Nitrogen-containing spirocyclic compound, preparation method therefor and use thereof

Abstract

Disclosed are an orexin receptor antagonist and the use thereof. Specifically disclosed are a compound represented by formula (I), and a stereoisomer, tautomer, crystal form, pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof. The compound is an orexin receptor antagonist, and can be used for preparing a drug for treating and / or preventing orexin-related diseases.

Description

Nitrogen-containing spiro compounds, preparation method and application thereof TECHNICAL FIELD

[0001] The present application relates to the field of medicine, in particular to a class of nitrogen-containing spiro compounds, preparation method and application thereof. BACKGROUND

[0002] Orexin is a neuropeptide discovered in 1998, which is synthesized and secreted by the lateral hypothalamic orexin neurons. There are two types of orexin A and orexin B, wherein orexin A contains 33 amino acids and orexin B contains 28 amino acids, which act on orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R) receptor subtypes coupled with G protein.

[0003] OX1R and OX2R are widely expressed in the central nervous system, and there is a complex relationship between them and other neuropeptides that affect eating. The wakefulness time of rodents injected with orexin in the peritoneal cavity is prolonged (Piper et al. J. Neurosci. 2000 12.726-730), and damage or mutation of OX2R leads to long-term sleep in dogs (Lin et al. Cell 1999, 365-376), and insufficient orexin signaling in cerebrospinal fluid will lead to long-term sleepiness in humans. All of these indicate that the wakefulness and sleep can be regulated by adjusting the two receptors. OX1R and OX2R play different roles in controlling non-rapid eye movement sleep (NREM, deep sleep) and rapid eye movement sleep (REM, brain activity is the same as when awake). OX2R is a key receptor for regulating wakefulness and NREM sleep, while REM sleep is controlled by both receptor subtypes. OX2R plays a dominant role in regulating sleep, while OX1R alone has little contribution to sleep induction, but works synergistically with OX2R to regulate REM sleep.

[0004] Orexin receptor antagonists are divided into selective OX1R antagonists, selective OX2R antagonists and dual OX1 / 2R antagonists according to their binding affinities. Several companies have dual OX1 / 2R antagonists on the market, Merck & Co's Suvorexant, Eisai's Lemborexant, and Johnson & Johnson's daridorexant. Acting on OX1R will change the normal physiological structure of REM and NREM, i.e. sacrificing NREM time, prolonging REM time, and thus increasing the risk of sleepiness.

[0005] Selective antagonists currently only have Johnson's Seltorexant in the third phase of clinical trials, which is indicated for severe depression, insomnia, etc., and its efficacy has been preliminarily verified.

[0006] However, the selectivity of the existing antagonists is still weak, and therefore, there is an urgent need in the art for an OX2R antagonist with high selectivity and high safety. SUMMARY

[0007] To solve the above problems, the present application provides an OX2R antagonist with high selectivity, high efficacy and high safety.

[0008] In a first aspect of the present application, a compound as shown in formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof is provided,

[0009] wherein,

[0010] n is 0, 1, 2 or 3;

[0011] a, b, a', b', d, e, d' and e' are each independently 0, 1, 2 or 3; and a+b is not 0; and d+e is not 0 (i.e., the N atom is not located at the ortho position of the spiro carbon atom); and a, b, d and e are not simultaneously 0; and a', b', d' and e' are not simultaneously 0;

[0012] R1is a substituent on the nitrogen-containing spiro ring, each R1is independently selected from the group consisting of none, H, hydroxyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, -C(O)-C 1-4 haloalkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, or two R1on the same carbon together form =O;

[0013] L1is selected from the group consisting of C(O), S(O)2, S(O);

[0014] Ar1is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl, and the aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3 or 4 R a ;

[0015] R a is selected from the group consisting of H, D, nitro, C 1-4 alkyl, C 1-4 alkoxy, halogen, cyano, -S(O)2(C 1-4 alkyl), C 1-4 haloalkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, 5-7 membered heteroaryl;

[0016] Ar2is selected from the group consisting of 5-6 membered heteroaryl, 9-10 membered heteroaryl, and said 5-6 membered heteroaryl and 9-10 membered heteroaryl are optionally substituted with 1, 2, or 3 R b substituted;

[0017] R b selected from the group consisting of H, D, halogen, hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, 3-7 membered cycloalkyl.

[0018] In another preferred embodiment, said heteroaryl is an aromatic cyclic group having 1, 2, 3, or 4 heteroatoms selected from N, O, or S in the ring backbone.

[0019] In another preferred embodiment, said heteroaryl is a monocyclic or fused ring.

[0020] In another preferred embodiment, said a, d, a', and d' are each independently 1, 2, or 3.

[0021] In another preferred embodiment, said a is 1, 2, or 3.

[0022] In another preferred embodiment, said b is 1, 2, or 3.

[0023] In another preferred embodiment, said d is 1, 2, or 3.

[0024] In another preferred embodiment, said e is 1, 2, or 3.

[0025] In another preferred embodiment, said a' is 1, 2, or 3.

[0026] In another preferred embodiment, said b' is 1, 2, or 3.

[0027] In another preferred embodiment, said d' is 1, 2, or 3.

[0028] In another preferred embodiment, said e' is 1, 2, or 3.

[0029] In another preferred embodiment, said a and b, a' and b', d and e, d' and e' are each independently not both 0.

[0030] In another preferred embodiment, 1≤a+b≤3.

[0031] In another preferred embodiment, 1≤d+e≤3.

[0032] In another preferred embodiment, 1≤a’+b’≤3.

[0033] In another preferred embodiment, 1≤d’+e’≤3.

[0034] In a preferred embodiment, each R1is independently selected from the group consisting of H, hydroxyl, methyl, hydroxymethyl, -C(O)CF3, -N(CH3)2, or two R1on the same carbon together form =O.

[0035] In a preferred embodiment, Ar1is substituted or unsubstituted selected from the group consisting of phenyl, naphthyl, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine.

[0036] In a preferred embodiment, R a is selected from the group consisting of H, D, C 1-4 1-6 alkyl, C 1-3 1-6 alkoxy, halogen, cyano, -S(O)2(C 1-3 1-6 alkyl), C 1-3 fluoroalkyl, -NH(C 1-3 1-6 alkyl), -N(C 1-3 1-6 alkyl)2, 5-6 membered heteroaryl;

[0037] In a preferred embodiment, R a is selected from the group consisting of H, D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, F, Cl, Br, cyano, -S(O)2-CH3, CF3, -N(CH3)2, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine.

[0038] In a preferred embodiment, Ar2is substituted or unsubstituted selected from the group consisting of 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl;

[0039] In a preferred embodiment, Ar2is substituted or unsubstituted selected from the group consisting of furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzoimidazole, benzopyridine, benzopyrimidine, benzopyrazine.

[0040] In a preferred embodiment, R b is selected from the group consisting of H, D, halogen, hydroxyl, cyano, nitro, C 1-3 1-6 alkyl, C 1-3 1-6 alkoxy, C 1-3 fluoroalkyl, 3-5 membered cycloalkyl;

[0041] In a preferred embodiment, R b is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, F, Cl, Br, I, hydroxyl, cyano, nitro, -CF3, cyclopropyl, cyclobutyl, cyclopentyl.

[0042] In another preferred embodiment, Ar2is substituted with 2 or 3 R b substituted, and one R b is substituted at the para position of Ar2, R b is F, Cl or Br.

[0043] In one preferred embodiment, the compound has the structure of Formula (II):

[0044] wherein n, d, e, d', e', R1, L1, Ar1and Ar2are as defined above.

[0045] In another preferred embodiment, the compound has the structure of Formula (III):

[0046] wherein m is 0, 1, 2, 3 or 4;

[0047] n, d, e, d', e', L1, R1, R a , and Ar2are as defined above.

[0048] In another preferred embodiment, the compound has the structure of Formula (IV):

[0049] wherein Ar3is a 5-6 membered nitrogen-containing heteroaryl; and said 5-6 membered nitrogen-containing heteroaryl is optionally substituted with 1, 2 or 3 R b ;

[0050] n, m, d, e, d', e', L1, R1, R a , and R b are as defined above.

[0051] In another preferred embodiment, the compound has the structure of Formula (V):

[0052] wherein n, m, d, e, d', e', L1, R1, R a , and R b are as defined above.

[0053] In another preferred embodiment, the compound has the structure of Formula (VI):

[0054] wherein n, d, e, d', e', L1, R1, R b are as defined above.

[0055] In another preferred embodiment, the compound has the structure of Formula (VII):

[0056] wherein n, d, e, d', e', R1, R b are as defined above.

[0057] In another preferred embodiment, the compound is selected from the group consisting of: is selected from the group consisting of:

[0058] wherein, is the point of attachment to Ar2or L1.

[0059] In another preferred embodiment, the N atom attached to Ar2is not located at the ortho position of the spiro carbon atom.

[0060] In another preferred embodiment, the compound is selected from the group consisting of: is selected from the group consisting of:

[0061] wherein, is the point of attachment to Ar2or L1.

[0062] In a preferred embodiment, the compound is selected from the group consisting of:

[0063] In a second aspect of the present application, there is provided a pharmaceutical composition comprising:

[0064] (i) a compound according to the first aspect of the present application, a stereoisomer, a tautomer, a salt, a hydrate, a solvate or a prodrug thereof; and

[0065] (ii) a pharmaceutically acceptable carrier, adjuvant or excipient.

[0066] In a third aspect of the present application, there is provided the use of a compound according to the first aspect of the present application, a stereoisomer, a tautomer, a salt, a hydrate, a solvate or a prodrug thereof, or a pharmaceutical composition according to the second aspect of the present application, for the manufacture of a medicament for the treatment and / or prevention of a disease associated with orexins.

[0067] Preferably, the orexin-related disorder is selected from the group consisting of sleep-wake cycle disorders, insomnia, restless leg syndrome, jet-lag syndrome, sleep disturbances, depression, Alzheimer's disease, sleep disorders secondary to neurological disorders, mania, depression, bipolar disorder, schizophrenia, pain syndromes, fibromyalgia, neuropathic pain, stress, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight or obesity, and conditions associated with overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, dyspnea, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, hypertension, tachycardia, arrhythmia, angina, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux.

[0068] It should be understood that, within the scope of the present application, the above-mentioned technical features of the present application and the technical features specifically described hereinafter (e.g. in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0069] After long-term and in-depth research, through a large number of screening, the inventors first developed an OX2R antagonist with high selectivity, high efficacy and high safety. Based on this, the inventors completed the present application.

[0070] Terminology

[0071] As used herein, the term "containing" or "including" can be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0072] As used herein, the term "alkyl" refers to a monovalent straight-chain or branched saturated hydrocarbon group consisting of carbon and hydrogen atoms, for example, "C 1-6 "Alkyl" means an alkyl group having 1-6 (e.g. 1, 2, 3, 4, 5 or 6) carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert-butyl, and the like. In the present application, alkyl is also intended to include deuterated alkyl groups, examples of deuterated alkyl groups include, but are not limited to, CD3, CD2CD3, CD2CD2CD3.

[0073] As used herein, the term "cycloalkyl" refers to a monovalent saturated carbocyclic group consisting of carbon and hydrogen atoms, for example, "C 3-8 "Cycloalkyl" means a cycloalkyl group containing 3-8 (e.g. 3, 4, 5, 6, 7 or 8) carbon atoms, preferably C 3-6Cycloalkyl. Cycloalkyl can be monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or the like, or bicyclic, such as a fused, bridged, or spirocyclic form.

[0074] As used herein, the term "alkoxy" refers to -O-alkyl, where examples of alkoxy groups include, but are not limited to: methoxy, ethoxy, isopropoxy, tert-butoxy, and the like.

[0075] As used herein, the term "hydroxyalkyl" refers to an alkyl group containing one or more hydroxyl groups, and alkyl is as defined above. Examples of hydroxyalkyl groups include, but are not limited to: -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, and the like.

[0076] As used herein, "halogen" refers to F, Cl, Br, I, and isotopes thereof, including but not limited to F, 18 F, Cl, 32 Cl, Br, I.

[0077] As used herein, the term "nitro" refers to -NO2.

[0078] As used herein, the term "cyano" refers to -CN.

[0079] As used herein, the term "haloalkyl" refers to a group resulting from the replacement of one or more hydrogens on an alkyl group as described above with the same or different halogen. Where "haloC 1-6 alkyl" is preferred. Examples of haloalkyl groups include, but are not limited to: -CH2Cl, -CH2CF3, -CH2CCl3, perfluoroalkyl (e.g., -CF3-, -CF2CF3), and the like. 1-4

[0080] As used herein, the term "aryl" refers to an aromatic cyclic hydrocarbon group (including monocyclic, bicyclic, or polycyclic groups), such as "C 6-12 aryl" refers to an aromatic cyclic hydrocarbon group having 6-12 (6, 7, 8, 9, 10, 11, or 12) ring carbon atoms. Where there are two or more aromatic rings (e.g., bicyclic or the like), the aromatic rings of the aryl group can be connected by a single bond (e.g., biphenyl) or fused (e.g., naphthyl, anthracenyl, or the like). Examples of aryl groups (especially monocyclic and bicyclic groups) include, but are not limited to: phenyl, biphenyl, or naphthyl. An aryl group can be fused to a heterocyclyl group through a single bond or any two adjacent ring carbon atoms, such as: benzotetrahydrofuranyl, benzotetrahydropyranyl, benzodioxanyl, and the like.

[0081] ​As used herein, the term "heteroaryl" refers to an aromatic cyclic group (including monocyclic, bicyclic, or polycyclic groups) whose cyclic skeleton contains 1, 2, 3, or 4 heteroatoms selected from N, S, or O. For example, "5-12-membered heteroaryl" refers to a monocyclic, bicyclic, or tricyclic group having 5 to 12 (5, 6, 7, 8, 9, 10, 11, or 12) ring atoms. Examples of heteroaryl groups include, but are not limited to: imidazole, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thiophene, furanyl, pyranyl, pyridinyl, pyrroleyl, pyrazolyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothiophene, benzothiaranyl, benzoimidazolyl, benzooxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiazolyl, benzopyranyl, indoleyl, isoindoleyl, triazolyl, triazinyl, quinoxolinyl, purine, quinazolinyl, quinazinyl, naphthidyl, pteridinyl, carbazoleyl, and azazolyl. basalt, diazoxide acridine group, etc.

