30 μL of [ 3 H]-ketanserin was added to each well of the 96-well plate. The plate was incubated at room temperature in the dark for 2 hours. Detection. The amount of [ 3 H]-ketanserin bound to the membranes was measured, and the affinity K 2A values of different compounds for 5-HT i receptors were obtained after further data processing. The results are shown in Table 3.

[0619] Table 5

[0620]

[0621]

[0622] The compounds of the present application have very weak affinity for 5-HT 2A receptors and have selectivity for D2 receptors and 5-HT 1A receptors over 5-HT 2A receptors. The results in Table 5 show that compounds I-A1, I-A2, I-A16, I-A20, I-A21, I-A28, I-A29, and I-B7 have very weak affinity for 5-HT 2AThe affinity of the receptor is weak. Comparing the data in Table 1, it can be seen that the compound of the present application has good D2 receptor selectivity over 5-HT 2A receptors.

[0623] Biological Test Example 6: Test of the rat pharmacokinetic properties of the compound of the present application

[0624] Test of the pharmacokinetic properties of the compound after single administration by gavage and intravenous injection to SD rats

[0625] (1) Purpose of the experiment

[0626] After single dose administration of the compound to male SD rats, blood samples were collected at different time points, the concentration of the compound in rat plasma was determined by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated to investigate the pharmacokinetic properties of the compound in rats.

[0627] (2) Experimental method

[0628] Male SD rats were provided by Suzhou Zhaoyan Experimental Animal Technology Co., Ltd. The SD rats were fasted for 12-14 h without water 1 day before administration, and fed 4 h after administration.

[0629] Each compound was divided into two groups of intravenous injection and gavage administration, with 3 rats in each group. Intravenous administration (dose 3 mg / kg, concentration 0.6 mL / kg) and gavage administration (dose 10 mg / kg, concentration 1 mL / kg) were both carried out with 5% DMSO + 5% Solutol + 90% physiological saline as the solvent.

[0630] Sample collection: 0.10 mL of blood was taken from each animal through the orbit, and EDTA K2 was used for anticoagulation. The collection time points were IV / PO groups: 5, 15, 30 min, 1, 2, 4, 6, 8, and 24 h after administration of the test substance. After blood sample collection, the blood was placed on ice, and the plasma was separated by centrifugation (centrifugation conditions: 5000 rpm / min, 10 min, 4°C) within 30 minutes. Before analysis, it was stored at -80°C.

[0631] Data processing: The data acquisition and control system software was Analyst 1.5.1 software (Applied Biosystem). The sample peak integration mode was automatic integration; the ratio of sample peak area to internal standard peak area was used as an indicator, and the sample concentration was regressed. Regression method: linear regression, weight coefficient 1 / X 2 . The pharmacokinetic parameters were analyzed and processed by non-compartment model using WinNonlin Professional v6.3 (Pharsight, USA). C max is the measured maximum plasma concentration, and the area under the plasma concentration-time curve AUC (0→t)Calculated by trapezoidal method, t max The blood concentration peak time after administration. The experimental data are expressed as "mean ± standard deviation" (Mean ± SD, n≥3) or "mean" (Mean, n=2).

[0632] (3) Experimental results

[0633] The metabolic properties of the compounds of the present application in SD rats are shown in Tables 6-8. As can be seen from the data listed in Tables 6-8, the compounds of the present application have good pharmacokinetic properties, reasonable half-lives and good oral bioavailability in SD rats.

[0634] Table 6: Metabolic properties of compounds I-A1 and I-A12 in rats

[0635]

[0636]

[0637] Table 7: Metabolic properties of compounds I-B7 and I-C1 in rats

[0638]

[0639] Table 8: Metabolic properties of compounds I-C2 and I-C7 in rats

[0640]

[0641]

[0642] Note: "--" means not applicable.

