Indole compound, pharmaceutical composition, and preparation method and application thereof

Abstract

The invention relates to an indole compound, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and a pharmaceutical composition containing the indole compound. The compounds, or pharmaceutically acceptable salts thereof, or stereoisomers thereof, and pharmaceutical compositions have agonistic activity against 5-HT receptors, and can be used as 5-HT receptor agonists for the prevention or treatment of diseases or various CNS diseases or conditions related to the activity or expression level of 5-HT receptors. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to indole compounds, including their pharmaceutically acceptable salts and stereoisomers, which are selective agonists of 5-hydroxytryptamine receptors (5-HT) and can be used as therapeutic compounds, especially in the treatment and / or prevention of various CNS diseases or disorders. Background Art

[0002] Depression is a type of mental illness characterized by affective disorders. Its clinical features are significant and persistent low mood, accompanied by decreased interest, pessimism, slow thinking, and even suicidal behavior, which seriously limits psychosocial functions and reduces the quality of life. There are more than 350 million depression patients in the world, with an increase of 18% in the past decade; the lifetime prevalence of depression in China is 6.8%, with a total of about 95 million patients.

[0003] Antidepressants are a recognized and effective treatment method. The main antidepressants currently include tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), etc. SSRIs are currently the first-line clinical treatment drugs. Compared with traditional tricyclic antidepressants, they are better tolerated and safer. They work by inhibiting the reabsorption of the central neurotransmitter serotonin (5-HT) and increasing the concentration of 5-HT in the synaptic cleft. However, SSRIs take effect slowly, and patients usually need to take the medicine for several weeks before it takes effect, and about 30-60% of patients do not respond adequately to the initial treatment drugs. Therefore, there is an urgent need to develop new antidepressants.

[0004] In March 2019, the US FDA approved S-configuration ketamine (esketamine) as a nasal spray for the combined treatment of patients with refractory depression (Am J Psychiatry, 2019, 176(6): 428-438; JAMA Psychiatry, 2019, 76(9): 893-903). Esketamine is the first drug approved by the FDA for depression with a new mechanism of action in 30 years. In terms of mechanism of action, esketamine is a non-selective N-methyl-D-aspartate (NMDA) receptor antagonist (Nature, 2021, 596(7871): 301-305), which has a rapid onset of action and can maintain therapeutic response with continuous use, which to some extent solves the problem of slow onset of traditional antidepressants. However, since it is a type of psychotropic drug, it is inconvenient to use clinically and there are risks of sedation, cognitive impairment, dissociation and abuse. In addition, it needs to be used in combination with first-line antidepressants to be effective, which limits its widespread use in clinical practice.

[0005] Psychedelics have great potential in treating depression, anxiety, drug addiction, post-traumatic stress disorder (PTSD) and other diseases (Cell, 2020, 181(1): 24-28). Psilocybin is a tryptamine alkaloid found in Psilocybin mushrooms. In the second phase of clinical trials, it showed rapid onset and lasting relief of depression (N Engl J Med, 2022, 387(18): 1637-1648). However, psilocybin has neuropsychedelic effects and the risk of abuse, and its clinical application will be subject to many restrictions. Current studies believe that psilocybin and other hallucinogens activate 5-HT 2A Receptor activation of different signaling pathways in cells produces hallucinations or antidepressant effects. The hallucinogenic effect of hallucinogens is closely related to the simultaneous activation of the 5-HT2A-Gq and β-arrestin2 transduction pathways. By changing the binding mode of ligands to receptors, the downstream β-arrestin2 signal is preferentially activated, which can separate the hallucinogenic effect from the antidepressant effect, thereby retaining the antidepressant effect without producing hallucinogenic effects (Science, 2022, 375(6579): 403-411).

[0006] Although a lot of meaningful research has been conducted in this field, there is still a need to continue researching and developing more effective small molecule 5-HT receptor selective agonists. Summary of the invention

[0007] The invention provides a 5-HT receptor agonist with a novel structure, and finds that the compound with such structure has good 5-HT receptor agonist activity.

[0008] The present invention provides a compound represented by formula (I), a pharmaceutically acceptable salt or stereoisomer thereof,

[0009]

[0010] in: (1)

[0012] R1 is selected from H, halogen, OH, or C 1-5 Alkoxy;

[0013] R2 is selected from H, halogen, OH, or C 1-5 Alkoxy;

[0014] R3 is selected from OR 3a ;

[0015] R 3a Selected from H, C 1-5 Alkyl or phenyl;

[0016] R4 is selected from -CHR 4cCH2-NR 4a R 4b 、-CH2R 4d 、-CHR 4c CH2R 4d ;

[0017] R 4a and R 4b Each independently selected from C 1-5 Alkyl, or C 3-6 Cycloalkyl;

[0018] R 4c Each independently selected from H, or phenyl;

[0019] R 4d Selected from

[0020] R 4d1 , R 4d2 , R 4d3 are independently selected from H, halogen, or C 1-5 alkyl;

[0021] R5 is selected from H, halogen, or C 1-6 Alkyl; or (2)

[0023] R1 is selected from H, halogen, OH, or C 1-5 Alkoxy;

[0024] R2 is selected from H, halogen, OH, or C 1-5 Alkoxy;

[0025] R3 is selected from H, or OR 3a ;

[0026] R 3a Selected from H, or C 1-5 alkyl;

[0027] R4 is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally replaced by R 4d replace;

[0028] R 4d Selected from -(CH2) n -R6, or -(CH2) n -OR6;

[0029] R5 is selected from H, halogen, or C 1-6 alkyl;

[0030] R6 is selected from phenyl, C 5-6 Cycloalkyl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl, the phenyl, C 5-6Cycloalkyl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl are optionally substituted by one or more R7;

[0031] R7 is selected from C 1-5 Alkoxy, oxo, or -NH(C=O)-N(CH3)2;

[0032] n is selected from 1, 2, 3, 4, 5, or 6; or (3)

[0034] R1 is selected from H, halogen, or C 1-5 Alkoxy;

[0035] R2 is selected from H, halogen, or OR 2a ;

[0036] R 2a Selected from H, C 1-5 Haloalkyl, or C 3-6 Cycloalkyl;

[0037] R3 is selected from R 3b , or OR 3b ;

[0038] R 3b is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by R 3c replace;

[0039] R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6;

[0040] R4 is selected from H, or halogen;

[0041] R5 is selected from H, halogen, or C 1-6 alkyl;

[0042] R6 is selected from phenyl, which is optionally substituted with one or more R7;

[0043] R7 is selected from C 1-5 Alkoxy;

[0044] n is selected from 1, 2, 3, 4, 5, or 6.

[0045] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer,

[0046] R1 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy;

[0047] R2 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy;

[0048] R3 is selected from OR 3a ;

[0049] R 3a is selected from H, methyl, ethyl, n-propyl, isopropyl, or phenyl;

[0050] R4 is selected from -CHR 4c CH2-NR 4a R 4b 、-CH2R 4d 、-CHR 4c CH2R 4d ;

[0051] R 4a and R 4b Each is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 4c Each independently selected from H, or phenyl;

[0052] R 4d Selected from R 4d1 , R 4d2 , R 4d3 is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0053] R5 is selected from H.

[0054] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer,

[0055] R1 is selected from H, F, Cl, Br, or I;

[0056] R2 is selected from H;

[0057] R3 is selected from OR 3a ;

[0058] R 3a is selected from H, methyl, ethyl, n-propyl, isopropyl, or phenyl;

[0059] R4 is selected from -CHR 4c CH2-NR 4a R 4b ;

[0060] R 4a and R 4b Each is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 4c Each independently selected from H, or phenyl;

[0061] R5 is selected from H.

[0062] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer,

[0063] R1 is selected from H, F, Cl, Br, or I;

[0064] R2 is selected from H;

[0065] R3 is selected from OR 3a ;

[0066] R 3a is selected from H, methyl, ethyl, n-propyl, isopropyl, or phenyl;

[0067] R4 is selected from -CHR 4c CH2-NR 4a R 4b ;

[0068] R 4a methyl, ethyl, n-propyl, or isopropyl;

[0069] R 4b Each is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0070] R 4c Each independently selected from H, or phenyl;

[0071] R5 is selected from H.

[0072] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R1 is selected from H, or F;

[0073] R2 is selected from H;

[0074] R3 is selected from OR 3a ;

[0075] R 3a is selected from H, methyl, or phenyl;

[0076] R4 is selected from -CHR 4c CH2-NR 4a R 4b ;

[0077] R 4a methyl, ethyl, n-propyl, or isopropyl;

[0078] R 4b Each is independently selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0079] R 4c Each independently selected from H, or phenyl;

[0080] R5 is selected from H.

[0081] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R1 is selected from H;

[0082] R2 is selected from H;

[0083] R3 is selected from OR 3a ;

[0084] R 3a Selected from H, or phenyl;

[0085] R4 is selected from -CHR 4c CH2-NR 4a R 4b ;

[0086] R 4a and R 4b each independently methyl, ethyl, n-propyl, or isopropyl;

[0087] R 4c are each independently selected from phenyl;

[0088] R5 is selected from H.

[0089] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R1 is selected from H;

[0090] R2 is selected from H;

[0091] R3 is selected from OR 3a ;

[0092] R 3a Selected from phenyl;

[0093] R4 is selected from -CH2CHR 4c -NR 4a R 4b ;

[0094] R 4a and R 4b each independently methyl, ethyl, n-propyl, or isopropyl;

[0095] R 4c Each independently selected from H, or phenyl;

[0096] R5 is selected from H.

[0097] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer, R1 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy;

[0098] R2 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy;

[0099] R3 is selected from OR 3a ;

[0100] R 3a is selected from H, methyl, ethyl, n-propyl, or isopropyl;

[0101] R4 is selected from R 4d Selected from -(CH2) n -R6, or -(CH2) n -OR6;

[0102] R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0103] R6 is selected from phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl, wherein the phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl is optionally substituted with one or more (e.g., 1, 2, 3) R7;

[0104] R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy, oxo, -NH(C=O)-N(CH3)2;

[0105] n is selected from 1, 2, 3, 4, 5, or 6.

[0106] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer,

[0107] R1 is selected from H, F, Cl, Br, or I;

[0108] R2 is selected from H;

[0109] R3 is selected from OR 3a ;

[0110] R 3a Selected from H;

[0111] R4 is selected from

[0112] R 4d Selected from -(CH2) n -R6, or -(CH2) n -OR6;

[0113] R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0114] R6 is selected from

[0115] R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy, oxo, -NH(C=O)-N(CH3)2;

[0116] n is selected from 1, 2, 3, 4, 5, or 6.

[0117] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer,

[0118] R1 is selected from H, F, Cl, Br, I, methoxy, or ethoxy;

[0119] R2 is selected from H, F, Cl, Br, I, or OR 2a ;

[0120] R 2a is selected from H, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0121] R3 is selected from R 3b , or OR 3b ;

[0122] R 3b Selected from

[0123] R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6;

[0124] R4 is selected from H, F, Cl, Br, or I;

[0125] R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0126] R6 is selected from phenyl, which is optionally substituted by one or more (e.g., 1, 2, 3) R7;

[0127] R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy;

[0128] n is selected from 1, 2, 3, 4, 5, or 6.

[0129] In some embodiments of the present invention, in the compound represented by formula (I), its pharmaceutically acceptable salt or stereoisomer,

[0130] R1 is selected from H;

[0131] R2 is selected from H, F, Cl, Br, I, or OR 2a ;

[0132] R 2a is selected from H, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;

[0133] R3 is selected from R 3b , or OR 3b ;

[0134] R 3b Selected from

[0135] R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6;

[0136] R4 is selected from H, F, Cl, Br, or I;

[0137] R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl;

[0138] R6 is selected from

[0139] R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy;

[0140] n is selected from 1, 2, 3, 4, 5, or 6.