[0082] In this invention, the alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups, unless otherwise specified, include substituted alkyl, cycloalkyl, heterocyclic, aryl, and heteroaryl groups. The substituents include, but are not limited to, halogen, hydroxyl, cyano, acyl, sulfonyl, ester, sulfinyl, alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, acyl, and ester groups.

[0083] As used herein, the term "substitution" refers to the replacement of one or more hydrogen atoms on a particular group by a particular substituent. The particular substituent is either the substituent described accordingly above or the substituent appearing in the various embodiments. Unless otherwise specified, a substituted group may have a substituent selected from a particular group at any substituted site of that group, and the substituents may be the same or different at each position. Those skilled in the art will understand that the combinations of substituents contemplated in this invention are those that are stable or chemically feasible.

[0084] Unless otherwise specified, the groups described in this invention may be substituted with substituents selected from the group consisting of: D, halogen, cyano, nitro, hydroxyl, amino, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, 3-12 membered heterocyclic groups, C3-C6 alkyl, ... 12 cycloalkyl, 5-10 heteroaryl and C6-C 10 Aryl.

[0085] In this document, “optionally” means that the event or condition described below may, but is not required to, occur, and the description includes both the possibility that the event or condition occurs and the possibility that the event or condition does not occur.

[0086] Abbreviations

[0087] Active ingredient

[0088] As used herein, "the compound of the present invention" refers to the compound shown in Formula (I), and also includes its stereoisomers, its optical isomers, its pharmaceutically acceptable salts, its crystal forms, its isotopic derivatives, its prodrugs, its metabolites, its solvates, or its hydrates.

[0089] Unless specifically noted, the structural formulas described herein are intended to include all stereoisomers (e.g., cis-trans isomers, enantiomeric, diastereomeric, and conformational isomers): the R, S configuration of asymmetric centers, the (Z), (E) isomers of double bonds, the syn, anti isomers of cycloalkanes, and the like. Thus, individual stereochemical isomers or mixtures of its enantiomers, diastereomers or conformational isomers, of the compounds of the present invention are within the scope of the present invention.

[0090] The compounds of the present invention can contain cis-trans isomers, one or more chiral carbon atoms, and thus can produce stereoisomeric forms such as cis-trans isomers, chiral isomers, enantiomeric, diastereomeric, and other combinations. Cis-trans isomerism refers to the phenomenon of diastereoisomerism in which the spatial arrangement of individual groups in a molecule of a compound is different due to the presence of a restriction factor for free rotation. This restriction factor is generally caused by the presence of a functional group in the structure of the organic compound such as C=C double bond, C=N double bond, C=S double bond, N=N double bond, heterocycle, or cycloalkane, etc. that cannot rotate freely. Organic molecules containing such isomers such as alkenes, azo compounds, cycloalkanes, etc. are considered cis-trans isomers, with cis referring to the same ligand being in an adjacent position, generally indicated by "cis" or "cis-"; trans refers to the same ligand being in a diagonal position, generally indicated by "trans" or "trans-". Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as racemates and optically pure forms. The preparation of the compounds of the present invention can select racemates, cis-trans isomers, chiral isomers, diastereomers, or enantiomers as starting materials or intermediates. The optically active isomers can be prepared using chiral synthons or chiral reagents, or by resolution using conventional techniques, such as crystallization and chiral chromatography, etc.

[0091] Conventional techniques for preparing / isolating individual optical isomers (i.e., cis-trans isomers and chiral isomers) include chiral synthesis from appropriate cis-trans precursors or optically pure precursors, or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography.

[0092] To design the synthesis of a specific stereoisomer of the compound of this invention, it can be prepared asymmetrically or derivatized with a chiral auxiliaries. The resulting stereo mixture is then separated, and the chiral auxiliaries are removed to obtain pure cis-trans monomers, chiral monomers, or mixed stereoisomers. If the molecule contains a cis-trans isomer center, it can be purified by column chromatography (normal-phase silica gel column or reverse-phase high-performance liquid chromatography) to obtain pure cis or trans products. Alternatively, if the molecule contains a basic functional group, such as an amino acid, or an acidic functional group, such as a carboxyl group, it can be formed with a suitable optically active acid or base to form a diastereomeric salt, which is then separated by conventional methods such as separation crystallization or chromatography to obtain pure enantiomers.

[0093] This invention also includes isotopically labeled compounds (i.e., isotopic derivatives), equivalent to the original compounds disclosed herein. However, it is common practice to see one or more atoms replaced by atoms with different atomic weights or mass numbers. Examples of isotopes in the isotopic derivatives of this invention include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine isotopes, respectively as follows: 2 H, 3 H, 13 C 11 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F and 36 Cl. Isotope derivatives of the compounds of this invention are all within the scope of protection of this invention. In this document, 3 H-labeled compounds and 14 C-labeled compounds are useful in tissue distribution experiments of drugs and substrates. Tritium (i.e., 3 H) and carbon-14 (i.e. 14 C) Labeled compounds are relatively easy to prepare and detect, making them the preferred choice among isotopes. Furthermore, heavier isotope substitutions, such as deuterium, are also possible. 2 H, due to its excellent metabolic stability, offers advantages in certain therapies, such as increasing half-life or reducing dosage in vivo, and therefore may be preferred in some cases. Isotopically labeled compounds can be prepared using general methods, by replacing the non-isotopic reagent with an readily available isotopically labeled reagent, according to the scheme disclosed in the examples.

[0094] As used herein, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0095] "Pharmaceutically acceptable acid addition salt" refers to salts of the free base which retain the biological effectiveness and non-toxicity of the free amine and which are, for example, not biologically or otherwise undesirable. Inorganic acids include but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Organic acids include but are not limited to carbonic acid, acetic acid, 2,2-dichloroacetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, octanoic acid, decanoic acid, undecylenic acid, glycolic acid, gluconic acid, lactic acid, sebacic acid, adipic acid, glutaric acid, malonic acid, oxalic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, stearic acid, oleic acid, cinnamic acid, lauric acid, malic acid, glutamic acid, pyroglutamic acid, aspartic acid, benzoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, alginic acid, ascorbic acid, salicylic acid, 4-aminosalicylic acid, naphthalene-2-sulfonic acid and the like. These may be prepared by methods known in the art.

[0096] "Pharmaceutically acceptable base addition salt" refers to salts of the free acid which retains the biological effectiveness and non-toxicity of the free acid and which are, for example, not biologically or otherwise undesirable. Salts derived from inorganic bases include but are not limited to sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include but are not limited to salts of primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethyl ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These may be prepared by methods known in the art.

[0097] Metabolites of the compounds of formula (I) and pharmaceutically acceptable salts thereof, and those compounds which exist in un-ionized (neutral) or ionized (charged) forms, are within the scope of the present application. Prodrugs of the compounds of formula (I) and pharmaceutically acceptable salts thereof can also be within the scope of the present application. Prodrugs are drugs prepared and administered in an inactive form that is converted to an active form (i.e., the drug) in vivo. For example, a prodrug can be a compound that is inactive when administered alone but becomes active when it is converted into the active drug inside the body. Prodrugs can be converted into the active drug by various processes, including enzymatic processes and / or metabolic processes. Prodrugs can be used to improve the delivery of a drug to a target site in the body, to improve the bioavailability of a drug, to improve the stability of a drug, and / or to reduce the side effects of a drug. Prodrugs can be prepared and administered in an inactive form that is converted to the active form (i.e., the drug) in vivo. For example, a prodrug can be a compound that is inactive when administered alone but becomes active when it is converted into the active drug inside the body. Prodrugs can be converted into the active drug by various processes, including enzymatic processes and / or metabolic processes. Prodrugs can be used to improve the delivery of a drug to a target site in the body, to improve the bioavailability of a drug, to improve the stability of a drug, and / or to reduce the side effects of a drug.

[0098] As used herein, the term "solvate" means a complex of a compound of formula (I) with solvent molecules in specific ratios.

[0099] As used herein, the term "hydrate" means a complex of a compound of formula (I) with water molecules in specific ratios.

[0100] As described herein, the compounds of the present application can be substituted with any number of substituents or functional groups to expand the scope of the application. In general, the term "substituted" means that a specified structure is replaced with a specified substituent group. When multiple positions in a structure are substituted with multiple specified substituents, the substituents can be the same or different at each position. The term "substituted" as used herein includes all permissible organic group substitutions. In the broadest sense, permissible substituents include non-cyclic, and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic organic radicals. As used herein, a heteroatom such as nitrogen can have hydrogen substituents or any permissible organic radical described hereinabove to complete its valence. Furthermore, the present application is not intended to be limited in any way by the permissible substituents listed herein. The present application contemplates combinations of substituents and variables in a stable compound, in disease treatmentally useful amounts. The term "stable" as used herein, means compounds that are sufficiently robust to survive isolation from a reaction mixture, and formulation into an efficacious therapeutic agent. As used herein, this term is intended to encompass compounds that are sufficiently robust to survive isolation from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0101] Pharmaceutical compositions and methods of administration

[0102] Since the compounds of the present application are capable of selectively inhibiting orexin receptor 2 (OX2R), and are useful in the treatment of diseases such as sleep-wake cycle disorder, insomnia, restless leg syndrome, jet lag, depression, Alzheimer's disease, etc. Therefore, the compounds of the present application and stereoisomers thereof, optical isomers thereof, pharmaceutically acceptable salts thereof, crystal forms thereof, isotopic derivatives thereof, prodrugs thereof, metabolites thereof, solvates thereof or hydrates thereof, and pharmaceutical compositions containing the compounds of the present application as the main active ingredient can be used for the prevention and / or treatment (stabilization, alleviation or cure) of diseases related to orexin (sleep-wake cycle disorder, insomnia, restless leg syndrome, jet lag, depression, Alzheimer's disease, etc.).

[0103] The pharmaceutical composition of the present application comprises a safe and effective amount of the compound of the present application and a pharmaceutically acceptable excipient or carrier. The "safe and effective amount" means the amount of the compound sufficient to significantly improve the condition without causing serious side effects. Generally, the pharmaceutical composition contains 1-2000 mg of the compound of the present application per dose, more preferably, 10-200 mg of the compound of the present application per dose. Preferably, the "one dose" is one capsule or tablet.

[0104] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid filler substances or gel materials, which are suitable for human use and which are of sufficient purity and sufficiently low toxicity. By "compatible" it is meant that the components of the composition are capable of being commingled with the compounds of the application, and with each other, in the dosage form with no interaction that significantly affects the efficacy of the compounds. Examples of suitable pharmaceutically acceptable carriers are celluloses and their derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose sodium, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyhydric alcohols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween 80®, Span 80®, lecithin, etc.), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like. ) emulsifiers (e.g., Tween 80®, Span 80®, lecithin, etc.), wetting agents (e.g., sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.

[0105] The mode of administration of the compounds or pharmaceutical compositions of the present application is not narrowly critical and representative modes of administration include, but are not limited to, oral, parenteral (intravenous, intramuscular or subcutaneous).

[0106] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert excipient (or carrier) such as sodium citrate or dicalcium phosphate, or with such other ingredients as are known in the art of preparing such dosage forms, e.g., binders, (a) fillers or extenders, e.g., starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) humectants, e.g., hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; (c) moistening agents, e.g., glycerol; (d) disintegrating agents, e.g., agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retarders, e.g., paraffin; (f) absoφtion accelerators, e.g., quaternary ammonium compounds; (g) wetting agents, e.g., cetyl alcohol and glycerol monostearate; (h) adsorbents, e.g., kaolin and bentonite; and (i) lubricants, e.g., talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets, and pills, the dosage form can also comprise buffering agents.

[0107] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings and shells known in the art. They can contain opacifying agents, and can also be of such composition that they release the active compound or compounds in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used are polymeric substances and waxes. The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

[0108] Liquid dosage forms for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups, or elixirs. In addition to the active compounds, the liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, and the like, or mixtures thereof.

[0109] Besides such inert diluents, the composition can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0110] Suspensions, in addition to the active ingredient, can contain suspending agents as for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, agar-agar, or mixtures thereof, and the like.

[0111] The compositions for parenteral injection comprise physiologically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols and the like, and suitable mixtures thereof.

[0112] Dosage forms of the compounds of the present application for topical administration include ointments, powders, sprays, and inhalers. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants as can be required.

[0113] The compounds of the present application can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0114] In combination therapy, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds. One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compounds can be used simultaneously, separately or sequentially with the compounds of the present application to prevent and / or treat orexin-related disorders.

[0115] The pharmaceutical composition is used in a safe and effective amount of the compounds of the present application to a mammal (e.g., human) in need of treatment, wherein the amount is administered in a pharmaceutically effective amount, and the amount is usually 1-2000 mg, preferably 20-500 mg, per day for a 60 kg body weight human. Of course, the specific dose will also be determined by the route of administration, the health condition of the patient, etc., which are within the skill of the skilled practitioner.

[0116] Methods of preparation

[0117] 1. When L1 is C(O), the general preparation method is as follows

[0118] 1.1 Preparation method 1

[0119] Step 1:

[0120] In DMF, aromatic carboxylic acid (Ar1-L1-OH) is reacted with oxalyl chloride to obtain the corresponding acyl chloride (Ar1-L1-Cl) with dichloromethane as the solvent;

[0121] In dichloromethane, the above acyl chloride is reacted with a single Boc-protected spiro-biamine compound A with N-N-diisopropyl ethylamine (DIEA) as the base to obtain the corresponding amide compound B.

[0122] Alternatively

[0123] In dichloromethane, the above acyl chloride is reacted with a single Boc-protected spiro-biamine compound A with N-N-diisopropyl ethylamine (DIEA) as the base to obtain the corresponding amide compound B.

[0124] Step 2:

[0125] In a trifluoroacetic acid and dichloromethane system, compound B obtained in step 1 is deprotected to obtain compound C, which is directly used in the next reaction.