[0643] Biological test example 7: brain penetration test of compounds intraperitoneally administered to C57 male mice

[0644] Using the same method as the pharmacokinetic experiment, 0.030 mL of blood was taken from each animal through the orbit at 0.5, 2.0, 4.0 hours, anticoagulated with EDTA-K2, and placed on ice after blood sample collection, and centrifuged to separate plasma (centrifugation conditions: 5000 rpm / min, 10 min, 4℃) within 30 minutes, and stored at -80℃ before analysis. After the animals were euthanized, brain tissue samples were taken, homogenized with 50% methanol according to the body weight 1:3 (m / v=1:3), and stored at -80℃ before homogenate analysis. The drug concentrations in plasma and brain tissue were analyzed by LC / MS / MS method and compared.

[0645] The drug concentrations in plasma and brain tissue and the ratios of the compounds are shown in Table 9. As can be seen from Table 9, the compounds of the present application have good brain penetration properties.

[0646] Table 9: Mouse brain penetration properties of compounds of the present application

[0647] I-A1 I-A12 I-B7 I-C1 I-C2 I-C7 0.5 h brain 1106±43 1399±220 392±15 1943±63 2805±208 1026±96 0.5 h plasma 2215±447 830±119 598±19 4062±367 3282±456 336±28 0.5 h ratio 0.499 1.69 0.656 0.478 0.855 3.05 2.0 h brain 236±25 455±61 73.0±129 732±56 1256±279 714±143 2.0 h plasma 397±26.3 202±56.2 114±67.9 1103±89 1506±545 267±47 2.0 h ratio 0.594 2.26 0.643 0.663 0.834 2.67 4.0 h brain -- -- -- 161±55 599±54 491±80 4.0 h plasma -- -- -- 297±106 558±100 219±15 4.0 h ratio -- -- -- 0.541 0.931 2.24 AUC brain -- -- -- 3385 5561 2767 AUC plasma -- -- -- 6289 6517 1022 AUC ratio -- -- -- 0.538 0.853 2.71

[0648] Note: Intraperitoneal administration, 5 mg / kg, vehicle 5% DMSO + 95% saline; “--” not tested; compound concentrations in plasma and brain are in ng / mL; AUC is in hr- ng / mL.

[0649] Biological Test Example 8: Pharmacodynamic testing of compounds in a schizophrenia-like animal behavioral model

[0650] Open field motor ability test

[0651] Experimental method: Experimental animals are C57B6 male mice, n = 8 per group. This model uses C57B6 mice as experimental animals, induces the behavioral characteristics of hyperlocomotion in an open field environment by acute injection of NMDA antagonist MK801, and is used to detect the inhibitory effect of different compounds on the MK801-induced hyperlocomotion phenotype. All mouse behavioral experiments are performed during the light period of the mice, and the experiments are recorded by a camera throughout and automatically tracked by behavioral tracking software and data statistics. Compounds are administered by intraperitoneal injection, and immediately after injection, the mice enter the open field and start recording the movement trajectory. After 30 minutes, the mice receive 0.2 mg / kg of MK801 by intraperitoneal injection, and immediately after administration, they return to the open field to continue recording the movement trajectory for 120 minutes. The cumulative distance of the mice is calculated according to every five minutes as a data sampling point. Data statistics are performed using Student-t-test, p < 0.05 is *, p < 0.01 is **, p < 0.001 is ***, and p < 0.0001 is ****. The total distance moved by mice within 0-45 minutes under the combined effect of different doses of compounds of the present application and MK801 (0.2 mg / kg) is shown in Table 10.

[0652] Table 10: Inhibitory activity of compounds of the present application on MK-801-induced hyperlocomotion in mice

[0653]

[0654] The open field motor ability test results shown in Table 10 show that compounds I-A1, I-A12 and I-B7, etc. of the present application can significantly inhibit the hyperlocomotion induced by MK801 in mice at different doses.