[0141] In some embodiments of the present invention, the present invention provides a compound represented by formula (II), or a pharmaceutically acceptable salt thereof,

[0142]

[0143] in,

[0144] R1 is selected from H, or halogen;

[0145] X1 and X2 are each independently selected from CH or N;

[0146] R 4d Selected from -(CH2) n -R6, or -(CH2)n -OR6;

[0147] R6 is selected from phenyl, C 5-6 Cycloalkyl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl, the phenyl, C 5-6 Cycloalkyl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl are optionally substituted by one or more (e.g., 1, 2, 3) R7;

[0148] R7 is selected from C 1-3 Alkoxy, oxo, -NH(C=O)-N(CH3)2;

[0149] n is selected from 1, 2, 3, 4, 5, or 6.

[0150] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R1 is selected from H, F, Cl, Br, or I; and other variables are as defined in the present invention.

[0151] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl, and the phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl is optionally substituted by one or more (e.g., 1, 2, 3) R7; R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy, oxo, -NH(C=O)-N(CH3)2; other variables are as defined in the present invention.

[0152] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy, -NH(C=O)-N(CH3)2; other variables are as defined in the present invention.

[0153] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy, oxo, -NH(C=O)-N(CH3)2; other variables are as defined in the present invention.

[0154] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy; other variables are as defined in the present invention.

[0155] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from R7 is selected from oxo; the other variables are as defined herein.

[0156] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from R7 is selected from -NH(C=O)-N(CH3)2; the other variables are as defined herein.

[0157] In some embodiments of the present invention, in the compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from Other variables are as defined herein.

[0158] In some embodiments of the present invention, the present invention provides a compound represented by formula (III), or a pharmaceutically acceptable salt thereof,

[0159]

[0160] in,

[0161] R2 is selected from H, halogen, or OR 2a ;

[0162] R 2a Selected from H, C 1-5 Haloalkyl, or C 3-6 Cycloalkyl;

[0163] R3 is selected from R 3b , or OR 3b ;

[0164] R 3b is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by R 3c replace;

[0165] R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6;

[0166] R4 is selected from H, or halogen;

[0167] R6 is selected from phenyl, which is optionally substituted by one or more (e.g., 1, 2, 3) R7;

[0168] R7 is selected from C 1-5 Alkoxy;

[0169] n is selected from 1, 2, 3, 4, 5, or 6.

[0170] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, R 2a is selected from H, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; and other variables are as defined herein.

[0171] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, R 3b Selected from Other variables are as defined herein.

[0172] In some embodiments of the present invention, in the compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, R6 is selected from R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy; other variables are as defined in the present invention.

[0173] In some embodiments of the present invention, provided are compounds as shown below, or pharmaceutically acceptable salts or stereoisomers thereof:

[0174]

[0175]

[0176] In some embodiments of the present invention, provided are compounds as shown below, or pharmaceutically acceptable salts or stereoisomers thereof:

[0177]

[0178] The present invention also provides a pharmaceutical composition, comprising any one of the above compounds or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical composition can be prepared into various pharmaceutically acceptable dosage forms, such as tablets, capsules, oral liquids, granules, injections or various sustained-release preparations. The pharmaceutical composition can be administered orally or parenterally (such as intravenously, subcutaneously or topically). The dosage can be appropriately adjusted according to the patient's age, gender and disease type, and the general daily dose is about 1-200 mg.

[0179] The present invention provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts and stereoisomers for treating and / or preventing patient diseases, and the use of the above-mentioned compounds or their pharmaceutically acceptable salts or stereoisomers or pharmaceutical compositions in preparing drugs. The present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts and stereoisomers for treating and / or preventing diseases related to the activity or expression of 5-HT receptors. The present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts or stereoisomers or pharmaceutical compositions in preparing drugs, which are used to prevent or treat CNS-related diseases. The diseases associated with the activity or expression of 5-HT receptors, and / or CNS-related diseases include: refractory depression, depression, bipolar disorder, body dysmorphic disorder, anxiety, mood disorders, mania, obsessive-compulsive disorder, post-traumatic stress disorder, trauma and stress-related diseases, borderline personality disorder, cognitive disorder, burnout, opioid dependence, nicotine dependence, amphetamine dependence, alcohol dependence, substance-related disorders, pain, anorexia nervosa, binge drinking-eating disorder, sleep disorder, fibromyalgia, psychological distress, post-Lyme syndrome, perceptual disorder, limb pain, amnesia, Alzheimer's disease, migraine, cluster headache, gastroesophageal reflux disease, gastrointestinal motility disorders, chemotherapy-induced nausea, constipation, irritable bowel syndrome; or other disease states and conditions obvious to those skilled in the art.

[0180] The present invention also provides the use of any of the above compounds, or a pharmaceutically acceptable salt, stereoisomer, or pharmaceutical composition thereof in the preparation of a drug for treating depression without producing hallucinogenic effects.

[0181] Definition and Description

[0182] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.

[0183] The term "pharmaceutically acceptable" as used herein refers to compounds, compositions and / or dosage forms that are, within the scope of reliable medical judgment, suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0184] The "pharmaceutically acceptable salts" mentioned in the present invention refer to salts of the compounds of the present invention, which are prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids and bases. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, organic acid salts; they also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic functional groups and can be converted into any acid addition salt.

[0185] Certain compounds of the present invention may possess asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0186] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present invention.

[0187] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. In general, the preparation method of the salt is: in water or an organic solvent or a mixture of the two, through the reaction of these compounds in free acid or base form with a stoichiometric amount of an appropriate base or acid to prepare.

[0188] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium representative of a carrier that can deliver an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient, including but not limited to: binders, fillers, lubricants, disintegrants, wetting agents, dispersants, solubilizers, suspending agents, etc.

[0189] The present invention is intended to include all isotopes of atoms present in the compounds of the present invention. Isotopes include those atoms having the same atomic number but different mass numbers. As a general example and without limitation, isotopes of hydrogen include deuterium and tritium. Isotopes of carbon include 13 C and 14C. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically labeled reagent in place of the non-labeled reagent otherwise employed.

[0190] Unless otherwise specified, the term "alkyl" is used to refer to a straight or branched saturated hydrocarbon group, which may be monosubstituted (such as -CH2F) or polysubstituted (such as -CF3), and may be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine). For example, C1-C6 means 1 to 6 carbon atoms, C 1-10 Selected from C1, C2, C3, C4, C5, C6; examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-butyl, isobutyl, s-butyl, t-butyl), pentyl (e.g., n-pentyl, isopentyl, neopentyl, 1-ethylpropyl), hexyl (e.g., n-hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl and 2-ethylbutyl), etc.

[0191]

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0192] Unless otherwise specified, "haloalkoxy" is used to indicate that an alkoxy group is substituted with one or more halogen atoms, wherein the alkoxy group has the meaning as described herein. For example, the term "C1-C6 haloalkoxy" is intended to include C1, C2, C3, C4, C5, C6 alkoxy groups substituted with one or more halogen atoms, etc. Unless otherwise specified, examples of C1-C6 haloalkoxy groups include, but are not limited to, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, pentafluoroethoxy, and pentachloroethoxy.

[0193] Unless otherwise specified, the term "cycloalkyl" includes any stable cyclic or polycyclic hydrocarbon radical, any carbon atom is saturated, can be monosubstituted or polysubstituted, can be monovalent, divalent or polyvalent. Examples of these cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0194] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent, which is a non-aromatic structure and contains 3-20 ring atoms, wherein 1, 2, 3 or more ring atoms are selected from N, O or S, and the remaining ring atoms are C. The heterocyclic group preferably contains 3-14 ring atoms, and further preferably contains 5-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The heteroatoms are preferably 1-4, more preferably 1-3 (i.e., 1, 2 or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, dihydropyrrolyl, piperidinyl, piperazinyl, pyranyl, morpholinyl, dioxanyl, etc. Examples of bicyclic heterocyclyl include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and the like.

[0195] Unless otherwise specified, "aryl" refers to a 6- to 10-membered all-carbon monocyclic or fused polycyclic (ie, rings which share adjacent pairs of carbon atoms) group having a conjugated pi-electron system, for example phenyl and naphthyl.

[0196] Unless otherwise specified, "heteroaryl" refers to a group of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic arrangement) having ring carbon atoms and 1-4 ring heteroatoms provided in an aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as valence permits. Heteroaryl bicyclic ring systems may include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems in which the above-mentioned heteroaryl rings are fused to one or more carbocyclyls or heterocyclyls, wherein the point of attachment is on the heteroaryl ring, and in such cases, the number of ring members continues to represent the number of ring members in the heteroaryl ring system.

[0197] Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to, azacycloheptatrienyl, oxacycloheptatrienyl, and thiacycloheptatrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indolinyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indazinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0198] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names. DETAILED DESCRIPTION

[0199] The present invention is further described below in conjunction with specific embodiments and test examples, but the scope of the present invention is not limited in any form.

[0200] Example 1

[0201]

[0202] Step 1: Synthesis of compound 1-2

[0203] Dissolve compound 1-1 (1.6 g, 6.63 mmol) in tetrahydrofuran (15 mL), add oxalyl chloride (2.1 g, 16.6 mmol) at 0°C under nitrogen protection. React at room temperature for 3 h. Concentrate the reaction solution directly to dryness to obtain compound 1-2 (2.2 g, crude product). LCMS=314.0[M+1] + (Hydrolysis products in water).

[0204] Step 2: Synthesis of Compound 1-3

[0205] Dissolve compound 1-2 (2.2 g, 6.63 mmol) in tetrahydrofuran (50 mL), add a tetrahydrofuran solution (10 mL) of compound N-methylcyclopropylamine (4.25 g, 59.69 mmol, 13.02 mL, 9 eq) dropwise at 0°C under nitrogen protection. React at room temperature for 12 h. Add water (50 mL) to quench the reaction, add ethyl acetate (50 mL×3) to extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and the residue is chromatographed on a silica gel column (ethyl acetate: petroleum ether 10-50%) to obtain compound 1-3 (1.2 g, yield: 50.9%, yellow oil). LCMS: 367.1

[0206] [M+H] + .

[0207] Step 3: Synthesis of Compound 1-4

[0208] Compound 1-3 (1.20 g, 3.28 mmol) was dissolved in tetrahydrofuran (20 mL), and LiAlH4 (2.5 M, 7.9 mL) was added at 0°C under nitrogen protection. The mixture was reacted at 65°C for 12 h. Water (0.75 mL), 15% sodium hydroxide (0.75 mL) and water (2.25 mL) were added in sequence at 0°C, filtered, and the filter cake was washed with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The concentrated residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 10-50%) to give compound 1-4 (0.7 g, yield 63.6%, yellow solid). LCMS: 339.2 [M+H] + .