[0126] Step 3:

[0127] In DMF, compound C obtained in step 2 and Ar2 halide (Ar2-X, wherein X is halogen) are directly subjected to SNAr reaction at high temperature 120°C with cesium carbonate as the base to obtain compound I for biological testing after purification.

[0128] 1.2. Preparation method 2

[0129] Step 1':

[0130] In DMF, compound A' and Ar2 halide (Ar2-X, wherein X is halogen) are directly subjected to SNAr reaction at high temperature 120°C with cesium carbonate as the base to obtain compound B' after purification.

[0131] Step 2':

[0132] In a trifluoroacetic acid and dichloromethane system, compound B obtained in step 1' is deprotected to obtain compound C, which is directly used in the next reaction.

[0133] Step 3':

[0134] The aromatic carboxylic acid (Ar1-L1-OH) is reacted with oxalyl chloride in DMF to give the corresponding acyl chloride (Ar1-L1-Cl) using dichloromethane as solvent;

[0135] The acyl chloride (Ar1-L1-Cl) is reacted with compound C' in dichloromethane using N-N-diisopropylethylamine (DIEA) as base to give the candidate molecule I, which is directly used for biological test.

[0136] Alternatively

[0137] The aromatic carboxylic acid (Ar1-COOH) is directly condensed with compound C' using HATU as condensing agent, DMF as solvent and N-N-diisopropylethylamine (DIEA) as base to give the candidate molecule I, which is directly used for biological test.

[0138] 2. When L1 is S(O)2, the general preparation method is as follows:

[0139] Step 1':

[0140] The single Boc-protected spiro-biamine compound A' and Ar2 halide (Ar2-X, wherein X is halogen) are directly subjected to SNAr reaction using cesium carbonate as base and DMF as solvent at high temperature of 120℃, and purification to give compound B'.

[0141] Step 2':

[0142] The compound B' obtained in step 1' is subjected to deprotection reaction in a system of trifluoroacetic acid and dichloromethane to give compound C', which is directly used for the next reaction.

[0143] Step 3":

[0144] The compound C' is reacted with sulfonyl chloride (Ar1-L1-Cl) using tetrahydrofuran as solvent to give the candidate molecule I, which is directly used for biological test.

[0145] The main advantages of the present application are:

[0146] 1. The OX2R antagonists of the present application have high selectivity for OX2R.

[0147] 2. Compared with the positive control by oral administration, SD rats administered with the OX2R antagonists of the present application show higher blood drug concentration, higher exposure and higher bioavailability.

[0148] 3. Compared with the positive control by oral administration, SD rats administered with the OX2R antagonists of the present application show higher drug concentration in brain and higher brain-blood ratio.

[0149] The application will be further described in conjunction with specific examples. It should be understood that these examples are only used to illustrate the application and not used to limit the scope of the application. The experimental methods in the following examples, if not otherwise specified, are usually carried out according to the conventional conditions or according to the conditions suggested by the manufacturers. Unless otherwise specified, the percentages and parts are weight percentages and weight parts.

[0150] Example 001

[0151] Preparation of compound 001 : (2-(4,6-dimethylpyrimidin-2-yl)-2,6-diazaspiro[3.4]octan-6-yl)(2-fluoro-6-2H-1,2,3-triazol-2-)phenylmethanone

[0152] First step

[0153] Dissolve 1 (250 mg, 1.21 mmol, 1 eq) and DMF (8.82 mg, 0.12 mmol, 0.1 eq) in DCM (5 mL), add oxalyl chloride ((COCl)2, 229.75 mg, 1.81 mmol, 1.5 eq) at room temperature. Stir the reaction mixture at room temperature for 1 h. TLC (PE / EtOAc = 0 / 1, take a small amount of methanol to quench) shows the reaction is complete. Prepare a 0.24 mol / L solution of 004-01 in DCM (5 mL), which is used directly in the next step.

[0154] Second step

[0155] Stir 001-02 (94.10 mg, 443.25 μmol, 1 eq) and N-N-diisopropylethylamine (DIEA) (114.58 mg, 886.50 μmol, 2 eq) in DCM (5 mL) for 5 min, then add 001-01 (100 mg, 443.25 μmol, 0.24 mol / L, 1 eq). Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture directly and purify by column. Purify the crude product by medium pressure liquid chromatography (MPLC, PE / EtOAc = 0-50%) to obtain 001-03 (90 mg, yield 51%) as a colorless oil.

[0156] Second step

[0157] Dissolve 001-03 (90 mg, 2224.19 μmol) in DCM (5 mL), add trifluoroacetic acid (TFA, 11 mL) and stir the reaction mixture at room temperature for 2 h. TLC shows the reaction is complete. Concentrate the reaction mixture directly to obtain 001-04 (256 mg, TFA salt) as a light yellow oil. The product is used directly in the next step.

[0158] Third step

[0159] To a solution of 001-04 (68 mg, 163.72 μmol, 1 eq), 2 (32.32 mg, 163.72 μmol, 1 eq) and Cs2C03(221.59 mg, 4491.15 μmol, 3 eq) in DMF (3 mL) was heated at 120 °C for 1.5 h under argon. TLC showed the reaction was completed. The reaction was diluted with water (15 mL) and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (50 mL), dried and concentrated to give the crude product. The crude product was purified by pre-HPLC (acetonitrile-water system) to give the product 001 (18.4 mg, 27.6% yield for 2 steps) as a white solid.

[0160] MS (ESI, m / z): 408.3 [M+H] + .

[0161] 1 H NMR (300 MHz, DMSO) δ 8.15-8.14 (m, 2H), 7.84-7.81 (m, 1H), 7.71-7.63 (m, 1H), 7.48-7.42 (m, 1H), 6.47-6.42 (m, 1H), 3.38-4.04 (m, 8H), 2.23-2.06 (m, 8H)

[0162] Example 002

[0163] Preparation of compound 002: (6-(4,6-dimethylpyrimidin-2-yl)-2,6-diazaspiro[3.4]-6- octane (2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methyl ketone

[0164] First step

[0165] To a solution of 002-01 (148.89 mg, 701.34 μmol, 1 eq), 2 (100 mg, 701.34 μmol, 1 eq) and Cs2C03(685.52 mg, 2.1 mmol, 3 eq) in DMF (3 mL) was heated at 120 °C for 2 h. TLC showed the reaction was completed. The reaction was diluted with water (15 mL) and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to give the crude product. The crude product was purified by MPLC (PE / EtOAc = 0-20%) to give the product 002-02 (161 mg, 72.2% yield) as a white solid.

[0166] MS (ESI, m / z): 319.22 [M+H] + .

[0167] Second Step

[0168] 002-02 (161 mg, 505.62 μmol, 1 eq) was dissolved in DCM (5 mL), TFA (1 mL) was added and the reaction was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction was directly concentrated to give 002-03 (176 mg, TFA salt) as a light yellow oil. The product was used directly in the next step.

[0169] Third Step

[0170] 002-03 (105 mg, 506.84 μmol, 1 eq), 1 (175.55 mg, 506.84 μmol, 1 eq), HATU (231.26 mg, 608.21 μmol, 1 eq) and DIEA (231.26 mg, 2.53 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 12 h. LC-MS showed the reaction was complete. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to give the crude product. The crude product was purified by prep-HPLC (acetonitrile-water) to give the product 002 (108.5 mg, 49.9% yield for 2 steps) as a white solid.

[0171] MS (ESI, m / z): 408.2 [M+H] + .

[0172] 1 H NMR (300 MHz, DMSO) δ 8.22 (s, 2H), 7.83 - 7.11 (m, 1H), 7.64 - 7.71 (m, 1H), 7.43 (t, J = 9 Hz, 1H), 7.47 (s, 1H), 4.01 - 4.06 (m, 2H), 3.71 - 3.98 (m, 3H), 3.41 - 3.65 (m, 3H), 2.11 - 2.26 (m, 8H)

[0173] Example 003

[0174] Preparation of Compound 003: 8-(4,6-dimethylpyrimidin-2-yl)-2,8-diazaspiro[5.5]undecane-2-yl)(2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methyl ketone

[0175] First Step

[0176] 003-01 (140.39 mg, 482.71 μmol, 1 eq), 1 (100 mg, 482.71 μmol, 1 eq), HATU (220.25 mg, 579.25 μmol, 1.2 eq) and DIEA (187.17 mg, 1.45 mmol) were dissolved in DMF (2.5 mL). The reaction was stirred at room temperature for 12 h. LCMS showed the reaction was completed. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to get the crude product. The crude product was purified by MPLC to get 003-02 (241 mg, contain a little DMF) as a yellow oil.

[0177] MS (ESI, m / z): 344.28 [M-100].

[0178] Second Step

[0179] 003-02 (241 mg, 543.38 μmol, 1 eq) was dissolved in DCM (3 mL), TFA (1 mL) was added and the reaction was stirred at room temperature for 1 h. TLC showed the reaction was completed. The reaction was directly concentrated to get 003-03 (248 mg, TFA salt) as a yellow oil. The product was used directly for the next step.

[0180] Third Step

[0181] 003-03 (248 mg, 542.16 μmol, 1 eq), 2 (77.30 mg, 542.36 μmol, 1 eq) and Cs2CO3 (529.94 mg, 1.63 mmol, 3 eq) were dissolved in DMF (2 mL), the reaction was heated at 120 °C for 2 h. LCMS showed the reaction was completed. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to get the crude product. The crude product was purified by prep-HPLC to get 003 (89.4 mg, 41.2% yield over 3 steps) as a white solid.

[0182] MS (ESI, m / z): 450.3 [M+H] + .

[0183] 1H NMR (300 MHz, DMSO) δ 8.13 - 8.05 (m, 2H), 7.86 - 7.59 (m, 3H), 6.33 - 6.31 (m, 1H), 4.14 - 3.55 (m, 4H), 3.22 - 2.79 (m, 4H), 2.20 - 2.03 (m, 6H), 1.84 - 1.11 (m, 8H)

[0184] Example 004

[0185] Compound 004: Preparation of (2-(4,6-dimethylpyrimidin-2-yl)-2,7- diazaspiro[3.5]-nonan-7-yl-(2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methanone

[0186] First Step

[0187] 004-02 (100.32 mg, 443.25 μmol, 1 eq) and DIEA (114.58 mg, 886.50 μmol, 2 eq) were stirred in DCM (5 mL) for 5 min, then 001-01 (100 mg, 443.25 μmol, 0.24 mol / L, 1 eq) was added. The reaction was stirred at room temperature overnight. The reaction was directly concentrated to get the crude product. The crude product was purified by MPLC (petroleum ether / ethyl acetate = 0-50%, Si02) to get 004-02 (140 mg, yield 76%) as colorless oil.

[0188] MS (ESI, m / z): 416.21 [M+H] + .

[0189] Second Step

[0190] 004-02 (140 mg, 336.96 μmol) was dissolved in DCM (5 mL), then TFA (2 mL) was added. The reaction was stirred at room temperature for 2 h. TLC showed the reaction was completed. The reaction was directly concentrated to get 004-03 (256 mg, TFA salt) as light yellow oil. The product was used directly for the next step.

[0191] Third Step

[0192] To a solution of 004-03 (106.26 mg, 336.96 pmol, 1 eq), 2 (48.05 mg, 336.96 pmol, 1 eq) and Cs2C03(329.36 mg, 1.01 mmol, 3 eq) in DMF (3 mL) was heated at 120 °C for 1.5 h under argon. TLC showed the reaction was completed. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times, combined the organic phase and washed with saturated brine (50 mL), dried and concentrated to get the crude product. The crude product was purified by prep-HPLC to get the product 005 (72.6 mg, 51% yield for 2 steps) as a white solid.

[0193] MS (ESI, m / z): 422.28 [M+H] + .

[0194] 1 H NMR (300 MHz, DMSO) δ 8.15 (s, 2H), 7.83-7.81 (m, 1H), 7.70-7.63 (m, 1H),

[0195] 7.43 (t, J = 9 Hz, 1H), 6.42 (s, 1H), 3.60-3.81 (m, 6H), 3.33-3.08 (m, 2H), 2.20 (s, 6H), 1.83-1.75 (m, 2H), 1.62-1.59 (m, 2H)

[0196] Example 005

[0197] Preparation of compound 005: (7-(4,6-dimethylpyrimidin-2-yl)-2,7-diazaspiro[3.5]-6- octane (2-fluoro-6-2H-l,2,3-triazol-2-yl)phenyl methyl ketone

[0198] First step

[0199] To a solution of 004-03 (106.26 mg, 336.96 pmol, 1 eq), 2 (48.05 mg, 336.96 pmol, 1 eq) and Cs2C03(329.36 mg, 1.01 mmol, 3 eq) in DMF (3 mL) was heated at 120 °C for 1.5 h under argon. TLC showed the reaction was completed. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times, combined the organic phase and washed with saturated brine (50 mL), dried and concentrated to get the crude product. The crude product was purified by prep-HPLC to get the product 005 (72.6 mg, 51% yield for 2 steps) as a white solid.

[0200] MS (ESI, m / z): 333.22 [M+H] + .

[0201] Second Step

[0202] 005-02 (190 mg, 511.36 μmol, 1 eq) was dissolved in DCM (5 mL), TFA (1 mL) was added and the reaction was stirred at room temperature for 1 h. TLC showed the reaction was completed. The reaction was directly concentrated to give 005-03 (256 mg, TFA salt) as a light yellow oil. The product was used directly for the next step.

[0203] Third Step

[0204] 005-03 (105 mg, 506.84 μmol, 1 eq), 1 (175.55 mg, 506.84 μmol, 1 eq) and DIEA (231.26 mg, 2.53 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 12 h. The reaction was monitored by mass spectrometry. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (50 mL), dried and concentrated to give the crude product. The crude product was purified by prep-HPLC to give the product 005 (37.0 mg, 2 step yield 17.2%) as a white solid.

[0205] MS (ESI, m / z): 422.3 [M+H] + .