Claims

1. A compound represented by Formula I, or a pharmaceutically acceptable salt thereof, in, X represents N, O, or NR. a or CR b ; Y is either C or N; It can be a double bond or a single bond; R a and R b Each is independently H or C1-C6 alkyl; L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d Each is independently represented by H; m can be 1, 2, 3, or 4; n1 and n2 are both 1; M is non-existent, -O-, or -NH-C(O)-; Ring Q is a saturated or partially unsaturated 4-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocycle, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or an 8-11 membered bicyclic ring; one ring of the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-7 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; R1 is a C1-C6 alkyl group; R2 can be F, Cl, Br, I, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, halo-C1-C6 alkyl, or halo-C1-C6 alkoxy, respectively. R3 can be F, Cl, Br, I, hydroxyl, C1-C6 alkyl, halo-C1-C6 alkyl, or -NH-C(O)R. e or -NH-S(O)2R e ; Alternatively, the two R3 atoms and the atoms attached to them can form 3-8 cycloalkyl groups; R e C1-C6 alkyl, -NH2, -NHR g -NR f R g Or 5-6 yuan of heteroaryl compounds; R f and R g Each is independently a C1-C6 alkyl group; R4 is an oxometalate (=O); p is 0; q and r are each independently 0, 1, or 2; The number of heteroatoms in the heterocycle, heteroaromatic ring and heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S. When ring Q is a saturated or partially unsaturated 4-8 member carbon ring, q is 1 or 2.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, R a and R b For H; And / or, in M, the nitrogen atom of -NH-C(O)- is bonded to L; And / or, R1 is independently methyl, ethyl or isopropyl; And / or, R3 is independently F, Cl, Br, I, hydroxyl, C1-C6 alkyl, -NH-C(O)R e or -NH-S(O)2R e ; And / or, ring Q is connected to M through C atoms; And / or, in ring Q, the 4-8 element carbon ring is a 4, 5, 6 or 7 element carbon ring; And / or, in ring Q, the 6-8 quinary heterocycle is a 6-quinary heterocycle; And / or, in ring Q, the heteroatom in the 6-8 member heterocycle is N or O; And / or, in ring Q, the 6-10 quintile aromatic ring is a benzene ring; And / or, in ring Q, the number of heteroatoms in the 5-10 membered heteroaromatic ring is 1 or 2; And / or, in ring Q, one ring in the 8-11 member bicyclic ring is a saturated or partially unsaturated 5-7 member heterocyclic ring, and the other ring is a benzene ring or a 5-6 member heteroaromatic ring, wherein the number of heteroatoms in the 5-7 member heterocyclic ring and the 5-6 member heteroaromatic ring is independently 1 or 2, and the heteroatoms are N.

3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, characterized in that, R3 is independently a C1-C6 alkyl group or -NH-C(O)R e ; And / or, in ring Q, the heteroatom in the 6-8 member heterocycle is N.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, Ring Q is 5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, characterized in that, for 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, characterized in that, for Among them, R 3-1 R3, R 3-2 It is H or R3.

7. The compound of claim 6, or a pharmaceutically acceptable salt thereof, characterized in that, for 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, For any of the following options: Option (1): for Option (2): for 9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, characterized in that, For any of the following options: Option (1): for Option (2): for Option (3): for Option (4): for 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, L and M are defined in any of the following cases: (1) L is -(CR) c R d )2-, M is either non-existent or -NH-C(O)-; (2) L is -(CR) c R d )3-, M is -O- or does not exist; (3) L is -(CR) c R d )4-, M is -O- or does not exist; (4) L is -(CR) c R d )-CH=CH-(CR c R d )-, M is -O-; (5) L is -(CR) c R d )-, M means it does not exist.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has any of the following structures: The definitions of L, M, ring Q, R1, R2, R3, R4, p, q, and r are as described in any one of claims 1 to 10.