[0209] Step 4: Synthesis of compound 1

[0210] Compound 1-4 (700 mg, 2.06 mmol) was dissolved in methanol (6 mL) and tetrahydrofuran (5 mL). Pd / C (219 mg, 0.206 mmol, 10%) was added, and the argon gas was replaced three times. The reaction was carried out for 4 hours at 50 Psi of hydrogen and 25°C. The filtrate was collected by filtration and concentrated under reduced pressure to obtain a crude product. The crude product was prepared by Prep-HPLC (chromatographic column: Welch Xtimate C18 250*50mm*10um; mobile phase: [A-water(NH3H2O+NH4HCO3):B-ACN]; gradient: 10% B+90% A-50% B+50% A over 20min) to obtain compound 1 (290 mg, yield 56.9%, pink solid). LCMS: 249.1[M+H] + . 1H NMR(400MHz, CDCl3)δppm 12.12-13.22(m,1H)7.86(br s,1H)6.80(d,J=2.00Hz,1H)6.54(dd,J=9.26,2.13Hz,1H)6.31(dd,J=11.63, 2.13Hz,1H)2.83-2.98(m,4H)2.51(s,3H)1.83-1.93(m,1H)0.38-0.60(m,4H).

[0211] Example 2

[0212]

[0213] Step 1: Synthesis of compound 2-2

[0214] Compound 2-1 (15 g, 76.5 mmol) was dissolved in dioxane (400 mL), and phenol (21.6 g, 229 mmol), Cs2CO3 (74.8 g, 229 mmol), CuI (14.6 g, 76.5 mmol) and N,N-dimethylglycine (4.72 g, 45.7 mmol) were added. The mixture was reacted at 100 °C for 15 h under nitrogen protection. Water (150 mL) was added to quench the reaction, and ethyl acetate (200 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0-20%) to obtain compound 2-2 (12.0 g, yield 75%, yellow oil). LCMS: 210.1 [M+H] + .

[0215] Step 2: Synthesis of compound 2-3

[0216] Dissolve compound 2-2 (1.3 g, 6.22 mmol) in tetrahydrofuran (15 mL), add oxalyl chloride (2.3 g, 18.1 mmol) at 0°C under nitrogen protection. React at room temperature for 3 h. Concentrate the reaction solution directly to dryness to obtain compound 2-3 (1.9 g, crude product). LCMS=282.1[M+1] + (Hydrolysis products in water).

[0217] Step 3: Synthesis of compound 2-4

[0218] Compound 2-3 (1.9 g, 6.22 mmol) was dissolved in tetrahydrofuran (50 mL), and N-methylamine (1.4 g, 31.0 mmol) was added at 0°C under nitrogen protection. The reaction was allowed to react at room temperature for 2 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 10-30%) to obtain compound 2-4 (1.4 g, yield: 73.4%, white solid). LCMS: 308.9 [M+H] +

[0219] Step 4: Synthesis of compound 2

[0220] Compound 2-4 (1.3 g, 4.22 mmol) was dissolved in tetrahydrofuran (20 mL), and LiAlH4 (2.5 M, 10.1 mL) was added at 0°C under nitrogen protection. The mixture was reacted at 65°C for 12 h. Water (0.96 mL), 15% sodium hydroxide (0.96 mL) and water (2.88 mL) were added in sequence at 0°C, filtered, and the filter cake was washed with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The concentrated residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 10-50%) to give compound 2 (0.25 g, yield 20.8%, yellow solid). LCMS: 281.2 [M+H] + . 1 HNMR (CDCl 3, 400MHz)δppm 1.86(s,2H),1.95-2.12(m,1H),2.25(s,6H)2.58-2.69(m,2H),2.92-3.01(m,2H),6.39-6.62(m, 1H), 6.59 (d, J = 7.50Hz, 1H), 6.99 (s, 1H), 7.01-7.16 (m, 5H), 7.34 (t, J = 7.19Hz, 2H), 8.19 (s, 1H).

[0221] Example 3

[0222]

[0223] Step 1 Synthesis of compound 3-2

[0224] Compound 3-1 (2 g, 8.96 mmol) was dissolved in hexafluoroisopropanol (100 mL), and trans-nitrostyrene (1.34 g, 8.96

[0225] mmol). The reaction was carried out at room temperature for 1 h. The reaction solution was concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-20%) to obtain compound 3-2 (3.2 g, yield: 95.9%, yellow oil). LCMS: 373.1 [M+H] + .

[0226] Step 2 Synthesis of compound 3-3

[0227] Compound 3-2 (3.2 g, 8.59 mmol) and NH4Cl (4.6 g, 85.9 mmol) were dissolved in methanol (30 mL) and tetrahydrofuran (30 mL), and Zn (5.6 g, 85.9 mmol) was added. The reaction was allowed to react at room temperature for 1 h. The reaction solution was filtered, the filtrate was concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-20%) to obtain compound 3-3 (2.2 g, yield: 76.8%, white solid). LCMS: 343.1 [M+H] + .

[0228] Step 3 Synthesis of Compound 3-4

[0229] Dissolve compound 3-3 (0.90 g, 2.64 mmol) in methanol (30 mL), add NaBH(OAc)3 (2.8 g, 13.2 mmol), and stir for 10 min. Add HCHO (0.64 g, 7.92 mmol, 37%), and react at room temperature for 1 h. Add water (50 mL) to quench the reaction, add ethyl acetate (50 mL×3) to extract, combine the organic phases, dry over anhydrous sodium sulfate, filter, concentrate, and purify the residue by silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%). Obtain compound 3-4 (0.7 g, yield 71.6%, yellow solid). LCMS: 371.1 [M+H] + .

[0230] Step 4 Synthesis of Compound 3

[0231] Compound 3-4 (500 mg, 1.35 mmol) and acetic acid (81 mg, 1.35 mmol) were dissolved in methanol (5 mL). Pd / C (50 mg, 0.0460 mmol, 10%) was added, and the atmosphere was replaced with nitrogen three times. The reaction was carried out for 4 h at 15 Psi of hydrogen and 25 °C. The filtrate was collected and concentrated under reduced pressure. The residue was purified by Prep-HPLC (chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: [A-water (ammonia hydroxide v / v): B-ACN]; gradient: 23% B+77% A-53% B+47% A over 10 min) to obtain compound 3 (173 mg, yield 45.7%, gray solid). LCMS: 281.0 [M+H]+ . 1 H NMR(400MHz, CDCl3)δ13.93-12.97(m,1H),7.80(br s,1H),7.41-7.35(m,2H),7.32-7.31(m,3H),7.08(t,J=8.0Hz,1H),6.85(d,J=8.0Hz,1H),6.63(d,J=7.6 Hz,1H),6.19(d,J=2.0Hz,1H),4.54(d,J=9.6Hz,1H),3.23-3.17(m,1H),3.07-3.03(m,1H),2.42(s,6H).

[0232] Example 4

[0233]

[0234] Step 1: Synthesis of compound 4-2

[0235] Compound 4-1 (10 g, 44.8 mmol), 1-benzyl-4-piperidone (25.4 g, 134 mmol), phosphoric acid (50 mL) and acetic acid (250 mL). React at 45 ° C for 1 h. Add DCM (100 mL) to dilute the reaction solution, cool to -30 ° C, slowly add ammonia water to quench, and adjust pH to 8. Slowly add 3L of water, add DCM (1L*2) to extract. Combine the organic phases, dry and concentrate. Concentrate the residue and chromatograph on a silica gel column (ethyl acetate: petroleum ether = 10-50%) to obtain compound 4-2 (3.2 g, yield 18.1%, white solid). LCMS: 395.2 [M+H] + .

[0236] Step 2: Synthesis of compound 4-3

[0237] Dissolve compound 4-2 (3.2 g, 8.11 mmol) in methanol (32 mL) and tetrahydrofuran (30 mL). Add Pd / C (0.86 g, 0.811 mmol, 10%), replace with argon three times, react for 4 h at 50 Psi of hydrogen and 25 ° C. Filter, collect the filtrate, and concentrate under reduced pressure to obtain compound 4-3 (1.7 g, crude product, dark green solid). LCMS: 217.1 [M+H] + .

[0238] Step 3: Synthesis of compound 4

[0239] Compound 4-3 (0.9 g, 4.17 mmol) was dissolved in tetrahydrofuran (20 mL), and 3-(2-methoxy-phenyl)-propanal (0.68 g, 4.17 mmol) and NaBH(OAc)3 (2.6 g, 12.5 mmol) were added. The mixture was reacted at room temperature for 2 h under nitrogen protection. Saturated sodium bicarbonate solution was added to adjust pH=8, and DCM (50 mL*3) was added for extraction. The organic phases were combined, dried, filtered, and concentrated. The residue was purified by Prep-HPLC (chromatographic column: Welch Xtimate C18 250*50mm*10um; mobile phase: [A-water(NH3H2O+NH4HCO3):B-ACN]; gradient: 30% B+70A-75% B+25% A over 20 min) to obtain compound 4 (0.27 g, yield 17.8%, light green solid). LCMS: 365.2 [M+H] + . 1 H NMR (400MHz, CD3OD) δppm 7.07-7.23 (m, 2H) 6.68-6.99 (m, 5H) 6.31 (br d, J=7.00Hz, 1H) 3.73-3.93 (m, 3H) 3.17 (br t, J=11.01Hz, 1H) 3.06 (br d,J=10.51Hz,2H)2.63(br t,J=7.25Hz,2H)2.36-2.52(m,2H)2.16(br d,J=11.13Hz,4H)1.85(br d,J=6.75Hz,2H)1.59-1.76(m,2H).

[0240] Example 5

[0241]

[0242] Step 1 Synthesis of Compound 5-2

[0243] Compound 5-1 (31 g, 139 mmol) and potassium hydroxide (19.9 g, 354 mmol) were dissolved in NMP (600 mL). The mixture was reacted at 75 °C for 0.5 h. The temperature was lowered to room temperature, and I2 (35 g, 139 mmol) was added, and the mixture was reacted at room temperature for 1 h. Water (1000 mL) was added to quench the reaction, and ethyl acetate (500 mL*3) was added for extraction. The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to obtain compound 5-2 (30 g, yield 31.8%, brown solid). LCMS: 350.1 [M+H] + .

[0244] Step 2 Synthesis of compound 5-3

[0245] Compound 5-2 (30 g, 85.9 mmol) was dissolved in DCM (400 mL). Boc2O (24.4 g, 112 mmol) and DMAP (14.7 g, 120 mmol) were added at 0°C under nitrogen protection. The reaction was allowed to react at room temperature for 12 h. Water (300 mL) was added to quench the reaction, and ethyl acetate (300 mL*3) was added for extraction. The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to obtain compound 5-3 (35 g, yield 90.7%, white solid). LCMS: 450.1 [M+H] + .

[0246] Step 3 Synthesis of compound 5-4

[0247] Compound 5-3 (15 g, 33.4 mmol) and N-Boc-piperazine (12.4 g, 66.8 mmol) were dissolved in 2-methyl-2-butanol (200 mL), and cesium carbonate (21.8 g, 66.8 mmol) and petroleum ether PPSI-Pd (2.1 g, 2.50 mmol) were added. The mixture was reacted at 100 °C for 4 h under nitrogen protection. The mixture was cooled to room temperature, water (300 mL) was added to quench the reaction, and ethyl acetate (300 mL*3) was added for extraction. The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to obtain compound 5-4 (7.5 g, yield 44.2%, white solid). LCMS: 508.3 [M+H] + .

[0248] Step 4 Synthesis of compound 5-5

[0249] Compound 5-4 (7.5 g, 14.8 mmol) was dissolved in DCM (60 mL) and TFA (46.0 g, 404 mmol) was added. The reaction was allowed to react at room temperature for 1 h. Aqueous potassium carbonate solution (100 mL, 5%) was added to quench the reaction and ethyl acetate (300 mL*3) was added for extraction. The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (MeOH:DCM=0-15%) to obtain compound 5-5 (3.6 g, yield 80.2%, white solid). LCMS: 308.3 [M+H] + .