[0206] 1 H NMR (300 MHz, DMSO) δ 8.22 (s, 2H), 7.82-7.80 (m, 1H), 7.64-7.71 (m, 1H), 7.47-7.41 (m, 1H), 6.36 (s, 1H), 3.78-3.55 (m, 8H), 2.20 (s, 6H), 1.68-1.67 (m, 4H)

[0207] Example 006

[0208] Preparation of Compound 006: (6-(4,6-dimethylpyrimidin-2-yl)-1,6-diazaspiro[3.3]heptan-1-yl)(2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methyl ketone

[0209] First Step

[0210] To a solution of 006-01 (95.70 mg, 482.71 μmol, 1 eq), 1 (100 mg, 482.71 μmol, 1 eq), HATU (220.25 mg, 579.25 μmol, 1.2 eq) and DIEA (187.17 mg, 1.45 mmol) in DMF (3 mL) was stirred at room temperature for 12 h. The reaction was monitored by LC-MS. The reaction was complete. The reaction was diluted with water (15 mL) and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with brine (25 mL), dried and concentrated to give a crude product. The crude product was purified by MPLC (petroleum ether / Ethyl acetate = 0-50%) to give 006-02 (165 mg, yield 88.2%) as colorless oil.

[0211] MS (ESI, m / z): 410.28 [M+23]

[0212] Second step

[0213] To a solution of 006-3 (165 mg, 425.90 μmol, 1 eq) in DCM (3 mL) was added TFA (1 mL) and stirred at room temperature for 1 h. The reaction was monitored by TLC. The reaction was complete. The reaction was directly concentrated to give 006-03 (170 mg, TFA salt) as yellowish oil. The product was used directly for the next step.

[0214] Third step

[0215] To a solution of 006-03 (170 mg, 423.60 μmol, 1 eq), 2 (60.40 mg, 423.60 μmol, 1 eq) and Cs2CO3 (690.09 mg, 2.12 mmol, 3 eq) in DMF (2 mL) was stirred at 120 °C for 2 h. The reaction was monitored by LC-MS. The reaction was complete. The reaction was diluted with water (15 mL) and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with brine (25 mL), dried and concentrated to give a crude product. The crude product was purified by prep-HPLC to give 006 (66 mg, 2 steps yield 39.4%) as white solid.

[0216] MS (ESI, m / z): 394.29 [M+H] + .

[0217] Example 007

[0218] Preparation of compound 007: (1-(4,6-dimethylpyrimidin-2-yl)-1,6-diazaspiro[3.3]heptan-6-yl)(2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methanone

[0219] First Step

[0220] 007-01 (80.00 mg, 403.50 μmol, 1 eq), 2 (57.53 mg, 403.50 μmol, 1 eq) and Cs2CO3 (394.40 mg, 1.21 mmol, 3 eq) were added into DMF (2 mL), the reaction was heated at 120 °C for 2 h. TLC showed the reaction was completed. Water (15 mL) was added into the reaction, and extracted with EtOAc (25 mL) for 3 times, the organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to get the crude product. The crude product was purified by MPLC (PE / EtOAc = 0-30%) to get 007-02 (150 mg, yield 96.2%) as colorless oil.

[0221] Second Step

[0222] 007-02 (150 mg, 387.17 μmol, 1 eq) was dissolved in DCM (3 mL), TFA (1 mL) was added, the reaction was stirred at room temperature for 1 h. TLC showed the reaction was completed. The reaction was directly concentrated to get 007-03 (155 mg, TFA salt) as light yellow oil, the product was directly used for the next step.

[0223] Third Step

[0224] 007-03 (155 mg, 486.96 μmol, 1 eq), 1 (100.88 mg, 486.96 μmol, 1 eq), HATU (222.19 mg, 584.35 μmol, 1.2 eq) and DIEA (314.69 mg, 2.43 mmol) were dissolved in DMF (2 mL), the reaction was stirred at room temperature for 12 h. Water (15 mL) was added into the reaction, and extracted with EtOAc (25 mL) for 3 times, the organic phase was combined and washed with saturated brine (25 mL), dried, concentrated to get the crude product. The crude product was purified by prep-HPLC to get 007 (12.2 mg, 2 steps yield 6.1%) as white solid.

[0225] MS (ESI, m / z): 394.3 [M+H] + .

[0226] Example: 008

[0227] Preparation of Compound 008: (6-(4,6-dimethylpyrimidin-2-yl)-2,6-diazaspiro[3.3]heptan-2-yl)(2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methanone

[0228] First Step

[0229] 008-01 (95.70 mg, 482.71 μmol, 1 eq), 1 (100 mg, 482.71 μmol, 1 eq), HATU (220.25 mg, 579.25 μmol, 1.2 eq) and DIEA (187.17 mg, 1.45 mmol) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 12 h. The reaction was monitored by mass spectrometry. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to give the crude product. The crude product was purified by MPLC (petroleum ether / ethyl acetate = 0-50%) to give 008-02 (171 mg, 91.4% yield) as colorless oil.

[0230] MS (ESI, m / z): 388.31 [M+H] +

[0231] Second Step

[0232] 008-02 (171 mg, 441.39 μmol, 1 eq) was dissolved in DCM (3 mL), TFA (1 mL) was added and the reaction was stirred at room temperature for 1 h. TLC showed the reaction was complete. The reaction was directly concentrated to give 008-03 (177 mg, TFA salt) as light yellow oil. The product was used directly in the next step.

[0233] Third Step

[0234] 008-03 (177 mg, 441.04 μmol, 1 eq), 2 (62.89 mg, 441.04 μmol, 1 eq) and Cs2CO3 (718.50 mg, 2.21 mmol, 3 eq) were added to DMF (2 mL). The reaction was stirred at 120 °C for 2 h. Water (15 mL) was added to the reaction and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried, concentrated to give the crude product. The crude product was purified by prep-HPLC to give 008 (44 mg, 25.3% yield for 2 steps) as white solid.

[0235] MS (ESI, m / z): 394.3 [M+H] + .

[0236] Example 009

[0237] Preparation of compound 009: (2-(4,6-dimethylpyrimidin-2-yl)-2,8-diazaspiro[4.5]-8-decane (2-fluoro-6-2H-1,2,3-triazol-2-yl)phenyl methyl ketone

[0238] First step

[0239] To a solution of 009-01 (168.56 mg, 701.32 μmol, 1 eq), 2 (100 mg, 701.32 μmol, 1 eq) and Cs2C03(685.52 mg, 2.1 mmol, 3 eq) in DMF (3 mL) was heated at 120 °C for 2 h. TLC showed the reaction was completed. The reaction was diluted with water (15 mL) and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to give the crude product. The crude product was purified by MPLC (PE / EtOAc = 0-20%) to give 009-02 (190 mg, 78.2% yield) as a white solid.

[0240] MS (ESI, m / z): 347.35 [M+H] + .

[0241] Second step

[0242] To a solution of 009-02 (190 mg, 548.38 μmol, 1 eq) in DCM (5 mL) was added TFA (1.5 mL) and stirred at room temperature for 1 h. TLC showed the reaction was completed. The reaction was directly concentrated to give 009-03 (200 mg, TFA salt) as a light yellow oil. The product was used directly for the next step.

[0243] Third step

[0244] To a solution of 009-03 (196.57 mg, 545.46 μmol, 1 eq), 1 (113.00 mg, 545.46 μmol, 1 eq), HATU (248.88 mg, 654.55 μmol, 1.2 eq) and DIEA (352.50 mg, 2.73 mmol) in DMF (3 mL) was stirred at room temperature for 12 h. The reaction was monitored by mass spectrometry. The reaction was diluted with water (15 mL) and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to give the crude product. The crude product was purified by prep-HPLC to give 009 (108.3 mg, 45.3% yield for 2 steps) as a white solid.

[0245] MS (ESI, m / z): 436.3 [M+H] + .

[0246] 1 H NMR (300 MHz, DMSO) δ 8.19-8.17 (s, 2H), 7.83-7.80 (m, 1H), 7.70-7.62 (m, 1H), 7.43 (t, J = 9 Hz, 1H), 6.42 (s, 1H), 3.72-3.43 (m, 5H), 3.32-3.13 (m, 3H), 2.24 (s, 6H), 1.92-1.56 (m, 4H), 1.40-1.37 (m, 2H)

[0247] Example 010

[0248] Preparation of compound 010: (8-(4,6-dimethylpyrimidin-2-yl)-2,8-diazaspiro[4.5]- 2-decan (2-fluoro-6-2H-l,2,3-triazol-2-yl)phenyl methyl ketone

[0249] First step

[0250] Dissolve 1 (100 mg, 482.71 μmol, 1 eq), 010-01 (116.02 mg, 482.71 μmol, 1 eq), HATU (220.25 mg, 579.25 μmol, 1.2 eq) and DIEA (187.17 mg, 1.45 mmol) in DMF (3 mL). Stir the reaction solution at room temperature for 12 h. TLC shows that the reaction is complete. Add water (15 mL) to the reaction solution, and extract with EtOAc (25 mL) three times, combine the organic phases and wash with saturated brine (25 mL), dry and concentrate to give the crude product. Purify the crude product by MPLC (PE / EtOAc = 0-30%) to give 010-02 (200 mg, yield 96.7%) as a light yellow oil. MS (ESI, m / z): 452.20 [M+H] + .

[0251] Second step

[0252] Dissolve 010-02 (200 mg, 465.66 μmol, 1 eq) in DCM (2 mL), add TFA (2 mL) and stir the reaction solution at room temperature for 1 h. TLC shows that the reaction is complete. Concentrate the reaction solution directly to give 010-03 (200 mg, TFA salt) as a light yellow oil. The product is used directly in the next step.

[0253] Third step

[0254] To a solution of 010-03 (200 mg, 451.06 pmol, 1 eq), 2 (64.31 mg, 701.32 pmol, 1 eq) and Cs2C03(440.89 mg, 1.35 mmol, 3 eq) in DMF (3 mL) was heated at 120 °C for 2 h. TLC showed the reaction was completed. The reaction was diluted with water (15 mL) and extracted with EtOAc (25 mL) for 3 times. The organic phase was combined and washed with saturated brine (25 mL), dried and concentrated to give the crude product. The crude product was purified by prep-HPLC to give 010 (49.3 mg, yield 24.3% / 2 steps) as a white solid.

[0255] MS (ESI, m / z): 436.2 [M+H] + .

[0256] 1 H NMR (300 MHz, DMSO) d 8.15 (s, 2H), 7.82-7.79 (m, 1H), 7.71-7.62 (m, 1H), 7.48-7.40 (m, 1H), 6.37-6.33 (d, J = 12 Hz, 1H), 3.88-3.43 (m, 6H), 3.28-3.07 (m, 2H), 2.22 (s, 3H), 2.18 (s, 3H), 1.87-1.76 (m, 2H), 1.61-1.42 (m, 4H)

[0257] Example 011

[0258] Preparation of compound 011: 1-(4,6-dimethylpyrimidin-2-yl)-7-(2-fluoro-6-(2H-1,2,3- triazol-2-yl)phenyl)-1,7-diazaspiro[4,4]nonan-2-one

[0259] First step

[0260] Compound 011-01 (30.0 mg, 124.84 μmol, 1.0 eq), 2 (17.8 mg, 124.84 μmol, 1.0 eq), Cs2CO3(122.0 mg, 374.53 μmol, 3.0 eq), Pd2(dba)3(5.7 mg, 6.24 μmol, 0.05 eq), Xantphos (10.8 mg, 18.73 μmol, 0.15 eq) were dissolved in 2 mL of 1,4-dioxane, the reaction system was placed in a 100 °C oil bath and stirred for about 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, the reaction solution was filtered through diatomite, washed with EtOAc (120 mL) for 3 times, then the organic phase was combined and washed with about 100 mL of saturated brine for 1 time, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product 011-02 (colorless oil, 38.3 mg, yield 88.6%).

[0261] MS (ESI, m / z): 347.3 [M+H] + , 291.2 [M-55] +

[0262] Second step

[0263] Compound 011-02 (38.3 mg, 110.56 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 011-03 (27.2 mg) was directly used in the next step reaction.

[0264] Third step

[0265] Compound 011-03 (27.2 mg, 110.55 μmol, 1.0 eq), 1 (22.9 mg, 110.55 μmol, 1.0 eq), HATU (50.4 mg, 132.66 μmol, 1.2 eq), DIEA (71.4 mg, 552.75 μmol, 5.0 eq) were dissolved in 2 mL of DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high pressure preparation to obtain the product 011 6.2 mg. MS (ESI, m / z): 436.3 [M+H] + .

[0266] Example 012

[0267] Preparation of compound 012: (8-(4,6-dimethylpyrimidin-2-yl)-1,8-diazaspiro[4,6]undecan-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0268] First step

[0269] Compound 012-01 (50.0 mg, 153.92 μmol, 1.0 eq), 1 (31.9 mg, 153.92 μmol, 1.0 eq), HATU (70.2 mg, 184.70 μmol, 1.2 eq), DIEA (99.5 mg, 769.59 μmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction was stirred at 25 °C for 16 h, the reaction process was monitored by LC-MS. After the reaction was completed, about 20 mL water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL saturated brine for 1 time, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-50% ethyl acetate / petroleum ether mobile phase gradient, the obtained fraction was concentrated under reduced pressure to remove the solvent, to obtain compound 012-02 (colorless oil, 67.1 mg, yield 91.3%).

[0270] Second step

[0271] Compound 012-02 (67.1 mg, 140.51 μmol, 1.0 eq) was dissolved in 2 mL DCM, then 2 mL TFA was added, heated to 80 °C and stirred for about 2 h, the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, the residue 012-03 (48.3 mg) was directly used in the next step reaction.

[0272] Third step

[0273] Compound 012-03 (48.3 mg, 14.85 μmol, 1.0 eq), 2 (20.1 mg, 140.85 μmol, 1.0 eq) and Cs2CO3 (137.5 mg, 421.95 μmol, 3.0 eq) were dissolved in 2 mL DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After cooling to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, then the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high pressure preparation to obtain product 012 33.7 mg. MS (ESI, m / z): 450.3 [M+H] + .