12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any of the following: ①In ring Q, the 4-8 element carbon ring is a 5-8 element carbon ring or a 4-6 element carbon ring; ②In ring Q, the 6-8 member heterocycle is a nitrogen-containing 6-membered heterocycle; ③ In ring Q, the 5-10 member heteroaromatic ring is ④ In ring Q, the 8-11 element double ring parallel ring is an 8-10 element double ring parallel ring; ⑤ In ring Q, one ring in the 8-11 element double ring is a saturated or partially unsaturated 5-7 element heterocyclic ring, and the 5-7 element heterocyclic ring in the ring is a 5-6 element heterocyclic ring. ⑥ In ring Q, one of the rings in the 8-11 member bicyclic ring is a saturated or partially unsaturated 5-7 member heterocyclic ring, which contains at most one N atom or at most one oxygen atom. ⑦L is -(CR) c R d )4-, M is -O-, and the benzene ring or 5-6 heterocyclic ring in the 8-11 member bicyclic ring is a 5-6 member aromatic heterocyclic ring; ⑧ Ring Q is a saturated 4-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or an 8-11 membered bicyclic ring; one ring of the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring.

13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any of the following: ①In ring Q, the 5-8 element carbon ring is a 5-7 element carbon ring; ②In ring Q, the 6-8 member heterocycle is hexahydropyridine; ③ In ring Q, one ring in the 8-11 quinary bicyclic ring is a saturated or partially unsaturated 5-7 quinary heterocyclic ring, and the 5-7 quinary heterocyclic ring in the latter is a 6-quinary heterocyclic ring; ④L is -(CR) c R d )2-, In ring Q, the saturated or partially unsaturated 5-7-membered heterocyclic rings in the 8-11-membered bicyclic rings contain at most one N; ⑤ Ring Q is a saturated 4-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocycle, a phenyl ring, a 5-10 membered heteroaromatic ring, or an 8-10 membered bicyclic ring; one ring of the 8-10 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-6 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring.

14. The compound of claim 13, or a pharmaceutically acceptable salt thereof, characterized in that, In ring Q, the 5-8 element carbon ring is a 6-7 element carbon ring.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, X represents N, O, or NR. a or CR b ; Y is either C or N; L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d Each is independently represented by H; m can be 1, 2, 3, or 4; n1 and n2 are both 1; p is 0; r is 0, 1, or 2; q is 0, 1, or 2; M is non-existent, -O-, or -NH-C(O)-; Ring Q is a saturated 4-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or an 8-11 membered bicyclic ring; one ring of the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; R1 is a C1-C6 alkyl group; R3 can be F, Cl, Br, I, hydroxyl, C1-C6 alkyl, or -NH-C(O)R. e or -NH-S(O)2R e Alternatively, the two R3 atoms and the atoms attached to them form a 3-8 cycloalkyl group; R e C1-C6 alkyl, -NH2, -NHR g -NR f R g Or 5-6 yuan of heteroaryl compounds; R f and R g Each is independently a C1-C6 alkyl group; R4 is an oxometalate (=O); The number of heteroatoms in the heterocycle, heteroaromatic ring and heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, characterized in that, L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d Each is independently represented by H; m can be 1, 2, 3, or 4; n1 and n2 are both 1; p is 0; r is 0, 1, or 2; q is 0, 1, or 2; M is non-existent, -O-, or -NH-C(O)-; Ring Q is a saturated 4-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocycle, a phenyl ring, a 5-10 membered heteroaromatic ring, or an 8-10 membered bicyclic fused ring; one ring of the 8-10 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-6 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; the 5-6 membered heterocycle in the saturated or partially unsaturated 5-6 membered heterocycle of the 8-10 membered bicyclic fused ring contains one oxygen atom, one nitrogen atom, two nitrogen atoms, or one oxygen atom and one nitrogen atom; R1 is a C1-C6 alkyl group; R3 is a hydroxyl group, a C1-C6 alkyl group, or a -NH-C(O)R group. e or -NH-S(O)2R e Alternatively, the two R3 atoms and the atoms attached to them form a 3-8 cycloalkyl group; R e C1-C6 alkyl, -NH2, -NHR g -NR f R g Or 5-6 yuan of heteroaryl compounds; R f and R g Each is independently a C1-C6 alkyl group; R4 is an oxometalate (=O); The number of heteroatoms in the heterocycle, heteroaromatic ring and heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S.