[0250] Step 5 Synthesis of Compound 5-6

[0251] Compound 5-5 (200 mg, 0.651 mmol), 1-(3-bromopropyl)-2-methoxybenzene (149 mg, 0.651 mmol) and triethylamine (198 mg, 1.95 mmol) were dissolved in DMF (5 mL). The mixture was reacted at 50 °C for 1 h. Water (30 mL) was added to quench the reaction, and ethyl acetate (30 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 10-50%) to obtain compound 5-6 (213 mg, yield 74.2%, yellow oil). LCMS: 456.3 [M+H] + .

[0252] Step 6 Synthesis of Compound 5

[0253] Compound 5-6 (150 mg, 0.329 mmol) and acetic acid (19.8 mg, 0.329 mmol) were dissolved in methanol (5 mL). Pd / C (17.5 mg, 16.5 mmol, 10%) was added, and the atmosphere was replaced with nitrogen three times. The reaction was carried out for 4 h at 15 Psi of hydrogen and 25 ° C. Filter, collect the filtrate, and concentrate under reduced pressure. The residue was purified by Prep-HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [A-water(HCl): B-ACN]; gradient: 10% B+90% A-40% B+60% A over 10 min) to obtain compound 5 (72 mg, yield 54.4%, gray solid). LCMS: 366.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.76(br s,2H),9.66(br s,1H),7.23-7.20(m,2H),7.00(d,J=7.6Hz,2H),6.91(m,2H),6.79(m,1H),6.41(m,1H), 3.81(s,3H),3.78(m,2H),3.63(m,2H),3.18(m,6H),2.62(t,J=7.6Hz,2H),2.02(m,2H).

[0254] Example 6

[0255]

[0256] Step 1 Synthesis of Compound 6-2

[0257] Compound 6-1 (2.2 g, 14.5 mmol) and ethoxycarbonyl methylene triphenylphosphine (6.1 g, 17.4 mmol) were dissolved in DCM (40 mL). The reaction was allowed to react at room temperature for 4 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-30%) to obtain compound 6-2 (3.0 g, yield 94.9%, white solid). LCMS: 219.0 [M+H] + .

[0258] Step 2 Synthesis of Compound 6-3

[0259] Compound 6-2 (1.4 g, 6.4 mmol) was dissolved in DCM (40 mL), replaced with nitrogen 3 times, cooled to -70 ° C, and DIBAL-H (1M, 19.24 mL) was added. The reaction was carried out at room temperature and under nitrogen protection for 2 h. The reaction solution was cooled to 0 ° C, and dilute hydrochloric acid (1N, 100 mL) was added to quench the reaction, and ethyl acetate (100 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-30%) to obtain compound 6-3 (0.95 g, yield 84.0%, white solid). LCMS: 177.0 [M+H] + .

[0260] Step 3 Synthesis of compound 6-4

[0261] Dissolve compound 6-3 (2.0 g, 11.2 mmol) in methanol (40 mL). Add Pd / C (1.2 g, 1.12 mmol, 10%), replace with nitrogen three times, react for 2 h at 15 Psi of hydrogen and 25 ° C. Filter, collect the filtrate, and concentrate under reduced pressure to obtain compound 6-4 (1.9 g, yield 96.4%, yellow oil). LCMS: 179.0 [M+H] + .

[0262] Step 4 Synthesis of Compound 6-5

[0263] Compound 6-4 (1.8 g, 10.1 mmol) and PPh3 (5.3 g, 20.2 mmol) were dissolved in DCM (40 mL), cooled to 0°C, and CBr4 (6.7 g, 20.2 mmol) was added under nitrogen protection. The mixture was reacted for 5 h at room temperature under nitrogen protection. The reaction solution was concentrated, and the residue was purified by rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0-5%) to obtain compound 6-5 (2.3 g, crude product). LCMS: 241.0 [M+H] + .

[0264] Step 5 Synthesis of Compound 6-6

[0265] Dissolve compound 6-5 (1 g, 4.15 mmol) and N-tert-butyloxycarbonylpiperazine (0.93 g, 4.98 mmol) in ethanol (30 mL), add potassium carbonate (2.9 g, 20.7 mmol). React at 80°C for 12 h. Filter the reaction solution, and concentrate the filtrate to obtain compound 6-6 (1.1 g, crude product). LCMS: 347.1 [M+H] + .

[0266] Step 6 Synthesis of Compound 6-7

[0267] Dissolve compound 6-6 (1.0 g, 3.03 mmol) in dioxane (2 mL), add HCl / dioxane (2 M, 7.58 mL). React at room temperature for 2 h. Concentrate the reaction solution to obtain compound 6-7 (0.85 g, crude product). LCMS: 247.2 [M+H] + .

[0268] Step 7 Synthesis of Compound 6-8

[0269] Compound 6-7 (0.69 g, 2.82 mmol), compound 4-3 (1.15 g, 2.56 mmol) and cesium carbonate (2.50 g, 7.68 mmol) were dissolved in dioxane (40 mL). Petroleum ether PPSIPd (0.22 g, 0.256 mmol) was added under nitrogen protection. The mixture was reacted at 100 ° C and nitrogen protection for 5 h. The reaction solution was concentrated and the residue was subjected to rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0-50%) to obtain compound 6-8 (0.30 g, yield 21.0%, yellow solid). LCMS: 568.3 [M+H] + .

[0270] Step 8 Synthesis of Compound 6

[0271] Compound 6-8 (330 mg, 581 μmol) was dissolved in DCM (10 mL), cooled to 0°C, and BCl3 (1 M, 2.91 mL) was added under nitrogen protection. The mixture was reacted at 0°C and under nitrogen protection for 1 h. Methanol (5 mL) was added to quench the reaction, and the reaction solution was concentrated. The residue was purified by prep-HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [A-water(HCl):B-ACN]; gradient: 10% B+90% A-40% B+60% A over 10 min) to obtain compound 6 (9.1 mg, yield 4.1%, green solid). LCMS: 378.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.58(s,1H),10.25(s,1H),9.50(s,1H),7.10(d,J=7.2Hz,1H),6.99(d,J=7.6Hz,1H),6.86-6.73(m,4H),6.34(d,J=7.2Hz ,1H),4.53(t,J=8.8Hz,2H),3.68-3.63(m,2H),3.58-3.55(m,2H),3.22- 3.12(m,6H),3.05-2.96(m,2H),2.56(t,J=7.6Hz,2H),2.05-1.96(m,2H).

[0272] Example 7

[0273]

[0274] Step 1 Synthesis of Compound 7-1

[0275] Compound 5-3 (4 g, 8.90 mmol) and N-cbz-piperazine (5.9 g, 26.7 mmol) were dissolved in 2-methyl-2-butanol (200 mL), and cesium carbonate (8.7 g, 26.7 mmol) and petroleum ether PPSI-Pd (0.374 g, 0.445 mmol) were added. The mixture was reacted at 100 °C under nitrogen protection for 4 h. The mixture was cooled to room temperature, water (300 mL) was added to quench the reaction, and ethyl acetate (300 mL*3) was added for extraction. The organic phases were combined, dried, filtered, and the filtrate was concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (ethyl acetate: petroleum ether = 0-30%) to obtain compound 7-1 (1.2 g, yield 24.9%, white solid). LCMS: 542.3 [M+H] + .

[0276] Step 2 Synthesis of Compound 7-2

[0277] Dissolve compound 7-1 (770 mg, 1.42 mmol) in methanol (20 mL). Add Pd / C (151 mg, 0.142 mmol, 10%), replace with argon three times, react for 4 hours at 50 Psi of hydrogen and 25°C. Filter, collect the filtrate, and concentrate under reduced pressure to obtain compound 7-2 (350 mg, crude product). LCMS: 318.3 [M+H] + .

[0278] Step 3 Synthesis of compound 7-4

[0279] Compound 7-3 (2 g, 13.7 mmol) and ethoxycarbonyl methylene triphenylphosphine (5.7 g, 16.4 mmol) were dissolved in DCM (40 mL). The reaction was allowed to react at room temperature for 4 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-10%) to obtain compound 7-4 (2.9 g, yield 98%, oil). LCMS: 217.1 [M+H] + .

[0280] Step 4 Synthesis of Compound 7-5

[0281] Compound 7-4 (2.1 g, 9.71 mmol) was dissolved in tetrahydrofuran (40 mL), replaced with nitrogen 3 times, cooled to 0°C, and LiAlH4 (2.5 M, 4.67 mL) was added. The reaction was carried out at room temperature and under nitrogen protection for 2 h. The reaction solution was cooled to 0°C, and H2O (0.45 mL), 15% NaOH (0.45 mL) and H2O (1.35 mL) were added to quench the reaction. The organic phases were filtered, combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-30%) to obtain compound 7-5 (0.95 g, yield 55.5%, oil). LCMS: 177.1 [M+H] + .

[0282] Step 5 Synthesis of Compound 7-6

[0283] Compound 7-5 (0.81 g, 4.59 mmol) was dissolved in PPh3 (2.4 g, 9.18 mmol) in DCM (40 mL), cooled to 0°C, and CBr4 (3.0 g, 9.16 mmol) was added under nitrogen protection. The reaction was carried out at room temperature and under nitrogen protection for 1 h. The reaction solution was concentrated, and the residue was subjected to rapid silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to obtain compound 7-6 (1 g, crude product). LCMS: 239.0 [M+H] + .

[0284] Step 6 Synthesis of compound 7-7

[0285] Compound 7-2 (340 mg, 1.07 mmol), compound 7-6 (282 mg, 1.18 mmol) and triethylamine (326 mg, 3.22 mmol) were dissolved in DMF (10 mL). Pd-PEPPSI reagent (0.22 g, 0.256 mmol) was added under nitrogen protection. The reaction was carried out at 50 ° C and nitrogen protection for 12 hours. The reaction solution was concentrated, and the residue was subjected to rapid silica gel column chromatography (MeOH: DCM = 0 ~ 15%) to obtain compound 7-7 (270 mg, yield 53.0%, yellow solid). LCMS: 476.2 [M + H] + .

[0286] Step 7 Synthesis of Compound 7

[0287] Compound 7-7 (240 mg, 505 μmol) was dissolved in DCM (10 mL), cooled to 0°C, and BCl3 (1 M, 1.52 mL) was added under nitrogen protection. The mixture was reacted at 0°C and under nitrogen protection for 0.5 h. Water (5 mL) was added to quench the reaction, and the reaction solution was concentrated. The residue was purified by prep-HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [A-water(HCl):B-ACN]; gradient: 13% B+87% A-43% B+57% Aover 10 min) to obtain compound 7 (101 mg, yield 47.6%, yellow solid). LCMS: 376.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.58(br s,1H),10.43-10.15(m,1H),9.65-9.31(m,1H),8.02(d,J=2.4Hz,1H),7.57-7.51(m,1H),7.22(d,J=4.8Hz,2H),6.98(d,J= 2.0Hz,1H),6.89-6.70(m,3H),6.34(d,J=7.2Hz,1H),6.69-6.58(m,4H),3.24(s,4H),3.07-2.89(m,4H),2.25-2.12(m,2H).

[0288] Example 8

[0289]

[0290] Step 1 Synthesis of Compound 8-2

[0291] Compound 8-1 (15 g, 91.9 mmol), potassium carbonate (12.7 g, 91.9 mmol) and 1,3-dibromopropane (92.8 g, 460 mmol) were dissolved in ethanol (150 mL). The mixture was reacted at 80 °C for 12 h. Water (200 mL) was added to quench the reaction, and ethyl acetate (200 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain compound 8-2 (15.9 g, yield 60.9%, yellow solid). LCMS: 284.0 [M+H] + .