[0274] Example 013

[0275] Preparation of compound 013: (2-(4,6-dimethylpyrimidin-2-yl)-3-methyl-2,8- diazaspiro [4, 5] decan-8-yl) (2-fluoro-6-(2H-1, 2, 3-triazol-2-yl) phenyl) methanone

[0276] First step

[0277] Compound 013-01 (50.0 mg, 153.92 μmol, 1.0 eq), 1 (31.9 mg, 153.92 μmol, 1.0 eq), HATU (70.2 mg, 184.70 μmol, 1.2 eq), DIEA (99.5 mg, 769.59 μmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, then the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 50% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to obtain compound 013-02 (colorless oil, 76.5 mg, yield 100%).

[0278] Second step

[0279] Compound 013-02 (76.5 mg, 160.20 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 2 mL of TFA was added, and the reaction was stirred at 80 °C for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the residue 013-03 (55.0 mg) was obtained by concentration under reduced pressure and was used directly in the next reaction.

[0280] Step 3

[0281] Compound 013-03 (55.0 mg, 160.16 μmol, 1.0 eq), 2 (22.8 mg, 160.16 μmol, 1.0 eq), and Cs2CO3 (156.6 mg, 480.48 μmol, 3.0 eq) were dissolved in 2 mL of DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h. The reaction was monitored by LC-MS. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, followed by extraction with EtOAc (20 mL) three times. The organic phases were combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-pressure preparation to obtain product 013 32.0 mg. MS (ESI, m / z): 450.3 [M+H] + .

[0282] Example 014

[0283] Preparation of compound 014: (8-(4,6-dimethylpyrimidin-2-yl)-3-methyl-2,8- diazaspiro[4,5]dec-2-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0284] Step 1

[0285] Compound 014-01 (50.0 mg, 153.92 μmol, 1.0 eq), 2 (22.0 mg, 153.92 μmol, 1.0 eq), and Cs2CO3 (150.5 mg, 461.75 μmol, 3.0 eq) were dissolved in 2 mL of DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h. The reaction was monitored by LC-MS. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, followed by extraction with EtOAc (20 mL) three times. The organic phases were combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product 014-02 (colorless oil, 47.2 mg, yield 77.7%).

[0286] Second step

[0287] Compound 014-02 (47.2 mg, 119.64 μmol, 1.0 eq) was dissolved in 2 mL of DCM, then 2 mL of TFA was added, and the reaction was stirred at 80 °C for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the residue 014-03 (31.2 mg) was obtained by concentration under reduced pressure and was used directly in the next reaction.

[0288] Third step

[0289] Compound 014-03 (32.0 mg, 122.89 μmol, 1.0 eq), 1 (25.5 mg, 122.89 μmol, 1.0 eq), HATU (56.1 mg, 147.47 μmol, 1.2 eq), and DIEA (79.4 mg, 614.47 μmol, 5.0 eq) were dissolved in 2 mL of DMF, and the reaction was stirred for 16 h. The reaction was monitored by LC-MS. After the reaction was completed, about 20 mL of water was added to the reaction solution, which was then extracted with EtOAc (20 mL) three times. The organic phases were combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-pressure preparation to obtain product 014 17.3 mg. MS (ESI, m / z): 450.3 [M+H] + .

[0290] Example 015

[0291] Preparation of compound 015: (9-(4,6-dimethylpyrimidin-2-yl)-3,9-diazaspiro[5,5]undecan-3-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0292] First step

[0293] Compound 015-01 (150.0 mg, 589.68 μmol, 1.0 eq), 2 (84.1 mg, 589.68 μmol, 1.0 eq), Cs2CO3(576.4 mg, 1.77 mmol, 3.0 eq) were added into 2 mL DMF, the reaction system was placed in 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, and then the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-30% ethyl acetate / petroleum ether mobile phase gradient, and the obtained fraction was concentrated under reduced pressure to obtain compound 015-02 (colorless oil, 147.5 mg, yield 69.4%).

[0294] Second step

[0295] Compound 015-02 (147.5 mg, 409.15 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 015-03 (106.6 mg) was directly used in the next step reaction.

[0296] Third step

[0297] Compound 015-03 (106.6 mg, 409.39 μmol, 1.0 eq), 1 (84.8 mg, 409.39 μmol, 1.0 eq), HATU (186.8 mg, 491.27 μmol, 1.2 eq), DIEA (264.6 mg, 2.05 mmol, 5.0 eq) were dissolved in 2 mL of DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, and then the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high-pressure preparation separation to obtain product 015 24.7 mg, purity 98.0%, MS (ESI, m / z): 450.3 [M+H] + .

[0298] Example 016

[0299] Preparation of compound 016: (2-(4,6-dimethylpyrimidin-2-yl)-2,6-diazaspiro[4,5]decane-6-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0300] First step

[0301] Compound 016-01 (90.0 mg, 374.46 μmol, 1.0 eq), 1 (77.6 mg, 374.46 μmol, 1.0 eq), HATU (170.9 mg, 449.35 μmol, 1.2 eq), DIEA (242.0 mg, 1.87 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction was stirred for 16 h at 25 °C, the reaction process was monitored by LC-MS. After the reaction was completed, about 20 mL water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL saturated brine for 1 time, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0% - 30% ethyl acetate / petroleum ether mobile phase gradient, the obtained fraction was concentrated under reduced pressure to remove the solvent, to obtain compound 016-02 (colorless oil, 36.2 mg, yield 22.5%). MS (ESI, m / z): 374.26 [M-55].

[0302] Second step

[0303] Compound 016-02 (36.2 mg, 84.28 μmol, 1.0 eq) was dissolved in 2 mL DCM, then 1 mL TFA was added, stirred for about 2 h at 25 °C, the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, the residue 016-03 (27.8 mg) was directly used in the next step reaction.

[0304] Third step

[0305] Compound 016-03 (27.8 mg, 84.40 μmol, 1.0 eq), 2 (12.0 mg, 84.40 μmol, 1.0 eq) and Cs2CO3 (82.8 mg, 253.20 μmol, 3.0 eq) were added into 2 mL DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, then the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high pressure preparation to obtain product 016 6.0 mg, purity 97.0%, MS (ESI, m / z): 436.3 [M+H] + .

[0306] Example 017

[0307] Preparation of compound 017: (6-(4,6-dimethylpyrimidin-2-yl)-1,6-diazaspiro[3,4]octan-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0308] First step

[0309] Compound 017-01 (90.0 mg, 423.94 μmol, 1.0 eq), 1 (87.8 mg, 423.94 μmol, 1.0 eq), HATU (193.44 mg, 508.73 μmol, 1.2 eq), DIEA (273.97 mg, 2.12 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, then the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 50% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 017-02 (colorless oil, 121.1 mg, yield 71.2%). MS (ESI, m / z): 424.26 [M-100+Na].

[0310] Second step

[0311] Compound 017-02 (121.1 mg, 301.66 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred at 25 °C for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 017-03 (90.9 mg) was directly used in the next reaction.

[0312] Third step

[0313] Compound 017-03 (90.9 mg, 301.67 μmol, 1.0 eq), 2 (43.0 mg, 301.67 μmol, 1.0 eq) and Cs2CO3 (294.9 mg, 905.00 μmol, 3.0 eq) were added to 2 mL of DMF, and the reaction was stirred in a 120 °C oil bath for about 2 h. The reaction was monitored by LC-MS. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, followed by extraction with EtOAc (20 mL) three times. The organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high-pressure preparation to obtain product 017 24.4 mg, purity 99.0%, MS (ESI, m / z): 408.3 [M+H] + .

[0314] 1 H NMR (300 MHz, CDCl3) δ 7.97-7.72 (m, 3H), 7.47 (td, J = 8.3, 5.9 Hz, 1H), 7.14 (td, J = 8.5, 1.0 Hz, 1H), 6.27 (s, 1H), 4.24-4.09 (m, 1H), 3.96 (t, J = 12.1 Hz, 2H), 3.82 (t, J = 7.7 Hz, 2H), 3.64 (m, 1H), 2.44 (t, J = 42.9 Hz, 2H), 2.30 (s, 6H), 2.23-2.07 (m, 2H).

[0315] Example 018

[0316] Preparation of compound 018: (7-(4,6-dimethylpyrimidin-2-yl)-1,7-diazaspiro[3,5]nonan-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0317] First step

[0318] Compound 018-01 (90.0 mg, 397.67 μmol, 1.0 eq), 2 (56.7 mg, 397.67 μmol, 1.0 eq), Cs2CO3(389.9 mg, 1.19 mmol, 3.0 eq) were dissolved in 2 mL of DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 30% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 018-02 (colorless oil, 107.7 mg, yield 81.5%), MS (ESI, m / z): 277.28 [M-55].

[0319] Second step

[0320] Compound 018-02 (107.7 mg, 323.96 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 018-03 (75.3 mg) was directly used in the next step reaction.

[0321] Third step

[0322] Compound 019-03 (75.3 mg, 324.11 μmol, 1.0 eq), 1 (67.1 mg, 324.11 μmol, 1.0 eq), HATU (147.9 mg, 388.93 μmol, 1.2 eq), DIEA (209.5 mg, 1.62 mmol, 5.0 eq) were dissolved in 2 mL of DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by high pressure preparation to obtain product 018 24.1 mg, purity 98.0%, MS (ESI, m / z): 422.3 [M+H] + .

[0323] Example 019

[0324] Preparation of compound 019: (1-(4,6-dimethylpyrimidin-2-yl)-1,7-diazaspiro[3,5]nonan-7-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0325] First step

[0326] Compound 019-01 (90.0 mg, 397.67 μmol, 1.0 eq), 1 (82.4 mg, 397.67 μmol, 1.0 eq), HATU (181.5 mg, 477.20 μmol, 1.2 eq), DIEA (257.0 mg, 1.99 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction was stirred for 16 h at 25 °C, the reaction process was monitored by LC-MS. After the reaction was completed, about 20 mL water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL saturated brine for 1 time, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-50% ethyl acetate / petroleum ether mobile phase gradient, the obtained fraction was concentrated under reduced pressure to remove the solvent, to obtain compound 019-02 (colorless oil, 117.7 mg, yield 71.2%). MS (ESI, m / z): 360.23 [M-55].

[0327] Second step

[0328] Compound 019-02 (117.7 mg, 283.29 μmol, 1.0 eq) was dissolved in 2 mL DCM, then 1 mL TFA was added, stirred for about 2 h at 25 °C, the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, the residue 019-03 (89.3 mg) was directly used in the next step reaction.

[0329] Third step

[0330] Compound 019: (7-(4,6-dimethylpyrimidin-2-yl)-2,7-diazaspiro[4.5]dec-2-yl)(2- chloro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone was prepared according to the procedure described above for compound 018, using compound 019-01 (80.0 mg, 332.85 pmol, 1.0 eq), 2 (69.0 mg, 332.85 pmol, 1.0 eq) and Cs2CO3(276.8 mg, 849.53 pmol, 3.0 eq). MS (ESI, m / z): 422.3 [M+H] + .

[0331] Example 020

[0332] Compound 020: (7-(4,6-dimethylpyrimidin-2-yl)-2,7-diazaspiro[4.5]dec-2-yl)(2- fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone was prepared according to the procedure described above for compound 018, using compound 020-01 (80.0 mg, 332.85 pmol, 1.0 eq), 2 (69.0 mg, 332.85 pmol, 1.0 eq) and Cs2CO3(276.8 mg, 849.53 pmol, 3.0 eq). MS (ESI, m / z): 422.3 [M+H]

[0333] First step

[0334] Compound 020: (7-(4,6-dimethylpyrimidin-2-yl)-2,7-diazaspiro[4.5]dec-2-yl)(2- fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone was prepared according to the procedure described above for compound 018, using compound 020-01 (80.0 mg, 332.85 pmol, 1.0 eq), 2 (69.0 mg, 332.85 pmol, 1.0 eq) and Cs2CO3(276.8 mg, 849.53 pmol, 3.0 eq). MS (ESI, m / z): 422.3 [M+H]

[0335] Second step

[0336] Compound 020-02 (167.3 mg, 389.52 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred at 25 °C for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 020-03 (108.0 mg) was directly used in the next reaction.

[0337] Third step

[0338] Compound 020-03 (108.0 mg, 327.89 μmol, 1.0 eq), 2 (46.8 mg, 327.89 μmol, 1.0 eq) and Cs2CO3 (320.5 mg, 983.67 μmol, 3.0 eq) were dissolved in 2 mL of DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h. The reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, followed by extraction with EtOAc (20 mL) for 3 times. The organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high-pressure preparation separation to obtain the product 020 26.6 mg. MS (ESI, m / z): 436.3 [M+H] + .

[0339] 1 H NMR (300 MHz, CDCl3) δ 7.95-7.75 (m, 3H), 7.46 (qd, J = 8.1, 6.0 Hz, 1H), 7.21-7.03 (m, 1H), 6.27-6.15 (m, 1H), 4.51-4.32 (m, 1H), 3.92-3.70 (m, 3H), 3.37 (dd, J = 13.1, 7.6 Hz, 1H), 3.14 (d, J = 2.9 Hz, 1H), 2.35-2.11 (m, 6H), 1.76-1.52 (m, 5H), 1.28 (d, J = 15.6 Hz, 1H).

[0340] Example 021

[0341] Preparation of compound 021: (6-(4,6-dimethylpyrimidin-2-yl)-2,6-diazaspiro[3,5]nonan-2-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0342] First step

[0343] Compound 021-01 (80.0 mg, 353.48 μmol, 1.0 eq), 1 (73.2 mg, 353.48 μmol, 1.0 eq), HATU (161.3 mg, 424.18 μmol, 1.2 eq), DIEA (228.4 mg, 1.77 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h at 25 °C, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-50% ethyl acetate / petroleum ether mobile phase gradient, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 021-02 (colorless oil, 86.3 mg, yield 58.7%).

[0344] Second step

[0345] Compound 021-02 (86.3 mg, 207.72 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and stirred for about 2 h at 25 °C, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 021-03 (65.5 mg) was directly used in the next step reaction.