17. The compound of claim 15, or a pharmaceutically acceptable salt thereof, characterized in that, X is N or O; Y is C; p is 0; r is 0, 1, or 2; q is 0, 1, or 2; L is -(CR) c R d ) m -;R c and R d Each is independently represented by H; m is 2, 3, or 4; When m is 2, M is absent or -NH-C(O)-, and ring Q is a saturated 5-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocycle, phenyl, a 5-10 membered heteroaromatic ring, or an 8-11 membered bicyclic fused ring; one ring of the 8-11 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-7 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; When m is 3, M is non-existent; ring Q is a partially unsaturated 6-8 member heterocycle or an 8-11 member bicyclic fused ring; one ring of the 8-11 member bicyclic fused ring is a saturated or partially unsaturated 5-7 member heterocycle, and the other ring is a benzene ring; When m is 4, M is -O-, and ring Q is an 8-11 quinary bicyclic ring; one ring of the 8-11 quinary bicyclic ring is a saturated or partially unsaturated 5-7 quinary heterocyclic ring, and the other ring is a 5-6 quinary heteroaromatic ring. If m is 4, then M does not exist; R1 is a C1-C6 alkyl group; R3 can be F, Cl, Br, I, C1-C6 alkyl, or -NH-C(O)R. e Alternatively, the two R3 atoms and the atoms attached to them form a 3-8 cycloalkyl group; R e C1-C6 alkyl, -NH2, -NHR g -NR f R g Or 5-6 yuan of heteroaryl compounds; R f and R g Each is independently a C1-C6 alkyl group; R4 is an oxometalate (=O); The number of heteroatoms in the heterocycle, heteroaromatic ring and heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S. The 5-7 member heterocycles in the saturated or partially unsaturated 5-7 member bicyclic rings of the 8-11 member bicyclic rings contain one oxygen atom, one nitrogen atom, two oxygen atoms, or one oxygen atom and one nitrogen atom.

18. The compound of claim 15, or a pharmaceutically acceptable salt thereof, characterized in that, X is N or O; Y is C; p is 0; r is 0, 1, or 2; q is 0, 1, or 2; L is -(CR) c R d ) m -;R c and R d Each is independently represented by H; m is 2, 3, or 4; When m is 2, M is absent or -NH-C(O)-, and ring Q is a saturated 5-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocycle, phenyl, a 5-10 membered heteroaromatic ring, or an 8-10 membered bicyclic fused ring; one ring of the 8-10 membered bicyclic fused ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-6 membered heterocycle, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; When m is 3, M is non-existent, and ring Q is a partially unsaturated 6-8 member heterocycle or an 8-10 member bicyclic ring; one ring of the 8-10 member bicyclic ring is a saturated or partially unsaturated 5-6 member heterocycle, and the other ring is a benzene ring. When m is 4, M is -O-, and ring Q is an 8-10 quinary bicyclic ring; one ring of the 8-10 quinary bicyclic ring is a saturated or partially unsaturated 5-6 quinary heterocyclic ring, and the other ring is a 5-6 quinary heteroaromatic ring. When m is 4, M is non-existent; ring Q is a saturated or partially unsaturated 6-8 member heterocyclic ring or an 8-10 member bicyclic ring; one ring of the 8-10 member bicyclic ring is a saturated or partially unsaturated 5-6 member heterocyclic ring, and the other ring is a benzene ring; R1 is a C1-C6 alkyl group; R3 is independently a C1-C6 alkyl group, -NH-C(O)R e Alternatively, the two R3 atoms and the atoms attached to them form a 3-8 cycloalkyl group; R e C1-C6 alkyl, -NH2, -NHR g -NR f R g Or 5-6 yuan of heteroaryl compounds; R f and R g Each is independently a C1-C6 alkyl group; R4 is an oxometalate (=O); The number of heteroatoms in the heterocycle, heteroaromatic ring and heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S. The 5-6 member heterocycle in the saturated or partially unsaturated 5-6 member of the 8-10 member bicyclic ring contains one oxygen atom, one nitrogen atom, or one oxygen atom and one nitrogen atom.