[0292] Step 2 Synthesis of compound 8-3

[0293] Compound 8-2 (0.14 g, 0.488 mmol), compound 5-5 (0.15 g, 0.488 mmol), triethylamine (0.074 g, 0.73 mmol) were dissolved in acetonitrile (5 mL). The mixture was reacted at 60 °C for 3 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-70%) to obtain compound 8-3 (0.18 g, yield 80.7%, yellow solid). LCMS: 511.3 [M+H] + .

[0294] Step 3 Synthesis of Compound 8

[0295] Compound 8-3 (200 mg, 392 μmol) was dissolved in DCM (10 mL), cooled to 0°C, and BCl3 (1 M, 1.57 mL) was added under nitrogen protection. The mixture was reacted at 0°C and under nitrogen protection for 5 h. Methanol (5 mL) was added to quench the reaction, and the reaction solution was concentrated. The residue was purified by prep-HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [A-water(HCl):B-ACN]; gradient: 5% B+95% A-35% B+65% A over10 min) to obtain compound 8 (41 mg, yield 26.1%, green solid). LCMS: 421.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.65-10.52(m,1H),10.05(s,1H),9.71-9.35(s,1H),7.08(d,J=8.3Hz,1H),6.91(br s,1H),6.89-6.83(m,1H),6.80-6.74(m,1H),6.53(dd,J=2.5,8.3Hz,1H),6 .47(d,J=2.5Hz,1H),6.37(d,J=7.4Hz,1H),4.02(t,J=5.8Hz,2H),3.68(br d,J=16.8Hz,4H),3.38-3.27(m,4H),3.11(br d, J=10.6Hz, 2H), 2.80 (t, J=7.5Hz, 2H), 2.43 (dd, J=6.7, 8.3Hz, 2H), 2.28-2.13 (m, 2H).

[0296] Example 9

[0297]

[0298] Step 1: Synthesis of compound 9-2

[0299] Compound 9-1 (20 g, 150 mmol), PPh3 (78.8 g, 300 mmol) and N-Boc-4-hydroxypiperidine (44.6 g, 222 mmol) were dissolved in tetrahydrofuran (200 mL), and ethyl acetate (47.1 g, 270 mmol) was added dropwise. The mixture was reacted at room temperature for 15 h. The reaction solution was filtered, the organic phase was dried and concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-20%) to obtain compound 9-2 (20 g, yield 42.2%, white oil). LCMS: 317.2 [M+H] + .

[0300] Step 2: Synthesis of compound 9-3

[0301] Compound 9-2 (10 g, 31.6 mmol) was dissolved in HCl / EtOAc (2 M, 50 mL). The reaction was allowed to react at room temperature for 16 h. The reaction solution was filtered, the filter cake was collected and dried to obtain compound 9-3 (6.6 g, yield 83.0%, white solid). LCMS: 217.1 [M+H] + .

[0302] Step 3: Synthesis of compound 9

[0303] Compound 9-3 (1.0 g, 4.62 mmol) and 2-methoxyphenylacetaldehyde (0.69 g, 4.62 mmol) were dissolved in DCM (20 mL), and NaBH3CN (0.87 g, 13.9 mmol) was added. The reaction solution was reacted at room temperature for 16 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL×3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC (chromatographic column: Welch Xtimate C18 40*200mm7um; mobile phase: [A-water(HCl):B-ACN]; gradient: 4% B+96% A-44% B+56% A over 20 min) to obtain the product compound 9 (0.64 g, yield 40%, white solid). LCMS: 351.1 [M+H] + . 1 HNMR (CDCl 3, 400MHz) δ1.91(d,J=17.13Hz,2H),1.98-2.08(m,2H),2.43(s,2H),2.53-2.59(m,2H),2.62-2.86(m,5H),3.73(s,3H),4.39-4.54(m,1H ),6.48(d,J=7.63Hz,1H),6.54-6.61(m,1H),6.72-6.85(m,2H),6.92(d,J=7.88Hz,1H),6.97-7.04(m,2H),7.04-7.16(m,2H),8.38(br s,1H).

[0304] Example 10

[0305]

[0306] Step 1 Synthesis of compound 10-2

[0307] Dissolve compound 10-1 (5.5 g, 23.6 mmol) in acetonitrile (230 mL) and add NBS (4.6 g, 25.9 mmol). React at room temperature for 1 h. Filter the reaction solution, dry and concentrate the organic phase, and chromatograph the residue on a silica gel column (ethyl acetate: petroleum ether = 0-10%) to obtain compound 10-2 (3.3 g, yield 44.6%, white solid). LCMS: 312.0 [M+H] + .

[0308] Step 2 Synthesis of compound 10-4

[0309] Compound 10-3 (2 g, 9.30 mmol) and tert-butyl piperazine-1-carboxylate (1.7 g, 9.30 mmol) were dissolved in acetonitrile (100 mL) and water (60 mL), and sodium carbonate (4.9 g, 46.5 mmol) was added. The mixture was reacted at 80°C for 12 h. Water (100 mL) was added to quench the reaction, and ethyl acetate (100 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-30%) to obtain compound 10-4 (2.5 g, yield 83.9%, yellow oil). LCMS: 321.2 [M+H] + .

[0310] Step 3 Synthesis of compound 10-5

[0311] Compound 10-4 (2.5 g, 7.80 mmol) was dissolved in DCM (50 mL) and TFA (10 mL) was added. The mixture was reacted at room temperature for 1 h. Saturated sodium bicarbonate (100 mL) was added to quench the reaction and ethyl acetate (100 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-60%) to obtain compound 10-5 (1.4 g, yield 81.4%, yellow oil). LCMS: 221.1 [M+H] + .

[0312] Step 4 Synthesis of compound 10-6

[0313] Compound 10-2 (900 mg, 2.88 mmol) and compound 10-5 (762 mg, 3.46 mmol) were dissolved in 2-methyl-2-butanol (20 mL), and K3PO4 (1.8 g, 8.65 mmol) and Pd-PEPPSI reagent (242 mg, 0.288 mmol) were added. The mixture was reacted at 100 °C under nitrogen protection for 5 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-60%) to obtain compound 10-6 (700 mg, yield 53.8%, yellow solid). LCMS: 452.2 [M+H] + .

[0314] Step 5 Synthesis of compound 10

[0315] Compound 10-6 (500 mg, 1.11 mmol) was dissolved in DCM (10 mL), and HCl / MeOH (2 M, 10 mL) was added. The reaction was allowed to react at room temperature for 12 h. The reaction solution was concentrated, and the residue was purified by Prep-HPLC (chromatographic column: Phenomenex luna C18 150*40mm*15um; mobile phase: [A-water(HCl):B-ACN]; gradient: 8% B+92% A-38% B+62% A over 15 min) to obtain compound 10 (250 mg, yield 57.6%, gray solid). LCMS: 352.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.98(br s,1H),10.93(br s,1H),7.36-7.22(m,3H),7.10(d,J=8.4Hz,1H),7.03(d,J=8.0Hz,1H),6.98-6.90(m,1H),6.69(d,J=8.4Hz,1H),6.57(br s,1H),3.84(m,5H),3.61(m,2H),3.39(m,2H),3.28(m,J=5.3Hz,2H),3.17-3.01(m,4H).

[0316] Embodiment 11

[0317]

[0318] Step 1 Synthesis of compound 11-2

[0319] Compound 11-1 (8 g, 49.6 mmol), potassium carbonate (13.7 g, 99.3 mmol) and 1,3-dibromopropane (50.1 g, 248 mmol) were dissolved in acetone (120 mL). The mixture was reacted at 60 °C for 12 h. Water (100 mL) was added to quench the reaction, and ethyl acetate (100 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-20%) to obtain compound 11-2 (5.4 g, yield 38.6%, white solid). LCMS: 281.9 [M+H] + .

[0320] Step 2 Synthesis of compound 11-3

[0321] Compound 11-2 (0.80 g, 2.84 mmol), compound 5-5 (1.0 g, 3.40 mmol), potassium iodide (0.47 g, 2.84 mmol) and triethylamine (2.9 g, 28.4 mmol) were dissolved in DMF (30 mL). The mixture was reacted at 50 °C for 24 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-70%) to obtain compound 11-3 (0.26 g, yield 18.0%, brown solid). LCMS: 509.2 [M+H] + .

[0322] Step 3 Synthesis of compound 11

[0323] Compound 11-3 (260 mg, 0.511 mmol) was dissolved in DCM (10 mL), cooled to 0°C, and BCl3 (2M, 1.02 mL) was added under nitrogen protection. The mixture was reacted at 0°C and under nitrogen protection for 5 h. Methanol (10 mL) was added to quench the reaction, and the reaction solution was concentrated. The residue was purified by prep-HPLC (HCl condition): chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [A-water(HCl):B-ACN]; gradient: 3% B+97% A-33% B+67% A over 10 min) to obtain compound 11 (20.4 mg, yield 8.8%, green solid). LCMS: 419.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ11.66(s,1H),10.62(s,1H),10.34(s,1H),9.56(s,1H),7.82(d,J=9.2Hz,1H),7.60(d,J=9.6Hz,1H),6.94-6.80(m,4 H),6.78-6.74(m,1H),6.39-6.28(m,2H),4.13(t,J=5.6Hz,2H),3.77- 3.63(m,4H),3.35-3.29(m,4H),3.15-2.99(m,2H),2.31-2.21(m.2H).

[0324] Example 12

[0325]

[0326] Step 1 Synthesis of compound 12-2

[0327] Compound 12-1 (5 g, 22.0 mmol) and ethoxycarbonyl methylene triphenylphosphine (8.4 g, 24.2 mmol) were dissolved in DCM (100 mL). The mixture was reacted at room temperature for 4 h. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (ethyl acetate: petroleum ether = 0-30%) to obtain compound 12-2 (5.5 g, yield 84.1%, white solid). LCMS: 298.2 [M+H] + .

[0328] Step 2 Synthesis of compound 12-3

[0329] Compound 12-2 (3.3 g, 11.1 mmol) was dissolved in DCM (60 mL), replaced with nitrogen 3 times, cooled to -70 °C, and DIBAL-H (1 M, 33.29 mL) was added. The reaction was carried out at room temperature and under nitrogen protection for 2 h. The reaction solution was cooled to 0 °C, and dilute hydrochloric acid (1N, 100 mL) was added to quench the reaction, and ethyl acetate (100 mL×3) was added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 12-3 (2.4 g, crude product) was obtained. LCMS: 256.2 [M+H] + .

[0330] Step 3 Synthesis of compound 12-4

[0331] Dissolve compound 12-3 (3.4 g, 13.3 mmol) in methanol (50 mL). Add Pd / C (1.4 g, 1.33 mmol, 10%), replace with nitrogen three times, react for 2 h at 15 Psi of hydrogen and 25 ° C. Filter, collect the filtrate, and concentrate under reduced pressure to obtain compound 12-4 (1.6, crude product). LCMS: 256.2 [M+H] + .

[0332] Step 4 Synthesis of compound 12-5

[0333] Compound 12-4 (0.75 g, 2.94 mmol), compound 5-5 (0.90 g, 2.94 mmol) and acetic acid (1.41 g, 23.5 mmol) were dissolved in methanol (30 mL), and NaBH3CN (0.92 g, 14.7 mmol) was added. The mixture was reacted for 4 h at room temperature under nitrogen protection. Water (50 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was chromatographed on a silica gel column (MeOH: DCM = 0-15%) to obtain compound 12-5 (1.1 g, yield 68.5%, white solid). LCMS: 547.3 [M+H] + .