[0346] Third step

[0347] Compound 021-03 (65.5 mg, 207.70 μmol, 1.0 eq), 2 (29.6 mg, 207.70 μmol, 1.0 eq) and Cs2CO3 (203.0 mg, 623.11 μmol, 3.0 eq) were dissolved in 2 mL DMF, and the reaction system was placed in a 120 °C oil bath pot and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high pressure preparation separation to obtain product 021 28.2 mg, purity 99.0%, MS (ESI, m / z): 422.3 [M+H] + .

[0348] 1H NMR (300 MHz, CDC13) δ 7.93 (s, 2H), 7.82 (d, J = 8.3 Hz, 1H), 7.46 (td, J = 8.3, 5.9 Hz, 1H), 7.19-7.08 (m, 1H), 6.24 (s, 1H), 4.03-3.92 (m, 3H), 3.83 (d, J = 9.8 Hz, 1H), 3.74 (s, 2H), 3.66 (d, J = 8.3 Hz, 1H), 3.50 (d, J = 8.3 Hz, 1H), 2.26 (s, 6H), 1.55 (s, 3H).

[0349] Example 022

[0350] Preparation of compound 022: (2-(4,6-dimethylpyrimidin-2-yl)-2,6-diazaspiro[3,5]nonan-6- yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0351] First step

[0352] Compound 022-01 (80.0 mg, 353.48 μmol, 1.0 eq), 2 (50.4 mg, 352.48 μmol, 1.0 eq), Cs2CO3(346.6 mg, 1.06 mmol, 3.0 eq) were dissolved in 2 mL of DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, then the organic phase was combined and washed with about 50 mL of saturated brine once, then dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 30% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 022-02 (colorless oil, 74.0 mg, yield 63.0%).

[0353] Second step

[0354] Compound 022-01 (74.0 mg, 222.59 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 022-02 (51.7 mg) was directly used in the next step reaction.

[0355] Third step

[0356] Compound 022-03 (51.7 mg, 222.53 μmol, 1.0 eq), 1 (46.1 mg, 222.53 μmol, 1.0 eq), HATU (101.5 mg, 267.03 μmol, 1.2 eq), DIEA (143.8 mg, 1.11 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high pressure preparation separation to obtain product 022 28.3 mg. MS (ESI, m / z): 422.3 [M+H] + .

[0357] Example 023

[0358] Preparation of compound 023: (2-(4,6-dimethylpyrimidin-2-yl)-2,5-diazaspiro[3,4]octan-5-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0359] First step

[0360] Compound 023-01 (90.0 mg, 423.94 μmol, 1.0 eq), 1 (87.8 mg, 423.94 μmol, 1.0 eq), HATU (193.4 mg, 508.73 μmol, 1.2 eq), DIEA (274.0 mg, 2.12 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 50% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 023-02 (colorless oil, 137.9 mg, yield 81.0%). MS (ESI, m / z): 346.27 M-5

[0361] Second step

[0362] Compound 023-02 (137.9 mg, 343.51 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred at 25 °C for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue 023-03 (103.5 mg) was used directly in the next reaction.

[0363] Third step

[0364] Compound 023-03 (103.5 mg, 343.48 μmol, 1.0 eq), 2 (49.0 mg, 343.48 μmol, 1.0 eq), and Cs2CO3 (335.7 mg, 1.03 mmol, 3.0 eq) were dissolved in 2 mL of DMF, and the reaction system was placed in a 120 °C oil bath and stirred for about 2 h. The reaction was monitored by LC-MS. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, followed by extraction with EtOAc (20 mL) three times. The organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent for high-pressure preparation separation to obtain product 023 72.6 mg.

[0365] MS (ESI, m / z): 408.3 [M+H] + .

[0366] 1 H NMR (300 MHz, CDCl3) δ 7.81 (s, 3H), 7.41 (td, J = 8.3, 5.9 Hz, 1H), 7.08 (td, J = 8.5, 1.0 Hz, 1H), 6.24 (s, 1H), 5.15 (d, J = 8.5, 3.8 Hz, 2H), 4.08 (d, J = 8.7 Hz, 2H), 3.42-3.20 (m, 2H), 2.43-2.22 (m, 8H), 1.87-1.71 (m, 2H).

[0367] Example 024

[0368] Preparation of compound 024: (6-(4,6-dimethylpyrimidin-2-yl)-1,6-diazaspiro[3,5]nonan-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0369] First step

[0370] Compound 024-01 (90.0 mg, 397.67 μmol, 1.0 eq), 1 (82.4 mg, 397.67 μmol, 1.0 eq), HATU (181.5 mg, 477.20 μmol, 1.2 eq), DIEA (257.0 mg, 1.99 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h at 25 °C, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-50% ethyl acetate / petroleum ether mobile phase gradient, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 024-02 (colorless oil, 124.4 mg, yield 75.3%). MS (ESI, m / z): 316.32 M-100+H.

[0371] Second step

[0372] Compound 024-02 (124.4 mg, 299.42 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and stirred for about 2 h at 25 °C, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 024-03 (94.4 mg) was directly used in the next step reaction.

[0373] Third step

[0374] Compound 024-03 (94.4 mg, 299.35 μmol, 1.0 eq), 2 (42.7 mg, 299.35 μmol, 1.0 eq) and Cs2CO3 (292.6 mg, 898.04 μmol, 3.0 eq) were dissolved in 2 mL DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high pressure preparation separation to obtain product 024 (16.4 mg, purity 99.0%). MS (ESI, m / z): 422.3 [M+H] + .

[0375] Example 025

[0376] Preparation of compound 025: (2-(4,6-dimethylpyrimidin-2-yl)-2,5-diazaspiro[3,5]non-1- yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0377] First step

[0378] Compound 025-01 (80.0 mg, 353.48 μmol, 1.0 eq), 1 (73.2 mg, 353.48 μmol, 1.0 eq), HATU (161.3 mg, 424.18 μmol, 1.2 eq), DIEA (228.4 mg, 1.77 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction was stirred for 16 h at 25 °C, the reaction process was monitored by LC-MS. After the reaction was completed, about 20 mL water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL saturated brine for 1 time, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-50% ethyl acetate / petroleum ether mobile phase gradient, the obtained fraction was concentrated under reduced pressure to remove the solvent, to obtain compound 025-02 (colorless oil, 111.0 mg, yield 75.6%).

[0379] Second step

[0380] Compound 025-02 (111.0 mg, 267.17 μmol, 1.0 eq) was dissolved in 2 mL DCM, then 1 mL TFA was added, stirred for about 2 h at 25 °C, the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, the residue 025-03 (84.2 mg) was directly used in the next step reaction.

[0381] Third step

[0382] Compound 025-03 (84.2 mg, 267.00 μmol, 1.0 eq), 2 (38.1 mg, 267.00 μmol, 1.0 eq) and Cs2CO3 (261.0 mg, 801.01 μmol, 3.0 eq) were dissolved in 2 mL DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent to high pressure preparation separation to obtain product 025 (6 mg, purity 94.8%). MS (ESI, m / z): 422.3 [M+H] + .

[0383] Example 026

[0384] Preparation of compound 026: (2-(4,6-dimethylpyrimidin-2-yl)-2,9-diazaspiro[5,5]undecan-9-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0385] First step

[0386] Compound 026-01 (90.0 mg, 353.81 μmol, 1.0 eq), 1 (73.3 mg, 353.81 μmol, 1.0 eq), HATU (161.4 mg, 424.57 μmol, 1.2 eq), DIEA (228.6 mg, 1.77 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 50% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 026-02 (colorless oil, 138 mg, yield 87.9%).

[0387] Second step

[0388] Compound 026-02 (138 mg, 311.15 μmol, 1.0 eq) was dissolved in 2 mL of DCM, then 1 mL of TFA was added, and the reaction was stirred at 25 °C for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue 026-03 (106.9 mg) was used directly in the next reaction.

[0389] Step 3

[0390] Compound 026-03 (106.9 mg, 311.29 μmol, 1.0 eq), 2 (44.4 mg, 311.29 μmol, 1.0 eq), and Cs2CO3 (304.3 mg, 933.88 μmol, 3.0 eq) were dissolved in 2 mL of DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h. The reaction was monitored by LC-MS. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, which was then extracted with EtOAc (20 mL) three times. The combined organic phase was washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent for high-pressure preparation separation to obtain the product 026 65 mg, purity 99.0%, MS (ESI, m / z): 450.3 [M+H] + .

[0391] Example 027

[0392] Preparation of compound 027: (7-(4,6-dimethylpyrimidin-2-yl)-1,7-diazaspiro[4,5]dec-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0393] Step 1

[0394] Compound 027-01 (80.0 mg, 332.85 μmol, 1.0 eq), 1 (69.0 mg, 332.85 μmol, 1.0 eq), HATU (151.9 mg, 399.42 μmol, 1.2 eq), DIEA (215.1 mg, 1.66 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-30% ethyl acetate / petroleum ether mobile phase gradient, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 027-02 (colorless oil, 115 mg, yield 80.4%). MS (ESI, m / z): 330.32 [M+H-100].

[0395] Second step

[0396] Compound 027-02 (115 mg, 267.75 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 027-03 (88.2 mg) was directly used in the next step reaction.

[0397] Third step

[0398] Compound 027-03 (88.2 mg, 267.78 μmol, 1.0 eq), 2 (38.2 mg, 267.78 μmol, 1.0 eq) and Cs2CO3 (261.7 mg, 803.33 μmol, 3.0 eq) were dissolved in 2 mL of DMF, and the reaction system was placed in a 120°C oil bath pot and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent to high-pressure preparation separation to obtain product 027 65 mg. MS (ESI, m / z): 436.3 [M+H] + .

[0399] Example 028

[0400] Preparation of compound 028: (2-(4,6-dimethylpyrimidin-2-yl)-2,7- diazaspiro[4,5]dec-7-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0401] First step

[0402] Compound 028-01 (90.0 mg, 374.46 μmol, 1.0 eq), 2 (53.4 mg, 374.46 μmol, 1.0 eq), Cs2CO3(366.0 mg, 1.12 mmol, 3.0 eq) were dissolved in 2 mL DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 30% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 028-02 (colorless oil, 132 mg, yield 100.0%).

[0403] Second step

[0404] Compound 028-02 (132 mg, 380.97 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 028-03 (93.8 mg) was directly used in the next step reaction.

[0405] Third step

[0406] Compound 028-03 (93.8 mg, 380.75 μmol, 1.0 eq), 1 (78.9 mg, 380.75 μmol, 1.0 eq), HATU (173.7 mg, 456.90 μmol, 1.2 eq), DIEA (246.1 mg, 1.90 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h at 25 °C, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and then sent to high pressure preparation separation to obtain the product 028 35 mg. MS (ESI, m / z): 436.3 [M+H] + .

[0407] Example 029

[0408] Preparation of compound 029: (8-(4,6-dimethylpyrimidin-2-yl)-1,8-diazaspiro[4,5]dec-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0409] First step

[0410] Compound 029-01 (100.0 mg, 416.07 μmol, 1.0 eq), 2 (59.3 mg, 416.07 μmol, 1.0 eq), Cs2CO3 (406.7 mg, 1.25 mmol, 3.0 eq) were added to 2 mL DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 30% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 029-02 (colorless oil, 117 mg, yield 81.2%).

[0411] Second step

[0412] Compound 029-02 (117 mg, 337.68 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred at 25 °C for about 2 h, during which the reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue 029-03 (83.2 mg) was used directly in the next reaction.

[0413] Step 3

[0414] Compound 029-03 (83.2 mg, 337.72 μmol, 1.0 eq), 1 (70.0 mg, 337.72 μmol, 1.0 eq), HATU (154.1 mg, 405.26 μmol, 1.2 eq), and DIEA (218.3 mg, 1.69 mmol, 5.0 eq) were dissolved in 2 mL of DMF, and the reaction was stirred for 16 h, during which the reaction was monitored by LC-MS. After the reaction was completed, about 20 mL of water was added to the reaction solution, which was then extracted with EtOAc (20 mL) three times. The combined organic phase was washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent for high-pressure preparation separation to obtain the product 029 (20 mg). MS (ESI, m / z): 436.3 [M+H] + .

[0415] Example 030

[0416] Preparation of compound 030: (7-(4,6-dimethylpyrimidin-2-yl)-2,7-diazaspiro[4,4]nonan-2-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0417] Step 1

[0418] Compound 030-01 (100.0 mg, 441.85 μmol, 1.0 eq), 2 (63.0 mg, 441.85 μmol, 1.0 eq), Cs2CO3(431.9 mg, 1.33 mmol, 3.0 eq) were added into 2 mL DMF, the reaction system was placed in 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, and then the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-30% ethyl acetate / petroleum ether mobile phase gradient, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 030-02 (colorless oil, 124 mg, yield 84.4%).

[0419] Second step

[0420] Compound 030-02 (124 mg, 372.99 μmol, 1.0 eq) was dissolved in 2 mL of DCM at 25 °C, and then 1 mL of TFA was added, and the reaction was stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 030-03 (86 mg) was directly used in the next step reaction.

[0421] Third step

[0422] Compound 030-03 (86 mg, 370.16 μmol, 1.0 eq), 1 (76.7 mg, 370.16 μmol, 1.0 eq), HATU (168.9 mg, 444.19 μmol, 1.2 eq), DIEA (239.2 mg, 1.85 mmol, 5.0 eq) were dissolved in 2 mL of DMF at 25 °C, and the reaction system was stirred for 16 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, and then the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and then sent to high-pressure preparation separation to obtain product 030 73 mg. MS (ESI, m / z): 422.3 [M+H] + .

[0423] 1H NMR (300 MHz, CDC13) δ 7.97 (s, 1H), 7.90-7.76 (m, 2H), 7.54-7.41 (m, 1H), 7.21-7.07 (m, 1H), 6.35-6.20 (s, 1H), 3.90 (dd, J = 21.6, 11.5 Hz, 1H), 3.75-3.63 (m, 2H), 3.52-3.42 (m, 2H), 3.28 (m, 1H), 2.38-2.24 (s, 6H), 2.17-2.04 (m, 2H), 2.00-1.84 (m, 2H).