19. The compound of claim 15, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any of the following schemes: Option (1): X is O; Y is C; p is 0; L is -(CR) c R d ) m -or-(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 -;R c and R d Each is independently represented by H; m can be 1, 2, 3, or 4; L is -(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 When n1 and n2 are 1, M is -O-, and ring Q is L is -(CR) c R d ) m - When m is 1, M does not exist, ring Q is a saturated 6-membered carbon ring, and R3 is a hydroxyl group; L is -(CR) c R d ) m When m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 4-8 membered carbon ring, hexahydropyridine, thiophene, phenyl, and R3 is independently a C1-C6 alkyl group or -NH-C(O)R. e R e It is a C1-C6 alkyl group; L is -(CR) c R d ) m When m is 3, M is -O-, and the ring Q is L is -(CR) c R d ) m When m is 4, M is -O- or does not exist, and ring Q is hexahydropyridine. When ring Q is hexahydropyridine, R3 is independently a C1-C6 alkyl group; Ring Q is When q is 0; R1 is a C1-C6 alkyl group; Option (2): X is N; Y is C; p is 0; L is -(CR) c R d ) m -;R c and R d Each is independently represented by H; m is 2 or 3; L is -(CR) c R d ) m When m is 2, M does not exist, ring Q is a saturated 5-7 membered carbon ring, and R3 is independently -NH-C(O)R. e R e It is a C1-C6 alkyl group; L is -(CR) c R d ) m When m is 3, M is -O-, and the ring Q is q is 0; R1 is a methyl group; Option (3): X is C; Y is N; p is 0; L is -(CR) c R d ) m -or-(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 -;R c and R d Each is independently represented by H; m is 3 or 4; L is -(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 When n1 and n2 are 1, M is -O-, and ring Q is L is -(CR) c R d ) m When m is 3, M is -O-, and the ring Q is L is -(CR) c R d ) m When m is 4, M is -O-, and the ring Q is Option (4): X is O; Y is C; p is 0; L is -(CR) c R d ) m -;R c and R d Each is independently represented by H; m is 2 or 4; L is -(CR) c R d ) m When m is 2, M is absent or -NH-C(O)-, and ring Q is a saturated 6-7 membered carbon ring, phenyl, or 8-11 membered bicyclic fused ring; one ring of the 8-11 membered bicyclic fused ring is a saturated 5-7 membered heterocycle, and the other ring is a 5-6 membered heteroaromatic ring; the 5-6 membered heteroaromatic ring contains one or two nitrogen atoms; L is -(CR) c R d ) m -, when m is 4, M is either non-existent or -O-; L is -(CR) c R d ) m - When m is 4 and M is absent, ring Q is a partially unsaturated 6-membered heterocycle or When ring Q is a partially unsaturated 6-membered heterocycle, the heteroatom in the partially unsaturated 6-membered heterocycle is a nitrogen atom, and the number of heteroatoms is independently 1, 2 or 3. L is -(CR) c R d ) m When m is 4 and M is -O-, ring Q is a partially unsaturated 6-membered heterocycle or R3 is independently F, C1-C6 alkyl, or -NH-C(O)R e R e It is a C1-C6 alkyl group; Option (5): X is O; Y is C; p is 0; L is -(CR) c R d ) m -or-(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 -;R c and R d Each is independently represented by H; m is 2 or 4; L is -(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 When n1 and n2 are 1, M is -O-, and ring Q is L is -(CR) c R d ) m When m is 2, M is absent or -NH-C(O)-, ring Q is a saturated 4-6 membered carbon ring, thiophene, or phenyl, and R3 is independently a C1-C6 alkyl group or -NH-C(O)R. e R e It is a C1-C6 alkyl group; L is -(CR) c R d ) m When m is 4, M is -O- or does not exist, and ring Q is hexahydropyridine. q is 0; R1 is a C1-C6 alkyl group.