[0334] Step 5 Synthesis of compound 12-6

[0335] Compound 12-5 (1.1 g, 2.01 mmol) was dissolved in DCM (30 mL) and TFA (4 mL) was added. The mixture was reacted at room temperature for 1 h. Saturated sodium bicarbonate aqueous solution (100 mL) was added to quench the reaction, and ethyl acetate (50 mL × 3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 12-6 (0.87 g, crude product) was obtained. LCMS: 447.3 [M+H] + .

[0336] Step 6 Synthesis of compound 12-7

[0337] Compound 12-6 (870 mg, 1.95 mmol) and triethylamine (591 mg, 5.84 mmol) were dissolved in DCM (30 mL), and dimethylaminoformyl chloride (209 mg, 1.95 mmol) was added at 0°C. The mixture was reacted at 80°C for 5 h. Saturated sodium bicarbonate aqueous solution (100 mL) was added to quench the reaction, and ethyl acetate (50 mL×3) was added to extract. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. Compound 12-7 (900 mg, crude product) was obtained. LCMS: 518.3 [M+H] + .

[0338] Step 7 Synthesis of Compound 12

[0339] Compound 12-7 (300 mg, 0.193 mmol) was dissolved in DCM (10 mL), cooled to 0°C, and BCl3 (1 M, 579 μL) was added under nitrogen protection. The mixture was reacted at 0°C and under nitrogen protection for 1 h. Methanol (3 mL) was added to quench the reaction, and the reaction solution was concentrated. The residue was purified by prep-HPLC (chromatographic column: Phenomenex luna C18 150*25mm*10um; mobile phase: [A-water(HCl):B-ACN]; gradient: 5% B+95% A-35% B+65% Aover 10 min) to obtain compound 12 (21.2 mg, yield 8.6%, yellow solid). LCMS: 428.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 10.53 (s, 1H), 9.89 (s, 1H), 9.41 (s, 1H), 6.87-6.78 (m,2H),6.77-6.71(m,1H),6.33(d,J=7.2Hz,1H),5.87(s,1H),3.69-3.63(m ,2H),3.59-3.53(m,3H),3.25-3.18(m,2H),3.13-3.06(m,2H),2.98-2.88(m ,2H),2.75(s,6H),1.80-1.70(s,6H),1.24-1.15(m,5H),1.00-0.89(m,2H).

[0340] Example 13

[0341]

[0342] Step 1 Synthesis of compound 13-4

[0343] Intermediate 13-3 (923.60 mg, 2.69 mmol), Pd(dppf)2Cl2 (91.56 mg, 0.011 mmol), potassium carbonate (929.76 mg, 6.73 mmol), water (3 mL) were added to the dioxane (15 mL) solution of intermediate 2, nitrogen was fully replaced, and the reaction was carried out at 70 ° C for 12 hours. After the reaction, the reaction solution was poured into ice water (100 mL), extracted with ethyl acetate (100 mL × 3), the combined organic phases were washed with saturated brine (50 mL × 2), and then the organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain intermediate 13-4 (1.2 g, 1.87 mmol, colorless oil, yield: 83.5%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 7.94 (d, J = 8.0 Hz, 1H), 7.67-7.51 (m, 1H), 7.41-7.36 (m, 5H), 6.91 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 3.6 Hz, 1H), 5.98-5.77 (m, 1H), 5.22 (s, 2H), 4.29-4.19 (m, 2H), 3.82-3.78 (m, 2H), 1.67 (s, 9H). Step 3 Synthesis of compound 13-5

[0344] The intermediate 13-4 (1.2 g, 1.87 mmol) was dissolved in hexafluoroisopropanol (10 mL) and passed through a 30 mL coil (flow rate 6 mL / min) at 220 ° C using microchannel fluid chemistry technology for a residence time of 5 minutes. After the reaction was completed, the reaction solution was poured into ice water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with saturated brine (100 mL×2), and then the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 10 / 1-1 / 1) to obtain intermediate 13-5 (0.33 g, 0.849 mmol, yellow solid, yield: 24.6%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.15 (br.s, 1H), 7.45-7.33 (m, 5H), 7.24-7.16 (m, 2H), 6.86 (d, J = 8.8Hz, 1H), 6.3 3(s,1H),5.99-5.83(m,1H),5.23(s,2H),5.16(s,1H),4.24(d,J=2.4Hz,2H),3.82(t,J=5.6Hz,2H),2.58(s,2H).

[0345] Step 4 Synthesis of Compound 13-6

[0346] Under nitrogen protection, wet palladium carbon (30 mg, purity: 10%) was added to a methanol (20 mL) solution of 13-5 (270 mg, 0.774 mmol). The solution was replaced with a hydrogen balloon three times, and then stirred at 25 ° C for 1 hour under the hydrogen balloon (15 Psi). After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure to obtain intermediate 13-6 (130 mg, 0.601 mmol, yellow solid, yield: 77.5%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 10.69 (br.s, 1H), 8.61-8.18 (m, 1H), 7.16 (t, J = 2.8Hz, 1H), 7.02-6.96 (m, 1H), 6.67-6.60 (m, 1H), 6. 52-6.40(m,1H),4.31-3.89(m,1H),3.28-3.22(m,1H),3.08-2.85(m,2H),2.64-2.56(m,1H),2.38-1.90(m,3H),1.63-1.36(m,2H).

[0347] Step 5 Synthesis of compound 13

[0348] Intermediate 13-6 (130 mg, 0.601 mmol), intermediate 13-7 (129.28 mg, 0.601 mmol), triethylamine (182.47 mg, 1.80 mmol) were added to N,N-dimethylformamide (1 mL) and stirred at 60 ° C for 2 hours under nitrogen. After the reaction, the reaction solution was diluted with acetonitrile (10 mL), and the solid was precipitated. It was slurried at 25 ° C for 10 minutes, then filtered and washed with acetonitrile (30 mL) to obtain product 13 (370 mg, 2.08 mmol, colorless oil, yield: 85.6%). 1 H NMR (400MHz, DMSO-d6)δ=10.70(br.s,1H),8.33(br.s,1H),7.23-7.12(m,3H),7.00( d,J=8.4Hz,1H),6.95(d,J=8.4Hz,1H),6.87(t,J=7.2Hz,1H),6.64(d,J=8.4Hz,1H), 6.40(s,1H),3.79(s,3H),3.19-3.09(m,1H),3.05(d,J=10.8Hz,2H),2.81-2.70(m,2 H),2.49-2.45(m,2H),2.39-2.24(m,2H),2.14-1.97(m,2H),1.51(d,J=11.2Hz,2H).

[0349] Embodiment 14

[0350]

[0351] Step 1 Synthesis of compound 14-3

[0352] The raw material 10-2 (400 mg, 1.28 mmol), the raw material 14-2 (360.33 mg, 1.54 mmol), potassium phosphate (815.99 mg, 3.84 mmol) and PEPPESIPd (107.66 mg, 0.13 mmol) were added to tert-amyl alcohol (20 mL), the nitrogen was replaced three times, and stirred at 100 ° C for 5 hours. After the reaction was completed, the reaction solution was filtered and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse phase separation (0.1% formic acid system and 0-55% acetonitrile) to obtain intermediate 14-3 (220 mg, yellow oil, yield 36.87%). LCMS: 466.3 [M + H] + .

[0353] Step 2 Synthesis of compound 15

[0354] The raw material 14-3 (200 mg) was dissolved in a hydrochloric acid aqueous solution (3M, 5 mL) and stirred at 60°C for 3 hours. After the reaction was completed, the crude product was purified by reverse phase separation (0.1% hydrochloric acid system and 0-45% acetonitrile) to obtain compound 14 (84.6 mg, yellow oil, yield 53.88%). LCMS: 366.4 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 11.37 (s, 1H), 11.13 (s, 1H), 7.32-7.28 (m, 1H), 7.24-7.14 (m, 3H), 6.98 (d, J = 8.0Hz, 1H), 6.90 (t, J = 7. 2Hz,1H),6.80-6.71(m,2H),4.15-3.97(m,4H),3.61-3.37(m,6H),3.25-3.09(m,4H),2.64(t,J=7.2Hz,2H),2.10-1.99(m,2H).

[0355] Compounds 15 (hydrochloride), 17 (hydrochloride), 18, and 20 (hydrochloride) were synthesized by similar preparation methods to Examples 10 and 14. The structures and characterization data of each compound are shown in the following table:

[0356]

[0357] Embodiment 15

[0358]

[0359] Step 1 Synthesis of Compound 21-2

[0360] Add the raw material 21-1 (1 g, 7.57 mmol), bis(2-chloroethyl)amine hydrochloride (1.62 g, 9.08 mmol) and potassium carbonate (2.09 g, 15.13 mmol) to isopropanol (15 mL) and stir at 90 ° C for 48 hours. After the reaction is completed, slurry is added with a mixed solvent of 50 mL of dichloromethane and 50 mL of methanol, and filtered to obtain a crude product intermediate 21-2 (1.3 g, brown solid). LCMS: 202.2 [M+H] + .

[0361] Step 2 Synthesis of Compound 21

[0362] The raw materials 21-2 (982.54 mg) and 21-3 (700 mg, 3.25 mmol) and triethylamine (1.36 mL, 9.76 mmol) were added to N, N-dimethylformamide (20 mL) and stirred at 60 ° C for 12 hours. After the reaction was completed, the reaction solution was diluted with 30 mL of saturated brine and extracted with ethyl acetate (30 mL × 3). The separated organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purification by silica chromatography (petroleum ether / ethyl acetate = 1 / 0-3 / 1) gave 21 (150 mg, brown solid, yield 13.74%). LCMS: 336.3 [M + H] + . 1 H NMR (400MHz, DMSO-d6) δ=11.02(s,1H),7.23(t,J=2.8Hz,1H),7.21-7.14(m,2H),7.04-6.99(m,1H),6.98-6.92(m,2H),6.87(t,J=7.8Hz ,1H),6.44(d,J=7.2Hz,1H),6.39-6.34(m,1H),3.34(s,3H),3.19-3.00(m,4H),2.82-2.72(m,2H),2.71-2.62(m,4H),2.58-2.51(m,2H).

[0363] Example 16

[0364]

[0365] Step 1 Synthesis of Compound 22-2

[0366] Add 22-1 (350 mg, 2.12 mmol) to ultra-dry tetrahydrofuran (5 mL) and stir at room temperature for 5 min. Protect the reaction solution with nitrogen, add oxalyl chloride (403.46 mg, 3.18 mmol, 0.28 mL) dropwise at 0°C, and allow the reaction system to rise to 20°C naturally after the addition is complete. Stir for 12 hours. After LCMS monitoring shows that the reaction has more than 50% of the product, directly use the 22-2 reaction solution for the next reaction. LCMS: 274.0 [M+Na] + .

[0367] Step 2 Synthesis of Compound 22-3

[0368] Dissolve methylcyclopropylamine (209 mg, 2.93 mmol, 3 eq) in dichloromethane (5 mL), and add N,N-diisopropylethylamine (379.19 mg, 2.93 mmol, 3 eq, 0.5 mL) dropwise. The reaction solution was stirred at 20°C for 30 min. Then, the reaction solution of step 2-2 (250 mg, 0.998 mmol) was added dropwise to the reaction system (5 mL) at 0°C, and the temperature was naturally raised to 20°C and stirred for 2.5 hours. After the reaction was monitored, saturated ammonium chloride (20 mL) was added dropwise to the reaction system at 20°C to quench the reaction and stirred for 5 min. The reaction solution was extracted with dichloromethane (10 mL × 3), and the mixed organic phase was added with anhydrous sodium sulfate for drying and then the solvent was removed by rotary evaporation. Then, it was purified by prep-HPLC (basic conditions) (chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: [water (ammonia hydroxide v / v)-ACN]; gradient: 13%-43% B over 10min) and lyophilized to obtain 22-3 (126mg, 434.05μmol, yield 44.38%). LCMS: 313.1[M+H] + .