[0424] Example 031

[0425] Preparation of compound 031 : (7-(4,6-dimethylpyrimidin-2-yl)-2,7-diazaspiro[4,4]nonan-2- yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0426] First step

[0427] Compound 031-01 (80.0 mg, 332.85 pmol, 1.0 eq), 1 (69.0 mg, 332.85 pmol, 1.0 eq), HATU (151.9 mg, 399.42 pmol, 1.2 eq), DIEA (215.1 mg, 1.66 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction was stirred for 16 h at 25 °C, the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL saturated brine once, dried over anhydrous Na2S04, concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-30% ethyl acetate / petroleum ether mobile phase gradient, the obtained fraction was concentrated under reduced pressure to remove the solvent, to obtain compound 031-02 (colorless oil, 115 mg, yield 80.4%). MS (ESI, m / z): 330.32

[0428] [M + H - 100].

[0429] Second step

[0430] Compound 031-02 (115 mg, 267.75 μmol, 1.0 eq) was dissolved in 2 mL of DCM at 25 °C, then 1 mL of TFA was added, and the reaction was stirred for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue 031-03 (88.2 mg) was used directly in the next reaction.

[0431] Step 3

[0432] Compound 031-03 (88.2 mg, 267.78 μmol, 1.0 eq), 3 (38.2 mg, 267.78 μmol, 1.0 eq), and Cs2CO3 (261.7 mg, 803.33 μmol, 3.0 eq) were added to 2 mL of DMF at 25 °C, and the reaction was stirred in a 120 °C oil bath for about 2 h. The reaction was monitored by LC-MS. After the reaction was completed and the reaction was cooled to room temperature, about 20 mL of water was added to the reaction, and then the reaction was extracted with EtOAc (20 mL) three times. The organic phases were combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent for high-pressure preparation separation to obtain the product 031-6 (65 mg). MS (ESI, m / z): 500.3, 502.2 [M+H] + .

[0433] 1 H NMR (300 MHz, MeOD) δ 8.06 (s, 1H), 7.97-7.96 (m, 1H), 7.92-7.83 (m, 1H), 7.69-7.58 (m, 1H), 7.35-7.26 (m, 1H), 3.81-3.41 (m, 8H), 2.51-2.45 (m, 6H), 2.18-1.93 (m, 4H).

[0434] Example 032

[0435] Preparation of compound 032: 2-(7-(2-fluoro-6-2H-1,2,3-triazol-2-yl)-2,7-diazaspiro[4.4]nonan-2-yl)-4,6-dimethylpyrimidine-5-carbonitrile

[0436] Dissolve 031 (100 mg, 199.85 pmol, 1 eq), zinc cyanide (Zn(CN)2, 70.40 mg, 599.55 pmol, 3 eq), tetrakis(triphenylphosphine)palladium (Pd(PPh3)4, 23.09 mg, 19.98 pmol, 0.1 eq) and Xantphos (11.56 mg, 19.98 pmol, 0.1 eq) in DMF (2 mL). Heat the reaction to 150 °C under N2for 7 h. LCMS shows starting material remaining and product formed. Add MeOH (10 mL), a large amount of white solid is formed, remove the solid by suction filtration, then concentrate the filtrate to get the crude product. Purify the crude product by prep-HPLC to get white solid 032 (28.6 mg, yield 32.1%).

[0437] MS (ESI, m / z): 447.3 [M+H] +

[0438] Example 033

[0439] Preparation of compound 033: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl-(7-(5- hydroxy-4,6-dimethylpyrimidin-2-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl ketone

[0440] Dissolve 031 (80 mg, 159.88 pmol, 1 eq), potassium hydroxide (KOH, 26.91 mg, 479.64 pmol, 3 eq), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3, 14.64 mg, 15.99 pmol, 0.1 eq) and 2-di-tert-butylphosphino-2',6'-dimethoxybiphenyl (t- butylSPhos, 27.16 mg, 63.96 pmol, 0.4 eq) in dioxane (1.5 mL)-water (1.5 mL). Heat the reaction to 100 °C under N2for 4 h. Add water (15 mL) to the reaction, extract with EtOAc (25 mL) for 3 times, combine the organic phase and wash with saturated brine (25 mL), dry, concentrate to get the crude product. Purify the crude product by prep-HPLC to get white solid 033 (1.7 mg, yield 2.4%).

[0441] MS (ESI, m / z): 438.2 [M+1] + , 897.3 [2M+23] +

[0442] Example 034

[0443] Synthetic method of compound 034 is the same as above

[0444] Example 035

[0445] Preparation of compound 035: (9-(4,6-dimethylpyrimidin-2-yl)-2,9- diazaspiro[5,5]undecan-2-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0446] First step

[0447] Compound 035-01 (90.0 mg, 353.81 μmol, 1.0 eq), 2 (50.5 mg, 353.81 μmol, 1.0 eq), Cs2CO3(345.8 mg, 1.06 mmol, 3.0 eq) were added to 2 mL of DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 30% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 035-02 (colorless oil, 117 mg, yield 91.7%).

[0448] Second step

[0449] Compound 035-02 (117 mg, 324.55 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by concentration under reduced pressure, and the residue 035-03 (84.5 mg) was directly used in the next step reaction.

[0450] Third step

[0451] Compound 035-03 (84.5 mg, 324.52 μmol, 1.0 eq), 1 (67.2 mg, 324.52 μmol, 1.0 eq), HATU (148.1 mg, 389.42 μmol, 1.2 eq), DIEA (209.7 mg, 1.62 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h at 25 °C, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and then sent to high pressure preparation separation to obtain the product 035 11 mg. MS (ESI, m / z): 450.3 [M+H] + .

[0452] Example 036

[0453] Preparation of compound 036: (5-(4,6-dimethylpyrimidin-2-yl)-2,5-diazaspiro[3,4]octan-2- yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0454] First step

[0455] Compound 036-01 (90.0 mg, 423.94 μmol, 1.0 eq), 2 (60.5 mg, 423.94 μmol, 1.0 eq), Cs2CO3 (414.4 mg, 1.27 mmol, 3.0 eq) were dissolved in 2 mL DMF, and the reaction system was stirred in a 120 °C oil bath for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with a gradient of 0% to 30% ethyl acetate / petroleum ether mobile phase, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 036-02 (colorless oil, 25.4 mg, yield 18.8%), MS (ESI, m / z): 263.27 [M-55].

[0456] Second step

[0457] Compound 036-02 (25.4 mg, 79.77 μmol, 1.0 eq) was dissolved in 2 mL of DCM, then 1 mL of TFA was added, and the reaction was stirred at 25 °C for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 036-03 (17.4 mg) was directly used in the next reaction.

[0458] Step 3

[0459] Compound 036-03 (17.4 mg, 79.71 μmol, 1.0 eq), 1 (16.5 mg, 79.71 μmol, 1.0 eq), HATU (36.4 mg, 95.65 μmol, 1.2 eq), and DIEA (51.5 mg, 398.53 μmol, 5.0 eq) were dissolved in 2 mL of DMF, and the reaction was stirred for 16 h. The reaction was monitored by LC-MS. After the reaction was completed, about 20 mL of water was added to the reaction solution, which was then extracted with EtOAc (20 mL) three times. The organic phases were combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent for high-pressure preparation separation to obtain product 036 2 mg with a purity of 97.0%, MS (ESI, m / z): 408.3 [M+H] + .

[0460] Example 037

[0461] Preparation of compound 037: (8-(4,6-dimethylpyrimidin-2-yl)-1,8-diazaspiro[5,5]undecan-1-yl)(2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone

[0462] Step 1

[0463] Compound 037-01 (100.0 mg, 393.12 μmol, 1.0 eq), 1 (81.4 mg, 393.12 μmol, 1.0 eq), HATU (179.4 mg, 471.75 μmol, 1.2 eq), DIEA (254.1 mg, 1.97 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction system was stirred for 16 h at 25 °C, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-50% ethyl acetate / petroleum ether mobile phase gradient, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 037-02 (colorless oil, 15 mg, yield 8.6%).

[0464] Second step

[0465] Compound 037-02 (15 mg, 33.82 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h at 25 °C, and the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 037-03 (10.0 mg) was directly used in the next step reaction.

[0466] Third step

[0467] Compound 037-03 (10.0 mg, 29.12 μmol, 1.0 eq), 2 (4.2 mg, 29.12 μmol, 1.0 eq) and Cs2CO3 (28.5 mg, 87.36 μmol, 3.0 eq) were dissolved in 2 mL of DMF, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, and then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high pressure preparation separation to obtain product 037 11 mg, purity 98.6%, MS (ESI, m / z): 450.4 [M+H] + .

[0468] Example 038

[0469] Preparation of compound 038: (l-(4,6-dimethylpyrimidin-2-yl)-l,6-diazaspiro[3,5]nonan-6- yl)(2-fluoro-6-(2H-l,2,3-triazol-2-yl)phenyl)methanone

[0470] First step

[0471] Compound 038-01 (90.0 mg, 397.67 μmol, 1.0 eq), 2 (56.7 mg, 397.67 μmol, 1.0 eq), Cs2CO3(388.7 mg, 1.19 mmol, 3.0 eq) were added to 2 mL of DMF, the reaction was stirred in a 120 °C oil bath for about 2 h, the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-30% ethyl acetate / petroleum ether mobile phase gradient, the obtained fraction was concentrated under reduced pressure, and the solvent was removed to obtain compound 038-02 (colorless oil, 22.0 mg, yield 16.6%).

[0472] Second step

[0473] Compound 038-02 (22.0 mg, 66.18 μmol, 1.0 eq) was dissolved in 2 mL of DCM, 1 mL of TFA was added, and the reaction was stirred for about 2 h, the reaction process was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 038-03 (15.4 mg) was directly used for the next step reaction.

[0474] Third step

[0475] Compound 038-03 (15.4 mg, 65.85 μmol, 1.0 eq), 1 (13.6 mg, 65.85 μmol, 1.0 eq), HATU (30.1 mg, 79.03 μmol, 1.2 eq), DIEA (42.6 mg, 329.27 μmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction was stirred for 16 h, the reaction process was monitored by liquid. After the reaction was completed, about 20 mL water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL saturated brine once, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high pressure preparation separation to obtain product 038 3 mg, purity 96.8%, MS (ESI, m / z): 422.3 [M+H] + .

[0476] Example 039

[0477] Preparation of compound 039: (8-(4,6-dimethylpyrimidin-2-yl)-3-hydroxy-1,8- diazaspiro [4, 5] decan-1-yl) (2-fluoro-6-(2H-1, 2, 3-triazol-2-yl) phenyl) methanone

[0478] First step

[0479] Compound 039-01 (100.0 mg, 390.10 μmol, 1.0 eq), 1 (80.8 mg, 390.10 μmol, 1.0 eq), HATU (178.0 mg, 468.12 μmol, 1.2 eq), DIEA (252.1 mg, 1.95 mmol, 5.0 eq) were dissolved in 2 mL DMF, the reaction was stirred for 16 h, the reaction process was monitored by liquid. After the reaction was completed, about 20 mL water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, the organic phase was combined and washed with about 50 mL saturated brine once, dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by MPLC, eluted with 0%-50% ethyl acetate / petroleum ether mobile phase gradient, the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 039-02 (colorless oil, 170 mg, yield 97.8%), MS (ESI, m / z): 390.31 M-5.

[0480] Second step

[0481] Compound 039-02 (15 mg, 33.82 μmol, 1.0 eq) was dissolved in 2 mL of DCM at 25 °C, then 1 mL of TFA was added, and the reaction was stirred for about 2 h. The reaction was monitored by TLC. After the reaction was completed, the solvent was removed by reduced pressure concentration, and the residue 039-03 (131.8 mg) was directly used in the next reaction.

[0482] Step 3

[0483] Compound 039-03 (131.8 mg, 381.61 μmol, 1.0 eq), 2 (54.4 mg, 381.61 μmol, 1.0 eq) and Cs2CO3 (373.0 mg, 1.14 mmol, 3.0 eq) were dissolved in 2 mL of DMF at 25 °C, and the reaction system was placed in a 120 °C oil bath for stirring for about 2 h. The reaction was monitored by liquid chromatography-mass spectrometry. After the reaction was completed and cooled to room temperature, about 20 mL of water was added to the reaction solution, then extracted with EtOAc (20 mL) for 3 times, and the organic phase was combined and washed with about 50 mL of saturated brine for 1 time, then dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and sent to high-pressure preparation separation to obtain the product 039 134 mg, purity 96.0%, MS (ESI, m / z): 452.4 [M+H] + .

[0484] 1 H NMR (300 MHz, CDCl3) δ 7.88-7.73 (m, 3H), 7.47 (m, 1H), 7.22-7.07 (m, 1H), 6.39 (t, J = 1.3 Hz, 1H), 4.83 (t, J = 12.9 Hz, 2H), 4.40 (d, J = 4.3 Hz, 1H), 3.50 (td, J = 11.5, 7.9 Hz, 1H), 3.39-3.01 (m, 4H), 2.54-2.39 (m, 7H), 2.27 (d, J = 4.7 Hz, 1H), 2.14 (dd, J = 13.6, 4.6 Hz, 1H), 2.03 (d, J = 11.3 Hz, 1H).

[0485] Example 040

[0486] Preparation of compound 040: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(7-(5-iodo-4,6- dimethylpyrimidin-2-yl)-2,7-diazaspiro[3,5]nonan-2-yl)methanone

[0487] Step 1

[0488] Compound 040-01 (100 mg, 242.50 μmol, 1.0 eq), 3 (65.1 mg, 242.50 μmol, 1.0 eq) and Cs2CO3 (237.0 mg, 727.5 μmol, 3.0 eq) were dissolved in 2 mL DMF, the reaction system was placed in a 120 °C oil bath and stirred for about 3 h, and the reaction process was monitored by liquid chromatography. After the reaction was cooled to room temperature, about 30 mL of water was added to the reaction solution, then extracted with EtOAc (30 mL) for 3 times, then the organic phase was combined and washed with about 80 mL of saturated brine once, then dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent to high pressure preparation separation to obtain product 040 88 mg, purity 97.2%, MS (ESI, m / z): 548.2 [M+H] + .