20. The compound of claim 15, or a pharmaceutically acceptable salt thereof, characterized in that, X represents N, O, or NR. a or CR b ; Y is either C or N; L is -(CR c R d ) m - or -(CR c R d ) n1 -CH=CH-(CR c R d ) n2 -; R c and R d Each is independently represented by H; m can be 1, 2, 3, or 4; n1 and n2 are both 1; p is 0; r is 0, 1, or 2; q is 0, 1, or 2; M is non-existent, -O-, or -NH-C(O)-; Ring Q is a saturated 4-8 membered carbon ring, a saturated or partially unsaturated 6-8 membered heterocyclic ring, a 6-10 membered aromatic ring, a 5-10 membered heteroaromatic ring, or an 8-11 membered bicyclic ring; one ring of the 8-11 membered bicyclic ring is a saturated or partially unsaturated 5-7 membered carbon ring, or a saturated or partially unsaturated 5-7 membered heterocyclic ring, and the other ring is a benzene ring or a 5-6 membered heteroaromatic ring; R1 is a C1-C6 alkyl group; R3 can be hydroxyl, C1-C6 alkyl, or -NH-C(O)R. e or -NH-S(O)2R e Alternatively, the two R3 atoms and the atoms attached to them form a 3-8 cycloalkyl group; R e C1-C6 alkyl, -NH2, -NHR g -NR f R g Or 5-6 yuan of heteroaryl compounds; R f and R g Each is independently a C1-C6 alkyl group; R4 is an oxometalate (=O); The number of heteroatoms in the heterocycle, heteroaromatic ring and heteroaryl group is independently 1, 2 or 3, and the heteroatoms are independently N, O or S.

21. The compound of claim 15, or a pharmaceutically acceptable salt thereof, characterized in that, The compound is any of the following schemes: Option (1): X is N; Y is C; p is 0; L is -(CR) c R d ) m -;R c and R d Each is independently represented by H; m is 2 or 3; L is -(CR) c R d ) m When m is 2, M does not exist, ring Q is a saturated 6-membered carbon ring, and R3 is independently -NH-C(O)R. e R e It is a C1-C6 alkyl group; L is -(CR) c R d ) m When m is 3, M is -O-, and the ring Q is q is 0; R1 is a methyl group; Option (2): X is C; Y is N; p is 0; L is -(CR) c R d ) m -or-(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 -;R c and R d Each is independently represented by H; m is 3 or 4; L is -(CR) c R d ) n1 -CH=CH-(CR c R d ) n2 When n1 and n2 are 1, M is -O-, and ring Q is L is -(CR) c R d ) m When m is 3, M is -O-, and the ring Q is L is -(CR) c R d ) m When m is 4, M is -O-, and the ring Q is 22. The compound of claim 1, or a pharmaceutically acceptable salt thereof, characterized in that, The compound has any of the following structures:

23. A method for preparing a compound of formula I, comprising the following steps: in a solvent, a compound of formula II and a compound of formula III are coupled together to obtain the compound of formula I. in, Hal is a halogen; X, Y, The definitions of L, M, ring Q, R1, R2, R3, R4, p, q, and r are as described in any one of claims 1 to 21.

24. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

25. Use of a compound as described in any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating mental illness or neurodegenerative diseases.

26. The use as described in claim 25, characterized in that, The mental illness or neurodegenerative disease mentioned is schizophrenia, depression, or Parkinson's disease.

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