[0369] Step 3 Synthesis of compound 22

[0370] 22-3 (100 mg, 0.35 mmol, 1 eq) was added to tetrahydrofuran (5 mL). After nitrogen replacement three times, the solution was placed in an ice bath and lithium aluminum tetrahydride solution (1.38 mL, 3.44 mmol, 2.5 M, 10 eq) was slowly added dropwise at 10 °C. After the addition was completed, the mixture was stirred at room temperature for 5 min, and then the reaction system was moved to a 70 °C oil bath. The reaction solution was stirred at 70 °C for 12 hours. After the reaction was complete as monitored by LCMS, water (0.13 mL), NaOH solution (15%, 0.13 mL) and water (0.39 mL) were added dropwise to the reaction solution at 0 °C to quench the reaction, and then an appropriate amount of anhydrous sodium sulfate was added to remove water and stirred for 30 min. The reaction solution was filtered, the solid was washed with ethyl acetate (50 mL), and the combined filtrate was concentrated by rotary evaporation to obtain a crude product, which was purified by preparative reverse phase column chromatography (chromatographic column: Phenomenex lunaC18 250*50mm*15um; mobile phase: [water(FA)-ACN]; gradient: 5%-35% Bover 65min), and lyophilized to obtain compound 22 (30 mg, yellow solid, formate, yield 31.9%). LCMS: 263.0 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ=10.79(br s,1H),8.17(s,1H),6.94(d,J=2.0Hz,1H),6.66(dd,J=2.0,9.6Hz,1H),6.35(dd,J=2.0,12.0Hz,1H),3.84(s,3H),2 .92-2.85(m,2H),2.74-2.68(m,2H),2.34(s,3H),1.70(qd,J=3.2,6.6Hz,1H),0.45-0.42(m,2H),0.34-0.27(m,2H).

[0371] Embodiment 17

[0372]

[0373] Step 1 Synthesis of Compound 23-3

[0374] Potassium hydroxide (5.03 g, 89.58 mmol) was added to an ethanol (50 mL) solution of 23-1 (5 g, 22.39 mmol) and 23-2 (6.25 g, 31.35 mmol). The mixture was stirred at 90 °C for 48 hours. After the reaction, the reaction solution was poured into an aqueous solution (200 mL) and extracted with ethyl acetate (200 mL × 3). The combined organic phases were washed with saturated brine (200 mL × 3), and then the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica column chromatography (petroleum ether / ethyl acetate = 1 / 0-1 / 1) to obtain a crude product, which was separated and purified by preparative prep-HPLC (neutral conditions; chromatographic column: Welch Ultimate XB-CN 250*50*10um; mobile phase [Hexane-EtOH]; gradient: 1%-40% B over 15min) and lyophilized to obtain 23-3 (0.7 g, 1.73 mmol, white solid, yield: 7.7%). 1 H NMR (400MHz, CDCl3-d) δ = 8.14 (br.s, 1H), 7.53-7.44 (m, 2H), 7.43-7.30 (m, 3H), 7.16-7.10 (m, 1H), 7.02 (d, J = 8.0Hz, 1H), 6.97 (d, J = 2. 0Hz,1H),6.63(d,J=7.6Hz,1H),5.84-5.74(m,1H),5.15(s,2H),4.01-3.81(m,2H),3.43-3.12(m,2H),2.61-2.36(m,2H),1.49(s,9H).

[0375] Step 2 Synthesis of Compound 23-4

[0376] Wet palladium carbon (500 mg, purity 10%) was added to a solution of 23-3 (500 mg, 1.24 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) under nitrogen protection. The reaction was replaced with hydrogen three times, and finally stirred at 20 ° C for 12 hours under hydrogen (hydrogen balloon, 15 Psi). After the reaction was completed, the reaction solution was filtered and the organic phase was concentrated under reduced pressure to obtain 23-4 (350 mg, 1.11 mmol, yellow colloid, yield: 89.4%). 1 H NMR (400MHz, CDCl3-d) δ = 8.04 (br, s, 1H), 7.04-6.95 (m, 2H), 6.94-6.85 (m, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.45 (d, J = 7.6 Hz, 1H), 4.38-4.11 (m, 2H), 3.35-3.22 (m, 1H), 2.98-2.80 (m, 2H), 2.31-2.03 (m, 2H), 1.60-1.47 (m, 11H). Step 3 Synthesis of compound 23-5

[0377] Trifluoroacetic acid (468.5 mg, 4.11 mmol) was added to dichloromethane (3 mL) of 23-4 (130 mg, 0.41 mmol) at 0°C, and the temperature was slowly raised to 25°C and stirred for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain 23-5 (150 mg, brown colloid, crude product), which was directly used for the next step without purification. LCMS: 217.2 [M+H] + .

[0378] Step 4 Synthesis of Compound 23

[0379] 23-5 (100 mg, crude product, 0.395 mmol), 14-6 (85.1 mg, 0.395 mmol), triethylamine (120.1 mg, 1.19 mmol) were added to N,N-dimethylformamide (1 mL) solution, replaced with nitrogen three times, and stirred at 60 ° C for 1 hour. After the reaction, the reaction solution was poured into an ice-water solution (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined and washed with saturated brine (30 mL × 3), and then the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by preparative prep-HPLC (neutral conditions; chromatographic column: Waters Xbridge 150*25mm*5um; mobile phase: [water(NH4HCO3)-ACN]; gradient: 30%-60% B over 9min) and lyophilized to obtain compound 23 (7.9 mg, 0.0218 mmol, gray solid, yield 5.5%, purity: 97.1%). LCMS: 351.1 [M+H] + . 1 H NMR (400MHz, METHNAOL-d4) δ = 7.23-7.10 (m, 2H), 6.93 (d, J = 8.0Hz, 1H), 6.90-6.77 (m, 4H), 6.35-6.26 (m, 1H), 3.84 (s, 3H),3.26-3.13(m,3H),2.94-2.85(m,2H),2.69-2.58(m,2H),2.39-2.27(m,2H),2.26-2.16(m,2H),1.86-1.67(m,2H).

[0380] Embodiment 18

[0381]

[0382] Step 1 Synthesis of Compound 24-2

[0383] 24-1 (2.52 g, 10.45 mmol) was dissolved in N,N-dimethylformamide (55 mL), and N-iodosuccinimide (2.58 g, 11.49 mmol) was added in batches at 0°C. After the addition was complete, the reaction solution was stirred at 25°C for 1 hour. After the reaction was completed by TLC monitoring, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 1-9 / 1) to obtain 24-2 (2.01 g, yield 52.61%, red solid). The product was directly used in the next step under nitrogen protection.

[0384] Step 2 Synthesis of Compound 24-3

[0385] 24-2 (1.19 g, 3.24 mmol) and 4-dimethylaminopyridine (800 mg, 6.55 mmol) were dissolved in tetrahydrofuran (15 mL) and replaced with nitrogen protection. Boc2O (1.06 g, 4.86 mmol) was slowly added at 0°C, and the mixture was reacted at 30°C for 12 hours. After the reaction was completed by TLC monitoring, ethyl acetate (25 mL) and water (30 mL) were added to the reaction solution, and the aqueous phase was extracted three times with 20 mL of ethyl acetate. The combined organic phase was washed once with 10 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 10 / 0-9 / 1) to obtain 24-3 (1.25 g, yield 82.54%, white solid). 1 H NMR (400MHz, CDCl3-d) δ = 7.63-7.53 (m, 4H), 7.44-7.32 (m, 3H), 6.56 (dd, J = 11.20, 2.13Hz, 1H), 5.20 (s, 2H), 1.66 (s, 9H).

[0386] Step 3 Synthesis of compound 24-5

[0387] 24-3 (1.01 g, 2.16 mmol), 24-4 (817.00 mg, 2.38 mmol), XPhos-G4 (202.00 mg, 0.235 mmol) and potassium carbonate (897 mg, 6.49 mmol) were dissolved in dioxane (25 mL) and water (5 mL). After nitrogen replacement three times, the reaction solution was stirred at 100 ° C for 2 hours. After the reaction was completed by HPLC monitoring, it was concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 100 / 0-83 / 7) to obtain 24-5 (968 mg, yield 93.74%, yellow oil). LCMS: 557.2 [M+H] + .

[0388] Step 4 Synthesis of Compound 24-6

[0389] 24-5 (960 mg, 1.72 mmol) was dissolved in tetrahydrofuran (10 mL) and flowed into a 30 mL coil reactor at a flow rate of 5 mL / min at 240°C using a flow chemistry method for 6 minutes. After cooling overnight, the reaction mixture was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel column, petroleum ether / ethyl acetate = 100 / 0-77 / 23) to obtain 24-6 (602 mg, yield 74.58%, yellow solid). LCMS: 457.2 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 11.14 (s, 1H), 7.48-7.46 (m, 2H), 7.39-7.33 (m, 8H), 7.11 (s, 1H), 6.76 (dd, J = 9.2, 2.06Hz, 1H), 6. 57(dd,J=12.0,2.0Hz,1H),5.73(br,s,1H),5.12(s,2H),5.08(s,2H),3.83(br,s,2H),3.29(t,J=5.60Hz,2H),2.58(s,2H).

[0390] Step 5 Synthesis of Compound 24-7

[0391] 24-6 (600 mg, 1.31 mmol) was dissolved in tetrahydrofuran (15 mL), palladium carbon was added under nitrogen atmosphere, hydrogen was replaced three times, and then stirred at 25°C under hydrogen balloon (15 psi) atmosphere for 2 hours. After the reaction was completed by LCMS monitoring, the mixture was filtered and the filtrate was concentrated under reduced pressure to obtain intermediate 24-7 (305 mg, yellow oil, yield 99.06%). LCMS: 235.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 10.68 (s, 1H), 7.36-7.14 (m, 1H), 6.91-6.85 (m, 1H), 6.56 (dd, J = 9.88, 2.0Hz, 1H), 6.20(dd,J=11.6,2.0Hz,1H),3.69-3.64(m,2H),3.13-3.01(m,3H),2.36(s,1H),1.82(m,2H),1.46(m,2H).

[0392] Step 6 Synthesis of Compound 24

[0393] 24-7 (119 mg, 0.51 mmol) and 24-8 (131 mg, 0.57 mmol) were dissolved in N,N-dimethylformamide (4 mL), and triethylamine (155 mg, 1.53 mmol) was added dropwise after nitrogen replacement three times. The reaction solution was stirred at 50°C for 12 hours. After the reaction was completed by LCMS monitoring, the reaction solution was purified by reverse phase separation (0.1% formic acid system and 0-80% acetonitrile) to obtain 24 (65.8 mg, yellow solid, yield 33.28%). LCMS: 383.1 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ = 10.65 (d, J = 0.8Hz, 1H), 9.80-9.77 (m, 1H), 8.21 (s, 1H, FA) ,7.21-7.10(m,2H),6.94(d,J=8.0Hz,1H),6.90-6.80(m,2H),6.50(dd,J=9.6,2.0H z,1H),6.14(dd,J=11.6,2.0Hz,1H),3.79(s,3H),3.05-2.95(m,3H),2.66-2.53(m, 2H), 2.38 (t, J = 7.6Hz, 2H), 2.13-1.93 (m, 4H), 1.78-1.66 (m, 2H), 1.64-1.51 (m, 2H).