[0489] The following compounds were synthesized by the same method as above

[0490] Example 135

[0491] Preparation of compound 135: (2-fluoro-6-(2H-1,2,3-triazol-2-yl)phenyl)(7-(quinoxalin-2-yl)-2,7-diazaspiro[3,5]nonan-2-yl)methanone

[0492] First step

[0493] Compound 135-01 (50.0 mg, 158.55 μmol, 1.0 eq), 4 (26.1 mg, 158.55 μmol, 1.0 eq) and K2CO3 (65.7 mg, 475.66 μmol, 3.0 eq) were dissolved in 2 mL DMF, the reaction system was placed in an 80 °C oil bath and stirred for about 24 h, and the reaction process was monitored by liquid chromatography. After cooling to room temperature, about 30 mL of water was added to the reaction solution, then extracted with EtOAc (30 mL) for 3 times, then the organic phase was combined and washed with about 80 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent to high pressure preparation separation to obtain product 135 13.1 mg, purity 97.0%, MS (ESI, m / z): 444.3 [M+H] + .

[0494] The following compounds were synthesized by the same method

[0495] Example 139

[0496] Preparation of compound 139: 7-(4,6-dimethylpyrimidin-2-yl)-2-((methoxyphenyl)sulfonyl)-2,7-diazaspiro[3,5]nonane

[0497] First step

[0498] Compound 006-03 (50.0 mg, 215.21 μmol, 1.0 eq), 5 (44.5 mg, 215.21 μmol, 1.0 eq), Et3N (65.3 mg, 645.63 μmol, 1.2 eq) were dissolved in 2 mL THF, the reaction system was stirred for 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, about 50 mL of water was added to the reaction solution, then extracted with EtOAc (30 mL) for 3 times, then the organic phase was combined and washed with about 50 mL of saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol and sent to high pressure preparation separation to obtain product 139 14 mg. MS (ESI, m / z): 403.3 [M+H] + .

[0499] The following compounds were synthesized by the same method

[0500] Example 194

[0501] Preparation of compound 194: (3-(2H-1,2,3-triazol-2-yl)pyridin-2-yl)(7-(4,6- dimethylpyrimidin-2-yl)-2,7-diazaspiro[4,5]dec-2-yl)methanone:

[0502] Compound 194-01 (100.0 mg, 525.87 μmol, 1.0 eq), DMF (3.8 mg, 52.59 μmol, 0.1 eq) were dissolved in 2 mL DCM and placed in a 50 mL three-necked flask, after nitrogen was pumped in and out, oxalyl chloride (80.1 mg, 631.04 μmol, 1.2 eq) was added dropwise by syringe, then the reaction system was stirred for 2 h, and the reaction process was monitored by liquid chromatography. After the reaction was completed, DIEA (135.9 mg, 1.05 mmol, 2.0 eq) and 195-03 (173.3 mg, 525.87 mmol, 1.0 eq) dissolved in 1 mL DCM were directly added by syringe, the reaction system was stirred overnight, and the reaction process was monitored by liquid chromatography. After the reaction was completed, the reaction was quenched by adding 1 mL KOH solution by syringe, then about 50 mL water was added to the reaction solution, followed by extraction with EtOAc (30 mL) for 3 times, then the organic phase was combined and washed with about 50 mL saturated brine once, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain the crude product. The crude product was dissolved in methanol, and then sent to high-pressure preparation separation to obtain product 194 6.8 mg. MS (ESI, m / z): 419.4 [M+H] + , 859.7 [2M+23] + .

[0503] The following compounds were synthesized by the same method

[0504] Test Example 1: Determination of the inhibitory activity of the compound on OX1 & PFSK-1 (OX2) receptors

[0505] 1. Cell information

[0506] 1.1 This study uses stable cell lines expressing OX1 receptors and PFSK-1 (OX2) cells, which are incubated with different concentrations of test compounds, and the inhibitory effect of the compounds on OX1 & OX2 receptors is determined by FLIPR CALCIUM 6 ASSAY KIT kit.

[0507] 1.2. OX1-CHO cell line was cultured in F12 medium containing 10% fetal bovine serum and 0.2 mg / mL Hygromycin B, PFSK-1 (OX2) was cultured in 1640 medium containing 10% fetal bovine serum, the culture temperature was 37°C, and the carbon dioxide concentration was 5%.

[0508] 1.3. Cell passage: remove old medium and wash once with PBS, then add 1 mL TrypLE Express solution, incubate at 37°C for about 2 min. When the cells are detached from the dish bottom, add about 5 mL of 37°C preheated complete medium. Gently blow the cell suspension with a pipette to separate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and centrifuge at 1000 rpm for 5 min.

[0509] 1.4. To maintain the physiological activity of the cells, the experimental cell fusion degree is controlled at about 80%.

[0510] 2. Experimental steps

[0511] 2.1 Cell plating: digest and collect OX1 & PFSK-1 (OX2)-CHO cells, count after resuspension, and inoculate into 384-well cell plates at a seeding density of 1.2 x 10 4 cells / 25 μL / well. Then place the cell plate in a 37°C, 5% CO2 incubator for about 16-20 h;

[0512] 2.1 Day 2: prepare Assay Buffer according to the FLIPR Calcium 6 Assay Kit instruction manual. Thaw 20x Component A to room temperature, dilute it to 1x loading buffer with Assay buffer, and place it at room temperature for standby;

[0513] 2.3 Remove the medium in the cell plate, quickly add 35 μL of 1x loading buffer to each well, and after centrifugation, place the cell plate in a 37°C incubator for 120 min in the dark;

[0514] 2.4 Prepare working solutions of positive compounds and test compounds, and transfer 5 μL to the corresponding cell wells, and incubate at 37°C in the dark for 30 min;

[0515] 2.5 Prepare agonists and transfer 20 μL / well to the 384-well compound source plate;

[0516] 2.6 Place the cell plate, source plate and head to the FLIPR instrument accordingly, use FLIPR Tetra to add 10 μL of diluted compound in step 5 to each well, and collect data at 515 nm-575 nm wavelength.

[0517] 2.7 Calculate IC by plotting signal value vs. compound concentration, and use GraphPad Prism software to perform nonlinear regression to fit the curve. 50

[0518] 3. Data analysis

[0519] 1) Z’ factor = 1-3*(SD Max+SD Min) / (AVG Max-AVG Min);

[0520] 2) CV Max = (SD Max / AVG Max)*100%;

[0521] 3) CV Min = (SD Min / AVG Min)*100%;

[0522] 4) S / B = Signal / Background;

[0523] 5) Calculate compound IC using GraphPad nonlinear fitting formula: 50

[0524] Y = Bottom + (Top-Bottom) / (1+10^((LogIC-X)*HillSlope)) 50

[0525] 6) % Inhibition formula:

[0526] Average of positive control.

[0527] Average of negative control (DMSO).

[0528] 4. Test results:

[0529] Wherein the positive compound is Seltorexant, and the structure is as follows:

[0530] Note 1: The test results of the positive control are slightly different each time, and each time 1 positive control and multiple test molecules are detected together.

[0531] ​​​Note 2: Selectivity ratio = IC50 for OX1R inhibition (nM) / IC50 for OX2R inhibition (nM)

[0532] 5. Experimental Conclusion

[0533] The compounds of the present application have good inhibitory effect on OX2R, and the effect is obviously better than that on OX1R, indicating that the compounds of the present application have excellent OX2R selectivity.

[0534] Test Example 2: Pharmacokinetic experiment evaluation

[0535] 1. Purpose of the study

[0536] 6-9 week old SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present application under oral administration.

[0537] 2. Formulation prescription

[0538] Injection administration: 1.00 mg of test drug was weighed into 2.00 mL of 20% hydroxypropyl-β-cyclodextrin (HPCD), and after mixing evenly, a solution or suspension with a concentration of 0.500 mg / mL was obtained.

[0539] Oral administration: 5.00 mg of test drug was weighed into 10.00 mL of 20% hydroxypropyl-β-cyclodextrin (HPCD), and after mixing evenly, a solution or suspension with a concentration of 0.500 mg / mL was obtained.

[0540] 3. Drug administration and sample collection

[0541] Five SD rats were selected and randomly divided into two groups, 3 for oral administration and 2 for injection administration,

[0542] Plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration, respectively.

[0543] 4. Data processing

[0544] LCMS / MS method was used for quantitative analysis of biological samples, and pharmacokinetic software was used for calculation of pharmacokinetic parameters.

[0545] 5. Test results

[0546] 6. Experimental Conclusion

[0547] The rat pharmacokinetic study showed that compared with the positive compound administered orally, the compound of the present application administered orally had a higher maximum plasma concentration (C max ), a higher exposure (AUC 0-inf ) and a higher bioavailability (F) in rats.

[0548] Test Example 3: Determination of drug concentration in brain tissue of rats after administration of test drug

[0549] Four SD rats were selected and administered with test drug by gavage. Two rats were randomly selected for euthanasia at 0.5 hour and 2 hours after administration, respectively, and blood plasma and brain tissue samples were collected. LCMS / MS method was used for quantitative analysis of biological samples.

[0550] Note 1: Brain / plasma ratio = individual brain concentration (ng / g) / individual plasma concentration (ng / mL)

[0551] Experimental conclusion:

[0552] As can be seen from the above table, compared with the positive control Seltorexant administered orally, the compound of the present application has higher drug concentration and brain-blood ratio in the brain tissue of rats after oral administration, indicating that the compound of the present application has more excellent blood-brain barrier permeability.

[0553] All the documents mentioned in the present application are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that various changes and modifications to the present application can be made by those skilled in the art after studying the above teaching of the present application and such equivalent forms should fall within the scope of the appended claims.

Claims

A compound as represented by formula (I), a stereoisomer, a tautomer, a crystal form, a pharmaceutically acceptable salt, a hydrate, a solvate or a prodrug thereof, wherein, n is 0, 1, 2, or 3; a, b, a', b', d, e, d', and e' are each independently 0, 1, 2, or 3; and a+b is not 0; and d+e is not 0 (i.e., the N atom is not located at the ortho position of the spiro carbon atom); and a, b, d, and e are not simultaneously 0; and a', b', d', and e' are not simultaneously 0; R1is a substituent on the nitrogen-containing spirocycle, each R1is independently selected from the group consisting of null, H, hydroxyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, -C(O)-C 1-4 haloalkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, or two R1on the same carbon together form =0; L1is selected from the group consisting of C(O), S(O)2, S(O); Ar1is selected from the group consisting of C 6-10 aryl, 5-10 membered heteroaryl, and said aryl and 5-10 membered heteroaryl are optionally substituted with 1, 2, 3, or 4 R a substituents; R a selected from the group consisting of H, D, nitro, C 1-4 alkyl, C 1-4 alkoxy, halogen, cyano, -S(O)2(C 1-4 alkyl), C 1-4 haloalkyl, -NH(C 1-4 alkyl), -N(C 1-4 alkyl)2, 5-7 membered heteroaryl; Ar2is selected from the group consisting of 5-6 membered heteroaryl, 9-10 membered heteroaryl, and said 5-6 membered heteroaryl and 9-10 membered heteroaryl is optionally substituted with 1, 2, or 3 R b substituents; R b selected from the group consisting of H, D, halogen, hydroxyl, cyano, nitro, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, 3-7 membered cycloalkyl. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof of claim 1, wherein, each R1is independently selected from the group consisting of H, hydroxyl, methyl, hydroxymethyl, -C(O)CF3, -N(CH3)2, or two R1on the same carbon together form =O. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof of claim 1, wherein, said Ar1is a substituted or unsubstituted group selected from the group consisting of phenyl, naphthyl, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof of claim 1, wherein, The R a Selected from the following groups: H, D, C 1-4 Alkyl, C 1-3 Alkyl groups, halogens, cyano groups, -S(O)2(C 1-3 Alkyl), C 1-3 Fluoroalkyl, -NH(C) 1-3 alkyl), -N(C) 1-3 alkyl) 2, 5-6 membered heteroaryl; Preferably, said R a is selected from the group consisting of H, D, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, F, CI, Br, cyano, -S(O)2-CH3, CF3, -N(CH3)2, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate or prodrug of the compound of claim 1, wherein, said Ar2is a substituted or unsubstituted group selected from the group consisting of 5-6 membered heteroaryl, benzo 5-6 membered heteroaryl; Preferably, said Ar2is a substituted or unsubstituted group selected from the group consisting of furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole, oxazole, thiazole, imidazole, pyridine, pyridazine, pyrimidine, pyrazine, benzofuran, benzothiophene, benzopyrrole, benzoxazole, benzothiazole, benzoimidazole, benzopyridine, benzopyrimidine, benzopyrazine. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof of claim 1, wherein, said R b selected from the group consisting of H, D, halogen, hydroxyl, cyano, nitro, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 fluoroalkyl, 3-5 membered cycloalkyl; Preferably, said R b selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, methoxy, ethoxy, F, Cl, Br, I, hydroxy, cyano, nitro, -CF3, cyclopropyl, cyclobutyl, cyclopentyl. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof of claim 1, wherein, The compound has a structure shown in formula (II): wherein, n, d, e, d', e', R1, L1, Ar1, and Ar2are as defined in claim 1. The compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof of claim 1, wherein, The compound is selected from the group consisting of: A pharmaceutical composition, characterized in that, The composition comprises: (i) a compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, as described in any one of claims 1-8; and (ii) a pharmaceutically acceptable carrier, adjuvant, or excipient. Use of a compound, stereoisomer, tautomer, crystalline form, pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof of any one of claims 1-8, or a pharmaceutical composition of claim 9, wherein, for the preparation of a medicament for the treatment and / or prevention of a disease related to orexin; Preferably, said disease related to orexin is selected from the group consisting of sleep-wake cycle disorder, insomnia, restless leg syndrome, jet-lag syndrome, sleep unrest, depression, Alzheimer's disease, sleep disorder secondary to a disease of neurological disorder, mania, depression, manic depression, schizophrenia, pain syndrome, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight or obesity, and conditions associated with overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, dyspnea, tachycardia, arrhythmia, angina, acute heart failure, ulcer, irritable bowel syndrome, diarrhea, gastroesophageal reflux.

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