[0394] Embodiment 19

[0395]

[0396] Step 1 Synthesis of compound 19

[0397] 19-1 (300 mg, 1.40 mmol), 19-2 (308.80 mg, 1.40 mmol), potassium phosphate (892.6 mg, 4.20 mmol) and [1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene] (3-chloropyridyl) dichloropalladium (II) (117.8 mg, 0.14 mmol) were dissolved in tert-amyl alcohol (5 mL) and replaced with nitrogen three times. The mixture was reacted at 100 ° C for 4 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The crude product was purified by reverse phase separation (0.1% hydrochloric acid system and 0-45% acetonitrile) to obtain compound 19 (150.00 mg, 0.425 mmol, yellow solid, yield 26.41%). LCMS: 354.1 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ=11.25(br s,1H),10.68(br s,1H),7.38(t,J=2.8Hz,1H),7.32-7.20(m,2H),7.13(dd,J=8.8,3.6Hz,1H),7.04(d,J=8.0Hz,1H),6.98-6.86(m,2 H), 6.54 (t, J = 2.2Hz, 1H), 3.83 (s, 3H), 3.69-3.63 (m, 4H), 3.51-3.40 (m, 2H), 3.38-3.19 (m, 4H), 3.11-3.01 (m, 2H).

[0398] Test Example 1.5-HT 2AFunctional activity test of receptors

[0399] 1. Test methods:

[0400] (1) FLIPR analysis

[0401] a. To detect 5-HT 2A Receptor-mediated downstream G q -PLC β After activation of the Ca-PI cascade, 2+ The release of 5-HT 2A The recipient HEK293 cells were diluted to 20,000 cells / 20 μL with DMEM medium and inoculated into 384-well poly-lysine-coated cell plates and cultured at 37° C., 5% CO 2 for 16-20 hours.

[0402] b. Use Echo to dilute the compound to be tested in a gradient manner, transfer 750 nL to the corresponding compound plate; add 30 μL of FLIPR buffered saline (HBSS+HEPE+0.5% BSA) to the corresponding compound plate, and centrifuge at 1000 rpm for 1 minute.

[0403] c. Take the cell plate prepared the day before out of the incubator, discard the culture medium, add 20 μL FLIPR assay buffer, and add 20 μL 2×Fluo-4 Direct TM Buffer, total volume is 40 μL. Incubate in 5% CO2, 37°C incubator for 50 minutes, then place at room temperature for 10 minutes.

[0404] d. Place the compound plate, cell plate and pipette tip into the instrument, run the FLIPR instrument software, add 10 μL of the test compound and reference compound of the established concentration to the cell plate according to the set program, and read the fluorescence signal.

[0405] Min", "R ethyl acetate d 1 to Maximum allowed" method to export data and calculate. Agonist Activation % = (RLU-

[0406] DMSO) / (HC-DMSO)*100

[0407] (2) β-arrestin analysis

[0408] a. To detect 5-HT 2A Receptor-mediated downstream β-arrestin signaling agonist activity, using transfected 5-HT 2A HEK 293 cell line expressing β-arrestin 2. Dilute the cells to 0.75 × 10 6cells / mL, 40 μL / well were seeded in a 384-well cell plate and cultured overnight at 37°C, 5% CO2.

[0409] b. Dilute the test compound using an Echo gradient, transfer 250 nL to the compound plate, and add 50 μL of assay buffer.

[0410] c. Dilute the Promega-N2013 detection reagent to the specified concentration using DMEM medium and add 5 μL / well to the cell plate.

[0411] d. Use Bravo to transfer 5 μL of compound to the cell plate, incubate at room temperature in the dark for 30 minutes, and read.

[0412] Activation% = (Signal-LC) / (HC-LC)*100

[0413] (3) Test results: The compounds of the present invention have an effect on 5-HT 2A The functional activity tests of the receptors are shown in Table 1.

[0414] Table 1 Effect of the compounds of the present invention on 5-HT 2A Functional activity test of receptors

[0415]

[0416] Note: + indicates maximum agonist activity (Emax) <20%; ++ indicates maximum agonist activity (Emax) of 21-40%; +++ indicates maximum agonist activity (Emax) of 41-60%; ++++ indicates maximum agonist activity (Emax) of 61-80%; +++++ indicates maximum agonist activity (Emax) of 81-100%.

[0417] As can be seen from Table 1, the compounds of the present invention have an 2A The receptors have moderate to strong agonist activity, and compounds 3, 4, 5, 6, 7, 8, 10, 11, and 12 have moderate to strong agonist activity on 5-HT 2A Receptor-mediated activation of β-arrestin2 signaling is selective.

Claims

1. A compound represented by formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, in: (1) R1 is selected from H, halogen, OH, C 1-5 Alkoxy; R2 is selected from H, halogen, OH, C 1-5 Alkoxy; R3 is selected from OR 3a ; R 3a Selected from H, C 1-5 Alkyl or phenyl; R4 is selected from -CHR 4c CH2-NR 4a R 4b 、-CH2R 4d 、-CHR 4c CH2R 4d ; R 4a and R 4b Each independently selected from C 1-5 Alkyl, or C 3-6 Cycloalkyl; R 4c Each independently selected from H, or phenyl; R 4d Selected from R 4d1 , R 4d2 , R 4d3 are independently selected from H, halogen, or C 1-5 alkyl; R5 is selected from H, halogen, or C 1-6 alkyl; or, (2) R1 is selected from H, halogen, OH, C 1-5 Alkoxy; R2 is selected from H, halogen, OH, C 1-5 Alkoxy; R3 is selected from H, OR 3a ; R 3a Selected from H, C 1-5 alkyl; R4 is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally replaced by R 4d replace; R 4d Selected from -(CH2) n -R6, or -(CH2) n -OR6; R5 is selected from H, halogen, or C 1-6 alkyl; R6 is selected from phenyl, C 5-6 Cycloalkyl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl, the phenyl, C 5-6 Cycloalkyl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl are optionally substituted with one or more R7; R7 is selected from C 1-5 Alkoxy, oxo, -NH(C=O)-N(CH3)2; n is selected from 1, 2, 3, 4, 5, or 6; or (3) R1 is selected from H, halogen, C 1-5 Alkoxy; R2 is selected from H, halogen, or OR 2a ; R 2a Selected from H, C 1-5 Haloalkyl, or C 3-6 Cycloalkyl; R3 is selected from R 3b , or OR 3b ; R 3b is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by R 3c replace; R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6; R4 is selected from H, or halogen; R5 is selected from H, halogen, or C 1-6 alkyl; R6 is selected from phenyl, which is optionally substituted with one or more R7; R7 is selected from C 1-5 Alkoxy; n is selected from 1, 2, 3, 4, 5, or 6.

2. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, in: (1) R1 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy; R2 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy; R3 is selected from OR 3a ; R 3a is selected from H, methyl, ethyl, n-propyl, isopropyl, or phenyl; R4 is selected from -CHR 4c CH2-NR 4a R 4b 、-CH2R 4d 、-CHR 4c CH2R 4d ; R 4a and R 4b Each is independently selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R 4c Each independently selected from H, or phenyl; R 4d Selected from R 4d1 , R 4d2 , R 4d3 is independently selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R5 is selected from H; or, (2) R1 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy; R2 is selected from H, F, Cl, Br, I, OH, methoxy, or ethoxy; R3 is selected from OR 3a ; R 3a is selected from H, methyl, ethyl, n-propyl, or isopropyl; R4 is selected from R 4d Selected from -(CH2) n -R6, or -(CH2) n -OR6; R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R6 is selected from phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl, wherein the phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl is optionally substituted with one or more (e.g., 1, 2, 3) R7; R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy, oxo, -NH(C=O)-N(CH3)2; n is selected from 1, 2, 3, 4, 5, or 6; or (3) R1 is selected from H R1 is selected from H, F, Cl, Br, I, methoxy, or ethoxy; R2 is selected from H, F, Cl, Br, I, or OR 2a ; R 2a is selected from H, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R3 is selected from R 3b , or OR 3b ; R 3b Selected from R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6; R4 is selected from H, F, Cl, Br, or I; R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R6 is selected from phenyl, which is optionally substituted with one or more R7; R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy; n is selected from 1, 2, 3, 4, 5, or 6.

3. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, which is a compound represented by formula (II), its pharmaceutically acceptable salt or stereoisomer, in, R1 is selected from H, or halogen; X1 and X2 are each independently selected from CH or N; R 4d Selected from -(CH2) n -R6, or -(CH2) n -OR6; R6 is selected from phenyl, C 5-6 Cycloalkyl, 5-10 membered heterocyclic group, or 5-10 membered heteroaryl, the phenyl, C 5-6 Cycloalkyl, 5-10 membered heterocyclyl, 5-10 membered heteroaryl are optionally substituted with one or more R7; R7 is selected from C 1-5 Alkoxy, oxo, -NH(C=O)-N(CH3)2; n is selected from 1, 2, 3, 4, 5, or 6.

4. The compound according to claim 3, its pharmaceutically acceptable salt or stereoisomer, wherein: R1 is selected from H, F, Cl, Br, or I; X1 and X2 are each independently selected from CH or N; R 4d Selected from -(CH2) n -R6, or -(CH2) n -OR6; R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R6 is selected from phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl, wherein the phenyl, cyclopentyl, cyclohexyl, 2,3-dihydrobenzofuranyl, benzofuranyl, 1,2,3,4-tetrahydroquinolyl, or 1,2-dihydroquinolyl is optionally substituted with one or more R7; R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy, oxo, or -NH(C=O)-N(CH3)2; n is selected from 1, 2, 3, 4, 5, or 6.

5. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, which is a compound represented by formula (III), its pharmaceutically acceptable salt or stereoisomer, in, R2 is selected from H, halogen, or OR 2a ; R 2a Selected from H, C 1-5 Haloalkyl, or C 3-6 Cycloalkyl; R3 is selected from R 3b , or OR 3b ; R 3b is selected from a 5-6 membered heterocyclic group, wherein the 5-6 membered heterocyclic group is optionally substituted by R 3c replace; R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6; R4 is selected from H, or halogen; R5 is selected from H, halogen, or C 1-6 alkyl; R6 is selected from phenyl, which is optionally substituted with one or more R7; R7 is selected from C 1-3 Alkoxy; n is selected from 1, 2, 3, 4, 5, or 6.

6. The compound according to claim 5, its pharmaceutically acceptable salt or stereoisomer, wherein: R2 is selected from H, F, Cl, Br, I, or OR 2a ; R 2a is selected from H, fluoromethoxy, chloromethoxy, difluoromethoxy, dichloromethoxy, trifluoromethoxy, trichloromethoxy, 2,2-difluoroethoxy, 2,2-dichloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; R3 is selected from R 3b , or OR 3b ; R 3b Selected from R 3c Selected from -(CH2) n -R6, or -(CH2) n -OR6; R4 is selected from H, F, Cl, Br, or I; R5 is selected from H, F, Cl, Br, I, methyl, ethyl, n-propyl, or isopropyl; R6 is selected from phenyl, which is optionally substituted with one or more R7; R7 is selected from methoxy, ethoxy, n-oxypropyl, isopropoxy; n is selected from 1, 2, 3, 4, 5, or 6.

7. The compound according to claim 1, its pharmaceutically acceptable salt or stereoisomer, which is selected from the following compounds, their pharmaceutically acceptable salts or stereoisomers:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt or stereoisomer thereof and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7, its pharmaceutically acceptable salt or stereoisomer, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing a disease associated with the activity or expression of a 5-HT receptor.

10. Use of the compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 8 in the preparation of a medicament for treating and / or preventing CNS-related diseases.

Images